METHODS AND COMPOSITIONS FOR DIAGNOSING AND TREATING DISEASES

Abstract

Methods and compositions are provided for assessing, treating, and preventing diseases, especially cancer, using cancer-associated targets (CAT). Methods and compositions are also provided for determining or predicting the effectiveness of a treatment for these diseases or for selecting a treatment, using CAT. Methods and compositions are further provided for modulating cell function using CAT. Also provided are compositions that modulate CAT (e.g., antagonists or agonists), such as antibodies, proteins, small molecule compounds, and nucleic acid agents (e.g., RNAi and antisense agents), as well as pharmaceutical compositions thereof. Further provided are methods of screening for agents that modulate CAT, and agents identified by these screening methods.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. non-provisional application Ser. No. 14/695,680, dated Apr. 24, 2015, which is a divisional application of U.S. non-provisional application Ser. No. 13/873,373, filed Apr. 30, 2013, which is a divisional application of U.S. non-provisional application Ser. No. 12/901,254, filed Oct. 8, 2010, which is a divisional application of U.S. non-provisional application of Ser. No. 11/802,321, filed May 22, 2007 (issued as U.S. Pat. No. 7,842,291 on Nov. 30, 2010), which claims priority to U.S. provisional application Ser. No. 60/802,152, filed May 22, 2006, and U.S. provisional application Ser. No. 60/802,153, filed May 22, 2006, and U.S. provisional application Ser. No. 60/802,151, filed May 22, 2006, and U.S. provisional application Ser. No. 60/810,183, filed Jun. 2, 2006, and U.S. provisional application Ser. No. 60/810,180, filed Jun. 2, 2006, and U.S. provisional application Ser. No. 60/810,179, filed Jun. 2, 2006, and U.S. provisional application Ser. No. 60/819,616, filed Jul. 11, 2006, and U.S. provisional application Ser. No. 60/819,612, filed Jul. 11, 2006, and U.S. provisional application Ser. No. 60/819,611, filed Jul. 11, 2006, and U.S. provisional application Ser. No. 60/833,470, filed Jul. 27, 2006, and U.S. provisional application Ser. No. 60/833,471, filed Jul. 27, 2006, and U.S. provisional application Ser. No. 60/835,419, filed Aug. 4, 2006, the contents of each of which are hereby incorporated by reference into this application.

FIELD OF THE INVENTION

[0002] This invention relates to the field of molecular biology. The invention provides compositions and methods for assessing and treating diseases, especially cancer. In particular, the invention provides the following targets and methods of using these targets: TMPRSS4, SLC5A6, ISGF4, ITGB6, GLG1, DB83, KIAA0152, Matriptase, AADACL1, Podocalyxin, and CD90 (Thy1), which are collectively referred to herein as "CAT" (cancer-associated targets).

BACKGROUND OF THE INVENTION

[0003] Cancer

[0004] Cancer is one of the leading causes of death worldwide, and cancer is difficult to diagnose and treat effectively. Accordingly, there is a need in the art for new compositions and methods for assessing and treating various cancers.

[0005] Targets

[0006] TMPRSS4 is a member of the serine protease family of proteins. TMPRSS4 is membrane-bound with an N-terminal anchor sequence and a glycosylated extracellular region containing the serine protease domain. The extracellular domain is typically larger than 300 amino acids in size. Two alternative transcripts encoding different isoforms have been described in the art.

[0007] SLC5A6 is a solute carrier with multiple extracellular domains (ECD). The largest ECD is greater than 70 amino acids in size.

[0008] ITGB6 (Integrin .beta.6) associates with integrin .alpha.v and functions as a cell surface receptor for fibronectin, tenascin, vitronectin and TGF .beta.1 latency-associated peptide (LAP). ITGB6 contains an ectodomain typically about 698 amino acids in size and typically recognizes RGD sequence in its ligand. ITGB6 induces protease activation and is associated with increased cell growth and motility.

[0009] GLG1 is a type I membrane protein with two isoforms that differ by 24 amino acids at the C-terminus. Isoform 1 is localized to Golgi, and the slightly longer isoform 2 is localized to the cell surface (J Cell Science (2005) 118:1725-1731). GLG1 has a single transmembrane domain, and one large extracellular domain that is typically more than 900aa in size. GLG1 is capably of binding E-selectin and mediating binding of neutrophils to endothelial cells; wherein fucosylation required (Nature (1995) 373:615-620). GLG1 binds to fibroblast growth factors and may chaperone to Golgi, suggesting the role in processing and targeting FGF in cells (JBC (2000) 275:15741-15748; J Cell Physiol (1997) 170:217-227). GLG1 is a component of the latent transforming growth factor-.beta. (TGF-.beta.) complex. This complex is thought to play a role in targeting TGF-.beta. to specific locations on the cell surface/extracellular matrix (Biochem J (1997) 324:427-434).

[0010] KIAA0152 is a cell surface protein that has an extracellular domain that typically is larger than 250 amino acids in size.

[0011] Matriptase, also referred to as ST14, is an integral membrane protease that has an extracellular domain which is typically greater than 600 amino acids in size.

[0012] AADACL1 (arylacetamide deacetylase-like 1; exemplary sequences are shown in Genbank gi146048176 and Swiss Prot Accession Number Q6PIU2) is a membrane-bound serine hydrolase expressed in the brain. AADACL1 has an extracellular domain that typically is 381 amino acids in size. AADACL1 binds the organophosphorous compound chlorpyrifos oxon (CPO). AADACL1 knockout mice demonstrate reduced levels of CPO labeling and hydrolytic metabolism. Thus, AADACL1 has been proposed to be an organophosphorous detoxification enzyme (Nomura et al. 2005. PNAS 102:6195-6200). Two discrete glycosylation states have been observed in AADACL1.

[0013] Podocalyxin-like protein (referred to herein simply as "podocalyxin") is an integral membrane glycoprotein which has a single transmembrane domain and a large extracellular domain (typically greater than 400 amino acid residues in size). Podocalyxin has highly conserved transmembrane and intracellular domains (.about.95%) with lower homology in ECD (.about.30%). Podocalyxin is heavily glycosylated and the extracellular domain contains five potential N-linked glycosylation sites and high Ser/Thr (39%) providing numerous potential O-linked sites. Podocalyxin has an anti-adhesive function which maintains slit diaphragms between foot processes through which urine is filtered (Mol Biol Cell (2000) 11, 3219-3232). Podocalyxin has a similar structure and sequence composition as stem-cell marker CD34. Podocalyxin is present on the luminal surface of high endothelial venules where it can serve as a ligand for leukocyte adhesion molecule, L-selectin (J. Exp. Med. (1998) 12, 1965-1975). A soluble form of podocalyxin has been detected in in vitro embryonal carcinoma culture and may be found in serum of patients with nonseminomatous germ cell tumors (Arch Biochem Biophys (1992) 298 538-543 and Eur. J. Cancer (1991) 27 300). Differentially sulfated forms of podocalyxin exist, and a sulfated form is present in HEV.

[0014] CD90 (also known as Thy1) (exemplary sequences are shown in Genbank P04216 and Swiss-Prot Accession Number P04216) is a 25-37 kDa GPI-anchored glycoprotein expressed on many cell types, including T cells and thymocytes in mice, and in neurons, endothelial cells, fibroblasts, and blood stem cells in humans (Lab Invest. (1986) 54, 122-135); J. Exp. Med. (1993) 177, 1331; Oncogene (2005) 24, 4710-4720). CD90 can promote T cell activation/inflammation. CD90 may play a role in cell-cell or cell-ligand interactions during synaptogenesis and other events in the brain.

