Patent application title: BIOMARKERS PREDICTIVE OF THE RESPONSIVENESS TO TNFALPHA INHIBITORS IN AUTOIMMUNE DISORDERS
Inventors:
Bruno Stuhlmüller (Berlin, DE)
Gerd-Reudiger Burmester (Berlin, DE)
Assignees:
Abbott Laboratories
IPC8 Class: AA61K39395FI
USPC Class:
4241421
Class name: Immunoglobulin, antiserum, antibody, or antibody fragment, except conjugate or complex of the same with nonimmunoglobulin material monoclonal antibody or fragment thereof (i.e., produced by any cloning technology) human
Publication date: 2012-02-16
Patent application number: 20120039900
Abstract:
The invention provides methods for predicting responsiveness to
TNFα inhibitors in a subject suffering from an autoimmune disorder,
such as rheumatoid arthritis. The methods involve assaying for expression
of one or more biomarkers in the subject that are predictive of
responsiveness to TNFα inhibitors. A preferred biomarker of the
invention is CD11c. The methods can further comprise selecting a
treatment regimen with a TNFα inhibitor in an autoimmune disorder
subject based upon expression of the biomarker(s) in the subject. The
methods can further comprise administering a TNFα inhibitor to the
subject according to the selected treatment regimen. Kits that include
means for measuring expression of one or more biomarkers that are
predictive of responsiveness to TNFα inhibitors for an autoimmune
disorder are also provided. Methods of preparing and using databases, and
computer program products therefore, for selecting an autoimmune disorder
subject for treatment with a TNFα inhibitor are also provided.Claims:
1. A method for predicting responsiveness to a TNFα inhibitor in a
subject having an autoimmune disorder, the method comprising: (i)
assaying the subject for expression of one or more biomarkers predictive
of responsiveness to a TNFα inhibitor in an autoimmune disorder,
and (ii) predicting responsiveness of the subject to the TNFα
inhibitor based on expression of the one or more biomarkers in the
subject, wherein the one or more biomarkers is encoded by a nucleic acid
molecule comprising a nucleotide sequence selected from the group
consisting of SEQ ID NO: 1-10, 12-28, 30-43, 45-61, 63, 64, 66-73, and
75-82, wherein decreased expression of the one or more biomarkers encoded
by a nucleic acid molecule comprising a nucleotide sequence selected from
the group consisting of SEQ ID NOs: 1-5, 8, 9, 12-14, 18, 20, 21, 23, 25,
26, 28, 30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 66-69, 71-73,
76-78, 80 and 81 is predictive of responsiveness of the subject to a
TNFα inhibitor; and/or wherein increased expression of the one or
more biomarkers encoded by a nucleic acid molecule comprising a
nucleotide sequence selected from the group consisting of SEQ ID NOs: 6,
7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43, 45-47, 49, 51, 54, 55, 57,
59, 61, 64, 70, 75, 79 and 82 is predictive of responsive of the subject
to a TNFα inhibitor.
2. A method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is selected from the group consisting of Aquaporin 3 (Genbank Accession No. NM--004925); Similar to ribosomal protein S24, clone MGC:8595 (Genbank Accession No. NM--033022); Transmembrane emp24 domain trafficking protein 2 (Genbank Accession No. NM--006815); Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (Genbank Accession No. NM--000454); Calmodulin 1 (phosphorylase kinase, delta) (Genbank Accession No. NM--006888); Guanine nucleotide binding protein (G protein), beta polypeptide 1 (Genbank Accession No. NM--002074); Prothymosin, alpha (gene sequence 28) (Genbank Accession No. NM--002823); Homo sapiens isocitrate dehydrogenase 1 (NADP.sup.+) soluble (IDH1) (Genbank Accession No. NM--005896); Tumor protein D52 (Genbank Accession Nos. NM--001025252, NM--001025253, NM--005079); Early growth response 1 (Genbank Accession No. NM--001964); Cytochrome c oxidase subunit VIIb (Genbank Accession No. NM--001866); CUG triplet repeat, RNA binding protein 2 (Genbank Accession No. NM--001025077, NM--001025076, NM--006561); Ubiquinol-cytochrome c reductase hinge protein (Genbank Accession No. NM--006004); Homo sapiens leptin receptor gene-related protein (HS0BRGRP) (Genbank Accession No. NM--017526); Wiskott-Aldrich syndrome protein interacting protein (Genbank Accession Nos. NM--001077269, NM--003387); CD97 antigen (Genbank Accession Nos. NM--001025160, NM--001784, NM--078481); Glutamate-cysteine ligase, catalytic subunit (Genbank Accession No. NM--001498); Crystallin, zeta (quinone reductase) (Genbank Accession No. NM--001889); Rap guanine nucleotide exchange factor (GEF) 2 (Genbank Accession No. NM--014247); Ataxin 1 (Genbank Accession No. NM--000332); Adaptor-related protein complex 1, sigma 2 subunit (Genbank Accession No. NM--003916); Ectonucleotide pyrophosphatase/phosphodiesterase 4 (Genbank Accession No. NM--014936); Desmocollin 2 (Genbank Accession Nos. NM--024422, NM--004949); MAL, T-cell differentiation protein (Genbank Accession Nos. NM--002371, NM--022438, NM--022439, NM--022440); Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (Genbank Accession No. NM--005476); Chemokine (C--C motif) ligand 3 (Genbank Accession Nos. NM--001001437, NM--021006); Carboxypeptidase A3 (Genbank Accession No. NM--001870); NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa (Genbank Accession No. NM--004545); Interleukin 8 receptor, beta (Genbank Accession No. NM--001557); Platelet factor 4 variant 1 (Genbank Accession No. NM--002620); Poly(A) binding protein interacting protein 1 (Genbank Accession No. NM--006451); ATP-binding cassette, sub-family C (CFTR/MRP), member 3 (Genbank Accession No. NM--003786); Actinin, alpha 1 (Genbank Accession No. NM--001102); NAD kinase (Genbank Accession No. NM--023018); Platelet/endothelial cell adhesion molecule (CD31 antigen) (Genbank Accession No. NM--000442); Esterase D/formylglutathione hydrolase (Genbank Accession No. NM--001984); Chromosome 20 open reading frame 111 (Genbank Accession No. NM--016470); Sterol-C4-methyl oxidase-like (Genbank Accession Nos. NM--001017369, NM--006745); PIM-1 oncogene (Genbank Accession No. NM--002648); GATA binding protein 2 (Genbank Accession No. NM--032638); Cathepsin Z (Genbank Accession No. NM--001336); Lectin, galactoside-binding, soluble, 8 (galectin 8) (Genbank Accession Nos. NM--006499, NM--201545); CD86 antigen (CD28 antigen ligand 2, B7-2 antigen) (Genbank Accession Nos. NM--006889, NM--175862); Interleukin 8 (Genbank Accession No. NM--000584); Fc fragment of IgE, high affinity I, receptor for alpha polypeptide (Genbank Accession No. NM--002001); Actin, gamma 1 (Genbank Accession No. NM--001614); KIAA0746 protein (Genbank Accession No. NM--015187); Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID) (Genbank Accession No. NM--002076); Transcription factor 4 (Genbank Accession Nos. BF592782, CR612521); Major histocompatibility complex, class II, DQ alpha 1 (Genbank Accession Nos. NM--002122, NM--020056); Cell division cycle 2-like 6 (CDK8-like) (Genbank Accession No. NM--015076); Major histocompatibility complex, class II, DQ beta 1 (Genbank Accession No. XM--942240); Phospholipase C-like 2 (Genbank Accession No. NM--015184); Coagulation factor II (thrombin) receptor-like 1 (Genbank Accession No. NM--005242); TM2 domain containing 1 (Genbank Accession No. NM--032027); Splicing factor 3b, subunit 1, 155 kDa (Genbank Accession No. NM--012433); SUB1 homolog (S. cerevisiae) (Genbank Accession No. NM--006713); MRNA, cDNA DKFZp564O0862 (Genbank Accession No. AI278204); Cytochrome b-5 (Genbank Accession Nos. NM--001914, NM--148923); Cold autoinflammatory syndrome 1 (Genbank Accession No. NM--183395); Ribosomal protein S26, 40S ribosomal protein (Genbank Accession No. XM--941927); CCR4-NOT transcription complex, subunit 6 (Genbank Accession No. NM--015455); Ubiquinol-cytochrome c reductase complex (7.2 kD) (Genbank Accession Nos. NM--013387, NM--001003684); Hepatocellular carcinoma-associated antigen 112 (Genbank Accession No. NM--018487); Kruppel-like factor 11 (Genbank Accession No. XM--001129527); GGA binding partner (Genbank Accession No. NM--018318); Cornichon homolog 4 (Drosophila) (Genbank Accession No. NM--014184); Hypothetical protein FLJ21616 (Genbank Accession No. NM--024567); Nuclear prelamin A recognition factor (Genbank Accession Nos. NM--012336, NM--001038618); Erythroblast membrane-associated protein (Genbank Accession Nos. NM--018538, NM--001017922); LR8 protein (Genbank Accession No. NM--014020); Likely ortholog of mouse limb-bud and heart gene (LBH) (Genbank Accession No. NM--030915); Calmin (calponin-like, transmembrane) (Genbank Accession No. NM--024734); Chromosome 14 open reading frame 156 (Genbank Accession No. NM--031210); Guanine nucleotide binding protein (G protein) alpha 12 (Genbank Accession No. NM--007353); and SRY (sex determining region Y)-box 18 (Genbank Accession No. NR--003287).
3. A method for predicting responsiveness to a TNFα inhibitor, which TNFα inhibitor is adalimumab, in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to adalimumab in an autoimmune disorder, and (ii) predicting responsiveness of the subject to adalimumab based on expression of the one or more biomarkers in the subject, wherein decreased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 12-14, 18, 20, 21, 23, 25, 26, 28, 30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 66-69, 71-73, 76-78, 80 and 81 is predictive of responsiveness of the subject to a TNFα inhibitor; and/or wherein increased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43, 45-47, 49, 51, 54, 55, 57, 59, 61, 64, 70, 75, 79 and 82 is predictive of responsive of the subject to a TNFα inhibitor.
4. The method of any of claims 1-3, wherein a sample from the subject is assayed for expression of mRNA encoding the one or more biomarkers.
5. The method of any of claims 1-3, wherein a sample from the subject is assayed for protein expression of the one or more biomarkers.
6. The method of any of claims 1-3, which further comprises selecting a treatment regimen with the TNFα inhibitor based upon expression of the one or more biomarkers in the subject.
7. The method of claim 6, which further comprises administering the TNFα inhibitor to the subject according to the treatment regimen such that the autoimmune disorder is inhibited in the subject.
8. The method of any of claims 1-3, wherein the TNFα inhibitor is an anti-tumor necrosis factor-alpha (TNFα) antibody, or antigen-binding portion thereof.
9. The method of claim 8, wherein the anti-TNFα antibody, or antigen-binding portion thereof, is a human antibody, a humanized antibody, a chimeric antibody or a multivalent antibody.
10. The method of claim 8, wherein the anti-TNFα antibody, or antigen-binding portion thereof, is adalimumab.
11. The method of claim 9, wherein the anti-TNFα antibody, or antigen-binding portion thereof, is selected from the group consisting of i) an isolated human antibody that dissociates from human TNFα with a Kd of 1.times.10.sup.-8 M or less and a Koff rate constant of 1.times.10.sup.-3 s-1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1.times.10.sup.-7 M or less; ii) an isolated human antibody with the following characteristics: a) dissociates from human TNFα with a Koff rate constant of 1.times.10-3 s-1 or less, as determined by surface plasmon resonance; b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 305, or modified from SEQ ID NO: 305 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9; c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 306, or modified from SEQ ID NO: 306 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12; and iii) an isolated human antibody with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 303 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 304.
12. The method of claim 1, wherein the TNFα inhibitor is etanercept.
13. The method of any one of claims 1-3, wherein the subject is a human.
14. The method of any one of claims 1-3, wherein the autoimmune disorder is rheumatoid arthritis.
15. A kit for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the kit comprising: a) means for isolating monocytes; b) means for measuring expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder; c) means for measuring expression of at least one housekeeping gene; and d) instructions for use of the kit to predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, wherein decreased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81 is predictive of responsiveness of the subject to a TNFα inhibitor and/or wherein increased expression of the one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43, 44-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82 is predictive of responsive of the subject to a TNFα inhibitor.
16. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 83-133, thereby monitoring the autoimmune disorder in the subject.
17. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-177, 110, 112, 118, 123 and 131, thereby monitoring the autoimmune disorder in the subject.
18. A method of monitoring an autoimmune disorder in a subject having an autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-292, 91 and 97, thereby monitoring the autoimmune disorder in the subject.
19. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 87, 97, 101, 293, 92, 272, 93, 107, 108, 121 and 123, and wherein the subject is monitored prior to treatment with a TNFα inhibitor, thereby monitoring the autoimmune disorder in the subject.
20. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 290, 209, 98, 112, 116, 121, 130, 155, 92, 289, 216 and 131, and wherein the subject is monitored after treatment with a TNFα inhibitor, thereby monitoring the autoimmune disorder in the subject.
21. A method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 97, 102, 29, 294, 295, 91, 131, 290, 100, 134, 296, 297, 298, 299, 136, 174 and 300, thereby monitoring the autoimmune disorder in the subject.
22. A method of selecting an autoimmune disorder subject for a treatment with a TNFα inhibitor, the method comprising: (i) identifying, in a database comprising a plurality of autoimmune disorder subjects, a subject whose database entry is associated with a biomarker expression pattern that is predictive of responsiveness to treatment with a TNFα inhibitor, and (ii) selecting the subject for treatment with a TNFα inhibitor, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82.
Description:
RELATED APPLICATIONS
[0001] This application is a continuation application of U.S. patent application Ser. No. 12/130,373, filed on May 30, 2008, which claims the benefit of priority to U.S. provisional patent application No. 60/932,888 filed on May 31, 2007. The contents of the above-mentioned priority application is hereby incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Autoimmune disorders are a significant and widespread medical problem. For example, rheumatoid arthritis (RA) is an autoimmune disease affecting more than two million people in the United States. RA causes chronic inflammation of the joints and typically is a progressive illness that has the potential to cause joint destruction and functional disability. The cause of rheumatoid arthritis is unknown, although genetic predisposition, infectious agents and environmental factors have all been implicated in the etiology of the disease. In active RA, symptoms can include fatigue, lack of appetite, low grade fever, muscle and joint aches and stiffness. Also during disease flare ups, joints frequently become red, swollen, painful and tender, due to inflammation of the synovium. Furthermore, since RA is a systemic disease, inflammation can affect organs and areas of the body other than the joints, including glands of the eyes and mouth, the lung lining, the pericardium, and blood vessels.
[0003] Traditional treatments for the management of RA and other autoimmune disorders include fast acting "first line drugs" and slower acting "second line drugs." The first line drugs reduce pain and inflammation. Example of such first line drugs include aspirin, naproxen, ibuprofen etodolac and other nonsteroidal anti-inflammatory drugs (NSAIDs), as well as corticosteroids, given orally or injected directly into tissues and joints. The second line drugs promote disease remission and prevent progressive joint destruction and are also referred to as disease-modifying anti-rheumatic drugs or DMARDs. Examples of second line drugs include gold, hydrochloroquine, azulfidine and immunosuppressive agents, such as methotrexate, azathioprine, cyclophosphamide, chlorambucil and cyclosporine. Many of these drugs, however, can have detrimental side-effects. Thus, additional therapies for rheumatoid arthritis and other autoimmune disorders have been sought.
[0004] More recently, biological therapies have been applied to the treatment of autoimmune disorders such as rheumatoid arthritis. For example, three TNFα inhibitors, REMICADE® (infliximab), a chimeric anti-TNFα mAb, ENBREL® (etanercept), a TNFR-Ig Fc fusion protein, and HUMIRA® (adalimumab), a human anti-TNFα mAb, have been approved by the FDA for treatment of rheumatoid arthritis. While such biologic therapies have demonstrated success in the treatment of rheumatoid arthritis and other autoimmune disorders, not all subjects treated respond, or respond well, to a TNFα inhibitor. The use of TNFα inhibitors such as TNFα inhibitors typically is more expensive than traditional treatments and usually requires administration by injection, which, at least for certain agents, may require that the patient visit a medical office on a frequent basis. Thus, it would be very helpful to predict in advance of treatment whether a rheumatoid arthritis patient is likely to be responsive to treatment with a TNFα inhibitor. Accordingly, ways for predicting responsiveness to a TNFα inhibitor in patients having autoimmune disorders, such as rheumatoid arthritis patients, are of particular interest.
SUMMARY OF THE INVENTION
[0005] This invention provides methods and compositions for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, such as rheumatoid arthritis, based on the discovery that the expression patterns of particular biomarkers in the subject correlate with responsiveness to a TNFα inhibitor. Using microarray analysis of monocytes from representative rheumatoid arthritis (RA) patients treated with an anti-TNFα monoclonal antibody, 82 differentially expressed genes predictive of responsiveness to TNFα inhibitor treatment were identified by pairwise comparisons between future RA responders and future RA non-responders to anti-TNFα therapy. Furthermore, hierarchical clustering and TaqMan®-PCR of RA responders/non-responders pre-treatment identified one gene of particular interest, CD11c, which was fully predictive of future response to anti-TNFα treatment.
[0006] Accordingly, in one aspect, the invention pertains to a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder (e.g., rheumatoid arthritis). The method comprises: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (corresponding to the sequences set forth in Table 9)
[0007] Within SEQ ID NOs: 1-82, certain genes were found to be upregulated in RA responders to TNFα inhibitors. Accordingly, in one embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82 (corresponding to sequences from Table 9 that are increased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 37, 44, 47, 62 and 70 (corresponding to sequences from Table 9 that are increased in ≧90% of responders vs. non-responders). Even more preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44. (corresponding to CD11c, from Table 9, which is increased in 100% of responders vs. non-responders). In each of these embodiments, increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0008] Within SEQ ID NOs: 1-82, certain genes were found to be downregulated in RA responders to TNFα inhibitors. Accordingly, in one embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81. (corresponding to sequences from Table 9 that are decreased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 29, 65, 73 and 74 (corresponding to sequences from Table 9 that are decreased in ≧90% of responders vs. non-responders). Even more preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 11 or SEQ ID NO: 74 (corresponding to sequences from Table 9 that are decreased in 100% of responders vs. non-responders). In each of these embodiments, decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0009] In another aspect, the invention provides a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is selected from the group consisting of Aquaporin 3 (Genbank Accession No. NM--004925); Similar to ribosomal protein S24, clone MGC:8595 (Genbank Accession No. NM--033022); Transmembrane emp24 domain trafficking protein 2 (Genbank Accession No. NM--006815; Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (Genbank Accession No. NM--000454); Calmodulin 1 (phosphorylase kinase, delta) (Genbank Accession No. NM--006888); Guanine nucleotide binding protein (G protein), beta polypeptide 1 (Genbank Accession No. NM--002074); Prothymosin, alpha (gene sequence 28) (Genbank Accession No. NM--002823); Homo sapiens isocitrate dehydrogenase 1 (NADP+) soluble (IDH1) (Genbank Accession No. NM--005896); Tumor protein D52 (Genbank Accession Nos. NM--001025252, NM--001025253, NM--005079); Early growth response 1 (Genbank Accession No. NM--001964); Homo sapiens predicted osteoblast protein (GS3786) (Genbank Accession Nos. NM--014888, NM--001040020); Cytochrome c oxidase subunit VIIb (Genbank Accession No. NM--001866); CUG triplet repeat, RNA binding protein 2 (Genbank Accession No. NM--001025077, NM--001025076, NM--006561); Ubiquinol-cytochrome c reductase hinge protein (Genbank Accession No. NM--006004); Homo sapiens leptin receptor gene-related protein (HS0BRGRP) (Genbank Accession No. NM--017526); Wiskott-Aldrich syndrome protein interacting protein (Genbank Accession Nos. NM--001077269, NM--003387); CD97 antigen (Genbank Accession Nos. NM--001025160, NM--001784, NM--078481); Glutamate-cysteine ligase, catalytic subunit (Genbank Accession No. NM--001498); Crystallin, zeta (quinone reductase) (Genbank Accession No. NM--001889); Rap guanine nucleotide exchange factor (GEF) 2 (Genbank Accession No. NM--014247); Ataxin 1 (Genbank Accession No. NM--000332); Adaptor-related protein complex 1, sigma 2 subunit (Genbank Accession No. NM--003916); Ectonucleotide pyrophosphatase/phosphodiesterase 4 (Genbank Accession No. NM--014936); Desmocollin 2 (Genbank Accession Nos. NM--024422, NM--004949); MAL, T-cell differentiation protein (Genbank Accession Nos. NM--002371, NM--022438, NM--022439, NM--022440); Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (Genbank Accession No. NM--005476); Chemokine (C--C motif) ligand 3 (Genbank Accession Nos. NM--001001437, NM--021006); Carboxypeptidase A3 (Genbank Accession No. NM--001870); Charcot-Leyden crystal protein (Genbank Accession No. NM--001828); NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa (Genbank Accession No. NM--004545); Interleukin 8 receptor, beta (Genbank Accession No. NM--001557); Platelet factor 4 variant 1 (Genbank Accession No. NM--002620); Poly(A) binding protein interacting protein 1 (Genbank Accession No. NM--006451); ATP-binding cassette, sub-family C (CFTR/MRP), member 3 (Genbank Accession No. NM--003786); Actinin, alpha 1 (Genbank Accession No. NM--001102); NAD kinase (Genbank Accession No. NM--023018); Platelet/endothelial cell adhesion molecule (CD31 antigen) (Genbank Accession No. NM--000442); Esterase D/formylglutathione hydrolase (Genbank Accession No. NM--001984); Chromosome 20 open reading frame 111 (Genbank Accession No. NM--016470); Sterol-C4-methyl oxidase-like (Genbank Accession Nos. NM--001017369, NM--006745); PIM-1 oncogene (Genbank Accession No. NM--002648); GATA binding protein 2 (Genbank Accession No. NM--032638); Cathepsin Z (Genbank Accession No. NM--001336); Integrin alpha-X (antigen CD11c) (Genbank Accession No. NM--000887); Lectin, galactoside-binding, soluble, 8 (galectin 8) (Genbank Accession Nos. NM--006499, NM--201545); CD86 antigen (CD28 antigen ligand 2, B7-2 antigen) (Genbank Accession Nos. NM--006889, NM--175862); Interleukin 8 (Genbank Accession No. NM--000584); Fc fragment of IgE, high affinity I, receptor for alpha polypeptide (Genbank Accession No. NM--002001); Actin, gamma 1 (Genbank Accession No. NM--001614); KIAA0746 protein (Genbank Accession No. NM--015187); Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID) (Genbank Accession No. NM--002076); Transcription factor 4 (Genbank Accession Nos. BF592782, CR612521); Major histocompatibility complex, class II, DQ alpha 1 (Genbank Accession Nos. NM--002122, NM--020056); Cell division cycle 2-like 6 (CDK8-like) (Genbank Accession No. NM--015076); Major histocompatibility complex, class II, DQ beta 1 (Genbank Accession No. XM--942240); Phospholipase C-like 2 (Genbank Accession No. NM--015184); Coagulation factor II (thrombin) receptor-like 1 (Genbank Accession No. NM--005242); TM2 domain containing 1 (Genbank Accession No. NM--032027); Splicing factor 3b, subunit 1, 155 kDa (Genbank Accession No. NM--012433); SUB1 homolog (S. cerevisiae) (Genbank Accession No. NM--006713); MRNA; cDNA DKFZp564O0862 (Genbank Accession No. AI278204); Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) (Genbank Accession Nos. NM--201413, NM--000484, NM--201414); Cytochrome b-5 (Genbank Accession Nos. NM--001914, NM--148923); Cold autoinflammatory syndrome 1 (Genbank Accession No. NM--183395); Neugrin, neurite outgrowth associated (Genbank Accession Nos. NM--016645, NM--001033088); Ribosomal protein S26, 40S ribosomal protein (Genbank Accession No. XM--941927); CCR4-NOT transcription complex, subunit 6 (Genbank Accession No. NM--015455); Ubiquinol-cytochrome c reductase complex (7.2 kD) (Genbank Accession Nos. NM--013387, NM--001003684); Hepatocellular carcinoma-associated antigen 112 (Genbank Accession No. NM--018487); Kruppel-like factor 11 (Genbank Accession No. XM--001129527); GGA binding partner (Genbank Accession No. NM--018318); Cornichon homolog 4 (Drosophila) (Genbank Accession No. NM--014184); Hypothetical protein FLJ21616 (Genbank Accession No. NM--024567); Homo sapiens hypothetical protein FLJ10134 (Genbank Accession No. NM--018004); Nuclear prelamin A recognition factor (Genbank Accession Nos. NM--012336, NM--001038618); Erythroblast membrane-associated protein (Genbank Accession Nos. NM--018538, NM--001017922); LR8 protein (Genbank Accession No. NM--014020); Likely ortholog of mouse limb-bud and heart gene (LBH) (Genbank Accession No. NM--030915); Calmin (calponin-like, transmembrane) (Genbank Accession No. NM--024734); Chromosome 14 open reading frame 156 (Genbank Accession No. NM--031210); Guanine nucleotide binding protein (G protein) alpha 12 (Genbank Accession No. NM--007353); and SRY (sex determining region Y)-box 18 (Genbank Accession No. NR--003287) (corresponding to biomarkers listed in Table 9).
[0010] Within the above-listed biomarkers, certain genes were found to be upregulated in RA responders to TNFα inhibitors. Accordingly, in one embodiment, the one or more biomarkers is selected from the group consisting of Guanine nucleotide binding protein (G protein), beta polypeptide 1; Prothymosin, alpha (gene sequence 28); Early growth response 1; Homo spaiens leptin receptor gene-related protein (HS0BRGRP); Wiskott-Aldrich syndrome protein interacting protein; CD97 antigen; Crystallin, zeta (quinone reductase); Adaptor-related protein complex 1, sigma 2 subunit; Desmocollin 2; Chemokine (C--C motif) ligand 3; Interleukin 8 receptor, beta; ATP-binding cassette, sub-family C (CFTR/MRP), member 3; Actinin, alpha 1; NAD kinase; Platelet/endothelial cell adhesion molecule (CD31 antigen); Esterase D/formylglutathione hydrolase; Chromosome 20 open reading frame 111; Cathepsin Z; Integrin alpha-X (antigen CD11c); Lectin, galactoside-binding, soluble, 8 (galectin 8); CD86 antigen (CD28 antigen ligand 2, B7-2 antigen); Interleukin 8; Actin, gamma 1; Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID); Cell division cycle 2-like 6 (CDK8-like); Major histocompatibility complex, class II, DQ beta 1; Coagulation factor II (thrombin) receptor-like 1; Splicing factor 3b, subunit 1, 155 kDa; mRNA; cDNA DKEZp564O0862; Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease); Cold autoinflammatory syndrome 1; Kruppel-like factor 11; Nuclear prelamin A recognition factor; Calmin (calponin-like, transmembrane); and SRY (sex determining region Y)-box 18 (corresponding to biomarkers from Table 9 that are increased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is selected from the group consisting of Interleukin 8 receptor, beta; Platelet/endothelial cell adhesion molecule (CD31 antigen); Integrin alpha-X (antigen CD11c); Interleukin 8; Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease); and Kruppel-like factor 11 (corresponding to biomarkers from Table 9 that are decreased in ≧80% of responders vs. non-responders). Even more preferably, the one or more biomarkers is Integrin alpha-X (antigen CD11c) (corresponding to a biomarker from Table 9 that is increased in 100% of responders vs. non-responders). In each of these embodiments, increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0011] Within the above-listed biomarkers, certain genes were found to be downregulated in RA responders to TNFα inhibitors. Accordingly, in one embodiment, the one or more biomarkers is selected from the group consisting of Aquaporin 3; Similar to ribosomal protein S24, clone MGC:8595; Transmembrane emp24 domain trafficking protein 2; Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1; Calmodulin 1 (phosphorylase kinase, delta); Homo sapiens isocitrate dehydrogenase 1 (NADP+) soluble (IDH1); Tumor protein D52; Homo sapiens predicted osteoblast protein (GS3786); Cytochrome c oxidase subunit VIIb; CUG triplet repeat, RNA binding protein 2; Ubiquinol-cytochrome c reductase hinge protein; Glutamate-cysteine ligase, catalytic subunit; Rap guanine nucleotide exchange factor (GEF) 2; Ataxin 1; Ectonucleotide pyrophosphatase/phosphodiesterase 4; MAL, T-cell differentiation protein; Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase; Carboxypeptidase A3; Charcot-Leyden crystal protein; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa; Platelet factor 4 variant 1; Poly(A) binding protein interacting protein 1; Sterol-C4-methyl oxidase-like; PIM-1 oncogene; GATA binding protein 2; Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide; KIAA0746 protein; Transcription factor 4; Major histocompatibility complex, class II, DQ alpha 1; Phospholipase C-like 2; TM2 domain containing 1; SUB1 homolog (S. cerevisiae); Cytochrome b-5; Neugrin, neurite outgrowth associated; Ribosomal protein S26, 40S ribosomal protein; CCR4-NOT transcription complex, subunit 6; Ubiquinol-cytochrome c reductase complex (7.2 kD); Hepatocellular carcinoma-associated antigen 112; GGA binding partner; Cornichon homolog 4 (Drosophila); Hypothetical protein FLJ21616; Homo sapiens hypothetical protein FLJ10134; Erythroblast membrane-associated protein; LR8 protein; Likely ortholog of mouse limb-bud and heart gene (LBH); Chromosome 14 open reading frame 156; and Guanine nucleotide binding protein (G protein) alpha 12 (corresponding to biomarkers from Table 9 that are decreased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is selected from the group consisting of Homo sapiens predicted osteoblast protein (GS3786); Charcot-Leyden crystal protein; Neugrin, neurite outgrowth associated; Hypothetical protein FLJ21616; and Homo sapiens hypothetical protein FLJ10134 (corresponding to biomarkers from Table 9 that are decreased in ≧90% of responders vs. non-responders). Even more preferably, the one or more biomarkers is Homo sapiens predicted osteoblast protein (GS3786) or Homo sapiens hypothetical protein FLJ10134 (corresponding to biomarkers from Table 9 that are decreased in 100% of responders vs. non-responders). In each of these embodiments, decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0012] In yet another aspect, the invention provides a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for increased expression of a biomarker, which biomarker is CD11c, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on increased expression of CD11c in the subject.
[0013] In yet another aspect, the invention provides a method for predicting responsiveness to a TNFα inhibitor, which TNFα inhibitor is adalimumab, in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to adalimumab in an autoimmune disorder, and (ii) predicting responsiveness of the subject to adalimumab based on expression of the one or more biomarkers in the subject. Preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (corresponding to biomarkers set forth in Table 9).
[0014] In one embodiment of the methods of the invention, a sample from the subject is assayed for expression of mRNA encoding the one or more biomarkers. In another embodiment of the methods of the invention, a sample from the subject is assayed for protein expression of the one or more biomarkers.
[0015] In one embodiment, the methods of the invention further comprise selecting a treatment regimen with the TNFα inhibitor based upon expression of the one or more biomarkers in the subject. In another embodiment, the methods of the invention further comprise administering the TNFα inhibitor to the subject according to the treatment regimen such that autoimmune disorder is inhibited in the subject.
[0016] A preferred TNFα inhibitor of the invention is an anti-tumor necrosis factor-alpha (TNFα) antibody, or antigen-binding portion thereof. The anti-TNFα antibody, or antigen-binding portion thereof, can be, for example, a humanized antibody, a chimeric antibody or a multivalent antibody. For example, the anti-TNFα antibody, or antigen-binding portion thereof, can be infliximab or golimumab. In another embodiment, the anti-TNFα antibody, or antigen-binding portion thereof, is a human antibody. For example, the anti-TNFα antibody, or antigen-binding portion thereof, can be an isolated human antibody that dissociates from human TNFα with a Kd of 1×10-8 M or less and a Koff rate constant of 1×10-3 s-1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10-7 M or less. In another embodiment, the anti-TNFα antibody, or antigen-binding portion thereof, is an isolated human antibody with the following characteristics:
[0017] a) dissociates from human TNFα with a Koff rate constant of 1×10-3 s-1 or less, as determined by surface plasmon resonance;
[0018] b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 305, or modified from SEQ ID NO: 305 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
[0019] c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 306, or modified from SEQ ID NO: 306 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0020] In another embodiment, the anti-TNFα antibody, or antigen-binding portion thereof, is an isolated human antibody with a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 303 and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 304. In yet another embodiment, the anti-TNFα antibody, or antigen-binding portion thereof, is adalimumab. Yet another example of a TNFα inhibitor is etanercept.
[0021] Preferably, in the methods of the invention, the subject is a human.
[0022] In another aspect, the invention pertains to a kit for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder (e.g., rheumatoid arthritis). The kit comprises:
[0023] a) means for isolating monocytes;
[0024] b) means for measuring expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder;
[0025] c) means for measuring expression of at least one housekeeping gene; and
[0026] d) instructions for use of the kit to predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82.
[0027] In one embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82, more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 37, 44, 47, 62 and 70, even more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44 (CD11c). In each of these embodiments, the instructions for use of the kit instruct that increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0028] In another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81, more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 29, 65, 73 and 74, even more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 11 or SEQ ID NO: 74. In each of these embodiments, the instructions for use of the kit instruct that decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0029] In one embodiment of the kit, the means for measuring expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder comprises a nucleic acid preparation sufficient to detect expression of mRNA encoding the biomarker in a sample from the subject. In another embodiment of the kit, the means for measuring expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder comprises an antibody preparation sufficient to detect protein expression of the biomarker in a sample from the subject. The kit can further comprise a TNFα inhibitor for treating the autoimmune disorder in the subject.
[0030] In another aspect, the invention pertains to methods of monitoring an autoimmune disorder (e.g., RA) in a subject having the autoimmune disorder (e.g., RA). These methods are based, at least in part, on microarray analysis of monocytes from representative rheumatoid arthritis (RA) patients treated with an anti-TNFα monoclonal antibody, including (i) hierarchical clustering with the genes resulting from a simultaneous comparison between RA versus ND and RA responders pre- versus post-anti-TNFα therapy, (ii) prediction analysis of microarrays (PAM); and (iii) hierarchical clustering based on the comparison between RA responders and non-responders post-treatment.
[0031] Accordingly, in another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 83-133 (corresponding to biomarkers set forth in Table 3), thereby monitoring the autoimmune disorder in the subject.
[0032] In another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-177, 110, 112, 118, 123 and 131 (corresponding to biomarkers set forth in Table 4), thereby monitoring the autoimmune disorder in the subject. In one embodiment, preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-150, 112, 118 and 131 (upregulated biomarkers from Table 4), wherein expression of the one or more biomarkers is increased in the subject. In another embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 151-177, 110 and 123 (downregulated biomarkers from Table 4), wherein expression of the one or more biomarkers is decreased in the subject.
[0033] In another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-292, 91 and 97 (corresponding to biomarkers set forth in Table 5), thereby monitoring the autoimmune disorder in the subject. In one embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-185; 187-200, 202, 203, 205-207; 211, 213, 214, 216, 220, 221, 226, 228, 229, 231, 232, 234, 235, 238-247, 249, 250, 253, 262-265, 268-282 and 285-288 (upregulated biomarkers from Table 5), wherein expression of the one or more biomarkers is increased in the subject. In another embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 186, 201, 204, 208, 209, 91, 210, 212, 97, 215, 217-219, 222-225, 227, 230, 233, 236, 237, 248, 251, 252, 254-261, 266, 267, 283, 284 and 289-292 (downregulated biomarkers from Table 5), wherein expression of the one or more biomarkers is decreased in the subject.
[0034] In another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 87, 97, 101, 293, 92, 272, 93, 107, 108, 121 and 123 (corresponding to pre-treatment biomarkers set forth in Table 6), and wherein the subject is monitored prior to treatment with a TNFα inhibitor, thereby monitoring the autoimmune disorder in the subject.
[0035] In another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 290, 209, 98, 112, 116, 121, 130, 155, 92, 289, 216 and 131 (corresponding to post-treatment biomarkers set forth in Table 6), and wherein the subject is monitored after treatment with a TNFα inhibitor, thereby monitoring the autoimmune disorder in the subject.
[0036] In yet another aspect, the invention provides a method of monitoring an autoimmune disorder in a subject having the autoimmune disorder, the method comprising: assaying the subject for expression of one or more biomarkers, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 97, 102, 29, 294, 295, 91, 131, 290, 100, 134, 296, 297, 298, 299, 136, 174 and 300 (corresponding to biomarkers set forth in Table 7), thereby monitoring the autoimmune disorder in the subject.
[0037] In yet another aspect, the invention pertains to a method of building a database for use in selecting a subject having an autoimmune disorder (e.g., RA) for treatment with a TNFα inhibitor. The method comprises: receiving, in a computer system, biomarker expression patterns from a plurality of subjects having an autoimmune disorder; and storing the biomarker expression pattern from each subject such that the biomarker expression pattern is associated with an identifier of the subject, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82. The identifier of the subject can be, for example, a numerical identifier coded to an identity of the subject. In a preferred embodiment, the method further comprises receiving, in the computer system, one or more treatment regimens for treatment of the autoimmune disorder in a subject such that the treatment regimen is associated with the biomarker expression pattern of the subject and the identifier of the subject.
[0038] The invention also pertains to a computer program product containing executable instructions that when executed cause a processor to perform operations comprising: receiving, in a computer system, a biomarker expression pattern of a subject at one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder; and storing the biomarker expression pattern such that the biomarker expression pattern is associated with an identifier of the subject, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82. The computer program can further cause the processor to perform an operation comprising: receiving, in the computer system, a treatment regimen for treatment of the autoimmune disorder in the subject such that the treatment regimen is associated with the biomarker expression pattern of the subject and the identifier of the subject.
[0039] In yet another aspect, the invention pertains to a method of selecting an autoimmune disorder subject for treatment with a TNFα inhibitor, the method comprising: (i) identifying, in a database comprising a plurality of autoimmune disorder subjects, a subject whose database entry is associated with a biomarker expression pattern that is predictive of responsiveness to treatment with a TNFα inhibitor, and (ii) selecting the subject for treatment with a TNFα inhibitor, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82. The method can further comprise selecting a treatment regimen by identifying, in the database, a treatment regimen that has been associated with the biomarker expression pattern of the subject and with an identifier of the subject.
[0040] The invention also pertains to a computer program product containing executable instructions that when executed cause a processor to perform operations comprising: (i) identifying, in a database including a plurality of autoimmune disorder subjects associated with biomarker expression patterns, a subject that is associated with a biomarker expression pattern that is predictive of responsiveness to treatment with a TNFα inhibitor; and (ii) outputting the identified subject as a subject to be treated with a TNFα inhibitor; wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82. In one embodiment, the computer program further causes the processor to perform an operation comprising outputting a treatment regimen that is associated with the subject to be treated with the TNFα inhibitor.
BRIEF DESCRIPTION OF THE DRAWINGS
[0041] FIG. 1 is a bar graph showing the results of experiments validating the predictive gene CD11c by quantitative real-time PCR. mRNA expression was compared in monocytes from normal donors (n=16), as well as future responders and future non-responders to therapy with anti-TNFα (RA-ATNF; filled circles ; 15 responders and 12 non-responders) or to combination therapy with anti-TNFα/methotrexate (RA-αTNF/MTX; empty circles ∘; 7 responders and 9 non-responders) The expression of CD11c is expressed as the means±standard error of the mean normalized to that of the house keeping gene glycerol-aldehyd-3-phosphate dehydrogenase (GAPDH; % expression). Except for 1 RA patient with a borderline ACR response of 30 and a CD11c mRNA level directly at the distinction threshold (who was therefore classified as a false negative), the threshold level (40%) almost fully distinguished future responders from nonresponders (100% specificity, 94% sensitivity, and 96% power). The threshold level to distinguish future responders from non-responders is indicated by a broken line (----); * P≦0.05, ** P≦0.01 as compared to normal donors; +++ P≦0.005 as compared to future responders to anti-TNFα therapy.
[0042] FIG. 2 is a graph showing the correlation between the mRNA expression of predictive CD11c in pre-treatment RA patients and their individual future ACR response (continuous ACR score). The horizontal and vertical broken lines indicate the thresholds for the separation between RA-responders and RA-non-responders, both in terms of the pre-treatment CD11c mRNA levels (40%) and their ACR response (continuous ACR score ≦30). Responders (continuous American College of Rheumatology [ACR] score ≧40; clustered as ND) and non-responders to anti-TNF therapy (continuous ACR score ≦30; clustered as RA) were defined according to the criteria of the ACR.
[0043] FIG. 3 is a graph showing the correlation between the mRNA expression of predictive CD11c in pre-treatment RA patients and their individual future strict ACR response in the following conventional used steps: ≧0%, ≧20%, ≧50%, and ≧70% (continuous ACR score).
DETAILED DESCRIPTION OF THE INVENTION
[0044] This invention provides methods for predicting responsiveness to a TNFα inhibitor in a subject suffering from an autoimmune disorder, and methods for selecting a treatment regimen with a TNFα inhibitor, based on expression of particular biomarkers in the subject to be treated. The invention is based, at least in part, on the observation that altered expression of particular biomarkers in a subject suffering from rheumatoid arthritis is associated with increased or decreased responsiveness to therapy with a TNFα inhibitor. Microarray analysis, hierarchical clustering and TaqMan®-PCR analysis were used to examine normal donors (NA) and rheumatoid arthritis (RA) patients, who were categorized as being responsive to treatment with an anti-TNFα antibody (RA responders) or nonresponsive to treatment with an anti-TNFα antibody (RA nonresponders). A panel of 82 genes were identified whose expression was altered (upregulated or downregulated) in patients identified as either future RA responders or future RA nonresponders, demonstrating the ability of these genes to act as biomarkers for predicting responsiveness to TNFα inhibitor treatment. In particular, one gene, encoding the antigen CD11c, was identified as fully predicting the future response to anti-TNFα treatment. Accordingly, the expression pattern of one or more biomarkers can be assessed in RA subjects for which TNFα inhibitor therapy is being considered, or subjects suffering from other autoimmune disorders amenable to TNFα inhibitor therapy, to thereby predict responsiveness of the subject to such therapy and/or to aid in the selection of an appropriate treatment regimen.
[0045] Furthermore, additional patterns of biomarker expression were identified by (i) hierarchical clustering with the genes resulting from a simultaneous comparison between RA versus ND and RA responders pre- versus post-anti-TNFα therapy; (ii) prediction analysis of microarrays; and (iii) hierarchical clustering based on the comparison between RA responders and non-responders post-treatment. Accordingly, the biomarker expression patterns described herein also can be using in monitoring an autoimmune disorder in a subject, e.g., monitoring the responsiveness of the subject to a particular therapy or assisting in the diagnosis or prognosis of the autoimmune disorder (e.g., RA) in the subject.
[0046] In order that the present invention may be more readily understood, certain terms are first defined. Additional definitions are set forth throughout the detailed description.
[0047] The term "predicting responsiveness to a TNFα inhibitor", as used herein, is intended to refer to an ability to assess the likelihood that treatment of a subject with a TNFα inhibitor will or will not be effective in (e.g., provide a measurable benefit to) the subject. In particular, such an ability to assess the likelihood that treatment will or will not be effective typically is exercised before treatment with the TNFα inhibitor is begun in the subject. However, it is also possible that such an ability to assess the likelihood that treatment will or will not be effective can be exercised after treatment has begun but before an indicator of effectiveness (e.g., an indicator of measurable benefit) has been observed in the subject.
[0048] The term "TNFα inhibitor" as used herein is intended to encompass agents including proteins, antibodies, antibody fragments, fusion proteins (e.g., Ig fusion proteins or Fc fusion proteins), multivalent binding proteins (e.g., DVD Ig), small molecule TNFα antagonists and similar naturally- or nonnaturally-occurring molecules, and/or recombinant and/or engineered forms thereof, that, directly or indirectly, inhibits TNFα activity, such as by inhibiting interaction of TNFα with a cell surface receptor for TNFα, inhibiting TNFα protein production, inhibiting TNFα gene expression, inhibiting TNFα secretion from cells, inhibiting TNFα receptor signaling or any other means resulting in decreased TNFα activity in a subject. The term "TNFα inhibitor" also includes agents which interfere with TNFα activity. Examples of TNFα inhibitors include etanercept (ENBREL®, Amgen), infliximab (REMICADE®, Johnson and Johnson), human anti-TNF monoclonal antibody adalimumab (D2E7/HUMIRA®, Abbott Laboratories), CDP 571 (Celltech), and CDP 870 (Celltech), as well as other compounds which inhibit TNFα activity, such that when administered to a subject suffering from or at risk of suffering from a disorder in which TNFα activity is detrimental (e.g., RA), the disorder is treated. The term also includes each of the anti-TNFα human antibodies and antibody portions described herein as well as those described in U.S. Pat. Nos. 6,090,382; 6,258,562; 6,509,015, and in U.S. patent application Ser. Nos. 09/801,185 (U.S. Publication No. 20030092059) and 10/302,356 (U.S. Publication No. 20030219438), each incorporated by reference herein.
[0049] The term "antibody" as referred to herein includes whole antibodies and any antigen binding fragment (i.e., "antigen-binding portion") or single chains thereof. An "antibody" refers to a glycoprotein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof. Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is comprised of three domains, CH1, CH2 and CH3. Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is comprised of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The constant regions of the antibodies may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
[0050] The term "antibody" is also intended to encompass dual-specific antibodies and bispecific antibodies. The term "dual-specific antibody", as used herein, refers to full-length antibodies that can bind two different antigens (or epitopes) in each of its two binding arms (a pair of HC/LC) (see e.g., PCT publication WO 02/02773). Accordingly a dual-specific binding protein has two identical antigen binding arms, with identical specificity and identical CDR sequences, and is bi-valent for each antigen it binds to. The term "bispecific antibody", as used herein, refers to full-length antibodies that are generated by quadroma technology (see Milstein, C. and A. C. Cuello (1983) Nature, 305:537-40), by chemical conjugation of two different mAbs (see Staerz, U. D., et al. (1985) Nature 314:628-31), or by knob-into-hole or similar approaches which introduces mutations in the Fc region (see Holliger, P., T. Prospero, and G. Winter (1993) Proc. Natl. Acad. Sci. USA 90:6444-8), resulting in multiple different immunogloblin species of which only one is the functional bispecific antibody. By molecular function, a bispecific antibody binds one antigen (or epitope) on one of its two binding arms (one pair of HC/LC), and binds a different antigen (or epitope) on its second arm (a different pair of HC/LC). By this definition, a bispecific antibody has two distinct antigen binding arms (in both specificity and CDR sequences), and is mono-valent for each antigen it binds to. Thus, when used herein, a "bispecific" antibody of the invention has one binding arm that is specific for an epitope of TNFα and a second binding arm that is specific for a different antigen or epitope.
[0051] The term "antigen-binding portion" of an antibody (or simply "antibody portion"), as used herein, refers to one or more fragments of an antibody that retain the ability to specifically bind to an antigen. It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody. Examples of binding fragments encompassed within the term "antigen-binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CH1 domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CH1 domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al., (1989) Nature 341:544-546), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR). Furthermore, although the two domains of the Fv fragment, VL and VH, are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al. (1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl. Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also intended to be encompassed within the term "antigen-binding portion" of an antibody. These antibody fragments are obtained using conventional techniques known to those with skill in the art, and the fragments are screened for utility in the same manner as are intact antibodies.
[0052] The terms "monoclonal antibody" or "monoclonal antibody composition" as used herein refer to a preparation of antibody molecules of single molecular composition. A monoclonal antibody composition displays a single binding specificity and affinity for a particular epitope.
[0053] The terms "chimeric antibody" or "chimeric monoclonal antibody" are intended to refer to antibodies in which the variable region sequences are derived from one species and the constant region sequences are derived from another species, such as an antibody in which the variable region sequences are derived from a mouse antibody and the constant region sequences are derived from a human antibody. Such "chimeric antibodies" can be prepared by standard recombinant technology well established in the art. For example, a nucleic acid encoding a VH region from a mouse antibody can be operatively linked to a nucleic acid encoding the heavy chain constant regions from a human antibody and, likewise, a nucleic acid encoding a VL region from a mouse antibody can be operatively linked to a nucleic acid encoding the light chain constant region from a human antibody.
[0054] The terms "humanized antibody" or "humanized monoclonal antibody" are intended to refer to antibodies in which CDR sequences derived from the germline of a non-human mammalian species, such as a mouse, have been grafted onto human framework sequences. Additional framework region modifications may be made within the human framework sequences. Such "humanized antibodies" can be prepared by standard recombinant technology well established in the art. For example, nucleic acids encoding the CDR1, CD2 and CDR3 regions from a VH region of a mouse antibody can be operatively linked to nucleic acids encoding the FR1, FR2, FR3 and FR4 regions of a human VH region, and the entire "CDR-grafted" VH region can be operatively linked to nucleic acid encoding the heavy chain constant regions from a human antibody. Likewise, nucleic acids encoding the CDR1, CD2 and CDR3 regions from a VL region of a mouse antibody can be operatively linked to nucleic acids encoding the FR1, FR2, FR3 and FR4 regions of a human VL region, and the entire "CDR-grafted" VL region can be operatively linked to nucleic acid encoding the light chain constant region from a human antibody.
[0055] The term "human antibody", as used herein, is intended to refer to antibodies having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the antibody contains a constant region, the constant region also is derived from human germline immunoglobulin sequences. Human antibodies may include amino acid residues not encoded by human germline immunoglobulin sequences (e.g., mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo).
[0056] The term "human monoclonal antibody" refers to antibodies displaying a single binding specificity which have variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Human monoclonal antibodies can be produced by a hybridoma which includes a B cell obtained from a transgenic nonhuman animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell. The term "human monoclonal antibody", as used herein, also includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom, (b) antibodies isolated from a host cell transformed to express the human antibody, e.g., from a transfectoma, (c) antibodies isolated from a recombinant, combinatorial human antibody library, and (d) antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences. Such recombinant human antibodies have variable regions in which the framework and CDR regions are derived from human germline immunoglobulin sequences. Such recombinant human antibodies, however, can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
[0057] The terms "Ig fusion protein" and "Fc fusion protein" are intended to refer to a recombinant, composite protein comprising a polypeptide of interest operatively linked to a constant region portion of immunoglobulin, typically the hinge, CH2 and CH3 domains of heavy chain constant region, more typically the human IgG1 hinge, CH2 and CH3 domains. The polypeptide of interest operatively linked to the Fc portion can be, for example, a full-length protein or only a portion of a full-length protein, such as one or more extracellular domains of a protein, e.g., one or more extracellular domains of a cell-surface protein. Such "Ig fusion proteins" can be prepared by standard recombinant technology well established in the art. For example, a nucleic acid encoding the polypeptide of interest can be operatively linked to a nucleic acid encoding the hinge, CH2 and CH3 domains of a heavy chain constant region.
[0058] The term "multivalent binding protein", as a form of TNFα inhibitor, is used in this specification to denote a binding protein comprising two or more antigen binding sites. Examples of multivalent binding proteins include dual variable domain (DVD) binding proteins. The multivalent binding protein is preferably engineered to have three or more antigen binding sites, and is generally not a naturally occurring antibody. A multivalent binding protein also can be a "multispecific binding protein." The term "multispecific binding protein" refers to a binding protein capable of binding two or more related or unrelated targets (wherein, with respect to this specification at least one of the targets is TNFα). Dual variable domain (DVD) binding proteins, as used herein, are binding proteins that comprise two or more antigen binding sites and are tetravalent or multivalent binding proteins. Such DVDs may be monospecific, i.e., capable of binding one antigen (e.g., TNFα) or multispecific, i.e., capable of binding two or more antigens (e.g., TNFα and one or more other antigens). DVD binding proteins comprising two heavy chain DVD polypeptides and two light chain DVD polypeptides are referred to as "DVD Ig." Each half of a DVD Ig comprises a heavy chain DVD polypeptide, and a light chain DVD polypeptide, and two antigen binding sites. Each binding site comprises a heavy chain variable domain and a light chain variable domain with a total of 6 CDRs involved in antigen binding per antigen binding site. DVD binding proteins and methods of making DVD binding proteins are disclosed in US. Publication No. 20070071675, the entire contents of which are specifically incorporated herein by reference.
[0059] As used herein, the term "biomarker" is intended to encompass a substance that is used as an indicator of a biologic state and includes genes (and nucleotide sequences of such genes), mRNAs (and nucleotide sequences of such mRNAs) and proteins (and amino acid sequences of such proteins). A "biomarker expression pattern" is intended to refer to a quantitative or qualitative summary of the expression of one or more biomarkers in a subject, such as in comparison to a standard or a control.
[0060] The terms "increased" or "increased expression" and "decreased" or "decreased expression", with respect to the expression pattern of a biomarker(s), are used herein as meaning that the level of expression is increased or decreased relative to a constant basal level of expression of a household, or housekeeping, gene, whose expression level does not significantly vary under different conditions. A nonlimiting example of such a household, or housekeeping, gene is GAPDH. Other suitable household, or housekeeping, gene are well-established in the art.
[0061] As used herein, the term "CD11c" refers to a protein having a full-length amino acid sequence as set forth at Genbank Accession No. NP--000878 (also shown as SEQ ID NO: 302) and encoded by a full-length nucleotide sequence as set forth at Genbank Accession No. NM--000887 (also shown as SEQ ID NO: 301). CD11c is also known in the art as CD11C, CD11c antigen, Integrin alpha X, complement component 3 receptor 4 subunit, ITGAX, LeuM5, Integrin alpha X precursor, Leukocyte adhesion glycoprotein p150,p95 alpha chain, and Leukocyte adhesion receptor p150 subunit, which terms may be used interchangeably herein to refer to CD11c.
[0062] As used herein, the term "Affymetrix ID" refers to a numerical identifier that corresponds to a sequence entry in an Affymetrix database, which entry includes the sequence as well as additional information relating to the sequence and corresponding protein. The sequence entries, and additional information in the entries, for each Affymetrix ID are publicly available (e.g., by entering the Affymetrix ID number into the Affymetrix database search engine, e.g., at https://www.affymetrix.com/analysis/netaffx/index.affx). All sequence entries (such as Genbank Accession numbers), and additional information provided for each entry, corresponding to each of the Affymetrix ID numbers disclosed herein are hereby specifically incorporated by reference in their entirety.
[0063] As used herein, the term "subject" includes humans, and non-human animals amenable to TNFα inhibitor therapy, e.g., preferably mammals, such as non-human primates, sheep, dogs, cats, horses and cows.
[0064] As used herein, the term "autoimmune disorder subject" or "AD subject" is intended to refer to a subject (e.g., human patient) suffering from an autoimmune disorder.
[0065] As used herein, the term "rheumatoid arthritis subject" or "RA subject" is intended to refer to a subject (e.g., human patient) suffering from rheumatoid arthritis.
[0066] As used herein, the term "treatment regimen" is intended to refer to one or more parameters selected for the treatment of a subject, e.g., with a TNFα inhibitor, which parameters can include, but are not necessarily limited to, the type of agent chosen for administration, the dosage, the formulation, the route of administration and the frequency of administration.
[0067] Various aspects of the invention are described in further detail in the following subsections.
Prediction of Responsiveness to a TNFα Inhibitor for Autoimmune Disorders
[0068] In one aspect, the invention pertains to a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, such as rheumatoid arthritis. Typically, the method comprises (i) assaying the subject for the expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on expression of the one or more biomarkers in the subject. As used herein, the term "one or more biomarkers" is intended to mean that at least one biomarker in a disclosed list of biomarkers is assayed and, in various embodiments, more than one biomarker set forth in the list may be assayed, such as two, three, four, five, ten, twenty, thirty, forty, fifty, more than fifty, or all the biomarkers in the list may be assayed.
[0069] Predicting responsiveness of the subject to the TNFα inhibitor "based on expression of the one or more biomarkers in the subject" typically involves comparing the level, or pattern, of expression of the one or more biomarkers in the subject to a known standard or control (which known standard or control may be derived from, for example, a normal subject, a pre-established TNFα inhibitor responder or a pre-established TNFα inhibitor non-responder). In a preferred embodiment, the level of expression of the biomarker(s) is measured in parallel with measurement of the level of expression of one or more "housekeeping" genes, such as GAPDH, whose expression level is not altered by the autoimmune disorder. The level of expression of the biomarker(s) is determined to be "increased" or "decreased" relative to a constant basal level of expression of the housekeeping gene. Examples of suitable housekeeping genes, such as GAPDH, that can be used for comparison purposes are well known in the art.
[0070] Preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (corresponding to sequences of the biomarkers set forth in Table 9). Thus, at least one of the biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 is assayed and, in various embodiments, for example, two, three, four, five, ten, twenty, thirty, forty, fifty, more than fifty, or all the biomarkers in the list may be assayed.
[0071] In a preferred embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82 (corresponding to sequences from Table 9 that are increased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 37, 44, 47, 62 and 70 (corresponding to sequences from Table 9 that are increased in ≧90% of responders vs. non-responders). Even more preferably, at least one of the biomarkers to be assayed is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44 (corresponding to the biomarker CD11c, which, as set forth in Table 9, is increased in 100% of responders vs. non-responders). In each of these embodiments, increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor (e.g., increased expression relative to a standard or control level of expression, which standard or control level of expression can be based, for example, on the level of expression in previously established TNFα inhibitor non-responder RA subjects).
[0072] In another preferred embodiment, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81 (corresponding to sequences from Table 9 that are decreased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 29, 65, 73 and 74 (corresponding to sequences from Table 9 that are decreased in ≧90% of responders vs. non-responders). Even more preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 11 or SEQ ID NO: 74 (corresponding to sequences from Table 9 that are decreased in 100% of responders vs. non-responders). In each of these embodiments, decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor (e.g., decreased expression relative to a standard or control level of expression, which standard or control level of expression can be based, for example, on the level of expression in previously established TNFα inhibitor non-responder RA subjects).
[0073] In another aspect, the invention provides a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in the autoimmune disorder, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on expression of the one or more biomarkers in the subject, wherein the one or more biomarkers is selected from the group consisting of Aquaporin 3 (Genbank Accession No. NM--004925); Similar to ribosomal protein S24, clone MGC:8595 (Genbank Accession No. NM--033022); Transmembrane emp24 domain trafficking protein 2 (Genbank Accession No. NM--006815; Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 (Genbank Accession No. NM--000454); Calmodulin 1 (phosphorylase kinase, delta) (Genbank Accession No. NM--006888); Guanine nucleotide binding protein (G protein), beta polypeptide 1 (Genbank Accession No. NM--002074); Prothymosin, alpha (gene sequence 28) (Genbank Accession No. NM--002823); Homo sapiens isocitrate dehydrogenase 1 (NADP.sup.+) soluble (IDH1) (Genbank Accession No. NM--005896); Tumor protein D52 (Genbank Accession Nos. NM--001025252, NM--001025253, NM--005079); Early growth response 1 (Genbank Accession No. NM--001964); Homo sapiens predicted osteoblast protein (GS3786) (Genbank Accession Nos. NM--014888, NM--001040020); Cytochrome c oxidase subunit VIIb (Genbank Accession No. NM--001866); CUG triplet repeat, RNA binding protein 2 (Genbank Accession No. NM--001025077, NM--001025076, NM--006561); Ubiquinol-cytochrome c reductase hinge protein (Genbank Accession No. NM--006004); Homo sapiens leptin receptor gene-related protein (HS0BRGRP) (Genbank Accession No. NM--017526); Wiskott-Aldrich syndrome protein interacting protein (Genbank Accession Nos. NM--001077269, NM--003387); CD97 antigen (Genbank Accession Nos. NM--001025160, NM--001784, NM--078481); Glutamate-cysteine ligase, catalytic subunit (Genbank Accession No. NM--001498); Crystallin, zeta (quinone reductase) (Genbank Accession No. NM--001889); Rap guanine nucleotide exchange factor (GEF) 2 (Genbank Accession No. NM--014247); Ataxin 1 (Genbank Accession No. NM--000332); Adaptor-related protein complex 1, sigma 2 subunit (Genbank Accession No. NM--003916); Ectonucleotide pyrophosphatase/phosphodiesterase 4 (Genbank Accession No. NM--014936); Desmocollin 2 (Genbank Accession Nos. NM--024422, NM--004949); MAL, T-cell differentiation protein (Genbank Accession Nos. NM--002371, NM--022438, NM--022439, NM--022440); Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (Genbank Accession No. NM--005476); Chemokine (C--C motif) ligand 3 (Genbank Accession Nos. NM--001001437, NM--021006); Carboxypeptidase A3 (Genbank Accession No. NM--001870); Charcot-Leyden crystal protein (Genbank Accession No. NM--001828); NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa (Genbank Accession No. NM--004545); Interleukin 8 receptor, beta (Genbank Accession No. NM--001557); Platelet factor 4 variant 1 (Genbank Accession No. NM--002620); Poly(A) binding protein interacting protein 1 (Genbank Accession No. NM--006451); ATP-binding cassette, sub-family C (CFTR/MRP), member 3 (Genbank Accession No. NM--003786); Actinin, alpha 1 (Genbank Accession No. NM--001102); NAD kinase (Genbank Accession No. NM--023018); Platelet/endothelial cell adhesion molecule (CD31 antigen) (Genbank Accession No. NM--000442); Esterase D/formylglutathione hydrolase (Genbank Accession No. NM--001984); Chromosome 20 open reading frame 111 (Genbank Accession No. NM--016470); Sterol-C4-methyl oxidase-like (Genbank Accession Nos. NM--001017369, NM--006745); PIM-1 oncogene (Genbank Accession No. NM--002648); GATA binding protein 2 (Genbank Accession No. NM--032638); Cathepsin Z (Genbank Accession No. NM--001336); Integrin alpha-X (antigen CD11c) (Genbank Accession No. NM--000887); Lectin, galactoside-binding, soluble, 8 (galectin 8) (Genbank Accession Nos. NM--006499, NM--201545); CD86 antigen (CD28 antigen ligand 2, B7-2 antigen) (Genbank Accession Nos. NM--006889, NM--175862); Interleukin 8 (Genbank Accession No. NM--000584); Fc fragment of IgE, high affinity I, receptor for alpha polypeptide (Genbank Accession No. NM--002001); Actin, gamma 1 (Genbank Accession No. NM--001614); KIAA0746 protein (Genbank Accession No. NM--015187); Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID) (Genbank Accession No. NM--002076); Transcription factor 4 (Genbank Accession Nos. BF592782, CR612521); Major histocompatibility complex, class II, DQ alpha 1 (Genbank Accession Nos. NM--002122, NM--020056); Cell division cycle 2-like 6 (CDK8-like) (Genbank Accession No. NM--015076); Major histocompatibility complex, class II, DQ beta 1 (Genbank Accession No. XM--942240); Phospholipase C-like 2 (Genbank Accession No. NM--015184); Coagulation factor II (thrombin) receptor-like 1 (Genbank Accession No. NM--005242); TM2 domain containing 1 (Genbank Accession No. NM--032027); Splicing factor 3b, subunit 1, 155 kDa (Genbank Accession No. NM--012433); SUB1 homolog (S. cerevisiae) (Genbank Accession No. NM--006713); mRNA; cDNA DKFZp564O0862 (Genbank Accession No. AI278204); Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease) (Genbank Accession Nos. NM--201413, NM--000484, NM--201414); Cytochrome b-5 (Genbank Accession Nos. NM--001914, NM--148923); Cold autoinflammatory syndrome 1 (Genbank Accession No. NM--183395); Neugrin, neurite outgrowth associated (Genbank Accession Nos. NM--016645, NM--001033088); Ribosomal protein S26, 40S ribosomal protein (Genbank Accession No. XM--941927); CCR4-NOT transcription complex, subunit 6 (Genbank Accession No. NM--015455); Ubiquinol-cytochrome c reductase complex (7.2 kD) (Genbank Accession Nos. NM--013387, NM--001003684); Hepatocellular carcinoma-associated antigen 112 (Genbank Accession No. NM--018487); Kruppel-like factor 11 (Genbank Accession No. XM--001129527); GGA binding partner (Genbank Accession No. NM--018318); Cornichon homolog 4 (Drosophila) (Genbank Accession No. NM--014184); Hypothetical protein FLJ21616 (Genbank Accession No. NM--024567); Homo sapiens hypothetical protein FLJ10134 (Genbank Accession No. NM--018004); Nuclear prelamin A recognition factor (Genbank Accession Nos. NM--012336, NM--001038618); Erythroblast membrane-associated protein (Genbank Accession Nos. NM--018538, NM--001017922); LR8 protein (Genbank Accession No. NM--014020); Likely ortholog of mouse limb-bud and heart gene (LBH) (Genbank Accession No. NM--030915); Calmin (calponin-like, transmembrane) (Genbank Accession No. NM--024734); Chromosome 14 open reading frame 156 (Genbank Accession No. NM--031210); Guanine nucleotide binding protein (G protein) alpha 12 (Genbank Accession No. NM--007353); and SRY (sex determining region Y)-box 18 (Genbank Accession No. NR--003287) (corresponding to biomarkers listed in Table 9).
[0074] In a preferred embodiment, the one or more biomarkers is selected from the group consisting of Guanine nucleotide binding protein (G protein), beta polypeptide 1; Prothymosin, alpha (gene sequence 28); Early growth response 1; Homo spaiens leptin receptor gene-related protein (HS0BRGRP); Wiskott-Aldrich syndrome protein interacting protein; CD97 antigen; Crystallin, zeta (quinone reductase); Adaptor-related protein complex 1, sigma 2 subunit; Desmocollin 2; Chemokine (C--C motif) ligand 3; Interleukin 8 receptor, beta; ATP-binding cassette, sub-family C (CFTR/MRP), member 3; Actinin, alpha 1; NAD kinase; Platelet/endothelial cell adhesion molecule (CD31 antigen); Esterase D/formylglutathione hydrolase; Chromosome 20 open reading frame 111; Cathepsin Z; Integrin alpha-X (antigen CD11c); Lectin, galactoside-binding, soluble, 8 (galectin 8); CD86 antigen (CD28 antigen ligand 2, B7-2 antigen); Interleukin 8; Actin, gamma 1; Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID); Cell division cycle 2-like 6 (CDK8-like); Major histocompatibility complex, class II, DQ beta 1; Coagulation factor II (thrombin) receptor-like 1; Splicing factor 3b, subunit 1, 155 kDa; mRNA; cDNA DKEZp564O0862; Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease); Cold autoinflammatory syndrome 1; Kruppel-like factor 11; Nuclear prelamin A recognition factor; Calmin (calponin-like, transmembrane); and SRY (sex determining region Y)-box 18 (corresponding to biomarkers listed in Table 9 that are increased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is selected from the group consisting of Interleukin 8 receptor, beta; Platelet/endothelial cell adhesion molecule (CD31 antigen); Integrin alpha-X (antigen CD11c); Interleukin 8; Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer disease); and Kruppel-like factor 11 (corresponding to biomarkers listed in Table 9 that are increased in ≧90% of responders vs. non-responders). Even more preferably, at least one of the biomarkers is Integrin alpha-X (antigen CD11c) (corresponding to a biomarker listed in Table 9 that is increased in 100% of responders vs. non-responders). In each of the embodiments, increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0075] In another preferred embodiment, the one or more biomarkers is selected from the group consisting of Aquaporin 3; Similar to ribosomal protein S24, clone MGC:8595; Transmembrane emp24 domain trafficking protein 2; Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1; Calmodulin 1 (phosphorylase kinase, delta); Homo sapiens isocitrate dehydrogenase 1 (NADP+) soluble (IDH1); Tumor protein D52; Homo sapiens predicted osteoblast protein (GS3786); Cytochrome c oxidase subunit VIIb; CUG triplet repeat, RNA binding protein 2; Ubiquinol-cytochrome c reductase hinge protein; Glutamate-cysteine ligase, catalytic subunit; Rap guanine nucleotide exchange factor (GEF) 2; Ataxin 1; Ectonucleotide pyrophosphatase/phosphodiesterase 4; MAL, T-cell differentiation protein; Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase; Carboxypeptidase A3; Charcot-Leyden crystal protein; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa; Platelet factor 4 variant 1; Poly(A) binding protein interacting protein 1; Sterol-C4-methyl oxidase-like; PIM-1 oncogene; GATA binding protein 2; Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide; KIAA0746 protein; Transcription factor 4; Major histocompatibility complex, class II, DQ alpha 1; Phospholipase C-like 2; TM2 domain containing 1; SUB1 homolog (S. cerevisiae); Cytochrome b-5; Neugrin, neurite outgrowth associated; Ribosomal protein S26, 40S ribosomal protein; CCR4-NOT transcription complex, subunit 6; Ubiquinol-cytochrome c reductase complex (7.2 kD); Hepatocellular carcinoma-associated antigen 112; GGA binding partner; Cornichon homolog 4 (Drosophila); Hypothetical protein FLJ21616; Homo sapiens hypothetical protein FLJ10134; Erythroblast membrane-associated protein; LR8 protein; Likely ortholog of mouse limb-bud and heart gene (LBH); Chromosome 14 open reading frame 156; and Guanine nucleotide binding protein (G protein) alpha 12 (corresponding to biomarkers listed in Table 9 that are decreased in ≧80% of responders vs. non-responders). More preferably, the one or more biomarkers is selected from the group consisting of Homo sapiens predicted osteoblast protein (GS3786); Charcot-Leyden crystal protein; Neugrin, neurite outgrowth associated; Hypothetical protein FLJ21616; and Homo sapiens hypothetical protein FLJ10134 (corresponding to biomarkers listed in Table 9 that are decreased in ≧90% of responders vs. non-responders). Even more preferably, the one or more biomarkers is Homo sapiens predicted osteoblast protein (GS3786) or Homo sapiens hypothetical protein FLJ10134 (corresponding to biomarkers listed in Table 9 that are decreased in 100% of responders vs. non-responders). In each of these embodiments, decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0076] In a particularly preferred aspect, the invention provides a method for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder the method comprising: (i) assaying the subject for increased expression of a biomarker, which biomarker is CD11c, and (ii) predicting responsiveness of the subject to the TNFα inhibitor based on increased expression of CD11c in the subject.
[0077] In yet another particularly preferred embodiment, the invention provides a method for predicting responsiveness to a TNFα inhibitor, which TNFα inhibitor is adalimumab, in a subject having an autoimmune disorder the method comprising: (i) assaying the subject for expression of one or more biomarkers predictive of responsiveness to adalimumab in the autoimmune disorder, and (ii) predicting responsiveness of the subject to adalimumab based on expression of the one or more biomarkers in the subject. Preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or selected from the group consisting of the biomarkers set forth in Table 9). In more preferred embodiments, the subsets of sequences within SEQ ID NO: 1-82 that are either increased or decreased, as set forth in detail above, can be assayed.
[0078] In the methods of the invention for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, the expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in the autoimmune disorder can be assayed in the subject using techniques well-established in the art. In a preferred embodiment, the expression of the one or more biomarkers in the subject is assayed by obtaining an mRNA sample from the subject (e.g., isolated from peripheral blood mononuclear cells, by standard methods) and detecting the expression of mRNA(s) encoding the one or more biomarkers in the mRNA sample using standard molecular biology techniques, such as PCR analysis. A preferred method of PCR analysis is revers transcriptase-polymerase chain reaction (RT-PCR). Other suitable systems for mRNA sample analysis include microarray analysis (e.g., using Affymetrix's microarray system or Illumina's BeadArray Technology).
[0079] Additionally or alternatively, in certain situations it may be possible to assay for the expression of one or more biomarkers at the protein level, using a detection reagent that detects the protein product encoded by the mRNA of the biomarker(s). For example, if an antibody reagent is available that binds specifically to the biomarker protein product to be detected, and not to other proteins, then such an antibody reagent can be used to detect the expression of the biomarker of interest in a cellular sample from the subject, or a preparation derived from the cellular sample, using standard antibody-based techniques known in the art, such as FACS analysis, ELISA and the like.
[0080] It will be readily understood by the ordinarily skilled artisan that essentially any technical means established in the art for detecting biomarkers, at either the nucleic acid or protein level, can be adapted to detection of the biomarkers discussed herein and applied in the methods of the current invention for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder.
[0081] The biomarkers described herein were originally identified in patients having rheumatoid arthritis (see the Examples) and thus a particularly preferred autoimmune disorder in which to apply the methods of the invention is rheumatoid arthritis. The mechanism of action of the TNFα pathway, however, is thought to be common to a large number of autoimmune disorders and TNFα inhibitors have been shown to be effective therapy in a variety of different autoimmune disorders. Accordingly, the method of the invention for predicting responsiveness to a TNFα inhibitor can be applied to essentially any autoimmune disorder in which TNFα inhibitor therapy is applied. Other preferred autoimmune disorders include Crohn's disease, ulcerative colitis, psoriasis, psoriatic arthritis, juvenile arthritis and ankylosing spondilitis, Other non-limiting examples of autoimmune disorders include autoimmune diabetes, multiple sclerosis, systemic lupus erythematosus, rheumatoid spondylitis, gouty arthritis, allergy, autoimmune uveitis, nephrotic syndrome, multisystem autoimmune diseases, autoimmune hearing loss, adult respiratory distress syndrome, shock lung, chronic pulmonary inflammatory disease, pulmonary sarcoidosis, pulmonary fibrosis, silicosis, idiopathic interstitial lung disease, chronic obstructive pulmonary disease, asthma, restenosis, spondyloarthropathies, Reiter's syndrome, autoimmune hepatitis, inflammatory skin disorders, vasculitis of large vessels, medium vessels or small vessels, endometriosis, prostatitis and Sjogren's syndrome.
Biomarkers for Monitoring an Autoimmune Disorder in a Subject
[0082] In another aspect, the invention provides methods of monitoring an autoimmune disorder in a subject having the autoimmune disorder based on biomarker expression patterns established using microarray analysis of, for example, RA subjects vs. normal donors, RA subjects vs. RA subjects treated with a TNFα inhibitor and/or RA subjects treated with a TNFα inhibitor vs. RA responders to TNFα inhibitors. In these monitoring methods, the subject is assayed for expression of one or more biomarkers (using techniques, for example, as described in the previous section), thereby monitoring the autoimmune disorder in the subject.
[0083] In one embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 83-133 (or the biomarkers set forth by name in Table 3, namely v-maf musculoaponeurotic fibrosarcoma oncogene homolog F; Diphtheria toxin receptor (DTR); DEAH (Asp-Glu-Ala-His) box polypeptide 15; Ribonucleotide reductase M2 polypeptide; Solute carrier family 6, member 8; 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3; Ferrochelatase (protoporphyria); Nuclear factor, interleukin 3 regulated; Thrombomodulin; Major histocompatibility complex, class II, DM beta; Forkhead box O3A; Hemoglobin, gamma A, gamma G; Synuclein, alpha (non A4 component of amyloid precursor); Hemoglobin, gamma A; Amphiregulin (schwannoma-derived growth factor); Lipoyltransferase 1; Solute carrier family 4, anion exchanger, member 1; S100 calcium binding protein A12 (calgranulin C); Keratin 1 (epidermolytic hyperkeratosis); Carbonic anhydrase I; CD1C antigen, c polypeptide; Tumor necrosis factor, alpha-induced protein 6; Ribonuclease, RNase A family, 2; Hemoglobin, delta; Transferrin receptor (p90, CD71); Ring finger protein 10; Chromosome 1 open reading frame 63; Hemoglobin, alpha 1, alpha 2; CD69 antigen (p60, early T-cell activation antigen; APEX nuclease (multifunctional DNA repair enzyme) 1; Membrane-spanning 4-domains, subfamily A, member 3; Heat shock 70 kDa protein 8; Hypothetical protein MGC12760; GABA(A) receptor-associated protein like 1, like 3; Aminolevulinate, delta-, synthase 2; Major histocompatibility complex, class II, DP alpha 1; Morf4 family associated protein 1-like 1; Aldehyde dehydrogenase 1 family, member A1; Formin binding protein 4; Zinc finger protein 24 (KOX 17); Hypothetical protein L0054103; Selenium binding protein 1; Hematopoietically expressed homeobox; Major histocompatibility complex, class II, DM alpha; Eukaryotic translation initiation factor 2-alpha kinase 1; Ankyrin repeat domain 49; Hypothetical protein FLJ20701; Zinc finger protein 331; Membrane-spanning 4-domains, subfamily A, member 4; Tensin 1; and Family with sequence similarity 46, member A, respectively).
[0084] In another embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-177, 110, 112, 118, 123 and 131 (or the biomarkers set forth by name in Table 4, namely Uncharacterized hypothalamus protein HT007; Dual specificity phosphatase 22; Proteasome (prosome, macropain) subunit, beta type, 7; Membrane-spanning 4-domains, subfamily A, member 4; DKFZP434C171 protein; Protein phosphatase 1, catalytic subunit, beta isoform; Splicing factor, arginine/serine-rich 5; Sorting nexin 11; Farnesyltransferase, CAAX box, alpha; Peroxisomal D3,D2-enoyl-CoA isomerise; Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide; UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1; Hypothetical protein FLJ11259; APEX nuclease (multifunctional DNA repair enzyme) 1; Geranylgeranyl diphosphate synthase 1; Down syndrome critical region gene 5; Calpain 7; Major histocompatibility complex, class II, DP alpha 1; Brix domain containing 5; Chromosome 21 open reading frame 59; Tumor necrosis factor (ligand) superfamily, member 10; Chromosome 10 open reading frame 86; CD1D antigen, d polypeptide; Ewing sarcoma breakpoint region 1; Ribonuclease P 40 kDa subunit; PHD finger protein 20; Thioredoxin interacting protein; Ubiquinol-cytochrome c reductase core protein II; Hypothetical protein FLJ22662; Preimplantation protein 3; DKFZP564G2022 protein; Dipeptidase 2; Hemoglobin, alpha 1, alpha 2; Frequently rearranged in advanced T-cell lymphomas; DEAD (Asp-Glu-Ala-Asp) box polypeptide 48; Tumor necrosis factor, alpha-induced protein 2; Nucleophosmin (nucleolar phosphoprotein B23, numatrin); Interleukin 13 receptor, alpha 1; Leukocyte specific transcript 1, LST1; CGI-121 protein; RAS p21 protein activator 4/hypothetical protein FLJ21767; Cathepsin S; CD63 antigen (melanoma 1 antigen); JTV1 gene; KIAA0174; Thrombospondin 1; Hypothetical protein L0054103; Interferon regulatory factor 1; and SEC11-like 1 (S. cerevisiae)).
[0085] More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-150, 112, 118 (or the biomarkers set forth by name in Table 4 as being upregulated, namely Uncharacterized hypothalamus protein HT007; Dual specificity phosphatase 22; Proteasome (prosome, macropain) subunit, beta type, 7; Membrane-spanning 4-domains, subfamily A, member 4; DKEZP434C171 protein; Protein phosphatase 1, catalytic subunit, beta isoform; Splicing factor, arginine/serine-rich 5; Sorting nexin 11; Farnesyltransferase, CAAX box, alpha; Peroxisomal D3,D2-enoyl-CoA isomerise; Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide; UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1; Hypothetical protein FLJ11259; APEX nuclease (multifunctional DNA repair enzyme) 1; Geranylgeranyl diphosphate synthase 1; Down syndrome critical region gene 5; Calpain 7; Major histocompatibility complex, class II, DP alpha 1; Brix domain containing 5; and Chromosome 21 open reading frame 59), wherein expression of the one or more biomarkers is increased in the subject.
[0086] Additionally or alternatively, more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 151-177, 110 and 123 (or the biomarkers set forth by name in Table 4 as being downregulated, namely Tumor necrosis factor (ligand) superfamily, member 10; Chromosome 10 open reading frame 86; CD1D antigen, d polypeptide; Ewing sarcoma breakpoint region 1; Ribonuclease P 40 kDa subunit; PHD finger protein 20; Thioredoxin interacting protein; Ubiquinol-cytochrome c reductase core protein II; Hypothetical protein FLJ22662; Preimplantation protein 3; DKFZP564G2022 protein; Dipeptidase 2; Hemoglobin, alpha 1, alpha 2; Frequently rearranged in advanced T-cell lymphomas; DEAD (Asp-Glu-Ala-Asp) box polypeptide 48; Tumor necrosis factor, alpha-induced protein 2; Nucleophosmin (nucleolar phosphoprotein B23, numatrin); Interleukin 13 receptor, alpha 1; Leukocyte specific transcript 1, LST1; CGI-121 protein; RAS p21 protein activator 4/hypothetical protein FLJ21767; Cathepsin S; CD63 antigen (melanoma 1 antigen); JTV1 gene; KIAA0174; Thrombospondin 1; Hypothetical protein L0054103; Interferon regulatory factor 1; and SEC11-like 1 (S. cerevisiae), wherein expression of the one or more biomarkers is decreased in the subject.
[0087] In yet another embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-292, 91 and 97 (or the biomarkers set forth by name in Table 5, namely HLA-B associated transcript-1 (D6S81E); Interleukin enhancer binding factor 2, 45 kD (ILF2); Isolate Liv chaperone protein HSP90 beta (HSP90BETA) mRNA; Lysyl-tRNA synthetase mRNA, complete cds; nuclear gene for mitochondrial product; alternatively spliced; Tryptophanyl-tRNA synthetase (WARS); Profilin 1 (PFN1), mRNA; Seryl-tRNA synthetase (SARS); Similar to KIAA1007 protein, clone MGC:692, mRNA, complete cds; CD59 antigen p18-20 (antigen identified by monoclonal antibodies 16.3A5, EJ16, EJ30, EL32 and G344); Homo sapiens KIAA0064 gene product (KIAA0064), mRNA; Chromosome segregation 1 (yeast homolog)-like (CSE1L), mRNA; Protein phosphatase 1, regulatory subunit 7 (PPP1R7), mRNA; DEADH (Asp-Glu-Ala-AspHis) box polypeptide 1 (DDX1), mRNA; Threonyl-tRNA synthetase (TARS), mRNA; Dead box protein 15 mRNA, complete cds; SRY (sex determining region Y)-box 4/DEF=Human DNA sequence from clone RP3-322L4 on chromosome 6; Galactosidase, beta 1 (GLB1), mRNA; ATP-binding cassette, sub-family E (OABP), member 1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6 (14 kD, B14) (NDUFA6), mRNA; Pericentriolar material 1 (PCM1), mRNA; Excision repair cross-complementing rodent repair deficiency, complementation group 3 (ERCC3), mRNA; KIAA0907 protein (KIAA0907), mRNA; v-crk avian sarcoma virus CT10 oncogene homolog; 6-phosphofructo-2-kinasefructose-2,6-biphosphatase 3 (PFKFB3), mRNA./PROD=6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3; KIAA0766 gene product (KIAA0766), mRNA; N-acetylgalactosaminidase, alpha- (NAGA), mRNA; Protein tyrosine phosphatase, non-receptor type substrate 1 (PTPNS1), mRNA; Crystallin, zeta (quinone reductase) (CRYZ), mRNA; KIAA0429 gene product (KIAA0429), mRNA; SET domain, bifurcated 1 (SETDB1), mRNA; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3 (12 kD, B12) (NDUFB3), mRNA; Diphtheria toxin receptor (DTR); Thrombomodulin (THBD), mRNA; Protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform (PPM1A), mRNA; CD37 antigen (CD37), mRNA; Hemoglobin, gamma G (HBG2), mRNA; Protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), mRNA; Hematopoietically expressed homeobox (HHEX), mRNA; Amphiregulin (schwannoma-derived growth factor) (AREG), mRNA; Early growth response 2 (Krox-20 (Drosophila) homolog) (EGR2), mRNA; 2,5-oligoadenylate synthetase 1 (40-46 kD) (OAS1), transcript variant E16, mRNA; Early growth response 3 (EGR3), mRNA./PROD=early growth response 3; Homo sapiens MD-2 protein (MD-2), mRNA; Homo sapiens MAX dimerization protein (MAD), mRNA; DKEZP586A011 protein (DKEZP586A011), mRNA; 78 kDa gastrin-binding protein mRNA, complete cds; Transferrin receptor (p90, CD71), clone MGC:3151, mRNA, complete cds; Homo sapiens mRNA; cDNA DKFZp564N1272 (from clone DKFZp564N1272); complete cds; GABA-A receptor-associated protein like 1 (GABARAPL1) mRNA, complete cds; Translocation protein 1; Homo sapiens clone 016b03 My027 protein mRNA, complete cds; Protein kinase-related oncogene (PIM1) mRNA, complete cds; MADS box transcription enhancer factor 2, polypeptide C (myocyte enhancer factor 2C); eIF-2-associated p67 homolog mRNA, complete cds; Human mRNA for hCREM (cyclic AMP-responsive element modulator) type 2 protein, complete cds; Apurinic endonuclease (APE) mRNA, complete cds./PROD=apurinic endonuclease; TATA box binding protein (TBP)-associated factor, RNA polymerase II, D, 100 kD; Human mRNA for ZFM1 protein alternatively spliced product, complete cds./PROD=ZFM1 protein, alternatively spliced product; Trachea cellular apoptosis susceptibility protein (CSE1) mRNA, complete cds; Similar to eukaryotic translation initiation factor 3, subunit 8 (110 kD), clone MGC:8693, mRNA, complete cds; GABA-A receptor-associated protein mRNA, complete cds./PROD=GABA-A receptor-associated protein; Human (clone 2-5) synuclein (NACP) mRNA, complete cds; Human putative ribosomal protein 51 mRNA; Aldehyde dehydrogenase 1, soluble (ALDH1), mRNA./PROD=aldehyde dehydrogenase 1, soluble; Homo sapiens mRNA for KIAA1057 protein, partial cds; RBP1-like protein; Ring finger protein 4; KIAA0197 protein; Homo sapiens mRNA; cDNA DKFZp586F1323 (from clone DKFZp586F1323); Homo sapiens mRNA; cDNA DKFZp5641052 (from clone DKFZp5641052); Homo sapiens mRNA for Hmob33 protein, 3 untranslated region; Homo sapiens mRNA; cDNA DKFZp586F1019 (from clone DKFZp586F1019); partial cds; Myosin, light polypeptide 4, alkali; atrial, embryonic; H. sapiens novel gene from PAC 117P20, chromosome 1; Homo sapiens clone 24582 mRNA sequence; Heterogeneous nuclear ribonucleoprotein H1 (H); Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide; Cyclin T2; cDNA: FLJ23227 fis, clone CAE00645, highly similar to AF052138; Hypothetical protein FLJ12619; C-terminal binding protein 1; SEC22, vesicle trafficking protein (S. cerevisiae)-like 1; Hemoglobin, alpha 1; Homo sapiens clone 24659 mRNA sequence/DEF=Homo sapiens clone 24659 mRNA sequence; Calcium channel, voltage-dependent, PQ type, alpha 1A subunit; H. sapiens SMAS mRNA; H. sapiens HEX gene encoding homeobox related protein; Mitogen-activated protein kinase kinase kinase 4; Serine palmitoyltransferase (LCB2) mRNA, partial cds; KIAA0971 protein/DEF=Homo sapiens cDNA FLJ11495 fis, clone HEMBA1001950, highly similar to Homo sapiens mRNA for KIAA0971 protein; ESTs, Hs.97109; ESTs, Weakly similar to ALU7_HUMAN ALU; DEAD-box protein abstrakt (ABS), mRNA; KIAA1513 protein (KIAA1513), mRNA; Cell division protein FtsJ (FJH1), mRNA; F-box only protein 3 (FBXO3), mRNA; Purinergic receptor (family A group 5) (P2Y5), mRNA; Integral inner nuclear membrane protein (MAN1), mRNA; Fanconi anemia, complementation group F (FANCF), mRNA; Hypothetical protein FLJ12820 (FLJ12820), mRNA; Hypothetical protein FLJ13119 (FLJ13119), mRNA; Hypothetical protein FLJ20189 (FLJ20189), mRNA; Hypothetical protein FLJ20701 (FLJ20701), mRNA; Homo sapiens chromosome 12 open reading frame 5 (C12ORF5), mRNA; Hypothetical protein FLJ22555 (FLJ22555), mRNA; Hypothetical protein FLJ11110 (FLJ11110), mRNA; CGI-12 protein (LOC51001), mRNA; Triggering receptor expressed on myeloid cells 1 (TREM1), mRNA; betaGlcNAc beta 1,4-galactosyltransferase. polypeptide 5; PNAS-25 mRNA, complete cds.; Homo sapiens mRNA for FLJ00043 protein, partial cds; Homo sapiens cDNA: FLJ21737 fis, clone COLF3396; Homo sapiens cDNA FLJ13399 fis, clone PLACE1001395/DEF=Homo sapiens cDNA FLJ13399 fis, clone PLACE1001395; Novel MAFF (v-maf musculoaponeurotic fibrosarcoma (avian) oncogene family, protein F) LIKE protein; Heparin-binding EGF-like growth factor mRNA, complete cds; E. coli 7,8-diamino-pelargonic acid (bioA), biotin synthetase (bioB), 7-keto-8-amino-pelargonic acid synthetase (bioF), bioC protein, and dethiobiotin synthetase (bioD), complete cds; Escherichia coli/REF=J04423/DEF=E. coli bioC protein corresponding to nucleotides 4609-4883 of J04423/LEN=777 (-5 and -3 represent transcript regions 5 prime and 3 prime respectively)).
[0088] More preferably, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-185; 187-200, 202, 203, 205-207; 211, 213, 214, 216, 220, 221, 226, 228, 229, 231, 232, 234, 235, 238-247, 249, 250, 253, 262-265, 268-282 and 285-288 (or the biomarkers set forth by name in Table 5 as being upregulated, namely HLA-B associated transcript-1 (D6S81E); Interleukin enhancer binding factor 2, 45 kD (ILF2); Isolate Liv chaperone protein HSP90 beta (HSP90BETA) mRNA; Lysyl-tRNA synthetase mRNA, complete cds; nuclear gene for mitochondrial product; alternatively spliced; Tryptophanyl-tRNA synthetase (WARS); Profilin 1 (PFN1), mRNA; Seryl-tRNA synthetase (SARS); Similar to KIAA1007 protein, clone MGC:692, mRNA, complete cds; Homo sapiens KIAA0064 gene product (KIAA0064), mRNA; Chromosome segregation 1 (yeast homolog)-like (CSE1L), mRNA; Protein phosphatase 1, regulatory subunit 7 (PPP1R7), mRNA; DEADH (Asp-Glu-Ala-AspHis) box polypeptide 1 (DDX1), mRNA; Threonyl-tRNA synthetase (TARS), mRNA; Dead box protein 15 mRNA, complete cds; SRY (sex determining region Y)-box 4/DEF=Human DNA sequence from clone RP3-322L4 on chromosome 6; Galactosidase, beta 1 (GLB1), mRNA; ATP-binding cassette, sub-family E (OABP), member 1; NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6 (14 kD, B14) (NDUFA6), mRNA; Pericentriolar material 1 (PCM1), mRNA; Excision repair cross-complementing rodent repair deficiency, complementation group 3 (ERCC3), mRNA; KIAA0907 protein (KIAA0907), mRNA; v-crk avian sarcoma virus CT10 oncogene homolog; KIAA0766 gene product (KIAA0766), mRNA; N-acetylgalactosaminidase, alpha- (NAGA), mRNA; Crystallin, zeta (quinone reductase) (CRYZ), mRNA; KIAA0429 gene product (KIAA0429), mRNA; SET domain, bifurcated 1 (SETDB1), mRNA; CD37 antigen (CD37), mRNA; Protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), mRNA; Hematopoietically expressed homeobox (HHEX), mRNA; 2,5-oligoadenylate synthetase 1 (40-46 kD) (OAS1), transcript variant E16, mRNA; DKFZP586A011 protein (DKFZP586A011), mRNA; 78 kDa gastrin-binding protein mRNA, complete cds; Homo sapiens clone 016b03 My027 protein mRNA, complete cds; MADS box transcription enhancer factor 2, polypeptide C (myocyte enhancer factor 2C); eIF-2-associated p67 homolog mRNA, complete cds; Apurinic endonuclease (APE) mRNA, complete cds./PROD=apurinic endonuclease; TATA box binding protein (TBP)-associated factor, RNA polymerase II, D, 100 kD; Trachea cellular apoptosis susceptibility protein (CSE1) mRNA, complete cds; Similar to eukaryotic translation initiation factor 3, subunit 8 (110 kD), clone MGC:8693, mRNA, complete cds; Human putative ribosomal protein 51 mRNA; Aldehyde dehydrogenase 1, soluble (ALDH1), mRNA./PROD=aldehyde dehydrogenase 1, soluble; Homo sapiens mRNA for KIAA1057 protein, partial cds; RBP1-like protein; Ring finger protein 4; KIAA0197 protein; Homo sapiens mRNA; cDNA DKFZp586F1323 (from clone DKFZp586F1323); Homo sapiens mRNA; cDNA DKFZp5641052 (from clone DKFZp5641052); Homo sapiens mRNA for Hmob33 protein, 3 untranslated region; Homo sapiens mRNA; cDNA DKFZp586F1019 (from clone DKFZp586F1019); partial cds; H. sapiens novel gene from PAC 117P20, chromosome 1; Homo sapiens clone 24582 mRNA sequence; Cyclin T2; H. sapiens HEX gene encoding homeobox related protein; Mitogen-activated protein kinase kinase kinase 4; Serine palmitoyltransferase (LCB2) mRNA, partial cds; KIAA0971 protein/DEF=Homo sapiens cDNA FLJ11495 fis, clone HEMBA1001950, highly similar to Homo sapiens mRNA for KIAA0971 protein; DEAD-box protein abstrakt (ABS), mRNA; KIAA1513 protein (KIAA1513), mRNA; Cell division protein FtsJ (FJH1), mRNA; F-box only protein 3 (FBXO3), mRNA; Purinergic receptor (family A group 5) (P2Y5), mRNA; Integral inner nuclear membrane protein (MAN1), mRNA; Fanconi anemia, complementation group F (FANCF), mRNA; Hypothetical protein FLJ12820 (FLJ12820), mRNA; Hypothetical protein FLJ13119 (FLJ13119), mRNA; Hypothetical protein FLJ20189 (FLJ20189), mRNA; Hypothetical protein FLJ20701 (FLJ20701), mRNA; Homo sapiens chromosome 12 open reading frame 5 (C12ORF5), mRNA; Hypothetical protein FLJ22555 (FLJ22555), mRNA; Hypothetical protein FLJ11110 (FLJ11110), mRNA; CGI-12 protein (LOC51001), mRNA; PNAS-25 mRNA, complete cds.; Homo sapiens mRNA for FLJ00043 protein, partial cds; Homo sapiens cDNA: FLJ21737 fis, clone COLF3396; Homo sapiens cDNA FLJ13399 fis, clone PLACE1001395/DEF=Homo sapiens cDNA FLJ13399 fis, clone PLACE1001395), wherein expression of the one or more biomarkers is increased in the subject.
[0089] Additionally or alternatively, more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 186, 201, 204, 208, 209, 91, 210, 212, 97, 215, 217-219, 222-225, 227, 230, 233, 236, 237, 248, 251, 252, 254-261, 266, 267, 283, 284 and 289-292 (or the biomarkers set forth by name in Table 5 as being down-regulated, namely CD59 antigen p18-20 (antigen identified by monoclonal antibodies 16.3A5, EJ16, EJ30, EL32 and G344); 6-phosphofructo-2-kinasefructose-2,6-biphosphatase 3 (PFKFB3), mRNA./PROD=6-phosphofructo-2-kinase-fructose-2,6-biphosphatase 3; Protein tyrosine phosphatase, non-receptor type substrate 1 (PTPNS1), mRNA; NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3 (12 kD, B12) (NDUFB3), mRNA; Diphtheria toxin receptor (DTR); Thrombomodulin (THBD), mRNA; Protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform (PPM1A), mRNA; Hemoglobin, gamma G (HBG2), mRNA; Amphiregulin (schwannoma-derived growth factor) (AREG), mRNA; Early growth response 2 (Krox-20 (Drosophila) homolog) (EGR2), mRNA; Early growth response 3 (EGR3), mRNA./PROD=early growth response 3; Homo sapiens MD-2 protein (MD-2), mRNA; Homo sapiens MAX dimerization protein (MAD), mRNA; Transferrin receptor (p90, CD71), clone MGC:3151, mRNA, complete cds; Homo sapiens mRNA; cDNA DKFZp564N1272 (from clone DKFZp564N1272); complete cds; GABA-A receptor-associated protein like 1 (GABARAPL1) mRNA, complete cds; Translocation protein 1; Protein kinase-related oncogene (PIM1) mRNA, complete cds; Human mRNA for hCREM (cyclic AMP-responsive element modulator) type 2 protein, complete cds; Human mRNA for ZFM1 protein alternatively spliced product, complete cds./PROD=ZFM1 protein, alternatively spliced product; GABA-A receptor-associated protein mRNA, complete cds./PROD=GABA-A receptor-associated protein; Human (clone 2-5) synuclein (NACP) mRNA, complete cds; Myosin, light polypeptide 4, alkali; atrial, embryonic; Heterogeneous nuclear ribonucleoprotein H1 (H); Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide; cDNA: FLJ23227 fis, clone CAE00645, highly similar to AF052138; Hypothetical protein FLJ12619; C-terminal binding protein 1; SEC22, vesicle trafficking protein (S. cerevisiae)-like 1; Hemoglobin, alpha 1; Homo sapiens clone 24659 mRNA sequence/DEF=Homo sapiens clone 24659 mRNA sequence; Calcium channel, voltage-dependent, PQ type, alpha 1A subunit; H. sapiens SMA5 mRNA; ESTs, Hs.97109; ESTs, Weakly similar to ALU7_HUMAN ALU; Triggering receptor expressed on myeloid cells 1 (TREM1), mRNA; betaGlcNAc beta 1,4-galactosyltransferase. polypeptide 5; Novel MAFF (v-maf musculoaponeurotic fibrosarcoma (avian) oncogene family, protein F) LIKE protein; Heparin-binding EGF-like growth factor mRNA, complete cds; E. coli 7,8-diamino-pelargonic acid (bioA), biotin synthetase (bioB), 7-keto-8-amino-pelargonic acid synthetase (bioF), bioC protein, and dethiobiotin synthetase (bioD), complete cds; Escherichia coli/REF=J04423/DEF=E. coli bioC protein corresponding to nucleotides 4609-4883 of J04423/LEN=777 (-5 and -3 represent transcript regions 5 prime and 3 prime respectively)), wherein expression of the one or more biomarkers is decreased in the subject.
[0090] In yet another embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 87, 97, 101, 293, 92, 272, 93, 107, 108, 121 and 123 (or the biomarkers set forth by name in Table 6 as pre-treatment biomarkers, namely Solute carrier family 6; Amphiregulin; Keratin 1; Hemoglobin, alpha 1; MHC-II, DM beta; Purinergic receptor P2Y, G-protein coupled 5; Forkhead box O3A; Transferrin receptor (p90, CD71); Ring finger protein 10; Formin binding protein 4; and Hypothetical protein LOC54103), wherein the subject is monitored prior to treatment with a TNFα inhibitor.
[0091] In yet another embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 290, 209, 98, 112, 116, 121, 130, 155, 92, 289, 216 and 131 (or the biomarkers set forth by name in Table 6 as post-treatment biomarkers, namely Diphteria toxin receptor; Heparin-binding EGF-like growth factor; Lipoyltransferase 1; APEX nuclease (multifunct. DNA repair enzyme) 1; GABA(A) receptor-associated protein like 1/3; Formin binding protein 4; Zinc finger protein 331; Ribonuclease P 40 kDa subunit; MHC class II, DM beta; v-maf fibrosarc. oncogene homolog F (avian); 2',5'-oligoadenylate synthetase 1, 40/46 kDa; and Membrane-spanning 4-domains, subfam. A, memb. 4), wherein the subject is monitored after treatment with a TNFα inhibitor.
[0092] In yet another embodiment of the monitoring method, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 97, 102, 29, 294, 295, 91, 131, 290, 100, 134, 296, 297, 298, 299, 136, 174 and 300 (or the biomarkers set forth by name in Table 7, namely Amphiregulin; Carbonic anhydrase 1; Charcot-Leyden crystal protein; Clusterin C; Tumor necrosis factor alpha induced protein 6; Thrombomodulin; Membrane-spanning 4-domains, subfamily A, member 4; Diptheria toxin receptor; S100 calcium binding protein A1; Uncharacterized hypothalamus protein HT007; MHC-class-II; HLA-DR alpha; Hypothetical protein L0054103; Tumor necrosis factor alpha; Interleukin 1 beta; Proteasome subunit beta type 7 precursor; and Protein KIAA0174; Microsomal signal peptidase 18 kDa subunit).
[0093] A preferred autoimmune disorder in which to apply the methods of the invention for monitoring an autoimmune disorder is rheumatoid arthritis. However, the monitoring methods can be applied to essentially any autoimmune disorder in which TNFα inhibitor therapy is applied, including the autoimmune disorders listed in the previous section.
Selection and Use of Treatment Regimens with TNFα Inhibitors
[0094] Given the observation that the expression pattern of particular biomarkers in an autoimmune disorder subject influences the responsiveness of the subject to a TNFα inhibitor, one can select an appropriate treatment regimen for the subject based on the expression of one or more biomarkers in the subject. Accordingly, in one embodiment, the above-described method for predicting the responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder further comprises selecting a treatment regimen with the TNFα inhibitor based upon expression of the one or more biomarkers in the subject. In another aspect, the method still further comprises administering the TNFα inhibitor to the subject according to the treatment regimen such that the autoimmune disorder is inhibited in the subject.
[0095] In another embodiment, the invention provides a method for selecting a treatment regimen for therapy with a TNFα inhibitor in a subject having an autoimmune disorder, the method comprising:
[0096] assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor for treatment of the autoimmune disorder; and
[0097] selecting a treatment regimen with a TNFα inhibitor based upon expression of the one or more biomarkers in the subject.
[0098] In yet another embodiment, the invention provides a method of treating a subject having an autoimmune disorder with a TNFα inhibitor, the method comprising:
[0099] assaying the subject for expression of one or more biomarkers predictive of responsiveness to a TNFα inhibitor for treatment of the autoimmune disorder;
[0100] selecting a treatment regimen with a TNFα inhibitor based upon expression of the one or more biomarkers in the subject; and
[0101] administering the TNFα inhibitor according to the treatment regimen such that the subject is treated for the autoimmune disorder.
[0102] The treatment regimen that is selected typically includes at least one of the following parameters and more typically includes many or all of the following parameters: the type of agent chosen for administration, the dosage, the formulation, the route of administration and/or the frequency of administration.
[0103] Particularly preferred TNFα inhibitors are biologic agents that have been approved by the FDA for use in humans in the treatment of rheumatoid arthritis, which agents include adalimumab (HUMIRA®), infliximab (REMICADE®) and etanercept (ENBREL®), most preferably adalimumab (HUMIRAT®).
[0104] In one embodiment, the TNFα inhibitor is an anti-tumor necrosis factor-alpha (TNFα) antibody, or antigen-binding portion thereof. For example, the anti-TNFα antibody, or antigen-binding portion thereof, can be a humanized antibody, a chimeric antibody or a multivalent antibody.
[0105] In another embodiment, the anti-TNFα antibody, or antigen-binding portion thereof, is a human antibody, preferably a human antibody, or antigen-binding portion thereof, that binds to human TNFα with high affinity and a low off rate, and has a high neutralizing capacity. Preferably, the human antibodies are recombinant, neutralizing human anti-hTNFα antibodies. The most preferred recombinant, neutralizing antibody used in the method of the invention is referred to herein as adalimumab, also referred to as HUMIRA® or D2E7 (the amino acid sequence of the adalimumab VL region is shown in SEQ ID NO: 303; the amino acid sequence of the adalimumab VH region is shown in SEQ ID NO: 304). The properties of D2E7 (adalimumab; Humira®) have been described in Salfeld et al., U.S. Pat. Nos. 6,090,382, 6,258,562, and 6,509,015, which are each incorporated by reference herein.
[0106] Other examples of TNFα antibodies include chimeric and humanized murine anti-hTNFα antibodies which have undergone clinical testing for treatment of rheumatoid arthritis (see e.g., Elliott et al. (1994) Lancet 344:1125-1127; Elliot et al. (1994) Lancet 344:1105-1110; Rankin et al. (1995) Br. J. Rheumatol. 34:334-342). In another embodiment, the TNFα antibody used in the invention is infliximab (Remicade®, Johnson and Johnson; described in U.S. Pat. No. 5,656,272, incorporated by reference herein), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), an anti-TNF dAb (Peptech), and CNTO 148 (golimumab; Medarex and Centocor, see also WO 02/12502).
[0107] In one embodiment, the TNFα inhibitors used in the methods of the invention include adalimumab antibodies and antibody portions, adalimumab-related antibodies and antibody portions, adalimumab-related DVD-Ig or dual specific antibodies, and other human antibodies and antibody portions with equivalent properties to adalimumab, such as high affinity binding to hTNFα with low dissociation kinetics and high neutralizing capacity. In one embodiment, a treatment regimen of the invention provides treatment with an isolated human antibody, or an antigen-binding portion thereof, that dissociates from human TNFα with a Kd of 1×10-8 M or less and a Koff rate constant of 1×10-3 s-1 or less, both determined by surface plasmon resonance, and neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10-7 M or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, dissociates from human TNFα with a Koff of 5×10-4 s-1 or less, or even more preferably, with a Koff of 1×10-4 s-1 or less. More preferably, the isolated human antibody, or antigen-binding portion thereof, neutralizes human TNFα cytotoxicity in a standard in vitro L929 assay with an IC50 of 1×10-8 M or less, even more preferably with an IC50 of 1×10-9 M or less and still more preferably with an IC50 of 1×10-10 M or less. In a preferred embodiment, the antibody is an isolated human recombinant antibody, or an antigen-binding portion thereof.
[0108] It is well known in the art that antibody heavy and light chain CDR3 domains play an important role in the binding specificity/affinity of an antibody for an antigen. Accordingly, in another aspect, the TNFα inhibitor used in the treatment method of the invention is a human anti-TNFα antibody that has slow dissociation kinetics for association with hTNFα and that has light and heavy chain CDR3 domains that structurally are identical to or related to those of adalimumab. Position 9 of the adalimumab VL CDR3 can be occupied by Ala or Thr without substantially affecting the Koff. Accordingly, a consensus motif for the adalimumab VL CDR3 comprises the amino acid sequence: Q-R-Y-N-R-A-P-Y-(T/A) (SEQ ID NO: 305). Additionally, position 12 of the adalimumab VH CDR3 can be occupied by Tyr or Asn, without substantially affecting the Koff. Accordingly, a consensus motif for the adalimumab VH CDR3 comprises the amino acid sequence: V-S-Y-L-S-T-A-S-S-L-D-(Y/N) (SEQ ID NO: 306). Moreover, as demonstrated in Example 2 of U.S. Pat. No. 6,090,382, the CDR3 domain of the adalimumab heavy and light chains is amenable to substitution with a single alanine residue (at position 1, 4, 5, 7 or 8 within the VL CDR3 or at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 within the VH CDR3) without substantially affecting the Koff. Still further, the skilled artisan will appreciate that, given the amenability of the adalimumab VL and VH CDR3 domains to substitutions by alanine, substitution of other amino acids within the CDR3 domains may be possible while still retaining the low off rate constant of the antibody, in particular substitutions with conservative amino acids. Preferably, no more than one to five conservative amino acid substitutions are made within the adalimumab VL and/or VH CDR3 domains. More preferably, no more than one to three conservative amino acid substitutions are made within the adalimumab VL and/or VH CDR3 domains. Additionally, conservative amino acid substitutions should not be made at amino acid positions critical for binding to hTNFα. Positions 2 and 5 of the adalimumab VL CDR3 and positions 1 and 7 of the adalimumab VH CDR3 appear to be critical for interaction with hTNFα and thus, conservative amino acid substitutions preferably are not made at these positions (although an alanine substitution at position 5 of the adalimumab VL CDR3 is acceptable, as described above) (see U.S. Pat. No. 6,090,382).
[0109] Accordingly, in another embodiment, the antibody or antigen-binding portion thereof preferably contains the following characteristics:
[0110] a) dissociates from human TNFα with a Koff rate constant of 1×10-3 s-1 or less, as determined by surface plasmon resonance;
[0111] b) has a light chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 305, or modified from SEQ ID NO: 305 by a single alanine substitution at position 1, 4, 5, 7 or 8 or by one to five conservative amino acid substitutions at positions 1, 3, 4, 6, 7, 8 and/or 9;
[0112] c) has a heavy chain CDR3 domain comprising the amino acid sequence of SEQ ID NO: 306, or modified from SEQ ID NO: 306 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11 or by one to five conservative amino acid substitutions at positions 2, 3, 4, 5, 6, 8, 9, 10, 11 and/or 12.
[0113] More preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNFα with a Koff of 5×10-4 s-1 or less. Even more preferably, the antibody, or antigen-binding portion thereof, dissociates from human TNFα with a Koff of 1×10-4 s-1 or less.
[0114] In yet another embodiment, the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 305, or modified from SEQ ID NO: 305 by a single alanine substitution at position 1, 4, 5, 7 or 8, and with a heavy chain variable region (HCVR) having a CDR3 domain comprising the amino acid sequence of SEQ ID NO: 306, or modified from SEQ ID NO: 306 by a single alanine substitution at position 2, 3, 4, 5, 6, 8, 9, 10 or 11. Preferably, the LCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 307 (i.e., the adalimumab VL CDR2) and the HCVR further has a CDR2 domain comprising the amino acid sequence of SEQ ID NO: 308 (i.e., the adalimumab VH CDR2). Even more preferably, the LCVR further has CDR1 domain comprising the amino acid sequence of SEQ ID NO: 309 (i.e., the adalimumab VL CDR1) and the HCVR has a CDR1 domain comprising the amino acid sequence of SEQ ID NO: 310 (i.e., the adalimumab VH CDR1). The framework regions for VL preferably are from the V.sub.κI human germline family, more preferably from the A20 human germline Vk gene and most preferably from the adalimumab VL framework sequences shown in FIGS. 1A and 1B of U.S. Pat. No. 6,090,382. The framework regions for VH preferably are from the VH3 human germline family, more preferably from the DP-31 human germline VH gene and most preferably from the adalimumab VH framework sequences shown in FIGS. 2A and 2B of U.S. Pat. No. 6,090,382.
[0115] Accordingly, in another embodiment, the antibody or antigen-binding portion thereof preferably contains a light chain variable region (LCVR) comprising the amino acid sequence of SEQ ID NO: 303 (i.e., the adalimumab VL) and a heavy chain variable region (HCVR) comprising the amino acid sequence of SEQ ID NO: 304 (i.e., the adalimumab VH). In certain embodiments, the antibody comprises a heavy chain constant region, such as an IgG1, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. Preferably, the heavy chain constant region is an IgG1 heavy chain constant region or an IgG4 heavy chain constant region. Furthermore, the antibody can comprise a light chain constant region, either a kappa light chain constant region or a lambda light chain constant region. Preferably, the antibody comprises a kappa light chain constant region. Alternatively, the antibody portion can be, for example, a Fab fragment or a single chain Fv fragment.
[0116] In other embodiments, the TNFα inhibitor of the invention is etanercept (described in WO 91/03553 and WO 09/406,476), infliximab (described in U.S. Pat. No. 5,656,272), CDP571 (a humanized monoclonal anti-TNF-alpha IgG4 antibody), CDP 870 (a humanized monoclonal anti-TNF-alpha antibody fragment), D2E7 (a human anti-TNF mAb), soluble TNF receptor Type I, or a pegylated soluble TNF receptor Type I (PEGs TNF-R1).
[0117] The TNFα antibody of the invention can be modified. In some embodiments, the TNFα antibody or antigen binding fragments thereof, is chemically modified to provide a desired effect. For example, pegylation of antibodies and antibody fragments of the invention may be carried out by any of the pegylation reactions known in the art, as described, for example, in the following references: Focus on Growth Factors 3:4-10 (1992); EP 0 154 316; and EP 0 401 384 (each of which is incorporated by reference herein in its entirety). Preferably, the pegylation is carried out via an acylation reaction or an alkylation reaction with a reactive polyethylene glycol molecule (or an analogous reactive water-soluble polymer). A preferred water-soluble polymer for pegylation of the antibodies and antibody fragments of the invention is polyethylene glycol (PEG). As used herein, "polyethylene glycol" is meant to encompass any of the forms of PEG that have been used to derivatize other proteins, such as mono (C1-C10) alkoxy- or aryloxy-polyethylene glycol.
[0118] Methods for preparing pegylated antibodies and antibody fragments of the invention will generally comprise the steps of (a) reacting the antibody or antibody fragment with polyethylene glycol, such as a reactive ester or aldehyde derivative of PEG, under conditions whereby the antibody or antibody fragment becomes attached to one or more PEG groups, and (b) obtaining the reaction products. It will be apparent to one of ordinary skill in the art to select the optimal reaction conditions or the acylation reactions based on known parameters and the desired result.
[0119] In yet another embodiment of the invention, TNFα antibodies or fragments thereof can be altered wherein the constant region of the antibody is modified to reduce at least one constant region-mediated biological effector function relative to an unmodified antibody. To modify an antibody of the invention such that it exhibits reduced binding to the Fc receptor, the immunoglobulin constant region segment of the antibody can be mutated at particular regions necessary for Fc receptor (FcR) interactions (see e.g., Canfield, S. M. and S. L. Morrison (1991) J. Exp. Med. 173:1483-1491; and Lund, J. et al. (1991) J. Immunol. 147:2657-2662). Reduction in FcR binding ability of the antibody may also reduce other effector functions which rely on FcR interactions, such as opsonization and phagocytosis and antigen-dependent cellular cytotoxicity.
[0120] An antibody or antibody portion of the invention can be derivatized or linked to another functional molecule (e.g., another peptide or protein). Accordingly, the antibodies and antibody portions of the invention are intended to include derivatized and otherwise modified forms of the anti-TNFα antibodies described herein, including immunoadhesion molecules. For example, an antibody or antibody portion of the invention can be functionally linked (by chemical coupling, genetic fusion, noncovalent association or otherwise) to one or more other molecular entities, such as another antibody (e.g., a bispecific antibody or a diabody), a detectable agent, a cytotoxic agent, a pharmaceutical agent, and/or a protein or peptide that can mediate associate of the antibody or antibody portion with another molecule (such as a streptavidin core region or a polyhistidine tag).
[0121] One type of derivatized antibody is produced by crosslinking two or more antibodies (of the same type or of different types, e.g., to create bispecific antibodies). Suitable crosslinkers include those that are heterobifunctional, having two distinctly reactive groups separated by an appropriate spacer (e.g., m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional (e.g., disuccinimidyl suberate). Such linkers are available from Pierce Chemical Company, Rockford, Ill.
[0122] Useful detectable agents with which an antibody or antibody portion of the invention may be derivatized include fluorescent compounds. Exemplary fluorescent detectable agents include fluorescein, fluorescein isothiocyanate, rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride, phycoerythrin and the like. An antibody may also be derivatized with detectable enzymes, such as alkaline phosphatase, horseradish peroxidase, glucose oxidase and the like. When an antibody is derivatized with a detectable enzyme, it is detected by adding additional reagents that the enzyme uses to produce a detectable reaction product. For example, when the detectable agent horseradish peroxidase is present, the addition of hydrogen peroxide and diaminobenzidine leads to a colored reaction product, which is detectable. An antibody may also be derivatized with biotin, and detected through indirect measurement of avidin or streptavidin binding.
[0123] Selection of the particular parameters of the treatment regimen can be based on known treatment parameters for the TNFα inhibitor previously established in the art. For example, a non-limiting example of a treatment regimen for adalimumab (HUMIRA®) is 40 mg every other week by subcutaneous injection. A non-limiting example of a treatment regimen for etanercept (ENBREL®) is 50 mg/week by subcutaneous injection. A non-limiting example of a treatment regimen for infliximab (REMICADE®) is 3 mg/kg by intravenous infusion at weeks 0, 2 and 6, then every 8 weeks. A treatment regimen can include administration of the TNFα inhibitor alone or can include combination of the TNFα inhibitor with other therapeutic agents, such as methotrexate (e.g., 10-20 mg/week) or prednisolone (e.g., 10 mg/week). Other suitable treatment regimens for the TNFα inhibitors discussed herein will be readily apparent to the ordinarily skilled artisan based on prior studies of preferred administration parameters for the TNFα inhibitor.
[0124] For administration to a subject, a TNFα inhibitor typically is formulated into a pharmaceutical composition containing the TNFα inhibitor and a pharmaceutically acceptable carrier. Therapeutic compositions typically must be sterile and stable under the conditions of manufacture and storage. Pharmaceutical compositions also can be administered in combination therapy, i.e., combined with other agents, such as other TNFα inhibitors and/or other therapeutic agents, such as traditional therapeutic agents for the treatment of autoimmune disorders, such as rheumatoid arthritis.
[0125] As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible. Preferably, the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral, spinal or epidermal administration (e.g., by injection or infusion). Depending on the route of administration, the active compound may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
[0126] The pharmaceutical compositions may include one or more pharmaceutically acceptable salts. A "pharmaceutically acceptable salt" refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S. M., et al. (1977) J. Pharm. Sci. 66:1-19). Examples of such salts include acid addition salts and base addition salts. Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like. Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as N,N'-dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
[0127] A pharmaceutical composition also may include a pharmaceutically acceptable anti-oxidant. Examples of pharmaceutically acceptable antioxidants include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
[0128] Examples of suitable aqueous and nonaqueous carriers that may be employed in the pharmaceutical compositions include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
[0129] These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of presence of microorganisms may be ensured both by sterilization procedures and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
[0130] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. The use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
[0131] A TNFα inhibitor of the present invention can be administered via one or more routes of administration using one or more of a variety of methods known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results. A preferred route of administration, particularly for antibody agents, is by intravenous injection or infusion. Other preferred routes of administration include intramuscular, intradermal, intraperitoneal, subcutaneous, spinal or other parenteral routes of administration, for example by injection or infusion. The phrase "parenteral administration" as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion. Alternatively, a TNFα inhibitor of the invention can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
[0132] In a preferred embodiment, the subject to be treated with the TNFα inhibitor is a human subject.
[0133] A preferred autoimmune disorder in which to apply the methods of the invention for selecting and using a treatment regimen is rheumatoid arthritis. However, these methods can be applied to essentially any autoimmune disorder in which TNFα inhibitor therapy is applied, including the autoimmune disorders listed in the previous sections
Kits of the Invention
[0134] In another aspect, the invention pertains to kits for carrying out the methods of the invention. For example, in one embodiment, the invention provides a kit for predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder. In one embodiment, the kit comprises:
[0135] a) means for isolating monocytes;
[0136] b) means for measuring expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder;
[0137] c) means for measuring expression of at least one housekeeping gene; and
[0138] d) instructions for use of the kit to predicting responsiveness to a TNFα inhibitor in a subject having an autoimmune disorder, wherein the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or the biomarkers set forth by name in Table 9, as described above)
[0139] In one embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82 (or the biomarkers set forth by name in Table 9 as being increased in ≧80% of responders vs. non-responders, as described above), more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 37, 44, 47, 62 and 70 (or the biomarkers set forth by name in Table 9 as being increased in ≧90% of responders vs. non-responders, as described above), and even more preferably at least one of the biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44 (or the CD11c biomarkers set forth by name in Table 9 as being increased in 100% of responders vs. non-responders). In each of these embodiments, preferably the instructions for use of the kit instruct that increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0140] In another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81 (or the biomarkers set forth by name in Table 9 as being decreased in ≧80% of responders vs. non-responders, as described above), more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 29, 65, 73 and 74 (or the biomarkers set forth by name in Table 9 as being decreased in ≧90% of responders vs. non-responders, as described above), and even more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 11 or SEQ ID NO: 74 (or the biomarkers set forth by name in Table 9 as being decreased in 100% of responders vs. non-responders, as described above). In each of these embodiments, preferably the instructions for use of the kit instruct that decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0141] In another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 83-133 (or the biomarkers set forth by name in Table 3, as described above).
[0142] In yet another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 134-177, 110, 112, 118, 123 and 131 (or the biomarkers set forth by name in Table 4, as described above), more preferably SEQ ID NO: 134-150, 112, 118 (or the biomarkers set forth by name in Table 4 as being upregulated, as described above), wherein the instructions instruct that expression of the one or more biomarkers is increased in the subject, and/or more preferably SEQ ID NO: 151-177, 110 and 123 (or the biomarkers set forth by name in Table 4 as being downregulated, as described above), wherein the instructions instruct that expression of the one or more biomarkers is decreased in the subject.
[0143] In yet another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 178-292, 91 and 97 (or the biomarkers set forth by name in Table 5, as described above), more preferably SEQ ID NO: 178-185; 187-200, 202, 203, 205-207; 211, 213, 214, 216, 220, 221, 226, 228, 229, 231, 232, 234, 235, 238-247, 249, 250, 253, 262-265, 268-282 and 285-288 (or the biomarkers set forth by name in Table 5 as being upregulated, as described above), wherein the instructions instruct that expression of the one or more biomarkers is increased in the subject, and/or more preferably SEQ ID NO: 186, 201, 204, 208, 209, 91, 210, 212, 97, 215, 217-219, 222-225, 227, 230, 233, 236, 237, 248, 251, 252, 254-261, 266, 267, 283, 284 and 289-292 (or the biomarkers set forth by name in Table 5 as being downregulated, as described above), wherein the instructions instruct that expression of the one or more biomarkers is decreased in the subject.
[0144] In yet another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 87, 97, 101, 293, 92, 272, 93, 107, 108, 121 and 123 (or the biomarkers set forth by name in Table 6 as pre-treatment biomarkers, as described above), wherein the instructions instruct that the subject is monitored prior to treatment with a TNFα inhibitor. In yet another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 290, 209, 98, 112, 116, 121, 130, 155, 92, 289, 216 and 131 (or the biomarkers set forth by name in Table 6 as post-treatment biomarkers, as described above), wherein the instructions instruct that the subject is monitored after treatment with a TNFα inhibitor.
[0145] In yet another embodiment of the kit, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 97, 102, 29, 294, 295, 91, 131, 290, 100, 134, 296, 297, 298, 299, 136, 174 and 300 (or the biomarkers set forth by name in Table 7, as described above).
[0146] In a preferred embodiment, the means for measuring expression in the subject of the one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder comprises a nucleic acid preparation sufficient to detect expression of mRNA encoding the one or more biomarkers in a sample from the subject, such as a peripheral blood mononuclear cell sample from which mRNA is obtained by standard methods. This nucleic acid preparation includes at least one, and may include more than one, nucleic acid probe or primer, the sequence(s) of which is designed such that the nucleic acid preparation can detect the expression of mRNA encoding the biomarker(s) of interest in the sample from the subject. A preferred nucleic acid preparation includes two or more PCR primers that allow for PCR amplification of a segment of the mRNA encoding the biomarker(s) of interest. In a particularly preferred embodiment, the kit comprises a nucleic acid preparation sufficient to detect expression of CD11c mRNA in a sample from the subject.
[0147] Alternatively, the means for detecting expression in the subject of one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder can comprise a reagent that detects the gene product of the mRNA encoding the biomarker(s) of interest sufficient to distinguish it from other gene products in a sample from the subject. A non-limiting example of such a reagent is a monoclonal antibody preparation (comprising one or more monoclonal antibodies) sufficient to detect protein expression of the biomarker(s) of interest in a sample from the subject, such as a peripheral blood mononuclear cell sample. In a particularly preferred embodiment, the kit comprises a monoclonal antibody preparation sufficient to detect expression of CD11c protein in a sample from the subject.
[0148] The means for measuring expression of the one or more biomarkers can also include, for example, buffers or other reagents for use in an assay for evaluating biomarker expression (e.g., at either the mRNA or protein level). The instructions can be, for example, printed instructions for performing the assay for evaluating the expression of the one or more biomarkers.
[0149] In a preferred embodiment, the means for measuring expression of at least one housekeeping gene comprises a nucleic acid preparation sufficient to detect expression of mRNA of the housekeeping gene (e.g., GAPDH) in a sample from the subject, such as a peripheral blood mononuclear cell sample from which mRNA is obtained by standard methods. This nucleic acid preparation includes at least one, and may include more than one, nucleic acid probe or primer, the sequence(s) of which is designed such that the nucleic acid preparation can detect the expression of mRNA of the housekeeping gene(s) in the sample from the subject. A preferred nucleic acid preparation includes two or more PCR primers that allow for PCR amplification of a segment of the mRNA of the housekeeping gene(s). Alternatively, the means for detecting expression in the subject of at least one housekeeping gene can comprise a reagent that detects the gene product of housekeeping gene sufficient to distinguish it from other gene products in a sample from the subject. A non-limiting example of such a reagent is a monoclonal antibody preparation (comprising one or more monoclonal antibodies) sufficient to detect protein expression of housekeeping gene product in a sample from the subject, such as a peripheral blood mononuclear cell sample.
[0150] The means for isolating monocytes can comprise one or more reagents that can be used to separate monocytes from other cell types in a sample of peripheral blood mononuclear cells, for example by positive selection of the monocytes or by negative selection in which all other cell types other than monocytes are removed. In one embodiment, a reagent that binds CD14 on monocytes (e.g., an anti-CD14 antibody) is included in the kit as means to isolate monocytes via positive selection. Alternatively, in another embodiment, reagents such as those commercially available in the Monocyte Isolation Kit II (Miltenyi Biotec, Auburn, Calif.) can be used for negative selection, in which non-monocytes (T cells, B cells, NK cells, dendritic cells, basophils) are indirectly magnetically labeled using a cocktail of biotin-conjugated antibodies against CD3, CD7, CD16, CD19, CD56, CD123 and CD235a (Glycophorin A), as well as anti-biotin MicroBeads, and then highly pure unlabeled monocytes are obtained by depletion of the magnetically labeled cells.
[0151] In another embodiment, the kit can further comprise a TNFα inhibitor for treating an autoimmune disorder in the subject. Preferred TNFα inhibitors for use in the kit include the TNFα inhibitors described in detail above with respect to treatment regimens, in particular anti-TNFα antibodies such as adalimumab, infliximab and/or golimumab, and/or Ig fusion proteins such as etanercept.
[0152] Preferably, the kit is designed for use with a human subject.
Databases and Computer Programs
[0153] In another aspect, the invention pertains to methods of building a database for use in selecting an autoimmune disorder subject for treatment with a TNFα inhibitor, or for use in selecting or monitoring a treatment regimen in an autoimmune disorder subject. The method can comprise receiving, in a computer system, biomarker expression patterns from a plurality of subjects having an autoimmune disorder; and storing the biomarker expression pattern from each subject such that the biomarker expression pattern is associated with an identifier of the subject, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or the biomarkers set forth by name in Table 9, as described above). The identifier of the subject can be, for example, the name of the subject or a numerical or symbolic identifier coded to the identity of the subject. The method can further comprise receiving, in the computer system, one or more treatment regimens for treatment of an autoimmune disorder in a subject such that the treatment regimen is associated with the biomarker expression pattern of the subject and the identifier of the subject. A user can enter the subject's biomarker expression pattern, and optionally the subject's treatment regimen(s), into the computer system. Alternatively, the subject's biomarker expression pattern can be received directly from equipment used in determining the expression of one or more biomarkers in a sample from the subject.
[0154] In another aspect, the invention provides a computer program product useful for building a database for use in selecting or monitoring an autoimmune disorder subject for treatment with a TNFα inhibitor. The computer program can contain executable instructions that when executed cause a processor to perform operations comprising: receiving, in a computer system, a biomarker expression pattern of a subject at one or more biomarkers predictive of responsiveness to a TNFα inhibitor in an autoimmune disorder; and storing the biomarker expression pattern such that the biomarker expression pattern is associated with an identifier of the subject, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or the biomarkers set forth by name in Table 9, as described above). Optionally, the computer program can further cause the processor to perform an operation comprising: receiving, in the computer system, a treatment regimen for treatment of an autoimmune disorder in the subject such that the treatment regimen is associated with the biomarker expression pattern of the subject and the identifier of the subject.
[0155] In another aspect, the invention provides a method of selecting an autoimmune disorder subject for a treatment with a TNFα inhibitor. The method can comprise: (i) identifying, in a database comprising a plurality of autoimmune disorder subjects, a subject whose database entry is associated with a biomarker expression pattern that is predictive of responsiveness to treatment with a TNFα inhibitor, and (ii) selecting the subject for treatment with a TNFα inhibitor, wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or the biomarkers set forth by name in Table 9, as described above). The method can further comprise selecting a treatment regimen by identifying, in the database, a treatment regimen that has been associated with the biomarker expression pattern of the subject and with an identifier of the subject.
[0156] In yet another aspect, the invention provides a computer program product useful for identifying and/or selecting a subject for treatment with a TNFα inhibitor. The computer program can contain executable instructions that when executed cause a processor to perform operations comprising: (i) identifying, in a database including a plurality of autoimmune disorder subjects associated with biomarker expression patterns, a subject that is associated with a biomarker expression pattern that is predictive of responsiveness to treatment with a TNFα inhibitor; and (ii) outputting the identified subject as a subject to be treated with a TNFα inhibitor; wherein the biomarker expression pattern reports expression in the subject of one or more biomarkers encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-82 (or the biomarkers set forth by name in Table 9, as described above). The computer program can further cause the processor to perform an operation comprising outputting a treatment regimen that is associated with the subject to be treated with the TNFα inhibitor.
[0157] In one embodiment of the above-described methods and computer program, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 6, 7, 10, 15-17, 19, 22, 24, 27, 31, 34-39, 43-47, 49, 51, 54, 55, 57, 59, 61, 62, 64, 70, 75, 79 and 82 (or the biomarkers set forth by name in Table 9 as being increased in ≧80% of responders vs. non-responders, as described above), more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 31, 37, 44, 47, 62 and 70 (or the biomarkers set forth by name in Table 9 as being increased in ≧90% of responders vs. non-responders, as described above), and even more preferably at least one of the biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 44 (or the biomarker, CD11c antigen, set forth by name in Table 9 as being increased in 100% of responders vs. non-responders, as described above). In each of these embodiments, increased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0158] In another embodiment of the above-described methods and computer programs, the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 1-5, 8, 9, 11-14, 18, 20, 21, 23, 25, 26, 28-30, 32, 33, 40-42, 48, 50, 52, 53, 56, 58, 60, 63, 65-69, 71-74, 76-78, 80 and 81 (or the biomarkers set forth by name in Table 9 as being decreased in ≧80% of responders vs. non-responders, as described above), more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of SEQ ID NOs: 11, 29, 65, 73 and 74 (or the biomarkers set forth by name in Table 9 as being decreased in ≧90% of responders vs. non-responders, as described above), and even more preferably the one or more biomarkers is encoded by a nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO: 11 or SEQ ID NO: 74 (or the biomarkers set forth by name in Table 9 as being decreased in 100% of responders vs. non-responders, as described above). In each of these embodiments, decreased expression of the one or more biomarkers is predictive of responsiveness of the subject to a TNFα inhibitor.
[0159] In another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 83-133 (or the biomarkers set forth by name in Table 3, as described above).
[0160] In yet another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 134-177, 110, 112, 118, 123 and 131 (or the biomarkers set forth by name in Table 4, as described above), more preferably SEQ ID NO: 134-150, 112, 118 (or the biomarkers set forth by name in Table 4 as having increased expression, as described above), wherein expression of the one or more biomarkers is increased in the subject, and/or more preferably SEQ ID NO: 151-177, 110 and 123 (or the biomarkers set forth by name in Table 4 as having decreased expression, as described above), wherein expression of the one or more biomarkers is decreased in the subject.
[0161] In yet another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 178-292, 91 and 97 (or the biomarkers set forth by name in Table 5, as described above), more preferably SEQ ID NO: 178-185; 187-200, 202, 203, 205-207; 211, 213, 214, 216, 220, 221, 226, 228, 229, 231, 232, 234, 235, 238-247, 249, 250, 253, 262-265, 268-282 and 285-288 (or the biomarkers set forth by name in Table 5 as having increased expression, as described above), wherein expression of the one or more biomarkers is increased in the subject, and/or more preferably SEQ ID NO: 186, 201, 204, 208, 209, 91, 210, 212, 97, 215, 217-219, 222-225, 227, 230, 233, 236, 237, 248, 251, 252, 254-261, 266, 267, 283, 284 and 289-292 (or the biomarkers set forth by name in Table 5 as having decreased expression, as described above), wherein expression of the one or more biomarkers is decreased in the subject.
[0162] In yet another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 87, 97, 101, 293, 92, 272, 93, 107, 108, 121 and 123 (or the biomarkers set forth by name in Table 6 as pre-treatment biomarkers, as described above), wherein the subject is monitored prior to treatment with a TNFα inhibitor. In yet another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 290, 209, 98, 112, 116, 121, 130, 155, 92, 289, 216 and 131 (or the biomarkers set forth by name in Table 6 as post-treatment biomarkers, as described above), wherein the subject is monitored after treatment with a TNFα inhibitor.
[0163] In yet another embodiment of the above-described methods and/or computer programs, the biomarker expression pattern(s) can be for one or more biomarkers selected from the group consisting of SEQ ID NO: 97, 102, 29, 294, 295, 91, 131, 290, 100, 134, 296, 297, 298, 299, 136, 174 and 300 (or the biomarkers set forth by name in Table 7, as described above).
[0164] Computer systems and database software well established in the art can be adapted for use in the methods and computer program products of the invention for building and searching a database for use in selecting or monitoring a treatment regimen for a subject having an autoimmune disorder or for selecting a particular autoimmune disorder subject for treatment with a TNFα inhibitor.
[0165] The present invention is further illustrated by the following examples which should not be construed as further limiting. The contents of all references, patents and published patent applications cited throughout this application are expressly incorporated herein by reference in their entirety.
EXAMPLES
Example 1
Materials and Methodologies
[0166] In this example, the materials and methodologies used in the subsequent Examples are described.
Patients
[0167] Purified monocytes (MO) derived from a total of 84 RA patients were used. The clinical data for the RA patients, pre- and post-anti-TNFα treatment, is summarized in Table 1. All patients fulfilled the revised American College of Rheumatology (ACR) criteria (Arnett, F. C. et al. (1988) Arthritis Rheum. 31:315-324). Patients were defined as responders (≧continuous ACR score 40) or non-responders (≦continuous ACR score 30) to anti-TNFα monotherapy, MTX monotherapy or combination therapy. In order to account for a gradual transition from clinical responders to non-responders to therapy, a continuous ACR response evaluation was performed by applying the ACR criteria, but by defining 10% response steps instead of the usual 20, 50, and 70% steps. This was also done to allow more detailed analyses of the correlation between the ACR response and the mRNA expression levels of the predictive marker CD11c.
[0168] For Affymetrix® microarray analysis, MO samples from 7 RA patients (RA1-RA7; all females) undergoing the Abbott DE011 trial were used (ReACT; monoclonal antibody Adalimumab®). In this multicenter, double-blinded study patients received Adalimumab® (20 mg weekly or 40 mg biweekly) in the outpatient Rheumatology Clinic of the Charite University Hospital in Berlin, Germany, for a total of 2 years. Non-steroidal anti-inflammatory drugs and 10 mg prednisolone-equivalent per week were allowed in addition to the anti-TNFα therapy. For TaqMan® real-time PCR, 26 patients (RA8-RA84 from the Abbott DE013 trial were used (ATTRACT). In this study Adalimumab®, methotrexate (MTX; 10-20 mg/week) or a combination of both therapeutics was applied.
[0169] The mean time interval between the two MO samples (blood sampling before and during therapy) was 9.4±1.8 months (mean±SEM; range 4-13.5 months), the mean age 50.3±3.9 years (range 39-70), and the mean disease duration 18.6±5.3 years (range 4-38). As controls, healthy individuals were recruited (n=7; 6 females, 1 male; mean age 36.1±7.4 years). RA patients RA1-RA84 were recruited from the Rheumatology Clinic of the Charite University Clinic, the Rheumaklinik of the Charite in Berlin-Buch, and from the Schlossparklinik in Berlin.
Separation of Peripheral Blood Mononuclear Cells, Purification of Monocytes, RNA Isolation
[0170] Peripheral blood (30 to 35 ml) was obtained by venopuncture, immediately stored in heparin-containing vacutainers (Beckton-Dickinson, Rutherford, N.J., USA), and cooled to 4° C. Blood samples were subjected to a Ficoll-Hypaque gradient (d=1.077 g/ml; Biochrom, Berlin, Germany). To enrich MO, negative selection magnetic cell sorting (MACS; Miltenyi; Bergisch Gladbach, Germany) was subsequently applied. Successful purification of MO (purity of 83-90%; 1.3-3.2×106 MO/patient) was validated by FACS analysis using CD14 and CD45 antibodies (Beckman-Coulter, Krefeld, Germany). In all cases, purified MO showed >98% vitality using propidiumiodide staining (Pharmingen, San-Diego, Calif., USA). MO preparation was performed at 4° C. After purification, MO were lysed in RLT lysis buffer and total RNA was isolated using the RNeasy mini elute kit (Quiagen, Dusseldorf, Germany; yield 1.5-3.2 μg/sample). Quantification and quality control of RNA was performed at 260/280 nm using a Bioanalyzer 2100 unit (Agilent, Palo Alto, Calif., USA).
RNA Amplification and Labeling
[0171] For target synthesis, 500 ng of total RNA were amplified using the standard protocol of the manufacturer (Affymetrix®, Palo Alto, Calif., USA) and the Megascript kit (Ambion, Camhridgeshire, UK).
Biotin-Labeling of cRNA and Gene-Chip Hybridization
[0172] Biotinylated cRNA target was generated from amplified cRNAs using the Bioarray high-yield transcription kit (Enzo, New York, N.Y., USA). Samples were hybridized to Affymetrix® test and HG-U133A GeneChip arrays.
[0173] Following washing and staining, arrays were scanned twice at 3 μm resolution using a confocal scanner with an argon laser instrument (Agilent® G2500A GeneArray Scanner; Agilent, CA, USA).
Bioinformatic Analysis of Differentially Expressed Genes in ND and RA Patients Pre- and Post Anti-TNFα Treatment
[0174] All GeneChips were analyzed for signal calculation and pairwise comparisons using the GCOS 1.4 software package with standard settings provided by Affymetrix®. Scaling was performed to a target value of 150 and normalization was set to "1". Pairwise comparison data were grouped to generate a percentage level of increased and decreased comparisons. Fold-changes were calculated from the mean of the SLR values in pairwise comparisons. Filtering was performed on the basis of "increased/decreased" comparisons with a percentage cutoff as indicated in the results. For hierarchical clustering, the software tool "Gene Expression Similarity Investigation Suite" (Genesis; Sturn, A. et al. (2002) Bioinformatics 18:207-208; http://genome.tugraz.at/Software/GenesisCenter.html) was applied using normalized signal intensities, Pearson distance correlation, and complete linkage clustering. Prediction analysis was performed using the PAM software (http://www.bioconductor.org; Khan, J. et al. (2001) Nat. Med. 7:673-679).
Data Sets of Publication
[0175] The complete ASCI-file datasets have been deposited in the microarray GEO database (http://www.ncbi.nlm.nih.gov/geo/).
TaqMan® Real Time PCR
[0176] Real-time PCR (RT-PC) was performed using a TaqMan® 7500 system and pre-designed TaqMan® low density gene expression primers (Applied Biosystems; Foster City, Calif., USA) or, in the case of CD11c, the primer Hs01015072_g1 (commercially available from Applied Biosystems) in a Bio-Rad iQ real time PCR system (Icycler; Bio-Rad; Munchen, Germany). The housekeeping gene GAPDH was used for normalization of the cDNA content. Quantification was performed using the SDS 2.2.0 software (Applied Biosystems); results were expressed as relative quantities of the logarithm of the ΔΔCT values (log RQ), as the relative quantity of expression (RQ; fold-change in comparison to normal donor expression), or as the % expression as normalized to GAPDH.
Literature-Associated Pathway Analysis Using Ingenuity
[0177] Gene ontology and gene interaction analyses were executed using the Ingenuity® Pathway analysis tool v.4.0 (Ingenuity, Redwood City, Calif., USA; Jenssen, T. K. et al. (2001) Nat. Genet. 28:21-28; http://www.ingenuity.com). Highest scoring neighborhood analysis of literature-based gene connections was performed by comparing up- and downregulated genes in anti-TNFα responders and non-responders (pre- and post-treatment). Significantly regulated genes in both comparisons were merged from the networks 1 to 5, complemented by transcription factors and finally overlayed with their relative expression values.
Expression-Based Pathway Analysis Using Kyoto Encyclopedia of Genes and Genomes (KEGG)
[0178] The KEGG pathway analysis (Kanehisa, M. and Bork, P. (2003) Nat. Genet. 33:305-310) was performed using selected genes from the comparison of microarray data in responders and non-responders either pre- or post-treatment with anti-TNFα. Upregulated genes and downregulated genes within the illustrated pathways were color-coded in a gradient fashion (SLR 0.5 to ≧1.5). A total of 4 pathways out of the 8 most highly ranked pathways were selected for illustration.
Statistical Analysis
[0179] The non-parametric Mann-Whitney U test was applied to analyze differences between data from RA patients and normal donors, from untreated and anti-TNFα-treated RA patients, and from responders and non-responders to anti-TNFα-therapy. Correlation analyses between experimental and clinical/laboratory parameters of the patients were performed using the Pearson test and the software SPSS 13.0® (SPSS Inc., Chicago, Ill., USA). For the U test, statistically significant differences were accepted for P≦0.05; for correlation analyses, the acceptance level was reduced to P≦0.01 to account for multiple comparisons.
Example 2
Clinical and Laboratory Assessments for RA Patients and Normal Donors
[0180] Two of the seven anti-TNFα-treated RA patients used for microarray analysis, i.e., patients RA4 and RA6, were non-responders to therapy according to the ACR improvement criteria (≦continuous ACR 30 score). In general, this was also reflected in the respective percent-reduction of other clinical parameters of local or systemic inflammation. The group of seven RA patients employed for microarray analysis in the present study constituted a representative RA cohort, as demonstrated by well-known correlations among clinical parameters pre- and post-anti-TNFα treatment, as summarized in Table 2.
[0181] The identification of patients RA4 and RA6 as non-responders was also confirmed by hierarchical clustering of clinical parameters.
Example 3
Gene Expression Profiling and Analysis
Differential Gene Expression in Responders Versus Non-Responders to Anti-TNFα-Therapy
[0182] A total of 119 differentially-expressed genes was identified by comparing RA and normal donors (ND; n=7 each; total of 49 comparisons). Hierarchical clustering of ND, as well as RA patients pre- and post-treatment with these genes also identified 5 responders and 2 non-responders (RAantiTNF4 and RAantiTNF6).
[0183] In order to select therapeutically relevant genes, a subpopulation of 51 differentially-expressed genes was then identified by the simultaneous comparison between RA versus normal donors (ND; total of 49 comparisons) and RA responders (n=5) pre- versus post-anti-TNFα therapy (25 comparisons). These genes showed an increase or decrease of the signal log ratio (SLR; between -4.36 and 4.61) in >70% of the pair-wise comparisons between RA and ND. These genes are summarized in Table 3.
[0184] Hierarchical clustering with these genes resulted in precise (100%) classification of ND, RA patients pre-treatment, and clinically-defined responders (≧continuous ACR score 40; clustered as ND) or non-responders (≦continuous ACR score 30; clustered as RA; note RAantiTNF4 and RAantiTNF6). This was confirmed by supervised pattern discovery using prediction analysis of microarrays (PAM analysis) at a threshold value of 4.3 in order to minimize the misclassification error. Table 4 summarizes the results of the PAM analysis, showing 49 selected genes, five of them overlapping with genes listed in Table 3. In this case, both non-responders (RAantiTNF4 and RAantiTNF6) were classified as RA patients, whereas the responders, RAantiTNF1-3, RAantiTNF5, and RAantiTNF7, were classified either as normals or as anti-TNFα-treated RA patients. Notably, ND showed the lowest misclassification error at the threshold value (0.00; i.e., the highest similarity among individuals), followed by pre-treatment RA patients (0.14), and anti-TNFα-treated RA patients (0.42).
[0185] Identification of responders/non-responders was also confirmed by hierarchical clustering of RA patients post-treatment. A total of 117 genes differentially expressed in RA responders versus RA non-responders was identified in post-anti-TNFα therapy samples, which showed an increase or decrease in 100% of the respective pair-wise comparisons (total of 10 comparisons). The 117 genes identified in this analysis are summarized in Table 5, three of which genes overlap with the genes summarized in Table 3. Hierarchical clustering with these genes resulted in precise (100%) classification of responders and non-responders to therapy.
[0186] A number of the differentially-expressed genes showed highly significant correlations with clinical or laboratory parameters pre- and/or post-anti-TNFα treatment, indicating a potential clinical relevance of the genes and contributing to the selection of genes for validation with TaqMan® real-time RT-PCR. These genes are summarized in Table 6.
Example 4
Real-Time RT-PCR Validation of Genes Differentiating Responders and Non-Responders
[0187] Sixteen genes with a likely pathogenetic importance in RA (and 6 control genes) from Affymetrix® gene expression profiling were selected for validation by TaqMan® real-time RT-PCR (n=10 anti-TNFα-treated RA patients prior to therapy; n=14 ND). The RT-PCR results confirmed the results of Affymetrix® gene expression profiling for 17 of 22 genes (approx. 77%), summarized in Table 7. This applied to genes regarded as differentially expressed in RA versus ND by Affymetrix® analysis (decreased: <-70%; increased: >70%) and to equally expressed control genes. By real-time RT-PCR, 18 genes showed significantly differential expression (p≦0.000 for 7 genes; p≦0.041 for the remaining) in MO from RA patients responding to anti-TNFα therapy versus ND, including genes 10 upregulated in RA (Amphiregulin, Charcot-Leyden crystal protein, TNFα-induced protein 6, thrombomodulin, membrane-spanning 4-domains, subfamily A--member 4, S100 calcium binding protein A1, TNFα, IL-1β, lipoyltransferase 1, and interferon regulatory protein 1), as well as 8 genes downregulated in RA (Uncharacterized hypothalamus protein HT007, MHC class II HLA-DR-alpha, hypothetical protein L0054103, proteasome subunit beta type 7 precursor, protein KIAA0174, microsomal signal peptidase 18 kDa subunit, ring zinc finger protein 361, and protein phosphatase 1, catalytic subunit, beta isoform). However, the expression for these genes showed no significant differences for the direct comparison between RA responders and non-responders to anti-TNFα therapy.
[0188] The potential clinical relevance of some of the differentially expressed genes is underlined by a significant correlation with the ACR response at different time points during anti-TNFα therapy, as summarized in Table 8.
[0189] Validation of the 22 selected genes by TaqMan® real-time RT-PCR confirmed the results of Affymetrix® gene expression profiling for 17 of 22 genes (approx. 77% true positives or negatives), in accordance with the rates reported in other gene expression studies and therefore underlining the validity of the present data. The 18 genes showing significantly differential expression in MO from RA patients responding to anti-TNFα therapy versus ND included several genes with a likely pathogenetic importance in RA (e.g., amphiregulin, TNFα-induced protein 6, thrombomodulin, membrane-spanning 4-domains, subfamily A--member 4, S100 calcium binding protein A1, TNFα, IL-1β, lipoyltransferase 1, interferon regulatory protein 1, MHC class II HLA-DR-alpha).
Example 5
Gene Expression Profiling and Analysis
Differential Gene Expression in Responders Versus Non-Responders Prior to Anti-TNFα-Therapy (Predictive Genes)
[0190] Using a threshold of ≧80% for the pairwise comparisons between future RA responders and future RA non-responders prior to anti-TNFα therapy, a total of 82 predictive genes was identified (11 genes for a threshold of ≧90%; 3 genes for 100%). These genes are summarized in Table 9. The latter group (100%) consisted of 2 known proteins (Homo sapiens predicted osteoblast protein (GS3786); integrin alpha-X (antigen CD11c) and an unknown protein (Homo sapiens hypothetical protein FLJ10134). In particular the antigen CD11e appears highly interesting, since it is a surface molecule on human MO (and other cells of the myelomonocytic lineage), and since it has known inflammatory functions. Hierarchical clustering with the selected genes resulted again in precise (100%) predictive classification of future responders and non-responders to therapy. Marginal co-clustering of the patient RA5 with the non-responders RA4 and RA6 at the threshold values 80% and 100% possibly identified RA5 as a `weak` responder, as also indicated by a marginal position in the hierarchical clustering of clinical parameters.
[0191] Interestingly, future responders to anti-TNFα-therapy (when directly compared to non-responders) showed a pattern shift from the recently described `inflammatory` MO to `resident` MO subsets (Gordon, S. et al. (2005) Nat. Immunol. 5:953-963) both prior to therapy and post-treatment. Although most of the individual molecules showed an identical pattern shift in both pre-treatment and post-treatment comparisons, in particular the activating (CD16a,b) and inhibiting Fcγ-receptors (CD32) displayed an opposite behavior. This pattern shift was observed despite the fact that all pre-treatment or post-treatment comparisons between RA patients (all, future responders, future non-responders) and ND indicated a dominance of `inflammatory` MO in the respective RA groups. Post-treatment, strikingly, responders to anti-TNFα-therapy became barely distinguishable from ND in contrast to non-responders, which still showed a clear `inflammatory` predominance. These results indicate that successful anti-TNFα-therapy acts by blocking TNFα signaling via TNFα-receptors 1 and 2 and by subsequent induction of a major change in the composition of pro-inflammatory and other MO subsets.
Example 6
Real-Time RT-PCR Validation of Predictive CD11c
[0192] TaqMan® real-time RT-PCR confirmed the discrimination of future RA responders (n=15) from future nonresponders (n=12) to anti-TNF monotherapy (at the level of continuous ACR score 30) on the basis of their CD11c mRNA expression in monocytes.
[0193] TaqMan® real-time RT-PCR confirmed the separation of future RA responders n=55 from future non-responders n=12 to anti-TNFα monotherapy on the basis of their CD11c mRNA expression in MO. The results are summarized in the bar graph of FIG. 1. This clear separation was lost in the case of combination therapy with anti-TNFα/MTX, possibly due to a differential importance of the CD11c mRNA expression for the anti-TNFα and MTX components.
[0194] Of the 3 genes identified by pairwise comparison between RA responders and RA non-responders prior to treatment at the level of 100% (and confirmed by TaqMan® real-time RT-PCR), the antigen CD11c appears of particular interest, since it is expressed on the surface of human MO (and other cells of the myelomonocytic lineage, e.g. dendritic cells), and since it has known functions in inflammatory reactions (e.g., as the complement receptor 4) and cell adhesion.
[0195] The validity of CD11c as a predictive biomarker is further underlined by a significant correlation (r=0.651, P=<0.0001, n=27) between the CD11c expression prior to therapy and the future percentage of the ACR response, illustrated in the graph of FIG. 2.
[0196] Except for 1 RA patient with a borderline ACR response of 30 and a CD11c mRNA level directly at the distinction threshold (who was therefore classified as a false negative), the threshold level (40%) almost fully distinguished future responders from nonresponders (100% specificity, 94% sensitivity, and 96% power). This clear separation was lost in the case of combination therapy with anti-TNF/methotrexate (MTX), possibly owing to a differential importance of the CD11c mRNA expression for the anti-TNF and MTX treatment components. This was further underlined by the fact that: i) future responders to MTX monotherapy did not significantly differ in their CD11c mRNA expression level from future nonresponders to MTX monotherapy; and ii) there was no significant correlation between the future ACR response of RA patients treated with MTX monotherapy and their CD11c mRNA expression (data not shown).
[0197] Strikingly, this was true not only for the continuous ACR score, but also for the clinically applied, discrete ACR criteria.
[0198] A significant correlation (r=0.656, P=<0.0001, n=27) was observed between CD11c expression and the future percentage of strict ACR response, illustrated in the graph in FIG. 3. This finding complements and expands previous reports on the identification of molecules capable of predicting a future response to anti-TNFα therapy (Lequerre, T. et al. (2006) Arthritis Res. Ther. 8:R105; Toh, M. L. et al. (2006) Arthritis Rheum. 54:2109-2118).
Example 7
Ingenuity® Pathway Analysis
[0199] Ingenuity® pathway analysis of the genes in Tables 3 and 5 indicated a direct or indirect influence of anti-TNFα therapy on several molecules thought to be relevant for the pathogenesis and/or severity of RA, e.g., HLA-DMA/B (Morel, J. et al. (2004) Ann. Rheum. Dis. 63:1581-1586), CD69 (Marzio, R. et al. (1999) Immunopharmacol. Immunotoxicol. 2:565-582) thrombomodulin (Cobankara, V. et al. (2004) Clin. Rheumatol. 23:430-434), membrane-spanning 4-domains, subfamily A--member 4 (Fujikado, N. et al. (2006) Arthritis Res. Ther. 8:1-13), and forkhead box 03a (Jonsson, H. et al. (2005) Nat. Med. 11:666-671). The present approach, therefore, represents a powerful tool to identify gene regulation patterns applicable for diagnosis, as well as for therapy stratification and monitoring in rheumatic diseases, in particular in view of the fact that blood MO are much more easily available than synovial tissue samples. This is further supported by the fact that a high number of individual genes show significant correlations with clinical parameters in RA patients pre- and/or post-anti-TNFα treatment (see Table 6).
[0200] Pairwise comparison between RA responders and RA non-responders prior to treatment yielded a number of genes suitable for the prediction of a future response to anti-TNFα therapy (82 genes for a threshold of ≧80%; 11 genes for ≧90%; 3 genes for 100%; summarized in Table 9), resulting in exact classification of future responders and non-responders upon hierarchical clustering. Using all genes differentially expressed in the above comparison at a threshold level of 70% (256 pre-treatment; 1295 post-treatment) for Ingenuity® pathway analysis, the differences between responders and non-responders either pre-treatment or post-treatment were concentrated in the functional gene ontology terms cellular movement, haematological system development, immune response, cell-to-cell signaling and interaction, as well as immunological disease.
[0201] In particular, numerous relevant mediators were identified: i) pro-inflammatory cytokines (e.g., interleukin-8 [IL8], chemokine (C--C motif) ligand 5 [CCL5], chemokine (C--X--C motif) ligand 5 [CXCL5], and chemokine (C--X--C motif) ligand 10 [CXCL10]); ii) pro-destructive enzymes (e.g., matrix metalloproteinase 9 [MMP9]); iii) adhesion molecules and Fcγ-receptors (galectin-8 [LGALS8], integrin alpha-X [ITGAX] or CD11c, Fc-gamma receptor IIb [FCGR2B] or CD32, CD86 [CD86] and platelet/endothelial cell adhesion molecule 1 [PECAM1] or CD31); iv) signal transduction molecules (e.g., protein kinase B [AKT1], apoptosis regulator Bel-2 [BCL2], p21-activated protein kinase 1 [PAK1]); and v) transcription factors (e.g., Mad-related protein 2 [SMAD2], interferon regulatory factor 1 [IRF1], c-myb [MYB], early growth response protein 1 [EGR1], signal transducer and activator of transcription 1 [STAT1], and nuclear factor NF-κB 1 [NFKB1]; for the remaining abbreviations see the respective gene cards [http://www.genecards.org/index.shtml]). These molecules were differentially expressed between RA responders and RA non-responders either pre-treatment or post-treatment and in some cases even inverted their expression upon anti-TNFα-therapy (see interleukin-8 receptor beta [IL8RB], Amyloid-beta A4 precursor [APP]; overexpressed in RA responders pre-treatment and underexpressed post-treatment). Similar opposite variations in transcript levels between RA responders and RA non-responders have recently been reported when comparing baseline to 3-month results (Lequerre, T. et al. (2006) Arthritis Res. Ther. 8:R105).
[0202] Most strikingly, the transcription of TNFα itself, as well the transcription of members of the subsequent NFKB-pathway (NFKB1 and inhibitor of NF-κB [IKBKB]), was upregulated in RA responders post-treatment. This previously unreported finding at first sight questions the central pro-inflammatory role of TNFα in RA. However, several caveats should be considered: i) The mRNA expression levels of TNFα measured in the present study may not be proportional to the levels of circulating TNFα protein and/or bioactivity, the latter apparently predictive of the clinical response to TNFα inhibition (Marotte, H. et al. (2005) Arthritis Res. Ther. 7:R149-155); ii) TNFα, in addition to its well-established pro-inflammatory properties, may also exhibit phase-dependent immunosuppressive properties (Kassiotis, G. et al. (2001) J. Exp. Med. 193:427-434).
[0203] Several interesting pathways with potential importance for the mechanisms underlying susceptibility to anti-TNFα-therapy were identified by KEGG pathway analysis; including Apotosis and the MAPK pathways.
TABLE-US-00001 TABLE 1 Clinical parameters of patients before and after anti-TNF treatment Methods Duration Affymetrix (A) of Disease Morning Swollen joint Painful joint real-time treatment, duration, Age, stiffness, min count 68 count 68 Patient (R/P) mo y y Gender RF (% reduction) (% reduction) (% reduction) RA1-1110006211 A/P 0 4 52 F + 320 10 19 RA1-aTNF A 13.5 15 (95) 3 (70) 8 (58) RA2-1110005181 A/P 0 9 53 F + 180 16 50 RA2-aTNF A 6 0 (100) 1 (94) 19 (62) RA3-1110005291 A/P 0 18 39 F + 0 10 28 RA3-aTNF A 5.5 0 (0) 2 (80) 8 (29) RA4-1110005031 A/P 0 12 47 F + 720 20 43 RA4-aTNF A 17 60 (92) 19 (5) 35 (19) RA5-1110004141 A/P 0 38 70 F + 120 11 56 RA5-aTNF A 15 120 (0) 2 (82) 61 (0) RA6-1110004131 A/P 0 38 51 F + 60 12 27 RA6-aTNF A 4 60 (0) 4 (67) 28 (0) RA7-1110006221 A/P 0 11 40 F + 150 18 44 RA7-aTNF A 4.5 10 (93) 5 (72) 25 (43) RA8-06507 R 0 <1 28 F - 120 14 17 RA8-aTNF/MTX R 6 0 (100) 0 (100) 3 (82) RA9-06513 R 0 1 53 F - 120 16 20 RA9-aTNF/MTX R 4.5 15 (87) 12 (25) 16 (20) RA10-05602 R 0 1 48 F + 180 8 40 RA10-MTX R 3.5 240 (0) 10 (0) 29 (27) RA11-05610 R/P 0 <1 38 F - 360 14 22 RA11-aTNF R 6 30 (92) 3 (79) 9 (59) RA12-05609 R/P 0 1 63 F + 60 17 29 RA12-aTNF R 6 10 (83) 5 (71) 9 (69) RA13-05608 R 0 2 44 F + 45 12 24 RA13-aTNF/MTX R 6 0 (100) 0 (100) 1 (96) RA14-05612 R/P 0 1 29 F + 60 8 11 RA14-aTNF/MTX R 6 0 (100) 0 (100) 0 (100) RA15-06504 R/P 0 2 47 F + 60 10 23 RA15-aTNF R 6 20 (67) 2 (80) 3 (87) RA16-06308 R/P 0 <1 60 F + 120 17 29 RA16-aTNF/MTX R 6 15 (87) 1 (94) 16 (45) RA17-06516 R 0 1 36 F + 30 17 17 RA11-aTNF R/P 6 15 (50) 11 (35) 0 (100) RA18-06309 R 0 1 83 F - 30 11 27 RA18-aTNF/MTX R 6 0 (100) 0 (100) 0 (100) RA19-05613 R/P 0 2 63 F + 120 25 43 RA19-aTNF R 6 15 (87) 9 (64) 17 (60) RA20-06304 R/P 0 <1 50 F - 60 12 29 RA20-aTNF R 6 0 (100) 2 (83) 5 (83) RA21-06514 R/P 0 2 56 F - 30 21 52 RA21-aTNF/MTX R 6 30 (0) 15 (29) 16 (69) RA22-05606 R/P 0 <1 36 F + 60 12 22 RA22-aTNF/MTX R 6 0 (100) 2 (83) 9 (83) RA23-06306 R/P 0 1 34 F + 30 13 27 RA23-aTNF R 3 30 (0) 18 (0) 27 (0) RA24-06305 R 0 n.d. 18 F + 30 14 20 RA24-MTX R 6 60 (0) 2 (86) 8 (60) RA25-06515 R/P 0 <1 54 M - 45 22 43 RA25-aTNF R 6 20 (66) 7 (68) 28 (35) RA26-06506 R/P 0 1 50 F - 60 9 23 RA26-aTNF R 6 120 (0) 20 (0) 45 (0) RA27-05601 R/P 0 1 42 F + 60 8 24 RA27-aTNF R 6.5 60 (0) 7 (12) 30 (0) RA28-1110004171 P 0 n.d. 34 F + 60 20 47 RA28-aTNF 3.5 0 (100) 4 (80) 4 (91) RA29-1110011271 P 0 11 62 F + 120 8 35 RA29-aTNF/MTX 0.5 120 (0) 9 (0) 44 (0) RA30-1110010101 P 0 7 35 F + 120 8 12 RA30-aTNF/MTX 10 0 (100) 2 (75) 7 (42) RA31-1110004121 P 0 13 33 F + 30 11 27 RA31-aTNF 6 20 (67) 2 (82) 7 (74) RA32-1110008092 P 0 20 43 F + 60 14 38 RA32-aTNF 6.5 0 (100) 6 (57) 7 (72) RA33-1110005121 P 0 8 61 F - 180 19 59 RA33-aTNF 17.5 120 (66) 2 (89) 12 (81) RA34-1110111281 P 0 12 66 F + 90 10 5 RA34-MTX 12 120 (0) 8 (20) 9 (0) RA35-1110112121 P 0 6 63 F + 180 8 20 RA35-MTX 9 0 3 (63) 4 (80) RA36-1110201231 P 0 10 36 F 0 60 30 19 RA36-MTX 4 30 (50) 0 (100) 0 (100) RA37-1110211051 P 0 1 59 F + 180 2 21 RA37-MTX 3 15 (92) 0 (100) 4 (81) RA38-1110309012 P 0 <1 32 F + 180 7 29 RA38-MTX 3 0 (100) 1 (85) 3 (90) RA39-1110309122 P 0 1 26 F + 180 6 23 RA39-MTX 3 15 (92) 1 (83) 9 (41) RA40-1110310302 P 0 1 45 F + 10 10 17 RA40-MTX 4 0 (100) 0 (100) 2 (88) RA41-1110411251 P 0 <1 58 F 0 180 6 16 RA41-MTX 3 0 (100) 0 (100) 2 (88) RA42-1110409071 P 0 1 52 F 0 0 9 4 RA42-MTX 3 0 (0) 0 (100) 0 (100) RA43-1110409141 P 0 <1 58 M + 10 8 22 RA43-MTX 3 10 (0) 0 (100) 5 (77) RA44-1110409223 P 0 1 67 F 0 60 12 20 RA44-MTX 3 0 (100) 0 (100) 4 (80) RA45-1110411291 P 0 <1 44 F 0 30 25 43 RA45-MTX 3 0 (100) 9 (64) 17 (60) RA46-1110602212 P 0 10 45 F + 120 3 13 RA46-aTNF/MTX 6 120 (0) 0 (100) 21 (0) RA47-1110503081 P 0 21 57 F + 360 8 10 RA47-TNF 6 180 (50) 7 (14) 11 (0) RA48-1110703082 P 0 7 60 F + 240 0 10 RA48-TNF 6 120 (50) 0 (0) 5 (50) RA49-1110309122 P 0 1 26 F + 180 6 24 RA49-MTX 9 15 (92) 1 (83) 9 (62) RA50-1100308202 P 0 6 63 F + 0 0 18 RA50-MTX 3 0 (0) 1 (0) 2 (89) RA51-1110309111 P 0 2 45 M + 180 16 30 RA51-MTX 3 120 (33) 9 (44) 24 (20) RA52-1110401081 P 0 1 62 F + 0 0 18 RA52-MTX 5.5 0 (0) 0 (0) 0 (100) RA53-1110406011 P 0 1 61 F + 30 10 33 RA53-MTX 3 5 (83) 0 (100) 1 (97) RA54-1110406112 P 0 3 61 M + 10 6 22 RA54-MTX 3 0 (100) 0 (100) 5 (77) RA55-1110406111 P 0 <1 57 F + 60 2 12 RA55-MTX 3 0 (100) 0 (100) 2 (83) RA56-1110407131 P 0 1 63 F + 30 9 30 RA56-MTX 3 0 (100) 0 (100) 6 (80) RA57-1110407281 P 0 2 56 F + 0 7 19 RA57-MTX 3 0 (0) 0 (100) 2 (89) RA58-1110409201 P 0 1 61 F + 10 5 16 RA58-MTX 3 0 (100) 0 (100) 4 (75) RA59-1110410271 P 0 6 35 M + 15 0 5 RA59-MTX 3 0 (100) 0 (0) 2 (60) RA60-1110503231 P 0 1 71 F + 30 6 23 RA60-MTX 3 0 (100) 0 (100) 5 (78) RA61-1110504061 P 0 1 51 F + 45 12 27 RA61-MTX 3 0 (100) 0 (100) 0 (100) RA62-1110505301 P 0 1 59 F 0 120 2 9 RA62-MTX 3 0 (100) 0 (100) 12 (0) RA63-1110507281 P 0 2 43 F + 30 10 17 RA63-MTX 3 0 (100) 6 (40) 15 (12) RA64-1110511281 P 0 <1 69 F + 90 7 21 RA64-MTX 3 0 (100) 1 (86) 2 (90) RA65-1110405273 P 0 5 55 F + 0 0 2 RA65-aTNF/MTX 4 10 (0) 6 (0) 16 (0) RA66-1110502091 P 0 36 62 F + 30 13 14 RA66-aTNF/MTX 30 15 (50) 2 (85) 14 (0) RA67-1110507261 P 0 25 43 F + 0 4 5 RA67-aTNF/MTX 25 0 (0) 0 (100) 1 (80) RA68-1110603141 P 0 12 72 F + 30 7 7 RA68-aTNF 12 60 (0) 0 (100) 0 (100) RA69-1110510181 P 0 2 33 F + 50 6 6 RA69-aTNF/MTX 12 0 (100) 0 (100) 0 (100) RA70-06303 P 0 1 53 F + 30 14 17 RA70-aTNF/MTX 6 10 (66) 0 (100) 0 (100) RA71-06516 P 0 3 79 F + 30 17 17 RA71-TNF 6 15 (50) 0 (100) 11 (35) RA72-06510 P 0 3 68 F + 10 25 34 RA72-TNF 6 10 (0) 2 (92) 0 (100) RA73-06309 P 0 1 36 F 0 45 11 27 RA73-TNF/MTX 6 0 (100) 0 (100) 0 (100) RA74-06310 P 0 3 48 F 0 360 14 22 RA74-TNF 12 15 6 (57) 14 (36) RA75-06307 P 0 2 51 F + 360 16 22 RA75-MTX 6 0 (100) 2 (87) 3 (86) RA76-06311 P 0 3 43 F + 120 14 36 RA76-TNF 3 0 (100) 0 (100) 0 (100) RA77-06513 P 0 1 53 F 0 120 16 20 RA77-TNF/MTX 4.5 15 (87) 12 (25) 16 (20) RA78-06512 P 0 1 83 F 0 30 15 53 RA78-MTX 5.5 15 (50) 27 (0) 63 (0) RA79-06514 P 0 2 56 F 0 30 21 52 RA79-TNF/MTX 6 30 (0) 15 (29) 16 (69) RA80-1110505241 P 0 4 47 F + 24 5 9 RA80-TNF/MTX 3.5 36 (0) 4 (20) 4 (56) RA81-06305 P 0 1 18 F + 30 8 20 RA81-MTX 6 60 (0) 2 (75) 14 (70) RA82-05602 P 0 1 48 F + 180 29 40 RA82-MTX 3.5 240 (0) 10 (66) 8 (20) RA83-05607 P 0 3 61 M + 120 25 40 RA83-MTX 8 0 (100) 3 (88) 3 (92) RA84-06302 P 0 3 42 F + 60 16 39 RA84-MTX 6 10 (83) 6 (62) 18 (51) ACR ESR, CRP, improvement mm/hr mg/L HAQ score DAS28 (% continuous Patient (% reduction) (% reduction) (% reduction) (% reduction) score) RA1-1110006211 69 57.5 2.0 6.0 RA1-aTNF 8 (88) 2.0 (97) 1.3 (35) 3.1 (48) 50 RA2-1110005181 46 52.2 1.6 6.3 RA2-aTNF 12 (74) 2.8 (94) 1.0 (37) 2.9 (54) 60 RA3-1110005291 72 61.1 1.5 6.1 RA3-aTNF 16 (78) 3.9 (93) 1.0 (33) 4.1 (33) 60 RA4-1110005031 58 85.3 2.1 6.9 RA4-aTNF 40 (31) 20.0 (77) 1.3 (38) 6.5 (6) 0 RA5-1110004141 80 41.5 2.1 6.3 RA5-aTNF 11 (86) 4.5 (88) 1.4 (33) 4.0 (37) 50 RA6-1110004131 46 36.0 1.6 5.9 RA6-aTNF 32 (30) 22.3 (39) 1.6 (0) 5.1 (14) 10 RA7-1110006221 30 17.3 1.9 6.0 RA1-aTNF 14 (53) 11.3 (35) 1.3 (32) 4.1 (32) 40 RA8-06507 30 <3.5 1.6 6.1 RA8-aTNF/MTX 4 (87) <3.5 (0) 0.0 (100) 2.4 (61) 70 RA9-06513 34 <3.5 1.3 6.2 RA9-aTNF/MTX 14 (59) <3.5 (0) 1.4 (0) 5.2 (26) 20 RA10-05602 31 <3.5 2.2 7.1 RA10-MTX 39 (0) <3.5 (0) 2.3 (0) 6.8 (4) 0 RA11-05610 40 39.2 1.4 6.5 RA11-aTNF 45 (0) 36.4 (7) 0.3 (79) 4.3 (34) 50 RA12-05609 22 14.3 0.5 6.6 RA12-aTNF 30 (0) <3.5 (100) 0.3 (40) 4.3 (35) 50 RA13-05608 32 5.1 0.8 6.1 RA13-aTNF/MTX 28 (12) <3.5 (100) 0.0 (100) 2.7 (56) 90 RA14-05612 35 13.1 1.0 5.0 RA14-aTNF/MTX 8 (77) <3.5 (100) 0.0 (100) 1.7 (66) 100 RA15-06504 28 <3.5 1.8 6.3 RA15-aTNF 24 (14) 4.1 (0) 1.3 (28) 3.5 (44) 50 RA16-06308 56 <3.5 1.8 7.3 RA16-aTNF/MTX 28 (50) <3.5 (0) 1.3 (28) 4.8 (44) 40 RA17-06516 80 22.8 1.8 6.5 RA17-aTNF 24 (30) 27.5 (0) 0.6 (67) 3.2 (51) 30 RA18-06309 24 39.4 1.3 6.5 RA18-aTNF/MTX 8 (67) 8.5 (78) 0.6 (54) 1.9 (71) 70 RA19-05613 53 31.5 2.3 8.5 RA19-aTNF 85 (0) 40.0 (0) 1.3 (43) 5.6 (34) 60 RA20-06304 24 10.0 1.0 6.6 RA20-aTNF 16 (33) 10.0 (0) 1.0 (0) 3.8 (42) 30 RA21-06514 34 <3.5 1.4 8.3 RA21-aTNF/MTX 6 (82) <3.5 (0) 0.9 (36) 5.4 (35) 20 RA22-05606 40 23.1 2.4 6.2 RA22-aTNF/MTX 30 (25) 7.3 (68) 0.8 (67) 4.2 (32) 50 RA23-06306 90 61.1 2.1 7.1 RA23-aTNF 62 (33) 53.4 (23) 2.0 (5) 7.2 (0) 0 RA24-06305 22 29.1 0.3 4.7 RA24-MTX 20 (10) 31.3 (0) 0.1 (33) 4.1 (13) 20 RA25-06515 34 <3.5 1.0 8.0 RA25-aTNF 9 (74) <3.5 (0) 1.6 (0) 5.8 (27) 0 RA26-06506 16 <3.5 1.5 5.9 RA26-aTNF 50 (0) <3.5 (0) 1.9 (0) 8.3 (0) 0 RA27-05601 30 6.8 1.1 5.8 RA27-aTNF 58 (0) 16.9 (0) 1.5 (0) 6.7 (0) 0 RA28-1110004171 30 7.0 1.8 6.2 RA28-aTNF 16 (47) 6.9 (1) 0.4 (78) 3.6 (42) 80 RA29-1110011271 19 16.5 n.d. 4.3 RA29-aTNF/MTX 9 (53) 3.0 (72) n.d. 4.1 (13) 0 RA30-1110010101 52 42.6 n.d. 5.3 RA30-aTNF/MTX 17 (63) 10.1 (76) n.d. 2.6 (51) 50 RA31-1110004121 33 7.8 1.3 5.2 RA31-aTNF 18 (45) 5.9 (24) 0.9 (31) 3.4 (35) 40 RA32-1110008092 29 18.4 n.d. 6.8 RA32-aTNF 28 (3) 21.0 (0) n.d. 3.4 (50) 50 RA33-1110005121 28 22.4 1.8 6.3 RA33-aTNF 26 (7) 14.0 (36) 1.9 (0) 4.1 (35) 20
RA34-1110111281 18 9.0 1.43 4.29 RA34-MTX 13 (28) 12.0 (0) 0.74 (49) 5.10 (0) 0 RA35-1110112121 17 66.0 2.67 6.3 RA35-MTX 12 (29) <3.5 (100) 0.67 (76) 3.5 (45) 60 RA36-1110201231 38 45.0 2.33 6.3 RA36-MTX 17 (55) 5.0 (89) 0.33 (86) 2.1 (67) 80 RA37-1110211051 27 11.0 2.44 5.5 RA37-MTX 8 (70) 5.0 (55) 1.44 (41) 2.9 (47) 40 RA38-1110309012 20 8.1 1.11 5.4 RA38-MTX 10 (50) 1.2 (85) 0.44 (60) 2.5 (54) 70 RA39-1110309122 101 33.0 2.67 6.5 RA39-MTX 81 (20) 44.5 (0) 2.10 (21) 5.6 (14) 20 RA40-1110310302 72 77.6 2.1 6.8 RA40-MTX 18 (75) 6.9 (91) 1.1 (49) 3.4 (50) 50 RA41-1110411251 17 <3.5 2.4 5.4 RA41-MTX 12 (29) <3.5 (0) 0 (100) 3.1 (43) 80 RA42-1110409071 37 22.0 2.1 5.7 RA42-MTX 5 (87) 6.6 (70) 0.4 (81) 1.1 (81) 80 RA43-1110409141 27 32.0 2.3 5.9 RA43-MTX 3 (89) 4.6 (86) 2.0 (13) 1.7 (71) 70 RA44-1110409223 55 62.6 1.33 3.13 RA44-MTX 12 (78) 3.80 (94) 1.40 (0) 4.93 (0) 70 RA45-1110411291 34 18.0 1.4 4.9 RA45-MTX 20 (41) 12.6 (30) 0 (100) 2.2 (65) 60 RA46-1110602212 74 17.8 1.7 5.8 RA46-aTNF/MTX 20 (63) 2.7 (85) 1.1 (35) 4.4 (24) 30 RA47-1110503081 74 <3.5 2.0 6.5 RA47-TNF 20 (0) <3.5 (0) 2.8 (0) 6.7 (0) 0 RA48-1110703082 28 106.0 1.1 6.2 RA48-TNF 120 (12) 83.6 (21) 1.0 (9) 4.1 (34) 0 RA49-1110309122 40 33.0 0.9 6.6 RA49-MTX 40 (0) 34.5 (0) 0.7 (22) 5.7 (14) 10 RA50-1100308202 28 9.8 1.4 4.6 RA50-MTX 21 (25) 9.9 (0) 1.7 (0) 4.0 (13) 0 RA51-1110309111 10 4.0 2.2 6.1 RA51-MTX 5 (50) 1.3 (77) 2.1 (5) 5.1 (16) 0 RA52-1110401081 30 6.5 1.1 4.4 RA52-MTX 25 (17) 4.8 (26) 0.1 (91) 2.3 (48) 90 RA53-1110406011 10 23.0 1.78 6.4 RA53-MTX 0 (100) 3.1 (87) 0.3 (83) 2.4 (62) 80 RA54-1110406112 10 9.0 0.7 5.2 RA54-MTX 20 (0) 16.7 (0) 1.9 (0) 3.3 (37) 40 RA55-1110406111 25 24.8 1.9 5.4 RA55-MTX 12 (52) 6.7 (73) 0.3 (84) 2.4 (56) 80 RA56-1110407131 55 37.8 1.67 8.8 RA56-MTX 14 (75) 1.0 (97) 1.10 (34) 3.7 (58) 30 RA57-1110407281 21 3.9 1.6 5.5 RA57-MTX 10 (52) <3.5 (100) 0.2 (87) 2.5 (55) 70 RA58-1110409201 20 <3.5 2.2 4.3 RA58-MTX 14 (30) <3.5 (0) 0.4 (82) 2.0 (53) 70 RA59-1110410271 12 <3.5 0.8 2.6 RA59-MTX 25 (0) 7.9 (0) 0.8 (0) 2.7 (0) 30 RA60-1110503231 14 5.6 2 5.9 RA60-MTX 8 (43) 4.9 (12) 0.9 (55) 3.1 (47) 40 RA61-1110504061 16 <3.5 2.5 7.0 RA61-MTX 4 (75) <3.5 (0) 0.4 (84) 1.0 (86) 70 RA62-1110505301 10 <3.5 2.1 4.7 RA62-MTX 6 (40) <3.5 (0) 1.1 (48) 3.2 (26) 40 RA63-1110507281 68 42.0 1.8 6.0 RA63-MTX 20 (71) 33.0 (21) 1.1 (39) 4.0 (33) 30 RA64-1110511281 25 14.5 1.2 5.8 RA64-MTX 10 (60) 27.0 (0) 0.9 (25) 3.0 (48) 20 RA65-1110405273 6 <3.5 1.2 3.0 RA65-aTNF/MTX 12 (0) <3.5 (0) 0.8 (33) 4.7 (0) 0 RA66-1110502091 10 <3.5 1.9 4.2 RA66-aTNF/MTX 12 (0) 4.2 (0) 0 (100) 4.1 (2) 40 RA67-1110507261 32 11.4 1.7 4.4 RA67-aTNF/MTX 16 (50) 7.7 (32) 1.1 (35) 2.8 (36) 30 RA68-1110603141 72 4.8 1.3 4.7 RA68-aTNF 4 (94) <3.5 (100) 0.0 (100) 2.4 (49) 30 RA69-1110510181 12 9.0 3.0 4.7 RA69-aTNF/MTX 26 (0) <3.5 (100) 1.1 (63) 2.4 (49) 80 RA70-06303 26 31.9 1.3 5.8 RA70-aTNF/MTX 6 (77) 0 (100) 0.1 (92) 1.6 (73) 70 RA71-06516 80 22.8 1.8 6.5 RA71-TNF 24 (70) 7.5 (67) 0.6 (67) 3.2 (49) 30 RA72-06510 80 41.6 2.1 8.2 RA72-TNF 58 (27) 21.4 (49) 1.5 (29) 2.6 (68) 70 RA73-06309 24 39.4 1.3 6.5 RA73-TNF/MTX 8 (75) 8.5 (78) 0.6 (54) 1.9 (71) 70 RA74-06310 30 21.9 3.0 8.1 RA74-TNF 13 (57) 14.3 (35) 2.3 (23) 2.9 (64) 50 RA75-06307 64 83.4 2.6 7.0 RA75-MTX 22 (66) 11.5 (86) 0.8 (69) 2.2 (69) 70 RA76-06311 32 53.1 0.8 7.0 RA76-TNF 8 (75) 4.9 (91) 0.1 (87) 1.7 (75) 80 RA77-06513 34 <3.5 1.3 6.2 RA77-TNF/MTX 14 (59) <3.5 (0) 1.4 (0) 5.3 (15) 20 RA78-06512 33 7.4 2.4 6.7 RA78-MTX 8 (76) 4.9 (34) 3.0 (0) 8.3 (0) 0 RA79-06514 34 <3.5 1.3 8.3 RA79-TNF/MTX 6 (82) <3.5 (0) 0.9 (31) 5.4 (35) 20 RA80-1110505241 24 10.2 1.3 4.4 RA80-TNF/MTX 36 (0) <3.5 (100) 1.1 (15) 4.1 (7) 20 RA81-06305 22 29.1 0.3 6.0 RA81-MTX 20 (9) 31.3 (0) 0.1 (33) 4.1 (32) 20 RA82-05602 31 <3.5 2.1 4.0 RA82-MTX 39 (0) <3.5 (0) 2.3 (0) 6.5 (0) 0 RA83-05607 29 4.6 2.5 7.8 RA83-MTX 12 (59) 0 (100) 1.3 (52) 3.1 (60) 60 RA84-06302 30 9.6 2.5 7.4 RA84-MTX 24 ( ) <3.5 (100) 0.8 (68) 5.3 (28) 60 A = Affymetrix; R = real-time RT-PCR (validation of gene expression); P = real-time RT-PCR (validation of predictive gene); RF = rheumatoid factor;; ESR = erythrocyte sedimentation rate; CRP = C-reactive protein concentration, HAQ = Health Assessment Questionnaire; DAS28 = disease activity score (28 joints); + = positive; - = negative; n.d. = not determined; aTNF = anti-TNF monoclonal antibody therapy; MTX = methotrexate therapy
TABLE-US-00002 TABLE 2 Correlations among clinical parameters (Pearson correlation test; pre- and post-anti-TNFα treatment) r-value p-value Morning stiffness/Swollen joint count 28 0.718 0.004 Morning stiffness/Swollen joint count 68 0.664 0.010 Swollen joint count 28/Swollen joint count 68 0.990 0.000 Painful joint count 28/Painful joint count 68 0.794 0.001 ESR/CRP 0.854 0.000 ESR/VAS (physician) 0.764 0.001 ESR/DAS 28 0.813 0.000 CRP/Morning stiffness 0.733 0.003 CRP/Swollen joint count 28 0.762 0.002 CRP/Swollen joint count 68 0.728 0.003 CRP/DAS 28 0.786 0.001 DAS 28/Swollen joint count 28 0.891 0.000 DAS 28/Swollen joint count 68 0.878 0.000 DAS 28/Painful joint count 28 0.660 0.010 VAS (physician)/Swollen joint count 68 0.672 0.008 VAS (physician)/Painful joint count 28 0.697 0.006 VAS (physician)/DAS 28 0.790 0.001 Different clinical parameters showed correlations in RA patients pre- and post anti-TNFα treatment (n = 14 in all cases). ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS 28 = disease activity score (28 joints); and VAS (physician) = visual analogue score (physican's global assessment)
TABLE-US-00003 TABLE 3 Genes differentially regulated in peripheral blood monocytes of both RA patients versus normal donors and RA patients pre-versus post-anti-TNFα Increased Decreased Fold Affymetrix (%) (%) change SLR ID Gene name RA vs. ND 36711_at v-maf musculoaponeurotic fibrosarcoma 71.43 14.29 3.44 1.78 oncogene homolog F 38037_at Diphtheria toxin receptor (DTR) 71.43 10.20 2.87 1.52 201386_s_at DEAH (Asp-Glu-Ala-His) box polypeptide 15 2.04 73.47 -1.66 -0.73 201890_at Ribonucleotide reductase M2 polypeptide 81.63 8.16 4.39 2.13 202219_at Solute carrier family 6, member 8 71.43 8.16 8.44 3.08 202464_s_at 6-phosphofructo-2-kinase/fructose-2,6- 81.63 -- 2.74 1.46 biphosphatase 3 203115_at Ferrochelatase (protoporphyria) 83.67 8.16 3.87 1.95 203574_at Nuclear factor, interleukin 3 regulated 77.55 -- 2.16 1.11 203887_s_at Thrombomodulin 71.43 16.33 2.49 1.32 203932_at Major histocompatibility complex, class II, 2.04 75.51 -1.82 -0.87 DM beta 204131_s_at Forkhead box O3A 77.55 4.08 2.21 1.14 204419_x_at Hemoglobin, gamma A, gamma G 75.51 6.12 2.88 1.52 204467_s_at Synuclein, alpha (non A4 component of 71.43 4.08 3.60 1.85 amyloid precursor) 204848_x_at Hemoglobin, gamma A 75.51 6.12 3.83 1.94 205239_at Amphiregulin (schwannoma-derived growth 81.63 4.08 6.13 2.62 factor) 205571_at Lipoyltransferase 1 -- 79.59 -1.90 -0.93 205592_at Solute carrier family 4, anion exchanger, 77.55 10.20 4.83 2.27 member 1 205863_at S100 calcium binding protein A12 71.43 4.08 1.69 0.76 (calgranulin C) 205900_at Keratin 1 (epidermolytic hyperkeratosis) 75.51 6.12 4.03 2.01 205950_s_at Carbonic anhydrase I 81.63 4.08 5.88 2.56 205987_at CD1C antigen, c polypeptide -- 87.76 -2.93 -1.55 206025_s_at Tumor necrosis factor, alpha-induced protein 6 71.43 -- 3.85 1.94 206111_at Ribonuclease, RNase A family, 2 73.47 -- 1.95 0.97 206834_at Hemoglobin, delta 83.67 10.20 4.08 2.03 207332_s_at Transferrin receptor (p90, CD71) 81.63 2.04 2.35 1.23 208632_at Ring finger protein 10 71.43 6.12 2.06 1.04 209007_s_at Chromosome 1 open reading frame 63 4.08 73.47 -2.14 -1.10 209458_x_at Hemoglobin, alpha 1, alpha 2 85.71 2.04 3.00 1.59 209795_at CD69 antigen (p60, early T-cell activation 71.43 12.24 2.95 1.56 antigen 210027_s_at APEX nuclease (multifunctional DNA repair -- 75.51 -1.93 -0.94 enzyme) 1 210254_at Membrane-spanning 4-domains, subfamily A, 73.47 16.33 3.41 1.77 member 3 210338_s_at Heat shock 70 kDa protein 8 6.12 71.43 -2.09 -1.06 211038_s_at Hypothetical protein MGC12760 -- 71.43 -2.07 -1.05 211458_s_at GABA(A) receptor-associated protein like 1, 71.43 -- 1.95 0.96 like 3 211560_s_at Aminolevulinate, delta-, synthase 2 87.76 4.08 24.35 4.61 211991_s_at Major histocompatibility complex, class II, DP 4.08 79.59 -3.01 -1.59 alpha 1 212199_at Morf4 family associated protein 1-like 1 2.04 75.51 -1.94 -0.96 212224_at Aldehyde dehydrogenase 1 family, member A1 4.08 75.51 -2.56 -1.36 212232_at Formin binding protein 4 -- 77.55 -1.83 -0.87 212534_at Zinc finger protein 24 (KOX 17) 6.12 71.43 -1.49 -0.58 213142_x_at Hypothetical protein LOC54103 4.08 73.47 -1.77 -0.82 214433_s_at Selenium binding protein 1 71.43 10.20 4.59 2.20 215933_s_at Hematopoietically expressed homeobox -- 75.51 -1.83 -0.87 217478_s_at Major histocompatibility complex, class II, 4.08 73.47 -2.02 -1.01 DM alpha 217736_s_at Eukaryotic translation initiation factor 2-alpha 75.51 -- 1.97 0.98 kinase 1 219069_at Ankyrin repeat domain 49 -- 73.47 -1.59 -0.67 219093_at Hypothetical protein FLJ20701 -- 85.71 -3.32 -1.73 219228_at Zinc finger protein 331 77.55 8.16 3.94 1.98 219607_s_at Membrane-spanning 4-domains, subfamily A, 91.84 -- 2.96 1.57 member 4 221748_s_at Tensin 1 81.63 4.08 4.29 2.10 221766_s_at Family with sequence similarity 46, member A -- 71.43 -1.71 -0.77 Increased Decreased Fold Increased Decreased Fold Affymetrix (%) (%) change SLR (%) (%) change SLR ID RA-aTNF vs. RA (all) RA-aTNF vs. RA (responder) 36711_at 28.57 61.22 -2.78 -1.48 12.00 80.00 -5.88 -2.56 38037_at 12.24 73.47 -2.59 -1.37 -- 84.00 -3.70 -1.89 201386_s_at 44.90 14.29 1.43 0.51 60.00 -- 1.81 0.85 201890_at 2.04 69.39 -3.86 -1.95 4.00 64.00 -3.88 -1.96 202219_at 12.24 59.18 -5.17 -2.37 4.00 72.00 -6.96 -2.80 202464_s_at 12.24 69.39 -2.18 -1.12 -- 84.00 -3.01 -1.59 203115_at 20.41 63.27 -2.18 -1.12 16.00 72.00 -2.25 -1.17 203574_at 10.20 53.06 -1.54 -0.62 -- 76.00 -2.06 -1.04 203887_s_at 12.24 65.31 -2.34 -1.23 -- 76.00 -3.14 -1.65 203932_at 63.27 4.08 1.64 0.71 84.00 -- 1.68 0.75 204131_s_at 18.37 55.10 -1.42 -0.50 4.00 64.00 -1.41 -0.50 204419_x_at 14.29 75.51 -3.18 -1.67 8.00 92.00 -4.16 -2.04 204467_s_at 24.49 65.31 -2.26 -1.18 16.00 80.00 -2.93 -1.55 204848_x_at 16.33 65.31 -3.22 -1.69 4.00 80.00 -4.63 -2.21 205239_at 20.41 71.43 -3.36 -1.75 -- 96.00 -5.91 -2.56 205571_at 51.02 12.24 1.35 0.44 72.00 -- 1.61 0.69 205592_at 16.33 65.31 -3.81 -1.93 8.00 76.00 -5.63 -2.49 205863_at 14.29 55.10 -1.49 -0.58 8.00 56.00 -1.56 -0.64 205900_at 20.41 67.35 -2.31 -1.21 16.00 84.00 -3.18 -1.67 205950_s_at 22.45 67.35 -2.87 -1.52 16.00 84.00 -4.14 -2.05 205987_at 63.27 2.04 1.72 0.79 68.00 -- 1.72 0.78 206025_s_at 12.24 59.18 -1.97 -0.98 4.00 72.00 -2.74 -1.46 206111_at 8.16 67.35 -1.59 -0.67 -- 72.00 -1.68 -0.75 206834_at 20.41 65.31 -3.13 -1.64 16.00 80.00 -4.59 -2.20 207332_s_at 2.04 79.59 -2.45 -1.29 -- 84.00 -2.57 -1.36 208632_at 12.24 59.18 -1.71 -0.78 4.00 68.00 -1.69 -0.76 209007_s_at 57.14 14.29 1.54 0.62 76.00 4.00 1.87 0.90 209458_x_at 8.16 63.27 -2.09 -1.06 4.00 76.00 -2.60 -1.38 209795_at 14.29 75.51 -3.18 -1.67 16.00 76.00 -3.77 -1.92 210027_s_at 67.35 10.20 1.64 0.72 84.00 -- 2.02 1.02 210254_at 14.29 79.59 -4.56 -2.19 20.00 76.00 -3.69 -1.88 210338_s_at 55.10 18.37 1.57 0.66 68.00 4.00 2.04 1.03 211038_s_at 42.86 16.33 1.29 0.37 56.00 4.00 1.46 0.55 211458_s_at 16.33 65.31 -1.92 -0.94 -- 84.00 -2.75 -1.46 211560_s_at 16.33 75.51 -10.81 -3.43 8.00 80.00 -20.53 -4.36 211991_s_at 75.51 8.16 2.37 1.24 80.00 4.00 2.54 1.34 212199_at 59.18 10.20 1.56 0.64 80.00 -- 2.11 1.08 212224_at 71.43 12.24 2.28 1.19 92.00 -- 2.74 1.45 212232_at 48.98 14.29 1.27 0.35 72.00 -- 1.57 0.65 212534_at 53.06 4.08 1.35 0.43 76.00 -- 1.45 0.53 213142_x_at 51.02 12.24 1.25 0.32 72.00 -- 1.51 0.60 214433_s_at 18.37 65.31 -3.08 -1.62 12.00 68.00 -3.55 -1.83 215933_s_at 55.10 6.12 1.51 0.59 76.00 0.00 1.85 0.88 217478_s_at 61.22 12.24 1.68 0.75 64.00 8.00 1.85 0.88 217736_s_at 14.29 51.02 -1.46 -0.54 8.00 60.00 -1.41 -0.50 219069_at 57.14 12.24 1.30 0.38 84.00 -- 1.58 0.66 219093_at 71.43 8.16 2.43 1.28 84.00 -- 2.59 1.37 219228_at 10.20 71.43 -3.26 -1.70 12.00 80.00 -4.62 -2.21 219607_s_at 6.12 73.47 -1.95 -0.96 -- 80.00 -2.06 -1.04 221748_s_at 24.49 65.31 -2.12 -1.08 16.00 80.00 -2.42 -1.28 221766_s_at 53.06 10.20 1.30 0.38 80.00 -- 1.66 0.73 The table presents the percentage of pairwise comparisons between the respective groups showing an increase or decrease for the fold-change/Signal Log Ratio (SLR; 51 candidate genes were selected); n = 7 each for the comparisons RA vs. ND and RA-αTNF vs. RA (all); n = 5 for the comparison RA-αTNF vs. RA (responder). The pairwise comparison RA-αTNF vs. RA (all) is shown in the central 4 columns to assess the effect of treatment on differential gene expression in all TNFα-treated RA patients. RA = rheumatoid arthritis (pre-anti-TNFα treatment); ND = normal donor; RA-αTNF = rheumatoid arthritis (post-anti-TNFα treatment)
TABLE-US-00004 TABLE 4 Genes differentially regulated in peripheral blood monocytes of both RA patients versus normal donors and RA patients pre-versus post-anti-TNFα therapy (PAM analysis) Affymetrix ID Gene title RA score 221622_s_at Uncharacterized hypothalamus protein HT007 0.7405 218845_at Dual specificity phosphatase 22 0.6694 200786_at Proteasome (prosome, macropain) subunit, beta type, 7 0.5297 219607_s_at Membrane-spanning 4-domains, subfamily A, member 4 0.4449 212886_at DKFZP434C171 protein 0.2690 201407_s_at Protein phosphatase 1, catalytic subunit, beta isoform 0.2653 212266_s_at Splicing factor, arginine/serine-rich 5 0.1771 53912_at Sorting nexin 11 0.1277 200090_at Farnesyltransferase, CAAX box, alpha 0.1167 218025_s_at Peroxisomal D3,D2-enoyl-CoA isomerase 0.1032 204232_at Fc fragment of IgE, high affinity I, receptor for; gamma polypeptide 0.0993 201722_s_at UDP-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 1 0.0942 218627_at Hypothetical protein FLJ11259 0.0841 210027_s_at APEX nuclease (multifunctional DNA repair enzyme) 1 0.0817 202322_s_at Geranylgeranyl diphosphate synthase 1 0.0646 221689_s_at Down syndrome critical region gene 5 0.0549 203356_at Calpain 7 0.0535 211991_s_at Major histocompatibility complex, class II, DP alpha 1 0.0515 218462_at Brix domain containing 5 0.0378 218123_at Chromosome 21 open reading frame 59 0.0173 214329_x_at Tumor necrosis factor (ligand) superfamily, member 10 -0.0025 219067_s_at Chromosome 10 open reading frame 86 -0.0046 205789_at CD1D antigen, d polypeptide -0.0104 209214_s_at Ewing sarcoma breakpoint region 1 -0.0111 213427_at Ribonuclease P 40 kDa subunit -0.0471 209422_at/206567_s_at PHD finger protein 20 -0.0480/-0.0698 201010_s_at Thioredoxin interacting protein -0.0520 200883_at Ubiquinol-cytochrome c reductase core protein II -0.0521 218454_at Hypothetical protein FLJ22662 -0.0544 202918_s_at Preimplantation protein 3 -0.0574 212204_at DKFZP564G2022 protein -0.0698 219452_at Dipeptidase 2 -0.0800 209458_x_at Hemoglobin, alpha 1, alpha 2 -0.0809 219889_at Frequently rearranged in advanced T-cell lymphomas -0.0832 201303_at DEAD (Asp-Glu-Ala-Asp) box polypeptide 48 -0.0836 202510_s_at Tumor necrosis factor, alpha-induced protein 2 -0.0872 221923_s_at Nucleophosmin (nucleolar phosphoprotein B23, numatrin) -0.0902 201887_at Interleukin 13 receptor, alpha 1 -0.1075 211582_x_at Leukocyte specific transcript 1, LST1 -0.1193 219030_at CGI-121 protein -0.1259 212706_at RAS p21 protein activator 4/hypothetical protein FLJ21767 -0.1393 202902_s_at Cathepsin S -0.1644 200663_at CD63 antigen (melanoma 1 antigen) -0.1764 202138_x_at/209971_x_at JTV1 gene -0.1950/-0.2868 200851_s_at KIAA0174 -0.2019 201109_s_at Thrombospondin 1 -0.2079 213142_x_at Hypothetical protein LOC54103 -0.2285 202531_at Interferon regulatory factor 1 -0.2904 216274_s_at SEC11-like 1 (S. cerevisiae) -0.6951 Positive RA scores indicate genes overexpressed in RA, negative RA scores indicate those underexpressed in RA. PAM = Prediction analysis of microarrays; bold and underlined letters indicate genes overlapping with the 51 genes identified by Affymetrix ® gene expression profiling and analysis (see Table 3).