[0015] ISGF4 (also referred to as IGSF4) is an integral membrane protein involved in cell adhesion. ISGF4 has a large extracellular domain that is typically greater than 300 amino acids in size.

[0016] DB83 is a multi-pass membrane protein. The largest extracellular domain of DB83 is typically greater than 50 amino acids in size (DNA Research (1998) 5:315-317).

DESCRIPTION OF THE SEQUENCE LISTING

[0017] The Sequence Listing discloses exemplary protein and nucleic acid sequences for each CAT (Cancer-Associated Target). Specifically, the Sequence Listing discloses amino acid sequences of CAT proteins and nucleic acid sequences of CAT transcripts that encode these CAT proteins, as set forth in the following table:

TABLE-US-00001 Cancer-Associated Target (CAT) Protein SEQ ID NO Transcript SEQ ID NO TMPRSS4 1-3 4-6 SLC5A6 7-9 10-12 ISGF4 13-17 18-22 ITGB6 23 24 GLG1 25-33 34-42 DB83 43-44 45-46 KIAA0152 47-48 49-50 Matriptase 51-52 53-55 AADACL1 56-59 60-63 Podocalyxin 64-67 68-71 CD90 (Thy1) 72-73 74-75

DESCRIPTION OF THE FIGURES

SLC5A6

[0018] FIG. 1. SLC5A6 is Overexpressed in Multiple Tumor Types, as indicated by IHC.

[0019] FIG. 2. SLC5A6 mRNA Expression Analysis in Multiple Tumor Tissues.

[0020] FIG. 3. mRNA sequence of SLC5A6, indicating siRNA target regions.

DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS OF THE INVENTION

[0021] The invention will best be understood by reference to the following detailed description of the exemplary embodiments, taken in conjunction with the accompanying figure(s). The discussion below is exemplary and is not to be taken as limiting the scope defined by the claims.

[0022] The invention generally relates to molecules that have been identified using proteomic analysis techniques such as MALDI-TOF/TOF LC/MS-based protein expression analysis to determine the expression levels of proteins in disease tissues and/or disease cell lines (tissues and cell lines may be collectively referred to as "samples") and in normal tissues and/or normal cell lines, such that proteins that are differentially expressed (e.g., over- or under-expressed) in disease samples compared with normal samples are identified.

[0023] Exemplary embodiments of the invention provide the following targets and methods of using these targets: TMPRSS4, SLC5A6, ISGF4, ITGB6, GLG1, DB83, KIAA0152, Matriptase, AADACL1, Podocalyxin, and CD90 (Thy1), which are collectively referred to herein as "CAT" (cancer-associated targets). Each of these targets is associated with specific types of cancers in particular, as shown in the Figures and described in section 13 of the Examples section ("Specific Examples of Results from Experimental Validation").

[0024] Based on the finding that certain proteins, referred to herein as CAT proteins, are differentially expressed in cancer samples in comparison with normal samples, exemplary embodiments of the invention provide methods and compositions for assessing, treating, and preventing diseases, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target, using CAT. Furthermore, the compositions and methods of the invention may be suitable for other types of cancer, particularly other epithelial cell-related cancers and solid tumors.

[0025] CAT proteins and fragments thereof, and CAT nucleic acid molecules and fragments thereof encoding CAT proteins, are collectively referred to as CAT or "targets" (which may be interchangeably referred to as "markers" or "biomarkers"). Exemplary CAT proteins are provided as SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73 and exemplary CAT transcript sequences (which encode the CAT proteins of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73) are provided as SEQ ID NOS:4-6, 10-12, 18-22, 24, 34-42, 45-46, 49-50, 53-55, 60-63, 68-71, and 74-75. These targets can be, for example, cell surface proteins, cytosolic proteins, or secreted proteins, as well as nucleic acid molecules that encode these proteins.

[0026] The terms "protein" and "polypeptide" are used herein interchangeably. Exemplary CAT proteins/polypeptides are provided as SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73. A "peptide" typically refers to a fragment of a protein/polypeptide. Thus, peptides are interchangeably referred to as fragments.

[0027] References herein to proteins, peptides, nucleic acid molecules, and antibodies typically are not limited to the full-size or full-length molecule, but also can encompass fragments of these molecules (unless a particular sequence or structure is explicitly stated).

[0028] Exemplary embodiments of the invention, which are discussed in greater detail below, provide antibodies, proteins, immunogenic peptides (e.g., peptides which induce a T-cell response), or other biomolecules, as well as small molecules, nucleic acid agents (e.g., RNAi and antisense nucleic acid agents), and other compositions that modulate the targets (e.g., agonists and antagonists), such as by binding to or otherwise interacting with or affecting the targets. These compositions can be used for assessing, treating, and preventing diseases, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target, as well as other uses. Moreover, the invention provides methods for assessing, treating, and preventing diseases such as these based on CAT, such as by using these compositions. Further provided are methods of screening for agents that modulate CAT, such as by affecting the function, activity, and/or expression level ("expression level" may be interchangeably referred to as "abundance level" or "level") of CAT, and agents identified by these screening methods.

[0029] Exemplary embodiments of the invention also provide methods of modulating cell function. In particular, the invention provides methods of modulating cell proliferation and/or apoptosis. For example, for cancer/tumor cells, the invention provides methods of inhibiting cell proliferation and/or stimulating apoptosis. Such methods can be applied to the treatment of diseases, especially cancer.

[0030] Exemplary embodiments of the invention further provide methods of determining or predicting effectiveness or response to a particular treatment, and methods of selecting a treatment for an individual. For example, targets that are differentially expressed by cells that are more or less responsive or resistant to a particular treatment, such as a cancer treatment, are useful for determining or predicting effectiveness or response to the treatment or for selecting a treatment for an individual. Exemplary embodiments of the invention also provide methods of selecting individuals for a clinical trial of a therapeutic agent. For example, the targets can be used to identify individuals for inclusion in a clinical trial who are more likely to respond to a particular treatment. Alternatively, the targets can be used to exclude individuals from a clinical trial who are less likely to respond to a particular treatment or who are more likely to experience toxic or other undesirable side effects from a particular treatment.

[0031] Further exemplary embodiments of the invention are described in greater detail below.

[0032] 1. CAT Proteins

[0033] Exemplary embodiments of the invention provide the following targets and methods of using these targets: TMPRSS4, SLC5A6, ISGF4, ITGB6, GLG1, DB83, KIAA0152, Matriptase, AADACL1, Podocalyxin, and CD90 (Thy1), which are collectively referred to herein as "CAT" (cancer-associated targets). In particular, the present invention provides methods of using these targets for diagnosing and treating cancer. Each of these targets is associated with specific types of cancers in particular, as shown in the Figures and described in section 13 of the Examples section ("Specific Examples of Results from Experimental Validation").

[0034] Exemplary embodiments of the invention provide isolated CAT proteins that consist of, consist essentially of, or comprise the amino acid sequences of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73 (which are encoded by the nucleotide sequences of SEQ ID NOS:4-6, 10-12, 18-22, 24, 34-42, 45-46, 49-50, 53-55, 60-63, 68-71, and 74-75, respectively), as well as all obvious variants of these proteins and nucleic acid molecules that are within the art to make and use. Examples of such obvious variants include, but are not limited to, naturally-occurring allelic variants, pre-processed or mature processed forms of a protein, non-naturally occurring recombinantly-derived variants, orthologs, and paralogs. Such variants can readily be generated using art-known techniques in the fields of recombinant nucleic acid technology and protein biochemistry.