TABLE-US-00005 TABLE 5 Genes differentially regulated in RA-anti-TNFα responders versus RA-anti-TNFα non-responders (post anti-TNFα therapy) In- De- creased creased Fold Affymetrix ID (%) (%) Gene title change SLR 200041_s_at 100 0 HLA-B associated transcript-1 (D6S81E) 2.53 1.34 200052_s_at 100 0 Interleukin enhancer binding factor 2, 45 kD (ILF2) 3.73 1.90 200064_at 100 0 Isolate Liv chaperone protein HSP90 beta (HSP90BETA) mRNA 2.66 1.41 200079_s_at 100 0 Lysyl-tRNA synthetase mRNA, complete cds; nuclear gene for mitochondrial product; 2.16 1.11 alternatively spliced 200629_at 100 0 Tryptophanyl-tRNA synthetase (WARS) 2.14 1.10 200634_at 100 0 Profilin 1 (PFN1), mRNA 2.16 1.11 200802_at 100 0 Seryl-tRNA synthetase (SARS) 2.20 1.14 200860_s_at 100 0 Similar to KIAA1007 protein, clone MGC: 692, mRNA, complete cds 2.11 1.08 200983_x_at 0 100 CD59 antigen p18-20 (antigen identified by monoclonal antibodies 16.3A5, EJ16, EJ30, -2.43 -1.28 EL32 and G344) 200991_s_at 100 0 Homo sapiens KIAA0064 gene product (KIAA0064), mRNA 2.71 1.44 201112_s_at 100 0 Chromosome segregation 1 (yeast homolog)-like (CSE1L), mRNA 2.01 1.01 201214_s_at 100 0 Protein phosphatase 1, regulatory subunit 7 (PPP1R7), mRNA 2.17 1.12 201241_at 100 0 DEADH (Asp-Glu-Ala-AspHis) box polypeptide 1 (DDX1), mRNA 2.30 1.20 201263_at 100 0 Threonyl-tRNA synthetase (TARS), mRNA 2.14 1.10 201386_s_at 100 0 Dead box protein 15 mRNA, complete cds 2.22 1.15 201417_at 100 0 SRY (sex determining region Y)-box 4 /DEF = Human DNA sequence from 3.18 1.67 clone RP3-322L4 on chromosome 6 201576_s_at 100 0 Galactosidase, beta 1 (GLB1), mRNA 2.00 1.00 201872_s_at 100 0 ATP-binding cassette, sub-family E (OABP), member 1 2.28 1.19 201892_s_at 100 0 NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 6 (14 kD, B14) (NDUFA6), mRNA 2.19 1.13 202174_s_at 100 0 Pericentriolar material 1 (PCM1), mRNA 2.08 1.06 202176_at 100 0 Excision repair cross-complementing rodent repair deficiency, complementation 2.93 1.55 group 3 (ERCC3), mRNA 202220_at 100 0 KIAA0907 protein (KIAA0907), mRNA 2.39 1.26 202225_at 100 0 v-crk avian sarcoma virus CT10 oncogene homolog 2.10 1.07 202464_s_at 0 100 6-phosphofructo-2-kinasefructose-2,6-biphosphatase 3 (PFKFB3), mRNA. /PROD = 6- -3.25 -1.70 phosphofructo-2-kinase-fructose-2,6-biphosphatase 3 202545_at 100 0 KIAA0766 gene product (KIAA0766), mRNA 1.38 0.46 202838_at 100 0 N-acetylgalactosaminidase, alpha-(NAGA), mRNA 1.82 0.86 202896_s_at 0 100 Protein tyrosine phosphatase, non-receptor type substrate 1 (PTPNS1), mRNA -2.00 -1.00 202950_at 100 0 Crystallin, zeta (quinone reductase) (CRYZ), mRNA 2.51 1.33 203037_s_at 100 0 KIAA0429 gene product (KIAA0429), mRNA 2.41 1.27 203155_at 100 0 SET domain, bifurcated 1 (SETDB1), mRNA 4.23 2.08 203371_s_at 0 100 NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 3 (12 kD, B12) (NDUFB3), mRNA -2.13 -1.09 203821_at 0 100 Diphtheria toxin receptor (DTR) -3.63 -1.86 203887_s_at 0 100 Thrombomodulin (THBD), mRNA -2.75 -1.46 203966_s_at 0 100 Protein phosphatase 1A (formerly 2C), magnesium-dependent, alpha isoform -2.73 -1.45 (PPM1A), mRNA 204192_at 100 0 CD37 antigen (CD37), mRNA 3.66 1.87 204419_x_at 0 100 Hemoglobin, gamma G (HBG2), mRNA -5.50 -2.46 204566_at 100 0 Protein phosphatase 1D magnesium-dependent, delta isoform (PPM1D), mRNA 2.00 1.00 204689_at 100 0 Hematopoietically expressed homeobox (HHEX), mRNA 2.04 1.03 205239_at 0 100 Amphiregulin (schwannoma-derived growth factor) (AREG), mRNA -3.38 -1.04 205249_at 0 100 Early growth response 2 (Krox-20 (Drosophila) homolog) (EGR2), mRNA -2.55 -1.35 205552_s_at 100 0 2,5-oligoadenylate synthetase 1 (40-46 kD) (OAS1), transcript variant E16, mRNA 2.08 1.06 206115_at 0 100 Early growth response 3 (EGR3), mRNA. /PROD = early growth response 3 -6.54 -2.71 206584_at 0 100 Homo sapiens MD-2 protein (MD-2), mRNA -2.16 -1.11 206877_at 0 100 Homo sapiens MAX dimerization protein (MAD), mRNA -3.92 -1.97 207170_s_at 100 0 DKFZP586A011 protein (DKFZP586A011), mRNA 2.20 1.14 208631_s_at 100 0 78 kDa gastrin-binding protein mRNA, complete cds 2.04 1.03 208691_at 0 100 Transferrin receptor (p90, CD71), clone MGC: 3151, mRNA, complete cds -2.30 -1.20 208868_s_at 0 100 Homo sapiens mRNA; cDNA DKFZp564N1272 (from clone DKFZp564N1272); -3.18 -1.67 complete cds 208869_s_at 0 100 GABA-A receptor-associated protein like 1 (GABARAPL1) mRNA, complete cds -3.29 -1.72 208942_s_at 0 100 Translocation protein 1 -2.93 -1.55 209092_s_at 100 0 Homo sapiens clone 016b03 My027 protein mRNA, complete cds 2.07 1.05 209193_at 0 100 Protein kinase-related oncogene (PIM1) mRNA, complete cds -2.51 -1.33 209200_at 100 0 MADS box transcription enhancer factor 2, polypeptide C (myocyte enhancer factor 2C) 2.48 1.31 209861_s_at 100 0 eIF-2-associated p67 homolog mRNA, complete cds 2.55 1.35 209967_s_at 0 100 Human mRNA for hCREM (cyclic AMP-responsive element modulator) type 2 protein, -3.07 -1.62 complete cds 210027_s_at 100 0 Apurinic endonuclease (APE) mRNA, complete cds. /PROD = apurinic endonuclease 2.23 1.16 210053_at 100 0 TATA box binding protein (TBP)-associated factor, RNA polymerase II, D, 100 kD 2.23 1.16 210172_at 0 100 Human mRNA for ZFM1 protein alternatively spliced product, complete cds. /PROD = ZFM1 -2.16 -1.11 protein, alternatively spliced product 210766_s_at 100 0 Trachea cellular apoptosis susceptibility protein (CSE1) mRNA, complete cds 2.28 1.19 210949_s_at 100 0 Similar to eukaryotic translation initiation factor 3, subunit 8 (110 kD), clone MGC: 2.53 1.34 8693, mRNA, complete cds 211458_s_at 0 100 GABA-A receptor-associated protein mRNA, complete cds. /PROD = GABA-A -3.18 -1.67 receptor-associated protein 211546_x_at 0 100 Human (clone 2-5) synuclein (NACP) mRNA, complete cds -4.92 -2.30 212199_at 100 0 Human putative ribosomal protein S1 mRNA 2.22 1.15 212224_at 100 0 Aldehyde dehydrogenase 1, soluble (ALDH1), mRNA. /PROD = aldehyde dehydrogenase 3.18 1.67 1, soluble 212388_at 100 0 Homo sapiens mRNA for KIAA1057 protein, partial cds 3.10 1.63 212591_at 100 0 RBP1-like protein 2.03 1.02 212696_s_at 100 0 Ring finger protein 4 3.05 1.61 212709_at 100 0 KIAA0197 protein 2.10 1.07 212714_at 100 0 Homo sapiens mRNA; cDNA DKFZp586F1323 (from clone DKFZp586F1323) 2.13 1.09 212893_at 100 0 Homo sapiens mRNA; cDNA DKFZp564I052 (from clone DKFZp564I052) 2.01 1.01 212989_at 100 0 Homo sapiens mRNA for Hmob33 protein, 3 untranslated region 2.25 1.17 213410_at 100 0 Homo sapiens mRNA; cDNA DKFZp586F1019 (from clone DKFZp586F1019); partial cds 2.53 1.34 213515_x_at 0 100 Myosin, light polypeptide 4, alkali; atrial, embryonic -4.69 -2.23 213528_at 100 0 H. sapiens novel gene from PAC 117P20, chromosome 1 2.87 1.52 213604_at 100 0 Homo sapiens clone 24582 mRNA sequence 2.07 1.05 213619_at 0 100 Heterogeneous nuclear ribonucleoprotein H1 (H) -2.48 -1.31 213655_at 0 100 Tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, -3.03 -1.60 epsilon polypeptide 213743_at 100 0 Cyclin T2 2.08 1.06 213788_s_at 0 100 cDNA: FLJ23227 fis, clone CAE00645, highly similar to AF052138 -2.20 -1.14 213872_at 0 100 Hypothetical protein FLJ12619 -4.29 -2.1 213979_s_at 0 100 C-terminal binding protein 1 -4.41 -2.14 214257_s_at 0 100 SEC22, vesicle trafficking protein (S. cerevisiae)-like 1 -2.97 -1.57 214414_x_at 0 100 Hemoglobin, alpha 1 -2.04 -1.03 214696_at 0 100 Homo sapiens clone 24659 mRNA sequence /DEF = Homo sapiens clone 24659 -2.93 -1.55 mRNA sequence 214933_at 0 100 Calcium channel, voltage-dependent, PQ type, alpha 1A subunit -2.17 -1.12 215043_s_at 0 100 H. sapiens SMA5 mRNA -4.08 -2.03 215933_s_at 100 0 H. sapiens HEX gene encoding homeobox related protein 2.17 1.12 216199_s_at 100 0 Mitogen-activated protein kinase kinase kinase 4 2.77 1.47 216202_s_at 100 0 Serine palmitoyltransferase (LCB2) mRNA, partial cds 2.75 1.46 216996_s_at 100 0 KIAA0971 protein /DEF = Homo sapiens cDNA FLJ11495 fis, clone HEMBA1001950, 2.20 1.14 highly similar to Homo sapiens mRNA for KIAA0971 protein 217554_at 0 100 ESTs, Hs.97109 -3.63 -1.86 217682_at 0 100 ESTs, Weakly similar to ALU7_HUMAN ALU -3.01 -1.59 217840_at 100 0 DEAD-box protein abstrakt (ABS), mRNA 2.39 1.26 218229_s_at 100 0 KIAA1513 protein (KIAA1513), mRNA 2.07 1.05 218356_at 100 0 Cell division protein FtsJ (FJH1), mRNA 2.20 1.14 218432_at 100 0 F-box only protein 3 (FBXO3), mRNA 2.16 1.11 218589_at 100 0 Purinergic receptor (family A group 5) (P2Y5), mRNA 2.68 1.42 218604_at 100 0 Integral inner nuclear membrane protein (MAN1), mRNA 2.04 1.03 218689_at 100 0 Fanconi anemia, complementation group F (FANCF), mRNA 8.94 3.16 218889_at 100 0 Hypothetical protein FLJ12820 (FLJ12820), mRNA 2.01 1.01 218973_at 100 0 Hypothetical protein FLJ13119 (FLJ13119), mRNA 2.07 1.05 219069_at 100 0 Hypothetical protein FLJ20189 (FLJ20189), mRNA 2.23 1.16 219093_at 100 0 Hypothetical protein FLJ20701 (FLJ20701), mRNA 3.32 1.73 219099_at 100 0 Homo sapiens chromosome 12 open reading frame 5 (C12ORF5), mRNA 2.13 1.09 219176_at 100 0 Hypothetical protein FLJ22555 (FLJ22555), mRNA 2.13 1.09 219243_at 100 0 Hypothetical protein FLJ11110 (FLJ11110), mRNA 2.07 1.05 219363_s_at 100 0 CGI-12 protein (LOC51001), mRNA 2.31 1.21 219434_at 0 100 Triggering receptor expressed on myeloid cells 1 (TREM1), mRNA -4.35 -2.12 221485_at 0 100 betaGlcNAc beta 1,4-galactosyltransferase. polypeptide 5 -2.71 -1.44 221652_s_at 100 0 PNAS-25 mRNA, complete cds. 2.55 1.35 221755_at 100 0 Homo sapiens mRNA for FLJ00043 protein, partial cds 3.44 1.09 221970_s_at 100 0 Homo sapiens cDNA: FLJ21737 fis, clone COLF3396 2.41 1.27 222127_s_at 0.1 0 Homo sapiens cDNA FLJ13399 fis, clone PLACE1001395 /DEF = Homo sapiens cDNA 2.31 1.21 FLJ13399 fis, clone PLACE1001395 36711_at 0 100 Novel MAFF (v-maf musculoaponeurotic fibrosarcoma (avian) oncogene family, protein F) -3.54 -1.16 LIKE protein 38037_at 0 100 Heparin-binding EGF-like growth factor mRNA, complete cds -3.63 -1.86 AFFX-BioB-M_at 0 100 E. coli 7,8-diamino-pelargonic acid (bioA), biotin synthetase (bioB), 7-keto-8-amino- -4.69 -2.58 pelargonic acid synthetase (bioF), bioC protein, and dethiobiotin synthetase (bioD), complete cds AFFX-r2-Ec-bioC- 0 100 Escherichia coli /REF = J04423 /DEF = E coli bioC protein corresponding to -4.22 -1.86 3_at nucleotides 4609-4883 of J04423 /LEN = 777 (-5 and -3 represent transcript regions 5 prime and 3 prime respectively) The listed genes (n = 117) show differential expression in 100% of the pairwise comparisons; bold and underlined letters indicate genes overlapping with the 51 genes identified by Affymetrix ® gene expression profiling and analysis (see Table 3)
TABLE-US-00006 TABLE 6 Correlations between clinical parameters and differentially expressed genes (Pearson correlation test; pre- and post-anti-TNFα treatment; n = 7 for all; bold letters identify genes occurring twice, bold and italics letters identify genes occurring ≧3 times) Affymetrix_ID Gene title r-value p-value Pre-anti-TNFα treatment Leuko/ 202219_at Solute carrier family 6 0.901 0.006** 205239_at Amphiregulin 0.879 0.009** Thromb/ 205900_at Keratin 1 0.923 0.003** Mono/ 204018_x_at Hemoglobin, alpha 1 -0.908 0.005** GPT/ 203932_at MHC-II, DM beta -0.912 0.004** 218589_s_at Purinergic receptor P2Y, G-protein coupled 5 -0.919 0.003** Hb/ 205900_at Keratin 1 -0.944 0.001** MoStiff/ 202219_at Solute carrier family 6 0.893 0.007** 203932_at MHC-II, DM beta -0.898 0.006** 204131_s_at Forkhead box O3A 0.917 0.004** 205239_at Amphiregulin 0.954 0.001** 207332_s_at Transferrin receptor (p90, CD71) 0.926 0.003** 208632_at Ring finger protein 10 0.913 0.004** DisDur/ 212232_at Formin binding protein 4 0.955 0.001** 213142_x_at Hypothetical protein LOC54103 0.877 0.009** Post-anti-TNFα treatment ESR/ 219228_at Zinc finger protein 331 0.894 0.007** CRP/ Thromb/ Granulo/ 213427_at Ribonuclease P 40 kDa subunit -0.875 0.010** Hb/ factor 203932_at MHC class II, DM beta 0.885 0.008** Dis_act/ 36711_at v-maf fibrosarc. oncogene homolog F (avian) 0.932 0.002** 205552_s_at 2',5'-oligoadenylate synthetase 1, 40/46 kDa -0.951 0.001** DAS28/ 36711 v-maf fibrosarc. oncogene homolog F (avian) 0.940 0.002** 205552_s_at 2',5'-oligoadenylate synthetase 1, 40/46 kDa -0.898 0.006** Sw28/ 219607_s_at Membrane-spanning 4-domains, subfam. A, memb. 4 0.931 0.002** GPT = glutamate pyruvic transferase; Hb = haemoglobin; MoStiff = Morning stiffness (minutes); DisDur = Disease duration (years); ESR = erythrocyte sedimentation rate; CRP = C-reactive protein; DAS 28 = disease activity score (28 joints); Sw = number of swollen joints (28 joints)
TABLE-US-00007 TABLE 7 TaqMan PCR validation in anti-TNFα-treated RA patients and normal donors PCR RA-αTNF (responder) Time Gene versus ND Max -ΔRQ p value point Description Gene title Applera ID (RQ; Means ± SEM) (Therapy) (U-Test) Validated genes BL AREG Amphiregulin Hs00155832_m1 10.23 ± 2.93 -7.60 0.000 BL CA-1 Carbonic anhydrase 1 Hs00266139_m1 6.83 ± 3.49 -5.93 n.s. BL CLC Charcot-Leyden crystal protein Hs00171342_m1 5.36 ± 4.82 -3.26 0.041 BL CLU Clusterin C Hs00156548_m1 3.94 ± 2.87 -2.77 n.s. BL TNFAIP6 Tumor necrosis factor alpha Hs00218482_m1 1.71 ± 0.40 0.82 0.000 induced protein 6 BL THBD Thrombomodulin Hs00264920_s1 1.58 ± 1.08 -0.53 0.041 BL MS4A4A Membrane-spanning 4-domains, Hs00254770_m1 1.54 ± 0.42 0.71 0.041 subfamily A, member 4 BL DTR Diptheria toxin receptor Hs00181813_m1 1.21 ± 0.44 -1.10 n.s. BL S100A12 S100 calcium binding protein A1 Hs00194525_m1 1.07 ± 0.21 0.11 0.041 BL HT007 Uncharacterized hypothalamus Hs00218482_m1 0.51 ± -0.09 0.01 0.000 protein HT007 BL HLA-DR MHC-class-II; HLA-DR alpha Hs00219578_m1 0.59 ± -0.15 0.09 0.000 BL LOC54103 Hypothetical protein LOC54103 Hs00367929_m1 0.90 ± -0.21 -0.24 0.041 BL TNF Tumor necrosis factor alpha Hs00174128_m1 1.22 ± 0.53 -0.84 0.041 BL IL1B Interleukin 1 beta Hs00174097_m1 1.14 ± 0.42 -0.28 0.041 BL PSMB7 Proteasome subunit beta type 7 Hs00160607_m1 0.72 ± -0.19 0.16 0.041 precursor BL KIAA0174 Protein KIAA0174 Hs00796085_sh 0.89 ± 0.30 0.08 0.041 BL SPC18 Microsomal signal peptidase Hs00819308_m1 0.96 ± 0.11 -0.25 0.041 18 kDa subunit Discrepancies between Affymetrix and TaqMan PCR BL LIPT1 Lipoyltransferase 1 Hs00376962_m1 2.17 ± 0.54 -0.68 0.000 BL ZNF361 Ring zinc finger protein 361 Hs00367929_m1 0.55 ± -0.11 -0.14 0.000 BL THBS1 Thrombospondin-1 Hs00170236_m1 0.88 ± 0.25 -0.34 n.s. BL IRF1 Interferon regulatory protein 1 Hs00233698_m1 4.95 ± 0.18 3.37 0.000 BL PPP1CB Protein phosphatase 1, catalytic Hs00160349_m1 0.93 ± 0.09 -0.28 0.041 subunit, beta isoform Affymetrix RA-αTNF FC RA-αTNF FC RA-αTNF (responder) (responder) RA-αTNF all all Time Affymetrix versus ND versus ND versus ND versus ND point ID (% of comp.) (Means) (% of comp.) (Means) Validated genes BL 205239_at 82.86 5.48 81.63 6.13 BL 205950_s_at 88.57 4.92 81.63 5.88 BL 206207_at 62.86 2.46 73.47 3.97 BL 222043_at 68.57 2.57 75.51 2.68 BL 206026_s_at 62.86 2.07 73.27 2.24 BL 203887_s_at 74.29 2.64 71.43 2.49 BL 219607_s_at 88.57 2.66 91.84 2.96 BL 38037_at 68.57 2.91 71.43 2.87 BL 205863_at 62.86 1.50 71.43 1.69 BL 221622_s_at -88.57 -1.74 -85.71 -1.66 BL 208894_at -65.71 -1.77 -75.51 -2.15 BL 222150_s_at -80.00 -1.84 -73.47 -1.71 BL 207113_s_at 34.29 1.03 -46.94 -1.28 BL 205067_at 57.14 1.62 57.02 1.44 BL 200786_at -54.29 -1.27 -57.74 -1.27 BL 200851_s_at -42.86 -1.17 -46.94 -1.23 BL 201290_at -17.14 -1.04 -72.24 -1.03 Discrepancies between Affymetrix and TaqMan PCR BL 205571_at -74.29 -1.74 -79.59 -1.90 BL 219228_at 77.14 4.19 77.55 3.94 BL 201110_s_at 85.71 16.35 77.55 12.60 BL 202531_at -40.00 -1.30 -55.70 -1.44 BL 201409_s_at 60.00 1.63 57.14 1.69 Validation of 22 selected genes from Affymetrix ® gene expression profiling by Taqman real-time RT-PCR (10 anti-TNFα-treated RA patients prior to therapy; 14 normal donors - ND); genes differentially expressed (decreased: <-70%; increased: >70%) in RA versus ND according to the Affymetrix ® analysis are shown in normal type, equally-expressed genes are displayed in italics; RQ = relative quantity; FC = fold-change; BL = baseline (pre-antiTNFα therapy)
TABLE-US-00008 TABLE 8 Correlations between TaqMan PCR results and the ACR response in anti-TNFα-treated RA patients Gene Time description point Gene title Applera ID r-value p n CA1 w 12 Carbonic anhydrase 1 Hs00266139_m1 0.642 0.045 10 CA1 w 26 0.962 0.000 9 CLC w 4 Charcot-Leyden crystal protein Hs00171342_m1 0.766 0.027 8 THBD w 4 Thrombomodulin Hs00264920_s1 0.766 0.027 8 THBS1 w 26 Thrombospondin 1 Hs00170236_m1 -0.710 0.032 9 IRF1 w 4 Interferon regulatory factor 1 Hs00233698 m1 0.778 0.023 8
TABLE-US-00009 TABLE 9 Genes differentially regulated in RA-anti-TNFα responders versus RA-anti-TNFα non-responders (pre-anti-TNFα therapy; predictive genes) Increased Decreased Fold- Affymetrix ID Gene title (%) (%) Change SLR 39248_at Aquaporin 3 10 80 -4.6 -2.19 200061_s_at Similar to ribosomal protein S24, clone MGC: 8595 0 80 -1.39 -0.47 200087_s_at Transmembrane emp24 domain trafficking protein 2 0 80 -1.6 -0.63 200642_at Superoxide dismutase 1, soluble (amyotrophic lateral sclerosis 1 0 80 -1.8 -0.84 200655_s_at Calmodulin 1 (phosphorylase kinase, delta) 0 80 -1.5 -0.59 200745_s_at Guanine nucleotide binding protein (G protein), beta polypeptide 1 80 0 1.6 0.66 200772_x_at Prothymosin, alpha (gene sequence 28) 80 0 1.7 0.75 201193_at Homo sapiens isocitrate dehydrogenase 1 (NADP+) soluble (IDH1) 0 80 -1.4 -0.49 201690_s_at Tumor protein D52 0 80 -3.3 -1.73 201693_s_at Early growth response 1 80 0 3.1 1.61 201889_at 0 -1.7 -0.74 202110_at Cytochrome c oxidase subunit VIIb 0 80 -1.6 -0.64 202157_s_at CUG triplet repeat, RNA binding protein 2 0 80 -1.6 -0.64 202233_s_at Ubiquinol-cytochrome c reductase hinge protein 0 80 -1.7 -0.74 202378_s_at Homos spaiens leptin receptor gene-related protein (HS0BRGRP) 80 20 1.15 0.20 202664_at Wiskott-Aldrich syndrome protein interacting protein 80 0 1.9 0.91 202910_s_at CD97 antigen 80 10 1.6 0.70 202922_at Glutamate-cysteine ligase, catalytic subunit 0 80 -2.3 -1.17 202950_at Crystallin, zeta (quinone reductase) 80 0 2.2 1.16 203097_s_at Rap guanine nucleotide exchange factor (GEF) 2 20 80 -1.3 -0.38 203231_s_at Ataxin 1 0 80 -8.2 -3.03 203300_x_at Adaptor-related protein complex 1, sigma 2 subunit 80 20 1.9 0.89 204160_s_at Ectonucleotide pyrophosphatase/phosphodiesterase 4 10 80 -2.4 -1.27 204750_s_at Desmocollin 2 80 0 12.9 3.69 204777_s_at MAL, T-cell differentiation protein 10 80 -2.6 -1.39 205042_at Glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase 0 80 -1.9 -0.95 205114_s_at Chemokine (C--C motif) ligand 3 80 0 2.0 0.96 205624_at Carboxypeptidase A3 0 80 -4.0 -2.00 206207_at Charcot-Leyden crystal protein 0 -4.9 -2.29 206790_s_at NADH dehydrogenase (ubiquinone) 1 beta subcomplex, 1, 7 kDa 0 80 -1.5 -0.61 207008_at Interleukin 8 receptor, beta 0 4.0 2.00 207815_at Platelet factor 4 variant 1 20 80 -2.4 -1.28 208051_s_at Poly(A) binding protein interacting protein 1 0 80 -1.6 -0.68 208161_s_at ATP-binding cassette, sub-family C (CFTR/MRP), member 3 80 0 4.3 2.10 208637_x_at Actinin, alpha 1 80 0 2.4 1.24 208918_s_at NAD kinase 80 0 1.5 0.59 208982_at Platelet/endothelial cell adhesion molecule (CD31 antigen) 0 1.6 0.71 209009_at Esterase D/formylglutathione hydrolase 80 20 1.5 0.54 209020_at Chromosome 20 open reading frame 111 80 20 1.5 0.54 209146_at Sterol-C4-methyl oxidase-like 0 80 -1.9 -0.89 209193_at PIM-1 oncogene 10 80 -2.3 -1.19 209710_at GATA binding protein 2 20 80 -3.5 -1.81 210042_s_at Cathepsin Z 80 20 1.9 0.94 210184_at 0 2.3 1.22 210732_s_at Lectin, galactoside-binding, soluble, 8 (galectin 8) 80 0 2.4 1.23 210895_s_at CD86 antigen (CD28 antigen ligand 2, B7-2 antigen) 80 10 1.9 0.92 211506_s_at Interleukin 8 0 3.2 1.67 211734_s_at Fc fragment of IgE, high affinity I, receptor for; alpha polypeptide 0 80 -5.0 -2.31 211995_x_at Actin, gamma 1 80 0 1.4 0.46 212314_at KIAA0746 protein 10 80 -1.7 -0.73 212335_at Glucosamine (N-acetyl)-6-sulfatase (Sanfilippo disease IIID) 80 0 1.5 0.54 212386_at Transcription factor 4 0 80 -2.5 -1.29 212671_s_at Major histocompatibility complex, class II, DQ alpha 1 10 80 -3.3 -1.72 212897_at Cell division cycle 2-like 6 (CDK8-like) 80 0 1.8 0.83 212999_x_at Major histocompatibility complex, class II, DQ beta 1 80 20 1.8 0.88 213309_at Phospholipase C-like 2 0 80 -1.9 -0.9 213506_at Coagulation factor II (thrombin) receptor-like 1 80 0 2.4 1.23 213883_s_at TM2 domain containing 1 10 80 -1.4 -0.46 214305_s_at Splicing factor 3b, subunit 1, 155 kDa 80 20 1.5 0.62 214512_s_at SUB1 homolog (S. cerevisiae) 0 80 -1.7 -0.76 214807_at MRNA; cDNA DKFZp564O0862 80 10 1.7 0.79 214953_s_at Amyloid beta (A4) precursor protein (peptidase nexin-II, Alzheimer 0 1.9 0.93 disease) 215726_s_at Cytochrome b-5 0 80 -2.1 -1.08 216016_at Cold autoinflammatory syndrome 1 80 0 6.1 2.60 217722_s_at Neugrin, neurite outgrowth associated 0 -1.9 -0.91 217753_s_at Ribosomal protein S26, 40S ribosomal protein 10 80 -2.9 -1.51 217970_s_at CCR4-NOT transcription complex, subunit 6 0 80 -1.9 -0.91 218190_s_at Ubiquinol-cytochrome c reductase complex (7.2 kD) 0 80 -2.0 -1.03 218345_at Hepatocellular carcinoma-associated antigen 112 10 80 -3.9 -1.95 218486_at Kruppel-like factor 11 0 2.1 1.06 218545_at GGA binding partner 0 80 -1.6 -0.67 218728_s_at Cornichon homolog 4 (Drosophila) 0 80 -1.8 -0.84 219269_at Hypothetical protein FLJ21616 0 90 -2.1 -1.06 219410_at 0 -4.7 -2.33 219862_s_at Nuclear prelamin A recognition factor 80 0 1.5 0.62 219905_at Erythroblast membrane-associated protein 0 80 -1.8 -0.85 220532_s_at LR8 protein 10 80 -5.2 -2.39 221011_s_at Likely ortholog of mouse limb-bud and heart gene (LBH) 0 80 -2.8 -1.47 221042_s_at Calmin (calponin-like, transmembrane) 80 0 1.9 0.89 221434_s_at Chromosome 14 open reading frame 156 0 80 -1.7 -0.72 221737_at Guanine nucleotide binding protein (G protein) alpha 12 10 80 -2.0 -1.96 AFFX-M27830_5_at SRY (sex determining region Y)-box 18 80 0 4.3 2.09 The criterion for gene selection (total of 82) was the percentage of pairwise comparisons between future RA responders and future RA non-responders to anti-TNFα therapy showing an increase or decrease for the fold-change/Signal Log Ratio prior to therapy; bold letters indicate a percentage of 80% for the pairwise comparisons (total of 10), bold and italic letters , bold, italic, and underlined letters in the latter case, also the gene names are shown in bold, italic, and underlined letters.
TABLE-US-00010 SUMMARY OF SEQUENCE LISTING SEQ ID NO: AffymetrixID Sequence 1 39248_at cttctacaggcttttgggaagtagggtggatgtg ggtagggctgggaggagggggccacagcttaggt ttggagctctggatgtacatacataagtaggagc agtgggacgtgtttctgtcataatgcaggcatga agggtggagtgaagtcaggtcataagtttcatgt ttgcttttgttttgttttgtttttaatgtatgta gcagatgttacagtcttagggatccgggatggga gaccccactttagaaagggtcgtcactcctttaa tcctcta 2 200061_s_at agatcgccatcatgaacgacaccgtaactatccgcactag aaagttcatgaccaaccgactacttcagaggaaacaaatg gtcattgatgtccttcaccccgggaaggcgacagtgccta agacagaaattcgggaaaaactagccaaaatgtacaagac cacaccggatgtcatctttgtatttggattcagaactcat tttggtggtggcaagacaactggctttggcatgatttatg attccctggattatgcaaagaaaaatgaacccaaacatag acttgcaagacatggcctgtatgagaagaaaaagacctca agaaagcaacgaaaggaacgcaagaacagaatgaagaaag tcagggggactgcaaaggccaatgttggtgctggcaaaaa gtgagctggagattggatcacagccgaaggagtaaaggtg ctgcaatgatgttagctgtggccactgtggatttttcgca aga 3 200087_s_at gggtactgaccatcagtgtcagcattagggtttt ggtttttgtttcttttgggtatttcttttttggc acatgtgaatcttgttttgtgtaaaatgaaatta ctttctcttgttctctgatgatgggtttaaaatt aaaagagcatccggttttggtatggggatgatcc aggattatgttgtgactgatacatattagttact tgtgctttttttttttttttttnggatctttgca agggcaaaactacaagtaacgagttttatataat taatttaaatttgttacaggttttcatgttcagg ataaaccatacttccaccttgggtgagaacactt gcaacagtttattaatgaggtgactttcacctta ggacaactgttgcatgccaagttttttgtgtgtg tgaaacacttcaaaactgatttaaaagatgtaaa tttaaaattggttgtatctaatatgccccagg 4 200642_at ctgaagggcgacggcccagtgcagggcatcatcaatttcg agcagaaggaaagtaatggaccagtgaaggtgtggggaag cattaaaggactgactgaaggcctgcatggattccatgtt catgagtttggagataatacggcaggctgtaccagtgcag gtcctcactttaatcctctatccagaaaacacggtgggcc aaaggatgaagagaggcatgttggagacttgggcaatgtg actgctgacaaagatggtgtggccgatgtgtctattgaag attctgtgatctcactctcaggagaccattgcatcattgg ccgcacactggtggtccatgaaaaagcagatgacttgggc aaaggtggaaatgaagaaagtacaaagacaggaaacgctg gaagtcgtttggcttgtggtgtaattgggatcgcccaata aacattcccttg 5 200655_s_at acctattcaaatgggttctagttcaatttgttta gtataaattgtcatagctggtttactgaaaacaa acacatttaaaattggtttacctcaggatgacgt gcagaaaaatgggtgaaggataaaccgttgagac gtggccccactggtaggatggtcctcttgtactt cgtgtgctccgacccatggtgacgatgacacacc ctggtggcatgcccgtgtatgttggtttagcgtt gtctgcattgttctagagtgaaacaggtgtcagg ctgtcactgttcacacaaatttttaataagaaac atttaccaagggagcatctttggactctctgttt ttaaaaccttctgaaccatgacttggagccggca gagtaggctgtggctgtggacttcagcacaacca tcaacattgctgttcaaagaaattacagtttacg tccattccaagttgt 6 200745_s_at gcgtgatcagagaatccttcaccttatgctgaaaagtgag ctcagatccagcaccaatgttcctcctgacccatcctgtc tatcttctcagttgagtttttaatctcactttgggtttcc ttgtgaagttggagggaagtttataatagcctaacactac cccacccccaactaggaggaacctctgttttcaagagaga tgcctgtcctgtgcttggatagtcagtcaattatttgtgt atgaaacaatgtacaaatcaatgttttgaaaataatgatc tcagactttctaagttaaagttttaaaaattttgattgtt tgccatattgggtgggtttactcttagaatcgcatgctgt agaaaatgctcaaaagtgcatatgggactcagtccttagg tgttctttttcttttaagaaataacctcttacagttgtaa ccattgcggctctgtccacttctcgttgctgctctgtggc acatatcggaagcagtacagcgcgcgg 7 200772_x_at gaaaagccatctttgcattgttcctcatccgncc tccttgctcngccgcagccgcctccgccgcgcgc ctcctccgccgccgcggactnccggcagctttat cgccagagtccctgaactctcgctttctttttaa tccccntgcatcggatcaccggcgtgccccacca tgtcagacgcagccgtagacaccagctccgaaat caccaccaaggacttaaaggagaagaaggaagtt gtggaagaggcagaaanatggaagaganncgccc ctgctnaacgggnaatgctnnananantgaggaa naatggggnagcaggaggctngacaatngaggta gacgaangaaganggaagananggtggggangga angagganggagganagaangaaggtgantggtg anggaangaggantggangantgaangatgagga agctgagtcagctacgggcaagcgggcagctgaa ngatgatgaggatgacgatgtcgataccaangaa gcagaagaccgacgaggatgactagacagc 8 201193_at tagccacagtattgctccctaaaatatgcataaagtagaa attcactgccttcccctcctgtccatgaccttgggcacag ggaagttctggtgtcatagatatcccgttttgtgaggtag agctgtgcattaaacttgcacatgactggaacgaagtatg agtgcaactcaaatgtgttgaagatactgcagtcattttt gtaaagaccttgctgaatgtttccaatagactaaatactg tttaggccgcaggagagtttggaatccggaataaatacta cctggagtcttgtcctctccatttttctctttctcctcct ggcctggcctgaatattatactactctaaatagcatattt catccaagtgcaataatgtaagctgaatcttttttggact tctgctggcctgttttatttcttttatataaatgtgattt ctcagaaattgatattaaacactatcttatcttctcctga actgttgatttt 9 201690_s_at atgatactgtagaacctgtctcctactttgaaaa ctgaatgtcagggctgagtgaatcaaagtgtcta gacatatttgcatagaggccaaggtattctattc taataactgcttactcaacactaccaccttttcc ttatactgtatatgattatggcctacaatgttgt atttgttatttattaaattgtgattgttttatta ttgtttatgccaaatgttaactgccaagcttgga gtgacctaaagcattttttaaaagcatggctaga tttacttcagtataaattatcttatgaaaaccaa attttaaaagccacaggtgttgattgttataaaa taacatgctgccattcttgattgctagagttttt gttagtactttggatgc 10 201693_s_at gggctttcggacatgacagcaaccttttctccca ggacaattgaaatttgctaaagggaaaggggaaa gaaagggaaaagggagaaaaagaaacacaagaga cttaaaggacaggaggaggagatggccataggag aggagggttcctcttaggtcagatggaggttctc agagccaagtcctccctctctactggagtggaag gtctattggccaacaatcctttctgcccacttcc ccttccccaattactattccctttgacttcagct gcctgaaacagccatgtccaagttcttcacctct atccaaagaacttgatttgcatggattttggata aatcatttcagtatcatctccatcatatgcctga ccccttgctcccttcaatgctagaaaatcgagtt ggcaaaatggggtttgggcccctcagagccctgc cctgcacccttgtacagtgtctgtgccatggatt tcgtttttcttggggtactcttgatt 11 201889_at Ttgaccccaaatgactttatacccaattctacataaaaat atagaagatctatctttttttgttaccttcagatgttcac taaataactcagtttttaagcagaagttttcagggcatta aatatatgttgtgtatgaagtatctcaaactggaacataa atttagtgatcaaactgccattcacagtgtaaggcagcac ttaaatttcgaacctaaagtttagatgcattgtataaaaa aacctaaaagcagtatctgttatttagctgtaaaccaagt tggaagctattcggataatttcttaaatattgatgaactt tggagtactgtttcttccttcaaactgaatgtaattaatt catgaataaatgcaccttatatgtttaaacaatctttgta tacttttgggatttttggtgcttatatgctaaatcacatt cagcatgtgtattttgacatttaaaatacttccctcaatt ctgtaaatt 12 202110_at tcagctcacttcaagggtacctgaagcgaattgg caccaaagcagcagctgtattgccgcagttctag cttcaccttcacgatgtttcccttggtcaaaagc gcactaaatcgtctccaagttcgaagcattcagc aaacaatggcaaggcagagccaccagaaacgtac acctgattttcatgacaaatacggtaatgctgta ttagctagtggagccactttctgtattgttacat ggacatatgtagcaacacaagtcggaatagaatg gaacctgtcccctgttggcagagttaccccaaag gaatggaggaatcagtaatcatcccagctggtgt aataatgaattgtttaaaaaacagctcataattg atgccaaattaaagcactgtgtacccattaagat a 13 202157_s_at tgtggcaaaaacgtttctttcttattttttttcttttcct aaaacagacttgaaagtattatacagggattggcattctt cccggtcactggtaacaatagcaatatgtgtccagggaca cagaatgttggtttctaacagactacttccaaaaacagtt tgagaaaaaaactgtctgattttaagtctctagaggtctg taatagtttttacatttttcaggcagtgtaaagttttttg ataaggccattttaggtggctcactttctcattaagatat atatatagaaccactttttgtagattagtataagaaaaat atttaccctgttttggggcaaatgctacctatttgtgtca ccttttgctgaactcacagttagacaatccatggtttaat gcacatgaaattacctatattttatactgtttcaatgtac aggagaaaggttactgtaaactgtgttatgttggtgcttc tgtgaattaagttgtggtttcatcatgagtc 14 202233_s_at gctcgtgttgaatctagaaccgtagccagacatgggactg gaggacgagcaaaagatgcttaccgaatccggagatcctg aggaggaggaagaggaagaggaggaattagtggatcccct aacaacagtgagagagcaatgcgagcagttggagaaatgt gtaaaggcccgggagcggctagagctctgtgatgagcgtg attcctctcgatcacatacagaagaggattgcacggagga gctctttgacttcttgcatgcgagggaccattgcgtggcc cacaaactctttaacaacttgaaataaatgtgtggactta agttgcaccccagtcttcatcatctgggcatcagaatatt tccttatggttttggatgtaccatttgtttcttatttgtg taactgtaagttcacatcaacctcatgggtttggcttgag gctggtagcttctatgtaattcgcaatgattccatctaaa 15 202378_s_at acatgtgcacatgcggcattttactatgaaatttaatatg ctgggttttttaatacctttatatatcatgttcactttaa gaaagacttcataagtaggagatgagttttattctcagca aatagacctgtcaaatttagattatgttactcaaattatg ttacttgtttggctgttcatgtagtcacggtgctctcaga aaatatattaacgcagtcttgtaggcagctgccaccttat gcagtgcatcgaaaccttttgcttggggatgtgcttggag aggcagataacgctgaagcaggcctctcatgacccaggaa ggccggggtggatccctctttgtgttgtagtccatgctat taaaagtgtggcccacagaccaagagcctcaacatttcct agagccttattagaaatgcagaatctgaagccccactctg gacccaggacattttgatgagatccaaaggagttgtatgc acatgaaagtttgagaagcatcatcatagagaagtaaaca tcacacccaacttccttatctttccagtggctaaac 16 202664_at gaaatcagagcttacatgtgtgtttttttataacattttc agataaatgtattcaacatgtaatacagtattttnacatt cacctcttattttatattgaaatgtattacagtattaaaa ctcagtgttcagtatttatttcactatgcattttatttag taaaagccaggagaaatgtttaatccaatggtgccttact ttgtgatttaaaagaaatcaacttttttttatgtctaagt agtagattatttgcatatttgtaaaaactgttaggtcttt atattttaaagtgtaataccagttttgttattttagtagc agaaatgggatgattgttaaagttccccaaaaatgttggc atgaaattaatttttccctccttatagtcaaggaccgtag aggaagaaaaactttttttttcatatcatgcactatgtaaa cagacacattttgctatctgtgtcatcaggatagtgtaag tggtagggtagagactaccctagacatctgcatctttgta agttagcca 17 202910_s_at ctgtggccacagcagctttgtacacgaagaccatccatcc tcccttcgtccaccactctactccctccaccctccctccc tgatcccgtgtgccaccaggagggagtggcagctatagtc tggcaccaaagtccaggacacccagtggggtggagtcgga gccactggtcctgctgctggctgcctctctgctccacctt gtgacccagggtggggacaggggctggcccagggctgcaa tgcagcatgttgccctggcacctgtggccagtactcggga cagactaagggcgcttgtcccatcctggacttttcctctc atgtctttgctgcagaactgaagagactaggcgctggggc tcagcttccctcttaagctaagactgatgtcagaggcccc atggcgaggccccttggggccactgcctgaggctcacggt acagaggcctgccctgcctggccgggcaggaggttctc 18 202922_at aaaaatggcgttcttctcttgtggcctgttattc tgattgctgctgtatacagtttngtcactcttta gtttttagttaagcatactgatagactttcctct aaaagccattcactccagattttacctggggaat attctacatactgcttactttctctataaaactc atcaataaatcatgaaaggcactgagttttgtaa atcaggaccctaaatgtttaattgtaaataagtt
tcagataattattatagctttgcgttgaagtttg ttgt 19 202950_at taacatgttagttgtcatttggcatgagtgtgcattccag taattcttaattgatatttgattaattccatacctttgat taaaacatgctagttcaaaataagactgctcagtttccaa gggttttcaagcctacttacctttataaaggttctctagt ctctgattagccatgactgtattggactttgaacattttc tgaactaaaaacctctattctaaactaatctcatttggat gtgtaagtcttttgtaaaggcaagaataaataatatccag gacaatttattagttttctcagtattttcccaaatattag aatatttacttcattattggttggctgccaatgaccccat atgttctgtgagaatagtagctttatctttgatataatac atagtctccaaataggtaatacttcgcaattgattagatt ttcagagtagatttagagttatctgtttttctggtgaggg tcaaat 20 203097_s_at tttccattaaattcagctgatcatattgatcagt agataaacgtaaatagcttcaaattttaaaagtg gaattgcagtgttttttcactgtatcaaacaatg tcagtgctttatttaataattctcttctgtatca tggcatttgtctacttgcttattacattgtcaat tatgcatttgtaattttacatgtaatatgcatta tttgccagttttattatataggctatggacctca tgtgcatatagaaagacagaaatctagctctacc acaagttgcacaaatgttatctaagcattaagta attgtagaacataggactgctaatctcagttcgc tctgtgatgtcaagtgcagaatgtacaattaact ggtgatttcctcatacttttgatactacttgtac ctgtatgtcttttagaaagacattggtggagtct gtatcccttttgtatttttaatacaataattgta catattggttatatttttgttgaagatggtagaa atgtactatgtttatgcttctacatccag 21 203231_s_at tgcaccaggtgaaaacagggccagcagactccatggccca attcggtttcttcggtggtgatgtgaaaggagagaattac actttttttttttttaagtggcgtggaggcctttgcttcc acatttgtttttaacccagaatttctgaaatagagaattt aagaacacatcaagtaataaatatacagagaatatacttt tttataaagcacatgcatctgctattgtgttgggttggtt tcctctcttttccacggacagtgttgtgtttctggcatag ggaaactccaaacaacttgcacacctctactccggagctg agatttcttttacatagatgacctcgcttcaaatacgtta ccttactgatgataggatcttttcttgtagcactatacct tgtgggaatttttttttaaatgtacacctgatttgagaag ctga 22 203300_x_at gaacttgttcagaccgttttagcacggaaaccta aaatgtgcagcttccttgagtggcgagatctgaa gattgtttacaaaagatatgctagtctgtatttt tgctgtgctattgaggatcaggacaatgaactaa ttaccctggaaataattcatcgttatgtggaatt acttgacaagtatttcggcagtgtctgtgaacta gatatcatctttaattttgagaaggcttatttta ttttggatgagtttcttttgggaggggaagttca ggaaacatccaagaaaaatgtccttaaagcaatt gagcaggctgatctactgcaggaggaagctgaaa ccccacgtagtgttcttgaagaaattggactgac ataactctcctcccttgttgatgacttcttgtgg catttcacacactgtagatggtcactcccttcat gtccatgttagctcatggtgtaagatgatgtctt gtcagtattactgttttgctaagccgcttcattc atgcctacacaatttt 23 204160_s_at ttgtggttgttgagaggcattttcaaaccctgta taaataatccatgctgttggtcataagttaactg tattaagaacagtaaaataaataaaaaccaatag tactaatttngctttaaaaaaatttctaattttt ttcacataaaacaattatcctaaaggttaatagt tgatcgaaacagaataatagaaaaattctncttt aatttccattaaaaagcaaatagcattgacacat ttaaagcttttcatttaaagtagtggatgttttt gaagtatctaaaatagtagcagaatattttatac ttggtccttgcaatggtgtgagttttaatgattg cattatcgtgattggtggttatgagtttcagaaa tctatacttggcatccaactcatgagtggatttt atataggatggaacaggaaggtatgtcctgtcag tatcttaaccctttcaacaagacatttacctatt tgtctttccttacgttctcaaaatat 24 204750_s_at gaccctcgcgatcttaatatttgccagtgatgcctgcaaa aatgtgacattacatgttccctccaaactagatgccgaga aacttgttggtagagttaacctgaaagagtgctttacagc tgcaaatctaattcattcaagtgatcctgacttccaaatt ttggaggatggttcagtctatacaacaaatactattctat tgtcctcggagaagagaagttttaccatattactttccaa cact 25 204777_s_at ggaagtcttcataaagccgcagtagaacttgagc tgaaaacccagatggtgttaactggccgccccac tttccggcataactttttagaaaacagaaatgcc cttgatggtggaaaaaagaaaacaaccacccccc cactgcccaaaaaaaaaagccctgccctgttgct cgtgggtgctgtgtttactctcccgtgtgccttc gcgtccgggttgggagcttgctgtgtctaacctc caactgctgtgctgtctgctagggtcacctcctg tttgtgaaaggggaccttcttgttcgggggtggg aagtggcgaccgtgacctgagaaggaaagaaaga tcctctgctgacccctggagcagctctcgagaac tacctgttggtattgtccacaagctctcccgagc gccccatcttgtgccatgttttaagtcttcatgg atgttctgcatgtcatggggactaaaactcaccc aacagatctttccagaggtccatggtgg 26 205042_at ttacatttgaactatatccttcctagtgggttagtgtgaa aaagagtttggctgattcctaaaactctgccagccctgca gtaatctccaggcctggttattgttcagacattccatggt gattcctgggaaggaagcttggctgctcagtttctgagtc tggggtgagataatgttctggaaggacatctgttctttgg tgtaatctctcatggtgaaatctgctctgtacatcagaca attgcattgctaccaagtttcataccaa 27 205114_s_at gattccacagaatttcatagctgactactttgagacgagc agccagtgctccaagcccggtgtcatcttcctaaccaagc gaagccggcaggtctgtgctgaccccagtgaggagtgggt ccagaaatatgtcagcgacctagagctgagtgcctgaggg gtccagaagcttcgaggcccagcgacctcggtgggccagt ggggaggagcaggagcctgagccttgggaaacatgcgtgt gacctccacagctacctcttctatggactggttgttgcca aacagccacactgtgggactcttcttaacttaaattttaa tttatttatactatttagtttttgtaatttattttcgatt tcacagtgtgtttgtgattgtttgctctgagagttcccct gtcccctcccccttccctcacaccgcgtctggtgacaacc gagtggctgtcatcagcctgtgtaggcagtcatggcacca aagccaccagactgacaaatgtgtatc 28 205624_at tatgaaacccgctacatctatggcccaatagaatcaacaa tttacccgatatcaggttcttctttagactgggcttatga cctgggcatcaaacacacatttgcctttgagctccgagat aaaggcaaatttggttttctccttccagaatcccggataa agccaacgtgcagagagaccatgctagctgtcaaatttat tgccaagtatatcctcaagcatacttcctaaagaactgcc ctctgtttggaataagccaattaatccttttttgtgcctt tcatcagaaagtcaatcttcagttatccccaaatgcagct tctatttcacctgaatccttctcttgctcatttaagtccc atgttactgctgtttgcttttacttactttcagtagcacc ataacgaagtagctttaagtgaaaccttttaactaccttt ctttgctccaagtgaagtttggacccagcagaaagcatta ttttgaaaggtgatatacagtggggcacagaaaacaaatg aaaaccctcagtttctcacagattttcaccatgtggcttc atcaa 29 206207_at aggagacaacaatgtccctgctacccgtgccatacacaga ggctgcctctttgtctactggttctactgtgacaatcaaa gggcgaccacttgtctgtttcttgaatgaaccatatctgc aggtggatttccacactgagatgaaggaggaatcagacat tgtcttccatttccaagtgtgctttggtcgtcgtgtggtc atgaacagccgtgagtatggggcctggaagcagcaggtgg aatccaagaacatgccctttcaggatggccaagaatttga actgagcatctcagtgctgccagataagtaccaggtaatg gtcaatggccaatcctcttacacctttgaccatagaatca agcctgaggctgtgaagatggtgcaagtgtggagagatat ctccctgaccaaatttaatgtcagctatttaaagagataa ccagacttcatgttgccaaggaatccctgtctctacgtga acttgggattcca 30 206790_s_at gaacttacttcagattgtgcgggaccactgggttcatgtt cttgtccctatgggatttgtcattggatgttatttagaca gaaagagtgatgaacggctaactgccttccggaacaagag tatgttatttaaaagggaattgcaacccagtgaagaagtt acctggaagtaaagactggctagattatcgaatgttcaca ttttaaagttctgagaga 31 207008_at acctaacgaagtatccttcagcctgaaagaggaatgaagt actcatacatgttacaacacggacgaaccttgaaaacttt atgctaagtgaaataagccagacatcaacagataaatagt ttatgattccacctacatgaggtactgagagtgaacaaat ttacagagacagaaagcagaacagtgattaccagggactg aggggaggggagcatgggaagtgacggtttaatgggcaca gggtttatgtttaggatgttgaaaaagttctgcagataaa cagtagtgatagttgtaccgcaatgtgacttaatgccact aaattgacacttaaaaatggtttaaatggtcaattttgtt atgtatattttatatcaatttaaaaaaaaacctgagcccc aaaaggtattttaatcaccaaggctgattaaaccaaggct agaaccacctgcc 32 207815_at caagccctgctgtacaagaaaatcattaaggaacatttgg agagttagctactagctgcctaagtgtgcactttcaatct aactgtgaaagaatcttctgatgtttgtattatccttctt atattatattaacaaaataaatcaagttgtggtatagtca atctatttcttaataatactgcaaaaataatgctgacaca tcacaatttcatattttaaaatttccagaattttaagcaa aaagcattatgaaggaaggcttggtttaataaagactgat tttgttcagtgttatatgttagctgatacatatttgttca tttatgtgattgcagtactttatagctacatatttacctt gaatgttacaattagcttgccaata 33 208051_s_at gaactcccagctaaacaaccaagacttcactgaagattta ttccaattctagaattgttctttttttattttttattttt tcaactgactaacttcattaccttaaagcctagaacatta ttctgctttatttatatggctttctcaattttattttgta gcatgggttgaatcgaactttttactagagaattttacta gatatttgtcattcaagttttcatctgctttataattgat acaccttgagggtcacttttctaatacttttacctataat gtggtacccacctcagcccctaataaataatatttttacc ctaatgtcaaatctttttcccaggctaactaaaaactgtg tacaaaaggattgcttgtaaatatgcatgtaaatagttct gttaataacccactgttttacatttggtacatctgtgtct gctaatacagttagctttctcacttttctgcttgtttgtt cagtctgaatt 34 208161_s_at gatagcaaacactgggggcaccttaagattttgcacctgt aaagtgccttacagggtaactgtgctgaatgctttagatg aggaaatgatccccaagtggtgaatgacacgcctaaggtc acagctagtttgagccagttagactagtcccccggtctcc cgattcccaactgagtgttatttgcacactgcactgtttt caaataacgattttatgaaatgacctctgtcctccctctg atttttcatattttcctaaagtttcgtttctgttttttaa taaaaagctttttcctcctggaacagaagacagctgctgg gtcaggccacccctaggaactcagtcctgtactctggggt gctgcctgaatccattaaaaat 35 208637_x_at ggtcccgaggagttcaaagcctgcctcatcagcttgggtt atgatattggcaacgacccccagggagaagcagaatttgc ccgcatcatgagcattgtggaccccaaccgcctgggggta gtgacattccaggccttcattgacttcatgtcccgcgaga cagccgacacagatacagcagaccaagtcatggcttcctt caagatcctggctggggacaagaactacattaccatggac gagctgcgccgcgagctgccacccgaccaggctgagtact gcatcgcgcggatggccccctacaccggccccgactccgt gccaggtgctctggactacatgtccttctccacggcgctg tacggcgagagtgacctctaatccaccccgcccggccgcc ctcgtcttgtgcgccgtgccctgccttgcacctccgccgt cgcccatctcctgcctgggttcggtttcagctcccagcct ccacccgggtgagctggggcccacgtggcatcgatcctcc ctgcccgcgaagtgacagtttac 36 208918_s_at gaaatgggctgggagtgcttctgtcctgctgacaccccgc ggtgggtccctggagcgcggcctccagctgccgcaatttc catgccaggatatttttccgcaaatcagtcggttgaaatt cagaggagtcagaatgactcgacctgtccttcaatgttga taata 37 208982_at attgcttgctaaagaagtggtctcctgaggtcttaagaca ttcctgacagtgtcttgagtgggtgggagagaggntgctg tcattgcgctgtggaatttcacagatgagaaccacgccta gccaaaatcacttttcctgtttgcctcagtgacacagctg cagggaccctcgtggatgttgtattaaat 38 209009_at gagcttccccaactcataaatgccaattttccagtggatc cccaaaggatgtctatttttggccactccatgggaggtca tggagctctgatctgtgctttgaaaaatcctggaaaatac aaatctgtgtcagcatttgctccaatttgcaaccctgtac tctgtccctggggcaaaaaagcctttagtggatatttggg aacagatcaaagtaaatggaaggcttatgatgctacccac cttgtgaaatcctatccaggatctcagctggacatactaa ttgatcaagggaaagatgaccagtttcttttagatggaca gttactccctgataacttcatagctgcctgtacag 39 209020_at caggggcagtcgttgagcctttgagaacttctgttccaag gctcccatcagagagtaagaaggaagactcctctgacgct
acccaagtcccccaagcaagtctcaaagccagtgatctct ctgactttcaatcagtttccaagctaaaccaggggcaagc catgcacatgcataggcaaggaatgccagtgtaagagatg gcatgatatggaagtgtattccttttcaggcctgcagagt gtccctcccttggctccagaacgaagatccacacttgagg actactctcagtcgctgcacgccagaactctgtctggctc tccccgatcctgttctgagcaagctcgagtcttcgtggat gatgtgaccattgaggacctgtcaggctacatggagtatt acttgtatattcccaagaaaatgtcccacatgggcagaaa tgatgtacacctgatagcaagaagctaattcatatgcttt aaaccaatgaaggcttgtcaaagagatttagttaatggca gaccttgtggccactttgtgtgagaagacatctctttctg ctca 40 209146_at gaacctcatcaattgatagcagtgagtgactgaagcttcc aaatcaagaaaagccggcaccaagaacttccattctaatc tagagctgaccagtttgagctgattctctctttgaagagt ccttcttgattgcagtgcagtactggcatttctgaatgga tgtaagtggagtattttagtctaaaggcttttcaaattac ttgaatttttttaaaaattgaggagctttatttctattta cccttccatttttgtatatcaaatttccattgtcattaaa aactgtatcttgaaactttgtgaactgacttgctgtattt gcactttgagctcttgaaa 41 209193_at gattgtagtggatctaatttttcagaaattttgcctttaa gttattttacctgtttttgtttcttgttttgaaagatgcg cattctaacctggaggtcaatgttatgtatttatttattt atttatttggttcccttcctattccaagcttccatagctg ctgccctagttttctttcctcctttcctcctctgacttgg ggaccttttgggggagggctgcgacgcttgctctgtttgt ggggtgacgggactcaggcgggacagtgctgcagctccct ggcttctgtggggcccctcacctacttacccaggtgggtc ccggctctgtgggtgatggggaggggcattgctgactgtg tatataggataattatgaaaagcagttctggatggtgtgc cttccagatcctctctggggctgtgttttgagcagcaggt agcctggctggttttatctgagtga 42 209710_at gatcccacagccctagtatgaaagctgggggtgg ggaggggcctttgctgcccttggtttctgggggc tggttggcatttgctggcctggcagggggtgaag gcaggagttgggggcaggtcaggaccaggaccca gggagaggctgtgtccctgctggggtctcaggtc cagctttactgtggctgtctggatccttcccaag gtacagctgtatataaacgtgtcccgagcttaga ttctgtatgcggtgacggcggggtgtggtggcct gtgaggggcccctggcccaggaggaggattgtgc tgatgtagtgaccaagtgcaatatgggcgggcag tcgctgcagggagcaccacggccagaagtaactt attttgtactagtgtccgcataagaaaaagaatc ggcagtattttctgtttttatgttttatttggct tgttttattttggattagtgaactaagttattgt taattatgtacaacatttatatattgtctgtaaa aaatgtatgctatcctcttattcct 43 210042_s_at gaaatctacgcaaatggtcccatcagctgtggaataatgg caacagaaagactggcaaactacaccggaggcatctatgc cgaataccaggacaccacatatataaaccatgtcgtttcc gtggctgggtggggcatcagtgatgggactgagtactgga ttgtccggaattcatggggtgaaccatggggcgagagagg ctggctgaggatcgtgaccagcacctataaggatgggaag ggcgccagatacaaccttgccatcgaggagcactgtacat ttggggaccccatcgtttaaggccatgtcactagaagcgc agtttaagaaaaggcatggtgacccatgaccagaggggat cctatggttatgtgtgccaggctggctggcaggaactggg gtggctatcaatattggatggcgaggacagcgtggtactg gctgcgagtgttcctgagagttgaaagtgggatgacttat gacacttgcacagcatggctctgcctcacaatgatgcagt cagccac 44 210184_at cagttctgaatatgctgctcatccccacctgtct tcaacagctccccattaccctcaggacaatgtct gaactctccagcttcgcgtgagaagtccccttcc atcccagagggtgggcttcagggcgcacagcatg agagcctctgtgcccccatcaccctcgtttccag tgaattagtgtcatgtcagcatcagctcagggct tcatcgtggggctctcagttccgattccccaggc tgaattgggagtgagatgcctgcatgctgggttc tgcacagctggcctcccgcggttgggtcaacatt gctggcctggaagggaggagcgccctctagggag ggacatggccccggtgcggctgcagctcaccagc cccaggggcagaagagacccaaccacttcctatt ttttgaggctatgaatatagtacctgaaaaaatg ccaagcactagattatttttttaaaaagcgtact ttaaatgtttgtgttaatacacattaaaacatcg cacaaaaacgatgcatctaccgctcc 45 210732_s_at cccagcttcctagtaatagaggaggagacatttctaaaat cgcacccagaactgtctacaccaagagcaaagattcgact gtcaatcacactttgacttgcaccaaaataccacctatga actatgtgtcaa 46 210895_s_at gtgtacataaatttgacctgctcatctatacacggttacc cagaacctaagaagatgagtgttttgctaagaaccaagaa ttcaactatcgagtatgatggtattatgcagaaatctcaa gataatgtcacagaactgtacgacgtttccatcagcttgt ctgtttcattccctgatgttacgagcaatatgaccatctt ctgtattctggaaactgacaagacgcggcttttatcttca cctttctctatagagcttgaggaccctcagcctcccccag accacattccttggattacagctgtacttccaacagttat tatatgtgtgatggttttctgtctaattctatggaaatgg aagaagaagaagcggcctcgcaactcttataaatgtgg 47 211506_s_at gtgtgaaggtgcagttttgccaaggagtgctaaa gaacttagatgtcagtgcataaagacatactcca aacctttccaccccaaatttatcaaagaactgag agtgattgagagtggaccacactgcgccaacaca gaaattattgtaaagctttctgatggaagagagc tctgtctggaccccaaggaaaactgggtgcagag ggttgtggagaa 48 211734_s_at acatctccattacaaatgccacagttgaagacag tggaacctactactgtacgggcaaagtgtggcag ctggactatgagtctgagcccctcaacattactg taataaaagctccgcgtgagaagtactggctaca attttttatcccattgttggtggtgattctgttt gctgtggacacaggattatttatctcaactcagc agcaggtcacatttctcttgaagattaagagaac caggaaaggcttcagacttctgaacccacatcct aagccaaaccccaaaaacaactgatataattact caagaaatatttgcaacattagtttttttccagc atcagcaattactactcaattgtcaaacacagct tgca 49 211995_x_at agtactcggtgtggatcggtggctccatcctggcctcact gtccaccttccagcagatgtggattagcaagcaggagtac gacgagtcgggcccctccatcgtccaccgcaaatgcttct aaacggactcagcagatgcgtagcatttgctgcatgggtt aattgagaatagaaatttgcccctggcaaatgcacacacc tcatgctagcctcacgaaactggaataagccttcgaaaag aaattgtccttgaagcttgtatctgatatcagcactggat tgtagaacttgttgctgattttgaccttgtattgaagtta actgttccccttggtatttgtttaataccctgtacatatc tttgagttcaacctttagtacgtgtggcttggtcacttcg tggctaaggtaagaacgtgcttgtggaagacaagtctgtg gcttggtgagtctgtgtggccagcagcctctgatctgtgc agggtattaacgtgtcagggctgagtgttctgggatttct ctagaggct 50 212314_at tattttggtacctgtgcttgccacagccctgttcctcaaa gctgaattgatagatttctctttgacttccaagacctagc agttataaggcaccttgaaataaattgtttgtgcctggaa atgcagggagggcaatagctttgtaaattggtttacattt ttctccttgaatttttctagggtcctagtgcttccgaatc atttaatggcattgtcggatatcttttacatttcaattgc aatccatgaaattacatttagaagattcttagtacttaac tgtagtcttctccatgaattacacgttagaatagactggc agcaacngaatatgcagcaagtaagcctctagcttatagt ttcatccctacccctcatgcctgcgtgagtctgtacaggg atatgtgtgtgtgtgtgtgtgtgtgtgtgttagagaggaa gaggaagagcagaatgtctgtatactacatgctgctaagg tagtgaataaatcagtaatgcaatattgtgggtccaaact actctttgcactact 51 212335_at accacgcttggctaagaacacctaaatttttatg tttcttggctcaaaaaccagttccatttctaatg ttgtcctcacaagaaggctaattggtggtgagac agcaggggaggaggaagagctgtggtttgtaact tgttcaactcaggcaataagcgattttagcttta tttaaagtcttctgtccagctttaagcactttgt aagacatggctgaaagtagcttttctatcagaat tgcagatagtcatgttgggctaacagtcaattgg atatattcctttacctcacatgaccccagcaact gtggtggtatctagaggtgaaacaggcaagtgaa atggacacctctgctgtgaatgttttagagaagg aaattcaaaaaatgttgtaactgaaagcactgtt gaatatgggtatcggctttctttttcactttgac tcttaacattatcagtcaacttccacattaatg 52 212386_at gagatttaccatgtatcagtgcctggctttttgt tataaagctttgtttgtctagtgctcttttgcta taaaatagactgtagtacaccctagtaggaaaaa aaaaaaactaaatttaaaaataaaaaatatattt ggcttatttttcgcaggagcaatccttttatacc atgaatatt 53 212671_s_at accaatgaggttcctgaggtcacagtgttttccaagtctc ccgtgacactgggtcagcccaacaccctcatctgtcttgt ggacaacatctttcctcctgtggtcaacatcacntggctg agcaatgggcactcagtcacagaaggtgtttctgagacca gcttcctctccaagagtgatcattccttcttcaagatcag ttacctcaccttcctcccttctgntgatgagatttatgac tgcaaggtggagcactggggcctggatgagcctcttctga aacactgggagcctg 54 212897_at aaggagacctttgaagctttttgagggcaaactttacctt tgtggtccccaaatgatggcatttctctttgaaatttatt agatactgttatgtcccccaagggtacaggaggggcatcc ctcagcctatgggnaacacccaaactaggaggggttattg acaggaaggaatgaatccaagtgaaggctttctgctcttc gtgttacaaaccagtttcagagttagctttctggggaggt gtgtgtttgtgaaaggaattcaagtgttgcaggacagatg agctcaaggtaaggtagctttggcagcagggctgatacta tgaggctgaaacaatccttgtgatgaagtagatcatgcag tgacatacaaagaccaaggattatgtatatttttatatct ctgtggttttgaaactttagtacttagaattttggccttc tgcactactcttttgctcttacgaacataatggactctta agaatggaaagggatgacatttacctatgtgtgctgcctc attcctggtgaagcaactgctacttgttctctatgcctct aaaat 55 212999_x_at cactgcagaatgaaggaacatcccttgaggtgac ccagccaacctgtggccagaaggaggnttgtacc ttgaaaagacactgaaagcattttggngtgtnaa gtaagggtgggcagaggaggtagaaaatcaattc aattgtcgcatcattcatggttctttaatattga tgctcagtgcantggcctnagaatatcccagcct ctcttctggtttgntgagtgctntntaagtaagc atggtngaattgtttggggncanatatagtganc cttggtcactggtgtttcaaacattctggnaagt cacatcnatcaagaatantttttanttttaagaa agcataaccagcaataaa 56 213309_at gtatgtagcaatcctgcgtgtgaaggcaaataaactcttt aacaggcaattatattgctggccaaaatatgctatatttg tatacaaagacattctaactcagttccagtatgaagaaag attattcactctagctccactgagaaacattttcctaagt gaaaacaatttcttaagatggaaatggattggattgtcaa attattatttattggagaaaaaaacctgatctacacattt ttacttatatggggttgccagagtctctgggttctagatg attttggtggcatgcttgctgagccataattactaaagag aatgtaagtggacgggttccctgaatccccggggtccttg gagagccatcgaggagaatgtgcaattggactgaagctcc ctggctgaagatacatgccgagtcagcacatgggtagaga t 57 213506_at gcacacagagatttgagaaccattgttctgaatgctgctt ccatttgacaaagtgccgtgataatttttgaaaagagaag caaacaatggtgtctcttttatgttcagcttataatgaaa tctgtttgttgacttattaggactttgaattatttcttta ttaaccctctgagttttngtatgtattattattaaagaaa aatgcaatcaggattttaaacatgtaaatacaaattttgt ataacttttgatgacttcagtgaaattttcaggtagtctg agtaatagattgttttgccacttagaatagcatttgccac ttagtattttaaaaaataattgttggagtatttattgtca gttttgttcacttgttatctaatacaaaattataaagcct tcagagggtttggaccacatctctttggaaa 58 213883_s_at agagaacttctagtgtatggatttaaagatttctcttttt cattcatataccattttatgagttctgtataattttttgt ggtttttgttttgttgagttaaagtatattattgtgagat ttatttaataggacttcctttgaaagctgtataatagtgt ttctcgggcttctgtctctatgagagatagcttattactc tgatactctttaatcttttacaaaggcaagttgccacttg tcatttttgtt 59 214305_s_at gttctgacccctggaaagacaccaattggcacaccagcca tgaacatggctacccctactccaggtcacataatgagtat gactcctgaacagcttcaggcttggcggtgggaaagagaa attgatgagagaaatcgcccactttctgatgaggaattag atgctatgttcccagaaggatataaggtacttcctcctcc agctaattatgttcctattcgaactccagctcgaaagctg
acagctactccaacacctttgggtggtatgactggtttcc acatgcaaactgaagatcgaactatgaaaagtgttaatga ccagccatctgg 60 214512_s_at gaccaagagggtgttcgactgctagagccgancgaagcga tgcctaaatcaaaggaacttgtttcttcaagctcttctgg cagtgattctgacagtgaggttgacaaaaagttaaagagg aaaaagcaagttgctccagaaaaacctgtaaagaaacaaa agacaggtgagacttcgagagccctgtcatcttctaaaca gagcagcagcagcagagatgataacatgtttcagattggg a 61 214807_at tcttcattccacgagaattttgatttttaacagcagtctc tctttttctcagcattgcaaatatatatgtatatatacat tcatgaccaaagtatcgcttactgaccatgcagctgtaaa ccttctgtgcctatcaaacaaatacatagcatgaanctaa ttttagaagtttcatgggggaattttaggggaaagtataa acctaagagtgagtgaatggagatgattcatggaaaaaaa aaanaaaaannnanatgtgctatnaggcagagttattaac ttcttttagttgttgtttgagatngngttctgctcttgtt ncccaggctggagtgcantggcgtgatctcgtctcnctgc aacctccgcctcccaggttcaagcgattctcctgccccag ctactttggaggctgaagtgtaagagttgcttgagc 62 214953_s_at atagattctctcctgattatttatcacatagccccttagc cagttgtatattattcttgtggtttgtgacccaattaagt cctactttacatatgctttaagaatcgatgggggatgctt catgtgaacgtgggagttcagctgcttctcttgcctaagt attcctttcctgatcactatgcattttaaagttaaacatt tttaagtatttcagatgctttagagagattttttttccat gactgcattttactgtacagattgctgcttctgctatatt tgtgatataggaattaagaggatacacacgtttgtttctt cgtgcctgttttatgtgcacacattaggcattgagacttc aagcttttctttttttgtccacgtatctttgggtctttga taaagaaaagaatccctgttcattgtaagcacttttacgg ggcgggtg 63 215726_s_at gacagaccaaagttaaacaagcctccggaaactcttatca ctactattgattctagttccagttggtggaccaactgggt gatccctgccatctctgcagtggccgtcgccttgatgtat cgcctatacatggcagaggactgaacacctcctcagaagt cagcgcaggaagagcctgctttggacacgggagaaaagaa gccattgctaactacttcaactgacagaaaccttcacttg aaaacaatgattttaatatatctctttctttttcttccga cattagaaacaaaacaaaaagaactgtcctttctgcgcnc aaatttttcgagtgtgcctttttattcatctactttattt tgatgtttccttaatgtgtaatt 64 216016_at gccaatgctaaaaagctgcagatccagcccagccagctgg aattgttctactgtttgtacgagatgcaggaggaggactt cgtgcaaagggccatggactatttccccaagattgagatc aatctctccaccagaatggaccacatggtttcttcctttt gcattgagaactgtcatcgggtggagtcactgtccctggg gtttctccataacatgcccaaggaggaagaggaggaggaa aaggaaggccgacaccttgatatggtgcagtgtgtcctcc caagctcctctcatgctgcctgttctcatgggtaaggaaa ctcggcttccaggtgcttcctcctgcttcctcgccagctt cttcttggcacctgcctcctctcatctcttttcaactatc ttccaaatactgttgccacagctacatcataatgccacca ctgtctgtttgagactccttcatgagcaaagattgatgta tggtaggtggat 65 217722_s_at ggagatgcctcgtgaaacacagctgggcaagtattaatgt atatggaacagcctggatttctgcatatggataagccacc ttggaataggaagaggtgttgagcctggactgtgggagga aagagctgcgtggatagattcaaacttcctgtggtagtgc tcccagtctgacctctgtagaccttcagtactcactcttc ttgcttaggctctctgtgtgttgaaagccatcccgtgttg catgtgttgttacaattttctgtgatacttgcaat 66 217753_s_at tggtcgtgccaaaaagggccgcggccacgtgcagcctatt cgctgcactaactgtgcccgatgcgtgcccaaggacaagg ccattaagaaattcgtcattcgaaacatagtggaggccgc agcagtcagggacatttctgaagcgagcgtcttcgatgcc tatgtgcttcccaagctgtatgtgaagctacattactgtg tgagttgtgcaattcacagcaaagtagtcaggaatcgatc tcgtgaagcccgcaaggaccgaacacccccaccccgattt agacctgcgggtgctgccccagctcccccaccaaagccca tgtaaggagctgagttctt 67 217970_s_at tgagctggagctggttggactaatgagactgagg aagcagcttttcctacgatctgcattatgtaatc acaggtccagagagctttatggaagcgggagagg aggagcacttactcatgttgtatttgttaatgga ggatgtcatcttttcatagatgctagaactagag tgcacttgttagatgctaaaggtttgagctttac acaaaatgtcttcatctgtatttgttattgtcta caatatatttgaatttggggcagcatattaagat gtaatggcctgttatgtcttgaaaatacttgttt tgcctcttccaggcatactgcattctgtggatca gtttgaacagcttctccaccttatttggacagtg ataaattgaaccaagagtgtagatttacaagtgt aaccttcaaaagaggaagaactatttggggtctg taggtaatgaacagtcacaccaaaatagactatg atgcttttgttaagaaaggtttcatgttttagat attttccgtgtcctaaataatt 68 218190_s_at tgaagaaacatggcggccgcgacgttgacttcgaaattgt actccctgctgttccgcaggacctccaccttcgccctcac catcatcgtgggcgtcatgttcttcgagcgcgccttcgat caaggcgcggacgctatctacgaccacatcaacgagggga agctgtggaaacacatcaagcacaagtatgagaacaagta gttccttggaggcccccatccaggccagaaggaccaggtc cacccagcagctgtttgcccagagctggagcctcagcttg aagatgatgctcaaggtactcttcatggaccaccattcgc tgttggcaagaaacggctttacttacaaaacagactcttt accttctgctgtgtttgaa 69 218345_at gatttccgatatggctactcttattacaacagtgcctgcc gcatctccagctcgagtgactggaacactccagcccccac tcagagtccagaagaagtcagaaggctacacctatgtacc tccttcatggacatgctgaaggccttgttcagaacccttc aggccatgctcttgggtgtttggattctgctgcttctggc atctctggcccctctgtggctgtactgctggagaatgttc ccaaccaaagggaaaagagaccagaaggaaatgttggaag tgagtggaatctagccatgcctctcctgattattagtgcc tggtgcttctgcaccgggcgtccctgcatctgactgctgg aagaagaaccagactgaggaaaagaggcttttcaacagcc ccagttatcctggccccatgaccgtggccacagccctgct ccagcagcacttgcccattccttacaccccttccccatcc tgctccgcttcatgtcccctcctgagtagtcatgtgataa taaactctcatgttattgttcccag 70 218486_at gactgtacacactataaatggcatcaaatttggatatttt tcttaattatgacatgcaaagtaatgtgagtcctgccagt attctggtggataaggtcttntgagtatttggttgcttgt cacaacattctccaagcagtgatatttctaaagaggagat acatgttgaaaacggttttaatttacacttccatttcctg attacatttggaaatactttgtgtaaaccatcccccttcc acctccatttgtctgttgaaagattttaagttggaaacag ttcctgtctgaaaactcttctgagaaccacaaaccttgtg tatggattcggcatggagccctcagctggcggctctgggt gctgacggccgctggagaggtgggctcccctcgtgcactt tattgcctgggcagttttgcttgatcttttgtgactttga gccttttaagtagtttgaatgataagacttaaaatgtttc ataattatgttttatgtaacagactttgacattatttaaa cgagcatgtgtaatgtaacttttctctttgaatcata 71 218545_at agcatggatttcaacatcacttatttatctgtataattgg aaataaaacaccgatatgatagagaatcattccggcatta cctaacctcttctgcagttggatctatgtattttcattgg tctactgaaaacgaacaatacaattaaaagcactaaagat tattatattaattcaactttgatctgatatatcacttaaa ctaaaggggtgtgtgtggtgtatgcttgtttcctatttct gctctttaaagatactttgaatcaataaaaccattagtct acaaatcaaattgtgaacttaatctctagaaagagaatat aactcagccatttataggaatttaggttcaagtacaggat atatgaaatcttttcccagtatttcagaatgtacttaatt cacaggcaggatgcttcaatgcaaaatcatgaatattttt aattcaaaactaaaatgtcattaatatgtatgtatgcaaa tgttttatcttattttctgaaatgcatctactttcatggg ctttgtacgtttctgagattt 72 218728_s_at atatcgatacattatggtgccgagtggtaacatgggagtg tttgatccaacagaaatacacaatcgagggcagctgaagt cacacatgaaagaagccatgatcaagcttggtttccactt gctctgcttcttcatgtatctttatagtatgatcttagct 73 219269_at aggctagaaaatcttgctgctccgtcttagcattccaaga gagtgcttccaggtatttagatagccctcagttctcaaat attagactacgtgtaaaatcttgggtacctttagattctt gtaacactagtctgtactcccttttccttccccaagactg ataggatgcaagctgaggtcgtggcacaggaatgacagac accatttggggagtatccacagagtcaaaggaacactaga atccccacctcagcgtgaggataattgatttccagctgca ataagccgtgcctcattatagccacactgtggctagatta tacttctttgggtgctgtgctaagaatgtcaatggaaaaa gccgatctcagattttgtttgaagttaacatgcctgacac agacatcctttcctctcacaagctgtgtgacttagtagat aaaatactgccttctgccttt 74 219410_at tgtttctcaccatatgcttttgttggcattatgcagtaac cattgtcatcgttggaatgaattatgctttcattacctgg ttggttaaatctagacttaagaggctctgctcctcagaag ttggacttctgaaaaatgctgaacgagaacaagaatcaga agaagaaatgtgactttgatgagcttccagtttttctaga taaaccttttcttttttacattgttcttggttttgtttct cgatcttttgtttggagaacagctggctaaggatgactct aagtgtactgtttgcatttccaatttggttaaagtatttg aatttaaatattttctttttagctttgaaaatattttggg tgatactttcattttgcacatcatgcacatcatggtattc aggggctagagtgatttttttccagattatctaaagttgg atgcccacactatgaaagaaatatttgttttatttgcctt atagatatgctcaaggttactgggcttgctactatttgta actccttgaccatggaattatacttgtttatcttgttgct gca 75 219862_s_at cggccaaggagctgttcaacgaggatgtggagga ggtcacttaccgagccctgagaaacaaagacttc caagaggtcacccttgagaagaacggagaggtgg tgttacgctttgctgcagcctatggctttcgaaa catccagaacatgatcctgaagcttaagaagggc aagttcccattccactttgtggaggtcctcgcct gtgctggaggatgcttaaatggcagaggccaagc ccagactccagacggacatgcggataaggccctg ctgcggcagatggaaggcatttacgctgacatcc ctgtgcggcgtccggagtccagtgcacacgtgca ggagctgtaccaggagtggctggaggggatcaac tcccccaaggcccgagaggtgctgcataccacgt accagagccaggagcgtggcacacacagcctgga catcaagtggtgaagtcaggccagggcctt 76 219905_at ggctcacgtgattatggaggcggttaaatcccaa gatctgcaggataagtcagcaagatggagtccca tgagagctgatggtttagttccagtctgatggca gcaggcttgacgccaaggaagagatgatgtttaa ttcaagtccgaaggcaaggaaaaagctgatggtc ctgtccaaaggctattaggcaggaagaattctct tagggcagagttagctcttttgttctattcaggc cttcaactgattcagcaaggcccgcccacatttg ggaggacagtctgcattactcagtctactgattt gaatgttaatgtcattgcgaaacaccctcacagg aacactcagaataatgtttgaccaaatagctggg catcttgtgacccagttaagtg 77 220532_s_at atctggcaaactgaaccctttttatacatcgacactgtgt gtgatcgctcagaccctgtcttccctaccactgggtacag atggatgcggcgaagtcaagagaaccaatggcagaaggag gagtgtagagcttacatgcagatgctgaggaagttgttca cagcaatccgtgccctgttcctggctgtctgtgtcttgaa ggtcattgtgtccttggtttccttgggagtaggtcttcga aacttgtgtggccagagctcccagcccctgaatgaggaag gatcagagaagaggctactgggggagaattcagtgccccc ttcgccctctagggagcagacctccactgccattgtcctg tgagccgccaaagaccccacggggtgcccgcatgtccctg tctagggcagcccagggcccccactcctggctcctcacac ttgcctcccctatggccgctctccagaccctcctcctttc ttctccccacatccgcacctgctgttcccactctggggtt ctcaagtccatga 78 221011_s_at gagtggttcatccatactctcattccctcgcctccccttg tggacgggggtcttgccttttcaattcctgtgttttggtg tcttcccttatctgctaccctgaatcacctgtcctggtct tgctgtgtgatgggaacatgcttgtaaactgcgtaacaaa tctactttgtgtatgtgtctgtttatgggggtggtttatt atttttgctggtccctagaccactttgtatgaccgtttgc agtctgagcaggccaggggctgacagctaatgtcaggacc ctcagcggtggagcctgctggggggacccagctgctcttg gacaagtggctgagctcctatctggcctcctctttttttt ttttttcaagtaatttgtgtgtatttctaactgattgtat tgaaaaaattcctagtatttcagtaaaaatgcctgttgtg agatgaacctcctgtaacttctatctgttcttttttgagg ctcaggga 79 221042_s_at tgaccccatggacagccatcagtcccaggaatcc ccaaacctggaaaacatagcaaaccccctagaag aaaatgtaacgaaagaatcaatcagtagtaaaaa aaaggaaaaaaggaaacatgtggaccacgtagaa agttcactatttgtagcaccaggaagtgttcaat cctcagatgacctagaagaagacagtagcgacta cagcattccttccaggactagtcacagtgactcc