[0035] A protein is said to be "isolated" or "purified" when it is substantially free of cellular material or free of chemical precursors or other chemicals. CAT proteins can be purified to homogeneity or other degrees of purity. The level of purification can be based on the intended use. The primary consideration is that the preparation allows for the desired function of the protein, even if in the presence of considerable amounts of other components.

[0036] In some uses, "substantially free of cellular material" includes preparations of a protein having less than about 30% (by dry weight) other proteins (i.e., contaminating protein), less than about 20% other proteins, less than about 10% other proteins, or less than about 5% other proteins. When the protein is recombinantly produced, it can also be substantially free of culture medium, i.e., culture medium represents less than about 20% of the volume of the protein preparation.

[0037] The language "substantially free of chemical precursors or other chemicals" includes preparations of a protein in which the protein is separated from chemical precursors or other chemicals that are involved in the protein's synthesis. In one embodiment, the language "substantially free of chemical precursors or other chemicals" includes preparations of a CAT protein having less than about 30% (by dry weight) chemical precursors or other chemicals, less than about 20% chemical precursors or other chemicals, less than about 10% chemical precursors or other chemicals, or less than about 5% chemical precursors or other chemicals.

[0038] Isolated CAT proteins can be purified from cells that naturally express it, purified from cells that have been altered to express it (recombinant), or synthesized using known protein synthesis methods (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y., (2001)). For example, a nucleic acid molecule encoding a CAT protein can be cloned into an expression vector, the expression vector introduced into a host cell, and the protein expressed in the host cell. The protein can then be isolated from the cells by an appropriate purification scheme using standard protein purification techniques.

[0039] A CAT protein or fragment thereof can be attached to heterologous sequences to form chimeric or fusion proteins. Such chimeric and fusion proteins comprise a protein operatively linked to a heterologous protein having an amino acid sequence not substantially homologous to the protein. "Operatively linked" indicates that the protein and the heterologous protein are fused in-frame. The heterologous protein can be fused to the N-terminus or C-terminus of the protein.

[0040] In some uses, the fusion protein does not affect the activity of the protein per se. For example, the fusion protein can include, but is not limited to, beta-galactosidase fusions, yeast two-hybrid GAL fusions, poly-His fusions, MYC-tagged, HI-tagged, and Ig fusions. Such fusion proteins, particularly poly-His fusions, can facilitate the purification of recombinant CAT proteins. In certain host cells (e.g., mammalian host cells), expression and/or secretion of a protein can be increased by using a heterologous signal sequence.

[0041] A chimeric or fusion CAT protein can be produced by standard recombinant DNA techniques. For example, DNA fragments coding for different protein sequences can be ligated together in-frame in accordance with conventional techniques. In another embodiment, a fusion gene can be synthesized by conventional techniques including automated DNA synthesizers. Alternatively, PCR amplification of gene fragments can be carried out using anchor primers that give rise to complementary overhangs between two consecutive gene fragments that can subsequently be annealed and re-amplified to generate a chimeric gene sequence (Ausubel et al., Current Protocols in Molecular Biology, 1992-2006). Moreover, many expression vectors are commercially available that already encode a fusion moiety (e.g., a GST protein). A CAT-encoding nucleic acid can be cloned into such an expression vector such that the fusion moiety is linked in-frame to the CAT protein.

[0042] To determine the percent identity of two amino acid sequences or two nucleic acid sequences, the sequences can be aligned for optimal comparison purposes (e.g., gaps can be introduced in one or both of a first and a second amino acid or nucleic acid sequence for optimal alignment and non-homologous sequences can be disregarded for comparison purposes). In an exemplary embodiment, at least 30%, 40%, 50%, 60%, 70%, 80%, or 90% or more of the length of a reference sequence can be aligned for comparison purposes. The amino acid residues or nucleotides at corresponding amino acid positions or nucleotide positions can then be compared. When a position in the first sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position (as used herein, amino acid or nucleic acid "identity" is equivalent to amino acid or nucleic acid "homology"). The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, that are introduced for optimal alignment of the two sequences.

[0043] The comparison of sequences and determination of percent identity and similarity between two sequences can be accomplished using a mathematical algorithm. (Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H. G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., Stockton Press, New York, 1991). In an exemplary embodiment, the percent identity between two amino acid sequences is determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package, using either a Blossom 62 matrix or a PAM250 matrix, a gap weight of 16, 14, 12, 10, 8, 6, or 4, and a length weight of 1, 2, 3, 4, 5, or 6. In another exemplary embodiment, the percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (Devereux et al., Nucleic Acids Res. 12(1):387 (1984)) using a NWSgapdna.CMP matrix and a gap weight of 40, 50, 60, 70, or 80, and a length weight of 1, 2, 3, 4, 5, or 6. In another exemplary embodiment, the percent identity between two amino acid or nucleotide sequences is determined using the algorithm of E. Myers and W. Miller (CABIOS, 4:11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12, and a gap penalty of 4.

[0044] The sequences of the proteins and nucleic acid molecules of the invention can further be used as a "query sequence" to perform a search against sequence databases to, for example, identify other protein family members or related sequences. Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul et al. (J. Mol. Biol. 215:403-10 (1990)). BLAST nucleotide searches can be performed with the NBLAST program, score=100, wordlength=12, to obtain nucleotide sequences homologous to the query nucleic acid molecule. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to the query proteins. To obtain gapped alignments for comparison purposes, Gapped BLAST can be utilized as described in Altschul et al. (Nucleic Acids Res. 25(17):3389-3402 (1997)). When utilizing BLAST and gapped BLAST programs, the default parameters of the respective programs (e.g., XBLAST and NBLAST) can be used.

[0045] As used herein, two proteins (or a region or domain of the proteins) have significant homology/identity (also referred to as substantial homology/identity) when the amino acid sequences are typically at least about 70-80%, 80-90%, 90-95%, 96%, 97%, 98%, or 99% identical A significantly homologous amino acid sequence can be encoded by a nucleic acid molecule that hybridizes to a CAT protein-encoding nucleic acid molecule under stringent conditions, as more fully described below.

[0046] Orthologs of a CAT protein typically have some degree of significant sequence homology to at least a portion of a CAT protein and are encoded by a gene from another organism. Preferred orthologs are isolated from mammals, preferably non-human primates, for the development of human therapeutic targets and agents. Such orthologs can be encoded by a nucleic acid molecule that hybridizes to a CAT protein-encoding nucleic acid molecule under moderate to stringent conditions, as more fully described below, depending on the degree of relatedness of the two organisms yielding the proteins.

[0047] Non-naturally occurring variants of the CAT proteins can readily be generated using recombinant techniques. Such variants include, but are not limited to, deletions, additions, and substitutions in the amino acid sequence of the CAT protein. For example, one class of substitutions is conserved amino acid substitutions. Such substitutions are those that substitute a given amino acid in a CAT protein by another amino acid of like characteristics. Typically seen as conservative substitutions are the replacements, one for another, among the aliphatic amino acids Ala, Val, Leu, and Ile; interchange of the hydroxyl residues Ser and Thr; exchange of the acidic residues Asp and Glu; substitution between the amide residues Asn and Gln; exchange of the basic residues Lys and Arg; and replacements among the aromatic residues Phe and Tyr. Guidance concerning which amino acid changes are likely to be phenotypically silent are found in Bowie et al., Science 247:1306-1310 (1990).

[0048] Variant CAT proteins can be fully functional or can lack function in one or more activities, e.g., ability to bind substrate, ability to phosphorylate substrate, ability to mediate signaling, etc. Fully functional variants typically contain only conservative variations or variation in non-critical residues or in non-critical regions.

[0049] Non-functional variants typically contain one or more non-conservative amino acid substitutions, deletions, insertions, inversions, or truncations, or a substitution, insertion, inversion, or deletion in a critical residue or critical region.