agcatttaccttcgacgacatactcataggtctt cggaatcggatcattttagctatgttcagttgag gaacgcagcagatctggatgacagaagaaaccga atattaaccaggaaggccaacagctcaggagaag ccatgtcactggggagccacagcccgcagagtga ctccctgacacagcttgtccagcagccggatatg atgtattttattctcttcctgtggctcctggtgt actgcttgctgctcttcccacaactggatgttag caggctctgatacgtg 80 221434_s_at cctcagcagcgcgaggtgctgcggcgctgcgtagaagtat caatcagccggttgcttttgtgagaagaattccttggact gcggcgtcgagtcagctgaaagaacactttgcacagttcg gccatgtcagaaggtgcattttaccttttgacaaggagac tggctttcacagaggtttgggttgggttcagttttcttca gaagaaggacttcggaatgcactacaacag 81 221737_at gaaatctatttttaactcttatgttcgtagagaaattgtt tcaaggattttgagtcataggtctgtaatttatagagatc tctagaattcttattgtaattttcctacttctttgataaa agaaaaataagtcagattgttaactccaagattgaaaaaa aaaactcttgaaagaagattattagttgtaactaatttgg gggttctgggcacagacatctaacctggtattgtaaggca gaggctcccattggaatggtagtggtccgggtcagttgtt catggtgtaagctttgcacagtgtattaacattgggaggg tctggcttgaaaatttggccaccctcagcc 82 AFFX- tagttttaccctactgatgatgtgttgttgccat M27830_5_at ggtaatcctgctcagtacgagaggaaccgcaggt tcagacatttggtgtatgtgcttggctga 83 36711_at ttgcacggatctaagttattctccccagccagag cccgngctnnctgctcccngggaaaagntggcgt antggncctgagctgggntttatattttatatct gcaaataaatnacattttatcntanatttaggga aagccngagagnaacaacaaaaaatgtttaagcc nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnntattgcccggc tcctagaatttatttatttcctgacttacagcaagcgagttatcgtcttc tgtattttg 84 38037_at ccactctatgagttggacttcagtcttgcctaggcgattt tgtctaccatttgtgttttgaaagcccaaggtgctgatgt caaagtgtaacagatatcagtgtctccccgtgtcctctcc ctgncaagtctcagaagaggttgggcttccatgcctgtag ctttcctggtccctcacccccatngccccaggcccacagc gtgggaactcactttcccttgtgtcaagacatttctnnnn nnnnnnnnnnnnnnnnnnnnnnactccatgcaggggtcag tgcagcagaggacagtctggagaaggtattagcaaagcaa aaggctgagaaggaacagggaacattggagctgactgttc ttggtaactgattacctgccaattgctaccgagaaggttg gaggtggggaaggctttgtataatcccacccacctcacca aaacgannnnnnnnnnnnnnnnnngtcctttctggaagtt tctggtgccatttc 85 201386_s_at Ggagatcatctgacactgctgaacgtctaccatgctttta aacaaaatcatgaatcggttcagtggtgttatgacaactt cattaactacaggtccctgatgtccgcagacaatgtacgc cagcagctatctcgaattatggacagatttaatttgcctc gtcgaagtactgactttacaagcagggactattatattaa tataagaaaagctttggttactgggtattttatgcaggtg gcacatttagaacgaacagggcattacttaactgtgaaag ataaccaggtggttcagttgcatccctctactgttcttga ccacaaacctgaatgggtgctttataatgagtttgttcta acaacaaagaattacatccggacatgtacagatatcaagc cagaatggttggtgaaaattgcccctcaatattatgacat gagcaatttcccacagtgtgaagcaaagagacagttggac cgcatcattgcc 86 201890_at gctactttgaattaatctgcctttatgtttgggagaagaa agctgagacattgcatgaaagatgatgagagataaatgtt gatcttttggccccatttgttaattgtattcagtatttga acgtcgtcctgtttattgttagttttcttcatcatttatt gtatagacaatttttaaatctctgtaatatgatacatttt cctatcttttaagttattgttacctaaagttaatccagat tatatggtccttatatgtgtacaacattaaaatgaaaggc tttgtcttgcattgtgaggtacaggcggaagttggaatca ggttttaggattctgtctctcattagctgaataatgtgag gattaacttctgccagct 87 202219_at aagcttcgagctgttgcgtgtgtgagtctgttgtgtggat gtgcgtgtgtggtccccagccccagactggattggaaaag tgcatggtgggggcctcggggctgtccccacgctgtccct ttgccacaagtctatggggcaagaggctgcaatattccgt cctgggtgtctgggctgctaacctggcctgctcaggcttc ccaccctgtgcggggcacacccccaggaagggaccctgga cacggctcccacgtccaggcttaaggtggatgcacttccc gcacctccagtcttctgtgtagcagctttaacccacgttt gtctgtcacgtccagtcccgagacggctgagtgaccccaa gaaaggcttccccgacacccagacagaggctgcagggctg gggctgggtgagggtggcgggcctgcggggacattctact gtgctaaa 88 202464_s_at tattctgtcctgagaccacgggcaaagctcttccattttg agagagaagaaaaactgtttggaaccacaccaatgatatt tttctttgtaatacttgaaatttatttttttattattttg atagcagatgtgctatttatttatttaatatatgtataag gagtcctaaacaatagaaagctgtagaagctgtagagata ggcttcagttgttaattggtttggagcctcctatgtgtga cttatgactctctgtgttctgtgtatttgtctgaattaat gacctgggatataaagctatgctagctttcaaacaggaga tgccttcagaaagctttgtatattttgcagttgccagacc aataaaatacc 89 203115_at aactccaattcaggagcccttgcgagtatatctgaagcac ttatttgctaaggaaacctgaattgatancagtactgtgc tgtctggaataatgtccttgatactgagttgggaccagac tggcttttatagtgacaggcaaagaggaatttattgagat cactgctcatggcatttgttgctgtaagaagtgttgcctt tgattgttactaaccacggatgggtaacggtcatacatta ggctagtgtttggtaggacaaaatctttttagagctttga gaattgtcatcctgttggtcaactttgaaatacaaatgtt tgccctggtaattagcaatgaactgctggcagtttcttca gctgtgtatatacggatctggcttttaattgatgaatcaa cttctacagaaacttttgcagggacagtgttgatgaggca gtttagcttgccagggtgatgataaagcccaggtccctgc atgtatagtgctcttctaaagaatatgcattcttgaacta cttaactttt 90 203574_at gtatggtacattcttctcttactcctttctcagtgcaagt gactaacattcaagattggtctctcaaatcggagcactgg catcaaaaagaactgagtggcaaaactcagaatagtttca aaactggagttgttgaaatgaaagacagtggctacaaagt ttctgacccagagaacttgtatttgaagcaggggatagca aacttatctgcagaggttgtctcactcaagagacttatag ccacacaaccaatctctgcttcagactctgggtaaattac tactgagtaagagctgggcatttagaaagatgtcatttgc aatagagcagtccattttgtattatgctgaattttcactg gacctgtgatgtcatttcactgtgatgtgcacatgttgtc tgtttggtgtctttttgtgcacagattatgatgaagatta gattgtgttatcactctgcctgtgtatagtcagatagtcc atgcgaaggctgtatat 91 203887_s_at cagggggtgtgtctgctcagtaatttgaggacaaccattc cagactgcttccaattttctggaatacatgaaatatagat cagttataagtagcaggccaagtcaggcccttattttcaa gaaactgaggaattttctttgtgtagctttgctctttggt agaaaaggctaggtacacagctctagacactgccacacag ggtctgcaaggtctttggttcagctaagctaggaatgaaa tcctgcttcagtgtatggaaataaatgtatcatagaaatg taacttttgtaagacaaaggttttcctcttctattttgta aactca 92 203932_at tcttacggggacacttacacctgtgtggtagagcacattg gggctcctgagcccatccttcgggactggacacctgggct gtcccccatgcagaccctgaaggtttctgtgtctgcagtg actctgggcctgggcctcatcatcttctctcttggtgtga tcagctggcggagagctggccactctagttacactcctct tcctgggtccaattattcagaaggatggcacatttcctag aggcagaatcctacaacttccactccaagtgagaaggaga ttcaaactcaatgatgctaccatgcctctccaacatcttc aaccccctgacattatcttggatcctatggtttctccatc caattctttgaatttcccagtctcccctatgtaaaactta gcaacttgggggacctcattcctgggactatgctgtaacc aaattattgtccaaggctatatttctgggatgaatataat ctgaggaagggagttaaagaccctcctggggctctcagtg tgccatagaggac 93 204131_s_at ttaccattccgggttcgagcatcacaagcttttgagcgca tggaactccataaactaacaaattacataaactaaagggg gattttctttcttcttttgtttggtagaaaattatccttt tctaaaaactgaacaatggcacaattgtttgctatgtgca cccgtccaggacagaaccgtgcataggcaaaaggagtgga gcacagcgtccggcccagtgtgtttccggttctgagtcag ggtgatctgtggacgggaccccagcaccaagtctacgggt gccagatcagtagggcctgtgatttcctgtcagtgtcctc agctaatgtgaacagtgttggtctgctggttagaaactag aatattgatattttcaggaaagaaatcagctcagctctcc actcattgccaaatgtcac 94 204419_x_at acactcgcttctggaacgtctgaggttatcaataagctcc tagtccagacgccatgggtcatttcacagaggaggacaag gctactatcacaagcctgtggggcaaggtgaatgtggaag atgctggaggagaaaccctgggaaggctcctggttgtcta cccatggacccagaggttctttgacagctttggcaacctg tcctctgcctctgccatcatgggcaaccccaaagtcaagg cacatggcaagaaggtgctgacttccttgggagatgccat aaagcacctggatgatctcaagggcacctttgcccagctg agtgaactgcactgtgacaagctgcatgtggatcctgaga acttcaagctcctgggaaatgtgctggtgaccgttttggc aatccatttcggcaaagaattcacccctgaggtgcaggct tcctggcagaagatggtgactggagtggccaatgccctgt cctccagataccactgagctcactgcc 95 204467_s_at ctcggaattccctgaagcaacactgccagaagtgtgtttt ggtatgcactggttccttaagtggctgtgattaattattg aaagtggggtgttgaagaccccaactactattgtagagta gtctatttctcccttcaatcctgtcaatgtttgctttatg tattttggggaactgttgtttgatgtgtatgtgtttataa ttgttatacatttttaattgagccttttattaacatatat tgttatttttgtctcgaaataattttttagttaaaatcta ttttgtctgatattggtgtgaatgctgta 96 204848_x_at acactcgcttctggaacgtctgagattatcaataagctcc tagtccagacgccatgggtcatttcacagaggaggacaag gctactatcacaagcctgtggggcaaggtgaatgtggaag atgctggaggagaaaccctgggaaggctcctggttgtcta cccatggacccagaggttctttgacagctttggcaacctg tcctctgcctctgccatcatgggcaaccccaaagtcaagg cacatggcaagaaggtgctgacttccttgggagatgccat aaagcacctggatgatctcaagggcacctttgcccagctg agtgaactgcactgtgacaagctgcatgtggatcctgaga acttcaagctcctgggaaatgtgctggtgaccgttttggc aatccatttcggcaaagaattcacccctgaggtgcaggct tcctggcagaagatggtgactgcagtggccagtgccctgt cctccagataccactgagcctcttgcccatgattcagagc t 97 205239_at atttcaaaatttctgcattcacggagaatgcaaatatata gagcacctggaagcagtaacatgcaaatgtcagcaagaat atttcggtgaacggtgtggggaaaagtccatgaaaactca cagcatgattgacagtagtttatcaaaaattgcattagca gccatagctgcctttatgtctgctgtgatcctcacagctg ttgctgttattacagtccagcttagaagacaatacgtcag gaaatatgaaggagaagctgaggaacgaaagaaacttcga caagagaatggaaatgtacatgctatagcataactgaaga taaaattacaggatatcacattggagtcactgccaagtca tagccataaatgatgactcggtcctctttccagtggatca taagacaatggaccctttttgttatgatggttttaaactt tcaattgtcactttttatgctatttctgtata 98 205571_at gatcaggagcaatgccactgctagcataccttccttagtg aaaaatcttttggaaaaggatcccactctgacctgtgaag tactaatgaatgctgttgctacagagtatgctgcctatca tcaaattgataatcacattcacctaataaacccaacggat gagacactgtttcctggaataaatagcaaagccaaagaac tgcaaacttgggagtggatatatggcaaaactccaaagtt tagtataaatacttcctttcatgtgttatatgaacagtca cacttggaaattaaagtattcatagacataaagaatggaa gaattgaaatttgtaatattgaagcacctgatcattggtt gccattggaaatacgtgacaaattaaattcaagtcttatt ggcagtaagttttgcccaactgaaactaccatgctaacaa atatattacttagaacatgtccacaagaccacaaact 99 205592_at tgggggccacagactcaacatgtgtgtgtggtggggttcc agcccaacatagagtaacattatttgtacctcccaggcta gctcagtccatgggaggctctcctgtccctgaaagctgac acccacctttcaccacttcgcccatgctacagttcagttt cctcgtctgtaaaatggggatgataatggtacctaccttg cagtgttgttataaggattaaaggagacagtgcaagaaaa ggccttggttggtgaagagcccaacctcggaggggagctg ctgggatcctccttatcttgactgggatgtccctgtctcc ccctccccttgctccttgaacatggccaaggaaagtgaaa aacaaaaattattcactctgctagcacccttccccttgat
gcctgggaataggttttgccaa 100 205863_at tagctccacattcctgtgcattgaggggttaacattaggc tgggaagatgacaaaacttgaagagcatctggagggaatt gtcaatatcttccaccaatactcagttcggaaggggcatt ttgacaccctctctaagggtgagctgaagcagctgcttac aaaggagcttgcaaacaccatcaagaatatcaaagataaa gctgtcattgatgaaatattccaaggcctggatgctaatc aagatgaacaggtcgactttcaagaattcatatccctggt agccattgcgctgaaggctgcccattaccacacccacaaa gagtaggtagctctctgaaggctttttacccagcaatgtc ct 101 205900_at tcaagtcctctggtggcagttccagcgtgaggtttgtttc taccacttattccggagtaaccagataaagagatgccctc tgtttcattagctctagttctcccccagcatcactaacaa atatgcttggcaagaccgaggtcgatttgtcccagcctta ccggagaaaagagctatggttagttacactagctcatcct attcccccagctctttcttttctgctgtttcccaatgaag ttttcagatcagtggcaatctcagttcccttgctatgacc ctgctttgttctttcccgagaaacagttcagcagtgacca ccacccacatgacatttcaagcaccaccttaagccagcca gagtaggaccagttagacctagggtgtggacagctccttg catcttaacactgtgc 102 205950_s_at gagccccattcacaaattttgacccctctactctccttcc ttcatccctggatttctggacctaccctggctctctgact catcctcctctttatgagagtgtaacttggatcatctgta aggagagcatcagtgtcagctcagagcagctggcacaatt ccgcagccttctatcaaatgttgaaggtgataacgctgtc cccatgcagcacaacaaccgcccaacccaacctctgaagg gcagaacagtgagagcttcattttgatgattctgagaaga aacttgtccttcctcaagaacacagccctgcttctgacat aatccagttaaaataataatttttaagaaataaatttatt tcaatattagcaagacagcatgccttcaaatcaatctgta aaactaagaaacttaaattttagttcttactgcttaattc aaataataattagtaagctagcaaatagtaatctgtaagc ataagcttatcttaaattcaagtttagtttgaggaattct ttaaaattacaactaagtgatttgtatgtctatttttttc 103 205987_at ccagctgttgctggtttgtcatgcctccggcttctaccca aagcctgtttgggtgacatggatgcggaatgaacaggagc aactgggcactaaacatggtgatattcttcctaatgctga tgggacatggtatcttcaggtgatcctggaggtggcatct gaggagcctgctggcctgtcttgtcgagtgagacacagca gtctaggaggccaggacatcatcctctactggggacacca ctcttccatgaattggattgccttggtagtgatagtgccc ttggtgattctaatagtccttgtgttatggtttaagaagc actgctcatatcaggacatcctgtgagactcttccccctg actcccccattgtgttaagaacccagcaacccaggagcct agtacaatatagtgatgccatcccgtcgactctccattta aattgtt 104 206025_s_at ggataccccattgtgaagccagggcccaactgtggatttg gaaaaactggcattattgattatggaatccgtctcaatag gagtgaaagatgggatgcctattgctacaacccacacgca aaggagtgtggtggcgtctttacagatccaaagcaaattt ttaaatctccaggcttcccaaatgagtacgaagataacca aatctgctactggcacattagactcaagtatggtcagcgt attcacctgagttttttagattttgaccttgaagatgacc caggttgcttggctgattatgttgaaatatatgacagtta cgatgatgtccatggctttgtgggaagatactgtggagat gagcttccagatgacatcatcagtacaggaaatgtcatga ccttgaagtttctaagtgatgcttcagtgacagctggagg tttccaaatcaaatatgttgcaatggatcctgtatccaaa tccagtcaag 105 206111_at Gtttacctgggctcaatggtttgaaacccagcac atcaatatgacctcccagcaatgcaccaatgcaa tgcaggtcattaacaattatcaacggcgatgcaa aaaccaaaatactttccttcttacaacttttgct aacgtagttaatgtttgtggtaacccaaatatga cctgtcctagtaacaaaactcgcaaaaattgtca ccacagtggaagccaggtgcctttaatccactgt aacctcacaactccaagtccacagaatatttcaa actgcaggtatgcgcagacaccagcaaacatgtt ctatatagttgcatgtgacaacagagatcaacga cgagaccctccacagtatccggtggttccagttc acctggatagaatcatctaagctcctgtatcagc actcctcatcatcactcatctgccaagctcctcaatcatagcca agatcccatctctccatatactttggg 106 206834_at Ggagaagactgctgtcaatgccctgtggggcaaa gtgaacgtggatgcagttggtggtgaggccctgg gcagattactggtggtctacccttggacccagag gttctttgagtcctttggggatctgtcctctcct gatgctgttatgggcaaccctaaggtgaaggctc atggcaagaaggtgctaggtgcctttagtgatgg cctggctcacctggacaacctcaagggcactttt tctcagctgagtgagctgcactgtgacaagctgc acgtggatcctgagaacttcaggctcttgggcaa tgtgctggtgtgtgtgctggcccgcaactttggc aaggaattcaccccacaaatgcaggctgcctatc agaaggtggtggctggtgtggctaatgccctggc tcacaagtaccattgagatcctggactgtttcct gataaccataagaagaccctatttccctagattc tattttctgaacttgggaacacaatgcctacttcaagggtatggcttc 107 207332_s_at aaggagagtcccctgaaggtctgacacgtctgcctaccca ttcgtggtgatcaattaaatgtaggtatgaataagttcga agctccgtgagtgaaccatcatataaacgtgtagtacagc tgtttgtcatagggcagttggaaacggcctcctagggaaa agttcatagggtctcttcaggttcttagtgtcacttacct agatttacagcctcacttgaatgtgtcactactcacagtc tctttaatcttcagttttatctttaatctcctcttttatc ttggactgacatttagcgtagctaagtgaaaaggtcatag ctgagattcctggttcgggtgttacgcacacgtacttaaa tgaaagcatgtggcatgttcatcgtataacacaatatgaa tacagggcatgcattttgcagcagtgagtctcttcagaaa acccttttctacagttagggttgagttacttcctatcaag ccagtacgtgctaacaggctcaatattcctgaatgaaata tcagactagtgacaagctcctggtcttgagatgtcttctc 108 208632_at aacccagaatggcacacactgctctgctgtagcatcatgt cagggcttcctggactcagtacacctctcagtttgtcttt taaaaaacagctgaatctttactacctatttagttctcct tgttaaagaaacaggggtgggaataaaatggatttaggna cacccagtttgaattgcagtttttttttttctgacacatg gccaggctgtggtgccagcttaatggagtaggctgtcctt ggcacttgcatgtgtgaaaggagggttttgcctcttcttg agcatggcttgagttggtaaggaaagctgtaactcacgaa gccctgagacctgctacccctaagatcgagcttgttttca gtgactggcttgagtcataggaggaggagtctggtacagc tgcaggagagcagggccatctgaagcggtagcattgccac catctccctctcatctagagcagttttcttatgccttggt tt 109 209007_s_at gaagatggaactcgaaatcccaatgaaaaacctacccagc aaagaagcatagcttttagctctaataattctgtagcaaa gccaatacaaaaatcagctaaagctgccacagaagaggca tcttcaagatcaccaaaaatagatcagaaaaaaagtccat atggactgtggatacctatctaaaagaagaaaactgatgg ctaagtttgcatgaaaactgcactttattgcaagttagtg tttctagcattatcccatccctttgagccattcaggggta cttgtgcatttaaaaaccaacacaaaaagatgtaaatact taacactcaaatattaacattttaggtttctcttgcagat atgagagatagcacagatggaccaaaggttatgcacaggt gggagtcttttgtatatagttgtaaatattgtcttggtta tgtaaaaatgaaattttttagacacagtaattgaactgta ttcctgttttgtat 110 209458_x_at agagaacccaccatggtgctgtctcctgccgacaagacca acgtcaaggccgcctggggtaaggtcggcgcgcacgctgg cgagtatggtgcggaggccctggagaggatgttcctgtcc ttccccaccaccaagacctacttcccgcacttcgacctga gccacggctctgcccaggttaagggccacggcaagaaggt ggccgacgcgctgaccaacgccgtggcgcacgtggacgac atgcccaacgcgctgtccgccctgagcgacctgcacgcgc acaagcttcgggtggacccggtcaacttcaagctcctaag ccactgcctgctggtgaccctggccgcccacctccccgcc gagttcacccctgcggtgcacgcctccctggacaagttcc tggcttctgtgagcaccgtgctgacctccaaataccgtta agctg 111 209795_at tagtctaattgaatcccttaaactcagggagcatttataa atggcaaatgcttatgaaactaagatttgtaatatttctc tctttttagagaaatttgccaatttactttgttatttttc cccaaaaagaatgggatgatcgtgtatttatttttttact tcctcagctgtagacaggtccttttcgatggtacatattt ctttgcctttataatcttttatacagtgtcttacagagaa aagacataagcaaagactatgaggaatatttgcaagacat agaatagtgttggaaaatgtgcaatatgtgatgtggcaaa tctctattaggaaatattctgtaatcttcagacctagaat aatactagtcttataataggtttgtgactttcctaaatca attctattacgtgcaatacttcaatacttcat 112 210027_s_at Tgggatgaagcctttcgcaagttcctgaagggcc tggcttcccgaaagccccttgtgctgtgtggaga cctcaatgtggcacatgaagaaattgaccttcgc aaccccaaggggaacaaaaagaatgctggcttca cgccacaagagcgccaaggcttcggggaattact gcaggctgtgccactggctgacagctttaggcac ctctaccccaacacaccctatgcctacacctttt ggacttatatgatgaatgctcgatccaagaatgt tggttggcgccttgattactttttgttgtcccac tctctgttacctgcattgtgtgacagcaagatcc gttccaaggccctcgcgagtgatcactgtcctat caccctatacctagcactgtgacaccacccctaa atcactttgagcctgggaaataagccccctcaac taccattccttctttaaacactcttcagagaaat ctgcattctatttctcatgtataaaacgaggaatcctccaaccaggct cctgtgataga 113 210254_at Atacaccagcagggcaattagcagcttggggaagttggaa gtctcgatgttgtgatagtagaccacggaggtgacagcag ccatgaacgccatcccggctggcatgtacaggtgcagatg gtgggattcggtcaccccatcagacaggatgccctctgca atctcacacaccaggacgaagagcagcatgaaggtcagga tccaccgcaggttgtgcccngggaaatgaagccatgtgct gtggtggatgtgcaccttggagctctgacttccccatcca atgaagaggatggggaaggtgatgaagagtaggaagacgt gcggcaccacgttgagcgcgtccacaaagcagccgttgtt gaggaccc 114 210338_s_at gaactgaatgctgacctgttccgtggcaccctggacccag tagagaaagcccttcgagatgccaaactagacaagtcaca gattcatgatattgtcctggttggtggttctactcgtatc cccaagattcagaagcttctccaagacttcttcaatggaa aagaactgaataagagcatcaaccctgatgaagctgttgc ttatggtgcagctgtccaggcagccatcttgtctggagac aagtctgagaatgttcaagatttgctgctcttggatgtca ctcctctttcccttggtattgaaactgctggtggagtcat gactgtcctcatcaagcgtaataccaccattcctaccaag cagacacagaccttcactacctattctgacaaccagcctg gtgtgcttattcag 115 211038_s_at tggtgttccttgaatgcctatcttccttttgtgcctcgga acctctcacgcctgccacaagttactcttttccttggtag ttctaaactttaaataaggtaatgcctgtaagaatgccat aaatgctcaataattgtcatctgttattattttcatcagt aacatcatctgaatcatcagtattgtctgcttttaacagc tgcatttttcattgtccaaatatagtcacatacatttgac cattttataattattgaataataaattcgttctgctattt tacaatgaaaaataatgctgcagagagcatttttgcacat gtatcgtggcagatgtaggccagaggctcttctttatcca tcctatggccaacctatgaatgtatacacgtttaatgaga ttttgccagcaatcaaagccttcagggaaaatgtccctag ctctttactacatcagatcaagaactctggataattggca taacatcctggaatagctgaaacagagatattattctctg ctgtcctctgttgtctttgtcttttcacgtcttaata 116 211458_s_at aaatagcattaaactggaattgacagagtgagttgagcat ctctgtctaacctgctctttctctctggtgctcctcatct cacccctaccttggaatttaataagcttcaggcatttcca attgcagactaaaaccacttctaccatctcctctagtatt ttccatgtatcaggacagagatgtcttatgtagggaaggg gcaggtatgaagtaaggtagattatctatacctctcactc attcaggattctcgctcccatgctgctgtcccttcattct cacactcacaggaatgctatgtgatggccagctgcttccc ttcttggttatccactgcagctgctagttagaaaggtttg cagggatgacttttagtaaatcatggggattttattgatt tattatcacttataggattttgtggggtgggagtggggag caggaattgcactcagacatgacatttcaattcatctctg caaatgaaaagggttcttcctcttgggggaaatctgtgtg tcagttctgtcagctgcaagttctt 117 211560_s_at tccccatccgggtgggcaatgcagcactcaacagcaagct ctgtgatctcctgctctccaagcatggcatctatgtgcag gccatcaactacccaactgtcccccggggtgaagagctcc tgcgcttggcaccctccccccaccacagccctcagatgat ggaagattttgtggagaagctgctgctggcttggactgcg gtggggctgcccctccaggatgtgtctgtggctgcctgca atttctgtcgccgtcctgtacactttgagctcatgagtga gtgggaacgttcctacttcgggaacatggggccccagtat gtcaccacctatgcctgagaagccagctgcctaggattca caccccacctgcgcttcacttgggtccaggcctactcctg tcttctgctttgttgtgtgcctctagctgaattgagccta a 118 211991_s_at Gcactgggaggcccaagagccaatccagatgcct gagacaacggagactgtgctctgtgccctgggcc
tggtgctgggcctagtnggcatcatcgtgggcac cgtcctcatcataaagtctctgcgttctg 119 212199_at attttgctgttacctttgtgacctgattgttttttggaac acgtcaagacgtgggatcagaatcttccaactttagaggt gcaatggaagacactacgctacttggttgagcctggtgaa gaatgtattaatgagactgctttgcataaaactgggaaga aagagaagacagttggagatggaagatggttttgtatata ttttggaactttagttcctctgtgagacgaaagaggagag ctatgttttgtgtcacattgtctgatatatattgtgtaac ctgtcaggtgagttgatttagacaacatagctgacctttt atgacaaggcagtttgaatagggactattgtaataccctc acacattatcggggcancagagaatggcatggaagagaca gtctacagagagctttaagaggccggagaaaggaaaagac attatcagggcctggaaagtctcttccagttcatcagggt ag 120 212224_at Acagtgttctctaatgttacagatgagatgcgca ttgccaaagaggagatttttggaccagtgcagca aatcatgaagtttaaatctttagatgacgtgatc aaaagagcaaacaatactttctatggcttatcag caggagtgtttaccaaagacattgataaagccat aacaatctcctctgctctgcaggcaggaacagtg tgggtgaattgctatggcgtggtaagtgcccagt gcccctttggntgggattcaagatgtctggaaat ggaagagaactgggagagtacggtttccatgaat atacagaggtcaaaacagtcacagtgaaaatctc tcagaagaactcataaagaaaatacaagagtggagaga agctcttcaatagctaagcatctccttacagtcactaatat 121 212232_at agaaggcagctctgcattctaccttgcttgactggaattg tctgaagctttttctggcctcttttctctagtcggccacc cctgaagtgctgaggtctaagtggtttacctcgtgctgat agatggccacactctttagagtagttctcataagttctag aactggtagctcggtcgtttcgcacactaggtggcataca ggcagcagcaggtgttcatatccttgattttgagaatttc ccctcaagtatgtggcagtaaatacaacaagacactctat gtattaatgtctccattgtcttaaccctgttccaaaacaa aattcacctcctttctttatgtg 122 212534_at gtggattgtttgtatcccttacctgctttctattgggtta tgtgtggatatattgtttttatttgttcagcatctccttc cccatcttctggtaacacaacctttatttatttgtgggga acctattccctgtggcttaggtgagcatgtgaccaggcct ggcctcctgagtcccacagcttcctagccacagtgataaa agaatgggntatataacttaagccaggctaaggaaagccc ttaacagaacttctgctggaactactggaaagaaggcttt atggagatcccaggaaccaaggaccatgtaagcctgaatt tgtgccatgtggagagagtctgtctgaggagaaactcgga tgctagcagaaatggaaagagaactaagttctgatgtcat ttttctggaggccctagatccagctgt 123 213142_x_at ctgctgccattttaatcttgctcattaaccttactccttt gagaattctttaacaatatttaaaattggtaacaaaaata gtttagccataattgtttagccatgtgagtttcaggttgg tacacgttcagacagaactgctgtatcacattccaatttt gaatagccagtgagcaatcaagtgtagagaaatgataaat ggcctaagaaggcatacagtggcataaacgatgctcttcc tagtagcttaataggccacaagctagtttctgttgcactc tgaaataaaatatgctttaaaaatgtagggaacagtgctt agaaaagcaaaaactaggtgtgtcattgaaataataggca taaaaattaaatgttacataagaacactatttggaaagag ggtccttttaaaaactgaatttgtactaaatcagatttgc catgtccagtacagaataatttgtacttagtatttgcagc agggtttgtctttgtga 124 214433_s_at cttcctcggaggcagcattgttaagggaggccctgtgcaa gtgctggaggacgaggaactaaagtcccagccagagcccc tagtggtcaagggaaaacgggtggctggaggccctcagat gatccagctcagcctggatgggaagcgcctctacatcacc acgtcgctgtacagtgcctgggacaagcagttttaccctg atctcatcagggaaggctctgtgatgctgcaggttgatgt agacacagtaaaaggagggctgaagttgaaccccaacttc ctggtggacttcgggaaggagccccttggcccagcccttg cccnatgagctccgctaccctgggggcgattgtagctctg acatctggatttgaaggctccaccctcatcacccacactc cctattttgggccctcacttccttggggacctggcttcat tctgctctctcttggcacccgacccttggcagcatgtacc acacagccaagctgagactgtggcaatgtgttgagtcata tacatttactgaccactgttgct 125 215933_s_at ggacagttcctgtgatcagaggcaagatttgcccagngaa cagaataaaggtgcttctttggatagctctcaatgttcgc cctcccctgcctcccaggaagaccttgaatcagagatttc agaggattctgatcaggaagtggacattgagggcgataaa agctattttaatgctggatgatgaccactggcattggcat gttcagaaaactggatttaggaataatgttttgctacaga aaatcttcatagaagaactggaaggctatataagaaaggg aatcaattctctggtattctggaaacctaaaaatatttgg tgcactgctcaattaacaaacctacatggagaccttaatt ttgacttaacaaatagtttatgtactgctcttaggttgtt ttgataaagtgacattatagtgattaaattctttccnctt taaaaaaacagntagtggttttcactatttataaatagga ccttcttgaacgacttttctg 126 217478_s_at ctgttttgtcagtaatctcttcccacccatgctgacagtg aactggcagcatcattccgtccctgtggaaggatttgggc ctacttttgtctcagctgtcgatggactcagcttccaggc cttttcttacttaaacttcacaccagaaccttctgacatt ttctcctgcattgtgactcacgaaattgaccgctacacag caattgcctattgggtaccccggaacgcactgccctcaga tctgctggagaatgtgctgtgtggcgtggcctttggcctg ggtgtgctgggcatcatcgtgggcattgttctcatcatct acttccggaagccttgctcaggtgactgattcttccagac cagaatttgatgccagcagcttcagccatccaaacagagg atgctcagatttctcacatcctgc 127 217736_s_at tctgtctggtcttcctctagaaggttctaccgcagaaatt gatgtgtgctccctgccctcgtcactgcccaagcccgggc ctgcacatactcactggactgttccagttttgacagctgc cagtcttcctgcccctttcacactgcagctgaagttcatt acctgaaggacgcctcatcatttcattccttggctccaaa ccttctgctgcctctaagataaaagctcaacttcttaaca gtgtacagtgtgcaacttccaacctttttatctgttctct ccaccttcagtttagcgtcattccaaaaccacacccttgc aaagctttgtactccgcaccccagatgatctccaggcagc tcagatctctttcctgcctttgccctgcactgttccccgg tacttcctcctttattgtagcactcagctccccagccaat ctgtacatccctcagaggcagcgatctgatgaattggttt ttgaatcccagaaacggtctgccatagagttcccagtcat cacggtagat 128 219069_at gaatattgtatactgcatcccctaccacaatttacacaat cctgtggatagtcctacctcaccctggtcaacctacatga tccttaagctaatggcgaatcacgatgaccttgtagacat gcacacaactatacctttgtccaacagatcataatatatc tgctatccaactggttttacctgcctaatcctactgattt gggcactgcttgtatagtctctcaagttcacaggaaatgt tgattttctaaggtcctcattt 129 219093_at tagagacccatgtcatcttaacctaaagggaaatcttatt gcgttatcataaaattgatgatatcttagggtcagaattg cccttttttttattttgaatgggaagctctcactaaaaca atcctgagatttcttaatttcatggttctttaaatattat aaacacagagtcaacatagaatgaaattgtatttgttaaa atacacacattggaggacaagagcagatgactacttttcg aagtaatgctgctccttcctaaaagtctgttttcaatcct ggtaatattaggggcactgcggcacctaagaagccttaaa tgagagctaatccaatttagagagcgatggtgtcagcatt tcggtctgcatatctgtgtgtccgtatctgcgtttgtgtg cgtgtacgtgtgcccctgtgtgtgggcccagttttcaggc atgtagaataagcatggagtcatattgaggaggactcact tcttgaagat 130 219228_at ggggttcgagcctcgttaagcacgagaggatacatacggg cgagaagccgtacaagtgcacagaatgtgggaaggccttc aattgtggctatcacctcactcagcacgagagaatccaca caggcgaaaccccgtataaatgtaaggagtgtgggaaggc tttcatttatggatcgagcctcgtgaaacatgagagaatt cataccggggtgaaaccctatgggtgtacagaatgtggga agagctttagtcacggccatcagcttacacaacatcagaa aacgcacagtggggcgaaatcctacgaatgtaaggagtgc gggaaggcatgtaaccacctaaaccatctccgagaacatc agaggatccacaacagttgaagagccttttgaacgcagta gcccgctcgtatctatggtttcgctttccacagtttgtta cctgca 131 219607_s_at atcaacacatttagcttggcgttttattcattccatcacc cttactgtaactactatggcaactcaaataattgtcatgg gactatgtccatcttaatgggtctggatggcatggtgctc ctcttaagtgtgctggaattctgcattgctgtgtccctct ctgcctttggatgtaaagtgctctgttgtacccctggtgg ggttgtgttaattctgccatcacattctcacatggcagaa acagcatctcccacaccacttaatgaggtttgaggccacc caaagatcaacagacaaatgctccagaaatctatgctgac tgtgacacaag 132 221748_s_at atattttgtatcatcgtgcctatagccgctgccaccgtgt ataaatcctggtgtntgctccttatcctggacatgaatgt attgtacactgacgcgtccccactcctgtacagctgcttt gtttctttgcaatgcattgtatggcttta 133 221766_s_at gatttccaggaagcctttgatcacctttgtaacaagatca ttgccaccaggaacccagaggaaatccgagggggaggcct gcttaagtactgcaacctcttggtgaggggctttaggccn gcctctgatgaaatcaagacccttcaaaggtatatgtgtt ccaggtttttcatcgacttctcagacattggagagcagca gagaaaactggagtcctatttgcagaaccactttgtggga ttggaagaccgcaagtatgagtatctcatgacccttcatg gagtggtaaatgagagcacagtgtgccntgatgggacatg aaagaagacagactttaaaccttatcaccatgctggctat ccgggtgttagctgaccaaaatgtcattcctaatgtggct aatgtcacttgctattaccagccagccccctatgtagcag atgccaactttagcaattactacattgcacaggttcagcc agtattcacgtgccagcaacagacctactccacttggcta ccctgcaattaaga 134 221622_s_at atgcatcattggctacacttccatttttgtctactgttgt tactgacaagctttttgtaattgatgctttgtattcagat aatataagcaaggaaaactgtgttttcagaagctcactga ttggcatagtttgtggtgttttctatcccagttctttggc ttttactaaaaatggacgcctggcaaccaagtatcatacc gttccactgccaccaaaaggaagggttttaatccattgga tgacgctttgtcaaacacaaatgaaattaattgcgattcc tctagtctttcagattatgtttggaatattaaatggctat accattatgcaagtatttgaaagagacacttgagaaaact atacatgaagagtaaccaaaaaaatgaatggttgctaact tagcaaaatgaagtttctataaagaggactcaggcattgc tgaaagagttaaaagtaactgtgaacaaataatttgttct gtgccttttgcctggtatatagc 135 218845_at aaaacattctggccgctccaggaattctgaagttctgggc ctttctcagaagactgtaatgtacctgaagtttctgaaat attgcaaacccacagagtttaggctggtgctgccaaaaag aaaagcaacatagagtttaagtatccagtagtgatttgta aacttgtttttcatttgaagctgaatatatacgtagtcat gtttatgttgagaactaaggatattctttagcaagagaaa atattttccccttatccccactgctgtggaggtttctgta cctcgcttggatgcctgtaaggatcccgggagccttgccg cactgccttgtgggtggcttggcgctcgtgattgcttcct gtgaacgcctcccaaggacgagcccagtgtagttgtgtgg gcgtgaactctgcccgtgtgttctcaaattccccagcttg ggaaatagcccttggtgtgggttttatctctggtttgtgt tctccgtggtggaattgaccgaaagctctatgttt 136 200786_at gttacattggtgcagccctagttttagggggagtagatgt tactggacctcacctctacagcatctatcctcatggatca actgataagttgccttatgtcaccatgggttctggctcct tggcagcaatggctgtatttgaagataagtttaggccaga catggaggaggaggaagccaagaatctggtgagcgaagcc atcgcagctggcatcttcaacgacctgggctccggaagca acattgacctctgcgtcatcagcaagaacaagctggattt tctccgcccatacacagtgcccaacaagaaggggaccagg cttggccggtacaggtgtgagaaagggactactgcagtcc tcactgagaaaatcactcctctggagattgaggtgctgga agaaacagtccaaacaatggacacttcctgaatggcatca gtgggtggctggccgcggttctggaaggtggtgagcattg aggcccagtaagacactcatgtgg 137 212886_at acaggcacatcaggctgcagaatgcgctttagaaagcatt gttttagtccaggcacagtggctcacgcctgtaatcccag cactttgggaggccgaggtgggtggatcacaaggttggga gattgagaccatcctggctaacacagtgaaaccctgtctc tactaaaaaaatacaaaaaattagcttggcgtggtggtgg gcgcctgtagtcccagcagcttgggaggctgaggctggag aatggtgtgaacccaggaggcggagcttgcagtgagccaa gatcgcgccactgcactccagcccgggtgacagagcaaga ctccgtctcaaaaaaaagaaaagaaaaaagaaagcattgt tttaattgagaggggcagggctggagaaggagcaagttgt ggggagccaggcttccctcacgcagcctgtggtggatgtg ggaaggagatcaacttctcctcactctgggacagacgatg tatggaaactaa 138 201407_s_at ggatgtgattctaaaagcttttattgagcattgtcaaatt tgtaagcttcatagggatggacatcatatctataatgccc ttctatatgtgctaccatagatgtgacatttttgacctta atatcgtctttgaaaatgttaaattgagaaacctgttaac ttacattttatgnattggcacattgtattacttactgcaa gagatatttcattttcagcacagtgcaaaagttctttaaa atgcatatgtctttttttctaattccgttttgttttaaag cacattttaaatgtagttttctcatttagtaaaagt
139 212266_s_at gttgagtttgcctcttatggtgacttaaagaatgctattg aaaaactttctggaaaggaaataaatgggagaaaaataaa attaattgaaggcagcaaaaggcacagtaggtcaagaagc aggtctcgatcccggaccagaagttcctctaggtctcgta gccgatcccgttcccgtagtcgcaaatcttacagccggtc aagaagcaggagcaggagccggagccggagcaagtcccgt tctgttagtaggtctcccgtgcctgagaagagccagaaac gtggttcttcaagtagatctaagtctccagcatctgtgga tcgccagaggtcccggtcccgatcaaggtccagatcagtt gacagtggcaattaaactgtaaataacttgccctgggggc ctttttttaaaaaacaaaaaccacaaaaattcccaaacca tacttgctaaaaattctggtaagtatgtgcttttctgtgg gggtgggatttggaaggggggttgggttgggctggatatc tttgt 140 53912_at acaatgaggcattctgtcctcctgctgccattcttcatct ccactgagagccagagctggtaggagccgagnnnccacag gcattctgcattgctctactcttaggtttgtgtgtgtgat ccttcccctccctgtcgcccactcctccctcctctggcta tcctaccctgtctgtgggctcttttactaccagcctatgc tgtgggactgtcatggcatttagttcagagtggaggggnn nnnnnnnnnnnnnaaatgcaagtatttnannnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnaanattgttgttgca atttgtgtctaacaagctgtagcagagaaggagggagtga gcgctggcagtatttcctttcataaatcatgaatttatca gtgtggaaataatgcttcagaactgtgctctgtagccctc ctgcannnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnngcgtgaaccttgttaggtatactttacctgatgc tgcttccatcctcgcagtctg 141 200090_at tccctttgcctgtggtgtaaaagtgcatcacacaggtatt gctttttaacaagaactgatgctccttgggtgctgctgct actcagactagctctaagtaatgtgattcttctaaagcaa agtcattggatgggaggaggaagaaaaagtcccataaagg aacttttgtagtcttatcaacatataatctaatcccttag catcagctcctccctcagtggtacatgcgtcaagatttgt agcagtaataactgcaggtcacttgtatgtaatggatgtg aggtagccgaagtttggttcagtaagcagggaatacagtc gttccatcagagctggtctgcacactcacattatcttgct atcactgtaaccaacta 142 218025_s_at ctccttgggctattcgatgccgtgtatgcatctgacaggg caacatttcatacaccatttagtcacctaggccaaagtcc ggaaggatgctcctcttacacttttccgaagataatgagc ccagccaaggcaacagagatgcttatttttggaaagaagt taacagcgggagaggcatgtgctcaaggacttgttactga agttttccctgatagcacttttcagaaagaagtctggacc aggctgaaggcatttgcaaagcttcccccaaatgccttga gaatttcaaaagaggtaatcaggaaaagagagagagaaaa actacacgctgttaatgctgaagaatgcaatgtccttcag ggaagatggctatcagatgaatgcacaaatgctgtggtga acttcttatccagaaaatcaaaactgtgatgaccactaca gcagagtaaagcatgtccaaggaaggatgtgctgttacct ctgatttccagtac 143 204232_at cgatctccagcccaagatgattccagcagtggtcttgctc ttactccttttggttgaacaagcagcggccctgggagagc ctcagctctgctatatcctggatgccatcctgtttctgta tggaattgtcctcaccctcctctactgtcgactgaagatc caagtgcgaaaggcagctataaccagctatgagaaatcag atggtgtttacacgggcctgagcaccaggaaccaggagac ttacgagactctgaagcatgagaaaccaccacagtagctt tagaatagatgcggtcatattcttctttggcttctggttc ttccagccctcatggttggcatcacatatgcctgcatgcc attaacaccagctggccctacccctataatgatcctgtgt cctaaattaatatacaccagtggttcctcctccctgttaa agactaatgctcagatgctgtttacggatatttatattct agtctcactctcttgtcccacccttcttctcttccccatt cccaactccagctaaaatat 144 201722_s_at attttgttttcatctgtgatagtcatggatgcttttattt tccttggggtgctgaaattgagctgaaaaaaaaaggctct ttgaatatagttttaatttctctctacagttttttttgtt tggtttgtgggctgttggaattgtaatttttaattgcctt ctaaaaaatggaaatttaacaatgtctgatctcagctgaa caaattagatgtttcagttgctcttgggtcaactggctta cagatttacatgtgcacacacacacaaatttcttatcaca ttttcgacttcttcacttgacctaactgattatgcgaaat acccaagattcatgctactgtaccacagatttgttttcac agcaataaatcttcagttctgttgtttatgattccactta acaaaaggcctgcagaagtgatttattatttgggtatttg gagataatacatttgatggttttttggaaaacctttttca ctccatactcagatatgcttcattgtcaaatgcatattta gattagattattgaattgtaatgtttatctgctgctttt 145 218627_at taatcatttctgggttcactgcgactcactgtagtgctgg ggatcccccttgtaacactggaactgaaaggcagtgatga aagctatgtcaagcattcattattctgaagaggaggagaa atgccacatacctttcccatgggacctgtggtggaatgaa tccatacttctgcctcacttcgagcagacttttgttctcg gcgctcctcacgatggagtttcatgcttcattttcacatc tctctgcacaattagattgggagctccttgagggcagagt acgtgccttaatctttatctttgtaatgccaccatgaaca gagtgcctcctggtacactgtaggagcttaagaaatactc actgaatgcatgaatgaatgaatgaacaaatgaaggaatg actaaggatgtttgtagtgctataatatagaatgggattt actctgctttacc 146 202322_s_at gttctcatttcctactattcatgctatttggtcaaggcct gaaagcacccaggtgcagaatatcttgcgccagagaacag aaaacatagatataaaaaaatactgtgtacattatcttga ggatgtaggttcttttgaatacactcgtaatacccttaaa gagcttgaagctaaagcctataaacagattgatgcacgtg gtgggaaccctgagctagtagccttagtaaaacacttaag taagatgttcaaagaagaaaatgaataatgttaagccatt cttgattggacctcatagcttattttagttaatctttttt ttgtcttttagccttaccaccttttaaaaaatttgttatt ctccagaaacagtaaataggtgagtaggggtggtgcaagt gaattcgttttcatttagaagcccctctgtacagataatc aaaattcaaagttgaaagaatcaaaagcagccacagttat gtaggtctgatttgaatgtcataattgcagtgacaggaca ttgccaccaactctatcctactaccatcaatgt 147 221689_s_at Accgtcgccattgccagaaagagcgatttatggctttgtt cttttcttaagctcccaatttggcttcatactttacctcg tgtgggcctttattcctgaatcttggctaaactctttagg tttaacctattggcctcaaaaatattgggcagttgcatta cctgtctacctccttattgctatagtaattggctacgtgc tcttgtttgggattaacatgatgagtacctctccactcga ctccatccatacaatcacagataactatgcaaaaaatcaa cagcagaagaaataccaagaggaggccattccagccttaa gagatatttctattagtgaagtaaaccaaatgttctttct tgcagccaaagaactttacaccaaaaactgaactgtgtgt aaccatagtaacaccaagcacgtatttatttataagtttt tgccattataattttgaccataaattaatttaaccatctc tcttattaatagagaagtaaaaaatgtaagttgaccttct cttagattat 148 203356_at tatacatcttgggcaactagttaccaaatgaattgtgcca ccataactgattttaattttgcattatttatgattttaaa atatttgttgcccaggtgttatgaaagaataaagctttta agtatagactaccttagcatgaagatgctcatgcctaaga atgaaaattgttgaggttatctcccattcaatcatgtagc aagaacttaaagaaattcactactgcagtttttattttta aaaaacagtaattgagatattgaagacattacaatttagt ttgtgtggtctttttttaaattgctgtatcgttcagtctc ttgtggcaatagcactttgaagaaaatagagaatttaata tatggtgattgggatatgtagcattcaaaaaaagtgaatt gccaagatactggtgtcatgtaaattcccactttacataa aaacccatcaggacagaatgatgctcaatattttaaaatt ctaaaaatagggtgggatttttcattgtctctactttata attatcaaaacttattttgtattgctactaccttaaattg aaa 149 218462_at aaatgagcagtgttcgtcttcgtaaagaaattaagagaag aggcaaggaccccacagaacacatacctgaaataattctg aataattttacaacacggctgggtcattcaattggacgta tgtttgcatctctctttcctcataatcctcaatttatcgg aaggcaggttgccacattccacaatcaacgggattacata ttcttcagatttcacagatacatattcaggagtgaaaaga aagtgggaattcaggaacttggaccacgttttaccttaaa attaaggtctcttcagaaaggaacctttgattctaaatat ggagagtatgaatgggtccataagccccgggaaatggata caagtagaagaaaattccatttataaagtactgagagaat gatattggattttgctgaacaggcctatcttgaactttgg taaattatttttgacagaatactcttttcaaaatggcatt tgctgatttcataaacctttcacgtctggacgaattacca aatgccatgaattgccactgtgtg 150 218123_at gtggaagccggtgtctgtgttaccatggagatggtgaaag atgccttggaccagcttcgaggcgcggtgatgattgttta ccccatggggttgccaccgtatgatcccatccgcatggag tttgaaaataaggaagacttgtcgggaacacaggcagggc tcaacgtcattaaagaggcagaggcgcagctgtggtgggc agccaaggagctgagaagaacgaagaagctttcagactac gtggggaagaatgaaaaaaccaaaattatcgccaagattc agcaaaggggacagggagctccagcccgagagcctattat tagcagtgaggagcagaagcagctgatgctgtactatcac agaagacaagaggagctcaagagattggaagaaaatgatg atgatgcctatttaaactcaccatgggcggataacactgc tttgaaaagacattttcatggagtgaaagacataaagtgg agaccaagatgaagttcaccagctgatgacacttccaaa 151 214329_x_at aggttgcagtgtggtgagatcatgccactacactccagcc tggcgacagagcgagacttggtttcnaaaaaaaaaaaaaa aaaaacttcagtaagtacgtgttatttttttcaataaaat tctattacagtatgtcatgtttgctgtagtgctcatattt attgttgtttttgttttagtactcacttgtttcataatat caagattactaaaaatgggggaaaggacttctaatctttt tttcataatatctttgacacatattacagaag 152 219067_s_at cgagaagatcctgataccccaatgtccttctttgactttg tggttgatcctcattctttcccccgtacagtggaaaacat ctttcatgtttccttcattatacgggatggttttgcaaga ataagacttgaccaagaccgactgccagtaatagagcctg ttagtattaatgaagaaaatgagggatttgaacataacac acaagttagaaatcaaggaattatagctttgagttaccgt gactgggaggagattgtgaagacctttgagatttcagagc ctgtgattactccaagtcagaggcagcagaagccaagtgc ttgatgctagctgaaggactcaaatggatagtgaagtcca aaacggaaagcggcatgtattgtaca 153 205789_at gtcatgaggcagctttcatcacacccttttaacatttatc taaaagaatttaaattctttttcaaaaattacactacaag tttataagcccaaatggctctgtgaaatcagaagtgcaaa ggtgtgcaaacttgtatctgaagacctaccagggacaagc aggtaagagctgatgtgagtgtgtgtgatgggatctgtaa ggaactggaacacacatgtcctatccaaaggaatcagctg cagctgcttgttgtcaagtataaagtcaggacctggcttg gctttaaccgtttttcaagaaaactggaaatctggatttt cagcgaacatgcctgattttaaaaggttgactcaagtttt tacaaaatactatgtgggacacctcaaatacatacctact gactgatgacaaacccaggagtttgtgtgtcttttataaa aagtttgccctggatgtcatat 154 209214_s_at cagtgtcccaatccgggttgtggaaaccagaacttcgcct ggagaacagagtgcaaccagtgtaaggccccaaagcctga aggcttcctcccgccaccctttccgcccccgggtggtgat cgtggcagaggtggccctggtggcatgcggggaggaagag gtggcctcatggatcgtggtggtcccggtggaatgttcag aggtggccgtggtggagacagaggtggcttccgtggtggc cggggcatggaccgaggtggctttggtggaggaagacgag gtggccctggggggccccctggacctttgatggaacagat gggaggaagaagaggaggacgtggaggacctggaaaaatg gataaaggcgagcaccgtcaggagcgcagagatcggccct actagatgcagagaccccgcagagctgcattgactaccag atttattttttaaaccagaaaatgttttaaatttataatt ccatatttataatgttggccacaacattatgattattcct tgtctgtactttagtatttttcacca 155 213427_at cgttgagagatctccagtgcccagtgctgcagagcagcga gctggagggaacgccagaggtgtcctgccgggctctggag ctcttcgactggctcggcgccgtcttcagtaatgtcgacc taaataatgagcctaataatttcatatcaacctattgctg tcctgagccaagcacagtggtggcaaaagcttatttgtgt acaatcactggcttcatacttccagagaagatctgtctcc tattggaacatctctgtcactactttgatgaaccgaagtt agctccatgggttacactgtccgttcaaggctttgcagac agccctgtttcttgggaaaaaaatgaacatggttttcgaa aaggaggagaacatttatataactttgtgatttttaataa tcaggactattggcttcagatggctgtt 156 209422_at Cagctcgggcgacaactgcaagactccatctcaaaaaaat aaaaataaaagaaaagaaagaaatatgtgcactacctaag ttttgtctttagaaaaactatccacctataaaaaattacc ttgacaaaaatagttccggtttgactaatcattttgtttc tttaagtggtaagtgtatgcaaggtggatccttgatgagc caacattgcactgtggatacatatctatgtttacgcgcta ttagaacagaaggcgctgtatatagaaatgttgctttgaa gcaatatttgcaaaacacgcagacttctgtatctg 157 201010_s_at gtgttctcctactgcaaatattttcatatgggaggatggt tttctcttcatgtaagtccttggaattgattctaaggtga tgttcttagcactttaattcctgtcaaattttttgttctc cccttctgccatcttaaatgtaagctgaaactggtctact gtgtctctagggttaagccaaaagacaaaaaaaattttac tacttttgagattgccccaatgtacagaattatataattc taacgcttaaatcatgtgaaagggttgctgctgtcagcct tgcccactgtgacttcaaacccaaggaggaactcttgatc
aagatgcccaaccctgtgatcagaacctccaaatactgcc atgagaaactagagggcaggtgttcataaaagccctttga acccccttcctgccctgtgttaggagatagggatattggc ccctcactgcagctgccagcacttggtcagtcactctcag ccatagcactttgttcactgtcctgtgtcagagcactgag ctccacccttttctgagagttat 158 200883_at ttgccaaggcaactcagcagccatttgatgtttctgcatt taatgccagttactcagattctggactctttgggatttat actatctcccaggccacagctgctggagatgttatcaagg ctgcctataatcaagtaaaaagaatagctcaaggaaacct ttccaacacagatgtccaagc 159 218454_at gtggctatccactgttagttcagaagctgggcttggacta ctcttatgatttagctccacgagccaaaattttccggcgt gaccaagggaaagtgactgatacggcatccatgaaatata tcatgcgatacaacaattataagaaggatccttacagtag aggtgacccctgtaataccatctgctgccgtgaggacctg aactcacctaacccaagtcctggaggttgttatgacacaa aggtggcagatatctacctagcatctcagtacacatccta tgccataagtggtcccacagtacaaggtggcctccctgtt tttcgctgggaccgtttcaacaaaactctacatcagggca tgccagaggtctacaactttgattttattaccatgaaacc aattttgaaacttgatataaaatgaaggagggagatgacg gactagaagactgtaaataagataccaaaggcactatttt agctatgtttttcccatcagaat 160 202918_s_at gagtgtcctgctatagactatactagacacacacttgatg gtgctgcatgtcttctgaatagcaataaatattttcccag cagggttagcataaaggaatcatctgtagcgaaactagga tcagtatgccgtaggatttacagaatattttcacatgctt attttcatcatcggcagatatttgatgaatatgaaaatga aacatttttgtgtcatcggtttactaagtttgtgatgaaa tacaatttgatgtccaaggataacctgattgtaccaattt tagaagaggaagtacagaattcagtttctggggaaagtga agcatgaagggaatcataggaaaaatgtactgatcatata attaacattatgtactgtatatatcattttagacacatca atcatgtatccatattatagcttctttgtttagtataggt ttttgtatgctgggtttgccttttaaaatgggaaatactt tttaagttattcataagctgtatattcaccagtgtggcac tcatggtttt 161 212204_at gcttaactcttttgacatctgctattgtgacacatcccat tgctggcaatgtggtgcacactccgaaacttttaactact gttttgtaagcctccaagggtggcattgcagggtccttag gcaatgttttgtttgcctttatgcagagaggtgctccaag tgctgtgattgagcaccgtgctagaggaactgtaatgctt cagaagttgtagcttatacaaaggaaacaggtcctgctgg cttaatttaaacagttattgcatgaagtagcgtggaggcc ctggactgctgctcgttctttaggatggactgttctggta tctggtattggtttagagactgttaataagggacatcaca aggtgatgggattcatttgaagcactctatttctgtttta atg 162 219452_at atcacttcgaccacatcaaggctgtcattggatccaagtt catcgggattggtggagattatgatggggccggcaaattc cctcaggggctggaagacgtgtccacatacccggtcctga tagaggagttgctgagtcgtggctggagtgaggaagagct tcagggtgtccttcgtggaaacctgctgcgggtcttcaga caagtggaaaaggtacaggaagaaaacaaatggcaaagcc ccttggaggacaagttcccggatgagcagctgagcagttc ctgccactccgacctctcacgtctgcgtcagagacagagt ctgacttcaggccaggaactcactgagattcccatacact ggacagccaagttaccagccaagtggtcagtctcagagtc ctccccccacatggccccagtccttgcagttgtggccacc ttcccagtccttattctgtggctctgatgacccagttagt cctgccagatgtcactgta 163 219889_at tactcaagcgggtggctctgggatcctgggggcctgggtt gggggctagggagacgccatgtgatggacactccagggac acacagcctagcacagcagcttataatgggctctccgggg ccatttgcaataacagctgcaattccctggatagacgagt tgatttcctccctctgcccctcccccagccataccagctg gcctttgtaagtgcaggaaaccgagtagaaaatgtgaccc tccaaatggagaagctgccagctttgccattgtgaaccat ggtgaagtgcttggaacatactgttcactcactctaaagg cgctgagactgtgctgttgttctcgtttttatagtcaatg gcttgttcatcatccagatgtggctactgacatatctaca cttcgcaccggagtgtctggaatt 164 201303_at caacttcactgtatcctcaatgcatggagacatgccccag aaagagcgggagtccatcatgaaggagttccggtcgggcg ccagccgagtgcttatttctacagatgtctgggccagggg gttggatgtccctcaggtgtccctcatcattaactatgat ctccctaataacagagaattgtacatacacagaattggga gatcaggtcgatacggccggaagggtgtggccattaactt tgtaaagaatgacgacatccgcatcctcagagatatcgag cagtactattccactcagattgatgagatgccgatgaacg ttgctgatcttatctgaagcagcagatcagtgggatgagg gagactgttcacctgctgtgtactcctgtttggaagtatt tagatccagattctacttaatggggtttatatggactttc ttctcataaatggcctgccgtctc 165 202510_s_at gtcgtctttctattttcaggtcagctgattagccacctta gttccatctgcaactttagttcccactggctgtgtaacct aacatagtcacaggctctggggactgtcacgtggacatct ttgggaggccgttattctgcccaccgcaccctccgttcat cccctgccctgccgggcacctcgctctaccccaggaaaat gtgagctcgttttcctgctcggcatgtgctccccctaagg ctctgctcctccctgggcctgaaagttccttctcagcctg agagggggcccttcgatctcaggcatgactcagcccggct gatgcctctgcagtgctgagtcaggatttggggccggctc tcttgggtctgtccccttttcccaggtactgccttacaaa gctgtggccaggaagtggccggtataaaggatgcccaagg tctttgtacgtgtg 166 221923_s_at tagtccatactgagtgtcatcaacaatccagactgaagtc ttctattttaatctcaatccccttttctgatttgccaccc atgcctcttcaggctggaaacaatctcttggttccctaaa gcactttcttctgactgctgtgattcagtgaaccttgccc tttgctttctattacttgtgcatttgcctcacctgacaat gttttaaatcgcctttgtatctccttagctgctcaataa 167 201887_at ctgggaagcaaaacccatgcctccccctagccatttttac tgttatcctatttagatggccatgaagaggatgctgtgaa attcccaacaaacattgatgctgacagtcatgcagtctgg gagtggggaagtgatcttttgttcccatcctcttctttta gcagtaaaatagctgagggaaaagggagggaaaaggaagt tatgggaatacctgtggtggttgtgatccctaggtcttgg gagctcttggaggtgtctgtatcagtggatttcccatccc ctgtgggaaattagtaggctcatttactgttttaggtcta gcctatgtggattttttcctaacatacctaagcaaaccca gtgtcaggatggtaattcttattctttcgttcagttaagt ttttcccttcatctgggcactgaagggatatgtgaaacaa tgttaacatttttggtagtcttcaaccagggattgtt 168 211582_x_at agcccacctgctggatgaggaacttgaggcaagtcaccag cccctgatcatttcgcctaaaagagcaaggactagagttc ctgacctccaggccagtccctgatccctgacctaatgtta tcgcggaatgatgatatatgtatctacgggggcctggggc tgggcgggctcctgcttctggcagtggtccttctgtccgc ctgcctgtgttggctgcatcgaagagcaccttctgtcctg gtcccaggcccagggctcctcagagcaggaactccactat gcatctctgcagaggctgccagtgcccagcagtgagggac ctgacctcaggggcagagacaagagaggcaccaaggagga tccaagagctgactatgcctgcattgctgagaacaaaccc acctgagcaccccagacaccttcctcaacccaggcgggtg gaca 169 219030_at agttaacacatcagctggacctatttcccgaatgcagggt aacccttctgttatttaaagatgtaaaaaatgcgggagac ttgagaagaaaggccatggaaggcaccatcgatggatcac tgataaatcctacagtgattgttgatccatttcagatact tgtggcagcaaacaaagcagttcacctctacaaactggga aaaatgaagacaagaactctatctactgaaattattttca acctttccccaaataacaatatttcagaggctttgaaaaa atttggtatctcagcaaatgacacttcaattctaattgtt tacattgaagagggagaaaaacaaataaatcaagaatacc taatatctcaagtagaaggtcatcaggtttctctgaaaaa tcttcctgaaataatgaatattacagaagtcaaaaagata tataaactctcttcacaagaagaaagtatcgggacattat tggatgctat 170 212706_at agatatttaggtgacttacagcaaccaatngcaacanaac aaaatgttaagaaatgatctttntatgaggcaatnggaaa tttgaacactgatcaactataggatgattggaattattaa tttttaaaggtgtgataagatactgcacttggctgggcac agtggcacatgcctgtaatcccagctacttggcaggctga ggtgggagaatcgcttaagctcaggagttcgagaccagcc tgggcaacgtggcgaaatccccgtctttacaaaaacaaac aaacaaacaaaaaagatattgcagttgtgttgtaagcgtc cttatctttcagagctacatagtggaatgtttatggaata tttaggataaatgatataggcatttgggatttgctgcaaa atgacccagagg 171 202902_s_at caaaatatcgtgctgccacatgttcaaagtacactgaact tccttatgggagagaagatgtcctgaaagaagctgtggcc aataaaggcccagtgtctgttggtgtagatgcgcgtcatc cttctttcttcctctacagaagtggtgtctactatgaacc atcctgtactcagaatgtgaatcatggtgtacttgtggtt ggctatggtgatcttaatgggaaagaatactggcttgtga aaaacagctggggccacaactttggtgaagaaggatatat tcggatggcaagaaataaaggaaatcattgtgggattgct agctttccctcttacccagaaatctagaggatctctcctt tttataacaaatcaagaaatatgaagcactttctcttaac ttaatttttcctgctgtat 172 200663_at tgtcttatgatcacgtttgccatctttctgtctcttatca tgttggtggaggtggccgcagccattgctggctatgtgtt tagagataaggtgatgtcagagtttaataacaacttccgg cagcagatggagaattacccgaaaaacaaccacactgctt cgatcctggacaggatgcaggcagattttaagtgctgtgg ggctgctaactacacagattgggagaaaatcccttccatg tcgaagaaccgagtccccgactcctgctgcattaatgtta ctgtgggctgtgggattaatttcaacgagaaggcgatcca taaggagggctgtgtggagaagattgggggctggctgagg aaaaatgtgctggtggtagctgcagcagcccttggaattg cttttgtcgaggttttgggaattgtctttgcctgctgcct cgtgaagagtat 173 202138_x_at cagaataaaaaacagccccgccaagactatcagctgggat tcactttaatttggaagaatgtgccgaagacgcagatgaa attcagcatccagacgatgtgccccatcgaaggcgaaggg aacattgcacgtttcttgttctctctgtttggccagaagc ataatgctgtcaacgcaacccttatagatagctgggtaga tattgcgatttttcagttaaaagagggaagcagtaaagaa aaagccgctgttttccgctccatgaactctgctcttggga agagcccttggctcgctgggaatgaactcaccgtagcaga cgtggtgctgtggtctgtactccagcagatcggaggctgc agtgtgacagtgccagccaatgtgcagaggtggatgaggt cttgtgaaaacctggctccttttaacacggccctcaagct ccttaagtgaattgccgtaactgattttaaagggtttaga ttttaagaatggtgctctttcatgcctattatcagta 174 200851_s_at gttgaaggcctcgcttagttgtactggattctcagggagc cctctgtggccttttgctttgcgtgctgtttcccttgtac cagagggcggcaccgtggaaattctgttttccctgtagca tattgtgttggattgcattactggcagagaaaggacaagg tgccattcaagtcctagggtgggcttccagctgccttaat agaagtactcaagtcttttgggtagtgagctggaaagcct acaggaaaagaggggtacctgttttcatttgaaaactttg attcatggaacctttaaaactaatctcagaaaaatttttg gtgcccatgcagctgtagttgttcactgctttcctggatg gatgggactcttatgtcataacttctgttactcctttggc ccatagctaaggtcatccttccccacaggggtggctttgg gattggatgatacagcttttgcttctgtgtagtatacctg tacatacttgtttcaggcagcctttc 175 201109_s_at tcatgatgctgactggcgttagctgattaacccatgtaaa taggcacttaaatagaagcaggaaagggagacaaagactg gcttctggacttcctccctgatccccacccttactcatca cctngcagtggccagaattagggaatcagaatcaaaccag tgtaaggcagtgctggctgccattgcctggtcacattgaa attggtggcttcattctagatgtagcttgtgcagatgtag caggaaaataggaaaacctaccatctcagtgagcaccagc tgcctcccaaaggaggggcagccgtgcttatatttttatg gttacaatggcacaaaattattatcaacctaactaaaaca ttccttttctcttttttcctgaattatcatggagttttct aattctctcttttggaatgtangattttttttaaatgctt tacgatgtaaaatatttattttttacttattctggaagat ctggctgaaggattattcatggaacaggaagaagcgtaaa gactatccatgtcatctttgttgagagtcttcgtgact 176 202531_at acaggagtcagtgtctggctttttcctctgagcccagctg cctggagagggtctcgctgtcactggctggctcctagggg aacagaccagtgaccccagaaaagcataacaccaatccca gggctggctctgcactaagcgaaaattgcactaaatgaat ctcgttccaaagaactaccccttttcagctgagccctggg gactgttccaaagccagtgaatgtgaaggaaactcccctc cttcggggcaatgctccctcagcctcagaggagctctacc ctgctccctgctttggctgaggggcttgggaaaaaaactt ggcactttttcgtgtggatcttgccacatttctgatcaga ggtgtacactaacatttcccccgagctcttggcctttgca tttatttatacagtgccttgctcggggcccaccaccccct caagccccagcagccctcaacaggcccagggagggaagtg tgagcgccttggtatgacttaa 177 216274_s_at ggaatgattgtctcatcggcactaatgatctggaaggggt taatggtaataactggaagtgaaagtccgattgtagtggt gctcagtggcagcatggaacctgcatttcatagaggagat cttctctttctaacaaatcgagttgaagatcccatacgag
tgggagaaattgttgttttcaggatagaaggaagagagat tcctatagttcaccgagtcttgaagattcatgaaaagcaa aatgggcatatcaagtttttgaccaaaggagataataatg cggttgatgaccgaggcctctataaacaaggacaacattg gctagagaaaaaagatgttgtggggagagccaggggattt gttccttatattggaatngtgacgatcctcatgaatgact atcctaaatttangtatgcagttctctttttgctgggttt attcgtgctggtncatcgtgagtaagaagcctgccttgct gttcctgggaagatgccatagttttcgttactg 178 200041_s_at agaggctttctcggtatcagcagtttaaagattttcaacg acgaattcttgtggctaccaacctatttggccgaggcatg gacatcgagcgggtgaacattgcttttaattatgacatgc ctgaggattctgacacctacctgcatcgggtggccagagc aggccggtttggcaccaagggcttggctatcacatttgtg tccgatgagaatgatgccaagatcctcaatgatgtgcagg atcgctttgaggtcaatattagtgagctgcctgatgagat agacatctcctcctacattgaacagacacggtagaagact cgcccattttggaatgtg 179 200052_s_at ggacatggtctgctatacagctcagactctcgtccgaatc ctctcacatggtggctttaggaagatccttggccaggagg gtgatgccagctatcttgcttctgaaatatctacctggga tggagtgatagtaacaccttcagaaaaggcttatgagaag ccaccagagaagaaggaaggagaggaagaagaggagaata cagaaagaaccacctcaaggagaggaagaagaaagcatgg aaactcaggagtgacattcccttcactccttttcctaccc aagggaaagactggagcctaagctgcctgctactggcttt acatggtgacagacattccgtggataggaagatagcagga gaaagtaactccatagagtgtcattccactggttgatatt ggcttagctgccagtctcccatttgtgacctatgccatcc atctataatggaggataccaacatttcttcctaatattct ataatctccaactcctga 180 200064_at aatagacttgtgtcttcaccttgctgcattgtgaccagca cctacggctggacagccaatatggagcggatcatgaaagc ccaggcacttcgggacaactccaccatgggctatatgatg gccaaaaagcacctggagatcaaccctgaccaccccattg tggagacgctgcggcagaaggctgaggccgacaagaatga taaggcagttaaggacctggtggtgctgctgtttgaaacc gccctgctatcttctggcttttcccttgaggatccccaga cccactccaaccgcatctatcgcatgatcaagctaggtct aggtattgatgaagatgaagtggcagcagaggaacccaat gctgcagttcctgatgagatcccccctctcgagggcgatg aggatgcgtctcgcatggaagaagtcgattaggttaggag ttcatagttggaaaacttgtgcccttgtatagtgtccc 181 200079_s_at agctgccagaaacgaacctctttgaaactgaagaaactcg caaaattcttgatgatatctgtgtggcaaaagctgttgaa tgccctccacctcggaccacagccaggctccttgacaagc ttgttggggagttcctggaagtgacttgcatcaatcctac attcatctgtgatcacccacagataatgagccctttggct aaatggcaccgctctaaagagggtctgactgagcgctttg agctgtttgtcatgaagaaagagatatgcaatgcgtatac tgagctgaatgatcccatgcggcagcggcagctttttgaa gaacaggccaaggccaaggctgcaggtgatgatgaggcca tgttcatagatgaaaacttctgtactgccctggaatatgg gctgccccccacagctggctggggcatgggcattgatcga gtcgccatgtttctcacggactccaacaacatcaaggaag tacttctgtttcctgccatgaaacccga 182 200629_at tccagtttactgaactccagaccatgcatgtagtccactc cagaaatcatgctcgcttcccttggcacaccagtgttctc ctgccaaatgaccctagaccctctgtcctgcagagtcagg gtggcttttcccctgactgtgtccgatgccaaggagtcct ggcctccgcagatgcttcattttgacccttggctgcagtg gaagtcagcacagagcagtgccctggctgtgtcctggacg ggtggacttagctagggagaaagtcgaggcagcagccctc gaggccctcacagatgtctaggcaggcctcatttcatcac gcagcatgtgcaggcctggaagagcaaagccaaatctcag ggaagtccttggttgatgtatctgggtctcctc 183 200634_at gaaaacgttcgtcaacatcacgccagctgaggtgggtgtc ctggttggcaaagaccggtcaagtttttacgtgaatgggc tgacacttgggggccagaaatgttcggtgatccgggactc actgctgcaggatggggaatttagcatggatcttcgtacc aagagcaccggtggggcccccaccttcaatgtcactgtca ccaagactgacaagacgctagtcctgctgatgggcaaaga aggtgtccacggtggtttgatcaacaagaaatgttatgaa atggcctcccaccttcggcgttcccagtactgacctcgtc tgtcccttccccttcaccgctccccacagctttgcacccc tttcctccccatacacacacaaaccattttattttttggg ccattaccccataccccttattgctgccaaaaccacatg 184 200802_at taattgcacggattaccaggctcgccggcttcgaatccga tatgggcaaaccaagaagatgatggacaaggtggagtttg tccatatgctcaatgctaccatgtgcgccactacccgtac catctgcgccatcctggagaactaccagacagagaagggc atcactgtgcctgagaaattgaaggagttcatgccgccag gactgcaagaactgatcccctttgtgaagcctgcgcccat tgagcaggagccatcaaagaagcagaagaagcaacatgag ggcagcaaaaagaaagcagcagcaagagacgtcaccctag aaaacaggctgcagaacatggaggtcaccgatgcttgaac attcctgcctccctatttgccaggctttcatttctgtctg ctgagatctcagagcctgcccaacagcagggaagccaagc acccattcatccccctgcccccatctgactgcgtagctga gaggggaacagtgccatgtaccacacagatgttcctgtct cctcgcatgggcatagggacc 185 200860_s_at acttcagttgcaccatgctgtacctttttgcagaggccaa tacggaagccatccaagaacagatcacaagagttctcttg gaacggttgattgtaaataggccacatccttggggtcttc ttattaccttcattgagctgattaaaaacccagcgtttaa gttctggaaccatgaatttgtacactgtgccccagaaatc gaaaagttattccagtcggtcgcacagtgctgcatgggac agaagcaggcccagcaagtaatggaagggacaggtgccag ttagacgaaactgcatctctgttgtacgtgtcagtctaga ggtctcactgcaccgagttcataaactgactgaagaatcc tttcagctcttcctgactttcccagccctttggtttgtgg gtatctgccccaactactgttgggatcagcctcctgtctt atgtgggcacgttcca 186 200983_x_at aggagttgagacctacttcacagtagttctgtggacaatc acaatgggaatccaaggagggtctgtcctgttcgggctgc tgctcgtcctggctgtcttctgccattcaggtcatagcct gcagtgctacaactgtcctaacccaactgctgactgcaaa acagccgtcaattgttcatctgattttgatgcgtgtctca ttaccaaagctgggttacaagtgtataacaagtgttggaa gtttgagcattgcaatttcaacgacgtcacaacccgcttg agggaaaatgagctaacgtactactgctgcaagaaggacc tgtgtaactttaacgaacagcttgaaaatggtgggacatc cttatcagagaaaacagttcttctgctggtgactccattt ctggcagcagcctggagccttcatccctaagtcaacacca ggagagcttctcccaaactccccgttcctgcgtagtccgc tttctcttgctgccacattctaaagg 187 200991_s_at tgccacccgggagtctatggtcaaactctcaagtaagctg agtgccgtgagcttgcggggaattggcagtcccagcacag atgccagtgccagtgatgtccacggcaatttcgccttcga gggcattggagatgaggatctgtaatctccactgcttgga tgtctgccctctaccccagaggaatttacagaaacttgcc ctgtgcctgtgtcccccatgctaggggcggaggggtcttt tccttcttctttcctacctaccccttttctcttggccagg ggcctcgtatcctacctttccttgtcccctgggctggctg cacagaggattgccccttctcttttcagagctggccctcg atgccaaattagcat 188 201112_s_at agatctgtgcggttggcataaccaacttactaacagaatg tcccccaatgatggacactgagtataccaaactgtggact ccattattacagtctttgattggtctttttgagttacccg aagatgataccattcctgatgaggaacattttattgacat agaagatacaccaggatatcagactgccttctcacagttg gcatttgctgggaaaaaagagcatgatcctgtaggtcaaa tggtgaataaccccaaaattcacctggcacagtcacttca catgttgtctaccgcctgtccaggaagggttc 189 201214_s_at agagctgcaagagttctggatgaacgacaatctccttgag agctggagcgacctcgacgagctgaagggagccaggagcc tggagacagtgtacctggagcggaaccccttgcagaagga cccccagtaccggcggaaggtcatgctcgccctcccctcc gtgcggcagatcgatgccacgttcgtcaggttctgagtcc ttcttggctcctcatgtggtccctctcctcggaagaactg cccagccacgggtttttaacccacctgttgctcctgaggt cgtcactatatcaacagtcacaaacccaatggcaataaag gcactgacgatagctggc 190 201241_at aggatgggtctggcaatttccctggtggcaacagaaaaag aaaaggtttggtaccatgtatgtagcagccgtggaaaagg gtgttataacacaagactcaaggaagatggaggctgtacc atatggtacaacgagatgcagttactatctgagatagaag aacacctgaactgtaccatttctcaggttgagccggatat aaaggtaccagtggatgaatttgatgggaaagttacctac ggtcagaaaagggctgctggtggtggaagctataaaggcc atgtggatattttggcacctactgttcaagagttggctgc ccttgaaaaggaggcgcagacatctttcctgcatcttggc taccttcctaaccagctgttcagaa 191 201263_at gatctggatccaggctgtacattgaataaaaagattcgaa atgcacagttagcacagtataacttcattttagttgttgg tgaaaaagagaaaatcactggcactgttaatatccgcaca agagacaataaggtccacggggaacgcaccatttctgaaa ctatcgagcggctacagcagctcaaagagttccgcagcaa acaggcagaagaagaattttaatgaaaaaattacccagat tggctccatggaaaaggaggaacagcgtttccgtaaaatt gactttgtactcgaaaacgtcaatttatattgaacttgga ggaggagtttggcaaagtctgaaataggtcaacctgcagg cgtaactattt 192 201386_s_at ggagatcatctgacactgctgaacgtctaccatgctttta aacaaaatcatgaatcggttcagtggtgttatgacaactt cattaactacaggtccctgatgtccgcagacaatgtacgc cagcagctatctcgaattatggacagatttaatttgcctc gtcgaagtactgactttacaagcagggactattatattaa tataagaaaagctttggttactgggtattttatgcaggtg gcacatttagaacgaacagggcattacttaactgtgaaag ataaccaggtggttcagttgcatccctctactgttcttga ccacaaacctgaatgggtgctttataatgagtttgttcta acaacaaagaattacatccggacatgtacagatatcaagc cagaatggttggtgaaaattgcccctcaatattatgacat gagcaatttcccacagtgtgaagcaaagagacagttggac cgcatcattgcc 193 201417_at gtaaaccacatcttttttgcactttttttataagcaaaaa cgtgccgtttaaaccactggatctatctaaatgccgattt gagttcgcgacactatgtactgcgtttttcattcttgtat ttgactatttaatcctttctacttgtcgctaaatataatt gttttagtcttatggcatgatgatagcatatgtgttcagg tttatagctgttgtgtttaaaaattgaaaaaagtggaaaa catctttgtacatttaagtctgtattataataagcaaaaa gattgtgtgtatgtatgtttaatataacatgacaggcact aggacgtctgcctttttaaggcagttccgttaagggtttt tgtttttaaacttttttttgccatccatcctgtgcaatat gccgtgta 194 201576_s_at aatggctttaaccttggccgctattggccagcccggggcc ctcagttgaccttgtttgtgccccagcacatcctgatgac ctcggccccaaacaccatcaccgtgctggaactggagtgg gcaccctgcagcagtgatgatccagaactatgtgctgtga cgttcgtggacaggccagttattggctcatctgtgaccta cgatcatccctccaaacctgttgaaaaaagactcatgccc ccacccccgcaaaaaaacaaagattcatggctggaccatg tatgatgatgaaagcctgtgtctttgagggattctaccct gaacatacctcacagatcctccctgtcatgccacatttca ctgattggaatgtggaaatggaaaaggaatttaggatgtg cattttcacctgaggtttccct 195 201872_s_at gagatccaaacaactataggccacgaataaacaaacttaa ttcaattaaggatgtagaacaaaagaagagtggaaactac tttttcttggatgattagactgactctgagaatattgata agccatttattaaaaggagtatttactagaattttttgtc atataaaacttgaatcaggattttatgccccacatactct ggaacttgaagtataatatacttaatataacataaaaagc cagttgggttctaaattgtagttgaaacacagaaaatgcc acttttctgttcctgaagaggctcttttgtgcataatatt ctaaaatgaagacatttcaagctatacaaattacttccaa gttttcatgatgtatgggaagattttcagtaggtgtatta tattcacggtaccaaatgctgaccagtgttgctccatttt ttaaatcttgaaaagggtttctgtacttacctggtttgcc aagtatgccagtgtaatgaaactgcccttattttaaaagc cagtcaaagattccactgattgacatttgat 196 201892_s_at tgtcagagtatgcacggcgctttggtgttccggtcattgc tgatggaggaatccaaaatgtgggtcatattgcgaaagcc ttggcccttggggcctccacagtcatgatgggctctctcc tggctgccaccactgaggcccctggtgaatacttcttttc cgatgggatccggctaaagaaatatcgcggtatgggttct ctcgatgccatggacaagcacctcagcagccagaacagat atttcagtgaagctgacaaaatcaaagtggcccagggagt gtctggtgctgtgcaggacaaagggtcaatccacaaattt gtcccttacctgattgctggcatccaacactcatgccagg acattggtgccaagagcttgacccaagtccgagccatgat gtactctggggagcttaagtttgagaagagaacgtcctca gcccaggtggaaggtggcgtccatagcctccattcgtatg agaagcggcttttctgaaaagggatccagcacacctcct 197 202174_s_at caacctttaaatagtgctgcccataaggagtcacctccta ctgttgattcaactcaacagcctaaccctttgccgttacg tttacctgaaatggaacccttagtgcctagagtcaaagaa gttaaatctgctcaggaaactcctgaaagctctctggctg gaagtcctgatactgaatctccagtgttagtgaatgacta tgaagcagaatctggtaatataagtcaaaagtctgatgaa
gaagattttgtaaaagttgaagatttaccactgaaactga caa 198 202176_at ggtgatcacgaaactcgctggcatggaggaggaagacttg gcgttttcgacaaaagaagagcaacagcagctcttacaga aagtcctggcagccactgacctggatgccgaggaggaggt ggtggctggggaatttggctccagatccagccaggcatct cggcgctttggcaccatgagttctatgtctggggccgacg acactgtgtacatggagtaccactcatcgcggagcaaggc gcccagcaaacatgtacacccgctcttcaagcgctttagg aaatgatgcttaggcagggtacttcgttcaagaccggcgc ttggcacccttgttggaaagggattttcagcataacattt tccttccacctctttgaccttccctccagcgttggccaaa ttgtgctgaggaagatgcatcaagggcttggctgtgcctt cataggtcatctagggttttataaaggaggaggagacaat attttttcaaactttttggggagtggggtcatttctgtat at 199 202220_at tgatccaaagctggcaccttcaggcacattggtctcatag ccattactgtttttattgcccttctaagatcctgtcttca gctgggtcagagaaaacttcttgactaaaactggtcagaa ctcatcacagaaatgaaatacagtggtctctctctcccag aactggttgcagctaaaacagagagatctgactgctggct ataggattttggacttaatgactgaaattgcaaattgtcc tttttcttggcattacagattttgccaaaataactttttg tatcaaatattgatgtgtgaaagtgaaggagctagtctgc tgaaccaggaatagtttgagatattgaactgtcatttttg cacatttgaatactttgcaggctggctttgtataaactta tcctctggtttcctatatgttgt 200 202225_at gatactgtaaagtccacacacacattaaatcttgttttcc tgaaagtatggcatcaaaaatacttgtagaaaaaccttgt cacaactgatttgaatgttcctattntnnnnnnctttgac tttgatattggcttgtaatgtctcttttcatcatatgtaa tatcagtggaacaggcagcgctactcaagtcctaaggatt cctcagtgatcagtgatccagggccgttcatgaaccactg ggctggatttgactgttgagtgtggcagttaatgcccctc aagaaatcaaaggatgtcttataagtgtcttccaaaaaaa agcaaatgctgaaatcctattggc 201 202464_s_at tattctgtcctgagaccacgggcaaagctcttccattttg agagagaagaaaaactgtttggaaccacaccaatgatatt tttctttgtaatacttgaaatttatttttttattattttg atagcagatgtgctatttatttatttaatatatgtataag gagtcctaaacaatagaaagctgtagaagctgtagagata ggcttcagttgttaattggtttggagcctcctatgtgtga cttatgactctctgtgttctgtgtatttgtctgaattaat gacctgggatataaagctatgctagctttcaaacaggaga tgccttcagaaagctttgtatattttgcagttgccagacc aataaaatacc 202 202545_at atcgcccctgagatcctacagggcctgaagtacacattct ctgtggactggtggtctttcggggtccttctgtacgagat gctcattggccagtcccccttccatggtgatgatgaggat gaactcttcgagtccatccgtgtggacacgccacattatc cccgctggatcaccaaggagtccaaggacatcctggagaa gctctttgaaagggaaccaaccaagaggctgggaatgacg ggaaacatcaaaatccaccccttcttcaagaccataaact ggactctgctggaaaagcggaggttggagccacccttcag gcccaaagtgaagtcacccagagactacagtaactttgac caggagttcctgaacgagaaggcgcgcctctcctacagcg acaagaacctcatcgactccatggaccagtctgcattcgc tggct 203 202838_at agaaagaggcgctgctcactgttttcctgcttcagttttt ctcttatagtaccatcactataatcaacgaacttctcttc tccacccagagatggcttttccaacacattttaattaaag gaactgagtacattaccctgatgtctaaatggaccaaaga tctgagatccattgtgattatatctgtatcaggtcagcag aagaaggaactgagcagttgaactctgagttcatcaattc taatatttggaaattatctacaatggaatcttccctctgt tctctgataacctacttgcttactcaatgcctttaagcca agtcaccctgttgcctatgggaggaggtggaaggatttgg caagctcaaccacatgctatttagttagcatcagttgtca ccaacagtctttctgcaaagggcaggagagctttggggga aaggaaaaggcttaccaggctgctatggtcaactcttcag aa 204 202896_s_at ccaccacccaactggggctagagtggggaagatttcccct ttagatcaaactgccccttccatggaaaagctggaaaaaa actctggaacccatatccaggcttggtgaggttgctgcca acagtcctggcctcccccatccctaggcaaagagccatga gtcctggaggaggagaggacccctcccaaaggactggaag caaaaccctctgcttccttgggtccctccaagactccctg gggcccaactgtgttgctccacccggacccatctctccct tctagacctgagcttgcccctccagctagcactaagcaac atctcgctgtaagcgcctgtaaattactgtgaaatgtgaa acgtgcaatcttgaaactgaggtgtt 205 202950_at taacatgttagttgtcatttggcatgagtgtgcattccag taattcttaattgatatttgattaattccatacctttgat taaaacatgctagttcaaaataagactgctcagtttccaa gggttttcaagcctacttacctttataaaggttctctagt ctctgattagccatgactgtattggactttgaacattttc tgaactaaaaacctctattctaaactaatctcatttggat gtgtaagtcttttgtaaaggcaagaataaataatatccag gacaatttattagttttctcagtattttcccaaatattag aatatttacttcattattggttggctgccaatgaccccat atgttctgtgagaatagtagctttatctttgatataatac atagtctccaaataggtaatacttcgcaattgattagatt ttcagagtagatttagagttatctgtttttctggtgaggg tcaaat 206 203037_s_at Agtagtgcctgtggtttagcccaccaatcttgatgactaa aagtagctgatgcattgtgcatatgatgcttgagatggtt tttgcaaaagcagaaatcgctgcaaggtaatcacaataga taaaagtggtattttaaacctttgaaataaatggatgtaa ctgtaccttggtacagcttttcacttgtttagtttttaaa cgttagtataatctgaataaataaaatgttgccaaattca atgtagaaagaatgtgacaacacaccttgggtagttctgc ttgtgtttttgcatattgtaaaagcagtgtcacagctaaa aagaaagaaatcgtttctaacagtaaattattgtgcttta gttgctagtttgtactgagagttgacctctccctgtgcag ttttttgttctaaacttgtataaataacaattgtgtaatg tgtctccctcctacattgtaacaatt 207 203155_at gtcttcgtggatacccatgatcttcgcttcccctgggtgg ccttctttgccagcaaaagaatccgggctgggacagaact tacttgggactacaactacgaggtgggcagtgtggaaggc aaggagctactctgttgctgtggggccattgaatgcagag gacgtcttctttagaggacagccttcttcccaacccttct tgaactgtcgtttcctcaggaactgggtcttcctgattgt tgaaccctgacccgaagtctctgggctagctactcccccc agctcctagttgatagaaatgggggttctggaccagatga tcccttccaatgtggtgctagcaggcaggatcccttctcc acctccaaaggccctaaagggtggggagagatcaccactc taacctcggcctgacatccctcccatcccatatttgtcca agtgttcctgcttctaacagactttgttcttagaatggag cctgtgtatctactatc 208 203371_s_at Ctttcctgccgtgagaaactcgaggtgaccaacctccgtt tccggttggctccggttgcagagttgagtgtcctgagagg tcagattgctgtcagacatggcccatgaacatggacatga gcatggacatcataaaatggaacttccagattatagacaa tggaagatagaagggacaccattagaaactatccagaaga agctggctgcaaaagggctaagggatccatggggccgcaa tgaagcttggagatacatgggtggctttgcaaagagtgtt tccttttctgatgtattctttaaaggattcaaatggggat ttgctgcatttgtggtagctgtaggagctgaatattacct ggagtccctgaataaagataagaagcatcactgaagataa tacctggaagcatcatagtggtttcttaactctccaaaat aagatttcttctctgtagcctacttgtctggtttatcc 209 203821_at gagccactctatgagttggacttcagtcttgcctaggcga ttttgtctaccatttgtgttttgaaagcccaaggtgctga tgtcaaagtgtaacagatatcagtgtctccccgtgtcctc tccctgccaagtctcagaagaggttgggcttccatgcctg tagctttcctggtccctcacccccatggccccaggccaca gcgtgggaactcactttcccttgtgtcaagacatttctct aactcctgccattcttctggtgctactccatgcaggggtc agtgcagcagaggacagtctggagaaggtattagcaaagc aaaaggctgagaaggaacagggaacattggagctgactgt tcttggtaactgattacctgccaattgctaccgagaaggt tggaggtggggaaggctttgtataatcccacccacctcac caaaacgatgaaggtatgctgtcatggtcctttctggaag tttctggtgccatttctgaactgttacaac 210 203966_s_at gatgcaacagatatatagccctttcaagtcatgttgtgtt tggacttggggttggaacagggagagcagcagccatgtca gctacacgctcaaatgtgcagatgattatggaaaataacc tcaaaatcttacaaagctgaacatccaaggagttattgaa aactatcttaaatgttcttggtaggggagttggcattgtt gataaagccagtcccttcatttaactgtctttcaggatgt tccttcgttgtttccatgagtattgcaggtaataatacag tgtgttccataagaatctcaatcttggggctaaatgcctt gtttctttgcacctcttttcaagtccttacatttaattac taattgataagcagcagcttcctacatatagtaggaaact gccacatttttgctatcat 211 204192_at tacccgcaggactggttccaagtcctcatcctgagaggta acgggtcggaggcgcaccgcgtgccctgctcctgctacaa cttgtcggcgaccaacgactccacaatcctagataaggtg atcttgccccagctcagcaggcttggacacctggcgcggt ccagacacagtgcagacatctgcgctgtccctgcagagag ccacatctaccgcgagggctgcgcgcagggcctccagaag tggctgcacaacaaccttatttccatagtgggcatttgcc tgggcgtcggcctactcgagctcgggttcatgacgctctc gatattcctgtgcagaaacctggaccacgtctacaa 212 204419_x_at acactcgcttctggaacgtctgaggttatcaataagctcc tagtccagacgccatgggtcatttcacagaggaggacaag gctactatcacaagcctgtggggcaaggtgaatgtggaag atgctggaggagaaaccctgggaaggctcctggttgtcta cccatggacccagaggttctttgacagctttggcaacctg tcctctgcctctgccatcatgggcaaccccaaagtcaagg cacatggcaagaaggtgctgacttccttgggagatgccat aaagcacctggatgatctcaagggcacctttgcccagctg agtgaactgcactgtgacaagctgcatgtggatcctgaga acttcaagctcctgggaaatgtgctggtgaccgttttggc aatccatttcggcaaagaattcacccctgaggtgcaggct tcctggcagaagatggtgactggagtggccagtgccctgt cctccagataccactgagctcactgcc 213 204566_at gccacttgtcttgaaaactgtgcaactttttaaagtaaat tattaagcagactggaaaagtgatgtattttcatagtgac ctgtgtttcacttaatgtttcttagagccaagtgtctttt aaacattattttttatttctgatttcataattcagaacta aatttttcatagaagtgttgagccatgctacagttagtct tgtcccaattaaaatactatgcagtatctcttacatcagt agcatttttctaaaaccttagtcatcagatatgcttacta aatcttcagcatagaaggaagtgtgtttgcctaaaacaat ctaaaacaattcccttctttttcatcccagaccaatggca ttattaggtcttaaagtagttactcccttctcgtgtttgc ttaaaatatgtgaagttttccttgctatttcaataacaga tggtgctgctaattcccaacatt 214 204689_at cttttctgtaatctgtttatctcccacttaatggaaaggc aaaggggtaccccaaatccagaggtgcctacatttcaggc agccttggagtattttaaaaggaaaacattctttactttt atatgacattcttatactgctgtctcaaatcctttttcat ttcagagctcttgtctcagagatgtgtgttctttttgtca gagatatggttgatgagaatcttaaatgcttgttttgcac tatcacttagtacctgtttgaccaaggtgttaagggatag tacctcccatcagcagagaaactg 215 205249_at ggaacgtagcaatatctgctccttttcgagttgtttgaga aatgtaggctattttttcagtgtatatccactcagatttt gtgtatttttgatgtacccacactgttctctaaattctga atctttgggaaaaaatgtaaagcatttatgatctcagagg ttaacttatttaagggggatgtacatattctctgaaacta ggatgcatgcaattgtgttggaagtgtccttggtcgcctt gtgtgatgtagacaaatgttacaaggctgcatgtaaatgg gttgccttattatggagaaaaaaatcactccctgagttta gtatggctgtatatttatgcctattaatatttggaatttt ttttagaaagtatatttttgtatgctttgttttgtgactt aaaagtgttacctttgtagtcaaatttcagataagaatgt acataatgttaccggagctgatttgtttggtcattagctc ttaatagttgtgaaaaaataaatctattctaacgcaaaac cact 216 205552_s_at gctcctgacggtctatgcttgggagcgagggagcatgaaa acacatttcaacacagcccaggaatttcggacggtcttgg aattagtcataaactaccagcaactctgcatctactggac aaagtattatgactttaaaaaccccattattgaaaagtac ctgagaaggcagctcacgaaacccacgcctgtgatcctgg acccggcggaccctacaggaaacttgggtggtggagaccc aaagcgttggaggcagctggcacaagaggctgaggcctgg ctgaattacccatgctttaagaattgg 217 206115_at ctcgctccttctggtatatgcatgtcactgcatgataatt gagttttcctttgttttaataaaactgttctcagacatta agctaaactaagagaaaaataactttgttgccaaaaggtt gtgctatccagattttttatatgtctgcatgtttaaaaaa aaaaaagcaacaaaagaaaatgcactctaacttatgtgaa ctgagagaaaaaaatcaggttttaaacaggaaaacctatg gggaatgatattttttgaaagacttttgtataaagttgag tacttagaaaaaagacaaaccagatgtaatatattttgtg gatgtttttatttcttggatttatagtaccttatactaag gttaaaaaaatatgcttgatattgtgaaaaggtgaaattc ttcaccaacatttcatttgctcctttgtcatattgtaatg ccaatataatatagttaatgaaaacagcatttttaaaaac
cgaaatattgaaatggtgtaatgttgtaccatttgcactg tgagc 218 206584_at tgatgattagttactgatcctctttgcatttgtaaagctt tggagatattgaatcatgttaccatttctgtttttttcca ccctgttttcttccatatttactgaagctcagaagcagta ttgggtctgcaactcatccgatgcaagtatttcatacacc tactgtgataaaatgcaatacccaatttcaattaatgtta acccctgtatagaattgaaaggatccaaaggattattgca cattttctacattccaaggagagatttaaagcaattatat ttcaatctctatataactgtcaacaccatgaatcttccaa agcgcaaagaagttatttgccgaggatctgatgacgatta ctctttttgcagagctctgaagggagagactgtgaataca acaatatcattctccttcaagggaataaaattttctaagg gaaaatacaaatgtgttgttgaagctatttctgggagccc agaagaaatgctcttttgcttggagtttg 219 206877_at gaaaagccgttcaccaaatcgaccagcttcagcgagagca gcgacacctgaagaggcagctggagaagctgggcattgag aggatccggatggacagcatcggctccaccgtctcctcgg agcgctccgactccgacagggaagaaatagacgttgacgt ggagagcacggactatctcacaggtgatctggactggagc agcagcagtgtgagcgactctgacgagcggggcagcatgc agagcctcggcagtgatgagggctattccagcaccagcat caagagaataaagctgcaggacagtcacaaggcgtgtctt ggtctctaagagagtgggcactgcggctgtctccttgaag gttctccctgttggttctgattaggtaacgtattggacct gcccacaactcccttgcacgtaaacttcagt 220 207170_s_at aaaacagcactcctttggctggagcacttgtgtccgtgca tgtacttgggtgtttccctccatcctttctgatatgacca aaaatcaagttgttttgttttttgtcaccttcactggcat gggctaaccacttctttttcaaaccctctgaacacctttt tctgatgggtaacttgcaggaatattctattggaaaagat aacaggaagtacaagtgcttcttgaccccttcctcaatgt ttctagccttcactctccattgtcttttctgggctgtatt acagccctctgtggatcttcaactctgctgcctccactgt gatgcagcagtccaactgtaactgacagtggctgccttct ctgggccatggatcaca 221 208631_s_at Ccagaactgctgacacagatggtgtccaagggcttcctag gtcgtaaatctgggaagggcttttacatctatcaggaggg tgtgaagaggaaggatttgaattctgacatggatagtatt ttagcgagtctgaagctgcctcctaagtctgaagtctcat cagacgaagacatccagttccgcctggtgacaagatttgt gaatgaggcagtcatgtgcctgcaagaggggatcttggcc acacctgcagagggagacatcggagccgtctttgggcttg gcttcccgccttgtctgggagggcctttccgctttgtgga tctgtatggcgcccagaagatagtggaccggctcaagaaa tatgaagctgcctatggaaaacagttcaccccatgccagc tgctagctgaccatgctaacagccctaacaagaagttcta ccagtgagcaggcctcatgcctcgctcagtcagtgcacta accccagctgccggcagtgctgattctccaacagagtg 222 208691_at gagttctgtcatgattcactattctagaacttacatgacc tttactgtgttagctctttgaatgttcttgaaattttaga ctttctttgtaaacaaataatatgtccttatcattgtata aaagctgttatgtgcaacagtgtggagattccttgtctga tttaataa 223 208868_s_at acatctagaaacattacaccacacacaccgtcatcacatt ttcacatgctcaattgatattttttgctgcttcctcggcc cagggagaaagcatgtcaggacagagctgttggattggct ttgatagaggaatggggatgatgtaagtttacagtattcc tggggtttaattgttgtgcagtttcatagatgggtcagga ggtggacaagttggggccagagatgatggcagtccagcag caactccctgtgctcccttctctttgggcagagattctat ttttgacatttgcacaagacaggtagggaaaggggacttg tggtagtggaccatacctggggaccaaaagagacccactg taattgatgcattgtggcccctgatcttccctgtctcaca cttcttttctcccatcccggttgcaatctcactcagacat cacagtaccaccccaggggtggcagtagacaacaacccag aaatttagacagggatctcttacctttggaaaataggggt taggcatgaaggtggttgtgattaagaagatggtt 224 208869_s_at Gactaaaaccactcttagcatctcctctagtattttccat gtatcaggacagaggtgtcttatgtagggagggggcaagt atgaagtaaggtaattatatactactctcattcaggattc ttgctcccatgctgctgtcccttcaggctcacatgcacag gaatgctacatgatggccagctgcttccctccttggttat catccactgcagctgctagttagaaaggtttggagggatg acttttagtaaatcatggggattttattgatttattttca cttttgggattttgtggggtgggagtggggagcaggaatt gcactcagacatgacatttcaattcatctctgctaatgaa aagggttctttctcttgggggaaatgtgtgtgtcagttct gtcagctgcaagttcttgtataatgaagtcaatgccatca ggccaaggaaataaaa 225 208942_s_at caacatggcggaacgcaggagacacaagaagcggatccag gaagttggtgaaccatctaaagaagagaaggctgtggcca agtatcttcgattcaactgtccaacaaagtccaccaatat gatgggtcaccgggttgattattttattgcttcaaaagca gtggactgtcttttggattcaaagtgggcaaaggccaaga aaggagaggaagctttatttacaaccagggagtctgtggt tgactactgcaacaggcttttaaagaagcagttttttcac cgagccctaaaagtaatg 226 209092_s_at aaatccaatcatgagtccaggtagagaacgcctgctgtaa tctacactgttgctgggactgcgcattctgtatataactg tgttggatgagtgacagatgattgtccagactaggacagc ggcatgaacatgactttggttgggattgcggatagttagg gttacctctgaatcgtgtagcttttatgagagcagctgtg caagtgaatccacattaatgccttgtcgtggtgccattcc cagcgcctgacgatacgctcttctattgtcttattctggc aggttttgacgttttaaattttttaaagaaattttattcc ttggaccaaaaggtttggttaaccacccccctcttacttg ctttcacattttgagtgtccagaggaaacagaaaggaatg agtgtgtgacgttgctgcacgcctgactctgtgcgagctt ctttctgtgtatat 227 209193_at gattgtagtggatctaatttttcagaaattttgcctttaa gttattttacctgtttttgtttcttgttttgaaagatgcg cattctaacctggaggtcaatgttatgtatttatttattt atttatttggttcccttcctattccaagcttccatagctg ctgccctagttttctttcctcctttcctcctctgacttgg ggaccttttgggggagggctgcgacgcttgctctgtttgt ggggtgacgggactcaggcgggacagtgctgcagctccct ggcttctgtggggcccctcacctacttacccaggtgggtc ccggctctgtgggtgatggggaggggcattgctgactgtg tatataggataattatgaaaagcagttctggatggtgtgc cttccagatcctctctggggctgtgttttgagcagcaggt agcctggctggttttatctgagtga 228 209200_at ggagcaatccaagccacatatcttctacatcaaatttttc cattttggttattttcataatctggtattgcattttgcct tccctgttcatacctcaaattgattcatacctcagtttaa ttcagagaggtcagttaagtgacggattctgttgtggttt gaatgcagtaccagtgttctcttcgagcaaagtagacctg ggtcactgtaggcataggacttggattgcttcagatggtt tgctgtatcatttttcttctttttcttttcctggggactt gtttccattaaatgagagtaattaaaatcgcttgtaaatg agggcatacaagcatttgcaacaaatattcaaatagaggc tcacagcggcataagctggactttgtcgccactagatgac aagatgttataactaagttaaaccacatctgtgtatctca agggact 229 209861_s_at aagtaaatacttgatggctctgaagaatctgtgtgacttg ggcattgtagatccatatccaccattatgtgacattaaag gatcatatacagcgcaatttgaacataccatcctgttgcg tccaacatgtaaagaagttgtcagcagaggagatgactat taaacttagtccaaagccacctcaacacctttattttctg agctttgttggaaaacatgataccagaattaatttgccac atgttgtctgttttaacagtggacccatgtaatactttta tccatgtttaaaaagaaggaatttggacaaaggcaaaccg tctaatgtaattaacca 230 209967_s_at ttcctaaaaatgcttcactgtacgtagttaagtcgtagct ataacttcaaattttttaaaagggacaaactgtaaaaaat gtgtgtattcttaaaatgcaatatttgtaaggcttgttcc aatgccacatacttgcagctcccattctatgtgtcatcaa tagtgtcctatgcaataaattatttgcaggtcttta 231 210027_s_at tgggatgaagcctttcgcaagttcctgaagggcctggctt cccgaaagccccttgtgctgtgtggagacctcaatgtggc acatgaagaaattgaccttcgcaaccccaaggggaacaaa aagaatgctggcttcacgccacaagagcgccaaggcttcg gggaattactgcaggctgtgccactggctgacagctttag gcacctctaccccaacacaccctatgcctacaccttttgg acttatatgatgaatgctcgatccaagaatgttggttggc gccttgattactttttgttgtcccactctctgttacctgc attgtgtgacagcaagatccgttccaaggccctcgcgagt gatcactgtcctatcaccctatacctagcactgtgacacc acccctaaatcactttgagcctgggaaataagccccctca actaccattccttctttaaacactcttcagagaaatctgc attctatttctcatgtataaaacgaggaatcctccaacca ggctcctgtgataga 232 210053_at aacgtagttactgtatggcactcaaaaactatgttaaatg atccactaactttttttttcttggcccatgattaatggaa tgtatgtaactaggtagggttcctttcttagatctagagg aagtacagccacccactgacatctgaatttatatacctgt tgagttttgagtgcacccaaacactcgataaaccaggtga agaaatttagcttccatgttctacttcagctaaaacagct acatacaacctagtacacttgaagtcagacagacatttca gttgcttacctccagtactgagccttgctttgggaaacta aaagatttagaccaagtcactgccagtttttgcctttg 233 210172_at Ggtaaatatacgttctgcatccaaatgcactttgagattg ttacgatttattctgagcaagatctgcattttttgaaagt ttgagattgtagttatcttttttgagatgagatactttca cgactttggtatcatctgtcagtttttgcccagtgagttc tgcatttgcagctccttgttttggtctgttcgtaactgca gtgttctccatgagtatcaggaaggtagggtttcacttag gagtaagaacagtccccagtccagcagccacccttttcag ctgctgttcattgccagttgatgaggtgagtgtcatctgc ctctctggacaggccccagtggagaacaccgcaggtactg taaaccaagtacttttcacagcgtggccttt 234 210766_s_at Ggttccatcaatggtgagcaccagcctgaatgcagaagcg ctccagtatctccaagggtaccttcaggcagccagtgtga cactgctttaaactgcatttttctnaatgggctaaaccca gatggtttcctaggaaatcacaggcttctgagcacagctg catt 235 210949_s_at acaaagtccgcaccatgctggttaggaagatccaggaaga gtcactgaggacctacctcttcacctacagcagtgtctat gactccatcagcatggagacgctgtcagacatgtttgagc tggatctgcccactgtgcactccatcatcagcaaaatgat cattaatgaggagctgatggcctccctggaccagccaaca cagacagtggtgatgcaccgcactgagcccactgcccagc agaacctggctctgcagctggccgagaagctgggcagcct ggtggagaacaacgaacgggtgtttgaccacaagcagggc acctacgggggctacttccgagaccagaaggacggctacc gcaaaaacgagggctacatgc 236 211458_s_at aaatagcattaaactggaattgacagagtgagttgagcat ctctgtctaacctgctctttctctctggtgctcctcatct cacccctaccttggaatttaataagcttcaggcatttcca attgcagactaaaaccacttctaccatctcctctagtatt ttccatgtatcaggacagagatgtcttatgtagggaaggg gcaggtatgaagtgaggtagattatctatacctctcactc attcaggattctcgctcccatgctgctgtcccttcattct cacactcacaggaatgctatgtgatggccagctgcttccc ttcttggttatccactgcagctgctagttagaaaggtttg cagggatgacttttagtaaatcatggggattttattgatt tattatcacttataggattttgtggggtgggagtggggag caggaattgcactcagacatgacatttcaattcatctctg caaatgaaaagggttcttcctcttgggggaaatctgtgtg tcagttctgtcagctgcaagttctt 237 211546_x_at gggagttgtggctgctgctgagaaaaccaaacagggtgtg gcagaagcagcaggaaagacaaaagagggtgttctctatg tagtggctgagaagaccaaagagcaagtgacaaatgttgg aggagcagtggtgacgggtgtgacagcagtagcccagaag acagtggagggagcagggagcattgcagcagccactggct ttgtcaaaaaggaccagttgggcaagaatgaagaaggagc cccacaggaaggaattctggaagatatgcctgtggatcct gacaatgaggcttatgaaatgccttctgagg 238 212199_at attttgctgttacctttgtgacctgattgttttttggaac acgtcaagacgtgggatcagaatcttccaactttagaggt gcaatggaagacactacgctacttggttgagcctggtgaa gaatgtattaatgagactgctttgcataaaactgggaaga aagagaagacagttggagatggaagatggttttgtatata ttttggaactttagttcctctgtgagacgaaagaggagag ctatgttttgtgtcacattgtctgatatatattgtgtaac ctgtcaggtgagttgatttagacaacatagctgacctttt atgacaaggcagtttgaatagggactattgtaataccctc acacattataggggcancagagaatggcatggaagagaca gtctacagagagctttaagaggccggagaaaggaaaagac attatcagggcctggaaagtctcttccagttcatcagggt ag 239 212224_at acagtgttctctaatgttacagatgagatgcgcattgcca aagaggagatttttggaccagtgcagcaaatcatgaagtt taaatctttagatgacgtgatcaaaagagcaaacaatact ttctatggcttatcagcaggagtgtttaccaaagacattg ataaagccataacaatctcctctgctctgcaggcaggaac agtgtgggtgaattgctatggcgtggtaagtgcccagtgc ccctttggntgggattcaagatgtctggaaatggaagaga actgggagagtacggtttccatgaatatacagaggtcaaa
acagtcacagtgaaaatctctcagaagaactcataaagaa aatacaagagtggagagaagctcttcaatagctaagcatc tccttacagtcactaatat 240 212388_at gtgacagttatgacaggcttaccttggaagagttgtcatt tttactgccaattttttggatgaagatgtttttataaacc tttcaaaatggtctgcaaacagagcaggaattgcacaatt aactcaataatgctgtgtgttctcaagaagctcccttagt gaggccgatcttaagatggccgattctgcccgttgaaggc atncctgggaaagaaaacaagcatcccagcgggcatctca ccacgacttctcctggagtcctcacacggtcactgacaac tacagtcagttttaggaactagagtgccgtatcatcagac ttaccctgtcctgccccaccttccctgctaacatcgaggt gtgtgcagttaccttctgagcttggaacaagcagactgga attttcctctgctacctcttgtgtataaaatcttgttt 241 212591_at ggcccagattgcagatggatttcgtattagagttgatctc gcatctgagacctcatctagagacaagagatcggtttttg tggggaatctcccttataaagttgaagaatctgccattga gaagcactttctggactgtggaagtatcatggccgtgagg attgtgagagacaaaatgacaggcatcggcaaagggtttg gctatgtgctctttgagaatacagattctgttcatcttgc tctgaaattaaataattctgaactcatggggagaaaactc agagtcatgcgttctgttaataaagaaaaatttaaacaac aaaattcaaatccacgattgaagaatgtcagtaaacctaa gcagggacttaattttacttccaaaactgcagaaggacat cctaaaagcttatttattggagaaaaagctgttctcctta aaacgaagaagaaaggacagaagaaaagtggacgccctaa gaaacagagaaaacagaaataacaaccaggaactgctttt tcttttcctgctgagtactgctaata 242 212696_s_at ctgaaggagtgtccctcctctatgtgaaaagaaaattgtt ttattcttncattctgactttttaancngttnggctcact tnccagttagtttgaatgaaaataataattttctacttgg nagttgaagagggcagaatccgcagctctcatcattgtga tgtgtagcatgtctgccctctgactggacatcattgccat taactttcttctgggcatcacggcaatgtcacgatgccca gacttggagcaaggcaaccttggagtcagtccactcataa aatatggtaacacccattttaaaatttaagttttgtcctt aaagacaacttcagtggttaattataaaagttgtgttact tcgtcctaaattaaattgatagaaagatttaaaaatgtgt tttgtttctactattcagaaactgcgaactagggaaaggt tggtatgaaaaaatgtctttccttttttcaatgtacatag ttcaactctttctttgttacatttaaactatatccatgga tatcagtctgctttggactcctctgctagtgttacagatg 243 212709_at tgcaaattaagactcaccttcactttccaaaatagctgag ggttgtnggcttgttgtagctgaccaccaaaagcagtcac tgcaaatcttttaattcttccctatcaccttttgtatttt aatgcaattattttggtccagaactgacctgtattttctg tattgtacacaaaagctaataattttgtgtactttttatt tattttggaggttttatatgatcttcaattgagtattaaa taatttgcctagattaagcctaaaatgatgaccagctaat taaagaagatattttgaatctggttctgagctaaagttga gtaaattcttagctaagaaaaaattggaaatccatcatct atattagcaacagattctcagagtaaattgttaacttcta tgatttatgataatcaagctggacttgatcatacaagtta gtctcataatgtattggaccaaaatgtaaacttcattggt cagatttagaagcattcatgctcacaagttttggga 244 212714_at aactttaggcttttgggcatatgctagtctgagcttccga aaagatacatatatgtttcccttttcattagctgaatgag gatattttaagaagttgaaagagaatttattttcaagttg tgagtaaatcctcctttgaaattcacctgattattagata acttaaagtttatttttaaaagctgacaactttttatgaa tcttcgagttgacagttcctaaaagcgtaactcagatatt aatgggctgtgtattaaatggttttattttcagttttgca gcacagaacactgttgaaatatccatatcaacttgatttt tttaacctaattcaggtgtcctttgcatctcttaaatgtt gggggtgggggtcagagccagttatccggcttctgttttg tcgattgcttagatttgttcctgttgtc 245 212893_at aattgtccttaattaccaacagtgaagcactacaggaggc aactgtggcattgcttccttaaccagctcatggtgtgtga atgttataaaattgtcactcagatatattttttaaatgta atgttatataagatgatcatgtgatgtgtacaaactatgg tgaaaagtgccagtggtagtaactgtgtaaagtttctaat tcacaacattaattcctttaaaatacacagccttctgcct ctgtatttggagttgtcagtacaactcatcaaagaaaact gcctaatataaaaatcatatatatggtaataatttccctc ttttgtagtctgcacaagatccataaaagattgtattttt attactatttaaacaagtgattaaatttagtctgcacagt gagcaaaggttcacatgcattcttttatactgctggattt tgttgtgcatcatttaaaacattttgtatgtttcttctta tctgtatat 246 212989_at gtcagagcctgttcacatattgtgatcaggtaacaatgac atgtaccacttaaattattttatcgtcgatttggtagttc nattttaactactcaatgaaaacagccatgaatatctttt cttaaagagagttttgaaaatgatcacttacctaaaactt gaaagctatgaattagttatccatactctcatgacaattt tgttggtgaacaacaaaaaagagatctatttctttaaaag atatttgtgcagaaactgcatgtaactctaagttttactc ctaacatacatatgtttggggaagtattctattctatact tgccaatgtggagaacaaaatagttttttaagaatgaaga agtatatatatccattctgtattttacgtgcagcagaatt atcttccgtaggatttt 247 213410_at gacaaattacggttgagttctgtggcttcttcacttgaag tgctaacatcagaatcaaacttaaagcttccactatttat gtctttgagaagtatgtagtacctcggtattaacagacct gctgtgatgcagttacactttcacgtatttttgaagtatg tcaagctacacgggtctaagatatgattattttggataaa atgttactttggtcaagagaacttttatccagatgacatt acaggttcaagtgggttaaggagacctcctgtacatctac agtgtttccttttaaattgtccagaaaaaaggtgtgttct tcataaacttcagtgcaggatttttcaaagacgagctgtt gtgcaatttgctgtatttaatgcatgttctgaaaggattc acttttgactttatatgacagttgatcaagaacaggtact accccttt 248 213515_x_at ggatgatctcaagggcacctttgcccagctgagtgaactg cactgtgacaagctgcatgtggatcctgagaacttcaagc nncctgggaaatgtgctggtgaccgttttggcaatccatt tcggcaaagaattcacccctgaggtgcaggcttcctggca gaagatggtgactggagtggccagtgccctgtcctccaga taccactgagctcactgcccatgatgcagagctt 249 213528_at Aactgcattcaagggagggtccaaagaaattcactttcaa gattataacagtatggtgattgatgaagtaaccttaccta atgtagtagctaactccactttggaagatgaagaaaatga tgtaaatgagccagatgtgaaaagatgcaggaaaccaaaa gtaacacaactatataaatgccgatttttttctggtgagt ggtctgagttttgtaagcttgtactaagtagtgaaaaact ttttgtaaaatatgatctcattctcacctcagaaaccatt tacaacccagattattatagtaatttgcaccagactttcc ttagactgttaagtaaaaatggacgtgtacttttggccag caaagcacattattttggtgtaggtggaggtgttcatctc tttcaga 250 213604_at gcaatgtcagtatccattttggcacataaagatttttgat gagccctgtttgcatagagccagatgttttcccctccccc aagagtatctacatcagggatgtgacttggtgcgaagagt caggggaaagaggaaaaacccaatttctaaatgacctcct tgcccaacttactaaaatggctgcagagcagacacaggat gaatttgaacctgacacaggatgaatttgaacctttggtc tcatttatggaaaaacttgtgcaattttttttctgtgcta cactacatacaaatcaccaaattacaaattacccttttgt gatccttggtgtactgagcagtttctttggggctttttct ttctgggaagcgggagggaaaggagcaaggtgtcatcctg ctcttc 251 213619_at aatcaaggcctcagaatttcatacaaacaccaagaccaaa atcctaagtattggtattgcgtctcaaatttttcccatta acttnaaaaaaaaaaaaagcttaaacttacgtgccttaca ggttattaaatgaaactagaattaacaaacatgccaaaat gtttcacttttaatagtagacacagctcctatattgtttt acaaaaaaataaaagcatgtctttcaacatgcatccaaaa cagtgttcaatttaacgtggcaaagggcaacatttaacat aattcaactgcttttacctaaatacgcttactgcttaagt acatcctataactaacttgagaaaagctggaacttaagtt taacagttatagtttactcagcttcactgttacatcctag atgagtattgtattcaaaaatactgggccttaagtcttca taacaatcctgatttccacttagagt 252 213655_at cttcaacgctaacctgcttcagtgggagagtaaagtaggc aagaatgagcagccacggattgttgaactgttaccagcac catgcttttcagcaacatttcagcggagttggaaacattt tttacagcaaaaccattacaacgaagtccctccccaaacc acctttaaccatctcaagctaacacccaattacttgcaaa cactggtataaaacacagtttaaacaattagaaaaatgaa aactgataccacttatgcctctatagtgtgattaacctct ctcttagatgcttgcatcacctataagtctaatggctttc aaatgtaatttccatttgctaatggtgatcttgccacatc tggcacggagacgacacagtaatgctgaaaaagcctctat gtagtcctgttagtgtcttaaagaacctaaaagctgggac cagtaaaatccacagaaattcactcttgccttta 253 213743_at ttgtgtgagctattcaaactcttcaacccctgaacagggt attaagcttccaaaataatgatggggataaatatggaaat cctttttaagttgtatttccattaaacaaaaacccttata attcatactatcatgaatttgctttatccatctcatttgc ataacagttcatctgtctggtcccattaggctctaccaaa gaaagactctgatgagtggacattattactgtgactcttg taagtagccataaataaaccaaaatagtatcaaatttagg tatgaaattccacatgtgcaaa 254 213788_s_at gtttcagtcatttccggactaactgtgacaacgcgtgagc agggagcaccgtgcgagtctccgggagggaatcctcctgg ggcccagagactcctccacccctggggagggcagagaggc tcgggagggcctggccaggccactggaggctggcagggag caggcatgtccacccgcaagcctgggaggctaactctggc attcctggccggagccgccatgctcattggtgggccagtt tgggacatccccgtactcaaagaccatatggcaggctctg ggaaaacaaaaccaaaacatcaccttctattaaactctgt atattattattttttacaatagaaagttaaaaatcaagac ttagatttactatacattttttctctcagattacaaagtt tatattatataactggggttccctaaattgatttctttta aaacagtcttaaagagaccagaagtgaatacaaaagaact aaacaaaataaaaaattagaatatgctgtagctgaaagct gtctatacctgtaagcctccaagtttcat 255 213872_at aaactggtcagctagagattcttttttctttctaagctga gcacgtagtctgttcagagcttgtttcttccgggagtttg ggtcccccattttgaaatncnggtggtactaaagcctttg gaaattgtcactaaactatgggcactttttcttaagactc aagtacaacagaaacaagtcattttttttcctgctaatat gattgattagcgaaaatcacgactataacccaaaaactgc accttctgtcaatattagcagactgtcatattacagggtc aagaaacaaaagctgctgtccagtcatgtttggacaataa cgtttggggtcagacgggaaaaagggaggaaagaaaggaa agaaagaggagaaaataactaactttctggaaaacacatt tggcttaactgccaaaataaaggctttgcggagaaatgaa aagcctataatcaggatttaggtgtgcaataaaacacagc tgacaccagaccaatccctaaaatccatccggattttccc ccctttttagaaaagggattaaggaacagggagggggaag tgtgatccttgctttc 256 213979_s_at aaatggttacagtcacaaacatgattttaaccaaaatatt gctagcctaccacatcagcaggacggcactggtgcaggca gggacgctgccaccctccacgtccccaggacagacgtcga tgggcagcgggcacgctcggcaccgcccaagcttttcctt ttggagctgcttcgtgatgccgtcttcatttggaacaagg gggggttcatgccaaaattaggaaaaacagcctttgtttt gtttttctaaattattctaaaaataagacaagcaggtaga aaaaacaatgcactgtgtggcataaaaagaaaaaggggaa ggattcattgtcctgagaagtttgccaactgcctcattct ggggcacgttccaacataca 257 214257_s_at attataacctgggcctgcctttgttctcatgaagccagga gcctctccatatcctatacttgctcttacgctaataacaa accaaatgctgcaaaataaaagtaataatgacccaaacta atttaagtcttttgtttaaggagtaaatgagagaaacatt ttagcttcttaatcaaggagtgctataatttcaaggcatc ttaatataattcacttaccctaaagcaattgtgcaataag caaattataaaaggaaaacaacaaaggttaactttctaca ggggccaatagacaagatctgtggagcacagcaattaacc ttcacatactggagtcttgtttaaaaggcgatcaaaaact cagattactga 258 214414_x_at tcaacttcaagctcctaagccactgcctgctggtgaccct ggccgcccacctccccgccgagttcaacccctgnggtgca cgcctccctgganaagttcctggcttctgtgagcaccgtg ctgacctccaaataccgttaagctggagcctcggtagccg ttcnnnnnncnngctnggcnntccaacgggccctcctccc ctccttgcaccggcccttcctggtctttgaataaagtctg agtg 259 214696_at gagtatacatcggtgcaggcttcctggatgacagttgggt gatatgtgtcatgtggcctaaaagcctccatgtcatttga cctacgaattctatctttgggaatttatcctaagaaanta cttanggatttanttngtgataagatgttcatcccagcat tgcaatggagaaaaatgggaagcaatggtttggttgggaa tttattccttttctgctgtaacgaaagtttgcaatagggg attgcttaagtaaattattgtatctccatccagatggtgg agtaccgcgcagacattaaaagtcatgtaaaagaacatct gactgaaagaaaaatgctccttgaatattaaaaggttgta aaaatagtgcatgttatgtgatttcaattttgttttttaa aatatgggtgtatgcttgtatacgtagagcagataaaaaa gacggaaggcatactaaaaaatgttgagtggttatctttg tatggtggaacaaagtcactgtaattttcatctttggtt
260 214933_at aatctttcctttccctgatgaagacagctggtggccgagt gcggnaangaagccagaaggaaccagaatcccagngccct acacccaccaccagacacactcacacccacacacgttctc agacacacacaagagtgcttgccggttataccaaacccta ctattactgcctgcagaaatcaatttaaaaaaataataat aacaataaacaattttaaaaaggacaaaaaaattaatgat tgagaaaagaggcatttttttctgacatttggtcctgctt gaaacaacaaaagaagaagaaaaacccaccatcaccaccg attcctttgcttcttttttccttttttcctaccttgtttg aaaaccgtgggcttgggactgtgaattattgcatgacat 261 215043_s_at Cagtctttcccagggaactccgatgaagtgttccaacaaa atgagcgagtgaaccaagaagaggatgacattagatccag gagatacaacagaggagataatctccaggatgcctgtgaa gaaagatccctggatcccaggatgattataggacaagttg ttcataatccagcaggccagaagacttccagggaaactca tt 262 215933_s_at ggacagttcctgtgatcagaggcaagatttgcccagngaa cagaataaaggtgcttctttggatagctctcaatgttcgc cctcccctgcctcccaggaagaccttgaatcagagatttc agaggattctgatcaggaagtggacattgagggcgataaa agctattttaatgctggatgatgaccactggcattggcat gttcagaaaactggatttaggaataatgttttgctacaga aaatcttcatagaagaactggaaggctatataagaaaggg aatcaattctctggtattctggaaacctaaaaatatttgg tgcactgctcaattaacaaacctacatggagaccttaatt ttgacttaacaaatagtttatgtactgctcttaggttgtt ttgataaagtgacattatagtgattaaattctttccnctt taaaaaaacagntagtggttttcactatttataaatagga ccttcttgaacgacttttctg 263 216199_s_at ctggagtctggggtatgttgtcatagagatgatgactggc aaggtttgcacagatgaagaatgaagcctagtagaatatg gacttggaaaattctcttaatcactactgtatgtaatatt tacataaagactgtgctgagaagcagtataagccttttta accttccaagactgaagactgcacaggtgacaagcgtcac ttctcctgctgctcctgtttgtctgatgtggcaaaaggcc ctctggagggctggtggccacgaggttaaagaagctgcat gttaagtgccattactactgtacacggaccatcgcctctg tctcctccgtgtctcgcgcgactgagaaccgtgacatcag cgtagtgttttgacctttctaggttcaaaagaagttgtag tgttatcaggcgtcccataccttgtttttaatctcctgtt tgttgagtgcactgactgtgaaacctttaccttttttgtt gttgttggcaagctgcaggttt 264 216202_s_at gttcacaaagagttttggtgcttctggaggatatattgga ggcaagaaggagctgatagactacctgcgaacacattctc atagtgcagtgtatgccacgtcattgtcacctcctgtagt ggagcagatcatcacctccatgaagtgcatcatggggc 265 216996_s_at gctgcatactttggatacttgtctaaaacttgatgatact gtctatctgagggacatagccttgtcactcccacagctgc cgcgggagctgccatcgtcacatacaaatgcaaaggtggc agaggtgctgagcagccttctgggaggtgaaggacacttc tcaaaggatgtgcacttgccacacaattatcatattgatt ttgaaatcagaatggacactaacaggaatcaagtgctacc actttctgatgtgatacaacttctgctacagatattcaaa gagtagctgtgctatgtgtttccagatctgcttattgttt gggttcaagccaccccagaggattccttgctatgaaaatg cggcatttgaatgcaatgggttttcatgtgatcttggtca ataactgggagatggacaaactagagatggaagatgcagt cacatttttgaagactaaaatctattcagtagaagctctt cctgttgctg 266 217554_at aatgctcaccaaattcacaggaaagaagtgcctaggtgat catttactgctatttactgcttcctggtatggagcaaaat tgccctctggtaggtaactacatttctaattagtatgaaa ggttctactattttcctttcttttgcttatttccccttaa gcacaatttgcagaccctacttctatttaactgatcatac ccttttaaatgccttgtcatcatttttcatagttcctgca tcctagaaaaaataaaaaatcatttaaaatattccttggt gtctagaaaagaaaatttctctaacaatagagatnatcat tttgctttctcacttaagctgatctgaatgatgatttggt actgcctttatgag 267 217682_at cacgaggtcaatttatggttatcaaataggtttttttttt tttttttgagactgagtgtcgctctatagcccaggctgga gtgtagtgctcactgcgacttccgcctcctgggttcaant gattctcgtgcctcagtctcccgagtagctgggattgtag gcgcctgccaccacgcccagctaatttttgtatttgtagt agnnatggggtttcatcatgttggcgaagctggtcttgaa cacctgacctcaagtgatctgccttagcctcactgcttgc ccctangtggtgggattgcaggtgtgagccactgtgctgg cctcaaatagtttttatcaaagctacttcaattagtggtt agcaaggcttaaagactaattcagtgctttattttgacac ttgttcgcaacatgttgctttttttcctgtgtcctatggg acctagtcatctgtatgttaga 268 217840_at gccatccagcacgtcatcaattatgacatgccagaggaga ttgagaactatgtacaccggattggccgcaccgggcgctc gggaaacacaggcatcgccactaccttcatcaacaaagcg tgtgatgagtcagtgctgatggacctcaaagcgctgctgc tagaagccaagcagaaggtgccgcccgtgctacaggtgct gcattgcggggatgagtccatgctggacattggaggagag cgcggctgtgccttctgcgggggcctgggtcatcggatca ctgactgccccaaactcgaggctatgcagaccaagcaggt cagcaacatcggtcgcaaggactacctggcccacagctcc atggacttctgagccgacagtcttcccttctctccaagag gcctcagtccccaagactgccaccagtctacacatacagc agccccctggacagaatcagcatttcagctcagctggcct gg 269 218229_s_at gacctcacagacaaagccattgctagaaatgtcattccaa tgatcagatctggaaacaggctgccataaccacttttcct tcttgtagactcagctcacctgtatatttaaactgttctt ggcatcttgaaacacctatttctactcaggtactcattgt cctgttactgattcacctttctgatccttttcaaccagtt ttcccccaaggggggaaattttacttaacctctagtattt gaacaactcaatatttgaattgttgccccatttgctttta cctgtactgtattcttggtcatctcaatggcgtctaaac ccagctactttgcattccagaagtttccattccctccaat tccacctaatttttcatctgtcctagttactggctctttc ttcatgtcttatttctcttgctttgggagcttaaaagatt ttacaagacctaattttgggttccttccttggagccatag ttaccctgccaa 270 218356_at Ctgaaatttccatctggggattaacttctgtctttctggt gaacaatatagcaattcacgcattcttcaagcagcaaaag ttcccggaacaattagggaagacgtatggtctgaatttat ccaggcagtgggtctgctttggtttttgctggaaatttat atcagtgtctgggctcc 271 218432_at gaaactatgtgactcattctgtgaaaagacttcttgcagt tgtgagttatttagaaatgatcaaaatttgtaattaggct aatccatttagtgattcctaatattttgtactcacagaga actaattgactaaacaacgaacgctagtggtttgtcct tagacaatctgtctttgaatttaaagtctttatcgctaag accttgactttaaatttttcatcactacaaccttgaattt aatttcaggtcttcaacatgatgaccttggatttaattta aagtcttcaacactatgcgctttatcatattattcacaga tgcatttttgaaatgtagtatgtaaaagtatgtaacgtgc tgtttattaacaaaagattgttcacaacatctcatgtagt ttaaatttgtaaatactgcttctgttttgtttctccttta tacacttgactgt 272 218589_at gggtaacaatgcctcagaagcctgctttgaaaattttcca gaagccacatggaaaacatatctctcaaggattgtaattt tcatcgaaatagtgggattttttattcctctaattttaaa tgtaacttgttctagtatggtgctaaaaactttaaccaaa ccagttacattaagtagaagcaaaataaacaaaactaagg ttttaaaaatgatttttgtacatttgatcatattctgttt ctgttttgttccttacaatatcaatcttattttatattct cttgtgagaacacaaacatttgttaattgctcagtagtgg cagcagtaaggacaatgtacccaatcactctctgtattgc tgtttccaactgttgttttgaccctatagtttactacttt acatcggacacaattcagaattcaataaaaatgaaaaact ggtctgtcaggagaagtgacttcagattctctgaagttca tggtgcagagaattttattcagcataacctacagacctta aaaagtaagatatttgacaatgaatctgctgcctgaa 273 218604_at tttgttttattgtatgcgttgggtttgcagcatgaacttg cacagataatgcacgttttctggttaagtaaacatgatgc acactattctgtaacagaaagccctattgtgccttacctg tgtgctttgtgggcaccttgtttatgaagaataaaaaat gatttgttatctgaagagaataaattttaaattctcagtt tatgtctcagatgctaacgtgtgaaaatataaatatatat aatatataaagtaaccagtcttcctgtattttatgtgcat catagtgatttatctgagcttagtgacccccatcttgtaa cctgttgcaagagtgaatgtaaaaaatagttgtggcattt taaaaggtcgcctttgatgcagatgcatctttttcttgct tctaaaacatatttcatgtaaacattgtacatttattatt gtaatatatactattatgcagcttattttacctgaaactg ttaagccgaccaagatccct 274 218689_at cctgggtgttccacagctgatagtgattgccttgaataaa ttcaagggcaatttattcatttttactagggagatagacc tttacagcaatcaagatatttttgtccatatccaggttag ctggtaagaggatttttttggagaaaaaaaatgatattta gaaagttaatttctaattccggaatggaataaaaacaata tgagtagtgtaatcttgtagaaaaagagttgtataatctt gtagaatttctcattctgtggtacaacccaggggtaaact attattccagtagtcagtacacttttctagataaatcttg agtgaaaaccagcaatttctttttccttgtggtctgattc ctttttctaatccatgaaggccatcttgtagattacattt atcattaatgcaagaataaagacaattcctcctgtcagtt gcgtgaattttttttaagaaacaacccagtgaagagttct accatagcaaggcctaatgttagctttagctttagaaaat aacagtttgtgaacttacttccctatatttgcagctgt 275 218889_at gcttgtattcaggttcattggcttttgctggatgatccac ctaaagaagttacctaatttggccttttaaaaaaggtgtt agtgtttattatagctactttcaaggaaagtttgaatatg attctagtctctaaagttcttcacgttttctgacattccc tggagggtgactggggaagaattgctccagggtagaagaa ccaggcccaagactttaccattctgatctagagacaaagg atactcaatgaggagcttttttcccctcttggaacaggta aaatgctttttcttattaatataattataaaacagtattt tatgtaacagctattcccatattctaggagtggcctaaga aatgcgtgtttcagtgactagatta 276 218973_at ctgcaagtgaaacctcagcgcctgatggcagctatgtaca catgtgacatcatggccactggtgatgttctcggtcgagt ctatgctgtcttgtcaaagagagaaggtcgggtacttcaa gaagaaatgaaagaagggacagacatgttcatcatcaagg ctgtgctgcctgttgctgaaagctttggttttgctgatga aatcaggaagaggacaagtggcctggccagcccacaacta gtattcagccattgggagatcattcccagtgaccccttct gggtgccaactactgaggaggaatacttgcactttgggga gaaggctgactctgagaaccaagcccggaagtacatgaac gcagtacgaaagcggaaggggctttatgtggaagaaaaga ttgtggagcatgcagaaaagcagaggacactcagcaaaaa taagtagctacctactactggtggattcttttccttatag tgaatttaaaagtatcatcaagggtttaatattgggaaaa tttctttttgccacattatctctgtttattcact 277 219069_at gaatattgtatactgcatcccctaccacaatttacacaat cctgtggatagtcctacctcaccctggtcaacctacatga tccttaagctaatggcgaatcacgatgaccttgtagacat gcacacaactatacctttgtccaacagatcataatatatc tgctatccaactggttttacctgcctaatcctactgattt gggcactgcttgtatagtctctcaagttcacaggaaatgt tgattttctaaggtcctcattt 278 219093_at tagagacccatgtcatcttaacctaaagggaaatcttatt gcgttatcataaaattgatgatatcttagggtcagaattg cccttttttttattttgaatgggaagctctcactaaaaca atcctgagatttcttaatttcatggttctttaaatattat aaacacagagtcaacatagaataaaattgtatttgttaaa atacacacattggaagacaagagcagatgactacttttcg aagtaatgctgctccttcctaaaagtctgttttcaatcct ggtaatattaggggcactgcggcacctaagaagccttaaa tgagagctaatccaatttagagagcgatggtgtcagcatt tcggtctgcatatctgtgtgtccgtatctgcgtttgtgtg cgtgtacgtgtgcccctgtgtgtgggcccagttttcaggc atgtagaataagcatggagtcatattgaggaggctcact tcttgaagat 279 219099_at aatggactgactgaaactcgctaaggttaaatctgcatca aaatctaaccaatttgagcctctgaagggagtgccattgg ctttatttacttctctcctctgctagtcctgatttggaaa cagttaaaagccaatttttagctccagtggaaccatagcc acataaaactttaatggacaaccatatagaattaacttat tttgtccaagtacagttggcattttccagaataattttac caccctgctagatgtcatctctggattgcacatggatgat gaaggaactcagcattgaaagttgggggattagtaacctt gttacaacggtttctttttcattttagcctattttaatgg ctattggtaagatactgtatgtttttagtatctcatccag tgcttagaagaaagaatggtttataattcccagtacatgt tt 280 219176_at Caacaggaggcatctccatttactatgatgagaaaggaag gaagtttgttaacatcctgatgtgcttttggtatctaacc agtgccaacatccccagtgaaactttaagaggagccagtg tattccaggttaagttggggaatcagaatgtggaaactaa acaacttcttagtgcaagctatgagtttcagagggagttc acacaaggagtaaagcctgactggaccattgcacggattg aacactcaaaattattagaataattttcttggaaaaatca gcttatggactttagcagttgctgtgaaaaactaaggaag aaaaattttggggtcatttgatcttcacttaatctaagtc
tgtgaattacttttatattattttgaaatactccttgcag tatattggcatgatacagtaaaagcattttccacagattg ttatcaccttcttt 281 219243_at tcttctagattctctctatgttggcagataatctcccctt gtagcttccactcacttattcttgcattcagagtcacaat gatcatcttacccatgtggtttttgagaaagaaagatcaa ttctttgtttgcagtgggtaatcttagagatggagatgat tgtagaattattcctagatgagtgtcaatttatttaattc cattgtcatataaggagtcaaattgtttcttatcatttgt tcattgaagaacagagacctgtctggaaaatcgatctcta caaattcaattaaataatgatccccaaatgctgaaaaagt gaaatacagcaattcaacagataatagagcaatgtttagt atattcagctgtatctgtagaaactctttgacgaacctca atttaaccaatttgatgaatacccagttctcttcttttct agagaaagatagttgcaacctcacctccctcactcaacac tttgaatacttattgtttggcaggtcatccacacact 282 219363_s_at tggtcagaaaagcaccatttttgctgaacttttcagtgga aagactggataaccagattggattttttcagaaggaactg gaacttagtgtgaagaagactagagatctggtagttcgtc tcccaaggctgctaactggaagtctggaacccgtgaagga aaatatgaaggtttatcgtcttgaacttggttttaaacat aacgaaattcaacatatgatcaccagaatcccaaagatgt taactgcaaataaaatgaaacttaccgagacgtttgattt tgtgcacaatgtgatgagcattccccaccacatcattgtca agttcccacaggtatttaatacaaggctgtttaaggtca aagaaagacacttgtttcttacctatttaggaagagcaca gtatgatccagcaaaacctaactacatctctttggacaaa ctagtatctattcctgatgaaatattttgtgaagagattg ccaaagcatcagtacaggact 283 219434_at ccatgatcatggtttactgcgcgtccgaatggtcaacctt caagtggaagattctggactgtatcagtgtgtgatctacc agcctcccaaggagcctcacatgctgttcgatcgcatccg cttggtggtgaccaagggtttttcagggacccctggctcc aatgagaattctacccagaatgtgtataagattcctccta ccaccactaaggccttgtgcccactctataccagccccag aactgtgacccaagctccacccaagtcaactgccgatgtc tccactcctgactctgaaatcaaccttacaaatgtgacag atatcatcagggttccggtgttcaacattgtcattctcct ggctggtggattcctgagtaagagcctggtcttctctgtc ctgtttgctgtcacgctgaggtcatttgtaccctaggccc acgaacccacgagaatgtcctctgact 284 221485_at aatgtgaccttgtgcatatattggtagctgaaaatcttca aggctactgatgggtggccccttaatcttgtctttgattg ctgtgtgcagggaaaggtgtccccgtttgttcatgctgtt ttggggggtgggggggtatttgcaagaatactcattttga cataataggtcctcttgtcagagatcctctaccacagaca ttaatagctgagcaggagccacatggattgattgtatcca ctcaccattgacgatggcattgagcgtagctagcttattt ccatcactacgtgtttttgagcttgctcttacgttttaag aggtgccaggggtacatttttgcactgaaatcta 285 221652_s_at ggccagtgtcgttattatccttgtggagaatagaatcaat actgccaattccagaaaacatcaggaatttgctggacgtt tgaactctgttaataacagagctgaactatatcaacatct taaagaggaaaatgggatggagacaacagaaaatggaaaa gccagccggcagtgaagagtgacttgaagaactaaattta gcatattgcaaaaatattttgtgcggaattcgatataagt acttttacagcaagatggtatagttatgttgcctggactg gtttttacatttttaaaatatttcagctgtcatttttgta ctaattataaaattggcacataattcaaaaatatacattt gagatgatttgtcctcccaaattatacaagtttattttat ggtataaagtgttctctctggaaatgtttttaaaaaaatt cttaggcttctctttgcgaaataaa 286 221755_at Ggagcctcatggagtcaggtgccaacaagctgcaggagga ggtgctgatccaggagtggttcaccctggtcaacaagaag nacgctctcatcnnnanncannnccngcnncnnnnnnnca tggaggagcaggacttggagcgaaggttcgagctgctgag ccgcgagctgcgggccatgctggccatcgaagactggcag aaaacgtccgctcagcagcaccgagagcagatcctactgg aggagctggtgtcgctggtgaaccagcgcgatgagctagt ccgggacctggaccacaaggagcggatcgccctggaggag gacgagcgcctggagcgcggcctggaacagcggcgccgca agctgagccggcagttgagccggcgggagcgc 287 221970_s_at gcgaaaatgctactatgactcttcctggaatacacccacc taccttgaaccagattatggattggatatgtctacttctg gatgcgaattttactgttgtngtaatgatgccagaagcaa agaggctactgataaatctttacaagcttgtaaaatctca gatatctgtttattctgagctcaacaagattgaagtaagt tttcgggagctacagaaattaaatcaagaaaagaataata gaggattatattcaattgaagtgctggagctcttctgata ttatcaattctccttcatagacattttataaagctctttt atgtgaactcttgcttcatccaggcaagaacggtgttttg tttgcgaccatctcagtgtcaagagaaacgtgtcagtgag tacctggaccatcacttaactgatgctccggggtaggact gcaggtttcacatgaacctgttntaggctgtggacattgg tgtggaga 288 222127_s_at ctcgctgttatcctggatctggtgttacaatggaattcac tattcaggacattctggattattgttccagcattgcacag tcccactaaaccttgtgaaagaagaaaagataactgaatg aagcatttgagtataacagacactataccaaaataccaag caactgttttgagaacccagacttaaaattttatgtatta ttaaatgttagataaatgggtagtaccatactacaaatat ttaaatgcaaaattaccaacctatatagcagttttatttg ccctataggttgcatactaacttaagcattcatgtcacca taaaatgcctttagcatttctcaatgactggatgggaaat tttcctttattgcctagctgcttgtgtttgagtggttgtc ctatgagcaatgcatttggagttcttcagctttcactact tctctgttgcttgctaatcatg 289 36711_at ttgcacggatctaagttattctccccagccagagcccgng ctnnctgctcccngggaaaagntggcgtantggncctgag ctgggntttatattttatatctgcaaataaatnacatttt atcntanatttagggaaagccngagagnaacaacaaaaaa tgtttaagccnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnn nnnnnnnnnnnnnnnnnnnnnnnnntattgcccggctcct agaatttatttatttcctgacttacagcaagcgagttatc gtcttctgtattttg 290 38037_at ccactctatgagttggacttcagtcttgcctaggcgattt tgtctaccatttgtgttttgaaagcccaaggtgctgatgt caaagtgtaacagatatcagtgtctccccgtgtcctctcc ctgncaagtctcagaagaggttgggcttccatgcctgtag ctttcctggtccctcacccccatngccccaggcccacagc gtgggaactcactttcccttgtgtcaagacatttctnnnn nnnnnnnnnnnnnnnnnnnnnnactccatgcaggggtcag tgcagcagaggacagtctggagaaggtattagcaaagcaa aaggctgagaaggaacagggaacattggagctgactgttc ttggtaactgattacctgccaattgctaccgagaaggttg gaggtggggaaggctttgtataatcccacccacctcacca aaacgannnnnnnnnnnnnnnnnngtcctttctggaagtt tctggtgccatttc 291 AFFX-BioB-M_at gccggagttttacggcaatatcatcaccacacgcacttat caggaacgcctcgatacgctggaaaaagtgcgcgatgccg ggatcaaagtctgttctggcggcattgtgggcttaggcga aacggtaaaagatcgcgccggattattgctgcaactggca aacctgccgacgccgccggaaagcgtgccaatcaacatgc tggtgaaggtgaaaggcacgccgcttgccgataacgatga tgtcgatgcctttgattt 292 AFFX-r2-Ec-bioC- cgctggtgcagggatcgttacccgaacgtcatcaggcgtg 3_at gcaggcggtggacgagcgtccgcatgctaatcgcttttta ccgccagatgaaatcgaacagtcgctgaacggcgtgcatt atcaacatcatattcagcccatcacgctgtggtttgatga tgcgctcagtgccatgcgttcgctgaaaggcatcggtgcc acgcatcttcatgaagggcgcgacccgcgaatattaacgc gttcgcagttgcagcgattgcaactggcctggccgc 293 204018_x_at ggtccccacagactcagagagaacccaccatggtgctgtc tcctgccgacaagaccaacgtcaaggccgcctggggtaag gtcggcgcgcacgctggcgagtatggtgcggaggccctgg agaggatgttcctgtccttccccaccaccaagacctactt cccgcacttcgacctgagccacggctctgcccaggttaag ggccacggcaagaaggtggccgacgccctgaccaacgccg tggcgcacgtggacgacatgcccaacgcgctgtccgccct gagcgacctgcacgcgcacaagcttcgggtggacccggtc aacttcaagctcctaagccactgcctgctggtgaccctgg ccgcccacctccccgccgagttcacccctgcggtgcacgc ctccctggacaagttcctggcttctgtgagcaccgtgctg acctccaaataccgttaagctg 294 222043_at tcgactctgctgctcatgggaagaacagaattgctcctgc atgcaactaattcaataaaactgtcttgtgagctgatcgc ttggagggtcctctttttatgttgagttgctgcttcccgg catgccttcattttgctatggggggcaggcaggggggatg gaaaataagtagaaacaaaaaagcagtggctaagatggta tagggactgtcataccagtgaagaataaaagggtgaagaa taaaagggatatgatgacaaggttgatccacttcaagaat tgcttgctttcaggaagagagatgtgtttcaacaagccaa cta 295 206026_s_at Tacaagtactacttctactggaaataaaaactttttagct ggaagatttagccacttataaaaaaaaaaaaggatgatca aaacacacagtgtttatgttggaatcttttggaactcctt tgatctcactgttattattaacatttatttattatttttc taaatgtgaaagaaatacataatttagggaaaattggaaa atataggaaactttaaacgagaaaatgaaacctctcataa tcccactgcatagaaataacaagcgttaacattttcatat ttttttctttcagtcatttttgtatttgtggtatatgtat atatgtacctatatgtatttgcatttgaaattttggaatc ctgctctatgtacagttttgtattatactttttaaatctt gaactttatgaacattttctgaaatcattgattattctac aaaaacatgattttaaacagctgtaaaatattctatgata tgaatgttttatgcattatttaagcctgtctctattgttg gaatttcaggtcattttcat 296 208894_at cgatcaccaatgtacctccagaggtaactgtgctcacgaa cagccctgtggaactgagagagcccaacgtcctcatctgt ttcatagacaagttcacccca 297 222150_s_at taatcttgctcattaaccttactcctttgagaattcttta acaatatttaaaattggtaacaaaaatagtttagccataa ttgtttagccatgtgagtttcaggttggtacacgttcaga cagaactgctgtatcacattccaattttgaatagccagtg agcaatcaagtgtagagaaatgataaatggcctaagaagg catacagtggcataaacgatgctcttcctagtagcttaat aggccacaagctagtttctgttgccctctgaaataaaata tgctttaaaaatgtagggaccagtgcttagaaaagcaaaa actaggtgtgtcattgaaataataggcataaaaattaaat gttacataagacccctatttggaaaaagggtccttttaaa aactgaatttgtactaaatcagatttgccatgtccagtac agaataatttgtacttagtatttgcagcagggtttgtctt tgtgaattcag 298 207113_s_at ccagaactcactggggcctacagctttgatccctgacatc tggaatctggagaccagggagcctttggttctggccagaa tgctgcaggacttgagaagacctcacctagaaattgacac aagtggaccttaggccttcctctctccagatgtttccaga cttccttgagacacggagcccagccctccccatggagcca gctccctctatttatgtttgcacttgtgattatttattat ttatttattatttatttatttacagatgaatgtatttatt tgggagaccggggtatcctgggggacccaatgtaggagct gccttggctcagacatgttttccgtgaaaacggaggctga acaataggctgttcccatgtagccccctggcctctgtgcc ttcttttgattatgttttttaaaatattatctgattaagt tgtctaaacaatgctgatttggtgaccaactgtcactcat tgctg 299 205067_at agctgtacccagagagtcctgtgctgaatgtggactcaat ccctagggctggcagaaagggaacagaaaggtttttgagt acggctatagcctggactttcctgttgtctacaccaatgc ccaactgcctgccttagggtagtgctaagaggatctcctg tccatcagccaggacagtcagctctctcctttcagggcca atccccagcccttttgttgagccaggcctctctcacctct cctactcacttaaagcccgcctgacagaaaccacggccac atttggttctaagaaaccctctgtcattcgctcccacatt ctgatgagcaaccgcttccctatttatttatttatttgtt tgtttgttttattcattggtctaatttattcaaagggggc aagaagtagcagtgtctgtaaaagagcctagtttttaata gctatggaatcaattcaatttggactggtgtgctctcttt aaatcaagtcc 300 201290_at gaacacacgtgttggtgcttctgggtagcactggtttgca ttagtttatgtttccatgccagagtttgtgtgggccgggcg catgtgcaccacagagtgcactcgaggggactttcagtca caggatttcataattgtcattgtcacactttcaaattttt gtacatcagtgaatttttttatattaaaaggttgagccaa aaagcccccagtgtttgtattttgaagccaagcttcactt ctaaagtgcctacagagacttgtaaatgaaaatgcagctc tgcacgactttgaaaccgtcatacctccttctattaggaa tggcatatactgaggtggtcgtaagtcttaacttct 301 agtaccttggtccagctcttcctgcaacggcccaggagct CD11c cagagctccacatctgaccttctagtcatgaccaggacca full-length n.t. gggcagcactcctcctgttcacagccttagcaacttctct aggtttcaacttggacacagaggagctgacagccttccgt gtggacagcgctgggtttggagacagcgtggtccagtatg ccaactcctgggtggtggttggagccccccaaaagataac
agctgccaaccaaacgggtggcctctaccagtgtggctac agcactggtgcctgtgagcccatcggcctgcaggtgcccc cggaggccgtgaacatgtccctgggcctgtccctggcgtc taccaccagcccttcccagctgctggcctgcggccccacc gtgcaccacgagtgcgggaggaacatgtacctcaccggac tctgcttcctcctgggccccacccagctcacccagaggct cccggtgtccaggcaggagtgcccaagacaggagcaggac attgtgttcctgatcgatggctcaggcagcatctcctccc gcaactttgccacgatgatgaacttcgtgagagctgtgat aagccagttccagagacccagcacccagttttccctgatg cagttctccaacaaattccaaacacacttcactttcgagg aattcaggcgcagctcaaaccccctcagcctgttggcttc tgttcaccagctgcaagggtttacatacacggccaccgcc atccaaaatgtcgtgcaccgattgttccatgcctcatatg gggcccgtagggatgccgccaaaattctcattgtcatcac tgatgggaagaaagaaggcgacagcctggattataaggat gtcatccccatggctgatgcagcaggcatcatccgctatg caattggggttggattagcttttcaaaacagaaattcttg gaaagaattaaatgacattgcatcgaagccctcccaggaa cacatatttaaagtggaggactttgatgctctgaaagata ttcaaaaccaactgaaggagaagatctttgccattgaggg tacggagaccacaagcagtagctccttcgaattggagatg gcacaggagggcttcagcgctgtgttcacacctgatggcc ccgttctgggggctgtggggagcttcacctggtctggagg tgccttcctgtaccccccaaatatgagccctaccttcatc aacatgtctcaggagaatgtggacatgagggactcttacc tgggttactccaccgagctggccctctggaaaggggtgca gagcctggtcctgggggccccccgctaccagcacaccggg aaggctgtcatcttcacccaggtgtccaggcaatggagga tgaaggccgaagtcacggggactcagatcggctcctactt cggggcctccctctgctccgtggacgtagacagcgacggc agcaccgacctggtcctcatcggggccccccattactacg agcagacccgagggggccaggtgtctgtgtgtcccttgcc cagggggtggagaaggtggtggtgtgatgctgttctctac ggggagcagggccacccctggggtcgctttggggcggctc tgacagtgctgggggatgtgaatggggacaagctgacaga cgtggtcatcggggccccaggagaggaggagaaccggggt gctgtctacctgtttcacggagtcttgggacccagcatca gcccctcccacagccagcggatcgcgggctcccagctctc ctccaggctgcagtattttgggcaggcactgagcgggggt caagacctcacccaggatggactggtggacctggctgtgg gggcccggggccaggtgctcctgctcaggaccagacctgt gctctgggtgggggtgagcatgcagttcatacctgccgag atccccaggtctgcgtttgagtgtcgggagcaggtggtct ctgagcagaccctggtacagtccaacatctgcctttacat tgacaaacgttctaagaacctgcttgggagccgtgacctc caaagctctgtgaccttggacctggccctcgaccctggcc gcctgagtccccgtgccaccttccaggaaacaaagaaccg gagtctgagccgagtccgagtcctcgggctgaaggcacac tgtgaaaacttcaacctgctgctcccgagctgcgtggagg actctgtgacccccattaccttgcgtctgaacttcacgct ggtgggcaagcccctccttgccttcagaaacctgcggcct atgctggccgccgatgctcagagatacttcacggcctccc taccctttgagaagaactgtggagccgaccatatctgcca ggacaatctcggcatctccttcagcttcccaggcttgaag tccctgctggtggggagtaacctggagctgaacgcagaag tgatggtgtggaatgacggggaagactcctacggaaccac catcaccttctcccaccccgcaggactgtcctaccgctac gtggcagagggccagaaacaagggcagctgcgttccctgc acctgacatgtgacagcgccccagttgggagccagggcac ctggagcaccagctgcagaatcaaccacctcatcttccgt ggcggcgcccagatcaccttcttggctacctttgacgtct cccccaaggctgtcctgggagaccggctgcttctgacagc caatgtgagcagtgagaacaacactcccaggaccagcaag accaccttccagctggagctcccggtgaagtatgctgtct acactgtggttagcagccacgaacaattcaccaaatacct caacttctcagagtctgaggagaaggaaagccatgtggcc atgcacagataccaggtcaataacctgggacagagggacc tgcctgtcagcatcaacttctgggtgcctgtggagctgaa ccaggaggctgtgtggatggatgtggaggtctcccacccc cagaacccatcccttcggtgctcctcagagaaaatcgcac ccccagcatctgacttcctggcgcacattcagaagaatcc cgtgctggactgctccattgctggctgcctgcggttccgc tgtgacgtcccctccttcagcgtccaggaggagctggatt tcaccctgaagggcaacctcagctttggctgggtccgcca gatattgcagaagaaggtgtcggtcgtgagtgtggctgaa attacgttcgacacatccgtgtactcccagcttccaggac aggaggcatttatgagagctcagacgacaacggtgctgga gaagtacaaggtccacaaccccacccccctcatcgtaggc agctccattgggggtctgttgctgctggcactcatcacag cggtactgtacaaagttggcttcttcaagcgtcagtacaa ggaaatgatggaggaggcaaatggacaaattgccccagaa aacgggacacagacccccagcccgcccagtgagaaatgat cccctctttgccttggacttcttctcccccgcgagttttc cccacttacttaccctcacctgtcaggcctgacggggagg aaccactgcaccaccgagagaggctgggatgggcctgctt cctgtctttgggagaaaacgtcttgcttgggaaggggcct ttgtcttgtcaaggttccaactggaaacccttaggacagg gtccctgctgtgttccccaaaggacttgacttgcaatttc tacctagaaatacatggacaatacccccaggcctcagtct cccttctcccatgaggcacgaatgatctttctttcctttc tttttttttttttttcttttcttttttttttttttgagac ggagtctcgctctgtcacccaggctggagtgcaatggcgt gatctcggctcactgcaacctccgcctcccgggttcaagt aattctgctgtctcagcctcctgagtagctgggactacag gcacacgccacctcgcccggcccgatctttctaaaataca gttctgaatatgctgctcatccccacctgtcttcaacagc tccccattaccctcaggacaatgtctgaactctccagctt cgcgtgagaagtccccttccatcccagagggtgggcttca gggcgcacagcatgagaggctctgtgcccccatcaccctc gtttccagtgaattagtgtcatgtcagcatcagctcaggg cttcatcgtggggctctcagttccgatttcccaggctgaa ttgggagtgagatgcctgcatgctgggttctgcacagctg gcctcccgcgttgggcaacattgctggctggaagggagga gcgccctctagggagggacatggccccggtgcggctgcag ctcacccagccccaggggcagaagagacccaaccacttct attttttgaggctatgaatatagtacctgaaaaaatgcca agacatgattatttttttaaaaagcgtactttaaatgttt gtgttaataaattaaaacatgcacaaaaagatgcatctac cgctcttgggaaatatgtcaaaggtctaaaaataaaaaag ccttctgtgaaaaaaaaaaaaaaaaa 302 mtrtraalllftalatslgfnldteeltafrvds CD11c agfgdsvvqyanswvvvgapqkitaanqtgglyq full-length a.a. cgystgacepiglqvppeavnmslglslasttsp sqllacgptvhhecgrnmyltglcfllgptqltq rlpvsrqecprqeqdivflidgsgsissrnfatm mnfvravisqfqrpstqfslmqfsnkfqthftfe efrrssnplsllasvhqlqgftytataiqnvvhr lfhasygarrdaakilivitdgkkegdsldykdv ipmadaagiiryaigvglafqnrnswkelndias kpsqehifkvedfdalkdiqnqlkekifaiegte ttssssfelemaqegfsavftpdgpvlgavgsft wsggaflyppnmsptfinmsqenvdmrdsylgys telalwkgvqslvlgapryqhtgkaviftqvsrq wrmkaevtgtqigsyfgaslcsvdvdsdgstdlv ligaphyyeqtrggqvsvcplprgwrrwwcdavl ygeqghpwgrfgaaltvlgdvngdkltdvvigap geeenrgavylfhgvlgpsispshsqriagsqls srlqyfgqalsggqdltqdglvdlavgargqvll lrtrpvlwvgvsmqfipaeiprsafecreqvvse qtlvqsniclyidkrsknllgsrdlqssvtldla ldpgrlspratfqetknrslsrvrvlglkahcen fnlllpscvedsvtpitlrlnftlvgkpllafrn lrpmlaadaqryftaslpfekncgadhicqdnlg isfsfpglksllvgsnlelnaevmvwndgedsyg ttitfshpaglsyryvaegqkqgqlrslhltcds apvgsqgtwstscrinhlifrggaqitflatfdv spkavlgdrllltanvssenntprtskttfqlel pvkyavytvvssheqftkylnfseseekeshvam hryqvnnlgqrdlpvsinfwvpvelnqeavwmdv evshpqnpslrcssekiappasdflahiqknpvl dcsiagclrfrcdvpsfsvqeeldftlkgnlsfg wvrqilqkkvsvvsvaeitfdtsvysqlpgqeaf mraqtttvlekykvhnptplivgssiggllllal itavlykvgffkrqykemmeeangqiapengtqt psppsek 303 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Adalimumab VL Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys 304 Glu Val Gln Leu Val Glu Ser Gly Gly Gly Adalimumab VH Leu Val Gln Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ser Ala Ile Thr Trp Asn Ser Gly His Ile Asp Tyr Ala Asp Ser Val Glu Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser 305 Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa Adalimumab Xaa = Thr or Ala VL CDR3 306 Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Adalimumab Asp Xaa VH CDR3 Xaa = Tyr or Asn 307 Ala Ala Ser Thr Leu Gln Ser Adalimumab VL CDR2 308 Ala Ile Thr Trp Asn Ser Gly His Ile Asp Adalimumab Tyr Ala Asp Ser Val Glu Gly VH CDR2 309 Arg Ala Ser Gln Gly Ile Arg Asn Tyr Leu Adalimumab Ala VL CDR1 310 Asp Tyr Ala Met His Adalimumab VH CDR1
Sequence CWU
1
3101279DNAHomo sapiensmisc_feature(1)..(279)AffymetrixID 39248_at
1cttctacagg cttttgggaa gtagggtgga tgtgggtagg gctgggagga gggggccaca
60gcttaggttt ggagctctgg atgtacatac ataagtagga gcagtgggac gtgtttctgt
120cataatgcag gcatgaaggg tggagtgaag tcaggtcata agtttcatgt ttgcttttgt
180tttgttttgt ttttaatgta tgtagcagat gttacagtct tagggatccg ggatgggaga
240ccccacttta gaaagggtcg tcactccttt aatcctcta
2792483DNAHomo sapiensmisc_feature(1)..(483)AffymetrixID 200061_s_at
2agatcgccat catgaacgac accgtaacta tccgcactag aaagttcatg accaaccgac
60tacttcagag gaaacaaatg gtcattgatg tccttcaccc cgggaaggcg acagtgccta
120agacagaaat tcgggaaaaa ctagccaaaa tgtacaagac cacaccggat gtcatctttg
180tatttggatt cagaactcat tttggtggtg gcaagacaac tggctttggc atgatttatg
240attccctgga ttatgcaaag aaaaatgaac ccaaacatag acttgcaaga catggcctgt
300atgagaagaa aaagacctca agaaagcaac gaaaggaacg caagaacaga atgaagaaag
360tcagggggac tgcaaaggcc aatgttggtg ctggcaaaaa gtgagctgga gattggatca
420cagccgaagg agtaaaggtg ctgcaatgat gttagctgtg gccactgtgg atttttcgca
480aga
4833474DNAHomo sapiensmisc_feature(227)..(227)n is a, c, g, or t
3gggtactgac catcagtgtc agcattaggg ttttggtttt tgtttctttt gggtatttct
60tttttggcac atgtgaatct tgttttgtgt aaaatgaaat tactttctct tgttctctga
120tgatgggttt aaaattaaaa gagcatccgg ttttggtatg gggatgatcc aggattatgt
180tgtgactgat acatattagt tacttgtgct tttttttttt ttttttngga tctttgcaag
240ggcaaaacta caagtaacga gttttatata attaatttaa atttgttaca ggttttcatg
300ttcaggataa accatacttc caccttgggt gagaacactt gcaacagttt attaatgagg
360tgactttcac cttaggacaa ctgttgcatg ccaagttttt tgtgtgtgtg aaacacttca
420aaactgattt aaaagatgta aatttaaaat tggttgtatc taatatgccc cagg
4744452DNAHomo sapiensmisc_feature(1)..(452)AffymetrixID 200642_at
4ctgaagggcg acggcccagt gcagggcatc atcaatttcg agcagaagga aagtaatgga
60ccagtgaagg tgtggggaag cattaaagga ctgactgaag gcctgcatgg attccatgtt
120catgagtttg gagataatac ggcaggctgt accagtgcag gtcctcactt taatcctcta
180tccagaaaac acggtgggcc aaaggatgaa gagaggcatg ttggagactt gggcaatgtg
240actgctgaca aagatggtgt ggccgatgtg tctattgaag attctgtgat ctcactctca
300ggagaccatt gcatcattgg ccgcacactg gtggtccatg aaaaagcaga tgacttgggc
360aaaggtggaa atgaagaaag tacaaagaca ggaaacgctg gaagtcgttt ggcttgtggt
420gtaattggga tcgcccaata aacattccct tg
4525457DNAHomo sapiensmisc_feature(1)..(457)AffymetrixID 200655_s_at
5acctattcaa atgggttcta gttcaatttg tttagtataa attgtcatag ctggtttact
60gaaaacaaac acatttaaaa ttggtttacc tcaggatgac gtgcagaaaa atgggtgaag
120gataaaccgt tgagacgtgg ccccactggt aggatggtcc tcttgtactt cgtgtgctcc
180gacccatggt gacgatgaca caccctggtg gcatgcccgt gtatgttggt ttagcgttgt
240ctgcattgtt ctagagtgaa acaggtgtca ggctgtcact gttcacacaa atttttaata
300agaaacattt accaagggag catctttgga ctctctgttt ttaaaacctt ctgaaccatg
360acttggagcc ggcagagtag gctgtggctg tggacttcag cacaaccatc aacattgctg
420ttcaaagaaa ttacagttta cgtccattcc aagttgt
4576507DNAHomo sapiensmisc_feature(1)..(507)AffymetrixID 200745_s_at
6gcgtgatcag agaatccttc accttatgct gaaaagtgag ctcagatcca gcaccaatgt
60tcctcctgac ccatcctgtc tatcttctca gttgagtttt taatctcact ttgggtttcc
120ttgtgaagtt ggagggaagt ttataatagc ctaacactac cccaccccca actaggagga
180acctctgttt tcaagagaga tgcctgtcct gtgcttggat agtcagtcaa ttatttgtgt
240atgaaacaat gtacaaatca atgttttgaa aataatgatc tcagactttc taagttaaag
300ttttaaaaat tttgattgtt tgccatattg ggtgggttta ctcttagaat cgcatgctgt
360agaaaatgct caaaagtgca tatgggactc agtccttagg tgttcttttt cttttaagaa
420ataacctctt acagttgtaa ccattgcggc tctgtccact tctcgttgct gctctgtggc
480acatatcgga agcagtacag cgcgcgg
5077540DNAHomo sapiensmisc_feature(32)..(32)n is a, c, g, or t
7gaaaagccat ctttgcattg ttcctcatcc gncctccttg ctcngccgca gccgcctccg
60ccgcgcgcct cctccgccgc cgcggactnc cggcagcttt atcgccagag tccctgaact
120ctcgctttct ttttaatccc cntgcatcgg atcaccggcg tgccccacca tgtcagacgc
180agccgtagac accagctccg aaatcaccac caaggactta aaggagaaga aggaagttgt
240ggaagaggca gaaanatgga agaganncgc ccctgctnaa cgggnaatgc tnnananant
300gaggaanaat ggggnagcag gaggctngac aatngaggta gacgaangaa ganggaagan
360anggtgggga nggaangagg anggaggana gaangaaggt gantggtgan ggaangagga
420ntggangant gaangatgag gaagctgagt cagctacggg caagcgggca gctgaangat
480gatgaggatg acgatgtcga taccaangaa gcagaagacc gacgaggatg actagacagc
5408492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 201193_at
8tagccacagt attgctccct aaaatatgca taaagtagaa attcactgcc ttcccctcct
60gtccatgacc ttgggcacag ggaagttctg gtgtcataga tatcccgttt tgtgaggtag
120agctgtgcat taaacttgca catgactgga acgaagtatg agtgcaactc aaatgtgttg
180aagatactgc agtcattttt gtaaagacct tgctgaatgt ttccaataga ctaaatactg
240tttaggccgc aggagagttt ggaatccgga ataaatacta cctggagtct tgtcctctcc
300atttttctct ttctcctcct ggcctggcct gaatattata ctactctaaa tagcatattt
360catccaagtg caataatgta agctgaatct tttttggact tctgctggcc tgttttattt
420cttttatata aatgtgattt ctcagaaatt gatattaaac actatcttat cttctcctga
480actgttgatt tt
4929391DNAHomo sapiensmisc_feature(1)..(391)AffymetrixID 201690_s_at
9atgatactgt agaacctgtc tcctactttg aaaactgaat gtcagggctg agtgaatcaa
60agtgtctaga catatttgca tagaggccaa ggtattctat tctaataact gcttactcaa
120cactaccacc ttttccttat actgtatatg attatggcct acaatgttgt atttgttatt
180tattaaattg tgattgtttt attattgttt atgccaaatg ttaactgcca agcttggagt
240gacctaaagc attttttaaa agcatggcta gatttacttc agtataaatt atcttatgaa
300aaccaaattt taaaagccac aggtgttgat tgttataaaa taacatgctg ccattcttga
360ttgctagagt ttttgttagt actttggatg c
39110501DNAHomo sapiensmisc_feature(1)..(501)AffymetrixID 201693_s_at
10gggctttcgg acatgacagc aaccttttct cccaggacaa ttgaaatttg ctaaagggaa
60aggggaaaga aagggaaaag ggagaaaaag aaacacaaga gacttaaagg acaggaggag
120gagatggcca taggagagga gggttcctct taggtcagat ggaggttctc agagccaagt
180cctccctctc tactggagtg gaaggtctat tggccaacaa tcctttctgc ccacttcccc
240ttccccaatt actattccct ttgacttcag ctgcctgaaa cagccatgtc caagttcttc
300acctctatcc aaagaacttg atttgcatgg attttggata aatcatttca gtatcatctc
360catcatatgc ctgacccctt gctcccttca atgctagaaa atcgagttgg caaaatgggg
420tttgggcccc tcagagccct gccctgcacc cttgtacagt gtctgtgcca tggatttcgt
480ttttcttggg gtactcttga t
50111489DNAHomo sapiensmisc_feature(1)..(489)AffymetrixID 201889_at
11ttgaccccaa atgactttat acccaattct acataaaaat atagaagatc tatctttttt
60tgttaccttc agatgttcac taaataactc agtttttaag cagaagtttt cagggcatta
120aatatatgtt gtgtatgaag tatctcaaac tggaacataa atttagtgat caaactgcca
180ttcacagtgt aaggcagcac ttaaatttcg aacctaaagt ttagatgcat tgtataaaaa
240aacctaaaag cagtatctgt tatttagctg taaaccaagt tggaagctat tcggataatt
300tcttaaatat tgatgaactt tggagtactg tttcttcctt caaactgaat gtaattaatt
360catgaataaa tgcaccttat atgtttaaac aatctttgta tacttttggg atttttggtg
420cttatatgct aaatcacatt cagcatgtgt attttgacat ttaaaatact tccctcaatt
480ctgtaaatt
48912409DNAHomo sapiensmisc_feature(1)..(409)AffymetrixID 202110_at
12tcagctcact tcaagggtac ctgaagcgaa ttggcaccaa agcagcagct gtattgccgc
60agttctagct tcaccttcac gatgtttccc ttggtcaaaa gcgcactaaa tcgtctccaa
120gttcgaagca ttcagcaaac aatggcaagg cagagccacc agaaacgtac acctgatttt
180catgacaaat acggtaatgc tgtattagct agtggagcca ctttctgtat tgttacatgg
240acatatgtag caacacaagt cggaatagaa tggaacctgt cccctgttgg cagagttacc
300ccaaaggaat ggaggaatca gtaatcatcc cagctggtgt aataatgaat tgtttaaaaa
360acagctcata attgatgcca aattaaagca ctgtgtaccc attaagata
40913511DNAHomo sapiensmisc_feature(1)..(511)AffymetrixID 202157_s_at
13tgtggcaaaa acgtttcttt cttatttttt ttcttttcct aaaacagact tgaaagtatt
60atacagggat tggcattctt cccggtcact ggtaacaata gcaatatgtg tccagggaca
120cagaatgttg gtttctaaca gactacttcc aaaaacagtt tgagaaaaaa actgtctgat
180tttaagtctc tagaggtctg taatagtttt tacatttttc aggcagtgta aagttttttg
240ataaggccat tttaggtggc tcactttctc attaagatat atatatagaa ccactttttg
300tagattagta taagaaaaat atttaccctg ttttggggca aatgctacct atttgtgtca
360ccttttgctg aactcacagt tagacaatcc atggtttaat gcacatgaaa ttacctatat
420tttatactgt ttcaatgtac aggagaaagg ttactgtaaa ctgtgttatg ttggtgcttc
480tgtgaattaa gttgtggttt catcatgagt c
51114480DNAHomo sapiensmisc_feature(1)..(480)AffymetrixID 202233_s_at
14gctcgtgttg aatctagaac cgtagccaga catgggactg gaggacgagc aaaagatgct
60taccgaatcc ggagatcctg aggaggagga agaggaagag gaggaattag tggatcccct
120aacaacagtg agagagcaat gcgagcagtt ggagaaatgt gtaaaggccc gggagcggct
180agagctctgt gatgagcgtg attcctctcg atcacataca gaagaggatt gcacggagga
240gctctttgac ttcttgcatg cgagggacca ttgcgtggcc cacaaactct ttaacaactt
300gaaataaatg tgtggactta agttgcaccc cagtcttcat catctgggca tcagaatatt
360tccttatggt tttggatgta ccatttgttt cttatttgtg taactgtaag ttcacatcaa