[0050] Amino acids that are essential for function can be identified by methods known in the art, such as site-directed mutagenesis or alanine-scanning mutagenesis (Cunningham et al., Science 244:1081-1085 (1989)). The latter procedure introduces single alanine mutations at every residue in the molecule. The resulting mutant molecules are then tested for biological activity or in assays such as in vitro proliferative activity. Sites that are critical for binding partner/substrate binding can also be determined by structural analysis such as crystallization, nuclear magnetic resonance, or photoaffinity labeling (Smith et al., J. Mol. Biol. 224:899-904 (1992); de Vos et al., Science 255:306-312 (1992)).

[0051] Exemplary embodiments of the invention provide fragments of a CAT, and peptides that comprise and consist of such fragments. An exemplary fragment typically comprises at least about 5, 6, 8, 10, 12, 14, 16, 18, 20 or more contiguous amino acid residues of a CAT protein. Such fragments can be chosen based on the ability to retain one or more of the biological activities of CAT or can be chosen for the ability to perform a function, e.g., bind a substrate or act as an immunogen. Particularly important fragments are biologically active fragments, such as peptides that are, for example, about 8 or more amino acids in length. Such fragments can include a domain or motif of a CAT, e.g., an active site, a transmembrane domain, or a binding domain. Further, possible fragments include, but are not limited to, soluble peptide fragments and fragments containing immunogenic structures. Domains and functional sites can readily be identified, for example, by computer programs well known and readily available to those of skill in the art (e.g., PROSITE analysis).

[0052] Proteins can contain amino acids other than the 20 amino acids commonly referred to as the 20 naturally-occurring amino acids. Further, many amino acids, including the terminal amino acids, can be modified by natural processes, such as processing and other post-translational modifications, or by chemical modification techniques well known in the art. Common modifications that occur naturally in proteins are well known to those of skill in the art.

[0053] Known modifications include, but are not limited to, acetylation, acylation, ADP-ribosylation, amidation, covalent attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent crosslinks, formation of cystine, formation of pyroglutamate, formylation, gamma carboxylation, glycosylation, GPI anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, tRNA-mediated addition of amino acids to proteins such as arginylation, and ubiquitination.

[0054] Such modifications are well known to those of skill in the art and have been described in the scientific literature. Several particularly common modifications, glycosylation, lipid attachment, sulfation, gamma-carboxylation of glutamic acid residues, hydroxylation and ADP-ribosylation, for instance, are described in most basic texts, such as Proteins-Structure and Molecular Properties, 2nd Ed., T. E. Creighton, W. H. Freeman and Company, New York (1993). Many detailed reviews are available on this subject, such as by Wold (Posttranslational Covalent Modification of Proteins, B. C. Johnson, Ed., Academic Press, New York 1-12 (1983)); Seifter et al. (Meth. Enzymol. 182: 626-646 (1990)); and Rattan et al. (Ann. N.Y. Acad. Sci. 663:48-62 (1992)).

[0055] Accordingly, exemplary CAT proteins and fragments thereof of the invention can also encompasses derivatives or analogs in which, for example, a substituted amino acid residue is not one encoded by the genetic code, in which a substituent group is included, in which a mature CAT is fused with another composition, such as a composition to increase the half-life of a CAT (e.g., polyethylene glycol or albumin), or in which additional amino acids are fused to a mature CAT, such as a leader or secretory sequence or a sequence for purification of a mature CAT or a pro-protein sequence.

[0056] 2. Antibodies to CAT Proteins

[0057] Exemplary embodiments of the invention provide antibodies to CAT proteins, including, for example, monoclonal and polyclonal antibodies; chimeric, humanized, and fully human antibodies; and antigen-binding fragments and variants thereof, as well as other embodiments.

[0058] Antibodies that selectively bind to a CAT protein can be made using standard procedures known to those of ordinary skills in the art. The term "antibody" is used in the broadest sense, and specifically covers, for example, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), chimeric antibodies, humanized antibodies, fully human antibodies, and antibody fragments (e.g., Fab, F(ab').sub.2, Fv and Fv-containing binding proteins), so long as they exhibit the desired biological activity. Antibodies (Ab's) and immunoglobulins (Ig's) are glycoproteins typically having the same structural characteristics. While antibodies exhibit binding specificity to a specific antigen, immunoglobulins include both antibodies and other antibody-like molecules that lack antigen specificity. Antibodies can be of the IgG, IgE, IgM, IgD, and IgA class or subclass thereof (e.g., IgG1, IgG2, IgG3, IgG4, IgA1 and IgA2). Antibodies may be interchangeably referred to as "antigen-binding molecules".

[0059] The term "monoclonal antibody", as used herein, refers to an antibody obtained from a population of substantially homogeneous antibodies, i.e., the individual antibodies comprising the population are substantially identical except for possible naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific and are typically directed against a single antigenic site. Furthermore, in contrast to polyclonal antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is typically directed against a single determinant on an antigen. In addition to their specificity, monoclonal antibodies are advantageous in that substantially homogenous antibodies can be produced by a hybridoma culture which is uncontaminated by other immunoglobulins or antibodies. The modifier "monoclonal" antibody indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies can be made by hybridoma methods such as described by Kohler and Milstein, Nature 256: 495-497 (1975), by recombinant methods (e.g., as described in U.S. Pat. No. 4,816,567), or can be isolated from phage antibody libraries such as by using the techniques described in Clackson et al., Nature 352: 624-628 (1991) or Marks et al., J. Mol. Biol. 222: 581-597 (1991).

[0060] "Humanized" forms of non-human (e.g., murine or rabbit) antibodies are chimeric immunoglobulins, immunoglobulin chains or fragments thereof (such as Fv, Fab, Fab', F(ab').sub.2 or other antigen-binding subsequences of antibodies) which contain minimal sequence derived from non-human immunoglobulin. Typically, humanized antibodies are human immunoglobulins (a recipient antibody) in which residues from a complementarity determining regions ("CDR") of the recipient are replaced by residues from a CDR of a non-human species (a donor antibody) such as mouse, rat, or rabbit having the desired specificity, affinity, and capacity. In some instances, Fv framework residues of the human immunoglobulin are replaced by corresponding non-human residues. Furthermore, a humanized antibody may comprise residues which are found neither in the recipient antibody nor in the imported CDR or framework region (FR) sequences. These modifications can be made to further refine and optimize antibody performance. In general, a humanized antibody can comprise substantially all of at least one, and typically two, variable domains, in which all or substantially all of the CDRs correspond to those of a non-human immunoglobulin and all or substantially all of the FRs are those of a human immunoglobulin consensus sequence. A humanized antibody can also comprise at least a portion of an immunoglobulin constant region (Fc), typically that of a human immunoglobulin. For further details concerning humanized antibodies, see: Jones et al., Nature 321:522-525 (1986); Reichmann et al., Nature 332:323-327 (1988); Presta, Curr. Op. Struct. Biol. 2:593-596 (1992); Queen et al., U.S. Pat. Nos. 5,530,101; 5,585,089; 5,693,762; and 6,180,370; and Winter, U.S. Pat. No. 5,225,539.