420cctcatgggt ttggcttgag gctggtagct tctatgtaat tcgcaatgat tccatctaaa
48015556DNAHomo sapiensmisc_feature(1)..(556)AffymetrixID 202378_s_at
15acatgtgcac atgcggcatt ttactatgaa atttaatatg ctgggttttt taataccttt
60atatatcatg ttcactttaa gaaagacttc ataagtagga gatgagtttt attctcagca
120aatagacctg tcaaatttag attatgttac tcaaattatg ttacttgttt ggctgttcat
180gtagtcacgg tgctctcaga aaatatatta acgcagtctt gtaggcagct gccaccttat
240gcagtgcatc gaaacctttt gcttggggat gtgcttggag aggcagataa cgctgaagca
300ggcctctcat gacccaggaa ggccggggtg gatccctctt tgtgttgtag tccatgctat
360taaaagtgtg gcccacagac caagagcctc aacatttcct agagccttat tagaaatgca
420gaatctgaag ccccactctg gacccaggac attttgatga gatccaaagg agttgtatgc
480acatgaaagt ttgagaagca tcatcataga gaagtaaaca tcacacccaa cttccttatc
540tttccagtgg ctaaac
55616529DNAHomo sapiensmisc_feature(75)..(75)n is a, c, g, or t
16gaaatcagag cttacatgtg tgttttttta taacattttc agataaatgt attcaacatg
60taatacagta ttttnacatt cacctcttat tttatattga aatgtattac agtattaaaa
120ctcagtgttc agtatttatt tcactatgca ttttatttag taaaagccag gagaaatgtt
180taatccaatg gtgccttact ttgtgattta aaagaaatca actttttttt atgtctaagt
240agtagattat ttgcatattt gtaaaaactg ttaggtcttt atattttaaa gtgtaatacc
300agttttgtta ttttagtagc agaaatggga tgattgttaa agttccccaa aaatgttggc
360atgaaattaa tttttccctc cttatagtca aggaccgtag aggaagaaaa actttttttt
420catatcatgc actatgtaaa cagacacatt ttgctatctg tgtcatcagg atagtgtaag
480tggtagggta gagactaccc tagacatctg catctttgta agttagcca
52917478DNAHomo sapiensmisc_feature(1)..(478)AffymetrixID 202910_s_at
17ctgtggccac agcagctttg tacacgaaga ccatccatcc tcccttcgtc caccactcta
60ctccctccac cctccctccc tgatcccgtg tgccaccagg agggagtggc agctatagtc
120tggcaccaaa gtccaggaca cccagtgggg tggagtcgga gccactggtc ctgctgctgg
180ctgcctctct gctccacctt gtgacccagg gtggggacag gggctggccc agggctgcaa
240tgcagcatgt tgccctggca cctgtggcca gtactcggga cagactaagg gcgcttgtcc
300catcctggac ttttcctctc atgtctttgc tgcagaactg aagagactag gcgctggggc
360tcagcttccc tcttaagcta agactgatgt cagaggcccc atggcgaggc cccttggggc
420cactgcctga ggctcacggt acagaggcct gccctgcctg gccgggcagg aggttctc
47818276DNAHomo sapiensmisc_feature(57)..(57)n is a, c, g, or t
18aaaaatggcg ttcttctctt gtggcctgtt attctgattg ctgctgtata cagtttngtc
60actctttagt ttttagttaa gcatactgat agactttcct ctaaaagcca ttcactccag
120attttacctg gggaatattc tacatactgc ttactttctc tataaaactc atcaataaat
180catgaaaggc actgagtttt gtaaatcagg accctaaatg tttaattgta aataagtttc
240agataattat tatagctttg cgttgaagtt tgttgt
27619486DNAHomo sapiensmisc_feature(1)..(486)AffymetrixID 202950_at
19taacatgtta gttgtcattt ggcatgagtg tgcattccag taattcttaa ttgatatttg
60attaattcca tacctttgat taaaacatgc tagttcaaaa taagactgct cagtttccaa
120gggttttcaa gcctacttac ctttataaag gttctctagt ctctgattag ccatgactgt
180attggacttt gaacattttc tgaactaaaa acctctattc taaactaatc tcatttggat
240gtgtaagtct tttgtaaagg caagaataaa taatatccag gacaatttat tagttttctc
300agtattttcc caaatattag aatatttact tcattattgg ttggctgcca atgaccccat
360atgttctgtg agaatagtag ctttatcttt gatataatac atagtctcca aataggtaat
420acttcgcaat tgattagatt ttcagagtag atttagagtt atctgttttt ctggtgaggg
480tcaaat
48620539DNAHomo sapiensmisc_feature(1)..(539)AffymetrixID 203097_s_at
20tttccattaa attcagctga tcatattgat cagtagataa acgtaaatag cttcaaattt
60taaaagtgga attgcagtgt tttttcactg tatcaaacaa tgtcagtgct ttatttaata
120attctcttct gtatcatggc atttgtctac ttgcttatta cattgtcaat tatgcatttg
180taattttaca tgtaatatgc attatttgcc agttttatta tataggctat ggacctcatg
240tgcatataga aagacagaaa tctagctcta ccacaagttg cacaaatgtt atctaagcat
300taagtaattg tagaacatag gactgctaat ctcagttcgc tctgtgatgt caagtgcaga
360atgtacaatt aactggtgat ttcctcatac ttttgatact acttgtacct gtatgtcttt
420tagaaagaca ttggtggagt ctgtatccct tttgtatttt taatacaata attgtacata
480ttggttatat ttttgttgaa gatggtagaa atgtactatg tttatgcttc tacatccag
53921444DNAHomo sapiensmisc_feature(1)..(444)AffymetrixID 203231_s_at
21tgcaccaggt gaaaacaggg ccagcagact ccatggccca attcggtttc ttcggtggtg
60atgtgaaagg agagaattac actttttttt tttttaagtg gcgtggaggc ctttgcttcc
120acatttgttt ttaacccaga atttctgaaa tagagaattt aagaacacat caagtaataa
180atatacagag aatatacttt tttataaagc acatgcatct gctattgtgt tgggttggtt
240tcctctcttt tccacggaca gtgttgtgtt tctggcatag ggaaactcca aacaacttgc
300acacctctac tccggagctg agatttcttt tacatagatg acctcgcttc aaatacgtta
360ccttactgat gataggatct tttcttgtag cactatacct tgtgggaatt tttttttaaa
420tgtacacctg atttgagaag ctga
44422526DNAHomo sapiensmisc_feature(1)..(526)AffymetrixID 203300_x_at
22gaacttgttc agaccgtttt agcacggaaa cctaaaatgt gcagcttcct tgagtggcga
60gatctgaaga ttgtttacaa aagatatgct agtctgtatt tttgctgtgc tattgaggat
120caggacaatg aactaattac cctggaaata attcatcgtt atgtggaatt acttgacaag
180tatttcggca gtgtctgtga actagatatc atctttaatt ttgagaaggc ttattttatt
240ttggatgagt ttcttttggg aggggaagtt caggaaacat ccaagaaaaa tgtccttaaa
300gcaattgagc aggctgatct actgcaggag gaagctgaaa ccccacgtag tgttcttgaa
360gaaattggac tgacataact ctcctccctt gttgatgact tcttgtggca tttcacacac
420tgtagatggt cactcccttc atgtccatgt tagctcatgg tgtaagatga tgtcttgtca
480gtattactgt tttgctaagc cgcttcattc atgcctacac aatttt
52623502DNAHomo sapiensmisc_feature(112)..(112)n is a, c, g, or t
23ttgtggttgt tgagaggcat tttcaaaccc tgtataaata atccatgctg ttggtcataa
60gttaactgta ttaagaacag taaaataaat aaaaaccaat agtactaatt tngctttaaa
120aaaatttcta atttttttca cataaaacaa ttatcctaaa ggttaatagt tgatcgaaac
180agaataatag aaaaattctn ctttaatttc cattaaaaag caaatagcat tgacacattt
240aaagcttttc atttaaagta gtggatgttt ttgaagtatc taaaatagta gcagaatatt
300ttatacttgg tccttgcaat ggtgtgagtt ttaatgattg cattatcgtg attggtggtt
360atgagtttca gaaatctata cttggcatcc aactcatgag tggattttat ataggatgga
420acaggaaggt atgtcctgtc agtatcttaa ccctttcaac aagacattta cctatttgtc
480tttccttacg ttctcaaaat at
50224244DNAHomo sapiensmisc_feature(1)..(244)AffymetrixID 204750_s_at
24gaccctcgcg atcttaatat ttgccagtga tgcctgcaaa aatgtgacat tacatgttcc
60ctccaaacta gatgccgaga aacttgttgg tagagttaac ctgaaagagt gctttacagc
120tgcaaatcta attcattcaa gtgatcctga cttccaaatt ttggaggatg gttcagtcta
180tacaacaaat actattctat tgtcctcgga gaagagaagt tttaccatat tactttccaa
240cact
24425504DNAHomo sapiensmisc_feature(1)..(504)AffymetrixID 204777_s_at
25ggaagtcttc ataaagccgc agtagaactt gagctgaaaa cccagatggt gttaactggc
60cgccccactt tccggcataa ctttttagaa aacagaaatg cccttgatgg tggaaaaaag
120aaaacaacca cccccccact gcccaaaaaa aaaagccctg ccctgttgct cgtgggtgct
180gtgtttactc tcccgtgtgc cttcgcgtcc gggttgggag cttgctgtgt ctaacctcca
240actgctgtgc tgtctgctag ggtcacctcc tgtttgtgaa aggggacctt cttgttcggg
300ggtgggaagt ggcgaccgtg acctgagaag gaaagaaaga tcctctgctg acccctggag
360cagctctcga gaactacctg ttggtattgt ccacaagctc tcccgagcgc cccatcttgt
420gccatgtttt aagtcttcat ggatgttctg catgtcatgg ggactaaaac tcacccaaca
480gatctttcca gaggtccatg gtgg
50426268DNAHomo sapiensmisc_feature(1)..(268)AffymetrixID 205042_at
26ttacatttga actatatcct tcctagtggg ttagtgtgaa aaagagtttg gctgattcct
60aaaactctgc cagccctgca gtaatctcca ggcctggtta ttgttcagac attccatggt
120gattcctggg aaggaagctt ggctgctcag tttctgagtc tggggtgaga taatgttctg
180gaaggacatc tgttctttgg tgtaatctct catggtgaaa tctgctctgt acatcagaca
240attgcattgc taccaagttt cataccaa
26827507DNAHomo sapiensmisc_feature(1)..(507)AffymetrixID 205114_s_at
27gattccacag aatttcatag ctgactactt tgagacgagc agccagtgct ccaagcccgg
60tgtcatcttc ctaaccaagc gaagccggca ggtctgtgct gaccccagtg aggagtgggt
120ccagaaatat gtcagcgacc tagagctgag tgcctgaggg gtccagaagc ttcgaggccc
180agcgacctcg gtgggccagt ggggaggagc aggagcctga gccttgggaa acatgcgtgt
240gacctccaca gctacctctt ctatggactg gttgttgcca aacagccaca ctgtgggact
300cttcttaact taaattttaa tttatttata ctatttagtt tttgtaattt attttcgatt
360tcacagtgtg tttgtgattg tttgctctga gagttcccct gtcccctccc ccttccctca
420caccgcgtct ggtgacaacc gagtggctgt catcagcctg tgtaggcagt catggcacca
480aagccaccag actgacaaat gtgtatc
50728565DNAHomo sapiensmisc_feature(1)..(565)AffymetrixID 205624_at
28tatgaaaccc gctacatcta tggcccaata gaatcaacaa tttacccgat atcaggttct
60tctttagact gggcttatga cctgggcatc aaacacacat ttgcctttga gctccgagat
120aaaggcaaat ttggttttct ccttccagaa tcccggataa agccaacgtg cagagagacc
180atgctagctg tcaaatttat tgccaagtat atcctcaagc atacttccta aagaactgcc
240ctctgtttgg aataagccaa ttaatccttt tttgtgcctt tcatcagaaa gtcaatcttc
300agttatcccc aaatgcagct tctatttcac ctgaatcctt ctcttgctca tttaagtccc
360atgttactgc tgtttgcttt tacttacttt cagtagcacc ataacgaagt agctttaagt
420gaaacctttt aactaccttt ctttgctcca agtgaagttt ggacccagca gaaagcatta
480ttttgaaagg tgatatacag tggggcacag aaaacaaatg aaaaccctca gtttctcaca
540gattttcacc atgtggcttc atcaa
56529493DNAHomo sapiensmisc_feature(1)..(493)AffymetrixID 206207_at
29aggagacaac aatgtccctg ctacccgtgc catacacaga ggctgcctct ttgtctactg
60gttctactgt gacaatcaaa gggcgaccac ttgtctgttt cttgaatgaa ccatatctgc
120aggtggattt ccacactgag atgaaggagg aatcagacat tgtcttccat ttccaagtgt
180gctttggtcg tcgtgtggtc atgaacagcc gtgagtatgg ggcctggaag cagcaggtgg
240aatccaagaa catgcccttt caggatggcc aagaatttga actgagcatc tcagtgctgc
300cagataagta ccaggtaatg gtcaatggcc aatcctctta cacctttgac catagaatca
360agcctgaggc tgtgaagatg gtgcaagtgt ggagagatat ctccctgacc aaatttaatg
420tcagctattt aaagagataa ccagacttca tgttgccaag gaatccctgt ctctacgtga
480acttgggatt cca
49330218DNAHomo sapiensmisc_feature(1)..(218)AffymetrixID 206790_s_at
30gaacttactt cagattgtgc gggaccactg ggttcatgtt cttgtcccta tgggatttgt
60cattggatgt tatttagaca gaaagagtga tgaacggcta actgccttcc ggaacaagag
120tatgttattt aaaagggaat tgcaacccag tgaagaagtt acctggaagt aaagactggc
180tagattatcg aatgttcaca ttttaaagtt ctgagaga
21831453DNAHomo sapiensmisc_feature(1)..(453)AffymetrixID 207008_at
31acctaacgaa gtatccttca gcctgaaaga ggaatgaagt actcatacat gttacaacac
60ggacgaacct tgaaaacttt atgctaagtg aaataagcca gacatcaaca gataaatagt
120ttatgattcc acctacatga ggtactgaga gtgaacaaat ttacagagac agaaagcaga
180acagtgatta ccagggactg aggggagggg agcatgggaa gtgacggttt aatgggcaca
240gggtttatgt ttaggatgtt gaaaaagttc tgcagataaa cagtagtgat agttgtaccg
300caatgtgact taatgccact aaattgacac ttaaaaatgg tttaaatggt caattttgtt
360atgtatattt tatatcaatt taaaaaaaaa cctgagcccc aaaaggtatt ttaatcacca
420aggctgatta aaccaaggct agaaccacct gcc
45332385DNAHomo sapiensmisc_feature(1)..(385)AffymetrixID 207815_at
32caagccctgc tgtacaagaa aatcattaag gaacatttgg agagttagct actagctgcc
60taagtgtgca ctttcaatct aactgtgaaa gaatcttctg atgtttgtat tatccttctt
120atattatatt aacaaaataa atcaagttgt ggtatagtca atctatttct taataatact
180gcaaaaataa tgctgacaca tcacaatttc atattttaaa atttccagaa ttttaagcaa
240aaagcattat gaaggaaggc ttggtttaat aaagactgat tttgttcagt gttatatgtt
300agctgataca tatttgttca tttatgtgat tgcagtactt tatagctaca tatttacctt
360gaatgttaca attagcttgc caata
38533491DNAHomo sapiensmisc_feature(1)..(491)AffymetrixID 208051_s_at
33gaactcccag ctaaacaacc aagacttcac tgaagattta ttccaattct agaattgttc
60tttttttatt ttttattttt tcaactgact aacttcatta ccttaaagcc tagaacatta
120ttctgcttta tttatatggc tttctcaatt ttattttgta gcatgggttg aatcgaactt
180tttactagag aattttacta gatatttgtc attcaagttt tcatctgctt tataattgat
240acaccttgag ggtcactttt ctaatacttt tacctataat gtggtaccca cctcagcccc
300taataaataa tatttttacc ctaatgtcaa atctttttcc caggctaact aaaaactgtg
360tacaaaagga ttgcttgtaa atatgcatgt aaatagttct gttaataacc cactgtttta
420catttggtac atctgtgtct gctaatacag ttagctttct cacttttctg cttgtttgtt
480cagtctgaat t
49134382DNAHomo sapiensmisc_feature(1)..(382)AffymetrixID 208161_s_at
34gatagcaaac actgggggca ccttaagatt ttgcacctgt aaagtgcctt acagggtaac
60tgtgctgaat gctttagatg aggaaatgat ccccaagtgg tgaatgacac gcctaaggtc
120acagctagtt tgagccagtt agactagtcc cccggtctcc cgattcccaa ctgagtgtta
180tttgcacact gcactgtttt caaataacga ttttatgaaa tgacctctgt cctccctctg
240atttttcata ttttcctaaa gtttcgtttc tgttttttaa taaaaagctt tttcctcctg
300gaacagaaga cagctgctgg gtcaggccac ccctaggaac tcagtcctgt actctggggt
360gctgcctgaa tccattaaaa at
38235543DNAHomo sapiensmisc_feature(1)..(543)AffymetrixID 208637_x_at
35ggtcccgagg agttcaaagc ctgcctcatc agcttgggtt atgatattgg caacgacccc
60cagggagaag cagaatttgc ccgcatcatg agcattgtgg accccaaccg cctgggggta
120gtgacattcc aggccttcat tgacttcatg tcccgcgaga cagccgacac agatacagca
180gaccaagtca tggcttcctt caagatcctg gctggggaca agaactacat taccatggac
240gagctgcgcc gcgagctgcc acccgaccag gctgagtact gcatcgcgcg gatggccccc
300tacaccggcc ccgactccgt gccaggtgct ctggactaca tgtccttctc cacggcgctg
360tacggcgaga gtgacctcta atccaccccg cccggccgcc ctcgtcttgt gcgccgtgcc
420ctgccttgca cctccgccgt cgcccatctc ctgcctgggt tcggtttcag ctcccagcct
480ccacccgggt gagctggggc ccacgtggca tcgatcctcc ctgcccgcga agtgacagtt
540tac
54336165DNAHomo sapiensmisc_feature(1)..(165)AffymetrixID 208918_s_at
36gaaatgggct gggagtgctt ctgtcctgct gacaccccgc ggtgggtccc tggagcgcgg
60cctccagctg ccgcaatttc catgccagga tatttttccg caaatcagtc ggttgaaatt
120cagaggagtc agaatgactc gacctgtcct tcaatgttga taata
16537189DNAHomo sapiensmisc_feature(75)..(75)n is a, c, g, or t
37attgcttgct aaagaagtgg tctcctgagg tcttaagaca ttcctgacag tgtcttgagt
60gggtgggaga gaggntgctg tcattgcgct gtggaatttc acagatgaga accacgccta
120gccaaaatca cttttcctgt ttgcctcagt gacacagctg cagggaccct cgtggatgtt
180gtattaaat
18938355DNAHomo sapiensmisc_feature(1)..(355)AffymetrixID 209009_at
38gagcttcccc aactcataaa tgccaatttt ccagtggatc cccaaaggat gtctattttt
60ggccactcca tgggaggtca tggagctctg atctgtgctt tgaaaaatcc tggaaaatac
120aaatctgtgt cagcatttgc tccaatttgc aaccctgtac tctgtccctg gggcaaaaaa
180gcctttagtg gatatttggg aacagatcaa agtaaatgga aggcttatga tgctacccac
240cttgtgaaat cctatccagg atctcagctg gacatactaa ttgatcaagg gaaagatgac
300cagtttcttt tagatggaca gttactccct gataacttca tagctgcctg tacag
35539564DNAHomo sapiensmisc_feature(1)..(564)AffymetrixID 209020_at
39caggggcagt cgttgagcct ttgagaactt ctgttccaag gctcccatca gagagtaaga
60aggaagactc ctctgacgct acccaagtcc cccaagcaag tctcaaagcc agtgatctct
120ctgactttca atcagtttcc aagctaaacc aggggcaagc catgcacatg cataggcaag
180gaatgccagt gtaagagatg gcatgatatg gaagtgtatt ccttttcagg cctgcagagt
240gtccctccct tggctccaga acgaagatcc acacttgagg actactctca gtcgctgcac
300gccagaactc tgtctggctc tccccgatcc tgttctgagc aagctcgagt cttcgtggat
360gatgtgacca ttgaggacct gtcaggctac atggagtatt acttgtatat tcccaagaaa
420atgtcccaca tgggcagaaa tgatgtacac ctgatagcaa gaagctaatt catatgcttt
480aaaccaatga aggcttgtca aagagattta gttaatggca gaccttgtgg ccactttgtg
540tgagaagaca tctctttctg ctca
56440339DNAHomo sapiensmisc_feature(1)..(339)AffymetrixID 209146_at
40gaacctcatc aattgatagc agtgagtgac tgaagcttcc aaatcaagaa aagccggcac
60caagaacttc cattctaatc tagagctgac cagtttgagc tgattctctc tttgaagagt
120ccttcttgat tgcagtgcag tactggcatt tctgaatgga tgtaagtgga gtattttagt
180ctaaaggctt ttcaaattac ttgaattttt ttaaaaattg aggagcttta tttctattta
240cccttccatt tttgtatatc aaatttccat tgtcattaaa aactgtatct tgaaactttg
300tgaactgact tgctgtattt gcactttgag ctcttgaaa
33941465DNAHomo sapiensmisc_feature(1)..(465)AffymetrixID 209193_at
41gattgtagtg gatctaattt ttcagaaatt ttgcctttaa gttattttac ctgtttttgt
60ttcttgtttt gaaagatgcg cattctaacc tggaggtcaa tgttatgtat ttatttattt
120atttatttgg ttcccttcct attccaagct tccatagctg ctgccctagt tttctttcct
180cctttcctcc tctgacttgg ggaccttttg ggggagggct gcgacgcttg ctctgtttgt
240ggggtgacgg gactcaggcg ggacagtgct gcagctccct ggcttctgtg gggcccctca
300cctacttacc caggtgggtc ccggctctgt gggtgatggg gaggggcatt gctgactgtg
360tatataggat aattatgaaa agcagttctg gatggtgtgc cttccagatc ctctctgggg
420ctgtgttttg agcagcaggt agcctggctg gttttatctg agtga
46542535DNAHomo sapiensmisc_feature(1)..(535)AffymetrixID 209710_at
42gatcccacag ccctagtatg aaagctgggg gtggggaggg gcctttgctg cccttggttt
60ctgggggctg gttggcattt gctggcctgg cagggggtga aggcaggagt tgggggcagg
120tcaggaccag gacccaggga gaggctgtgt ccctgctggg gtctcaggtc cagctttact
180gtggctgtct ggatccttcc caaggtacag ctgtatataa acgtgtcccg agcttagatt
240ctgtatgcgg tgacggcggg gtgtggtggc ctgtgagggg cccctggccc aggaggagga
300ttgtgctgat gtagtgacca agtgcaatat gggcgggcag tcgctgcagg gagcaccacg
360gccagaagta acttattttg tactagtgtc cgcataagaa aaagaatcgg cagtattttc
420tgtttttatg ttttatttgg cttgttttat tttggattag tgaactaagt tattgttaat
480tatgtacaac atttatatat tgtctgtaaa aaatgtatgc tatcctctta ttcct
53543527DNAHomo sapiensmisc_feature(1)..(527)AffymetrixID 210042_s_at
43gaaatctacg caaatggtcc catcagctgt ggaataatgg caacagaaag actggcaaac
60tacaccggag gcatctatgc cgaataccag gacaccacat atataaacca tgtcgtttcc
120gtggctgggt ggggcatcag tgatgggact gagtactgga ttgtccggaa ttcatggggt
180gaaccatggg gcgagagagg ctggctgagg atcgtgacca gcacctataa ggatgggaag
240ggcgccagat acaaccttgc catcgaggag cactgtacat ttggggaccc catcgtttaa
300ggccatgtca ctagaagcgc agtttaagaa aaggcatggt gacccatgac cagaggggat
360cctatggtta tgtgtgccag gctggctggc aggaactggg gtggctatca atattggatg
420gcgaggacag cgtggtactg gctgcgagtg ttcctgagag ttgaaagtgg gatgacttat
480gacacttgca cagcatggct ctgcctcaca atgatgcagt cagccac
52744536DNAHomo sapiensmisc_feature(1)..(536)AffymetrixID 210184_at
44cagttctgaa tatgctgctc atccccacct gtcttcaaca gctccccatt accctcagga
60caatgtctga actctccagc ttcgcgtgag aagtcccctt ccatcccaga gggtgggctt
120cagggcgcac agcatgagag cctctgtgcc cccatcaccc tcgtttccag tgaattagtg
180tcatgtcagc atcagctcag ggcttcatcg tggggctctc agttccgatt ccccaggctg
240aattgggagt gagatgcctg catgctgggt tctgcacagc tggcctcccg cggttgggtc
300aacattgctg gcctggaagg gaggagcgcc ctctagggag ggacatggcc ccggtgcggc
360tgcagctcac cagccccagg ggcagaagag acccaaccac ttcctatttt ttgaggctat
420gaatatagta cctgaaaaaa tgccaagcac tagattattt ttttaaaaag cgtactttaa
480atgtttgtgt taatacacat taaaacatcg cacaaaaacg atgcatctac cgctcc
53645132DNAHomo sapiensmisc_feature(1)..(132)AffymetrixID 210732_s_at
45cccagcttcc tagtaataga ggaggagaca tttctaaaat cgcacccaga actgtctaca
60ccaagagcaa agattcgact gtcaatcaca ctttgacttg caccaaaata ccacctatga
120actatgtgtc aa
13246398DNAHomo sapiensmisc_feature(1)..(398)AffymetrixID 210895_s_at
46gtgtacataa atttgacctg ctcatctata cacggttacc cagaacctaa gaagatgagt
60gttttgctaa gaaccaagaa ttcaactatc gagtatgatg gtattatgca gaaatctcaa
120gataatgtca cagaactgta cgacgtttcc atcagcttgt ctgtttcatt ccctgatgtt
180acgagcaata tgaccatctt ctgtattctg gaaactgaca agacgcggct tttatcttca
240cctttctcta tagagcttga ggaccctcag cctcccccag accacattcc ttggattaca
300gctgtacttc caacagttat tatatgtgtg atggttttct gtctaattct atggaaatgg
360aagaagaaga agcggcctcg caactcttat aaatgtgg
39847216DNAHomo sapiensmisc_feature(1)..(216)AffymetrixID 211506_s_at
47gtgtgaaggt gcagttttgc caaggagtgc taaagaactt agatgtcagt gcataaagac
60atactccaaa cctttccacc ccaaatttat caaagaactg agagtgattg agagtggacc
120acactgcgcc aacacagaaa ttattgtaaa gctttctgat ggaagagagc tctgtctgga
180ccccaaggaa aactgggtgc agagggttgt ggagaa
21648378DNAHomo sapiensmisc_feature(1)..(378)AffymetrixID 211734_s_at
48acatctccat tacaaatgcc acagttgaag acagtggaac ctactactgt acgggcaaag
60tgtggcagct ggactatgag tctgagcccc tcaacattac tgtaataaaa gctccgcgtg
120agaagtactg gctacaattt tttatcccat tgttggtggt gattctgttt gctgtggaca
180caggattatt tatctcaact cagcagcagg tcacatttct cttgaagatt aagagaacca
240ggaaaggctt cagacttctg aacccacatc ctaagccaaa ccccaaaaac aactgatata
300attactcaag aaatatttgc aacattagtt tttttccagc atcagcaatt gctactcaat
360tgtcaaacac agcttgca
37849529DNAHomo sapiensmisc_feature(1)..(529)AffymetrixID 211995_x_at
49agtactcggt gtggatcggt ggctccatcc tggcctcact gtccaccttc cagcagatgt
60ggattagcaa gcaggagtac gacgagtcgg gcccctccat cgtccaccgc aaatgcttct
120aaacggactc agcagatgcg tagcatttgc tgcatgggtt aattgagaat agaaatttgc
180ccctggcaaa tgcacacacc tcatgctagc ctcacgaaac tggaataagc cttcgaaaag
240aaattgtcct tgaagcttgt atctgatatc agcactggat tgtagaactt gttgctgatt
300ttgaccttgt attgaagtta actgttcccc ttggtatttg tttaataccc tgtacatatc
360tttgagttca acctttagta cgtgtggctt ggtcacttcg tggctaaggt aagaacgtgc
420ttgtggaaga caagtctgtg gcttggtgag tctgtgtggc cagcagcctc tgatctgtgc
480agggtattaa cgtgtcaggg ctgagtgttc tgggatttct ctagaggct
52950535DNAHomo sapiensmisc_feature(327)..(327)n is a, c, g, or t
50tattttggta cctgtgcttg ccacagccct gttcctcaaa gctgaattga tagatttctc
60tttgacttcc aagacctagc agttataagg caccttgaaa taaattgttt gtgcctggaa
120atgcagggag ggcaatagct ttgtaaattg gtttacattt ttctccttga atttttctag
180ggtcctagtg cttccgaatc atttaatggc attgtcggat atcttttaca tttcaattgc
240aatccatgaa attacattta gaagattctt agtacttaac tgtagtcttc tccatgaatt
300acacgttaga atagactggc agcaacngaa tatgcagcaa gtaagcctct agcttatagt
360ttcatcccta cccctcatgc ctgcgtgagt ctgtacaggg atatgtgtgt gtgtgtgtgt
420gtgtgtgtgt tagagaggaa gaggaagagc agaatgtctg tatactacat gctgctaagg
480tagtgaataa atcagtaatg caatattgtg ggtccaaact actctttgca ctact
53551475DNAHomo sapiensmisc_feature(1)..(475)AffymetrixID 212335_at
51accacgcttg gctaagaaca cctaaatttt tatgtttctt ggctcaaaaa ccagttccat
60ttctaatgtt gtcctcacaa gaaggctaat tggtggtgag acagcagggg aggaggaaga
120gctgtggttt gtaacttgtt caactcaggc aataagcgat tttagcttta tttaaagtct
180tctgtccagc tttaagcact ttgtaagaca tggctgaaag tagcttttct atcagaattg
240cagatagtca tgttgggcta acagtcaatt ggatatattc ctttacctca catgacccca
300gcaactgtgg tggtatctag aggtgaaaca ggcaagtgaa atggacacct ctgctgtgaa
360tgttttagag aaggaaattc aaaaaatgtt gtaactgaaa gcactgttga atatgggtat
420cggctttctt tttcactttg actcttaaca ttatcagtca acttccacat taatg
47552179DNAHomo sapiensmisc_feature(1)..(179)AffymetrixID 212386_at
52gagatttacc atgtatcagt gcctggcttt ttgttataaa gctttgtttg tctagtgctc
60ttttgctata aaatagactg tagtacaccc tagtaggaaa aaaaaaaaac taaatttaaa
120aataaaaaat atatttggct tatttttcgc aggagcaatc cttttatacc atgaatatt
17953295DNAHomo sapiensmisc_feature(114)..(114)n is a, c, g, or t
53accaatgagg ttcctgaggt cacagtgttt tccaagtctc ccgtgacact gggtcagccc
60aacaccctca tctgtcttgt ggacaacatc tttcctcctg tggtcaacat cacntggctg
120agcaatgggc actcagtcac agaaggtgtt tctgagacca gcttcctctc caagagtgat
180cattccttct tcaagatcag ttacctcacc ttcctccctt ctgntgatga gatttatgac
240tgcaaggtgg agcactgggg cctggatgag cctcttctga aacactggga gcctg
29554565DNAHomo sapiensmisc_feature(134)..(134)n is a, c, g, or t
54aaggagacct ttgaagcttt ttgagggcaa actttacctt tgtggtcccc aaatgatggc
60atttctcttt gaaatttatt agatactgtt atgtccccca agggtacagg aggggcatcc
120ctcagcctat gggnaacacc caaactagga ggggttattg acaggaagga atgaatccaa
180gtgaaggctt tctgctcttc gtgttacaaa ccagtttcag agttagcttt ctggggaggt
240gtgtgtttgt gaaaggaatt caagtgttgc aggacagatg agctcaaggt aaggtagctt
300tggcagcagg gctgatacta tgaggctgaa acaatccttg tgatgaagta gatcatgcag
360tgacatacaa agaccaagga ttatgtatat ttttatatct ctgtggtttt gaaactttag
420tacttagaat tttggccttc tgcactactc ttttgctctt acgaacataa tggactctta
480agaatggaaa gggatgacat ttacctatgt gtgctgcctc attcctggtg aagcaactgc
540tacttgttct ctatgcctct aaaat
56555358DNAHomo sapiensmisc_feature(61)..(61)n is a, c, g, or t
55cactgcagaa tgaaggaaca tcccttgagg tgacccagcc aacctgtggc cagaaggagg
60nttgtacctt gaaaagacac tgaaagcatt ttggngtgtn aagtaagggt gggcagagga
120ggtagaaaat caattcaatt gtcgcatcat tcatggttct ttaatattga tgctcagtgc
180antggcctna gaatatccca gcctctcttc tggtttgntg agtgctntnt aagtaagcat
240ggtngaattg tttggggnca natatagtga nccttggtca ctggtgtttc aaacattctg
300gnaagtcaca tcnatcaaga atanttttta nttttaagaa agcataacca gcaataaa
35856441DNAHomo sapiensmisc_feature(1)..(441)AffymetrixID 213309_at
56gtatgtagca atcctgcgtg tgaaggcaaa taaactcttt aacaggcaat tatattgctg
60gccaaaatat gctatatttg tatacaaaga cattctaact cagttccagt atgaagaaag
120attattcact ctagctccac tgagaaacat tttcctaagt gaaaacaatt tcttaagatg
180gaaatggatt ggattgtcaa attattattt attggagaaa aaaacctgat ctacacattt
240ttacttatat ggggttgcca gagtctctgg gttctagatg attttggtgg catgcttgct
300gagccataat tactaaagag aatgtaagtg gacgggttcc ctgaatcccc ggggtccttg
360gagagccatc gaggagaatg tgcaattgga ctgaagctcc ctggctgaag atacatgccg
420agtcagcaca tgggtagaga t
44157431DNAHomo sapiensmisc_feature(178)..(178)n is a, c, g, or t
57gcacacagag atttgagaac cattgttctg aatgctgctt ccatttgaca aagtgccgtg
60ataatttttg aaaagagaag caaacaatgg tgtctctttt atgttcagct tataatgaaa
120tctgtttgtt gacttattag gactttgaat tatttcttta ttaaccctct gagttttngt
180atgtattatt attaaagaaa aatgcaatca ggattttaaa catgtaaata caaattttgt
240ataacttttg atgacttcag tgaaattttc aggtagtctg agtaatagat tgttttgcca
300cttagaatag catttgccac ttagtatttt aaaaaataat tgttggagta tttattgtca
360gttttgttca cttgttatct aatacaaaat tataaagcct tcagagggtt tggaccacat
420ctctttggaa a
43158251DNAHomo sapiensmisc_feature(1)..(251)AffymetrixID 213883_s_at
58agagaacttc tagtgtatgg atttaaagat ttctcttttt cattcatata ccattttatg
60agttctgtat aattttttgt ggtttttgtt ttgttgagtt aaagtatatt attgtgagat
120ttatttaata ggacttcctt tgaaagctgt ataatagtgt ttctcgggct tctgtctcta
180tgagagatag cttattactc tgatactctt taatctttta caaaggcaag ttgccacttg
240tcatttttgt t
25159332DNAHomo sapiensmisc_feature(1)..(332)AffymetrixID 214305_s_at
59gttctgaccc ctggaaagac accaattggc acaccagcca tgaacatggc tacccctact
60ccaggtcaca taatgagtat gactcctgaa cagcttcagg cttggcggtg ggaaagagaa
120attgatgaga gaaatcgccc actttctgat gaggaattag atgctatgtt cccagaagga
180tataaggtac ttcctcctcc agctggttat gttcctattc gaactccagc tcgaaagctg
240acagctactc caacaccttt gggtggtatg actggtttcc acatgcaaac tgaagatcga
300actatgaaaa gtgttaatga ccagccatct gg
33260241DNAHomo sapiensmisc_feature(32)..(32)n is a, c, g, or t
60gaccaagagg gtgttcgact gctagagccg ancgaagcga tgcctaaatc aaaggaactt
60gtttcttcaa gctcttctgg cagtgattct gacagtgagg ttgacaaaaa gttaaagagg
120aaaaagcaag ttgctccaga aaaacctgta aagaaacaaa agacaggtga gacttcgaga
180gccctgtcat cttctaaaca gagcagcagc agcagagatg ataacatgtt tcagattggg
240a
24161436DNAHomo sapiensmisc_feature(156)..(156)n is a, c, g, or t
61tcttcattcc acgagaattt tgatttttaa cagcagtctc tctttttctc agcattgcaa
60atatatatgt atatatacat tcatgaccaa agtatcgctt actgaccatg cagctgtaaa
120ccttctgtgc ctatcaaaca aatacatagc atgaanctaa ttttagaagt ttcatggggg
180aattttaggg gaaagtataa acctaagagt gagtgaatgg agatgattca tggaaaaaaa
240aaanaaaaan nnanatgtgc tatnaggcag agttattaac ttcttttagt tgttgtttga
300gatngngttc tgctcttgtt ncccaggctg gagtgcantg gcgtgatctc gtctcnctgc
360aacctccgcc tcccaggttc aagcgattct cctgccccag ctactttgga ggctgaagtg
420taagagttgc ttgagc
43662448DNAHomo sapiensmisc_feature(1)..(448)AffymetrixID 214953_s_at
62atagattctc tcctgattat ttatcacata gccccttagc cagttgtata ttattcttgt
60ggtttgtgac ccaattaagt cctactttac atatgcttta agaatcgatg ggggatgctt
120catgtgaacg tgggagttca gctgcttctc ttgcctaagt attcctttcc tgatcactat
180gcattttaaa gttaaacatt tttaagtatt tcagatgctt tagagagatt ttttttccat
240gactgcattt tactgtacag attgctgctt ctgctatatt tgtgatatag gaattaagag
300gatacacacg tttgtttctt cgtgcctgtt ttatgtgcac acattaggca ttgagacttc
360aagcttttct ttttttgtcc acgtatcttt gggtctttga taaagaaaag aatccctgtt
420cattgtaagc acttttacgg ggcgggtg
44863383DNAHomo sapiensmisc_feature(319)..(319)n is a, c, g, or t
63gacagaccaa agttaaacaa gcctccggaa actcttatca ctactattga ttctagttcc
60agttggtgga ccaactgggt gatccctgcc atctctgcag tggccgtcgc cttgatgtat
120cgcctataca tggcagagga ctgaacacct cctcagaagt cagcgcagga agagcctgct
180ttggacacgg gagaaaagaa gccattgcta actacttcaa ctgacagaaa ccttcacttg
240aaaacaatga ttttaatata tctctttctt tttcttccga cattagaaac aaaacaaaaa
300gaactgtcct ttctgcgcnc aaatttttcg agtgtgcctt tttattcatc tactttattt
360tgatgtttcc ttaatgtgta att
38364492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 216016_at
64gccaatgcta aaaagctgca gatccagccc agccagctgg aattgttcta ctgtttgtac
60gagatgcagg aggaggactt cgtgcaaagg gccatggact atttccccaa gattgagatc
120aatctctcca ccagaatgga ccacatggtt tcttcctttt gcattgagaa ctgtcatcgg
180gtggagtcac tgtccctggg gtttctccat aacatgccca aggaggaaga ggaggaggaa
240aaggaaggcc gacaccttga tatggtgcag tgtgtcctcc caagctcctc tcatgctgcc
300tgttctcatg ggtaaggaaa ctcggcttcc aggtgcttcc tcctgcttcc tcgccagctt
360cttcttggca cctgcctcct ctcatctctt ttcaactatc ttccaaatac tgttgccaca
420gctacatcat aatgccacca ctgtctgttt gagactcctt catgagcaaa gattgatgta
480tggtaggtgg at
49265275DNAHomo sapiensmisc_feature(1)..(275)AffymetrixID 217722_s_at
65ggagatgcct cgtgaaacac agctgggcaa gtattaatgt atatggaaca gcctggattt
60ctgcatatgg ataagccacc ttggaatagg aagaggtgtt gagcctggac tgtgggagga
120aagagctgcg tggatagatt caaacttcct gtggtagtgc tcccagtctg acctctgtag
180accttcagta ctcactcttc ttgcttaggc tctctgtgtg ttgaaagcca tcccgtgttg
240catgtgttgt tacaattttc tgtgatactt gcaat
27566339DNAHomo sapiensmisc_feature(1)..(339)AffymetrixID 217753_s_at
66tggtcgtgcc aaaaagggcc gcggccacgt gcagcctatt cgctgcacta actgtgcccg
60atgcgtgccc aaggacaagg ccattaagaa attcgtcatt cgaaacatag tggaggccgc
120agcagtcagg gacatttctg aagcgagcgt cttcgatgcc tatgtgcttc ccaagctgta
180tgtgaagcta cattactgtg tgagttgtgc aattcacagc aaagtagtca ggaatcgatc
240tcgtgaagcc cgcaaggacc gaacaccccc accccgattt agacctgcgg gtgctgcccc
300agctccccca ccaaagccca tgtaaggagc tgagttctt
33967532DNAHomo sapiensmisc_feature(1)..(532)AffymetrixID 217970_s_at
67tgagctggag ctggttggac taatgagact gaggaagcag cttttcctac gatctgcatt
60atgtaatcac aggtccagag agctttatgg aagcgggaga ggaggagcac ttactcatgt
120tgtatttgtt aatggaggat gtcatctttt catagatgct agaactagag tgcacttgtt
180agatgctaaa ggtttgagct ttacacaaaa tgtcttcatc tgtatttgtt attgtctaca
240atatatttga atttggggca gcatattaag atgtaatggc ctgttatgtc ttgaaaatac
300ttgttttgcc tcttccaggc atactgcatt ctgtggatca gtttgaacag cttctccacc
360ttatttggac agtgataaat tgaaccaaga gtgtagattt acaagtgtaa ccttcaaaag
420aggaagaact atttggggtc tgtaggtaat gaacagtcac accaaaatag actatgatgc
480ttttgttaag aaaggtttca tgttttagat attttccgtg tcctaaataa tt
53268379DNAHomo sapiensmisc_feature(1)..(379)AffymetrixID 218190_s_at
68tgaagaaaca tggcggccgc gacgttgact tcgaaattgt actccctgct gttccgcagg
60acctccacct tcgccctcac catcatcgtg ggcgtcatgt tcttcgagcg cgccttcgat
120caaggcgcgg acgctatcta cgaccacatc aacgagggga agctgtggaa acacatcaag
180cacaagtatg agaacaagta gttccttgga ggcccccatc caggccagaa ggaccaggtc
240cacccagcag ctgtttgccc agagctggag cctcagcttg aagatgatgc tcaaggtact
300cttcatggac caccattcgc tgttggcaag aaacggcttt acttacaaaa cagactcttt
360accttctgct gtgtttgaa
37969545DNAHomo sapiensmisc_feature(1)..(545)AffymetrixID 218345_at
69gatttccgat atggctactc ttattacaac agtgcctgcc gcatctccag ctcgagtgac
60tggaacactc cagcccccac tcagagtcca gaagaagtca gaaggctaca cctatgtacc
120tccttcatgg acatgctgaa ggccttgttc agaacccttc aggccatgct cttgggtgtt
180tggattctgc tgcttctggc atctctggcc cctctgtggc tgtactgctg gagaatgttc
240ccaaccaaag ggaaaagaga ccagaaggaa atgttggaag tgagtggaat ctagccatgc
300ctctcctgat tattagtgcc tggtgcttct gcaccgggcg tccctgcatc tgactgctgg
360aagaagaacc agactgagga aaagaggctt ttcaacagcc ccagttatcc tggccccatg
420accgtggcca cagccctgct ccagcagcac ttgcccattc cttacacccc ttccccatcc
480tgctccgctt catgtcccct cctgagtagt catgtgataa taaactctca tgttattgtt
540cccag
54570557DNAHomo sapiensmisc_feature(101)..(101)n is a, c, g, or t
70gactgtacac actataaatg gcatcaaatt tggatatttt tcttaattat gacatgcaaa
60gtaatgtgag tcctgccagt attctggtgg ataaggtctt ntgagtattt ggttgcttgt
120cacaacattc tccaagcagt gatatttcta aagaggagat acatgttgaa aacggtttta
180atttacactt ccatttcctg attacatttg gaaatacttt gtgtaaacca tcccccttcc
240acctccattt gtctgttgaa agattttaag ttggaaacag ttcctgtctg aaaactcttc
300tgagaaccac aaaccttgtg tatggattcg gcatggagcc ctcagctggc ggctctgggt
360gctgacggcc gctggagagg tgggctcccc tcgtgcactt tattgcctgg gcagttttgc
420ttgatctttt gtgactttga gccttttaag tagtttgaat gataagactt aaaatgtttc
480ataattatgt tttatgtaac agactttgac attatttaaa cgagcatgtg taatgtaact
540tttctctttg aatcata
55771541DNAHomo sapiensmisc_feature(1)..(541)AffymetrixID 218545_at
71agcatggatt tcaacatcac ttatttatct gtataattgg aaataaaaca ccgatatgat
60agagaatcat tccggcatta cctaacctct tctgcagttg gatctatgta ttttcattgg
120tctactgaaa acgaacaata caattaaaag cactaaagat tattatatta attcaacttt
180gatctgatat atcacttaaa ctaaaggggt gtgtgtggtg tatgcttgtt tcctatttct
240gctctttaaa gatactttga atcaataaaa ccattagtct acaaatcaaa ttgtgaactt
300aatctctaga aagagaatat aactcagcca tttataggaa tttaggttca agtacaggat
360atatgaaatc ttttcccagt atttcagaat gtacttaatt cacaggcagg atgcttcaat
420gcaaaatcat gaatattttt aattcaaaac taaaatgtca ttaatatgta tgtatgcaaa
480tgttttatct tattttctga aatgcatcta ctttcatggg ctttgtacgt ttctgagatt
540t
54172160DNAHomo sapiensmisc_feature(1)..(160)AffymetrixID 218728_s_at
72atatcgatac attatggtgc cgagtggtaa catgggagtg tttgatccaa cagaaataca
60caatcgaggg cagctgaagt cacacatgaa agaagccatg atcaagcttg gtttccactt
120gctctgcttc ttcatgtatc tttatagtat gatcttagct
16073461DNAHomo sapiensmisc_feature(1)..(461)AffymetrixID 219269_at
73aggctagaaa atcttgctgc tccgtcttag cattccaaga gagtgcttcc aggtatttag
60atagccctca gttctcaaat attagactac gtgtaaaatc ttgggtacct ttagattctt
120gtaacactag tctgtactcc cttttccttc cccaagactg ataggatgca agctgaggtc
180gtggcacagg aatgacagac accatttggg gagtatccac agagtcaaag gaacactaga
240atccccacct cagcgtgagg ataattgatt tccagctgca ataagccgtg cctcattata
300gccacactgt ggctagatta tacttctttg ggtgctgtgc taagaatgtc aatggaaaaa
360gccgatctca gattttgttt gaagttaaca tgcctgacac agacatcctt tcctctcaca
420agctgtgtga cttagtagat aaaatactgc cttctgcctt t
46174563DNAHomo sapiensmisc_feature(1)..(563)AffymetrixID 219410_at
74tgtttctcac catatgcttt tgttggcatt atgcagtaac cattgtcatc gttggaatga
60attatgcttt cattacctgg ttggttaaat ctagacttaa gaggctctgc tcctcagaag
120ttggacttct gaaaaatgct gaacgagaac aagaatcaga agaagaaatg tgactttgat
180gagcttccag tttttctaga taaacctttt cttttttaca ttgttcttgg ttttgtttct
240cgatcttttg tttggagaac agctggctaa ggatgactct aagtgtactg tttgcatttc
300caatttggtt aaagtatttg aatttaaata ttttcttttt agctttgaaa atattttggg
360tgatactttc attttgcaca tcatgcacat catggtattc aggggctaga gtgatttttt
420tccagattat ctaaagttgg atgcccacac tatgaaagaa atatttgttt tatttgcctt
480atagatatgc tcaaggttac tgggcttgct actatttgta actccttgac catggaatta
540tacttgttta tcttgttgct gca
56375472DNAHomo sapiensmisc_feature(1)..(472)AffymetrixID 219862_s_at
75cggccaagga gctgttcaac gaggatgtgg aggaggtcac ttaccgagcc ctgagaaaca
60aagacttcca agaggtcacc cttgagaaga acggagaggt ggtgttacgc tttgctgcag
120cctatggctt tcgaaacatc cagaacatga tcctgaagct taagaagggc aagttcccat
180tccactttgt ggaggtcctc gcctgtgctg gaggatgctt aaatggcaga ggccaagccc
240agactccaga cggacatgcg gataaggccc tgctgcggca gatggaaggc atttacgctg
300acatccctgt gcggcgtccg gagtccagtg cacacgtgca ggagctgtac caggagtggc
360tggaggggat caactccccc aaggcccgag aggtgctgca taccacgtac cagagccagg
420agcgtggcac acacagcctg gacatcaagt ggtgaagtca ggccagggcc tt
47276396DNAHomo sapiensmisc_feature(1)..(396)AffymetrixID 219905_at
76ggctcacgtg attatggagg cggttaaatc ccaagatctg caggataagt cagcaagatg
60gagtcccatg agagctgatg gtttagttcc agtctgatgg cagcaggctt gacgccaagg
120aagagatgat gtttaattca agtccgaagg caaggaaaaa gctgatggtc ctgtccaaag
180gctattaggc aggaagaatt ctcttagggc agagttagct cttttgttct attcaggcct
240tcaactgatt cagcaaggcc cgcccacatt tgggaggaca gtctgcatta ctcagtctac
300tgatttgaat gttaatgtca ttgcgaaaca ccctcacagg aacactcaga ataatgtttg
360accaaatagc tgggcatctt gtgacccagt taagtg
39677533DNAHomo sapiensmisc_feature(1)..(533)AffymetrixID 220532_s_at
77atctggcaaa ctgaaccctt tttatacatc gacactgtgt gtgatcgctc agaccctgtc
60ttccctacca ctgggtacag atggatgcgg cgaagtcaag agaaccaatg gcagaaggag
120gagtgtagag cttacatgca gatgctgagg aagttgttca cagcaatccg tgccctgttc
180ctggctgtct gtgtcttgaa ggtcattgtg tccttggttt ccttgggagt aggtcttcga
240aacttgtgtg gccagagctc ccagcccctg aatgaggaag gatcagagaa gaggctactg
300ggggagaatt cagtgccccc ttcgccctct agggagcaga cctccactgc cattgtcctg
360tgagccgcca aagaccccac ggggtgcccg catgtccctg tctagggcag cccagggccc
420ccactcctgg ctcctcacac ttgcctcccc tatggccgct ctccagaccc tcctcctttc
480ttctccccac atccgcacct gctgttccca ctctggggtt ctcaagtcca tga
53378488DNAHomo sapiensmisc_feature(1)..(488)AffymetrixID 221011_s_at
78gagtggttca tccatactct cattccctcg cctccccttg tggacggggg tcttgccttt
60tcaattcctg tgttttggtg tcttccctta tctgctaccc tgaatcacct gtcctggtct
120tgctgtgtga tgggaacatg cttgtaaact gcgtaacaaa tctactttgt gtatgtgtct
180gtttatgggg gtggtttatt atttttgctg gtccctagac cactttgtat gaccgtttgc
240agtctgagca ggccaggggc tgacagctaa tgtcaggacc ctcagcggtg gagcctgctg
300gggggaccca gctgctcttg gacaagtggc tgagctccta tctggcctcc tctttttttt
360ttttttcaag taatttgtgt gtatttctaa ctgattgtat tgaaaaaatt cctagtattt
420cagtaaaaat gcctgttgtg agatgaacct cctgtaactt ctatctgttc ttttttgagg
480ctcaggga
48879526DNAHomo sapiensmisc_feature(1)..(526)AffymetrixID 221042_s_at
79tgaccccatg gacagccatc agtcccagga atccccaaac ctggaaaaca tagcaaaccc
60cctagaagaa aatgtaacga aagaatcaat cagtagtaaa aaaaaggaaa aaaggaaaca
120tgtggaccac gtagaaagtt cactatttgt agcaccagga agtgttcaat cctcagatga
180cctagaagaa gacagtagcg actacagcat tccttccagg actagtcaca gtgactccag
240catttacctt cgacgacata ctcataggtc ttcggaatcg gatcatttta gctatgttca
300gttgaggaac gcagcagatc tggatgacag aagaaaccga atattaacca ggaaggccaa
360cagctcagga gaagccatgt cactggggag ccacagcccg cagagtgact ccctgacaca
420gcttgtccag cagccggata tgatgtattt tattctcttc ctgtggctcc tggtgtactg
480cttgctgctc ttcccacaac tggatgttag caggctctga tacgtg
52680230DNAHomo sapiensmisc_feature(1)..(230)AffymetrixID 221434_s_at
80cctcagcagc gcgaggtgct gcggcgctgc gtagaagtat caatcagccg gttgcttttg
60tgagaagaat tccttggact gcggcgtcga gtcagctgaa agaacacttt gcacagttcg
120gccatgtcag aaggtgcatt ttaccttttg acaaggagac tggctttcac agaggtttgg
180gttgggttca gttttcttca gaagaaggac ttcggaatgc actacaacag
23081350DNAHomo sapiensmisc_feature(1)..(350)AffymetrixID 221737_at
81gaaatctatt tttaactctt atgttcgtag agaaattgtt tcaaggattt tgagtcatag
60gtctgtaatt tatagagatc tctagaattc ttattgtaat tttcctactt ctttgataaa
120agaaaaataa gtcagattgt taactccaag attgaaaaaa aaaactcttg aaagaagatt
180attagttgta actaatttgg gggttctggg cacagacatc taacctggta ttgtaaggca
240gaggctccca ttggaatggt agtggtccgg gtcagttgtt catggtgtaa gctttgcaca
300gtgtattaac attgggaggg tctggcttga aaatttggcc accctcagcc
3508297DNAHomo sapiensmisc_feature(1)..(97)AffymetrixID AFFX-M27830_5_at
82tagttttacc ctactgatga tgtgttgttg ccatggtaat cctgctcagt acgagaggaa
60ccgcaggttc agacatttgg tgtatgtgct tggctga
9783535DNAHomo sapiensmisc_feature(39)..(39)n is a, c, g, or t
83ttgcacggat ctaagttatt ctccccagcc agagcccgng ctnnctgctc ccngggaaaa
60gntggcgtan tggncctgag ctgggnttta tattttatat ctgcaaataa atnacatttt
120atcntanatt tagggaaagc cngagagnaa caacaaaaaa tgtttaagcc nnnnnnnnnn
180nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
240nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
300nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
360nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
420nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnntattg cccggctcct
480agaatttatt tatttcctga cttacagcaa gcgagttatc gtcttctgta ttttg
53584494DNAHomo sapiensmisc_feature(124)..(124)n is a, c, g, or t
84ccactctatg agttggactt cagtcttgcc taggcgattt tgtctaccat ttgtgttttg
60aaagcccaag gtgctgatgt caaagtgtaa cagatatcag tgtctccccg tgtcctctcc
120ctgncaagtc tcagaagagg ttgggcttcc atgcctgtag ctttcctggt ccctcacccc
180catngcccca ggcccacagc gtgggaactc actttccctt gtgtcaagac atttctnnnn
240nnnnnnnnnn nnnnnnnnnn nnactccatg caggggtcag tgcagcagag gacagtctgg
300agaaggtatt agcaaagcaa aaggctgaga aggaacaggg aacattggag ctgactgttc
360ttggtaactg attacctgcc aattgctacc gagaaggttg gaggtgggga aggctttgta
420taatcccacc cacctcacca aaacgannnn nnnnnnnnnn nnnngtcctt tctggaagtt
480tctggtgcca tttc
49485492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 201386_s_at
85ggagatcatc tgacactgct gaacgtctac catgctttta aacaaaatca tgaatcggtt
60cagtggtgtt atgacaactt cattaactac aggtccctga tgtccgcaga caatgtacgc
120cagcagctat ctcgaattat ggacagattt aatttgcctc gtcgaagtac tgactttaca
180agcagggact attatattaa tataagaaaa gctttggtta ctgggtattt tatgcaggtg
240gcacatttag aacgaacagg gcattactta actgtgaaag ataaccaggt ggttcagttg
300catccctcta ctgttcttga ccacaaacct gaatgggtgc tttataatga gtttgttcta
360acaacaaaga attacatccg gacatgtaca gatatcaagc cagaatggtt ggtgaaaatt
420gcccctcaat attatgacat gagcaatttc ccacagtgtg aagcaaagag acagttggac
480cgcatcattg cc
49286378DNAHomo sapiensmisc_feature(1)..(378)AffymetrixID 201890_at
86gctactttga attaatctgc ctttatgttt gggagaagaa agctgagaca ttgcatgaaa
60gatgatgaga gataaatgtt gatcttttgg ccccatttgt taattgtatt cagtatttga
120acgtcgtcct gtttattgtt agttttcttc atcatttatt gtatagacaa tttttaaatc
180tctgtaatat gatacatttt cctatctttt aagttattgt tacctaaagt taatccagat
240tatatggtcc ttatatgtgt acaacattaa aatgaaaggc tttgtcttgc attgtgaggt
300acaggcggaa gttggaatca ggttttagga ttctgtctct cattagctga ataatgtgag
360gattaacttc tgccagct
37887448DNAHomo sapiensmisc_feature(1)..(448)AffymetrixID 202219_at
87aagcttcgag ctgttgcgtg tgtgagtctg ttgtgtggat gtgcgtgtgt ggtccccagc
60cccagactgg attggaaaag tgcatggtgg gggcctcggg gctgtcccca cgctgtccct
120ttgccacaag tctgtggggc aagaggctgc aatattccgt cctgggtgtc tgggctgcta
180acctggcctg ctcaggcttc ccaccctgtg cggggcacac ccccaggaag ggaccctgga
240cacggctccc acgtccaggc ttaaggtgga tgcacttccc gcacctccag tcttctgtgt
300agcagcttta acccacgttt gtctgtcacg tccagtcccg agacggctga gtgaccccaa
360gaaaggcttc cccgacaccc agacagaggc tgcagggctg gggctgggtg agggtggcgg
420gcctgcgggg acattctact gtgctaaa
44888371DNAHomo sapiensmisc_feature(1)..(371)AffymetrixID 202464_s_at
88tattctgtcc tgagaccacg ggcaaagctc ttccattttg agagagaaga aaaactgttt
60ggaaccacac caatgatatt tttctttgta atacttgaaa tttatttttt tattattttg
120atagcagatg tgctatttat ttatttaata tatgtataag gagtcctaaa caatagaaag
180ctgtagaagc tgtagagata ggcttcagtt gttaattggt ttggagcctc ctatgtgtga
240cttatgactc tctgtgttct gtgtatttgt ctgaattaat gacctgggat ataaagctat
300gctagctttc aaacaggaga tgccttcaga aagctttgta tattttgcag ttgccagacc
360aataaaatac c
37189530DNAHomo sapiensmisc_feature(69)..(69)n is a, c, g, or t
89aactccaatt caggagccct tgcgagtata tctgaagcac ttatttgcta aggaaacctg
60aattgatanc agtactgtgc tgtctggaat aatgtccttg atactgagtt gggaccagac
120tggcttttat agtgacaggc aaagaggaat ttattgagat cactgctcat ggcatttgtt
180gctgtaagaa gtgttgcctt tgattgttac taaccacgga tgggtaacgg tcatacatta
240ggctagtgtt tggtaggaca aaatcttttt agagctttga gaattgtcat cctgttggtc
300aactttgaaa tacaaatgtt tgccctggta attagcaatg aactgctggc agtttcttca
360gctgtgtata tacggatctg gcttttaatt gatgaatcaa cttctacaga aacttttgca
420gggacagtgt tgatgaggca gtttagcttg ccagggtgat gataaagccc aggtccctgc
480atgtatagtg ctcttctaaa gaatatgcat tcttgaacta cttaactttt
53090497DNAHomo sapiensmisc_feature(1)..(497)AffymetrixID 203574_at
90gtatggtaca ttcttctctt actcctttct cagtgcaagt gactaacatt caagattggt
60ctctcaaatc ggagcactgg catcaaaaag aactgagtgg caaaactcag aatagtttca
120aaactggagt tgttgaaatg aaagacagtg gctacaaagt ttctgaccca gagaacttgt
180atttgaagca ggggatagca aacttatctg cagaggttgt ctcactcaag agacttatag
240ccacacaacc aatctctgct tcagactctg ggtaaattac tactgagtaa gagctgggca
300tttagaaaga tgtcatttgc aatagagcag tccattttgt attatgctga attttcactg
360gacctgtgat gtcatttcac tgtgatgtgc acatgttgtc tgtttggtgt ctttttgtgc
420acagattatg atgaagatta gattgtgtta tcactctgcc tgtgtatagt cagatagtcc
480atgcgaaggc tgtatat
49791326DNAHomo sapiensmisc_feature(1)..(326)AffymetrixID 203887_s_at
91cagggggtgt gtctgctcag taatttgagg acaaccattc cagactgctt ccaattttct
60ggaatacatg aaatatagat cagttataag tagcaggcca agtcaggccc ttattttcaa
120gaaactgagg aattttcttt gtgtagcttt gctctttggt agaaaaggct aggtacacag
180ctctagacac tgccacacag ggtctgcaag gtctttggtt cagctaagct aggaatgaaa
240tcctgcttca gtgtatggaa ataaatgtat catagaaatg taacttttgt aagacaaagg
300ttttcctctt ctattttgta aactca
32692533DNAHomo sapiensmisc_feature(1)..(533)AffymetrixID 203932_at
92tcttacgggg acacttacac ctgtgtggta gagcacattg gggctcctga gcccatcctt
60cgggactgga cacctgggct gtcccccatg cagaccctga aggtttctgt gtctgcagtg
120actctgggcc tgggcctcat catcttctct cttggtgtga tcagctggcg gagagctggc
180cactctagtt acactcctct tcctgggtcc aattattcag aaggatggca catttcctag
240aggcagaatc ctacaacttc cactccaagt gagaaggaga ttcaaactca atgatgctac
300catgcctctc caacatcttc aaccccctga cattatcttg gatcctatgg tttctccatc
360caattctttg aatttcccag tctcccctat gtaaaactta gcaacttggg ggacctcatt
420cctgggacta tgctgtaacc aaattattgt ccaaggctat atttctggga tgaatataat
480ctgaggaagg gagttaaaga ccctcctggg gctctcagtg tgccatagag gac
53393419DNAHomo sapiensmisc_feature(1)..(419)AffymetrixID 204131_s_at
93ttaccattcc gggttcgagc atcacaagct tttgagcgca tggaactcca taaactaaca
60aattacataa actaaagggg gattttcttt cttcttttgt ttggtagaaa attatccttt
120tctaaaaact gaacaatggc acaattgttt gctatgtgca cccgtccagg acagaaccgt
180gcataggcaa aaggagtgga gcacagcgtc cggcccagtg tgtttccggt tctgagtcag
240ggtgatctgt ggacgggacc ccagcaccaa gtctacgggt gccagatcag tagggcctgt
300gatttcctgt cagtgtcctc agctaatgtg aacagtgttg gtctgctggt tagaaactag
360aatattgata ttttcaggaa agaaatcagc tcagctctcc actcattgcc aaatgtcac
41994507DNAHomo sapiensmisc_feature(1)..(507)AffymetrixID 204419_x_at
94acactcgctt ctggaacgtc tgaggttatc aataagctcc tagtccagac gccatgggtc
60atttcacaga ggaggacaag gctactatca caagcctgtg gggcaaggtg aatgtggaag
120atgctggagg agaaaccctg ggaaggctcc tggttgtcta cccatggacc cagaggttct
180ttgacagctt tggcaacctg tcctctgcct ctgccatcat gggcaacccc aaagtcaagg
240cacatggcaa gaaggtgctg acttccttgg gagatgccat aaagcacctg gatgatctca
300agggcacctt tgcccagctg agtgaactgc actgtgacaa gctgcatgtg gatcctgaga
360acttcaagct cctgggaaat gtgctggtga ccgttttggc aatccatttc ggcaaagaat
420tcacccctga ggtgcaggct tcctggcaga agatggtgac tggagtggcc agtgccctgt
480cctccagata ccactgagct cactgcc
50795309DNAHomo sapiensmisc_feature(1)..(309)AffymetrixID 204467_s_at
95ctcggaattc cctgaagcaa cactgccaga agtgtgtttt ggtatgcact ggttccttaa
60gtggctgtga ttaattattg aaagtggggt gttgaagacc ccaactacta ttgtagagtg
120gtctatttct cccttcaatc ctgtcaatgt ttgctttatg tattttgggg aactgttgtt
180tgatgtgtat gtgtttataa ttgttataca tttttaattg agccttttat taacatatat
240tgttattttt gtctcgaaat aattttttag ttaaaatcta ttttgtctga tattggtgtg
300aatgctgta
30996521DNAHomo sapiensmisc_feature(1)..(521)AffymetrixID 204848_x_at
96acactcgctt ctggaacgtc tgagattatc aataagctcc tagtccagac gccatgggtc
60atttcacaga ggaggacaag gctactatca caagcctgtg gggcaaggtg aatgtggaag
120atgctggagg agaaaccctg ggaaggctcc tggttgtcta cccatggacc cagaggttct
180ttgacagctt tggcaacctg tcctctgcct ctgccatcat gggcaacccc aaagtcaagg
240cacatggcaa gaaggtgctg acttccttgg gagatgccat aaagcacctg gatgatctca
300agggcacctt tgcccagctg agtgaactgc actgtgacaa gctgcatgtg gatcctgaga
360acttcaagct cctgggaaat gtgctggtga ccgttttggc aatccatttc ggcaaagaat
420tcacccctga ggtgcaggct tcctggcaga agatggtgac tgcagtggcc agtgccctgt
480cctccagata ccactgagcc tcttgcccat gattcagagc t
52197472DNAHomo sapiensmisc_feature(1)..(472)AffymetrixID 205239_at
97atttcaaaat ttctgcattc acggagaatg caaatatata gagcacctgg aagcagtaac
60atgcaaatgt cagcaagaat atttcggtga acggtgtggg gaaaagtcca tgaaaactca
120cagcatgatt gacagtagtt tatcaaaaat tgcattagca gccatagctg cctttatgtc
180tgctgtgatc ctcacagctg ttgctgttat tacagtccag cttagaagac aatacgtcag
240gaaatatgaa ggagaagctg aggaacgaaa gaaacttcga caagagaatg gaaatgtaca
300tgctatagca taactgaaga taaaattaca ggatatcaca ttggagtcac tgccaagtca
360tagccataaa tgatgagtcg gtcctctttc cagtggatca taagacaatg gacccttttt
420gttatgatgg ttttaaactt tcaattgtca ctttttatgc tatttctgta ta
47298477DNAHomo sapiensmisc_feature(1)..(477)AffymetrixID 205571_at
98gatcaggagc aatgccactg ctagcatacc ttccttagtg aaaaatcttt tggaaaagga
60tcccactctg acctgtgaag tactaatgaa tgctgttgct acagagtatg ctgcctatca
120tcaaattgat aatcacattc acctaataaa cccaacggat gagacactgt ttcctggaat
180aaatagcaaa gccaaagaac tgcaaacttg ggagtggata tatggcaaaa ctccaaagtt
240tagtataaat acttcctttc atgtgttata tgaacagtca cacttggaaa ttaaagtatt
300catagacata aagaatggaa gaattgaaat ttgtaatatt gaagcacctg atcattggtt
360gccattggaa atacgtgaca aattaaattc aagtcttatt ggcagtaagt tttgcccaac
420tgaaactacc atgctaacaa atatattact tagaacatgt ccacaagacc acaaact
47799422DNAHomo sapiensmisc_feature(1)..(422)AffymetrixID 205592_at
99tgggggccac agactcaaca tgtgtgtgtg gtggggttcc agcccaacat agagtaacat
60tatttgtacc tcccaggcta gctcagtcca tgggaggctc tcctgtccct gaaagctgac
120acccaccttt caccacttcg cccatgctac agttcagttt cctcgtctgt aaaatgggga
180tgataatggt acctaccttg cagtgttgtt ataaggatta aaggagacag tgcaagaaaa
240ggccttggtt ggtgaagagc ccaacctcgg aggggagctg ctgggatcct ccttatcttg
300actgggatgt ccctgtctcc ccctcccctt gctccttgaa catggccaag gaaagtgaaa
360aacaaaaatt attcactctg ctagcaccct tccccttgat gcctgggaat aggttttgcc
420aa
422100362DNAHomo sapiensmisc_feature(1)..(362)AffymetrixID 205863_at
100tagctccaca ttcctgtgca ttgaggggtt aacattaggc tgggaagatg acaaaacttg
60aagagcatct ggagggaatt gtcaatatct tccaccaata ctcagttcgg aaggggcatt
120ttgacaccct ctctaagggt gagctgaagc agctgcttac aaaggagctt gcaaacacca
180tcaagaatat caaagataaa gctgtcattg atgaaatatt ccaaggcctg gatgctaatc
240aagatgaaca ggtcgacttt caagaattca tatccctggt agccattgcg ctgaaggctg
300cccattacca cacccacaaa gagtaggtag ctctctgaag gctttttacc cagcaatgtc
360ct
362101416DNAHomo sapiensmisc_feature(1)..(416)AffymetrixID 205900_at
101tcaagtcctc tggtggcagt tccagcgtga ggtttgtttc taccacttat tccggagtaa
60ccagataaag agatgccctc tgtttcatta gctctagttc tcccccagca tcactaacaa
120atatgcttgg caagaccgag gtcgatttgt cccagcctta ccggagaaaa gagctatggt
180tagttacact agctcatcct attcccccag ctctttcttt tctgctgttt cccaatgaag
240ttttcagatc agtggcaatc tcagttccct tgctatgacc ctgctttgtt ctttcccgag
300aaacagttca gcagtgacca ccacccacat gacatttcaa gcaccacctt aagccagcca
360gagtaggacc agttagacct agggtgtgga cagctccttg catcttaaca ctgtgc
416102560DNAHomo sapiensmisc_feature(1)..(560)AffymetrixID 205950_s_at
102gagccccatt cacaaatttt gacccctcta ctctccttcc ttcatccctg gatttctgga
60cctaccctgg ctctctgact catcctcctc tttatgagag tgtaacttgg atcatctgta
120aggagagcat cagtgtcagc tcagagcagc tggcacaatt ccgcagcctt ctatcaaatg
180ttgaaggtga taacgctgtc cccatgcagc acaacaaccg cccaacccaa cctctgaagg
240gcagaacagt gagagcttca ttttgatgat tctgagaaga aacttgtcct tcctcaagaa
300cacagccctg cttctgacat aatccagtta aaataataat ttttaagaaa taaatttatt
360tcaatattag caagacagca tgccttcaaa tcaatctgta aaactaagaa acttaaattt
420tagttcttac tgcttaattc aaataataat tagtaagcta gcaaatagta atctgtaagc
480ataagcttat cttaaattca agtttagttt gaggaattct ttaaaattac aactaagtga
540tttgtatgtc tatttttttc
560103447DNAHomo sapiensmisc_feature(1)..(447)AffymetrixID 205987_at
103ccagctgttg ctggtttgtc atgcctccgg cttctaccca aagcctgttt gggtgacatg
60gatgcggaat gaacaggagc aactgggcac taaacatggt gatattcttc ctaatgctga
120tgggacatgg tatcttcagg tgatcctgga ggtggcatct gaggagcctg ctggcctgtc
180ttgtcgagtg agacacagca gtctaggagg ccaggacatc atcctctact ggggacacca
240ctcttccatg aattggattg ccttggtagt gatagtgccc ttggtgattc taatagtcct
300tgtgttatgg tttaagaagc actgctcata tcaggacatc ctgtgagact cttccccctg
360actcccccat tgtgttaaga acccagcaac ccaggagcct agtacaatat agtgatgcca
420tcccgtcgac tctccattta aattgtt
447104490DNAHomo sapiensmisc_feature(1)..(490)AffymetrixID 206025_s_at
104ggatacccca ttgtgaagcc agggcccaac tgtggatttg gaaaaactgg cattattgat
60tatggaatcc gtctcaatag gagtgaaaga tgggatgcct attgctacaa cccacacgca
120aaggagtgtg gtggcgtctt tacagatcca aagcaaattt ttaaatctcc aggcttccca
180aatgagtacg aagataacca aatctgctac tggcacatta gactcaagta tggtcagcgt
240attcacctga gttttttaga ttttgacctt gaagatgacc caggttgctt ggctgattat
300gttgaaatat atgacagtta cgatgatgtc catggctttg tgggaagata ctgtggagat
360gagcttccag atgacatcat cagtacagga aatgtcatga ccttgaagtt tctaagtgat
420gcttcagtga cagctggagg tttccaaatc aaatatgttg caatggatcc tgtatccaaa
480tccagtcaag
490105479DNAHomo sapiensmisc_feature(1)..(479)AffymetrixID 206111_at
105gtttacctgg gctcaatggt ttgaaaccca gcacatcaat atgacctccc agcaatgcac
60caatgcaatg caggtcatta acaattatca acggcgatgc aaaaaccaaa atactttcct
120tcttacaact tttgctaacg tagttaatgt ttgtggtaac ccaaatatga cctgtcctag
180taacaaaact cgcaaaaatt gtcaccacag tggaagccag gtgcctttaa tccactgtaa
240cctcacaact ccaagtccac agaatatttc aaactgcagg tatgcgcaga caccagcaaa
300catgttctat atagttgcat gtgacaacag agatcaacga cgagaccctc cacagtatcc
360ggtggttcca gttcacctgg atagaatcat ctaagctcct gtatcagcac tcctcatcat
420cactcatctg ccaagctcct caatcatagc caagatccca tctctccata tactttggg
479106524DNAHomo sapiensmisc_feature(1)..(524)AffymetrixID 206834_at
106ggagaagact gctgtcaatg ccctgtgggg caaagtgaac gtggatgcag ttggtggtga
60ggccctgggc agattactgg tggtctaccc ttggacccag aggttctttg agtcctttgg
120ggatctgtcc tctcctgatg ctgttatggg caaccctaag gtgaaggctc atggcaagaa
180ggtgctaggt gcctttagtg atggcctggc tcacctggac aacctcaagg gcactttttc
240tcagctgagt gagctgcact gtgacaagct gcacgtggat cctgagaact tcaggctctt
300gggcaatgtg ctggtgtgtg tgctggcccg caactttggc aaggaattca ccccacaaat
360gcaggctgcc tatcagaagg tggtggctgg tgtggctaat gccctggctc acaagtacca
420ttgagatcct ggactgtttc ctgataacca taagaagacc ctatttccct agattctatt
480ttctgaactt gggaacacaa tgcctacttc aagggtatgg cttc
524107560DNAHomo sapiensmisc_feature(1)..(560)AffymetrixID 207332_s_at
107aaggagagtc ccctgaaggt ctgacacgtc tgcctaccca ttcgtggtga tcaattaaat
60gtaggtatga ataagttcga agctccgtga gtgaaccatc atataaacgt gtagtacagc
120tgtttgtcat agggcagttg gaaacggcct cctagggaaa agttcatagg gtctcttcag
180gttcttagtg tcacttacct agatttacag cctcacttga atgtgtcact actcacagtc
240tctttaatct tcagttttat ctttaatctc ctcttttatc ttggactgac atttagcgta
300gctaagtgaa aaggtcatag ctgagattcc tggttcgggt gttacgcaca cgtacttaaa
360tgaaagcatg tggcatgttc atcgtataac acaatatgaa tacagggcat gcattttgca
420gcagtgagtc tcttcagaaa acccttttct acagttaggg ttgagttact tcctatcaag
480ccagtacgtg ctaacaggct caatattcct gaatgaaata tcagactagt gacaagctcc
540tggtcttgag atgtcttctc
560108482DNAHomo sapiensmisc_feature(159)..(159)n is a, c, g, or t
108aacccagaat ggcacacact gctctgctgt agcatcatgt cagggcttcc tggactcagt
60acacctctca gtttgtcttt taaaaaacag ctgaatcttt actacctatt tagttctcct
120tgttaaagaa acaggggtgg gaataaaatg gatttaggna cacccagttt gaattgcagt
180tttttttttt ctgacacatg gccaggctgt ggtgccagct taatggagta ggctgtcctt
240ggcacttgca tgtgtgaaag gagggttttg cctcttcttg agcatggctt gagttggtaa
300ggaaagctgt aactcacgaa gccctgagac ctgctacccc taagatcgag cttgttttca
360gtgactggct tgagtcatag gaggaggagt ctggtacagc tgcaggagag cagggccatc
420tgaagcggta gcattgccac catctccctc tcatctagag cagttttctt atgccttggt
480tt
482109494DNAHomo sapiensmisc_feature(1)..(494)AffymetrixID 209007_s_at
109gaagatggaa ctcgaaatcc caatgaaaaa cctacccagc aaagaagcat agcttttagc
60tctaataatt ctgtagcaaa gccaatacaa aaatcagcta aagctgccac agaagaggca
120tcttcaagat caccaaaaat agatcagaaa aaaagtccat atggactgtg gatacctatc
180taaaagaaga aaactgatgg ctaagtttgc atgaaaactg cactttattg caagttagtg
240tttctagcat tatcccatcc ctttgagcca ttcaggggta cttgtgcatt taaaaaccaa
300cacaaaaaga tgtaaatact taacactcaa atattaacat tttaggtttc tcttgcagat
360atgagagata gcacagatgg accaaaggtt atgcacaggt gggagtcttt tgtatatagt
420tgtaaatatt gtcttggtta tgtaaaaatg aaatttttta gacacagtaa ttgaactgta
480ttcctgtttt gtat
494110445DNAHomo sapiensmisc_feature(1)..(445)AffymetrixID 209458_x_at
110agagaaccca ccatggtgct gtctcctgcc gacaagacca acgtcaaggc cgcctggggt
60aaggtcggcg cgcacgctgg cgagtatggt gcggaggccc tggagaggat gttcctgtcc
120ttccccacca ccaagaccta cttcccgcac ttcgacctga gccacggctc tgcccaggtt
180aagggccacg gcaagaaggt ggccgacgcg ctgaccaacg ccgtggcgca cgtggacgac
240atgcccaacg cgctgtccgc cctgagcgac ctgcacgcgc acaagcttcg ggtggacccg
300gtcaacttca agctcctaag ccactgcctg ctggtgaccc tggccgccca cctccccgcc
360gagttcaccc ctgcggtgca cgcctccctg gacaagttcc tggcttctgt gagcaccgtg
420ctgacctcca aataccgtta agctg
445111432DNAHomo sapiensmisc_feature(1)..(432)AffymetrixID 209795_at
111tagtctaatt gaatccctta aactcaggga gcatttataa atggcaaatg cttatgaaac
60taagatttgt aatatttctc tctttttaga gaaatttgcc aatttacttt gttatttttc
120cccaaaaaga atgggatgat cgtgtattta tttttttact tcctcagctg tagacaggtc
180cttttcgatg gtacatattt ctttgccttt ataatctttt atacagtgtc ttacagagaa
240aagacataag caaagactat gaggaatatt tgcaagacat agaatagtgt tggaaaatgt
300gcaatatgtg atgtggcaaa tctctattag gaaatattct gtaatcttca gacctagaat
360aatactagtc ttataatagg tttgtgactt tcctaaatca attctattac gtgcaatact
420tcaatacttc at
432112535DNAHomo sapiensmisc_feature(1)..(535)AffymetrixID 210027_s_at
112tgggatgaag cctttcgcaa gttcctgaag ggcctggctt cccgaaagcc ccttgtgctg
60tgtggagacc tcaatgtggc acatgaagaa attgaccttc gcaaccccaa ggggaacaaa
120aagaatgctg gcttcacgcc acaagagcgc caaggcttcg gggaattact gcaggctgtg
180ccactggctg acagctttag gcacctctac cccaacacac cctatgccta caccttttgg
240acttatatga tgaatgctcg atccaagaat gttggttggc gccttgatta ctttttgttg
300tcccactctc tgttacctgc attgtgtgac agcaagatcc gttccaaggc cctcgcgagt
360gatcactgtc ctatcaccct atacctagca ctgtgacacc acccctaaat cactttgagc
420ctgggaaata agccccctca actaccattc cttctttaaa cactcttcag agaaatctgc
480attctatttc tcatgtataa aacgaggaat cctccaacca ggctcctgtg ataga
535113368DNAHomo sapiensmisc_feature(220)..(220)n is a, c, g, or t
113atacaccagc agggcaatta gcagcttggg gaagttggaa gtctcgatgt tgtgatagta
60gaccacggag gtgacagcag ccatgaacgc catcccggct ggcatgtaca ggtgcagatg
120gtgggattcg gtcaccccat cagacaggat gccctctgca atctcacaca ccaggacgaa
180gagcagcatg aaggtcagga tccaccgcag gttgtgcccn gggaaatgaa gccatgtgct
240gtggtggatg tgcaccttgg agctctgact tccccatcca atgaagagga tggggaaggt
300gatgaagagt aggaagacgt gcggcaccac gttgagcgcg tccacaaagc agccgttgtt
360gaggaccc
368114414DNAHomo sapiensmisc_feature(1)..(414)AffymetrixID 210338_s_at
114gaactgaatg ctgacctgtt ccgtggcacc ctggacccag tagagaaagc ccttcgagat
60gccaaactag acaagtcaca gattcatgat attgtcctgg ttggtggttc tactcgtatc
120cccaagattc agaagcttct ccaagacttc ttcaatggaa aagaactgaa taagagcatc
180aaccctgatg aagctgttgc ttatggtgca gctgtccagg cagccatctt gtctggagac
240aagtctgaga atgttcaaga tttgctgctc ttggatgtca ctcctctttc ccttggtatt
300gaaactgctg gtggagtcat gactgtcctc atcaagcgta ataccaccat tcctaccaag
360cagacacaga ccttcactac ctattctgac aaccagcctg gtgtgcttat tcag
414115557DNAHomo sapiensmisc_feature(1)..(557)AffymetrixID 211038_s_at
115tggtgttcct tgaatgccta tcttcctttt gtgcctcgga acctctcacg cctgccacaa
60gttactcttt tccttggtag ttctgaactt taaataaggt aatgcctgta agaatgccat
120aaatgctcaa taattgtcat ctgttattat tttcatcagt aacatcatct gaatcatcag
180tattgtctgc ttttaacagc tgcatttttc attgtccaaa tatagtcaca tacatttgac
240cattttataa ttattgaata ataaattcgt tctgctattt tacaatgaaa aataatgctg
300cagagagcat ttttgcacat gtatcgtggc agatgtaggc cagaggctct tctttatcca
360tcctatggcc aacctatgaa tgtatacacg tttaatgaga ttttgccagc aatcaaagcc
420ttcagggaaa atgtccctag ctctttacta catcagatca aggactctgg ataattggca
480taacatcctg gaatagctga aacagagata ttattctctg ctgtcctctg ttgtctttgt
540cttttcacgt cttaata
557116545DNAHomo sapiensmisc_feature(1)..(545)AffymetrixID 211458_s_at
116aaatagcatt aaactggaat tgacagagtg agttgagcat ctctgtctaa cctgctcttt
60ctctctggtg ctcctcatct cacccctacc ttggaattta ataagcttca ggcatttcca
120attgcagact aaaaccactt ctaccatctc ctctagtatt ttccatgtat caggacagag
180atgtcttatg tagggaaggg gcaggtatga agtgaggtag attatctata cctctcactc
240attcaggatt ctcgctccca tgctgctgtc ccttcattct cacactcaca ggaatgctat
300gtgatggcca gctgcttccc ttcttggtta tccactgcag ctgctagtta gaaaggtttg
360cagggatgac ttttagtaaa tcatggggat tttattgatt tattatcact tataggattt
420tgtggggtgg gagtggggag caggaattgc actcagacat gacatttcaa ttcatctctg
480caaatgaaaa gggttcttcc tcttggggga aatctgtgtg tcagttctgt cagctgcaag
540ttctt
545117441DNAHomo sapiensmisc_feature(1)..(441)AffymetrixID 211560_s_at
117tccccatccg ggtgggcaat gcagcactca acagcaagct ctgtgatctc ctgctctcca
60agcatggcat ctatgtgcag gccatcaact acccaactgt cccccggggt gaagagctcc
120tgcgcttggc accctccccc caccacagcc ctcagatgat ggaagatttt gtggagaagc
180tgctgctggc ttggactgcg gtggggctgc ccctccagga tgtgtctgtg gctgcctgca
240atttctgtcg ccgtcctgta cactttgagc tcatgagtga gtgggaacgt tcctacttcg
300ggaacatggg gccccagtat gtcaccacct atgcctgaga agccagctgc ctaggattca
360caccccacct gcgcttcact tgggtccagg cctactcctg tcttctgctt tgttgtgtgc
420ctctagctga attgagccta a
441118131DNAHomo sapiensmisc_feature(85)..(85)n is a, c, g, or t
118gcactgggag gcccaagagc caatccagat gcctgagaca acggagactg tgctctgtgc
60cctgggcctg gtgctgggcc tagtnggcat catcgtgggc accgtcctca tcataaagtc
120tctgcgttct g
131119482DNAHomo sapiensmisc_feature(377)..(377)n is a, c, g, or t
119attttgctgt tacctttgtg acctgattgt tttttggaac acgtcaagac gtgggatcag