[0061] Antibodies, as used herein, include antibody fragments, particularly antigen-binding fragments, as well as other modified antibody structures and antigen-binding scaffolds (such as modified antibody structures that are smaller or have less than all domains or chains compared with a typical naturally occurring, full-size human antibody). Examples of antibody fragments and other modified antibody structures and antigen-binding scaffolds are known in the art by such terms as minibodies (e.g., U.S. Pat. No. 5,837,821), Nanobodies (llama heavy chain antibodies; Ablynx, Ghent, Belgium), Adnectins (fibronectin domains; Adnexus Therapeutics, Waltham, Mass.), Affibodies (protein-binding domain of Staphylococcus aureus protein A; Affibody, Stockholm, Sweden), peptide aptamers (synthetic peptides; Aptanomics, Lyon, France), Avimers (A-domains derived from cell surface receptors; Avidia, Mountain View, Calif. (acquired by Amgen)), Transbodies (transferrin; BioRexis Pharmaceuticals, King of Prussia, Pa. (acquired by Pfizer)), trimerized tetranectin domains (Borean Pharma, Aarhus, Denmark), Domain antibodies (heavy or light chain antibodies; Domantis, Cambridge, UK (acquired by GlaxoSmithKline)), Evibodies (derived from V-like domains of T-cell receptors CTLA-4, CD28 and inducible T-cell costimulator; EvoGenix Therapeutics, Sydney, Australia), scFV fragments (stable single chain antibody fragments; ESBATech, Zurich, Switzerland), Unibodies (monovalent IgG4 mAbs fragments; Genmab, Copenhagen, Denmark), BiTEs (bispecific, T-cell activating single-chain antibody fragments; Micromet, Munich, Germany), DARPins (designed ankyrin repeat proteins; Molecular Partners, Zurich, Switzerland), Anticalins (derived from lipocalins; Pieris, Freising-Weihenstephan, Germany), Affilins (derived from human lens protein gamma crystalline; Scil Proteins, Halle, Germany), and SMIPs (small modular immunopharmaceuticals; Trubion Pharmaceuticals, Seattle, Wash.) (Sheridan, Nature Biotechnology, 2007 April; 25(4):365-6).

[0062] An "isolated" or "purified" antibody is one that has been identified and separated and/or recovered from a component of the environment in which it is produced. Contaminant components of its production environment are materials that would interfere with diagnostic or therapeutic uses for the antibody, and may include enzymes, hormones, and other proteinaceous or nonproteinaceous solutes. In exemplary embodiments, the antibody can be purified as measurable by any of at least three different methods: 1) to greater than 95% by weight of antibody as determined by the Lowry method, preferably more than 99% by weight; 2) to a degree sufficient to obtain at least 15 residues of N-terminal or internal amino acid sequence by use of a spinning cup sequenator; or 3) to homogeneity by SDS-PAGE under reducing or non-reducing conditions using Coomasie blue or silver stain. Isolated antibody can include an antibody in situ within recombinant cells since at least one component of the antibody's natural environment will not be present. Ordinarily, however, an isolated antibody can be be prepared by at least one purification step.

[0063] An "antigenic region", "antigenic determinant", or "epitope" includes any protein determinant capable of specific binding to an antibody. This is the site on an antigen to which each distinct antibody molecule binds. Epitopic determinants can be active surface groupings of molecules such as amino acids or sugar side chains and may have specific three-dimensional structural characteristics or charge characteristics.

[0064] "Antibody specificity" refers to an antibody that has a stronger binding affinity for an antigen from a first subject species than it has for a homologue of that antigen from a second subject species. Typically, an antibody "binds specifically" to a human antigen (e.g., has a binding affinity (Kd) value of no more than about 1.times.10.sup.-7 M, preferably no more than about 1.times.10.sup.-8 M, and most preferably no more than about 1.times.10.sup.-9 M) but has a binding affinity for a homologue of the antigen from a second subject species which is at least about 50-fold, or at least about 500-fold, or at least about 1000-fold, weaker than its binding affinity for the human antigen. The antibodies can be of any of the various types of antibodies as described herein, such as humanized or fully human antibodies.

[0065] An antibody "selectively" or "specifically" binds a target protein when the antibody binds the target protein and does not significantly bind to unrelated proteins. An antibody can still be considered to selectively or specifically bind a target protein even if it also binds to other proteins that are not substantially homologous with the target protein as long as such proteins share homology with a fragment or domain of the target protein. In this case, it would be understood that antibody binding to the target protein is still selective despite some degree of cross-reactivity.

[0066] Exemplary embodiments of the invention provide an "antibody variant", which refers to an amino acid sequence variant of an antibody wherein one or more of the amino acid residues have been modified. Such variants necessarily have less than 100% sequence identity with the amino acid sequence of the antibody, and have at least 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% amino acid sequence identity with the amino acid sequence of either the heavy or light chain variable domain of the antibody.

[0067] The term "antibody fragment" refers to a portion of a full-length antibody, including the antigen binding or variable region or the antigen-binding portion thereof. Examples of antibody fragments include Fab, Fab', F(ab').sub.2 and Fv fragments. Papain digestion of antibodies typically produces two identical antigen binding fragments, called the Fab fragment, each with a single antigen binding site, and a residual "Fc" fragment. Pepsin treatment typically yields an F(ab').sub.2 fragment that has two antigen binding fragments which are capable of crosslinking antigen, and a residual other fragment (which is termed pFc'). Examples of additional antigen-binding fragments can include diabodies, triabodies, tetrabodies, single-chain Fv, single-chain Fv-Fc, SMIPs, and multispecific antibodies formed from antibody fragments. A "functional fragment", with respect to antibodies, typically refers to an Fv, F(ab), F(ab').sub.2 or other antigen-binding fragments comprising one or more CDRs that has substantially the same antigen-binding specificity as an antibody.

[0068] An "Fv" fragment is an example of an antibody fragment that contains a complete antigen recognition and binding site. This region typically consists of a dimer of one heavy and one light chain variable domain in a tight, non-covalent association (V.sub.H-V.sub.L dimer). It is in this configuration that the three CDRs of each variable domain interact to define an antigen-binding site on the surface of the V.sub.H-V.sub.L dimer. Collectively, the six CDRs confer antigen-binding specificity to the antibody. However, even a single variable domain (or half of an Fv comprising only three CDRs specific for an antigen) has the ability to recognize and bind antigen.

[0069] An "Fab" fragment (also designated as "F(ab)") also contains the constant domain of the light chain and the first constant domain (CH1) of the heavy chain. Fab' fragments differ from Fab fragments by the addition of a few residues at the carboxyl terminus of the heavy chain CH1 domain, including one or more cysteines from the antibody hinge region. Fab'-SH is the designation for Fab' in which the cysteine residue(s) of the constant domains have a free thiol group. F(ab') fragments are produced by cleavage of the disulfide bond at the hinge cysteines of the F(ab').sub.2 pepsin digestion product. Additional chemical couplings of antibody fragments are known to those of ordinary skill in the art.

[0070] A "single-chain Fv" or "scFv" antibody fragment contains V.sub.H and V.sub.L domains, wherein these domains are present in a single polypeptide chain. Typically, the Fv polypeptide further comprises a polypeptide linker between the V.sub.H and V.sub.L domains that enables the scFv to form the desired structure for antigen binding. For a review of scFv, see Pluckthun in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., Springer-Verlag, New York, pp. 269-315 (1994). A single chain Fv-Fc is an scFv linked to a Fc region.

[0071] A "diabody" is a small antibody fragment with two antigen-binding sites, which fragments comprise a variable heavy domain (V.sub.H) connected to a variable light domain (V.sub.L) in the same polypeptide chain. By using a linker that is too short to allow pairing between the two domains on the same chain, the domains are forced to pair with the complementary domains of another chain and create two antigen-binding sites. Diabodies are described more fully in, for example, EP 0 404 097; WO 93/11161; and Hollinger et al., Proc. Natl. Acad. Sci. USA 90:6444-6448 (1993). Triabodies, tetrabodies and other antigen-binding antibody fragments have been described by Hollinger and Hudson, 2005, Nature Biotechnology 23:1126.

[0072] A "small modular immunopharmaceutical" (or "SMIP") is a single-chain polypeptide including a binding domain (e.g., an scFv or an antigen binding portion of an antibody), a hinge region, and an effector domain (e.g., an antibody Fc region or a portion thereof). SMIPs are described in published U.S. Patent Application No. 20050238646.

[0073] Many methods are known for generating and/or identifying antibodies to a given target protein. Several such methods are described by Kohler et al., 1975, Nature 256: 495-497; Lane, 1985, J. Immunol. Meth. 81:223-228; Harlow et al., 1988, Antibodies: A Laboratory Manual. Cold Spring Harbor Laboratory Press; Harlow et al., 1998, Using Antibodies, Cold Spring Harbor Press; Zhong et al., 1997, J. Indust. Microbiol. Biotech. 19(1):71-76; and Berry et al., 2003, Hybridoma and Hybridomics 22(1): 23-31.

[0074] Polyclonal antibodies can be prepared by any known method or modifications of these methods, including obtaining antibodies from patients. In certain exemplary methods for generating antibodies such as polyclonal antibodies, an isolated protein can be used as an immunogen which is administered to a mammalian organism, such as a rat, rabbit, or mouse. For example, a complex of an immunogen such as a CAT protein (or fragment thereof) and a carrier protein can be prepared and an animal immunized by the complex. Serum or plasma containing antibodies against the protein can be recovered from the immunized animal and the antibodies separated and purified (in the same manner as for monoclonal antibodies, for example). The gamma globulin fraction or the IgG antibodies can be obtained, for example, by use of saturated ammonium sulfate or DEAE SEPHADEX, or other techniques known to those skilled in the art. The antibody titer in the antiserum can be measured in the same manner as in the supernatant of a hybridoma culture.

[0075] A full-length CAT protein, an antigenic peptide fragment, or a fusion protein thereof, can be used as an immunogen. A protein used as an immunogen is not limited to any particular type of immunogen. In one aspect, antibodies can be prepared from regions or discrete fragments (e.g., functional domains, extracellular domains, or portions thereof) of a CAT protein. Antibodies can be prepared from any region of a protein as described herein. In particular, the proteins can be selected from the group consisting of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73 and fragments thereof. An antigenic fragment can typically comprise at least 8, 10, 12, 14, 16, or more contiguous amino acid residues, for example. Such fragments can be selected based on a physical property, such as fragments that correspond to regions located on the surface of a protein (e.g., hydrophilic regions) or can be selected based on sequence uniqueness.

[0076] Antibodies can also be produced by inducing production in a lymphocyte population or by screening antibody libraries or panels of highly specific binding reagents, such as disclosed in Orlandi et al. (Proc. Natl. Acad. Sci. 86:3833-3837 (1989)) or Winter et al. (Nature 349:293-299 (1991)). A protein can be used in screening assays of phagemid or B-lymphocyte immunoglobulin libraries to identify antibodies having a desired specificity. Numerous protocols for competitive binding or immunoassays using either polyclonal or monoclonal antibodies with established specificities are well known in the art (e.g., Smith, Curr. Opin. Biotechnol. 2: 668-673 (1991)).

[0077] Antibodies can also be generated using various phage display methods known in the art. In representative phage display methods, functional antibody domains are displayed on the surface of phage particles which carry nucleic acid molecules that encode the antibody domains. In particular, such phage can be utilized to display antigen-binding domains expressed from a repertoire or combinatorial antibody library (e.g., human or murine). Phage expressing an antigen binding domain that binds an antigen of interest can be selected or identified with the antigen, e.g., using labeled antigen or antigen bound or captured to a solid surface or bead. Phage used in methods such as these can typically be filamentous phage including fd and M13 binding domains expressed from phage with Fab, Fv, or disulfide stabilized Fv antibody domains recombinantly fused to either the phage gene III or gene VIII protein. Examples of phage display methods that can be used to make antibodies include methods described in Brinkman et al., J. Immunol. Methods 182:41-50 (1995); Ames et al., J. Immunol. Methods 184:177-186 (1995); Kettleborough et al., Eur. J. Immunol. 24:952-958 (1994); Persic et al., Gene 187:9-18 (1997); Burton et al., Advances in Immunology 57:191-280 (1994); PCT application No. PCT/GB91/01134; PCT publications WO 90/02809; WO 91/10737; WO 92/01047; WO 92/18619; WO 93/11236; WO 95/15982; WO 95/20401; and U.S. Pat. Nos. 5,698,426; 5,223,409; 5,403,484; 5,580,717; 5,427,908; 5,750,753; 5,821,047; 5,571,698; 5,427,908; 5,516,637; 5,780,225; 5,658,727; 5,733,743 and 5,969,108; each of which is incorporated herein by reference in its entirety.

[0078] Antibodies, antigen binding fragments, and/or antibody variants can be produced by recombinant and genetic engineering methods well known in the art. For example, methods of expressing heavy and light chain genes in E. coli are described in PCT publication numbers WO901443, WO901443, and WO9014424, and in Huse et al., 1989 Science 246:1275-1281. When using recombinant techniques, such as to produce an antibody variant, the antibody variant can be produced intracellularly, in the periplasmic space, or directly secreted into the medium. If an antibody variant is produced intracellularly, as a first step, the particulate debris, either host cells or lysed fragments, can be removed, for example, by centrifugation or ultrafiltration. Carter et al. (Bio/Technology 10: 163-167 (1992)) describe a procedure for isolating antibodies that are secreted to the periplasmic space of E. coli. Briefly, cell paste can be thawed in the presence of sodium acetate (pH 3.5), EDTA, and phenylmethylsulfonylfluoride (PMSF) over about 30 minutes. Cell debris can be removed by centrifugation. Where an antibody variant is secreted into the medium, supernatants from such expression systems can first be concentrated using a commercially available protein concentration filter (e.g., an Amicon or Millipore PELLICON ultrafiltration unit). A protease inhibitor such as PMSF can be included in any of the foregoing steps to inhibit proteolysis, and antibiotics can be included to prevent the growth of contaminating microorganisms.

[0079] An antibody composition prepared from cells can be purified using, for example, affinity chromatography, hydroxylapatite chromatography, gel electrophoresis, and/or dialysis. The suitability of protein A as an affinity ligand typically depends on the species and isotype of the immunoglobulin Fc domain of an antibody. Protein A can be used to purify antibodies that are based on human delta1, delta2, or delta4 heavy chains (Lindmark et al., J. Immunol Meth. 62: 1-13 (1983)). Protein G can be used for all mouse isotypes and for human delta3 (Guss et al., EMBO J. 5: 1567-1575 (1986)). The matrix to which the affinity ligand is attached can be, for example, agarose or mechanically stable matrices such as controlled pore glass or poly(styrenedivinyl)benzene. Where the antibody comprises a CH3 domain, the BAKERBOND ABX.TM. resin (J.T. Baker, Phillipsburg, N.J.) can be used for purification. Other exemplary techniques for antibody purification include, but are not limited to, fractionation on an ion-exchange column, ethanol precipitation, reverse phase HPLC, chromatography on silica, chromatography on heparin hepharos, chromatography on an anion or cation exchange resin (such as a polyaspartic acid column), chromatofocusing, SDS-PAGE, and ammonium sulfate precipitation.

[0080] Following any preliminary purification step(s), contaminants in a mixture containing an antibody of interest can be removed by low pH hydrophobic interaction chromatography using an elution buffer at a pH between about 2.5-4.5, preferably performed at low salt concentrations (e.g., from about 0-0.25M salt).