60aatcttccaa ctttagaggt gcaatggaag acactacgct acttggttga gcctggtgaa
120gaatgtatta atgagactgc tttgcataaa actgggaaga aagagaagac agttggagat
180ggaagatggt tttgtatata ttttggaact ttagttcctc tgtgagacga aagaggagag
240ctatgttttg tgtcacattg tctgatatat attgtgtaac ctgtcaggtg agttgattta
300gacaacatag ctgacctttt atgacaaggc agtttgaata gggactattg taataccctc
360acacattata ggggcancag agaatggcat ggaagagaca gtctacagag agctttaaga
420ggccggagaa aggaaaagac attatcaggg cctggaaagt ctcttccagt tcatcagggt
480ag
482120419DNAHomo sapiensmisc_feature(249)..(249)n is a, c, g, or t
120acagtgttct ctaatgttac agatgagatg cgcattgcca aagaggagat ttttggacca
60gtgcagcaaa tcatgaagtt taaatcttta gatgacgtga tcaaaagagc aaacaatact
120ttctatggct tatcagcagg agtgtttacc aaagacattg ataaagccat aacaatctcc
180tctgctctgc aggcaggaac agtgtgggtg aattgctatg gcgtggtaag tgcccagtgc
240ccctttggnt gggattcaag atgtctggaa atggaagaga actgggagag tacggtttcc
300atgaatatac agaggtcaaa acagtcacag tgaaaatctc tcagaagaac tcataaagaa
360aatacaagag tggagagaag ctcttcaata gctaagcatc tccttacagt cactaatat
419121343DNAHomo sapiensmisc_feature(1)..(343)AffymetrixID 212232_at
121agaaggcagc tctgcattct accttgcttg actggaattg tctgaagctt tttctggcct
60cttttctcta gtcggccacc cctgaagtgc tgaggtctaa gtggtttacc tcgtgctgat
120agatggccac actctttaga gtagttctca taagttctag aactggtagc tcggtcgttt
180cgcacactag gtggcataca ggcagcagca ggtgttcata tccttgattt tgagaatttc
240ccctcaagta tgtggcagta aatacaacaa gacactctat gtattaatgt ctccattgtc
300ttaaccctgt tccaaaacaa aattcacctc ctttctttat gtg
343122427DNAHomo sapiensmisc_feature(209)..(209)n is a, c, g, or t
122gtggattgtt tgtatccctt acctgctttc tattgggtta tgtgtggata tattgttttt
60atttgttcag catctccttc cccatcttct ggtaacacaa cctttattta tttgtgggga
120acctattccc tgtggcttag gtgagcatgt gaccaggcct ggcctcctga gtcccacagc
180ttcctagcca cagtgataaa agaatgggnt atataactta agccaggcta aggaaagccc
240ttaacagaac ttctgctgga actactggaa agaaggcttt atggagatcc caggaaccaa
300ggaccatgta agcctgaatt tgtgccatgt ggagagagtc tgtctgagga gaaactcgga
360tgctagcaga aatggaaaga gaactaagtt ctgatgtcat ttttctggag gccctagatc
420cagctgt
427123497DNAHomo sapiensmisc_feature(1)..(497)AffymetrixID 213142_x_at
123ctgctgccat tttaatcttg ctcattaacc ttactccttt gagaattctt taacaatatt
60taaaattggt aacaaaaata gtttagccat aattgtttag ccatgtgagt ttcaggttgg
120tacacgttca gacagaactg ctgtatcaca ttccaatttt gaatagccag tgagcaatca
180agtgtagaga aatgataaat ggcctaagaa ggcatacagt ggcataaacg atgctcttcc
240tagtagctta ataggccaca agctagtttc tgttgcactc tgaaataaaa tatgctttaa
300aaatgtaggg aacagtgctt agaaaagcaa aaactaggtg tgtcattgaa ataataggca
360taaaaattaa atgttacata agaacactat ttggaaagag ggtcctttta aaaactgaat
420ttgtactaaa tcagatttgc catgtccagt acagaataat ttgtacttag tatttgcagc
480agggtttgtc tttgtga
497124543DNAHomo sapiensmisc_feature(324)..(324)n is a, c, g, or t
124cttcctcgga ggcagcattg ttaagggagg ccctgtgcaa gtgctggagg acgaggaact
60aaagtcccag ccagagcccc tagtggtcaa gggaaaacgg gtggctggag gccctcagat
120gatccagctc agcctggatg ggaagcgcct ctacatcacc acgtcgctgt acagtgcctg
180ggacaagcag ttttaccctg atctcatcag ggaaggctct gtgatgctgc aggttgatgt
240agacacagta aaaggagggc tgaagttgaa ccccaacttc ctggtggact tcgggaagga
300gccccttggc ccagcccttg cccnatgagc tccgctaccc tgggggcgat tgtagctctg
360acatctggat ttgaaggctc caccctcatc acccacactc cctattttgg gccctcactt
420ccttggggac ctggcttcat tctgctctct cttggcaccc gacccttggc agcatgtacc
480acacagccaa gctgagactg tggcaatgtg ttgagtcata tacatttact gaccactgtt
540gct
543125501DNAHomo sapiensmisc_feature(37)..(37)n is a, c, g, or t
125ggacagttcc tgtgatcaga ggcaagattt gcccagngaa cagaataaag gtgcttcttt
60ggatagctct caatgttcgc cctcccctgc ctcccaggaa gaccttgaat cagagatttc
120agaggattct gatcaggaag tggacattga gggcgataaa agctatttta atgctggatg
180atgaccactg gcattggcat gttcagaaaa ctggatttag gaataatgtt ttgctacaga
240aaatcttcat agaagaactg gaaggctata taagaaaggg aatcaattct ctggtattct
300ggaaacctaa aaatatttgg tgcactgctc aattaacaaa cctacatgga gaccttaatt
360ttgacttaac aaatagttta tgtactgctc ttaggttgtt ttgataaagt gacattatag
420tgattaaatt ctttccnctt taaaaaaaca gntagtggtt ttcactattt ataaatagga
480ccttcttgaa cgacttttct g
501126424DNAHomo sapiensmisc_feature(1)..(424)AffymetrixID 217478_s_at
126ctgttttgtc agtaatctct tcccacccat gctgacagtg aactggcagc atcattccgt
60ccctgtggaa ggatttgggc ctacttttgt ctcagctgtc gatggactca gcttccaggc
120cttttcttac ttaaacttca caccagaacc ttctgacatt ttctcctgca ttgtgactca
180cgaaattgac cgctacacag caattgccta ttgggtaccc cggaacgcac tgccctcaga
240tctgctggag aatgtgctgt gtggcgtggc ctttggcctg ggtgtgctgg gcatcatcgt
300gggcattgtt ctcatcatct acttccggaa gccttgctca ggtgactgat tcttccagac
360cagagtttga tgccagcagc ttcggccatc caaacagagg atgctcagat ttctcacatc
420ctgc
424127530DNAHomo sapiensmisc_feature(1)..(530)AffymetrixID 217736_s_at
127tctgtctggt cttcctctag aaggttctac cgcagaaatt gatgtgtgct ccctgccctc
60gtcactgccc aagcccgggc ctgcacatac tcactggact gttccagttt tgacagctgc
120cagtcttcct gcccctttca cactgcagct gaagttcatt acctgaagga cgcctcatca
180tttcattcct tggctccaaa ccttctgctg cctctaagat aaaagctcaa cttcttaaca
240gtgtacagtg tgcaacttcc aaccttttta tctgttctct ccaccttcag tttagcgtca
300ttccaaaacc acacccttgc aaagctttgt actccgcacc ccagatgatc tccaggcagc
360tcagatctct ttcctgcctt tgccctgcac tgttccccgg tacttcctcc tttattgtag
420cactcagctc cccagccaat ctgtacatcc ctcagaggca gcgatctgat gaattggttt
480ttgaatccca gaaagggtct gccatggagt tggcagtcat cacggtagat
530128262DNAHomo sapiensmisc_feature(1)..(262)AffymetrixID 219069_at
128gaatattgta tactgcatcc cctaccacaa tttacacaat cctgtggata gtcctacctc
60accctggtca acctacatga tccttaagct aatggcgaat cacgatgacc ttgtagacat
120gcacacaact atacctttgt ccaacagatc ataatatatc tgctatccaa ctggttttac
180ctgcctaatc ctactgattt gggcactgct tgtatagtct ctcaagttca caggaaatgt
240tgattttcta aggtcctcat tt
262129490DNAHomo sapiensmisc_feature(1)..(490)AffymetrixID 219093_at
129tagagaccca tgtcatctta acctaaaggg aaatcttatt gcgttatcat aaaattgatg
60atatcttagg gtcagaattg cccttttttt tattttgaat gggaagctct cactaaaaca
120atcctgagat ttcttaattt catggttctt taaatattat aaacacagag tcaacataga
180atgaaattgt atttgttaaa atacacacat tggaggacaa gagcagatga ctacttttcg
240aagtaatgct gctccttcct aaaagtctgt tttcaatcct ggtaatatta ggggcactgc
300ggcacctaag aagccttaaa tgagagctaa tccaatttag agagcgatgg tgtcagcatt
360tcggtctgca tatctgtgtg tccgtatctg cgtttgtgtg cgtgtacgtg tgcccctgtg
420tgtgggccca gttttcaggc atgtagaata agcatggagt catattgagg aggactcact
480tcttgaagat
490130446DNAHomo sapiensmisc_feature(1)..(446)AffymetrixID 219228_at
130ggggttcgag cctcgttaag cacgagagga tacatacggg cgagaagccg tacaagtgca
60cagaatgtgg gaaggccttc aattgtggct atcacctcac tcagcacgag agaatccaca
120caggcgaaac cccgtataaa tgtaaggagt gtgggaaggc tttcatttat ggatcgagcc
180tcgtgaaaca tgagagaatt cataccgggg tgaaacccta tgggtgtaca gaatgtggga
240agagctttag tcacggccat cagcttacac aacatcagaa aacgcacagt ggggcgaaat
300cctacgaatg taaggagtgc gggaaggcat gtaaccacct aaaccatctc cgagaacatc
360agaggatcca caacagttga agagcctttt gaacgcagta gcccgctcgt atctatggtt
420tcgctttcca cagtttgtta cctgca
446131331DNAHomo sapiensmisc_feature(1)..(331)AffymetrixID 219607_s_at
131atcaacacat ttagcttggc gttttattca ttccatcacc cttactgtaa ctactatggc
60aactcaaata attgtcatgg gactatgtcc atcttaatgg gtctggatgg catggtgctc
120ctcttaagtg tgctggaatt ctgcattgct gtgtccctct ctgcctttgg atgtaaagtg
180ctctgttgta cccctggtgg ggttgtgtta attctgccat cacattctca catggcagaa
240acagcatctc ccacaccact taatgaggtt tgaggccacc caaagatcaa cagacaaatg
300ctccagaaat ctatgctgac tgtgacacaa g
331132149DNAHomo sapiensmisc_feature(55)..(55)n is a, c, g, or t
132atattttgta tcatcgtgcc tatagccgct gccaccgtgt ataaatcctg gtgtntgctc
60cttatcctgg acatgaatgt attgtacact gacgcgtccc cactcctgta cagctgcttt
120gtttctttgc aatgcattgt atggcttta
149133534DNAHomo sapiensmisc_feature(120)..(120)n is a, c, g, or t
133gatttccagg aagcctttga tcacctttgt aacaagatca ttgccaccag gaacccagag
60gaaatccgag ggggaggcct gcttaagtac tgcaacctct tggtgagggg ctttaggccn
120gcctctgatg aaatcaagac ccttcaaagg tatatgtgtt ccaggttttt catcgacttc
180tcagacattg gagagcagca gagaaaactg gagtcctatt tgcagaacca ctttgtggga
240ttggaagacc gcaagtatga gtatctcatg acccttcatg gagtggtaaa tgagagcaca
300gtgtgccntg atgggacatg aaagaagaca gactttaaac cttatcacca tgctggctat
360ccgggtgtta gctgaccaaa atgtcattcc taatgtggct aatgtcactt gctattacca
420gccagccccc tatgtagcag atgccaactt tagcaattac tacattgcac aggttcagcc
480agtattcacg tgccagcaac agacctactc cacttggcta ccctgcaatt aaga
534134503DNAHomo sapiensmisc_feature(1)..(503)AffymetrixID 221622_s_at
134atgcatcatt ggctacactt ccatttttgt ctactgttgt tactgacaag ctttttgtaa
60ttgatgcttt gtattcagat aatataagca aggaaaactg tgttttcaga agctcactga
120ttggcatagt ttgtggtgtt ttctatccca gttctttggc ttttactaaa aatggacgcc
180tggcaaccaa gtatcatacc gttccactgc caccaaaagg aagggtttta atccattgga
240tgacgctttg tcaaacacaa atgaaattaa ttgcgattcc tctagtcttt cagattatgt
300ttggaatatt aaatggctat accattatgc aagtatttga aagagacact tgagaaaact
360atacatgaag agtaaccaaa aaaatgaatg gttgctaact tagcaaaatg aagtttctat
420aaagaggact caggcattgc tgaaagagtt aaaagtaact gtgaacaaat aatttgttct
480gtgccttttg cctggtatat agc
503135515DNAHomo sapiensmisc_feature(1)..(515)AffymetrixID 218845_at
135aaaacattct ggccgctcca ggaattctga agttctgggc ctttctcaga agactgtaat
60gtacctgaag tttctgaaat attgcaaacc cacagagttt aggctggtgc tgccaaaaag
120aaaagcaaca tagagtttaa gtatccagta gtgatttgta aacttgtttt tcatttgaag
180ctgaatatat acgtagtcat gtttatgttg agaactaagg atattcttta gcaagagaaa
240atattttccc cttatcccca ctgctgtgga ggtttctgta cctcgcttgg atgcctgtaa
300ggatcccggg agccttgccg cactgccttg tgggtggctt ggcgctcgtg attgcttcct
360gtgaacgcct cccaaggacg agcccagtgt agttgtgtgg gcgtgaactc tgcccgtgtg
420ttctcaaatt ccccagcttg ggaaatagcc cttggtgtgg gttttatctc tggtttgtgt
480tctccgtggt ggaattgacc gaaagctcta tgttt
515136504DNAHomo sapiensmisc_feature(1)..(504)AffymetrixID 200786_at
136gttacattgg tgcagcccta gttttagggg gagtagatgt tactggacct cacctctaca
60gcatctatcc tcatggatca actgataagt tgccttatgt caccatgggt tctggctcct
120tggcagcaat ggctgtattt gaagataagt ttaggccaga catggaggag gaggaagcca
180agaatctggt gagcgaagcc atcgcagctg gcatcttcaa cgacctgggc tccggaagca
240acattgacct ctgcgtcatc agcaagaaca agctggattt tctccgccca tacacagtgc
300ccaacaagaa ggggaccagg cttggccggt acaggtgtga gaaagggact actgcagtcc
360tcactgagaa aatcactcct ctggagattg aggtgctgga agaaacagtc caaacaatgg
420acacttcctg aatggcatca gtgggtggct ggccgcggtt ctggaaggtg gtgagcattg
480aggcccagta agacactcat gtgg
504137492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 212886_at
137acaggcacat caggctgcag aatgcgcttt agaaagcatt gttttagtcc aggcacagtg
60gctcacgcct gtaatcccag cactttggga ggccgaggtg ggtggatcac aaggttggga
120gattgagacc atcctggcta acacagtgaa accctgtctc tactaaaaaa atacaaaaaa
180ttagcttggc gtggtggtgg gcgcctgtag tcccagcagc ttgggaggct gaggctggag
240aatggtgtga acccaggagg cggagcttgc agtgagccaa gatcgcgcca ctgcactcca
300gcccgggtga cagagcaaga ctccgtctca aaaaaaagaa aagaaaaaag aaagcattgt
360tttaattgag aggggcaggg ctggagaagg agcaagttgt ggggagccag gcttccctca
420cgcagcctgt ggtggatgtg ggaaggagat caacttctcc tcactctggg acagacgatg
480tatggaaact aa
492138316DNAHomo sapiensmisc_feature(173)..(173)n is a, c, g, or t
138ggatgtgatt ctaaaagctt ttattgagca ttgtcaaatt tgtaagcttc atagggatgg
60acatcatatc tataatgccc ttctatatgt gctaccatag atgtgacatt tttgacctta
120atatcgtctt tgaaaatgtt aaattgagaa acctgttaac ttacatttta tgnattggca
180cattgtatta cttactgcaa gagatatttc attttcagca cagtgcaaaa gttctttaaa
240atgcatatgt ctttttttct aattccgttt tgttttaaag cacattttaa atgtagtttt
300ctcatttagt aaaagt
316139525DNAHomo sapiensmisc_feature(1)..(525)AffymetrixID 212266_s_at
139gttgagtttg cctcttatgg tgacttaaag aatgctattg aaaaactttc tggaaaggaa
60ataaatggga gaaaaataaa attaattgaa ggcagcaaaa ggcacagtag gtcaagaagc
120aggtctcgat cccggaccag aagttcctct aggtctcgta gccgatcccg ttcccgtagt
180cgcaaatctt acagccggtc aagaagcagg agcaggagcc ggagccggag caagtcccgt
240tctgttagta ggtctcccgt gcctgagaag agccagaaac gtggttcttc aagtagatct
300aagtctccag catctgtgga tcgccagagg tcccggtccc gatcaaggtc cagatcagtt
360gacagtggca attaaactgt aaataacttg ccctgggggc ctttttttaa aaaacaaaaa
420ccacaaaaat tcccaaacca tacttgctaa aaattctggt aagtatgtgc ttttctgtgg
480gggtgggatt tggaaggggg gttgggttgg gctggatatc tttgt
525140581DNAHomo sapiensmisc_feature(72)..(74)n is a, c, g, or t
140acaatgaggc attctgtcct cctgctgcca ttcttcatct ccactgagag ccagagctgg
60taggagccga gnnnccacag gcattctgca ttgctctact cttaggtttg tgtgtgtgat
120ccttcccctc cctgtcgccc actcctccct cctctggcta tcctaccctg tctgtgggct
180cttttactac cagcctatgc tgtgggactg tcatggcatt tagttcagag tggaggggnn
240nnnnnnnnnn nnnaaatgca agtatttnan nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
300nnnnnaanat tgttgttgca atttgtgtct aacaagctgt agcagagaag gagggagtga
360gcgctggcag tatttccttt cataaatcat gaatttatca gtgtggaaat aatgcttcag
420aactgtgctc tgtagccctc ctgcannnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
480nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnngcgt gaaccttgtt
540aggtatactt tacctgatgc tgcttccatc ctcgcagtct g
581141377DNAHomo sapiensmisc_feature(1)..(377)AffymetrixID 200090_at
141tccctttgcc tgtggtgtaa aagtgcatca cacaggtatt gctttttaac aagaactgat
60gctccttggg tgctgctgct actcagacta gctctaagta atgtgattct tctaaagcaa
120agtcattgga tgggaggagg aagaaaaagt cccataaagg aacttttgta gtcttatcaa
180catataatct aatcccttag catcagctcc tccctcagtg gtacatgcgt caagatttgt
240agcagtaata actgcaggtc acttgtatgt aatggatgtg aggtagccga agtttggttc
300agtaagcagg gaatacagtc gttccatcag agctggtctg cacactcaca ttatcttgct
360atcactgtaa ccaacta
377142494DNAHomo sapiensmisc_feature(1)..(494)AffymetrixID 218025_s_at
142ctccttgggc tattcgatgc cgtgtatgca tctgacaggg caacatttca tacaccattt
60agtcacctag gccaaagtcc ggaaggatgc tcctcttaca cttttccgaa gataatgagc
120ccagccaagg caacagagat gcttattttt ggaaagaagt taacagcggg agaggcatgt
180gctcaaggac ttgttactga agttttccct gatagcactt ttcagaaaga agtctggacc
240aggctgaagg catttgcaaa gcttccccca aatgccttga gaatttcaaa agaggtaatc
300aggaaaagag agagagaaaa actacacgct gttaatgctg aagaatgcaa tgtccttcag
360ggaagatggc tatcagatga atgcacaaat gctgtggtga acttcttatc cagaaaatca
420aaactgtgat gaccactaca gcagagtaaa gcatgtccaa ggaaggatgt gctgttacct
480ctgatttcca gtac
494143540DNAHomo sapiensmisc_feature(1)..(540)AffymetrixID 204232_at
143cgatctccag cccaagatga ttccagcagt ggtcttgctc ttactccttt tggttgaaca
60agcagcggcc ctgggagagc ctcagctctg ctatatcctg gatgccatcc tgtttctgta
120tggaattgtc ctcaccctcc tctactgtcg actgaagatc caagtgcgaa aggcagctat
180aaccagctat gagaaatcag atggtgttta cacgggcctg agcaccagga accaggagac
240ttacgagact ctgaagcatg agaaaccacc acagtagctt tagaatagat gcggtcatat
300tcttctttgg cttctggttc ttccagccct catggttggc atcacatatg cctgcatgcc
360attaacacca gctggcccta cccctataat gatcctgtgt cctaaattaa tatacaccag
420tggttcctcc tccctgttaa agactaatgc tcagatgctg tttacggata tttatattct
480agtctcactc tcttgtccca cccttcttct cttccccatt cccaactcca gctaaaatat
540144559DNAHomo sapiensmisc_feature(1)..(559)AffymetrixID 201722_s_at
144attttgtttt catctgtgat agtcatggat gcttttattt tccttggggt gctgaaattg
60agctgaaaaa aaaaggctct ttgaatatag ttttaatttc tctctacagt tttttttgtt
120tggtttgtgg gctgttggaa ttgtaatttt taattgcctt ctaaaaaatg gaaatttaac
180aatgtctgat ctcagctgaa caaattagat gtttcagttg ctcttgggtc aactggctta
240cagatttaca tgtgcacaca cacacaaatt tcttatcaca ttttcgactt cttcacttga
300cctaactgat tatgcgaaat acccaagatt catgctactg taccacagat ttgttttcac
360agcaataaat cttcagttct gttgtttatg attccactta acaaaaggcc tgcagaagtg
420atttattatt tgggtatttg gagataatac atttgatggt tttttggaaa acctttttca
480ctccatactc agatatgctt cattgtcaaa tgcatattta gattagatta ttgaattgta
540atgtttatct gctgctttt
559145453DNAHomo sapiensmisc_feature(1)..(453)AffymetrixID 218627_at
145taatcatttc tgggttcact gcgactcact gtagtgctgg ggatccccct tgtaacactg
60gaactgaaag gcagtgatga aagctatgtc aagcattcat tattctgaag aggaggagaa
120atgccacata cctttcccat gggacctgtg gtggaatgaa tccatacttc tgcctcactt
180cgagcagact tttgttctcg gcgctcctca cgatggagtt tcatgcttca ttttcacatc
240tctctgcaca attagattgg gagctccttg agggcagagt acgtgcctta atctttatct
300ttgtaatgcc acaatgaaca gagtgcctcc tggtacactg taggagctta agaaatactc
360actgaatgca tgaatgaatg aatgaacaaa tgaaggaatg actaaggatg tttgtagtgc
420tataatatag aatgggattt actctgcttt acc
453146553DNAHomo sapiensmisc_feature(1)..(553)AffymetrixID 202322_s_at
146gttctcattt cctactattc atgctatttg gtcaaggcct gaaagcaccc aggtgcagaa
60tatcttgcgc cagagaacag aaaacataga tataaaaaaa tactgtgtac attatcttga
120ggatgtaggt tcttttgaat acactcgtaa tacccttaaa gagcttgaag ctaaagccta
180taaacagatt gatgcacgtg gtgggaaccc tgagctagta gccttagtaa aacacttaag
240taagatgttc aaagaagaaa atgaataatg ttaagccatt cttgattgga cctcatagct
300tattttagtt aatctttttt ttgtctttta gccttaccac cttttaaaaa atttgttatt
360ctccagaaac agtaaatagg tgagtagggg tggtgcaagt gaattcgttt tcatttagaa
420gcccctctgt acagataatc aaaattcaaa gttgaaagaa tcaaaagcag ccacagttat
480gtaggtctga tttgaatgtc ataattgcag tgacaggaca ttgccaccaa ctctatccta
540ctaccatcaa tgt
553147530DNAHomo sapiensmisc_feature(1)..(530)AffymetrixID 221689_s_at
147accgtcgcca ttgccagaaa gagcgattta tggctttgtt cttttcttaa gctcccaatt
60tggcttcata ctttacctcg tgtgggcctt tattcctgaa tcttggctaa actctttagg
120tttaacctat tggcctcaaa aatattgggc agttgcatta cctgtctacc tccttattgc
180tatagtaatt ggctacgtgc tcttgtttgg gattaacatg atgagtacct ctccactcga
240ctccatccat acaatcacag ataactatgc aaaaaatcaa cagcagaaga aataccaaga
300ggaggccatt ccagccttaa gagatatttc tattagtgaa gtaaaccaaa tgttctttct
360tgcagccaaa gaactttaca ccaaaaactg aactgtgtgt aaccatagta acaccaagca
420cgtatttatt tataagtttt tgccattata attttgacca taaattaatt tgaccatctc
480tcttattaat agagaagtaa aaaatgtaag ttgaccttct cttagattat
530148563DNAHomo sapiensmisc_feature(1)..(563)AffymetrixID 203356_at
148tatacatctt gggcaactag ttaccaaatg aattgtgcca ccataactga ttttaatttt
60gcattattta tgattttaaa atatttgttg cccaggtgtt atgaaagaat aaagctttta
120agtatagact accttagcat gaagatgctc atgcctaaga atgaaaattg ttgaggttat
180ctcccattca atcatgtagc aagaacttaa agaaattcac tactgcagtt tttattttta
240aaaaacagta attgagatat tgaagacatt acaatttagt ttgtgtggtc tttttttaaa
300ttgctgtatc gttcagtctc ttgtggcaat agcactttga agaaaataga gaatttaata
360tatggtgatt gggatatgta gcattcaaaa aaagtgaatt gccaagatac tggtgtcatg
420taaattccca ctttacataa aaacccatca ggacagaatg atgctcaata ttttaaaatt
480ctaaaaatag ggtgggattt ttcattgtct ctactttata attatcaaaa cttattttgt
540attgctacta ccttaaattg aaa
563149544DNAHomo sapiensmisc_feature(1)..(544)AffymetrixID 218462_at
149aaatgagcag tgttcgtctt cgtaaagaaa ttaagagaag aggcaaggac cccacagaac
60acatacctga aataattctg aataatttta caacacggct gggtcattca attggacgta
120tgtttgcatc tctctttcct cataatcctc aatttatcgg aaggcaggtt gccacattcc
180acaatcaacg ggattacata ttcttcagat ttcacagata catattcagg agtgaaaaga
240aagtgggaat tcaggaactt ggaccacgtt ttaccttaaa attaaggtct cttcagaaag
300gaacctttga ttctaaatat ggagagtatg aatgggtcca taagccccgg gaaatggata
360caagtagaag aaaattccat ttataaagta ctgagagaat gatattggat tttgctgaac
420aggcctatct tgaactttgg taaattattt ttgacagaat actcttttca aaatggcatt
480tgctgatttc ataaaccttt cacgtctgga cgaattacca aatgccatga attgccactg
540tgtg
544150519DNAHomo sapiensmisc_feature(1)..(519)AffymetrixID 218123_at
150gtggaagccg gtgtctgtgt taccatggag atggtgaaag atgccttgga ccagcttcga
60ggcgcggtga tgattgttta ccccatgggg ttgccaccgt atgatcccat ccgcatggag
120tttgaaaata aggaagactt gtcgggaaca caggcagggc tcaacgtcat taaagaggca
180gaggcgcagc tgtggtgggc agccaaggag ctgagaagaa cgaagaagct ttcagactac
240gtggggaaga atgaaaaaac caaaattatc gccaagattc agcaaagggg acagggagct
300ccagcccgag agcctattat tagcagtgag gagcagaagc agctgatgct gtactatcac
360agaagacaag aggagctcaa gagattggaa gaaaatgatg atgatgccta tttaaactca
420ccatgggcgg ataacactgc tttgaaaaga cattttcatg gagtgaaaga cataaagtgg
480agaccaagat gaagttcacc agctgatgac acttccaaa
519151272DNAHomo sapiensmisc_feature(66)..(66)n is a, c, g, or t
151aggttgcagt gtggtgagat catgccacta cactccagcc tggcgacaga gcgagacttg
60gtttcnaaaa aaaaaaaaaa aaaaacttca gtaagtacgt gttatttttt tcaataaaat
120tctattacag tatgtcatgt ttgctgtagt gctcatattt attgttgttt ttgttttagt
180actcacttgt ttcataatat caagattact aaaaatgggg gaaaggactt ctaatctttt
240tttcataata tctttgacac atattacaga ag
272152386DNAHomo sapiensmisc_feature(1)..(386)AffymetrixID 219067_s_at
152cgagaagatc ctgatacccc aatgtccttc tttgactttg tggttgatcc tcattctttc
60ccccgtacag tggaaaacat ctttcatgtt tccttcatta tacgggatgg ttttgcaaga
120ataagacttg accaagaccg actgccagta atagagcctg ttagtattaa tgaagaaaat
180gagggatttg aacataacac acaagttaga aatcaaggaa ttatagcttt gagttaccgt
240gactgggagg agattgtgaa gacctttgag atttcagagc ctgtgattac tccaagtcag
300aggcagcaga agccaagtgc ttgatgctag ctgaaggact caaatggata gtgaagtcca
360aaacggaaag cggcatgtat tgtaca
386153462DNAHomo sapiensmisc_feature(1)..(462)AffymetrixID 205789_at
153gtcatgaggc agctttcatc acaccctttt aacatttatc taaaagaatt taaattcttt
60ttcaaaaatt acactacaag tttataagcc caaatggctc tgtgaaatca gaagtgcaaa
120ggtgtgcaaa cttgtatctg aagacctacc agggacaagc aggtaagagc tgatgtgagt
180gtgtgtgatg ggatctgtaa ggaactggaa cacacatgtc ctatccaaag gaatcagctg
240cagctgcttg ttgtcaagta taaagtcagg acctggcttg gctttaaccg tttttcaaga
300aaactggaaa tctggatttt cagcgaacat gcctgatttt aaaaggttga ctcaagtttt
360tacaaaatac tatgtgggac acctcaaata catacctact gactgatgac aaacccagga
420gtttgtgtgt cttttataaa aagtttgccc tggatgtcat at
462154546DNAHomo sapiensmisc_feature(1)..(546)AffymetrixID 209214_s_at
154cagtgtccca atccgggttg tggaaaccag aacttcgcct ggagaacaga gtgcaaccag
60tgtaaggccc caaagcctga aggcttcctc ccgccaccct ttccgccccc gggtggtgat
120cgtggcagag gtggccctgg tggcatgcgg ggaggaagag gtggcctcat ggatcgtggt
180ggtcccggtg gaatgttcag aggtggccgt ggtggagaca gaggtggctt ccgtggtggc
240cggggcatgg accgaggtgg ctttggtgga ggaagacgag gtggccctgg ggggccccct
300ggacctttga tggaacagat gggaggaaga agaggaggac gtggaggacc tggaaaaatg
360gataaaggcg agcaccgtca ggagcgcaga gatcggccct actagatgca gagaccccgc
420agagctgcat tgactaccag atttattttt taaaccagaa aatgttttaa atttataatt
480ccatatttat aatgttggcc acaacattat gattattcct tgtctgtact ttagtatttt
540tcacca
546155428DNAHomo sapiensmisc_feature(1)..(428)AffymetrixID 213427_at
155cgttgagaga tctccagtgc ccagtgctgc agagcagcga gctggaggga acgccagagg
60tgtcctgccg ggctctggag ctcttcgact ggctcggcgc cgtcttcagt aatgtcgacc
120taaataatga gcctaataat ttcatatcaa cctattgctg tcctgagcca agcacagtgg
180tggcaaaagc ttatttgtgt acaatcactg gcttcatact tccagagaag atctgtctcc
240tattggaaca tctctgtcac tactttgatg aaccgaagtt agctccatgg gttacactgt
300ccgttcaagg ctttgcagac agccctgttt cttgggaaaa aaatgaacat ggttttcgaa
360aaggaggaga acatttatat aactttgtga tttttaataa tcaggactat tggcttcaga
420tggctgtt
428156315DNAHomo sapiensmisc_feature(1)..(315)AffymetrixID 209422_at
156cagctcgggc gacaactgca agactccatc tcaaaaaaat aaaaataaaa gaaaagaaag
60aaatatgtgc actacctaag ttttgtcttt agaaaaacta tccacctata aaaaattacc
120ttgacaaaaa tagttccggt ttgactaatc attttgtttc tttaagtggt aagtgtatgc
180aaggtggatc cttgatgagc caacattgca ctgtggatac atatctatgt ttacgcgcta
240ttagaacaga aggcgctgta tatagaaatg ttgctttgaa gcaatatttg caaaacacgc
300agacttctgt atctg
315157543DNAHomo sapiensmisc_feature(1)..(543)AffymetrixID 201010_s_at
157gtgttctcct actgcaaata ttttcatatg ggaggatggt tttctcttca tgtaagtcct
60tggaattgat tctaaggtga tgttcttagc actttaattc ctgtcaaatt ttttgttctc
120cccttctgcc atcttaaatg taagctgaaa ctggtctact gtgtctctag ggttaagcca
180aaagacaaaa aaaattttac tacttttgag attgccccaa tgtacagaat tatataattc
240taacgcttaa atcatgtgaa agggttgctg ctgtcagcct tgcccactgt gacttcaaac
300ccaaggagga actcttgatc aagatgccca accctgtgat cagaacctcc aaatactgcc
360atgagaaact agagggcagg tgttcataaa agccctttga acccccttcc tgccctgtgt
420taggagatag ggatattggc ccctcactgc agctgccagc acttggtcag tcactctcag
480ccatagcact ttgttcactg tcctgtgtca gagcactgag ctccaccctt ttctgagagt
540tat
543158181DNAHomo sapiensmisc_feature(1)..(181)AffymetrixID 200883_at
158ttgccaaggc aactcagcag ccatttgatg tttctgcatt taatgccagt tactcagatt
60ctggactctt tgggatttat actatctccc aggccacagc tgctggagat gttatcaagg
120ctgcctataa tcaagtaaaa agaatagctc aaggaaacct ttccaacaca gatgtccaag
180c
181159503DNAHomo sapiensmisc_feature(1)..(503)AffymetrixID 218454_at
159gtggctatcc actgttagtt cagaagctgg gcttggacta ctcttatgat ttagctccac
60gagccaaaat tttccggcgt gaccaaggga aagtgactga tacggcatcc atgaaatata
120tcatgcgata caacaattat aagaaggatc cttacagtag aggtgacccc tgtaatacca
180tctgctgccg tgaggacctg aactcaccta acccaagtcc tggaggttgt tatgacacaa
240aggtggcaga tatctaccta gcatctcagt acacatccta tgccataagt ggtcccacag
300tacaaggtgg cctccctgtt tttcgctggg accgtttcaa caaaactcta catcagggca
360tgccagaggt ctacaacttt gattttatta ccatgaaacc aattttgaaa cttgatataa
420aatgaaggag ggagatgacg gactagaaga ctgtaaataa gataccaaag gcactatttt
480agctatgttt ttcccatcag aat
503160530DNAHomo sapiensmisc_feature(1)..(530)AffymetrixID 202918_s_at
160gagtgtcctg ctatagacta tactagacac acacttgatg gtgctgcatg tcttctgaat
60agcaataaat attttcccag cagggttagc ataaaggaat catctgtagc gaaactagga
120tcagtatgcc gtaggattta cagaatattt tcacatgctt attttcatca tcggcagata
180tttgatgaat atgaaaatga aacatttttg tgtcatcggt ttactaagtt tgtgatgaaa
240tacaatttga tgtccaagga taacctgatt gtaccaattt tagaagagga agtacagaat
300tcagtttctg gggaaagtga agcatgaagg gaatcatagg aaaaatgtac tgatcatata
360attaacatta tgtactgtat atatcatttt agacacatca atcatgtatc catattatag
420cttctttgtt tagtataggt ttttgtatgc tgggtttgcc ttttaaaatg ggaaatactt
480tttaagttat tcataagctg tatattcacc agtgtggcac tcatggtttt
530161403DNAHomo sapiensmisc_feature(1)..(403)AffymetrixID 212204_at
161gcttaactct tttgacatct gctattgtga cacatcccat tgctggcaat gtggtgcaca
60ctccgaaact tttaactact gttttgtaag cctccaaggg tggcattgca gggtccttag
120gcaatgtttt gtttgccttt atgcagagag gtgctccaag tgctgtgatt gagcaccgtg
180ctagaggaac tgtaatgctt cagaagttgt agcttataca aaggaaacag gtcctgctgg
240cttaatttaa acagttattg catgaagtag cgtggaggcc ctggactgct gctcgttctt
300taggatggac tgttctggta tctggtattg gtttagagac tgttaataag ggacatcaca
360aggtgatggg attcatttga agcactctat ttctgtttta atg
403162499DNAHomo sapiensmisc_feature(1)..(499)AffymetrixID 219452_at
162atcacttcga ccacatcaag gctgtcattg gatccaagtt catcgggatt ggtggagatt
60atgatggggc cggcaaattc cctcaggggc tggaagacgt gtccacatac ccggtcctga
120tagaggagtt gctgagtcgt ggctggagtg aggaagagct tcagggtgtc cttcgtggaa
180acctgctgcg ggtcttcaga caagtggaaa aggtacagga agaaaacaaa tggcaaagcc
240ccttggagga caagttcccg gatgagcagc tgagcagttc ctgccactcc gacctctcac
300gtctgcgtca gagacagagt ctgacttcag gccaggaact cactgagatt cccatacact
360ggacagccaa gttaccagcc aagtggtcag tctcagagtc ctccccccac atggccccag
420tccttgcagt tgtggccacc ttcccagtcc ttattctgtg gctctgatga cccagttagt
480cctgccagat gtcactgta
499163424DNAHomo sapiensmisc_feature(1)..(424)AffymetrixID 219889_at
163tactcaagcg ggtggctctg ggatcctggg ggcctgggtt gggggctagg gagacgccat
60gtgatggaca ctccagggac acacagccta gcacagcagc ttataatggg ctctccgggg
120ccatttgcaa taacagctgc aattccctgg atagacgagt tgatttcctc cctctgcccc
180tcccccagcc atgccagctg gcctttgtaa gtgcaggaaa ccgagtagaa aatgtgaccc
240tccaaatgga gaagctgcca gctttgccat tgtgaaccat ggtgaagtgc ttggaacata
300ctgttcactc actctaaagg cgctgagact gtgctgttgt tctcgttttt atagtcaatg
360gcttgttcat catccagatg tggctactga catatctaca cttcgcaccg gagtgtctgg
420aatt
424164464DNAHomo sapiensmisc_feature(1)..(464)AffymetrixID 201303_at
164caacttcact gtatcctcaa tgcatggaga catgccccag aaagagcggg agtccatcat
60gaaggagttc cggtcgggcg ccagccgagt gcttatttct acagatgtct gggccagggg
120gttggatgtc cctcaggtgt ccctcatcat taactatgat ctccctaata acagagaatt
180gtacatacac agaattggga gatcaggtcg atacggccgg aagggtgtgg ccattaactt
240tgtaaagaat gacgacatcc gcatcctcag agatatcgag cagtactatt ccactcagat
300tgatgagatg ccgatgaacg ttgctgatct tatctgaagc agcagatcag tgggatgagg
360gagactgttc acctgctgtg tactcctgtt tggaagtatt tagatccaga ttctacttaa
420tggggtttat atggactttc ttctcataaa tggcctgccg tctc
464165454DNAHomo sapiensmisc_feature(1)..(454)AffymetrixID 202510_s_at
165gtcgtctttc tattttcagg tcagctgatt agccacctta gttccatctg caactttagt
60tcccactggc tgtgtaacct aacatagtca caggctctgg ggactgtcac gtggacatct
120ttgggaggcc gttattctgc ccaccgcacc ctccgttcat cccctgccct gccgggcacc
180tcgctctacc ccaggaaaat gtgagctcgt tttcctgctc ggcatgtgct ccccctaagg
240ctctgctcct ccctgggcct gaaagttcct tctcagcctg agagggggcc cttcgatctc
300aggcatgact cagcccggct gatgcctctg cagtgctgag tcaggatttg gggccggctc
360tcttgggtct gtcccctttt cccaggtact gccttacaaa gctgtggcca ggaagtggcc
420ggtataaagg atgcccaagg tctttgtacg tgtg
454166239DNAHomo sapiensmisc_feature(1)..(239)AffymetrixID 221923_s_at
166tagtccatac tgagtgtcat caacaatcca gactgaagtc ttctatttta atctcaatcc
60ccttttctga tttgccaccc atgcctcttc aggctggaaa caatctcttg gttccctaaa
120gcactttctt ctgactgctg tgattcagtg aaccttgccc tttgctttct attacttgtg
180catttgcctc acctgacaat gttttaaatc gcctttgtat ctccttagct gctcaataa
239167477DNAHomo sapiensmisc_feature(1)..(477)AffymetrixID 201887_at
167ctgggaagca aaacccatgc ctccccctag ccatttttac tgttatccta tttagatggc
60catgaagagg atgctgtgaa attcccaaca aacattgatg ctgacagtca tgcagtctgg
120gagtggggaa gtgatctttt gttcccatcc tcttctttta gcagtaaaat agctgaggga
180aaagggaggg aaaaggaagt tatgggaata cctgtggtgg ttgtgatccc taggtcttgg
240gagctcttgg aggtgtctgt atcagtggat ttcccatccc ctgtgggaaa ttagtaggct
300catttactgt tttaggtcta gcctatgtgg attttttcct aacataccta agcaaaccca
360gtgtcaggat ggtaattctt attctttcgt tcagttaagt ttttcccttc atctgggcac
420tgaagggata tgtgaaacaa tgttaacatt tttggtagtc ttcaaccagg gattgtt
477168444DNAHomo sapiensmisc_feature(1)..(444)AffymetrixID 211582_x_at
168agcccacctg ctggatgagg aacttgaggc aagtcaccag cccctgatca tttcgcctaa
60aagagcaagg actagagttc ctgacctcca ggccagtccc tgatccctga cctaatgtta
120tcgcggaatg atgatatatg tatctacggg ggcctggggc tgggcgggct cctgcttctg
180gcagtggtcc ttctgtccgc ctgcctgtgt tggctgcatc gaagagcacc ttctgtcctg
240gtcccaggcc cagggctcct cagagcagga actccactat gcatctctgc agaggctgcc
300agtgcccagc agtgagggac ctgacctcag gggcagagac aagagaggca ccaaggagga
360tccaagagct gactatgcct gcattgctga gaacaaaccc acctgagcac cccagacacc
420ttcctcaacc caggcgggtg gaca
444169490DNAHomo sapiensmisc_feature(1)..(490)AffymetrixID 219030_at
169agttaacaca tcagctggac ctatttcccg aatgcagggt aacccttctg ttatttaaag
60atgtaaaaaa tgcgggagac ttgagaagaa aggccatgga aggcaccatc gatggatcac
120tgataaatcc tacagtgatt gttgatccat ttcagatact tgtggcagca aacaaagcag
180ttcacctcta caaactggga aaaatgaaga caagaactct atctactgaa attattttca
240acctttcccc aaataacaat atttcagagg ctttgaaaaa atttggtatc tcagcaaatg
300acacttcaat tctaattgtt tacattgaag agggagaaaa acaaataaat caagaatacc
360taatatctca agtagaaggt catcaggttt ctctgaaaaa tcttcctgaa ataatgaata
420ttacagaagt caaaaagata tataaactct cttcacaaga agaaagtatc gggacattat
480tggatgctat
490170412DNAHomo sapiensmisc_feature(30)..(30)n is a, c, g, or t
170agatatttag gtgacttaca gcaaccaatn gcaacanaac aaaatgttaa gaaatgatct
60ttntatgagg caatnggaaa tttgaacact gatcaactat aggatgattg gaattattaa
120tttttaaagg tgtgataaga tactgcactt ggctgggcac agtggcacat gcctgtaatc
180ccagctactt ggcaggctga ggtgggagaa tcgcttgagc tcaggagttc gagaccagcc
240tgggcaacgt ggcgaaatcc ccgtctttac aaaaacaaac aaacaaacaa aaaagatatt
300gcagttgtgt tgtaagcgtc cttatctttc agagctacat agtggaatgt ttatggaata
360tttaggataa atgatatagg catttgggat ttgctgcaaa atgacccaga gg
412171419DNAHomo sapiensmisc_feature(1)..(419)AffymetrixID 202902_s_at
171caaaatatcg tgctgccaca tgttcaaagt acactgaact tccttatggg agagaagatg
60tcctgaaaga agctgtggcc aataaaggcc cagtgtctgt tggtgtagat gcgcgtcatc
120cttctttctt cctctacaga agtggtgtct actatgaacc atcctgtact cagaatgtga
180atcatggtgt acttgtggtt ggctatggtg atcttaatgg gaaagaatac tggcttgtga
240aaaacagctg gggccacaac tttggtgaag aaggatatat tcggatggca agaaataaag
300gaaatcattg tgggattgct agctttccct cttacccaga aatctagagg atctctcctt
360tttataacaa atcaagaaat atgaagcact ttctcttaac ttaatttttc ctgctgtat
419172452DNAHomo sapiensmisc_feature(1)..(452)AffymetrixID 200663_at
172tgtcttatga tcacgtttgc catctttctg tctcttatca tgttggtgga ggtggccgca
60gccattgctg gctatgtgtt tagagataag gtgatgtcag agtttaataa caacttccgg
120cagcagatgg agaattaccc gaaaaacaac cacactgctt cgatcctgga caggatgcag
180gcagatttta agtgctgtgg ggctgctaac tacacagatt gggagaaaat cccttccatg
240tcgaagaacc gagtccccga ctcctgctgc attaatgtta ctgtgggctg tgggattaat
300ttcaacgaga aggcgatcca taaggagggc tgtgtggaga agattggggg ctggctgagg
360aaaaatgtgc tggtggtagc tgcagcagcc cttggaattg cttttgtcga ggttttggga
420attgtctttg cctgctgcct cgtgaagagt at
452173517DNAHomo sapiensmisc_feature(1)..(517)AffymetrixID 202138_x_at
173cagaataaaa aacagccccg ccaagactat cagctgggat tcactttaat ttggaagaat
60gtgccgaaga cgcagatgaa attcagcatc cagacgatgt gccccatcga aggcgaaggg
120aacattgcac gtttcttgtt ctctctgttt ggccagaagc ataatgctgt caacgcaacc
180cttatagata gctgggtaga tattgcgatt tttcagttaa aagagggaag cagtaaagaa
240aaagccgctg ttttccgctc catgaactct gctcttggga agagcccttg gctcgctggg
300aatgaactca ccgtagcaga cgtggtgctg tggtctgtac tccagcagat cggaggctgc
360agtgtgacag tgccagccaa tgtgcagagg tggatgaggt cttgtgaaaa cctggctcct
420tttaacacgg ccctcaagct ccttaagtga attgccgtaa ctgattttaa agggtttaga
480ttttaagaat ggtgctcttt catgcctatt atcagta
517174506DNAHomo sapiensmisc_feature(1)..(506)AffymetrixID 200851_s_at
174gttgaaggcc tcgcttagtt gtactggatt ctcagggagc cctctgtggc cttttgcttt
60gcgtgctgtt tcccttgtac cagagggcgg caccgtggaa attctgtttt ccctgtagca
120tattgtgttg gattgcatta ctggcagaga aaggacaagg tgccattcaa gtcctagggt
180gggcttccag ctgccttaat agaagtactc aagtcttttg ggtagtgagc tggaaagcct
240acaggaaaag aggggtacct gttttcattt gaaaactttg attcatggaa cctttaaaac
300taatctcaga aaaatttttg gtgcccatgc agctgtagtt gttcactgct ttcctggatg
360gatgggactc ttatgtcata acttctgtta ctcctttggc ccatagctaa ggtcatcctt
420ccccacaggg gtggctttgg gattggatga tacagctttt gcttctgtgt agtatacctg
480tacatacttg tttcaggcag cctttc
506175558DNAHomo sapiensmisc_feature(124)..(124)n is a, c, g, or t
175tcatgatgct gactggcgtt agctgattaa cccatgtaaa taggcactta aatagaagca
60ggaaagggag acaaagactg gcttctggac ttcctccctg atccccaccc ttactcatca
120cctngcagtg gccagaatta gggaatcaga atcaaaccag tgtaaggcag tgctggctgc
180cattgcctgg tcacattgaa attggtggct tcattctaga tgtagcttgt gcagatgtag
240caggaaaata ggaaaaccta ccatctcagt gagcaccagc tgcctcccaa aggaggggca
300gccgtgctta tatttttatg gttacaatgg cacaaaatta ttatcaacct aactaaaaca
360ttccttttct cttttttcct gaattatcat ggagttttct aattctctct tttggaatgt
420angatttttt ttaaatgctt tacgatgtaa aatatttatt ttttacttat tctggaagat
480ctggctgaag gattattcat ggaacaggaa gaagcgtaaa gactatccat gtcatctttg
540ttgagagtct tcgtgact
558176502DNAHomo sapiensmisc_feature(1)..(502)AffymetrixID 202531_at
176acaggagtca gtgtctggct ttttcctctg agcccagctg cctggagagg gtctcgctgt
60cactggctgg ctcctagggg aacagaccag tgaccccaga aaagcataac accaatccca
120gggctggctc tgcactaagc gaaaattgca ctaaatgaat ctcgttccaa agaactaccc
180cttttcagct gagccctggg gactgttcca aagccagtga atgtgaagga aactcccctc
240cttcggggca atgctccctc agcctcagag gagctctacc ctgctccctg ctttggctga
300ggggcttggg aaaaaaactt ggcacttttt cgtgtggatc ttgccacatt tctgatcaga
360ggtgtacact aacatttccc ccgagctctt ggcctttgca tttatttata cagtgccttg
420ctcggggccc accaccccct caagccccag cagccctcaa caggcccagg gagggaagtg
480tgagcgcctt ggtatgactt aa
502177513DNAHomo sapiensmisc_feature(378)..(378)n is a, c, g, or t
177ggaatgattg tctcatcggc actaatgatc tggaaggggt taatggtaat aactggaagt
60gaaagtccga ttgtagtggt gctcagtggc agcatggaac ctgcatttca tagaggagat
120cttctctttc taacaaatcg agttgaagat cccatacgag tgggagaaat tgttgttttc
180aggatagaag gaagagagat tcctatagtt caccgagtct tgaagattca tgaaaagcaa
240aatgggcata tcaagttttt gaccaaagga gataataatg cggttgatga ccgaggcctc
300tataaacaag gacaacattg gctagagaaa aaagatgttg tggggagagc caggggattt
360gttccttata ttggaatngt gacgatcctc atgaatgact atcctaaatt tangtatgca
420gttctctttt tgctgggttt attcgtgctg gtncatcgtg agtaagaagc ctgccttgct
480gttcctggga agatgccata gttttcgtta ctg
513178338DNAHomo sapiensmisc_feature(1)..(338)AffymetrixID 200041_s_at
178agaggctttc tcggtatcag cagtttaaag attttcaacg acgaattctt gtggctacca
60acctatttgg ccgaggcatg gacatcgagc gggtgaacat tgcttttaat tatgacatgc
120ctgaggattc tgacacctac ctgcatcggg tggccagagc aggccggttt ggcaccaagg
180gcttggctat cacatttgtg tccgatgaga atgatgccaa gatcctcaat gatgtgcagg
240atcgctttga ggtcaatatt agtgagctgc ctgatgagat agacatctcc tcctacattg
300aacagacacg gtagaagact cgcccatttt ggaatgtg
338179498DNAHomo sapiensmisc_feature(1)..(498)AffymetrixID 200052_s_at
179ggacatggtc tgctatacag ctcagactct cgtccgaatc ctctcacatg gtggctttag
60gaagatcctt ggccaggagg gtgatgccag ctatcttgct tctgaaatat ctacctggga
120tggagtgata gtaacacctt cagaaaaggc ttatgagaag ccaccagaga agaaggaagg
180agaggaagaa gaggagaata cagaaagaac cacctcaagg agaggaagaa gaaagcatgg
240aaactcagga gtgacattcc cttcactcct tttcctaccc aagggaaaga ctggagccta
300agctgcctgc tactggcttt acatggtgac agacattccg tggataggaa gatagcagga
360gaaagtaact ccatagagtg tcattccact ggttgatatt ggcttagctg ccagtctccc
420atttgtgacc tatgccatcc atctataatg gaggatacca acatttcttc ctaatattct
480ataatctcca actcctga
498180478DNAHomo sapiensmisc_feature(1)..(478)AffymetrixID 200064_at
180aatagacttg tgtcttcacc ttgctgcatt gtgaccagca cctacggctg gacagccaat
60atggagcgga tcatgaaagc ccaggcactt cgggacaact ccaccatggg ctatatgatg
120gccaaaaagc acctggagat caaccctgac caccccattg tggagacgct gcggcagaag
180gctgaggccg acaagaatga taaggcagtt aaggacctgg tggtgctgct gtttgaaacc
240gccctgctat cttctggctt ttcccttgag gatccccaga cccactccaa ccgcatctat
300cgcatgatca agctaggtct aggtattgat gaagatgaag tggcagcaga ggaacccaat
360gctgcagttc ctgatgagat cccccctctc gagggcgatg aggatgcgtc tcgcatggaa
420gaagtcgatt aggttaggag ttcatagttg gaaaacttgt gcccttgtat agtgtccc
478181508DNAHomo sapiensmisc_feature(1)..(508)AffymetrixID 200079_s_at
181agctgccaga aacgaacctc tttgaaactg aagaaactcg caaaattctt gatgatatct
60gtgtggcaaa agctgttgaa tgccctccac ctcggaccac agccaggctc cttgacaagc
120ttgttgggga gttcctggaa gtgacttgca tcaatcctac attcatctgt gatcacccac
180agataatgag ccctttggct aaatggcacc gctctaaaga gggtctgact gagcgctttg
240agctgtttgt catgaagaaa gagatatgca atgcgtatac tgagctgaat gatcccatgc
300ggcagcggca gctttttgaa gaacaggcca aggccaaggc tgcaggtgat gatgaggcca
360tgttcataga tgaaaacttc tgtactgccc tggaatatgg gctgcccccc acagctggct
420ggggcatggg cattgatcga gtcgccatgt ttctcacgga ctccaacaac atcaaggaag
480tacttctgtt tcctgccatg aaacccga
508182393DNAHomo sapiensmisc_feature(1)..(393)AffymetrixID 200629_at
182tccagtttac tgaactccag accatgcatg tagtccactc cagaaatcat gctcgcttcc
60cttggcacac cagtgttctc ctgccaaatg accctagacc ctctgtcctg cagagtcagg
120gtggcttttc ccctgactgt gtccgatgcc aaggagtcct ggcctccgca gatgcttcat
180tttgaccctt ggctgcagtg gaagtcagca cagagcagtg ccctggctgt gtcctggacg
240ggtggactta gctagggaga aagtcgaggc agcagccctc gaggccctca cagatgtcta
300ggcaggcctc atttcatcac gcagcatgtg caggcctgga agagcaaagc caaatctcag
360ggaagtcctt ggttgatgta tctgggtctc ctc
393183439DNAHomo sapiensmisc_feature(1)..(439)AffymetrixID 200634_at
183gaaaacgttc gtcaacatca cgccagctga ggtgggtgtc ctggttggca aagaccggtc
60aagtttttac gtgaatgggc tgacacttgg gggccagaaa tgttcggtga tccgggactc
120actgctgcag gatggggaat ttagcatgga tcttcgtacc aagagcaccg gtggggcccc
180caccttcaat gtcactgtca ccaagactga caagacgcta gtcctgctga tgggcaaaga
240aggtgtccac ggtggtttga tcaacaagaa atgttatgaa atggcctccc accttcggcg
300ttcccagtac tgacctcgtc tgtcccttcc ccttcaccgc tccccacagc tttgcacccc
360tttcctcccc atacacacac aaaccatttt attttttggg ccattacccc atacccctta
420ttgctgccaa aaccacatg
439184541DNAHomo sapiensmisc_feature(1)..(541)AffymetrixID 200802_at
184taattgcacg gattaccagg ctcgccggct tcgaatccga tatgggcaaa ccaagaagat
60gatggacaag gtggagtttg tccatatgct caatgctacc atgtgcgcca ctacccgtac
120catctgcgcc atcctggaga actaccagac agagaagggc atcactgtgc ctgagaaatt
180gaaggagttc atgccgccag gactgcaaga actgatcccc tttgtgaagc ctgcgcccat
240tgagcaggag ccatcaaaga agcagaagaa gcaacatgag ggcagcaaaa agaaagcagc
300agcaagagac gtcaccctag aaaacaggct gcagaacatg gaggtcaccg atgcttgaac
360attcctgcct ccctatttgc caggctttca tttctgtctg ctgagatctc agagcctgcc
420caacagcagg gaagccaagc acccattcat ccccctgccc ccatctgact gcgtagctga
480gaggggaaca gtgccatgta ccacacagat gttcctgtct cctcgcatgg gcatagggac
540c
541185456DNAHomo sapiensmisc_feature(1)..(456)AffymetrixID 200860_s_at
185acttcagttg caccatgctg tacctttttg cagaggccaa tacggaagcc atccaagaac
60agatcacaag agttctcttg gaacggttga ttgtaaatag gccacatcct tggggtcttc
120ttattacctt cattgagctg attaaaaacc cagcgtttaa gttctggaac catgaatttg
180tacactgtgc cccagaaatc gaaaagttat tccagtcggt cgcacagtgc tgcatgggac
240agaagcaggc ccagcaagta atggaaggga caggtgccag ttagacgaaa ctgcatctct
300gttgtacgtg tcagtctaga ggtctcactg caccgagttc ataaactgac tgaagaatcc
360tttcagctct tcctgacttt cccagccctt tggtttgtgg gtatctgccc caactactgt
420tgggatcagc ctcctgtctt atgtgggcac gttcca
456186506DNAHomo sapiensmisc_feature(1)..(506)AffymetrixID 200983_x_at
186aggagttgag acctacttca cagtagttct gtggacaatc acaatgggaa tccaaggagg
60gtctgtcctg ttcgggctgc tgctcgtcct ggctgtcttc tgccattcag gtcatagcct
120gcagtgctac aactgtccta acccaactgc tgactgcaaa acagccgtca attgttcatc
180tgattttgat gcgtgtctca ttaccaaagc tgggttacaa gtgtataaca agtgttggaa
240gtttgagcat tgcaatttca acgacgtcac aacccgcttg agggaaaatg agctaacgta
300ctactgctgc aagaaggacc tgtgtaactt taacgaacag cttgaaaatg gtgggacatc
360cttatcagag aaaacagttc ttctgctggt gactccattt ctggcagcag cctggagcct
420tcatccctaa gtcaacacca ggagagcttc tcccaaactc cccgttcctg cgtagtccgc
480tttctcttgc tgccacattc taaagg
506187375DNAHomo sapiensmisc_feature(1)..(375)AffymetrixID 200991_s_at
187tgccacccgg gagtctatgg tcaaactctc aagtaagctg agtgccgtga gcttgcgggg
60aattggcagt cccagcacag atgccagtgc cagtgatgtc cacggcaatt tcgccttcga
120gggcattgga gatgaggatc tgtaatctcc actgcttgga tgtctgccct ctaccccaga
180ggaatttaca gaaacttgcc ctgtgcctgt gtcccccatg ctaggggcgg aggggtcttt
240tccttcttct ttcctaccta ccccttttct cttggccagg ggcctcgtat cctacctttc
300cttgtcccct gggctggctg cacagaggat tgccccttct cttttcagag ctggccctcg
360atgccaaatt agcat
375188312DNAHomo sapiensmisc_feature(1)..(312)AffymetrixID 201112_s_at
188agatctgtgc ggttggcata accaacttac taacagaatg tcccccaatg atggacactg
60agtataccaa actgtggact ccattattac agtctttgat tggtcttttt gagttacccg
120aagatgatac cattcctgat gaggaacatt ttattgacat agaagataca ccaggatatc
180agactgcctt ctcacagttg gcatttgctg ggaaaaaaga gcatgatcct gtaggtcaaa
240tggtgaataa ccccaaaatt cacctggcac agtcacttca catgttgtct accgcctgtc
300caggaagggt tc
312189338DNAHomo sapiensmisc_feature(1)..(338)AffymetrixID 201214_s_at
189agagctgcaa gagttctgga tgaacgacaa tctccttgag agctggagcg acctcgacga
60gctgaaggga gccaggagcc tggagacagt gtacctggag cggaacccct tgcagaagga
120cccccagtac cggcggaagg tcatgctcgc cctcccctcc gtgcggcaga tcgatgccac
180gttcgtcagg ttctgagtcc ttcttggctc ctcatgtggt ccctctcctc ggaagaactg
240cccagccacg ggtttttaac ccacctgttg ctcctgaggt cgtcactata tcaacagtca
300caaacccaat ggcaataaag gcactgacga tagctggc
338190385DNAHomo sapiensmisc_feature(1)..(385)AffymetrixID 201241_at
190aggatgggtc tggcaatttc cctggtggca acagaaaaag aaaaggtttg gtaccatgta
60tgtagcagcc gtggaaaagg gtgttataac acaagactca aggaagatgg aggctgtacc
120atatggtaca acgagatgca gttactatct gagatagaag aacacctgaa ctgtaccatt
180tctcaggttg agccggatat aaaggtacca gtggatgaat ttgatgggaa agttacctac
240ggtcagaaaa gggctgctgg tggtggaagc tataaaggcc atgtggatat tttggcacct
300actgttcaag agttggctgc ccttgaaaag gaggcgcaga catctttcct gcatcttggc
360taccttccta accagctgtt cagaa
385191371DNAHomo sapiensmisc_feature(1)..(371)AffymetrixID 201263_at
191gatctggatc caggctgtac attgaataaa aagattcgaa atgcacagtt agcacagtat
60aacttcattt tagttgttgg tgaaaaagag aaaatcactg gcactgttaa tatccgcaca
120agagacaata aggtccacgg ggaacgcacc atttctgaaa ctatcgagcg gctacagcag
180ctcaaagagt tccgcagcaa acaggcagaa gaagaatttt aatgaaaaaa ttacccagat
240tggctccatg gaaaaggagg aacagcgttt ccgtaaaatt gactttgtac tcgaaaacgt
300caatttatat tgaacttgga ggaggagttt ggcaaagtct gaaataggtc aacctgcagg
360cgtaactatt t
371192492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 201386_s_at
192ggagatcatc tgacactgct gaacgtctac catgctttta aacaaaatca tgaatcggtt
60cagtggtgtt atgacaactt cattaactac aggtccctga tgtccgcaga caatgtacgc
120cagcagctat ctcgaattat ggacagattt aatttgcctc gtcgaagtac tgactttaca
180agcagggact attatattaa tataagaaaa gctttggtta ctgggtattt tatgcaggtg
240gcacatttag aacgaacagg gcattactta actgtgaaag ataaccaggt ggttcagttg
300catccctcta ctgttcttga ccacaaacct gaatgggtgc tttataatga gtttgttcta
360acaacaaaga attacatccg gacatgtaca gatatcaagc cagaatggtt ggtgaaaatt
420gcccctcaat attatgacat gagcaatttc ccacagtgtg aagcaaagag acagttggac
480cgcatcattg cc
492193408DNAHomo sapiensmisc_feature(1)..(408)AffymetrixID 201417_at
193gtaaaccaca tcttttttgc acttttttta taagcaaaaa cgtgccgttt aaaccactgg
60atctatctaa atgccgattt gagttcgcga cactatgtac tgcgtttttc attcttgtat
120ttgactattt aatcctttct acttgtcgct aaatataatt gttttagtct tatggcatga
180tgatagcata tgtgttcagg tttatagctg ttgtgtttaa aaattgaaaa aagtggaaaa
240catctttgta catttaagtc tgtattataa taagcaaaaa gattgtgtgt atgtatgttt
300aatataacat gacaggcact aggacgtctg cctttttaag gcagttccgt taagggtttt
360tgtttttaaa cttttttttg ccatccatcc tgtgcaatat gccgtgta
408194422DNAHomo sapiensmisc_feature(1)..(422)AffymetrixID 201576_s_at
194aatggcttta accttggccg ctattggcca gcccggggcc ctcagttgac cttgtttgtg
60ccccagcaca tcctgatgac ctcggcccca aacaccatca ccgtgctgga actggagtgg
120gcaccctgca gcagtgatga tccagaacta tgtgctgtga cgttcgtgga caggccagtt
180attggctcat ctgtgaccta cgatcatccc tccaaacctg ttgaaaaaag actcatgccc
240ccacccccgc aaaaaaacaa agattcatgg ctggaccatg tatgatgatg aaagcctgtg
300tctttgaggg attctaccct gaacatacct cacagatcct ccctgtcatg ccacatttca
360ctgattggaa tgtggaaatg gaaaaggaat ttaggatgtg cattttcacc tgaggtttcc
420ct
422195551DNAHomo sapiensmisc_feature(1)..(551)AffymetrixID 201872_s_at
195gagatccaaa caactatagg ccacgaataa acaaacttaa ttcaattaag gatgtagaac
60aaaagaagag tggaaactac tttttcttgg atgattagac tgactctgag aatattgata
120agccatttat taaaaggagt atttactaga attttttgtc atataaaact tgaatcagga
180ttttatgccc cacatactct ggaacttgaa gtataatata cttaatataa cataaaaagc
240cagttgggtt ctaaattgta gttgaaacac agaaaatgcc acttttctgt tcctgaagag
300gctcttttgt gcataatatt ctaaaatgaa gacatttcaa gctatacaaa ttacttccaa
360gttttcatga tgtatgggaa gattttcagt aggtgtatta tattcacggt accaaatgct
420gaccagtgtt gctccatttt ttaaatcttg aaaagggttt ctgtacttac ctggtttgcc
480aagtatgcca gtgtaatgaa actgccctta ttttaaaagc cagtcaaaga ttccactgat
540tgacatttga t
551196519DNAHomo sapiensmisc_feature(1)..(519)AffymetrixID 201892_s_at
196tgtcagagta tgcacggcgc tttggtgttc cggtcattgc tgatggagga atccaaaatg
60tgggtcatat tgcgaaagcc ttggcccttg gggcctccac agtcatgatg ggctctctcc
120tggctgccac cactgaggcc cctggtgaat acttcttttc cgatgggatc cggctaaaga
180aatatcgcgg tatgggttct ctcgatgcca tggacaagca cctcagcagc cagaacagat
240atttcagtga agctgacaaa atcaaagtgg cccagggagt gtctggtgct gtgcaggaca
300aagggtcaat ccacaaattt gtcccttacc tgattgctgg catccaacac tcatgccagg
360acattggtgc caagagcttg acccaagtcc gagccatgat gtactctggg gagcttaagt
420ttgagaagag aacgtcctca gcccaggtgg aaggtggcgt ccatagcctc cattcgtatg
480agaagcggct tttctgaaaa gggatccagc acacctcct
519197283DNAHomo sapiensmisc_feature(1)..(283)AffymetrixID 202174_s_at
197caacctttaa atagtgctgc ccataaggag tcacctccta ctgttgattc aactcaacag
60cctaaccctt tgccgttacg tttacctgaa atggaaccct tagtgcctag agtcaaagaa
120gttaaatctg ctcaggaaac tcctgaaagc tctctggctg gaagtcctga tactgaatct
180ccagtgttag tgaatgacta tgaagcagaa tctggtaata taagtcaaaa gtctgatgaa
240gaagattttg taaaagttga agatttacca ctgaaactga caa
283198522DNAHomo sapiensmisc_feature(1)..(522)AffymetrixID 202176_at
198ggtgatcacg aaactcgctg gcatggagga ggaagacttg gcgttttcga caaaagaaga
60gcaacagcag ctcttacaga aagtcctggc agccactgac ctggatgccg aggaggaggt
120ggtggctggg gaatttggct ccagatccag ccaggcatct cggcgctttg gcaccatgag
180ttctatgtct ggggccgacg acactgtgta catggagtac cactcatcgc ggagcaaggc
240gcccagcaaa catgtacacc cgctcttcaa gcgctttagg aaatgatgct taggcagggt
300acttcgttca agaccggcgc ttggcaccct tgttggaaag ggattttcag cataacattt
360tccttccacc tctttgacct tccctccagc gttggccaaa ttgtgctgag gaagatgcat
420caagggcttg gctgtgcctt cataggtcat ctagggtttt ataaaggagg aggagacaat
480attttttcaa actttttggg gagtggggtc atttctgtat at
522199423DNAHomo sapiensmisc_feature(1)..(423)AffymetrixID 202220_at
199tgatccaaag ctggcacctt caggcacatt ggtctcatag ccattactgt ttttattgcc
60cttctaagat cctgtcttca gctgggtcag agaaaacttc ttgactaaaa ctggtcagaa
120ctcatcacag aaatgaaata cagtggtctc tctctcccag aactggttgc agctaaaaca
180gagagatctg actgctggct ataggatttt ggacttaatg actgaaattg caaattgtcc
240tttttcttgg cattacagat tttgccaaaa taactttttg tatcaaatat tgatgtgtga
300aagtgaagga gctagtctgc tgaaccagga atagtttgag atattgaact gtcatttttg
360cacatttgaa tactttgcag gctggctttg tataaactta tcctctggtt tcctatatgt
420tgt
423200344DNAHomo sapiensmisc_feature(106)..(106)n is a, c, g, or t
200gatactgtaa agtccacaca cacattaaat cttgttttcc tgaaagtatg gcatcaaaaa
60tacttgtaga aaaaccttgt cacaactgat ttgaatgttc ctattntnnn nnnctttgac
120tttgatattg gcttgtaatg tctcttttca tcatatgtaa tatcagtgga acaggcagcg
180ctactcaagt cctaaggatt cctcagtgat cagtgatcca gggccgttca tgaaccactg
240ggctggattt gactgttgag tgtggcagtt aatgcccctc aagaaatcaa aggatgtctt
300ataagtgtct tccaaaaaaa agcaaatgct gaaatcctat tggc
344201371DNAHomo sapiensmisc_feature(1)..(371)AffymetrixID 202464_s_at
201tattctgtcc tgagaccacg ggcaaagctc ttccattttg agagagaaga aaaactgttt
60ggaaccacac caatgatatt tttctttgta atacttgaaa tttatttttt tattattttg
120atagcagatg tgctatttat ttatttaata tatgtataag gagtcctaaa caatagaaag
180ctgtagaagc tgtagagata ggcttcagtt gttaattggt ttggagcctc ctatgtgtga
240cttatgactc tctgtgttct gtgtatttgt ctgaattaat gacctgggat ataaagctat
300gctagctttc aaacaggaga tgccttcaga aagctttgta tattttgcag ttgccagacc
360aataaaatac c
371202445DNAHomo sapiensmisc_feature(1)..(445)AffymetrixID 202545_at
202atcgcccctg agatcctaca gggcctgaag tacacattct ctgtggactg gtggtctttc
60ggggtccttc tgtacgagat gctcattggc cagtccccct tccatggtga tgatgaggat
120gaactcttcg agtccatccg tgtggacacg ccacattatc cccgctggat caccaaggag
180tccaaggaca tcctggagaa gctctttgaa agggaaccaa ccaagaggct gggaatgacg
240ggaaacatca aaatccaccc cttcttcaag accataaact ggactctgct ggaaaagcgg
300aggttggagc cacccttcag gcccaaagtg aagtcaccca gagactacag taactttgac
360caggagttcc tgaacgagaa ggcgcgcctc tcctacagcg acaagaacct catcgactcc
420atggaccagt ctgcattcgc tggct
445203482DNAHomo sapiensmisc_feature(1)..(482)AffymetrixID 202838_at
203agaaagaggc gctgctcact gttttcctgc ttcagttttt ctcttatagt accatcacta
60taatcaacga acttctcttc tccacccaga gatggctttt ccaacacatt ttaattaaag
120gaactgagta cattaccctg atgtctaaat ggaccaaaga tctgagatcc attgtgatta
180tatctgtatc aggtcagcag aagaaggaac tgagcagttg aactctgagt tcatcaattc
240taatatttgg aaattatcta caatggaatc ttccctctgt tctctgataa cctacttgct
300tactcaatgc ctttaagcca agtcaccctg ttgcctatgg gaggaggtgg aaggatttgg
360caagctcaac cacatgctat ttagttagca tcagttgtca ccaacagtct ttctgcaaag
420ggcaggagag ctttggggga aaggaaaagg cttaccaggc tgctatggtc aactcttcag
480aa
482204386DNAHomo sapiensmisc_feature(1)..(386)AffymetrixID 202896_s_at
204ccaccaccca actggggcta gagtggggaa gatttcccct ttagatcaaa ctgccccttc
60catggaaaag ctggaaaaaa actctggaac ccatatccag gcttggtgag gttgctgcca
120acagtcctgg cctcccccat ccctaggcaa agagccatga gtcctggagg aggagaggac
180ccctcccaaa ggactggaag caaaaccctc tgcttccttg ggtccctcca agactccctg
240gggcccaact gtgttgctcc acccggaccc atctctccct tctagacctg agcttgcccc
300tccagctagc actaagcaac atctcgctgt aagcgcctgt aaattactgt gaaatgtgaa
360acgtgcaatc ttgaaactga ggtgtt
386205486DNAHomo sapiensmisc_feature(1)..(486)AffymetrixID 202950_at
205taacatgtta gttgtcattt ggcatgagtg tgcattccag taattcttaa ttgatatttg
60attaattcca tacctttgat taaaacatgc tagttcaaaa taagactgct cagtttccaa
120gggttttcaa gcctacttac ctttataaag gttctctagt ctctgattag ccatgactgt
180attggacttt gaacattttc tgaactaaaa acctctattc taaactaatc tcatttggat
240gtgtaagtct tttgtaaagg caagaataaa taatatccag gacaatttat tagttttctc
300agtattttcc caaatattag aatatttact tcattattgg ttggctgcca atgaccccat
360atgttctgtg agaatagtag ctttatcttt gatataatac atagtctcca aataggtaat
420acttcgcaat tgattagatt ttcagagtag atttagagtt atctgttttt ctggtgaggg
480tcaaat
486206466DNAHomo sapiensmisc_feature(1)..(466)AffymetrixID 203037_s_at
206agtagtgcct gtggtttagc ccaccaatct tgatgactaa aagtagctga tgcattgtgc
60atatgatgct tgagatggtt tttgcaaaag cagaaatcgc tgcaaggtaa tcacaataga
120taaaagtggt attttaaacc tttgaaataa atggatgtaa ctgtaccttg gtacagcttt
180tcacttgttt agtttttaaa cgttagtata atctgaataa ataaaatgtt gccaaattca
240atgtagaaag aatgtgacaa cacaccttgg gtagttctgc ttgtgttttt gcatattgta
300aaagcagtgt cacagctaaa aagaaagaaa tcgtttctaa cagtaaatta ttgtgcttta
360gttgctagtt tgtactgaga gttgacctct ccctgtgcag ttttttgttc taaacttgta
420taaataacaa ttgtgtaatg tgtctccctc ctacattgta acaatt
466207497DNAHomo sapiensmisc_feature(1)..(497)AffymetrixID 203155_at
207gtcttcgtgg atacccatga tcttcgcttc ccctgggtgg ccttctttgc cagcaaaaga
60atccgggctg ggacagaact tacttgggac tacaactacg aggtgggcag tgtggaaggc
120aaggagctac tctgttgctg tggggccatt gaatgcagag gacgtcttct ttagaggaca
180gccttcttcc caacccttct tgaactgtcg tttcctcagg aactgggtct tcctgattgt
240tgaaccctga cccgaagtct ctgggctagc tactcccccc agctcctagt tgatagaaat
300gggggttctg gaccagatga tcccttccaa tgtggtgcta gcaggcagga tcccttctcc
360acctccaaag gccctaaagg gtggggagag atcaccactc taacctcggc ctgacatccc
420tcccatccca tatttgtcca agtgttcctg cttctaacag actttgttct tagaatggag
480cctgtgtatc tactatc
497208478DNAHomo sapiensmisc_feature(1)..(478)AffymetrixID 203371_s_at
208ctttcctgcc gtgagaaact cgaggtgacc aacctccgtt tccggttggc tccggttgca
60gagttgagtg tcctgagagg tcagattgct gtcagacatg gcccatgaac atggacatga
120gcatggacat cataaaatgg aacttccaga ttatagacaa tggaagatag aagggacacc
180attagaaact atccagaaga agctggctgc aaaagggcta agggatccat ggggccgcaa
240tgaagcttgg agatacatgg gtggctttgc aaagagtgtt tccttttctg atgtattctt
300taaaggattc aaatggggat ttgctgcatt tgtggtagct gtaggagctg aatattacct
360ggagtccctg aataaagata agaagcatca ctgaagataa tacctggaag catcatagtg
420gtttcttaac tctccaaaat aagatttctt ctctgtagcc tacttgtctg gtttatcc
478209510DNAHomo sapiensmisc_feature(1)..(510)AffymetrixID 203821_at
209gagccactct atgagttgga cttcagtctt gcctaggcga ttttgtctac catttgtgtt
60ttgaaagccc aaggtgctga tgtcaaagtg taacagatat cagtgtctcc ccgtgtcctc
120tccctgccaa gtctcagaag aggttgggct tccatgcctg tagctttcct ggtccctcac
180ccccatggcc ccaggccaca gcgtgggaac tcactttccc ttgtgtcaag acatttctct
240aactcctgcc attcttctgg tgctactcca tgcaggggtc agtgcagcag aggacagtct
300ggagaaggta ttagcaaagc aaaaggctga gaaggaacag ggaacattgg agctgactgt
360tcttggtaac tgattacctg ccaattgcta ccgagaaggt tggaggtggg gaaggctttg
420tataatccca cccacctcac caaaacgatg aaggtatgct gtcatggtcc tttctggaag
480tttctggtgc catttctgaa ctgttacaac
510210419DNAHomo sapiensmisc_feature(1)..(419)AffymetrixID 203966_s_at
210gatgcaacag atatatagcc ctttcaagtc atgttgtgtt tggacttggg gttggaacag
60ggagagcagc agccatgtca gctacacgct caaatgtgca gatgattatg gaaaataacc
120tcaaaatctt acaaagctga acatccaagg agttattgaa aactatctta aatgttcttg
180gtaggggagt tggcattgtt gataaagcca gtcccttcat ttaactgtct ttcaggatgt
240tccttcgttg tttccatgag tattgcaggt aataatacag tgtgttccat aagaatctca
300atcttggggc taaatgcctt gtttctttgc acctcttttc aagtccttac atttaattac
360taattgataa gcagcagctt cctacatata gtaggaaact gccacatttt tgctatcat
419211356DNAHomo sapiensmisc_feature(1)..(356)AffymetrixID 204192_at
211tacccgcagg actggttcca agtcctcatc ctgagaggta acgggtcgga ggcgcaccgc
60gtgccctgct cctgctacaa cttgtcggcg accaacgact ccacaatcct agataaggtg
120atcttgcccc agctcagcag gcttggacac ctggcgcggt ccagacacag tgcagacatc
180tgcgctgtcc ctgcagagag ccacatctac cgcgagggct gcgcgcaggg cctccagaag
240tggctgcaca acaaccttat ttccatagtg ggcatttgcc tgggcgtcgg cctactcgag
300ctcgggttca tgacgctctc gatattcctg tgcagaaacc tggaccacgt ctacaa
356212507DNAHomo sapiensmisc_feature(1)..(507)AffymetrixID 204419_x_at
212acactcgctt ctggaacgtc tgaggttatc aataagctcc tagtccagac gccatgggtc
60atttcacaga ggaggacaag gctactatca caagcctgtg gggcaaggtg aatgtggaag
120atgctggagg agaaaccctg ggaaggctcc tggttgtcta cccatggacc cagaggttct
180ttgacagctt tggcaacctg tcctctgcct ctgccatcat gggcaacccc aaagtcaagg
240cacatggcaa gaaggtgctg acttccttgg gagatgccat aaagcacctg gatgatctca
300agggcacctt tgcccagctg agtgaactgc actgtgacaa gctgcatgtg gatcctgaga
360acttcaagct cctgggaaat gtgctggtga ccgttttggc aatccatttc ggcaaagaat
420tcacccctga ggtgcaggct tcctggcaga agatggtgac tggagtggcc agtgccctgt
480cctccagata ccactgagct cactgcc
507213463DNAHomo sapiensmisc_feature(1)..(463)AffymetrixID 204566_at
213gccacttgtc ttgaaaactg tgcaactttt taaagtaaat tattaagcag actggaaaag
60tgatgtattt tcatagtgac ctgtgtttca cttaatgttt cttagagcca agtgtctttt
120aaacattatt ttttatttct gatttcataa ttcagaacta aatttttcat agaagtgttg
180agccatgcta cagttagtct tgtcccaatt aaaatactat gcagtatctc ttacatcagt
240agcatttttc taaaacctta gtcatcagat atgcttacta aatcttcagc atagaaggaa
300gtgtgtttgc ctaaaacaat ctaaaacaat tcccttcttt ttcatcccag accaatggca
360ttattaggtc ttaaagtagt tactcccttc tcgtgtttgc ttaaaatatg tgaagttttc
420cttgctattt caataacaga tggtgctgct aattcccaac att
463214304DNAHomo sapiensmisc_feature(1)..(304)AffymetrixID 204689_at
214cttttctgta atctgtttat ctcccactta atggaaaggc aaaggggtac cccaaatcca
60gaggtgccta catttcaggc agccttggag tattttaaaa ggaaaacatt ctttactttt
120atatgacatt cttatactgc tgtctcaaat cctttttcat ttcagagctc ttgtctcaga
180gatgtgtgtt ctttttgtca gagatatggt tgatgagaat cttaaatgct tgttttgcac
240tatcacttag tacctgtttg accaaggtgt taagggatag tacctcccat cagcagagaa
300actg
304215524DNAHomo sapiensmisc_feature(1)..(524)AffymetrixID 205249_at
215ggaacgtagc aatatctgct ccttttcgag ttgtttgaga aatgtaggct attttttcag
60tgtatatcca ctcagatttt gtgtattttt gatgtaccca cactgttctc taaattctga
120atctttggga aaaaatgtaa agcatttatg atctcagagg ttaacttatt taagggggat
180gtacatattc tctgaaacta ggatgcatgc aattgtgttg gaagtgtcct tggtcgcctt
240gtgtgatgta gacaaatgtt acaaggctgc atgtaaatgg gttgccttat tatggagaaa
300aaaatcactc cctgagttta gtatggctgt atatttatgc ctattaatat ttggaatttt
360ttttagaaag tatatttttg tatgctttgt tttgtgactt aaaagtgtta cctttgtagt
420caaatttcag ataagaatgt acataatgtt accggagctg atttgtttgg tcattagctc
480ttaatagttg tgaaaaaata aatctattct aacgcaaaac cact
524216307DNAHomo sapiensmisc_feature(1)..(307)AffymetrixID 205552_s_at
216gctcctgacg gtctatgctt gggagcgagg gagcatgaaa acacatttca acacagccca
60gggatttcgg acggtcttgg aattagtcat aaactaccag caactctgca tctactggac
120aaagtattat gactttaaaa accccattat tgaaaagtac ctgagaaggc agctcacgaa
180acccacgcct gtgatcctgg acccggcgga ccctacagga aacttgggtg gtggagaccc
240aaagcgttgg aggcagctgg cacaagaggc tgaggcctgg ctgaattacc catgctttaa
300gaattgg
307217525DNAHomo sapiensmisc_feature(1)..(525)AffymetrixID 206115_at
217ctcgctcctt ctggtatatg catgtcactg catgataatt gagttttcct ttgttttaat
60aaaactgttc tcagacatta agctaaacta agagaaaaat aactttgttg ccaaaaggtt
120gtgctatcca gattttttat atgtctgcat gtttaaaaaa aaaaaagcaa caaaagaaaa
180tgcactctaa cttatgtgaa ctgagagaaa aaaatcaggt tttaaacagg aaaacctatg
240gggaatgata ttttttgaaa gacttttgta taaagttgag tacttagaaa aaagacaaac
300cagatgtaat atattttgtg gatgttttta tttcttggat ttatagtacc ttatactaag
360gttaaaaaaa tatgcttgat attgtgaaaa ggtgaaattc ttcaccaaca tttcatttgc
420tcctttgtca tattgtaatg ccaatataat atagttaatg aaaacagcat ttttaaaaac
480cgaaatattg aaatggtgta atgttgtacc atttgcactg tgagc
525218509DNAHomo sapiensmisc_feature(1)..(509)AffymetrixID 206584_at
218tgatgattag ttactgatcc tctttgcatt tgtaaagctt tggagatatt gaatcatgtt
60accatttctg tttttttcca ccctgttttc ttccatattt actgaagctc agaagcagta
120ttgggtctgc aactcatccg atgcaagtat ttcatacacc tactgtgata aaatgcaata
180cccaatttca attaatgtta acccctgtat agaattgaaa ggatccaaag gattattgca
240cattttctac attccaagga gagatttaaa gcaattatat ttcaatctct atataactgt
300caacaccatg aatcttccaa agcgcaaaga agttatttgc cgaggatctg atgacgatta