[0081] Full-length antibodies, as well as antibody fragments, can also be expressed and isolated from bacteria such as E. coli, such as described in Mazor et al., "Isolation of engineered, full-length antibodies from libraries expressed in Escherichia coli", Nat Biotechnol. 2007 May; 25(5):563-5 and Sidhu, "Full-length antibodies on display", Nat Biotechnol. 2007 May; 25(5):537-8.

[0082] Further details regarding antibodies are set forth in the following U.S. Pat. No. 6,248,516 (Winter et al.); U.S. Pat. No. 6,291,158 (Winter et al.); U.S. Pat. No. 5,885,793 (Griffiths et al.); U.S. Pat. No. 5,969,108 (McCafferty et al.); U.S. Pat. No. 5,939,598 (Kucherlapati et al.); U.S. Pat. No. 4,816,397 (Boss et al.); U.S. Pat. No. 4,816,567 (Cabilly et al.); U.S. Pat. No. 6,331,415 (Cabilly et al.); U.S. Pat. No. 5,770,429 (Lonberg et al.); U.S. Pat. No. 5,639,947 (Hiatt et al.); and U.S. Pat. No. 5,260,203 (Ladner et al.), each of which is incorporated herein by reference, and in the following published U.S. patent applications: US20040132101 (Lazar et al.), US20050064514 (Stavenhagen et al.), US20040261148 (Dickey et al.), and US20050014934 (Hinton et al.), each of which is incorporated herein by reference.

[0083] 3. Antibody-Drug Conjugates to CAT Proteins

[0084] An antibody against CAT can be coupled (e.g., covalently bonded) to a suitable therapeutic agent (as further discussed herein) either directly or indirectly (e.g., via a linker group). A direct reaction between an antibody and a therapeutic agent is possible when each possesses a substituent capable of reacting with the other. For example, a nucleophilic group, such as an amino or sulfhydryl group, on one molecule may be capable of reacting with a carbonyl-containing group, such as an anhydride or an acid halide, or with an alkyl group containing a good leaving group (e.g., a halide) on the other molecule.

[0085] Alternatively, it may be desirable to couple a therapeutic agent and an antibody via a linker group. A linker group can function as a spacer to distance an antibody from an agent in order to avoid interference with binding capabilities. A linker group can also serve to increase the chemical reactivity of a substituent on an agent or an antibody, and thus increase the coupling efficiency. An increase in chemical reactivity may also facilitate the use of agents, or functional groups on agents, which otherwise would not be possible.

[0086] A variety of bifunctional or polyfunctional reagents, both homo- and hetero-functional (such as those described in the catalog of the Pierce Chemical Co., Rockford, Ill.), can be employed as the linker group. Coupling can be effected, for example, through amino groups, carboxyl groups, sulfhydryl groups, or oxidized carbohydrate residues (e.g., U.S. Pat. No. 4,671,958).

[0087] Where a therapeutic agent is more potent when free from the antibody portion of an immunoconjugate, it may be desirable to use a linker group that is cleavable during or upon internalization into a cell. A number of different cleavable linker groups have been described. Mechanisms for the intracellular release of an agent from these linker groups include cleavage by reduction of a disulfide bond (e.g., U.S. Pat. No. 4,489,710), by irradiation of a photolabile bond (e.g., U.S. Pat. No. 4,625,014), by hydrolysis of derivatized amino acid side chains (e.g., U.S. Pat. No. 4,638,045), by serum complement-mediated hydrolysis (e.g., U.S. Pat. No. 4,671,958), by protease cleavable linker (e.g., U.S. Pat. No. 6,214,345), and by acid-catalyzed hydrolysis (e.g., U.S. Pat. No. 4,569,789).

[0088] It may be desirable to couple more than one agent to an antibody. Multiple molecules of an agent can be coupled to one antibody molecule, and more than one type of agent can be coupled to the same antibody. For example, about 1, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, or 22 (or any other number in-between) molecules of therapeutic agents can be coupled to an antibody. The average number or quantitative distribution of therapeutic agent molecules per antibody molecule in a preparation of conjugation reactions can be determined by conventional means such as mass spectroscopy, ELISA, or HPLC. Separation, purification, and characterization of homogeneous antibody-drug conjugates having a certain number of therapeutic agents conjugated thereto can be achieved by means such as reverse phase HPLC or electrophoresis (see, e.g., Hamblett et al., Clinical Cancer Res. 10:7063-70 (2004).

[0089] Examples of suitable therapeutic agents that can be conjugated to an antibody include, but are not limited to, chemotherapeutic agents (e.g., cytotoxic or cytostatic agents or immunomodulatory agents), radiotherapeutic agents, therapeutic antibodies, small molecule drugs, peptide drugs, immunomodulatory agents, differentiation inducers, and toxins.

[0090] Examples of useful classes of cytotoxic or immunomodulatory agents include, but are not limited to, antitubulin agents, auristatins, DNA minor groove binders, DNA replication inhibitors, alkylating agents (e.g., platinum complexes such as cis-platin, mono(platinum), bis(platinum) and tri-nuclear platinum complexes and carboplatin), anthracyclines, antibiotics, antifolates, antimetabolites, chemotherapy sensitizers, duocarmycins, etoposides, fluorinated pyrimidines, ionophores, lexitropsins, nitrosoureas, platinols, pre-forming compounds, purine antimetabolites, puromycins, radiation sensitizers, steroids, taxanes, topoisomerase inhibitors, vinca alkaloids, and the like.

[0091] Examples of individual cytotoxic or immunomodulatory agents include, but are not limited to, androgen, anthramycin (AMC), asparaginase, 5-azacytidine, azathioprine, bleomycin, busulfan, buthionine sulfoximine, calicheamicin or calicheamicin derivatives, camptothecin or camptothecins derivatives, carboplatin, carmustine (BSNU), CC-1065, chlorambucil, cisplatin, colchicine, cyclophosphamide, cytidine arabinoside (cytarabine), cytochalasin B, dacarbazine, dactinomycin (formerly actinomycin), daunorubicin, decarbazine, docetaxel, doxorubicin, etoposide, estrogen, 5-fluordeoxyuridine, 5-fluorouracil, gemcitabine, gramicidin D, hydroxyurea, idarubicin, ifosfamide, irinotecan, lomustine (CCNU), maytansine, mechlorethamine, melphalan, 6-mercaptopurine, methotrexate, mithramycin, mitomycin C, mitoxantrone, nitroimidazole, paclitaxel, palytoxin, plicamycin, procarbizine, rhizoxin, streptozotocin, tenoposide, 6-thioguanine, thioTEPA, topotecan, vinblastine, vincristine, vinorelbine, VP-16, and VM-26.

[0092] Examples of other suitable cytotoxic agents include, but are not limited to, DNA minor groove binders (e.g., enediynes and lexitropsins, a CBI compound; see also U.S. Pat. No. 6,130,237), duocarmycins, taxanes (e.g., paclitaxel and docetaxel), puromycins, vinca alkaloids, CC-1065, SN-38, topotecan, morpholino-doxorubicin, rhizoxin, cyanomorpholino-doxorubicin, echinomycin, combretastatin, netropsin, epothilone A and B, estramustine, cryptophysins, cemadotin, a maytansinoid, discodermolide, eleutherobin, and mitoxantrone.