360ctctttttgc agagctctga agggagagac tgtgaataca acaatatcat tctccttcaa
420gggaataaaa ttttctaagg gaaaatacaa atgtgttgtt gaagctattt ctgggagccc
480agaagaaatg ctcttttgct tggagtttg
509219431DNAHomo sapiensmisc_feature(1)..(431)AffymetrixID 206877_at
219gaaaagccgt tcaccaaatc gaccagcttc agcgagagca gcgacacctg aagaggcagc
60tggagaagct gggcattgag aggatccgga tggacagcat cggctccacc gtctcctcgg
120agcgctccga ctccgacagg gaagaaatcg acgttgacgt ggagagcacg gactatctca
180caggtgatct ggactggagc agcagcagtg tgagcgactc tgacgagcgg ggcagcatgc
240agagcctcgg cagtgatgag ggctattcca gcaccagcat caagagaata aagctgcagg
300acagtcacaa ggcgtgtctt ggtctctaag agagtgggca ctgcggctgt ctccttgaag
360gttctccctg ttggttctga ttaggtaacg tattggacct gcccacaact cccttgcacg
420taaacttcag t
431220377DNAHomo sapiensmisc_feature(1)..(377)AffymetrixID 207170_s_at
220aaaacagcac tcctttggct ggagcacttg tgtccgtgca tgtacttggg tgtttccctc
60catcctttct gatatgacca aaaatcaagt tgttttgttt tttgtcacct tcactggcat
120gggctaacca cttctttttc aaaccctctg aacacctttt tctgatgggt aacttgcagg
180aatattctat tggaaaagat aacaggaagt acaagtgctt cttgacccct tcctcaatgt
240ttctagcctt cactctccat tgtcttttct gggctgtatt acagccctct gtggatcttc
300aactctgctg cctccactgt gatgcagcag tccaactgta actgacagtg gctgccttct
360ctgggccatg gatcaca
377221518DNAHomo sapiensmisc_feature(1)..(518)AffymetrixID 208631_s_at
221ccagaactgc tgacacagat ggtgtccaag ggcttcctag gtcgtaaatc tgggaagggc
60ttttacatct atcaggaggg tgtgaagagg aaggatttga attctgacat ggatagtatt
120ttagcgagtc tgaagctgcc tcctaagtct gaagtctcat cagacgaaga catccagttc
180cgcctggtga caagatttgt gaatgaggca gtcatgtgcc tgcaagaggg gatcttggcc
240acacctgcag agggagacat cggagccgtc tttgggcttg gcttcccgcc ttgtctggga
300gggcctttcc gctttgtgga tctgtatggc gcccagaaga tagtggaccg gctcaagaaa
360tatgaagctg cctatggaaa acagttcacc ccatgccagc tgctagctga ccatgctaac
420agccctaaca agaagttcta ccagtgagca ggcctcatgc ctcgctcagt cagtgcacta
480accccagctg ccggcagtgc tggttctcca acagagtg
518222168DNAHomo sapiensmisc_feature(1)..(168)AffymetrixID 208691_at
222gagttctgtc atgattcact attctagaac ttgcatgacc tttactgtgt tagctctttg
60aatgttcttg aaattttaga ctttctttgt aaacaaataa tatgtcctta tcattgtata
120aaagctgtta tgtgcaacag tgtggagatt ccttgtctga tttaataa
168223555DNAHomo sapiensmisc_feature(1)..(555)AffymetrixID 208868_s_at
223acatctagaa acattacacc acacacaccg tcatcacatt ttcacatgct caattgatat
60tttttgctgc ttcctcggcc cagggagaaa gcatgtcagg acagagctgt tggattggct
120ttgatagagg aatggggatg atgtaagttt acagtattcc tggggtttaa ttgttgtgca
180gtttcataga tgggtcagga ggtggacaag ttggggccag agatgatggc agtccagcag
240caactccctg tgctcccttc tctttgggca gagattctat ttttgacatt tgcacaagac
300aggtagggaa aggggacttg tggtagtgga ccatacctgg ggaccaaaag agacccactg
360taattgatgc attgtggccc ctgatcttcc ctgtctcaca cttcttttct cccatcccgg
420ttgcaatctc actcagacat cacagtacca ccccaggggt ggcagtagac aacaacccag
480aaatttagac agggatctct tacctttgga aaataggggt taggcatgaa ggtggttgtg
540attaagaaga tggtt
555224456DNAHomo sapiensmisc_feature(1)..(456)AffymetrixID 208869_s_at
224gactaaaacc actcttagca tctcctctag tattttccat gtatcaggac agaggtgtct
60tatgtaggga gggggcaagt atgaagtaag gtaattatat actactctca ttcaggattc
120ttgctcccat gctgctgtcc cttcaggctc acatgcacag gaatgctaca tgatggccag
180ctgcttccct ccttggttat catccactgc agctgctagt tagaaaggtt tggagggatg
240acttttagta aatcatgggg attttattga tttattttca cttttgggat tttgtggggt
300gggagtgggg agcaggaatt gcactcagac atgacatttc aattcatctc tgctaatgaa
360aagggttctt tctcttgggg gaaatgtgtg tgtcagttct gtcagctgca agttcttgta
420taatgaagtc aatgccatca ggccaaggaa ataaaa
456225298DNAHomo sapiensmisc_feature(1)..(298)AffymetrixID 208942_s_at
225caacatggcg gaacgcagga gacacaagaa gcggatccag gaagttggtg aaccatctaa
60agaagagaag gctgtggcca agtatcttcg attcaactgt ccaacaaagt ccaccaatat
120gatgggtcac cgggttgatt attttattgc ttcaaaagca gtggactgtc ttttggattc
180aaagtgggca aaggccaaga aaggagagga agctttattt acaaccaggg agtctgtggt
240tgactactgc aacaggcttt taaagaagca gttttttcac cgagccctaa aagtaatg
298226454DNAHomo sapiensmisc_feature(1)..(454)AffymetrixID 209092_s_at
226aaatccaatc atgagtccag gtagagaacg cctgctgtaa tctacactgt tgctgggact
60gcgcattctg tatataactg tgttggatga gtgacagatg attgtccaga ctaggacagc
120ggcatgaaca tgactttggt tgggattgcg gatagttagg gttacctctg aatcgtgtag
180cttttatgag agcagctgtg caagtgaatc cacattaatg ccttgtcgtg gtgccattcc
240cagcgcctga cgatacgctc ttctattgtc ttattctggc aggttttgac gttttaaatt
300ttttaaagaa attttattcc ttggaccaaa aggtttggtt aaccaccccc ctcttacttg
360ctttcacatt ttgagtgtcc agaggaaaca gaaaggaatg agtgtgtgac gttgctgcac
420gcctgactct gtgcgagctt ctttctgtgt atat
454227465DNAHomo sapiensmisc_feature(1)..(465)AffymetrixID 209193_at
227gattgtagtg gatctaattt ttcagaaatt ttgcctttaa gttattttac ctgtttttgt
60ttcttgtttt gaaagatgcg cattctaacc tggaggtcaa tgttatgtat ttatttattt
120atttatttgg ttcccttcct attccaagct tccatagctg ctgccctagt tttctttcct
180cctttcctcc tctgacttgg ggaccttttg ggggagggct gcgacgcttg ctctgtttgt
240ggggtgacgg gactcaggcg ggacagtgct gcagctccct ggcttctgtg gggcccctca
300cctacttacc caggtgggtc ccggctctgt gggtgatggg gaggggcatt gctgactgtg
360tatataggat aattatgaaa agcagttctg gatggtgtgc cttccagatc ctctctgggg
420ctgtgttttg agcagcaggt agcctggctg gttttatctg agtga
465228447DNAHomo sapiensmisc_feature(1)..(447)AffymetrixID 209200_at
228ggagcaatcc aagccacata tcttctacat caaatttttc cattttggtt attttcataa
60tctggtattg cattttgcct tccctgttca tacctcaaat tgattcatac ctcagtttaa
120ttcagagagg tcagttaagt gacggattct gttgtggttt gaatgcagta ccagtgttct
180cttcgagcaa agtagacctg ggtcactgta ggcataggac ttggattgct tcagatggtt
240tgctgtatca tttttcttct ttttcttttc ctggggactt gtttccatta aatgagagta
300attaaaatcg cttgtaaatg agggcataca agcatttgca acaaatattc aaatagaggc
360tcacagcggc ataagctgga ctttgtcgcc actagatgac aagatgttat aactaagtta
420aaccacatct gtgtatctca agggact
447229337DNAHomo sapiensmisc_feature(1)..(337)AffymetrixID 209861_s_at
229aagtaaatac ttgatggctc tgaagaatct gtgtgacttg ggcattgtag atccatatcc
60accattatgt gacattaaag gatcatatac agcgcaattt gaacatacca tcctgttgcg
120tccaacatgt aaagaagttg tcagcagagg agatgactat taaacttagt ccaaagccac
180ctcaacacct ttattttctg agctttgttg gaaaacatga taccagaatt aatttgccac
240atgttgtctg ttttaacagt ggacccatgt aatactttta tccatgttta aaaagaagga
300atttggacaa aggcaaaccg tctaatgtaa ttaacca
337230196DNAHomo sapiensmisc_feature(1)..(196)AffymetrixID 209967_s_at
230ttcctaaaaa tgcttcactg tacgtagtta agtcgtagct ataacttcaa attttttaaa
60agggacaaac tgtaaaaaat gtgtgtattc ttaaaatgca atatttgtaa ggcttgttcc
120aatgccacat acttgcagct cccattctat gtgtcatcaa tagtgtccta tgcaataaat
180tatttgcagg tcttta
196231535DNAHomo sapiensmisc_feature(1)..(535)AffymetrixID 210027_s_at
231tgggatgaag cctttcgcaa gttcctgaag ggcctggctt cccgaaagcc ccttgtgctg
60tgtggagacc tcaatgtggc acatgaagaa attgaccttc gcaaccccaa ggggaacaaa
120aagaatgctg gcttcacgcc acaagagcgc caaggcttcg gggaattact gcaggctgtg
180ccactggctg acagctttag gcacctctac cccaacacac cctatgccta caccttttgg
240acttatatga tgaatgctcg atccaagaat gttggttggc gccttgatta ctttttgttg
300tcccactctc tgttacctgc attgtgtgac agcaagatcc gttccaaggc cctcgcgagt
360gatcactgtc ctatcaccct atacctagca ctgtgacacc acccctaaat cactttgagc
420ctgggaaata agccccctca actaccattc cttctttaaa cactcttcag agaaatctgc
480attctatttc tcatgtataa aacgaggaat cctccaacca ggctcctgtg ataga
535232358DNAHomo sapiensmisc_feature(1)..(358)AffymetrixID 210053_at
232aacgtagtta ctgtatggca ctcaaaaact atgttaaatg atccactaac tttttttttc
60ttggcccatg attaatggaa tgtatgtaac taggtagggt tcctttctta gatctagagg
120aagtacagcc acccactgac atctgaattt atatacctgt tgagttttga gtgcacccaa
180acactcgata aaccaggtga agaaatttag cttccatgtt ctacttcagc taaaacagct
240acatacaacc tagtacactt gaagtcagac agacatttca gttgcttacc tccagtactg
300agccttgctt tgggaaacta aaagatttag accaagtcac tgccagtttt tgcctttg
358233391DNAHomo sapiensmisc_feature(1)..(391)AffymetrixID 210172_at
233ggtaaatata cgttctgcat ccaaatgcac tttgagattg ttacgattta ttctgagcaa
60gatctgcatt ttttgaaagt ttgagattgt agttatcttt tttgagatga gatactttca
120cgactttggt atcatctgtc agtttttgcc cagtgagttc tgcatttgca gctccttgtt
180ttggtctgtt cgtaactgca gtgttctcca tgagtatcag gaaggtaggg tttcacttag
240gagtaagaac agtccccagt ccagcagcca cccttttcag ctgctgttca ttgccagttg
300atgaggtgag tgtcatctgc ctctctggac aggccccagt ggagaacacc gcaggtactg
360taaaccaagt acttttcaca gcgtggcctt t
391234164DNAHomo sapiensmisc_feature(105)..(105)n is a, c, g, or t
234ggttccatca atggtgagca ccagcctgaa tgcagaagcg ctccagtatc tccaagggta
60ccttcaggca gccagtgtga cactgcttta aactgcattt ttctnaatgg gctaaaccca
120gatggtttcc taggaaatca caggcttctg agcacagctg catt
164235381DNAHomo sapiensmisc_feature(1)..(381)AffymetrixID 210949_s_at
235acaaagtccg caccatgctg gttaggaaga tccaggaaga gtcactgagg acctacctct
60tcacctacag cagtgtctat gactccatca gcatggagac gctgtcagac atgtttgagc
120tggatctgcc cactgtgcac tccatcatca gcaaaatgat cattaatgag gagctgatgg
180cctccctgga ccagccaaca cagacagtgg tgatgcaccg cactgagccc actgcccagc
240agaacctggc tctgcagctg gccgagaagc tgggcagcct ggtggagaac aacgaacggg
300tgtttgacca caagcagggc acctacgggg gctacttccg agaccagaag gacggctacc
360gcaaaaacga gggctacatg c
381236545DNAHomo sapiensmisc_feature(1)..(545)AffymetrixID 211458_s_at
236aaatagcatt aaactggaat tgacagagtg agttgagcat ctctgtctaa cctgctcttt
60ctctctggtg ctcctcatct cacccctacc ttggaattta ataagcttca ggcatttcca
120attgcagact aaaaccactt ctaccatctc ctctagtatt ttccatgtat caggacagag
180atgtcttatg tagggaaggg gcaggtatga agtgaggtag attatctata cctctcactc
240attcaggatt ctcgctccca tgctgctgtc ccttcattct cacactcaca ggaatgctat
300gtgatggcca gctgcttccc ttcttggtta tccactgcag ctgctagtta gaaaggtttg
360cagggatgac ttttagtaaa tcatggggat tttattgatt tattatcact tataggattt
420tgtggggtgg gagtggggag caggaattgc actcagacat gacatttcaa ttcatctctg
480caaatgaaaa gggttcttcc tcttggggga aatctgtgtg tcagttctgt cagctgcaag
540ttctt
545237311DNAHomo sapiensmisc_feature(1)..(311)AffymetrixID 211546_x_at
237gggagttgtg gctgctgctg agaaaaccaa acagggtgtg gcagaagcag caggaaagac
60aaaagagggt gttctctatg tagtggctga gaagaccaaa gagcaagtga caaatgttgg
120aggagcagtg gtgacgggtg tgacagcagt agcccagaag acagtggagg gagcagggag
180cattgcagca gccactggct ttgtcaaaaa ggaccagttg ggcaagaatg aagaaggagc
240cccacaggaa ggaattctgg aagatatgcc tgtggatcct gacaatgagg cttatgaaat
300gccttctgag g
311238482DNAHomo sapiensmisc_feature(377)..(377)n is a, c, g, or t
238attttgctgt tacctttgtg acctgattgt tttttggaac acgtcaagac gtgggatcag
60aatcttccaa ctttagaggt gcaatggaag acactacgct acttggttga gcctggtgaa
120gaatgtatta atgagactgc tttgcataaa actgggaaga aagagaagac agttggagat
180ggaagatggt tttgtatata ttttggaact ttagttcctc tgtgagacga aagaggagag
240ctatgttttg tgtcacattg tctgatatat attgtgtaac ctgtcaggtg agttgattta
300gacaacatag ctgacctttt atgacaaggc agtttgaata gggactattg taataccctc
360acacattata ggggcancag agaatggcat ggaagagaca gtctacagag agctttaaga
420ggccggagaa aggaaaagac attatcaggg cctggaaagt ctcttccagt tcatcagggt
480ag
482239419DNAHomo sapiensmisc_feature(249)..(249)n is a, c, g, or t
239acagtgttct ctaatgttac agatgagatg cgcattgcca aagaggagat ttttggacca
60gtgcagcaaa tcatgaagtt taaatcttta gatgacgtga tcaaaagagc aaacaatact
120ttctatggct tatcagcagg agtgtttacc aaagacattg ataaagccat aacaatctcc
180tctgctctgc aggcaggaac agtgtgggtg aattgctatg gcgtggtaag tgcccagtgc
240ccctttggnt gggattcaag atgtctggaa atggaagaga actgggagag tacggtttcc
300atgaatatac agaggtcaaa acagtcacag tgaaaatctc tcagaagaac tcataaagaa
360aatacaagag tggagagaag ctcttcaata gctaagcatc tccttacagt cactaatat
419240438DNAHomo sapiensmisc_feature(203)..(203)n is a, c, g, or t
240gtgacagtta tgacaggctt accttggaag agttgtcatt tttactgcca attttttgga
60tgaagatgtt tttataaacc tttcaaaatg gtctgcaaac agagcaggaa ttgcacaatt
120aactcaataa tgctgtgtgt tctcaagaag ctcccttagt gaggccgatc ttaagatggc
180cgattctgcc cgttgaaggc atncctggga aagaaaacaa gcatcccagc gggcatctca
240ccacgacttc tcctggagtc ctcacacggt cactgacaac tacagtcagt tttaggaact
300agagtgccgt atcatcagac ttaccctgtc ctgccccacc ttccctgcta acatcgaggt
360gtgtgcagtt accttctgag cttggaacaa gcagactgga attttcctct gctacctctt
420gtgtataaaa tcttgttt
438241546DNAHomo sapiensmisc_feature(1)..(546)AffymetrixID 212591_at
241ggcccagatt gcagatggat ttcgtattag agttgatctc gcatctgaga cctcatctag
60agacaagaga tcggtttttg tggggaatct cccttataaa gttgaagaat ctgccattga
120gaagcacttt ctggactgtg gaagtatcat ggccgtgagg attgtgagag acaaaatgac
180aggcatcggc aaagggtttg gctatgtgct ctttgagaat acagattctg ttcatcttgc
240tctgaaatta aataattctg aactcatggg gagaaaactc agagtcatgc gttctgttaa
300taaagaaaaa tttaaacaac aaaattcaaa tccacgattg aagaatgtca gtaaacctaa
360gcagggactt aattttactt ccaaaactgc agaaggacat cctaaaagct tatttattgg
420agaaaaagct gttctcctta aaacgaagaa gaaaggacag aagaaaagtg gacgccctaa
480gaaacagaga aaacagaaat aacaaccagg aactgctttt tcttttcctg ctgagtactg
540ctaata
546242560DNAHomo sapiensmisc_feature(49)..(49)n is a, c, g, or t
242ctgaaggagt gtccctcctc tatgtgaaaa gaaaattgtt ttattcttnc attctgactt
60tttaancngt tnggctcact tnccagttag tttgaatgaa aataataatt ttctacttgg
120nagttgaaga gggcagaatc cgcagctctc atcattgtga tgtgtagcat gtctgccctc
180tgactggaca tcattgccat taactttctt ctgggcatca cggcaatgtc acgatgccca
240gacttggagc aaggcaacct tggagtcagt ccactcataa aatatggtaa cacccatttt
300aaaatttaag ttttgtcctt aaagacaact tcagtggtta attataaaag ttgtgttact
360tcgtcctaaa ttaaattgat agaaagattt aaaaatgtgt tttgtttcta ctattcagaa
420actgcgaact agggaaaggt tggtatgaaa aaatgtcttt ccttttttca atgtacatag
480ttcaactctt tctttgttac atttaaacta tatccatgga tatcagtctg ctttggactc
540ctctgctagt gttacagatg
560243516DNAHomo sapiensmisc_feature(47)..(47)n is a, c, g, or t
243tgcaaattaa gactcacctt cactttccaa aatagctgag ggttgtnggc ttgttgtagc
60tgaccaccaa aagcagtcac tgcaaatctt ttaattcttc cctatcacct tttgtatttt
120aatgcaatta ttttggtcca gaactgacct gtattttctg tattgtacac aaaagctaat
180aattttgtgt actttttatt tattttggag gttttatatg atcttcaatt gagtattaaa
240taatttgcct agattaagcc taaaatgatg accagctaat taaagaagat attttgaatc
300tggttctgag ctaaagttga gtaaattctt agctaagaaa aaattggaaa tccatcatct
360atattagcaa cagattctca gagtaaattg ttaacttcta tgatttatga taatcaagct
420ggacttgatc atacaagtta gtctcataat gtattggacc aaaatgtaaa cttcattggt
480cagatttaga agcattcatg ctcacaagtt ttggga
516244428DNAHomo sapiensmisc_feature(1)..(428)AffymetrixID 212714_at
244aactttaggc ttttgggcat atgctagtct gagcttccga aaagatacat atatgtttcc
60cttttcatta gctgaatgag gatattttaa gaagttgaaa gagaatttat tttcaagttg
120tgagtaaatc ctcctttgaa attcacctga ttattagata acttaaagtt tatttttaaa
180agctgacaac tttttatgaa tcttcgagtt gacagttcct aaaagcgtaa ctcagatatt
240aatgggctgt gtattaaatg gttttatttt cagttttgca gcacagaaca ctgttgaaat
300atccatatca acttgatttt tttaacctaa ttcaggtgtc ctttgcatct cttaaatgtt
360gggggtgggg gtcagagcca gttatccggc ttctgttttg tcgattgctt agatttgttc
420ctgttgtc
428245489DNAHomo sapiensmisc_feature(1)..(489)AffymetrixID 212893_at
245aattgtcctt aattaccaac agtgaagcac tacaggaggc aactgtggca ttgcttcctt
60aaccagctca tggtgtgtga atgttataaa attgtcactc agatatattt tttaaatgta
120atgttatata agatgatcat gtgatgtgta caaactatgg tgaaaagtgc cagtggtagt
180aactgtgtaa agtttctaat tcacaacatt aattccttta aaatacacag ccttctgcct
240ctgtatttgg agttgtcagt acaactcatc aaagaaaact gcctaatata aaaatcatat
300atatggtaat aatttccctc ttttgtagtc tgcacaagat ccataaaaga ttgtattttt
360attactattt aaacaagtga ttaaatttag tctgcacagt gagcaagggt tcacatgcat
420tcttttatac tgctggattt tgttgtgcat catttaaaac attttgtatg tttcttctta
480tctgtgtat
489246417DNAHomo sapiensmisc_feature(81)..(81)n is a, c, g, or t
246gtcagagcct gttcacatat tgtgatcagg tagcaatgac atgtaccact taaattattt
60tatcgtcgat ttggtagttc nattttaact actcaatgaa aacagccatg aatatctttt
120cttaaagaga gttttgaaaa tgatcactta cctaaaactt gaaagctatg aattagttat
180ccatactctc atgacaattt tgttggtgaa caacaaaaaa gagatctatt tctttaaaag
240atatttgtgc agaaactgca tgtaactcta agttttactc ctaacataca tatgtttggg
300gaagtattct attctatact tgccaatgtg gagaacaaaa tagtttttta agaatgaaga
360agtatatata tccattctgt attttacgtg cagcagaatt atcttccgta ggatttt
417247448DNAHomo sapiensmisc_feature(1)..(448)AffymetrixID 213410_at
247gacaaattac ggttgagttc tgtggcttct tcacttgaag tgctaacatc agaatcaaac
60ttaaagcttc cactatttat gtctttgaga agtatgtagt acctcggtat taacagacct
120gctgtgatgc agttacactt tcacgtattt ttgaagtatg tcaagctaca cgggtctaag
180atatgattat tttggataaa atgttacttt ggtcaagaga acttttatcc agatgacatt
240acaggttcaa gtgggttaag gagacctcct gtacatctac agtgtttcct tttaaattgt
300ccagaaaaaa ggtgtgttct tcataagctt cagtgcagga tttttcaaag acgagctgtt
360gtgcaatttg ctgtatttaa tgcatgttct gaaaggattc acttttgact ttatatgaca
420gttgatcaag aacaggtact accccttt
448248234DNAHomo sapiensmisc_feature(81)..(82)n is a, c, g, or t
248ggatgatctc aagggcacct ttgcccagct gagtgaactg cactgtgaca agctgcatgt
60ggatcctgag aacttcaagc nncctgggaa atgtgctggt gaccgttttg gcaatccatt
120tcggcaaaga attcacccct gaggtgcagg cttcctggca gaagatggtg actggagtgg
180ccagtgccct gtcctccaga taccactgag ctcactgccc atgatgcaga gctt
234249407DNAHomo sapiensmisc_feature(1)..(407)AffymetrixID 213528_at
249aactgcattc aagggagggt ccaaagaaat tcactttcaa gattataaca gtatggtgat
60tgatgaagta accttaccta atgtagtagc taactccact ttggaagatg aagaaaatga
120tgtaaatgag ccagatgtga aaagatgcag gaaaccaaaa gtaacacaac tatataaatg
180ccgatttttt tctggtgagt ggtctgagtt ttgtaagctt gtactaagta gtgaaaaact
240ttttgtaaaa tatgatctca ttctcacctc agaaaccatt tacaacccag attattatag
300taatttgcac cagactttcc ttagactgtt aagtaaaaat ggacgtgtac ttttggccag
360caaagcacat tattttggtg taggtggagg tgttcatctc tttcaga
407250406DNAHomo sapiensmisc_feature(1)..(406)AffymetrixID 213604_at
250gcaatgtcag tatccatttt ggcacataaa gatttttgat gagccctgtt tgcatagagc
60cagatgtttt cccctccccc aagagtatct acatcaggga tgtgacttgg tgcgaagagt
120caggggaaag aggaaaaacc caatttctaa atgacctcct tgcccagctt actaaaatgg
180ctgcagagca gacacaggat gaatttgaac ctgacacagg atgaatttga acctttggtc
240tcatttatgg aaaaacttgt gcaatttttt ttctgtgcta cactacatac aaatcaccaa
300attacaaatt acccttttgt gatccttggt gtactgagca gtttctttgg ggctttttct
360ttctgggaag cgggagggaa aggagcaagg tgtcatcctg ctcttc
406251466DNAHomo sapiensmisc_feature(85)..(85)n is a, c, g, or t
251aatcaaggcc tcagaatttc atacaaacac caagaccaaa atcctaagta ttggtattgc
60gtctcaaatt tttcccatta acttnaaaaa aaaaaaaagc ttaaacttac gtgccttaca
120ggttattaaa tgaaactaga attaacaaac atgccaaaat gtttcacttt taatagtaga
180cacagctcct atattgtttt acaaaaaaat aaaagcatgt ctttcaacat gcatccaaaa
240cagtgttcaa tttaacgtgg caaagggcaa catttaacat aattcaactg cttttaccta
300aatacgctta ctgcttaagt acatcctata actaacttga gaaaagctgg aacttaagtt
360taacagttat agtttactca gcttcactgt tacatcctag atgagtattg tattcaaaaa
420tactgggcct taagtcttca taacaatcct gatttccact tagagt
466252474DNAHomo sapiensmisc_feature(1)..(474)AffymetrixID 213655_at
252cttcaacgct aacctgcttc agtgggagag taaagtaggc aagaatgagc agccacggat
60tgttgaactg ttaccagcac catgcttttc agcaacattt cagcggagtt ggaaacattt
120tttacagcaa aaccattaca acgaagtccc tccccaaacc acctttaacc atctcaagct
180aacacccaat tacttgcaaa cactggtata aaacacagtt taaacaatta gaaaaatgaa
240aactgatacc acttatgcct ctatagtgtg attaacctct ctcttagatg cttgcatcac
300ctataagtct aatggctttc aaatgtaatt tccatttgct aatggtgatc ttgccacatc
360tggcacggag acgacacagt aatgctgaaa aagcctctat gtagtcctgt tagtgtctta
420aagaacctaa aagctgggac cagtaaaatc cacagaaatt cactcttgcc ttta
474253302DNAHomo sapiensmisc_feature(1)..(302)AffymetrixID 213743_at
253ttgtgtgagc tattcaaact cttcaacccc tgaacagggt attaagcttc caaaataatg
60atggggataa atatggaaat cctttttaag ttgtatttcc attaaacaaa aacccttata
120attcatacta tcatgaattt gctttatcca tctcatttgc ataacagttc atctgtctgg
180tcccattagg ctctaccaaa gaaagactct gatgagtgga cattattact gtgactcttg
240taagtagcca taaataaacc aaaatagtat caaatttagg tatgaaattc cacatgtgca
300aa
302254549DNAHomo sapiensmisc_feature(1)..(549)AffymetrixID 213788_s_at
254gtttcagtca tttccggact aactgtgaca acgcgtgagc agggagcacc gtgcgagtct
60ccgggaggga atcctcctgg ggcccagaga ctcctccacc cctggggagg gcagacaggc
120tcgggagggc ctggccaggc cactggaggc tggcagggag caggcatgtc cacccgcaag
180cctgggaggc taactctggc attcctggcc ggagccgcca tgctcattgg tgggccagtt
240tgggacatcc ccgtactcaa agaccatatg gcagcctctg ggaaaacaaa accaaaacat
300caccttctat taaactctgt atattattat tttttacaat agaaagttaa aaatcaagac
360ttagatttac tatacatttt ttctctcaga ttacaaagtt tatattatat aactggggtt
420ccctaaattg atttctttta aaacagtctt aaagagacca gaagtgaata caaaagaact
480aaacaaaata aaaaattaga atgtgctgta gctgaaagct gtctatacct gtaagcctcc
540aagtttcat
549255576DNAHomo sapiensmisc_feature(99)..(99)n is a, c, g, or t
255aaactggtca gctagagatt cttttttctt tctaagctga gcacgtagtc tgttcagagc
60ttgtttcttc cgggagtttg ggtcccccat tttgaaatnc nggtggtact aaagcctttg
120gaaattgtca ctaaactatg ggcacttttt cttaagactc aagtacaaca gaaacaagtc
180attttttttc ctgctaatat gattgattag cgaaaatcac gactataacc caaaaactgc
240accttctgtc aatattagca gactgtcata ttacagggtc aagaaacaaa agctgctgtc
300cagtcatgtt tggacaataa cgtttggggt cagacgggaa aaagggagga aagaaaggaa
360agaaagagga gaaaataact aactttctgg aaaacacatt tggcttaact gccaaaataa
420aggctttgcg gagaaatgaa aagcctataa tcaggattta ggtgtgcaat aaaacacagc
480tgacaccaga ccaatcccta aaatccatcc ggattttccc ccctttttag aaaagggatt
540aaggaacagg gagggggaag tgtgatcctt gctttc
576256380DNAHomo sapiensmisc_feature(1)..(380)AffymetrixID 213979_s_at
256aaatggttac agtcacaaac atgattttaa ccaaaatatt gctagcctac cacatcagca
60ggacggcact ggtgcaggcg gggacgctgc caccctccac gtccccagga cagacgtcga
120tgggcagcgg gcacgctggg caccgcccaa gcttttcctt ttggagctgc ttcgtgatgc
180cgtcttcatt tggaacaagg gggggttcat gccaaaatta ggaaaaacag cctttgtttt
240gtttttctaa attattctaa aaataagaca agcaggtaga aaaaacaatg cactgtgtgg
300cataaaaaga aaaacgggaa ggattcattg tcctgagaag tttgccaact gcctcattct
360ggggcacgtt ccaacataca
380257371DNAHomo sapiensmisc_feature(1)..(371)AffymetrixID 214257_s_at
257attataacct gggcctgcct ttgttctcat gaagccaggg gcctctccat atcctatact
60tgctcttacg ctaataacaa accaaatgct gcaaaataaa agtaataatg acccaaacta
120atttaagtct tttgtttaag gagtaaatga gagaaacatt ttagcttctt aatcaaggag
180tgctataatt tcaaggcatc ttaatataat tcacttaccc taaagcaatt gtgcaataag
240caaattataa aaggaaaaca acaaaggtta actttctaca ggggccaata gacaagatct
300gtggagcaca gcaattaacc ttcacatact ggagtcttgt ttaaaaggcc atcaaaaact
360cagattactg a
371258244DNAHomo sapiensmisc_feature(74)..(74)n is a, c, g, or t
258tcaacttcaa gctcctaagc cactgcctgc tggtgaccct ggccgcccac ctccccgccg
60agttcaaccc ctgnggtgca cgcctccctg ganaagttcc tggcttctgt gagcaccgtg
120ctgacctcca aataccgtta agctggagcc tcggtagccg ttcnnnnnnc nngctnggcn
180ntccaacggg ccctcctccc ctccttgcac cggcccttcc tggtctttga ataaagtctg
240agtg
244259519DNAHomo sapiensmisc_feature(118)..(118)n is a, c, g, or t
259gagtatacat cggtgcaggc ttcctggatg acagttgggt gatatgtgtc atgtggccta
60aaagcctcca tgtcatttga cctacgaatt ctatctttgg gaatttatcc taagaaanta
120cttanggatt tanttngtga taagatgttc atcccagcat tgcaatggag aaaaatggga
180agcaatggtt tggttgggaa tttattcctt ttctgctgta acgaaagttt gcaatagggg
240attgcttaag taaattattg tatctccatc cagatggtgg agtaccgcgc agacattaaa
300agtcatgtaa aagaacatct gactgaaaga aaaatgctcc ttgaatatta aaaggttgta
360aaaatagtgc atgttatgtg atttcaattt tgttttttaa aatatgggtg tatgcttgta
420tacgtagagc agataaaaaa gacggaaggc atactaaaaa atgttgagtg gttatctttg
480tatggtggaa caaagtcact gtaattttca tctttggtt
519260399DNAHomo sapiensmisc_feature(45)..(45)n is a, c, g, or t
260aatctttcct ttccctgatg aagacagctg gtggccgagt gcggnaanga agccagaagg
60aaccagaatc ccagngccct acacccacca ccagacacac tcacacccac acacgttctc
120agacacacac aagagtgctt gccggttata ccaaacccta ctattactgc ctgcagaaat
180caatttaaaa aaataataat aacaataaac aattttaaaa aggacaaaaa aattaatgat
240tgagaaaaga ggcatttttt tctgacattt ggtcctgctt gaaacaacaa aagaagaaga
300aaaacccacc atcaccaccg attcctttgc ttcttttttc cttttttcct accttgtttg
360aaaaccgtgg gcttgggact gtgaattatt gcatgacat
399261202DNAHomo sapiensmisc_feature(1)..(202)AffymetrixID 215043_s_at
261cagtctttcc cagggaactc cgatgaagtg ttccaacaaa atgagcgagt gaaccaagaa
60gaggatgaca ttagatccag gagatacaac agaggagata atctccagga tgcctgtgaa
120gaaagatccc tggatcccag gatgattata ggacaagttg ttcataatcc agcaggccag
180aagacttcca gggaaactca tt
202262501DNAHomo sapiensmisc_feature(37)..(37)n is a, c, g, or t
262ggacagttcc tgtgatcaga ggcaagattt gcccagngaa cagaataaag gtgcttcttt
60ggatagctct caatgttcgc cctcccctgc ctcccaggaa gaccttgaat cagagatttc
120agaggattct gatcaggaag tggacattga gggcgataaa agctatttta atgctggatg
180atgaccactg gcattggcat gttcagaaaa ctggatttag gaataatgtt ttgctacaga
240aaatcttcat agaagaactg gaaggctata taagaaaggg aatcaattct ctggtattct
300ggaaacctaa aaatatttgg tgcactgctc aattaacaaa cctacatgga gaccttaatt
360ttgacttaac aaatagttta tgtactgctc ttaggttgtt ttgataaagt gacattatag
420tgattaaatt ctttccnctt taaaaaaaca gntagtggtt ttcactattt ataaatagga
480ccttcttgaa cgacttttct g
501263502DNAHomo sapiensmisc_feature(1)..(502)AffymetrixID 216199_s_at
263ctggagtctg gggtgtgttg tcatagagat ggtgactggc aaggtttgca cagatgaaga
60atgaagccta gtagaatatg gacttggaaa attctcttaa tcactactgt atgtaatatt
120tacataaaga ctgtgctgag aagcagtata agccttttta accttccaag actgaagact
180gcacaggtga caagcgtcac ttctcctgct gctcctgttt gtctgatgtg gcaaaaggcc
240ctctggaggg ctggtggcca cgaggttaaa gaagctgcat gttaagtgcc attactactg
300tacacggacc atcgcctctg tctcctccgt gtctcgcgcg actgagaacc gtgacatcag
360cgtagtgttt tgacctttct aggttcaaaa gaagttgtag tgttatcagg cgtcccatac
420cttgttttta atctcctgtt tgttgagtgc actgactgtg aaacctttac cttttttgtt
480gttgttggca agctgcaggt tt
502264158DNAHomo sapiensmisc_feature(1)..(158)AffymetrixID 216202_s_at
264gttcacaaag agttttggtg cttctggagg atatattgga ggcaagaagg agctgataga
60ctacctgcga acacattctc atagtgcagt gtatgccacg tcattgtcac ctcctgtagt
120ggagcagatc atcacctcca tgaagtgcat catggggc
158265490DNAHomo sapiensmisc_feature(1)..(490)AffymetrixID 216996_s_at
265gctgcatact ttggatactt gtctaaaact tgatgatact gtctatctga gggacatagc
60cttgtcactc ccacagctgc cgcgggagct gccatcgtca catacaaatg caaaggtggc
120agaggtgctg agcagccttc tgggaggtga aggacacttc tcaaaggatg tgcacttgcc
180acacaattat catattgatt ttgaaatcag aatggacact aacaggaatc aagtgctacc
240actttctgat gtgatacaac ttctgctaca gatattcaaa gagtagctgt gctatgtgtt
300tccagatctg cttattgttt gggttcaagc caccccagag gattccttgc tatgaaaatg
360cggcatttga atgcaatggg ttttcatgtg atcttggtca ataactggga gatggacaaa
420ctagagatgg aagatgcagt cacatttttg aagactaaaa tctattcagt agaagctctt
480cctgttgctg
490266374DNAHomo sapiensmisc_feature(315)..(315)n is a, c, g, or t
266aatgctcacc aaattcacag gaaagaagtg cctaggtgat catttactgc tatttactgc
60ttcctggtat ggagcaaaat tgccctctgg taggtaacta catttctaat tagtatgaaa
120ggttctacta ttttcctttc ttttgcttat ttccccttaa gcacaatttg cagaccctac
180ttctatttaa ctgatcatac ccttttaaat gccttgtcat catttttcat agttcctgca
240tcctagaaaa aataaaaaat catttaaaat attccttggt gtctagaaaa gaaaatttct
300ctaacaatag agatnatcat tttgctttct cacttaagct gatctgaatg atgatttggt
360actgccttta tgag
374267462DNAHomo sapiensmisc_feature(119)..(119)n is a, c, g, or t
267cacgaggtca atttatggtt atcaaatagg tttttttttt tttttttgag actgagtgtc
60gctctatagc ccaggctgga gtgtagtgct cactgcgact tccgcctcct gggttcaant
120gattctcgtg cctcagtctc ccgagtagct gggattgtag gcgcctgcca ccacgcccag
180ctaatttttg tatttgtagt agnnatgggg tttcatcatg ttggcgaagc tggtcttgaa
240cacctgacct caagtgatct gccttagcct cactgcttgc ccctangtgg tgggattgca
300ggtgtgagcc actgtgctgg cctcaaatag tttttatcaa agctacttca attagtggtt
360agcaaggctt aaagactaat tcagtgcttt attttgacac ttgttcgcaa catgttgctt
420tttttcctgt gtcctatggg acctagtcat ctgtatgtta ga
462268482DNAHomo sapiensmisc_feature(1)..(482)AffymetrixID 217840_at
268gccatccagc acgtcatcaa ttatgacatg ccagaggaga ttgagaacta tgtacaccgg
60attggccgca ccgggcgctc gggaaacaca ggcatcgcca ctaccttcat caacaaagcg
120tgtgatgagt cagtgctgat ggacctcaaa gcgctgctgc tagaagccaa gcagaaggtg
180ccgcccgtgc tgcaggtgct gcattgcggg gatgagtcca tgctggacat tggaggagag
240cgcggctgtg ccttctgcgg gggcctgggt catcggatca ctgactgccc caaactcgag
300gctatgcaga ccaagcaggt cagcaacatc ggtcgcaagg actacctggc ccacagctcc
360atggacttct gagccgacag tcttcccttc tctccaagag gcctcagtcc ccaagactgc
420caccagtcta cacatacagc agccccctgg acagaatcag catttcagct cagctggcct
480gg
482269492DNAHomo sapiensmisc_feature(1)..(492)AffymetrixID 218229_s_at
269gacctcacag acaaagccat tgctagaaat gtcattccaa tgatcagatc tggaaacagg
60ctgccataac cacttttcct tcttgtagac tcagctcacc tgtatattta aactgttctt
120ggcatcttga aacacctatt tctactcagg tactcattgt cctgttactg attcaccttt
180ctgatccttt tcaaccagtt ttcccccaag gggggaaatt ttacttaacc tctagtattt
240gaacaactca atatttgaat tgttgcccca tttgctttta cctgtactgt attcttggtc
300atctcaaatg gcgtctaaac ccagctactt tgcattccag aagtttccat tccctccaat
360tccacctaat ttttcatctg tcctagttac tggctctttc ttcatgtctt atttctcttg
420ctttgggagc ttaaaagatt ttacaagacc taattttggg ttccttcctt ggagccatag
480ttaccctgcc aa
492270177DNAHomo sapiensmisc_feature(1)..(177)AffymetrixID 218356_at
270ctgaaatttc catctgggga ttaacttctg tctttctggt gaacaatata gcaattcacg
60cattcttcaa gcagcaaaag ttcccggaac aattagggaa gacgtatggt ctgaatttat
120ccaggcagtg ggtctgcttt ggtttttgct ggaaatttat atcagtgtct gggctcc
177271453DNAHomo sapiensmisc_feature(1)..(453)AffymetrixID 218432_at
271gaaactatgt gactcattct gtgaaaagac ttcttgcagt tgtgagttat ttagaaatga
60tcaaaatttg taattaggct aatccattta gtgattccta atattttgta ctcacagaga
120actaattgac taaacaactt gaacgctagt ggtttgtcct tagacaatct gtctttgaat
180ttaaagtctt tatcgctaag accttgactt taaatttttc atcactacaa ccttgaattt
240aatttcaggt cttcaacatg atgaccttgg atttaattta aagtcttcaa cactatgcgc
300tttatcatat tattcacaga tgcatttttg aaatgtagta tgtaaaagta tgtaacgtgc
360tgtttattaa caaaagattg ttcacaacat ctcatgtagt ttaaatttgt aaatactgct
420tctgttttgt ttctccttta tacacttgac tgt
453272557DNAHomo sapiensmisc_feature(1)..(557)AffymetrixID 218589_at
272gggtaacaat gcctcagaag cctgctttga aaattttcca gaagccacat ggaaaacata
60tctctcaagg attgtaattt tcatcgaaat agtgggattt tttattcctc taattttaaa
120tgtaacttgt tctagtatgg tgctaaaaac tttaaccaaa ccagttacat taagtagaag
180caaaataaac aaaactaagg ttttaaaaat gatttttgta catttgatca tattctgttt
240ctgttttgtt ccttacaata tcaatcttat tttatattct cttgtgagaa cacaaacatt
300tgttaattgc tcagtagtgg cagcagtaag gacaatgtac ccaatcactc tctgtattgc
360tgtttccaac tgttgttttg accctatagt ttactacttt acatcggaca caattcagaa
420ttcaataaaa atgaaaaact ggtctgtcag gagaagtgac ttcagattct ctgaagttca
480tggtgcagag aattttattc agcataacct acagacctta aaaagtaaga tatttgacaa
540tgaatctgct gcctgaa
557273500DNAHomo sapiensmisc_feature(1)..(500)AffymetrixID 218604_at
273tttgttttat tgtatgcgtt gggtttgcag catgaacttg cacagataat gcacgttttc
60tggttaagta aacatgatgc acactattct gtaacagaaa gccctattgt gccttacctg
120tgtgcttttg tgggcacctt gtttatgaag aataaaaaat gatttgttat ctgaagagaa
180taaattttaa attctcagtt tatgtctcag atgctaacgt gtgaaaatat aaatatatat
240aatatataaa gtaaccagtc ttcctgtatt ttatgtgcat catagtgatt tatctgagct
300tagtgacccc catcttgtaa cctgttgcaa gagtgaatgt aaaaaatagt tgtggcattt
360taaaaggtcg cctttgatgc agatgcatct ttttcttgct tctaaaacat atttcatgta
420aacattgtac atttattatt gtaatatata ctattatgca gcttatttta cctgaaactg
480ttaagccgac caagatccct
500274558DNAHomo sapiensmisc_feature(1)..(558)AffymetrixID 218689_at
274cctgggtgtt ccacagctga tagtgattgc cttgaataaa ttcaagggca atttattcat
60ttttactagg gagatagacc tttacagcaa tcaagatatt tttgtccata tccaggttag
120ctggtaagag gatttttttg gagaaaaaaa atgatattta gaaagttaat ttctaattcc
180ggaatggaat aaaaacaata tgagtagtgt aatcttgtag aaaaagagtt gtataatctt
240gtagaatttc tcattctgtg gtacaaccca ggggtaaact attattccag tagtcagtac
300acttttctag ataaatcttg agtgaaaacc agcaatttct ttttccttgt ggtctgattc
360ctttttctaa tccatgaagg ccatcttgta gattacattt atcattaatg caagaataaa
420gacaattcct cctgtcagtt gcgtgaattt tttttaagaa acaacccagt gaagagttct
480accatagcaa ggcctaatgt tagctttagc tttagaaaat aacagtttgt gaacttactt
540ccctatattt gcagctgt
558275385DNAHomo sapiensmisc_feature(1)..(385)AffymetrixID 218889_at
275gcttgtattc aggttcattg gcttttgctg gatgatccac ctaaagaagt tacctaattt
60ggccttttaa aaaaggtgtt agtgtttatt atagctactt tcaaggaaag tttgaatatg
120attctagtct ctaaagttct tcacgttttc tgacattccc tggagggtga ctggggaaga
180attgctccag ggtagaagaa ccaggcccaa gactttacca ttctgatcta gagacaaagg
240atactcaatg aggagctttt ttcccctctt ggaacaggta aaatgctttt tcttattaat
300ataattataa aacagtattt tatgtaacag ctattcccat attctaggag tggcctaaga
360aatgcgtgtt tcagtgacta gatta
385276554DNAHomo sapiensmisc_feature(1)..(554)AffymetrixID 218973_at
276ctgcaagtga aacctcagcg cctgatggca gctatgtaca catgtgacat catggccact
60ggtgatgttc tcggtcgagt ctatgctgtc ttgtcaaaga gagaaggtcg ggtacttcaa
120gaagaaatga aagaagggac agacatgttc atcatcaagg ctgtgctgcc tgttgctgaa
180agctttggtt ttgctgatga aatcaggaag aggacaagtg gcctggccag cccacaacta
240gtattcagcc attgggagat cattcccagt gaccccttct gggtgccaac tactgaggag
300gaatacttgc actttgggga gaaggctgac tctgagaacc aagcccggaa gtacatgaac
360gcagtacgaa agcggaaggg gctttatgtg gaagaaaaga ttgtggagca tgcagaaaag
420cagaggacac tcagcaaaaa taagtagcta cctactactg gtggattctt ttccttatag
480tgaatttaaa agtatcatca agggtttaat attgggaaaa tttctttttg ccacattatc
540tctgtttatt cact
554277262DNAHomo sapiensmisc_feature(1)..(262)AffymetrixID 219069_at
277gaatattgta tactgcatcc cctaccacaa tttacacaat cctgtggata gtcctacctc
60accctggtca acctacatga tccttaagct aatggcgaat cacgatgacc ttgtagacat
120gcacacaact atacctttgt ccaacagatc ataatatatc tgctatccaa ctggttttac
180ctgcctaatc ctactgattt gggcactgct tgtatagtct ctcaagttca caggaaatgt
240tgattttcta aggtcctcat tt
262278490DNAHomo sapiensmisc_feature(1)..(490)AffymetrixID 219093_at
278tagagaccca tgtcatctta acctaaaggg aaatcttatt gcgttatcat aaaattgatg
60atatcttagg gtcagaattg cccttttttt tattttgaat gggaagctct cactaaaaca
120atcctgagat ttcttaattt catggttctt taaatattat aaacacagag tcaacataga
180atgaaattgt atttgttaaa atacacacat tggaggacaa gagcagatga ctacttttcg
240aagtaatgct gctccttcct aaaagtctgt tttcaatcct ggtaatatta ggggcactgc
300ggcacctaag aagccttaaa tgagagctaa tccaatttag agagcgatgg tgtcagcatt
360tcggtctgca tatctgtgtg tccgtatctg cgtttgtgtg cgtgtacgtg tgcccctgtg
420tgtgggccca gttttcaggc atgtagaata agcatggagt catattgagg aggactcact
480tcttgaagat
490279442DNAHomo sapiensmisc_feature(1)..(442)AffymetrixID 219099_at
279aatggactga ctgaaactcg ctaaggttaa atctgcatca aaatctaacc aatttgagcc
60tctgaaggga gtgccattgg ctttatttac ttctctcctc tgctagtcct gatttggaaa
120cagttaaaag ccaattttta gctccagtgg aaccatagcc acataaaact ttaatggaca
180accatataga attaacttat tttgtccaag tacagttggc attttccaga ataattttac
240caccctgcta gatgtcatct ctggattgca catggatgat gaaggaactc agcattgaaa
300gttgggggat tagtaacctt gttacaacgg tttctttttc attttagcct attttaatgg
360ctattggtaa gatactgtat gtttttagta tctcatccag tgcttagaag aaagaatggt
420ttataattcc cagtacatgt tt
442280454DNAHomo sapiensmisc_feature(1)..(454)AffymetrixID 219176_at
280caacaggagg catctccatt tactatgatg agaaaggaag gaagtttgtt aacatcctga
60tgtgcttttg gtatctaacc agtgccaaca tccccagtga aactttaaga ggagccagtg
120tattccaggt taagttgggg aatcagaatg tggaaactaa acaacttctt agtgcaagct
180atgagtttca gagggagttc acacaaggag taaagcctga ctggaccatt gcacggattg
240aacactcaaa attattagaa taattttctt ggaaaaatca gcttatggac tttagcagtt
300gctgtgaaaa actaaggaag aaaaattttg gggtcatttg atcttcactt aatctaagtc
360tgtgaattac ttttatatta ttttgaaata ctccttgcag tatattggca tgatacagta
420aaagcatttt ccacagattg ttatcacctt cttt
454281517DNAHomo sapiensmisc_feature(1)..(517)AffymetrixID 219243_at
281tcttctagat tctctctatg ttggcagata atctcccctt gtagcttcca ctcacttatt
60cttgcattca gagtcacaat gatcatctta cccatgtggt ttttgagaaa gaaagatcaa
120ttctttgttt gcagtgggta atcttagaga tggagatgat tgtagaatta ttcctagatg
180agtgtcaatt tatttaattc cattgtcata taaggagtca aattgtttct tatcatttgt
240tcattgaaga acagagacct gtctggaaaa tcgatctcta caaattcaat taaataatga
300tccccaaatg ctgaaaaagt gaaatacagc aattcaacag ataatagagc aatgtttagt
360atattcagct gtatctgtag aaactctttg acgaacctca atttaaccaa tttgatgaat
420acccagttct cttcttttct agagaaagat agttgcaacc tcacctccct cactcaacac
480tttgaatact tattgtttgg caggtcatcc acacact
517282501DNAHomo sapiensmisc_feature(1)..(501)AffymetrixID 219363_s_at
282tggtcagaaa agcaccattt ttgctgaact tttcagtgga aagactggat aaccagattg
60gattttttca gaaggaactg gaacttagtg tgaagaagac tagagatctg gtagttcgtc
120tcccaaggct gctaactgga agtctggaac ccgtgaagga aaatatgaag gtttatcgtc
180ttgaacttgg ttttaaacat aacgaaattc aacatatgat caccagaatc ccaaagatgt
240taactgcaaa taaaatgaaa cttaccgaga cgtttgattt tgtgcacaat gtgatgagca
300ttccccacca catcattgtc aagttcccac aggtatttaa tacaaggctg tttaaggtca
360aagaaagaca cttgtttctt acctatttag gaagagcaca gtatgatcca gcaaaaccta
420actacatctc tttggacaaa ctagtatcta ttcctgatga aatattttgt gaagagattg
480ccaaagcatc agtacaggac t
501283467DNAHomo sapiensmisc_feature(1)..(467)AffymetrixID 219434_at
283ccatgatcat ggtttactgc gcgtccgaat ggtcaacctt caagtggaag attctggact
60gtatcagtgt gtgatctacc agcctcccaa ggagcctcac atgctgttcg atcgcatccg
120cttggtggtg accaagggtt tttcagggac ccctggctcc aatgagaatt ctacccagaa
180tgtgtataag attcctccta ccaccactaa ggccttgtgc ccactctata ccagccccag
240aactgtgacc caagctccac ccaagtcaac tgccgatgtc tccactcctg actctgaaat
300caaccttaca aatgtgacag atatcatcag ggttccggtg ttcaacattg tcattctcct
360ggctggtgga ttcctgagta agagcctggt cttctctgtc ctgtttgctg tcacgctgag
420gtcatttgta ccctaggccc acgaacccac gagaatgtcc tctgact
467284354DNAHomo sapiensmisc_feature(1)..(354)AffymetrixID 221485_at
284aatgtgacct tgtgcatata ttggtagctg aaaatcttca aggctactga tgggtggccc
60cttaatcttg tctttgattg ctgtgtgcag ggaaaggtgt ccccgtttgt tcatgctgtt
120ttggggggtg ggggggtatt tgcaagaata ctcattttga cataataggt cctcttgtca
180gagatcctct accacagaca ttaatagctg agcaggagcc acatggattg attgtatcca
240ctcaccattg acgatggcat tgagcgtagc tagcttattt ccatcactac gtgtttttga
300gcttgctctt acgttttaag aggtgccagg ggtacatttt tgcactgaaa tcta
354285465DNAHomo sapiensmisc_feature(1)..(465)AffymetrixID 221652_s_at
285ggccagtgtc gttattatcc ttgtggagaa tagaatcaat actgccaatt ccagaaaaca
60tcaggaattt gctggacgtt tgaactctgt taataacaga gctgaactat atcaacatct
120taaagaggaa aatgggatgg agacaacaga aaatggaaaa gccagccggc agtgaagagt
180gacttgaaga actaaattta gcatattgca aaaatatttt gtgcggaatt cgatataagt
240acttttacag caagatggta tagttatgtt gcctggactg gtttttacat ttttaaaata
300tttcagctgt catttttgta ctaattataa aattggcaca taattcaaaa atatacattt
360gagatgattt gtcctcccaa attatacaag tttattttat ggtataaagt gttctctctg
420gaaatgtttt taaaaaaatt cttaggcttc tctttgcgaa ataaa
465286392DNAHomo sapiensmisc_feature(81)..(81)n is a, c, g, or t
286ggagcctcat ggagtcaggt gccaacaagc tgcaggagga ggtgctgatc caggagtggt
60tcaccctggt caacaagaag nacgctctca tcnnnannca nnnccngcnn cnnnnnnnca
120tggaggagca ggacttggag cgaaggttcg agctgctgag ccgcgagctg cgggccatgc
180tggccatcga agactggcag aaaacgtccg ctcagcagca ccgagagcag ctcctactgg
240aggagctggt gtcgctggtg aaccagcgcg atgagctagt ccgggacctg gaccacaagg
300agcggatcgc cctggaggag gacgagcgcc tggagcgcgg cctggaacag cggcgccgca
360agctgagccg gcagttgagc cggcgggagc gc
392287488DNAHomo sapiensmisc_feature(101)..(101)n is a, c, g, or t
287gcgaaaatgc tactatgact cttcctggaa tacacccacc taccttgaac cagattatgg
60attggatatg tctacttctg gatgcgaatt ttactgttgt ngtaatgatg ccagaagcaa
120agaggctact gataaatctt tacaagcttg taaaatctca gatatctgtt tattctgagc
180tcaacaagat tgaagtaagt tttcgggagc tacagaaatt aaatcaagaa aagaataata
240gaggattata ttcaattgaa gtgctggagc tcttctgata ttatcaattc tccttcatag
300acattttata aagctctttt atgtgaactc ttgcttcatc caggcaagaa cggtgttttg
360tttgcgacca tctcagtgtc aagagaaacg tgtcagtgag tacctggacc atcacttaac
420tgatgctccg gggtaggact gcaggtttca catgaacctg ttntaggctg tggacattgg
480tgtggaga
488288462DNAHomo sapiensmisc_feature(1)..(462)AffymetrixID 222127_s_at
288ctcgctgtta tcctggatct ggtgttacaa tggaattcac tattcaggac attctggatt
60attgttccag cattgcacag tcccactaaa ccttgtgaaa gaagaaaaga taactgaatg
120aagcatttga gtataacaga cactatacca aaataccaag caactgtttt gagaacccag
180acttaaaatt ttatgtatta ttaaatgtta gataaatggg tagtaccata ctacaaatat
240ttaaatgcaa aattaccaac ctatatagca gttttatttg ccctataggt tgcatactaa
300cttaagcatt catgtcacca taaaatgcct ttagcatttc tcaatgactg gatgggaaat
360tttcctttat tgcctagctg cttgtgtttg agtggttgtc ctatgagcaa tgcatttgga
420gttcttcagc tttcactact tctctgttgc ttgctaatca tg
462289535DNAHomo sapiensmisc_feature(39)..(39)n is a, c, g, or t
289ttgcacggat ctaagttatt ctccccagcc agagcccgng ctnnctgctc ccngggaaaa
60gntggcgtan tggncctgag ctgggnttta tattttatat ctgcaaataa atnacatttt
120atcntanatt tagggaaagc cngagagnaa caacaaaaaa tgtttaagcc nnnnnnnnnn
180nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
240nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
300nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
360nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn
420nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnnnnnnn nnnnntattg cccggctcct
480agaatttatt tatttcctga cttacagcaa gcgagttatc gtcttctgta ttttg
535290494DNAHomo sapiensmisc_feature(124)..(124)n is a, c, g, or t
290ccactctatg agttggactt cagtcttgcc taggcgattt tgtctaccat ttgtgttttg
60aaagcccaag gtgctgatgt caaagtgtaa cagatatcag tgtctccccg tgtcctctcc
120ctgncaagtc tcagaagagg ttgggcttcc atgcctgtag ctttcctggt ccctcacccc
180catngcccca ggcccacagc gtgggaactc actttccctt gtgtcaagac atttctnnnn
240nnnnnnnnnn nnnnnnnnnn nnactccatg caggggtcag tgcagcagag gacagtctgg
300agaaggtatt agcaaagcaa aaggctgaga aggaacaggg aacattggag ctgactgttc
360ttggtaactg attacctgcc aattgctacc gagaaggttg gaggtgggga aggctttgta
420taatcccacc cacctcacca aaacgannnn nnnnnnnnnn nnnngtcctt tctggaagtt
480tctggtgcca tttc
494291258DNAE. colimisc_feature(1)..(258)AffymetrixID AFFX-BioB-M_at
291gccggagttt tacggcaata tcatcaccac acgcacttat caggaacgcc tcgatacgct
60ggaaaaagtg cgcgatgccg ggatcaaagt ctgttctggc ggcattgtgg gcttaggcga
120aacggtaaaa gatcgcgccg gattattgct gcaactggca aacctgccga cgccgccgga
180aagcgtgcca atcaacatgc tggtgaaggt gaaaggcacg ccgcttgccg ataacgatga
240tgtcgatgcc tttgattt
258292276DNAE. colimisc_feature(1)..(276)AffymetrixID
AFFX-r2-Ec-bioC-3_at 292cgctggtgca gggatcgtta cccgaacgtc atcaggcgtg
gcaggcggtg gacgagcgtc 60cgcatgctaa tcgcttttta ccgccagatg aaatcgaaca
gtcgctgaac ggcgtgcatt 120atcaacatca tattcagccc atcacgctgt ggtttgatga
tgcgctcagt gccatgcgtt 180cgctgaaagg catcggtgcc acgcatcttc atgaagggcg
cgacccgcga atattaacgc 240gttcgcagtt gcagcgattg caactggcct ggccgc
276293462DNAHomo
sapiensmisc_feature(1)..(462)AffymetrixID 204018_x_at 293ggtccccaca
gactcagaga gaacccacca tggtgctgtc tcctgccgac aagaccaacg 60tcaaggccgc
ctggggtaag gtcggcgcgc acgctggcga gtatggtgcg gaggccctgg 120agaggatgtt
cctgtccttc cccaccacca agacctactt cccgcacttc gacctgagcc 180acggctctgc
ccaggttaag ggccacggca agaaggtggc cgacgccctg accaacgccg 240tggcgcacgt
ggacgacatg cccaacgcgc tgtccgccct gagcgacctg cacgcgcaca 300agcttcgggt
ggacccggtc aacttcaagc tcctaagcca ctgcctgctg gtgaccctgg 360ccgcccacct
ccccgccgag ttcacccctg cggtgcacgc ctccctggac aagttcctgg 420cttctgtgag
caccgtgctg acctccaaat accgttaagc tg
462294323DNAHomo sapiensmisc_feature(1)..(323)AffymetrixID 222043_at
294tcgactctgc tgctcatggg aagaacagaa ttgctcctgc atgcaactaa ttcaataaaa
60ctgtcttgtg agctgatcgc ttggagggtc ctctttttat gttgagttgc tgcttcccgg
120catgccttca ttttgctatg gggggcaggc aggggggatg gaaaataagt agaaacaaaa
180aagcagtggc taagatggta tagggactgt cataccagtg aagaataaaa gggtgaagaa
240taaaagggat atgatgacaa ggttgatcca cttcaagaat tgcttgcttt caggaagaga
300gatgtgtttc aacaagccaa cta
323295540DNAHomo sapiensmisc_feature(1)..(540)AffymetrixID 206026_s_at
295tacaagtact acttctactg gaaataaaaa ctttttagct ggaagattta gccacttata
60aaaaaaaaaa aggatgatca aaacacacag tgtttatgtt ggaatctttt ggaactcctt
120tgatctcact gttattatta acatttattt attatttttc taaatgtgaa agaaatacat
180aatttaggga aaattggaaa atataggaaa ctttaaacga gaaaatgaaa cctctcataa
240tcccactgca tagaaataac aagcgttaac attttcatat ttttttcttt cagtcatttt
300tgtatttgtg gtatatgtat atatgtacct atatgtattt gcatttgaaa ttttggaatc
360ctgctctatg tacagttttg tattatactt tttaaatctt gaactttatg aacattttct
420gaaatcattg attattctac aaaaacatga ttttaaacag ctgtaaaata ttctatgata
480tgaatgtttt atgcattatt taagcctgtc tctattgttg gaatttcagg tcattttcat
540296101DNAHomo sapiensmisc_feature(1)..(101)AffymetrixID 208894_at
296cgatcaccaa tgtacctcca gaggtaactg tgctcacgaa cagccctgtg gaactgagag
60agcccaacgt cctcatctgt ttcatagaca agttcacccc a
101297491DNAHomo sapiensmisc_feature(1)..(491)AffymetrixID 222150_s_at
297taatcttgct cattaacctt actcctttga gaattcttta acaatattta aaattggtaa
60caaaaatagt ttagccataa ttgtttagcc atgtgagttt caggttggta cacgttcaga
120cagaactgct gtatcacatt ccaattttga atagccagtg agcaatcaag tgtagagaaa
180tgataaatgg cctaagaagg catacagtgg cataaacgat gctcttccta gtagcttaat
240aggccacaag ctagtttctg ttgccctctg aaataaaata tgctttaaaa atgtagggac
300cagtgcttag aaaagcaaaa actaggtgtg tcattgaaat aataggcata aaaattaaat
360gttacataag acccctattt ggaaaaaggg tccttttaaa aactgaattt gtactaaatc
420agatttgcca tgtccagtac agaataattt gtacttagta tttgcagcag ggtttgtctt
480tgtgaattca g
491298485DNAHomo sapiensmisc_feature(1)..(485)AffymetrixID 207113_s_at
298ccagaactca ctggggccta cagctttgat ccctgacatc tggaatctgg agaccaggga
60gcctttggtt ctggccagaa tgctgcagga cttgagaaga cctcacctag aaattgacac
120aagtggacct taggccttcc tctctccaga tgtttccaga cttccttgag acacggagcc
180cagccctccc catggagcca gctccctcta tttatgtttg cacttgtgat tatttattat
240ttatttatta tttatttatt tacagatgaa tgtatttatt tgggagaccg gggtatcctg
300ggggacccaa tgtaggagct gccttggctc agacatgttt tccgtgaaaa cggaggctga
360acaataggct gttcccatgt agccccctgg cctctgtgcc ttcttttgat tatgtttttt
420aaaatattat ctgattaagt tgtctaaaca atgctgattt ggtgaccaac tgtcactcat
480tgctg
485299491DNAHomo sapiensmisc_feature(1)..(491)AffymetrixID 205067_at
299agctgtaccc agagagtcct gtgctgaatg tggactcaat ccctagggct ggcagaaagg
60gaacagaaag gtttttgagt acggctatag cctggacttt cctgttgtct acaccaatgc
120ccaactgcct gccttagggt agtgctaaga ggatctcctg tccatcagcc aggacagtca
180gctctctcct ttcagggcca atccccagcc cttttgttga gccaggcctc tctcacctct
240cctactcact taaagcccgc ctgacagaaa ccacggccac atttggttct aagaaaccct
300ctgtcattcg ctcccacatt ctgatgagca accgcttccc tatttattta tttatttgtt
360tgtttgtttt attcattggt ctaatttatt caaagggggc aagaagtagc agtgtctgta
420aaagagccta gtttttaata gctatggaat caattcaatt tggactggtg tgctctcttt
480aaatcaagtc c
491300356DNAHomo sapiensmisc_feature(1)..(356)AffymetrixID 201290_at
300gaacacacgt gttggtgctt ctgggtagca ctggtttgca ttagtttatg tttccatgcc
60agagtttgtg tgggcgggcg catgtgcacc acagagtgca ctcgagggga ctttcagtca
120caggatttca taattgtcat tgtcacactt tcaaattttt gtacatcagt gaattttttt
180atattaaaag gttgagccaa aaagccccca gtgtttgtat tttgaagcca agcttcactt
240ctaaagtgcc tacagagact tgtaaatgaa aatgcagctc tgcacgagtt tgaaaccgtc
300atacctcctt ctattaggaa tggcatatac tgaggtggtc gtaagtctta acttct
3563014666DNAHomo sapiensmisc_feature(1)..(4666)CD11c full-length n.t.
301agtaccttgg tccagctctt cctgcaacgg cccaggagct cagagctcca catctgacct
60tctagtcatg accaggacca gggcagcact cctcctgttc acagccttag caacttctct
120aggtttcaac ttggacacag aggagctgac agccttccgt gtggacagcg ctgggtttgg
180agacagcgtg gtccagtatg ccaactcctg ggtggtggtt ggagcccccc aaaagataac
240agctgccaac caaacgggtg gcctctacca gtgtggctac agcactggtg cctgtgagcc
300catcggcctg caggtgcccc cggaggccgt gaacatgtcc ctgggcctgt ccctggcgtc
360taccaccagc ccttcccagc tgctggcctg cggccccacc gtgcaccacg agtgcgggag
420gaacatgtac ctcaccggac tctgcttcct cctgggcccc acccagctca cccagaggct
480cccggtgtcc aggcaggagt gcccaagaca ggagcaggac attgtgttcc tgatcgatgg
540ctcaggcagc atctcctccc gcaactttgc cacgatgatg aacttcgtga gagctgtgat
600aagccagttc cagagaccca gcacccagtt ttccctgatg cagttctcca acaaattcca
660aacacacttc actttcgagg aattcaggcg cagctcaaac cccctcagcc tgttggcttc
720tgttcaccag ctgcaagggt ttacatacac ggccaccgcc atccaaaatg tcgtgcaccg
780attgttccat gcctcatatg gggcccgtag ggatgccgcc aaaattctca ttgtcatcac
840tgatgggaag aaagaaggcg acagcctgga ttataaggat gtcatcccca tggctgatgc
900agcaggcatc atccgctatg caattggggt tggattagct tttcaaaaca gaaattcttg
960gaaagaatta aatgacattg catcgaagcc ctcccaggaa cacatattta aagtggagga
1020ctttgatgct ctgaaagata ttcaaaacca actgaaggag aagatctttg ccattgaggg
1080tacggagacc acaagcagta gctccttcga attggagatg gcacaggagg gcttcagcgc
1140tgtgttcaca cctgatggcc ccgttctggg ggctgtgggg agcttcacct ggtctggagg
1200tgccttcctg taccccccaa atatgagccc taccttcatc aacatgtctc aggagaatgt
1260ggacatgagg gactcttacc tgggttactc caccgagctg gccctctgga aaggggtgca
1320gagcctggtc ctgggggccc cccgctacca gcacaccggg aaggctgtca tcttcaccca
1380ggtgtccagg caatggagga tgaaggccga agtcacgggg actcagatcg gctcctactt
1440cggggcctcc ctctgctccg tggacgtaga cagcgacggc agcaccgacc tggtcctcat
1500cggggccccc cattactacg agcagacccg agggggccag gtgtctgtgt gtcccttgcc
1560cagggggtgg agaaggtggt ggtgtgatgc tgttctctac ggggagcagg gccacccctg
1620gggtcgcttt ggggcggctc tgacagtgct gggggatgtg aatggggaca agctgacaga
1680cgtggtcatc ggggccccag gagaggagga gaaccggggt gctgtctacc tgtttcacgg
1740agtcttggga cccagcatca gcccctccca cagccagcgg atcgcgggct cccagctctc
1800ctccaggctg cagtattttg ggcaggcact gagcgggggt caagacctca cccaggatgg
1860actggtggac ctggctgtgg gggcccgggg ccaggtgctc ctgctcagga ccagacctgt
1920gctctgggtg ggggtgagca tgcagttcat acctgccgag atccccaggt ctgcgtttga
1980gtgtcgggag caggtggtct ctgagcagac cctggtacag tccaacatct gcctttacat
2040tgacaaacgt tctaagaacc tgcttgggag ccgtgacctc caaagctctg tgaccttgga
2100cctggccctc gaccctggcc gcctgagtcc ccgtgccacc ttccaggaaa caaagaaccg
2160gagtctgagc cgagtccgag tcctcgggct gaaggcacac tgtgaaaact tcaacctgct
2220gctcccgagc tgcgtggagg actctgtgac ccccattacc ttgcgtctga acttcacgct
2280ggtgggcaag cccctccttg ccttcagaaa cctgcggcct atgctggccg ccgatgctca
2340gagatacttc acggcctccc taccctttga gaagaactgt ggagccgacc atatctgcca
2400ggacaatctc ggcatctcct tcagcttccc aggcttgaag tccctgctgg tggggagtaa
2460cctggagctg aacgcagaag tgatggtgtg gaatgacggg gaagactcct acggaaccac
2520catcaccttc tcccaccccg caggactgtc ctaccgctac gtggcagagg gccagaaaca
2580agggcagctg cgttccctgc acctgacatg tgacagcgcc ccagttggga gccagggcac
2640ctggagcacc agctgcagaa tcaaccacct catcttccgt ggcggcgccc agatcacctt
2700cttggctacc tttgacgtct cccccaaggc tgtcctggga gaccggctgc ttctgacagc
2760caatgtgagc agtgagaaca acactcccag gaccagcaag accaccttcc agctggagct
2820cccggtgaag tatgctgtct acactgtggt tagcagccac gaacaattca ccaaatacct
2880caacttctca gagtctgagg agaaggaaag ccatgtggcc atgcacagat accaggtcaa
2940taacctggga cagagggacc tgcctgtcag catcaacttc tgggtgcctg tggagctgaa
3000ccaggaggct gtgtggatgg atgtggaggt ctcccacccc cagaacccat cccttcggtg
3060ctcctcagag aaaatcgcac ccccagcatc tgacttcctg gcgcacattc agaagaatcc
3120cgtgctggac tgctccattg ctggctgcct gcggttccgc tgtgacgtcc cctccttcag
3180cgtccaggag gagctggatt tcaccctgaa gggcaacctc agctttggct gggtccgcca
3240gatattgcag aagaaggtgt cggtcgtgag tgtggctgaa attacgttcg acacatccgt
3300gtactcccag cttccaggac aggaggcatt tatgagagct cagacgacaa cggtgctgga
3360gaagtacaag gtccacaacc ccacccccct catcgtaggc agctccattg ggggtctgtt
3420gctgctggca ctcatcacag cggtactgta caaagttggc ttcttcaagc gtcagtacaa
3480ggaaatgatg gaggaggcaa atggacaaat tgccccagaa aacgggacac agacccccag
3540cccgcccagt gagaaatgat cccctctttg ccttggactt cttctccccc gcgagttttc
3600cccacttact taccctcacc tgtcaggcct gacggggagg aaccactgca ccaccgagag
3660aggctgggat gggcctgctt cctgtctttg ggagaaaacg tcttgcttgg gaaggggcct
3720ttgtcttgtc aaggttccaa ctggaaaccc ttaggacagg gtccctgctg tgttccccaa
3780aggacttgac ttgcaatttc tacctagaaa tacatggaca atacccccag gcctcagtct
3840cccttctccc atgaggcacg aatgatcttt ctttcctttc tttttttttt tttttctttt
3900cttttttttt tttttgagac ggagtctcgc tctgtcaccc aggctggagt gcaatggcgt
3960gatctcggct cactgcaacc tccgcctccc gggttcaagt aattctgctg tctcagcctc
4020ctgagtagct gggactacag gcacacgcca cctcgcccgg cccgatcttt ctaaaataca
4080gttctgaata tgctgctcat ccccacctgt cttcaacagc tccccattac cctcaggaca
4140atgtctgaac tctccagctt cgcgtgagaa gtccccttcc atcccagagg gtgggcttca
4200gggcgcacag catgagaggc tctgtgcccc catcaccctc gtttccagtg aattagtgtc
4260atgtcagcat cagctcaggg cttcatcgtg gggctctcag ttccgatttc ccaggctgaa
4320ttgggagtga gatgcctgca tgctgggttc tgcacagctg gcctcccgcg ttgggcaaca
4380ttgctggctg gaagggagga gcgccctcta gggagggaca tggccccggt gcggctgcag
4440ctcacccagc cccaggggca gaagagaccc aaccacttct attttttgag gctatgaata
4500tagtacctga aaaaatgcca agacatgatt atttttttaa aaagcgtact ttaaatgttt
4560gtgttaataa attaaaacat gcacaaaaag atgcatctac cgctcttggg aaatatgtca
4620aaggtctaaa aataaaaaag ccttctgtga aaaaaaaaaa aaaaaa
46663021163PRTHomo sapiensmisc_feature(1)..(1163)CD11c full-length a.a.
302Met Thr Arg Thr Arg Ala Ala Leu Leu Leu Phe Thr Ala Leu Ala Thr1
5 10 15Ser Leu Gly Phe Asn Leu
Asp Thr Glu Glu Leu Thr Ala Phe Arg Val 20 25
30Asp Ser Ala Gly Phe Gly Asp Ser Val Val Gln Tyr Ala
Asn Ser Trp 35 40 45Val Val Val
Gly Ala Pro Gln Lys Ile Thr Ala Ala Asn Gln Thr Gly 50
55 60Gly Leu Tyr Gln Cys Gly Tyr Ser Thr Gly Ala Cys
Glu Pro Ile Gly65 70 75
80Leu Gln Val Pro Pro Glu Ala Val Asn Met Ser Leu Gly Leu Ser Leu
85 90 95Ala Ser Thr Thr Ser Pro
Ser Gln Leu Leu Ala Cys Gly Pro Thr Val 100
105 110His His Glu Cys Gly Arg Asn Met Tyr Leu Thr Gly
Leu Cys Phe Leu 115 120 125Leu Gly
Pro Thr Gln Leu Thr Gln Arg Leu Pro Val Ser Arg Gln Glu 130
135 140Cys Pro Arg Gln Glu Gln Asp Ile Val Phe Leu
Ile Asp Gly Ser Gly145 150 155
160Ser Ile Ser Ser Arg Asn Phe Ala Thr Met Met Asn Phe Val Arg Ala
165 170 175Val Ile Ser Gln
Phe Gln Arg Pro Ser Thr Gln Phe Ser Leu Met Gln 180
185 190Phe Ser Asn Lys Phe Gln Thr His Phe Thr Phe
Glu Glu Phe Arg Arg 195 200 205Ser
Ser Asn Pro Leu Ser Leu Leu Ala Ser Val His Gln Leu Gln Gly 210
215 220Phe Thr Tyr Thr Ala Thr Ala Ile Gln Asn
Val Val His Arg Leu Phe225 230 235
240His Ala Ser Tyr Gly Ala Arg Arg Asp Ala Ala Lys Ile Leu Ile
Val 245 250 255Ile Thr Asp
Gly Lys Lys Glu Gly Asp Ser Leu Asp Tyr Lys Asp Val 260
265 270Ile Pro Met Ala Asp Ala Ala Gly Ile Ile
Arg Tyr Ala Ile Gly Val 275 280
285Gly Leu Ala Phe Gln Asn Arg Asn Ser Trp Lys Glu Leu Asn Asp Ile 290
295 300Ala Ser Lys Pro Ser Gln Glu His
Ile Phe Lys Val Glu Asp Phe Asp305 310
315 320Ala Leu Lys Asp Ile Gln Asn Gln Leu Lys Glu Lys
Ile Phe Ala Ile 325 330
335Glu Gly Thr Glu Thr Thr Ser Ser Ser Ser Phe Glu Leu Glu Met Ala
340 345 350Gln Glu Gly Phe Ser Ala
Val Phe Thr Pro Asp Gly Pro Val Leu Gly 355 360
365Ala Val Gly Ser Phe Thr Trp Ser Gly Gly Ala Phe Leu Tyr
Pro Pro 370 375 380Asn Met Ser Pro Thr
Phe Ile Asn Met Ser Gln Glu Asn Val Asp Met385 390
395 400Arg Asp Ser Tyr Leu Gly Tyr Ser Thr Glu
Leu Ala Leu Trp Lys Gly 405 410
415Val Gln Ser Leu Val Leu Gly Ala Pro Arg Tyr Gln His Thr Gly Lys
420 425 430Ala Val Ile Phe Thr
Gln Val Ser Arg Gln Trp Arg Met Lys Ala Glu 435
440 445Val Thr Gly Thr Gln Ile Gly Ser Tyr Phe Gly Ala
Ser Leu Cys Ser 450 455 460Val Asp Val
Asp Ser Asp Gly Ser Thr Asp Leu Val Leu Ile Gly Ala465
470 475 480Pro His Tyr Tyr Glu Gln Thr
Arg Gly Gly Gln Val Ser Val Cys Pro 485
490 495Leu Pro Arg Gly Trp Arg Arg Trp Trp Cys Asp Ala
Val Leu Tyr Gly 500 505 510Glu
Gln Gly His Pro Trp Gly Arg Phe Gly Ala Ala Leu Thr Val Leu 515
520 525Gly Asp Val Asn Gly Asp Lys Leu Thr
Asp Val Val Ile Gly Ala Pro 530 535
540Gly Glu Glu Glu Asn Arg Gly Ala Val Tyr Leu Phe His Gly Val Leu545
550 555 560Gly Pro Ser Ile
Ser Pro Ser His Ser Gln Arg Ile Ala Gly Ser Gln 565
570 575Leu Ser Ser Arg Leu Gln Tyr Phe Gly Gln
Ala Leu Ser Gly Gly Gln 580 585
590Asp Leu Thr Gln Asp Gly Leu Val Asp Leu Ala Val Gly Ala Arg Gly
595 600 605Gln Val Leu Leu Leu Arg Thr
Arg Pro Val Leu Trp Val Gly Val Ser 610 615
620Met Gln Phe Ile Pro Ala Glu Ile Pro Arg Ser Ala Phe Glu Cys
Arg625 630 635 640Glu Gln
Val Val Ser Glu Gln Thr Leu Val Gln Ser Asn Ile Cys Leu
645 650 655Tyr Ile Asp Lys Arg Ser Lys
Asn Leu Leu Gly Ser Arg Asp Leu Gln 660 665
670Ser Ser Val Thr Leu Asp Leu Ala Leu Asp Pro Gly Arg Leu
Ser Pro 675 680 685Arg Ala Thr Phe
Gln Glu Thr Lys Asn Arg Ser Leu Ser Arg Val Arg 690
695 700Val Leu Gly Leu Lys Ala His Cys Glu Asn Phe Asn
Leu Leu Leu Pro705 710 715
720Ser Cys Val Glu Asp Ser Val Thr Pro Ile Thr Leu Arg Leu Asn Phe
725 730 735Thr Leu Val Gly Lys
Pro Leu Leu Ala Phe Arg Asn Leu Arg Pro Met 740
745 750Leu Ala Ala Asp Ala Gln Arg Tyr Phe Thr Ala Ser
Leu Pro Phe Glu 755 760 765Lys Asn
Cys Gly Ala Asp His Ile Cys Gln Asp Asn Leu Gly Ile Ser 770
775 780Phe Ser Phe Pro Gly Leu Lys Ser Leu Leu Val
Gly Ser Asn Leu Glu785 790 795
800Leu Asn Ala Glu Val Met Val Trp Asn Asp Gly Glu Asp Ser Tyr Gly
805 810 815Thr Thr Ile Thr
Phe Ser His Pro Ala Gly Leu Ser Tyr Arg Tyr Val 820
825 830Ala Glu Gly Gln Lys Gln Gly Gln Leu Arg Ser
Leu His Leu Thr Cys 835 840 845Asp
Ser Ala Pro Val Gly Ser Gln Gly Thr Trp Ser Thr Ser Cys Arg 850
855 860Ile Asn His Leu Ile Phe Arg Gly Gly Ala
Gln Ile Thr Phe Leu Ala865 870 875
880Thr Phe Asp Val Ser Pro Lys Ala Val Leu Gly Asp Arg Leu Leu
Leu 885 890 895Thr Ala Asn
Val Ser Ser Glu Asn Asn Thr Pro Arg Thr Ser Lys Thr 900
905 910Thr Phe Gln Leu Glu Leu Pro Val Lys Tyr
Ala Val Tyr Thr Val Val 915 920
925Ser Ser His Glu Gln Phe Thr Lys Tyr Leu Asn Phe Ser Glu Ser Glu 930
935 940Glu Lys Glu Ser His Val Ala Met
His Arg Tyr Gln Val Asn Asn Leu945 950
955 960Gly Gln Arg Asp Leu Pro Val Ser Ile Asn Phe Trp
Val Pro Val Glu 965 970
975Leu Asn Gln Glu Ala Val Trp Met Asp Val Glu Val Ser His Pro Gln
980 985 990Asn Pro Ser Leu Arg Cys
Ser Ser Glu Lys Ile Ala Pro Pro Ala Ser 995 1000
1005Asp Phe Leu Ala His Ile Gln Lys Asn Pro Val Leu
Asp Cys Ser 1010 1015 1020Ile Ala Gly
Cys Leu Arg Phe Arg Cys Asp Val Pro Ser Phe Ser 1025
1030 1035Val Gln Glu Glu Leu Asp Phe Thr Leu Lys Gly
Asn Leu Ser Phe 1040 1045 1050Gly Trp
Val Arg Gln Ile Leu Gln Lys Lys Val Ser Val Val Ser 1055
1060 1065Val Ala Glu Ile Thr Phe Asp Thr Ser Val
Tyr Ser Gln Leu Pro 1070 1075 1080Gly
Gln Glu Ala Phe Met Arg Ala Gln Thr Thr Thr Val Leu Glu 1085
1090 1095Lys Tyr Lys Val His Asn Pro Thr Pro
Leu Ile Val Gly Ser Ser 1100 1105
1110Ile Gly Gly Leu Leu Leu Leu Ala Leu Ile Thr Ala Val Leu Tyr
1115 1120 1125Lys Val Gly Phe Phe Lys
Arg Gln Tyr Lys Glu Met Met Glu Glu 1130 1135
1140Ala Asn Gly Gln Ile Ala Pro Glu Asn Gly Thr Gln Thr Pro
Ser 1145 1150 1155Pro Pro Ser Glu Lys
1160303107PRTHomo sapiensmisc_feature(1)..(107)Adalimumab VL 303Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly1
5 10 15Asp Arg Val Thr Ile Thr Cys
Arg Ala Ser Gln Gly Ile Arg Asn Tyr 20 25
30Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu
Leu Ile 35 40 45Tyr Ala Ala Ser
Thr Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55
60Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro65 70 75
80Glu Asp Val Ala Thr Tyr Tyr Cys Gln Arg Tyr Asn Arg Ala Pro Tyr
85 90 95Thr Phe Gly Gln Gly Thr
Lys Val Glu Ile Lys 100 105304121PRTHomo
sapiensmisc_feature(1)..(121)Adalimumab VH 304Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Arg1 5 10
15Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe
Asp Asp Tyr 20 25 30Ala Met
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45Ser Ala Ile Thr Trp Asn Ser Gly His Ile
Asp Tyr Ala Asp Ser Val 50 55 60Glu
Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr65
70 75 80Leu Gln Met Asn Ser Leu
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95Ala Lys Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu
Asp Tyr Trp Gly 100 105 110Gln
Gly Thr Leu Val Thr Val Ser Ser 115
1203059PRTArtificial SequenceSynthetic consensus motif for adalimumab VL
CDR3 305Gln Arg Tyr Asn Arg Ala Pro Tyr Xaa1
530612PRTArtificial SequenceSynthetic consensus motif for adalimumab VH
CDR3 306Val Ser Tyr Leu Ser Thr Ala Ser Ser Leu Asp Xaa1
5 103077PRTHomo sapiensmisc_feature(1)..(7)Adalimumab
VL CDR2 307Ala Ala Ser Thr Leu Gln Ser1 530817PRTHomo
sapiensmisc_feature(1)..(17)Adalimumab VH CDR2 308Ala Ile Thr Trp Asn Ser
Gly His Ile Asp Tyr Ala Asp Ser Val Glu1 5
10 15Gly30911PRTHomo
sapiensmisc_feature(1)..(11)Adalimumab VL CDR1 309Arg Ala Ser Gln Gly Ile
Arg Asn Tyr Leu Ala1 5 103105PRTHomo
sapiensmisc_feature(1)..(5)Adalimumab VH CDR1 310Asp Tyr Ala Met His1
5
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