[0093] Examples of other suitable agents include, but are not limited to, radionuclides, differentiation inducers, drugs, toxins, and derivatives thereof. Exemplary radionuclides include .sup.90Y, .sup.123I, .sup.125I, .sup.131I, .sup.186Re, .sup.188Re, .sup.211At, and .sup.212Bi. Exemplary drugs include methotrexate, and pyrimidine and purine analogs. Exemplary differentiation inducers include phorbol esters and butyric acid. Exemplary toxins include ricin, abrin, diptheria toxin, cholera toxin, gelonin, Pseudomonas exotoxin, Shigella toxin, and pokeweed antiviral protein.

[0094] In some embodiments, the therapeutic agent used in an antibody-drug conjugate is an anti-tubulin agent. Examples of anti-tubulin agents include, but are not limited to, taxanes (e.g., Taxol.RTM. (paclitaxel), Taxotere.RTM. (docetaxel)), T67 (Tularik) and vinca alkyloids (e.g., vincristine, vinblastine, vindesine, and vinorelbine). Other antitubulin agents include, for example, baccatin derivatives, taxane analogs (e.g., epothilone A and B), nocodazole, colchicine and colcimid, estramustine, cryptophysins, cemadotin, maytansinoid, combretastatins, discodermolide, and eleutherobin.

[0095] In certain embodiments, the cytotoxic agent is a maytansinoid, another group of anti-tubulin agents. For example, in specific embodiments, the maytansinoid is maytansine, DM-1 (ImmunoGen, Inc.; see also Chari et al., Cancer Res. 52:127-131 (1992)) or DM-4. In some embodiments, the therapeutic agent is an auristatin, such as auristatin E (also known in the art as dolastatin-10) or a derivative thereof. Typically, an auristatin E derivative is, e.g., an ester formed between auristatin E and a keto acid. For example, auristatin E can be reacted with paraacetyl benzoic acid or benzoylvaleric acid to produce AEB and AEVB, respectively. Other typical auristatin derivatives include AFP, MMAF, and MMAE. The synthesis and structure of auristatin derivatives are described in U.S. Patent Application Publication Nos. 2003-0083263, 2005-0238649 and 2005-0009751; PCT Publication Nos WO 04/010957 and WO 02/088172, and U.S. Pat. Nos. 6,323,315; 6,239,104; 6,034,065; 5,780,588; 5,665,860; 5,663,149; 5,635,483; 5,599,902; 5,554,725; 5,530,097; 5,521,284; 5,504,191; 5,410,024; 5,138,036; 5,076,973; 4,986,988; 4,978,744; 4,879,278; 4,816,444; and 4,486,414.

[0096] 4. CAT Nucleic Acid Molecules

[0097] Exemplary isolated CAT nucleic acid molecules of the invention consist of, consist essentially of, or comprise a nucleotide sequence that encodes a CAT protein of the invention, an allelic variant thereof, or an ortholog or paralog thereof, for example. As used herein, an "isolated" nucleic acid molecule is one that is separated from other nucleic acid present in the natural source of the nucleic acid. Preferably, an "isolated" nucleic acid is free of sequences which naturally flank the nucleic acid (i.e., sequences located at the 5' and 3' ends of the nucleic acid) in the genomic DNA of the organism from which the nucleic acid is derived. However, there can be some flanking nucleotide sequences, for example up to about 5 kilobases (KB), 4 KB, 3 KB, 2 KB, or 1 KB or less, particularly contiguous protein-encoding sequences and protein-encoding sequences within the same gene but separated by introns in the genomic sequence, and flanking nucleotide sequences that contain regulatory elements. The primary consideration is that the nucleic acid is isolated from remote and unimportant flanking sequences such that it can be subjected to the specific manipulations described herein such as recombinant expression, preparation of probes and primers, and other uses specific to the nucleic acid molecules. Moreover, an "isolated" nucleic acid molecule, such as a transcript/cDNA molecule, can be substantially free of other cellular material, or culture medium when produced by recombinant techniques, or chemical precursors or other chemicals when chemically synthesized.

[0098] A nucleic acid molecule can be fused to other coding or regulatory sequences and still be considered isolated. Isolated nucleic acid molecules can include heterologous nucleotide sequences, such as heterologous nucleotide sequences that are fused to a nucleic acid molecule by recombinant techniques. For example, recombinant DNA molecules contained in a vector are considered isolated. Further examples of isolated DNA molecules include recombinant DNA molecules maintained in heterologous host cells, or purified (partially or substantially) DNA molecules in solution. Isolated RNA molecules include in vivo or in vitro RNA transcripts of isolated DNA molecules. Isolated nucleic acid molecules further include such molecules produced synthetically.

[0099] Isolated nucleic acid molecules can encode a mature protein plus additional amino or carboxyl-terminal amino acids, or amino acids interior to the mature protein (when the mature form has more than one peptide chain, for instance). Such sequences may play a role in processing of a protein from precursor to a mature form, facilitate protein trafficking, prolong or shorten protein half-life, or facilitate manipulation of a protein for assay or production, among other things. As generally is the case in situ, additional amino acids may be processed away from the mature protein by cellular enzymes.

[0100] Isolated nucleic acid molecules include, but are not limited to, sequences encoding a CAT protein alone, sequences encoding a mature protein with additional coding sequences (such as a leader or secretory sequence (e.g., a pre-pro or pro-protein sequence)), and sequences encoding a mature protein (with or without additional coding sequences) plus additional non-coding sequences (e.g., introns and non-coding 5' and 3' sequences such as transcribed but non-translated sequences that play a role in transcription, mRNA processing (including splicing and polyadenylation signals), ribosome binding, and/or stability of mRNA). In addition, nucleic acid molecules can be fused to a marker sequence encoding, for example, a peptide that facilitates purification.

[0101] Isolated nucleic acid molecules can be in the form of RNA, such as mRNA, or in the form of DNA, including cDNA and genomic DNA obtained by cloning or produced by chemical synthetic techniques or by a combination thereof. Nucleic acid molecules, especially DNA, can be double-stranded or single-stranded. Single-stranded nucleic acid can be the coding strand (sense strand) or the non-coding strand (anti-sense strand).

[0102] Exemplary embodiments of the invention further provide isolated nucleic acid molecules that encode fragments of a CAT protein as well as nucleic acid molecules that encode obvious variants of a CAT protein. Such nucleic acid molecules may be naturally occurring, such as allelic variants (same locus), paralogs (different locus), and orthologs (different organism), or can be constructed by recombinant DNA methods or by chemical synthesis. Such non-naturally occurring variants can be made by mutagenesis techniques, including those applied to nucleic acid molecules, cells, or organisms. Accordingly, nucleic acid molecule variants can contain nucleotide substitutions, deletions, inversions, and/or insertions. Variations can occur in either or both the coding and non-coding regions, and variations can produce conservative and/or non-conservative amino acid substitutions.

[0103] A fragment of a nucleic acid molecule typically comprises a contiguous nucleotide sequence at least 8, 10, 12, 15, 16, 18, 20, 22, 25, 30, 40, 50, 100, 150, 200, 250, 500 (or any other number in-between) or more nucleotides in length. The length of a fragment can be based on its intended use. For example, a fragment can encode epitope bearing regions of a protein, or can be used as DNA probes and primers. Isolated fragments can be produced by synthesizing an oligonucleotide probe using known techniques, for example, and can optionally be labeled and used to screen a cDNA library, genomic DNA, or mRNA, for example. Primers can be used in PCR reactions to clone specific regions of a gene.

[0104] A probe/primer typically comprises substantially a purified oligonucleotide or oligonucleotide pair. An oligonucleotide typically comprises a nucleotide sequence that hybridizes under stringent conditions to at least about 8, 10, 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 40, 50 (or any other number in-between) or more contiguous nucleotides.

[0105] Allelic variants, orthologs, and homologs can be identified using methods well known in the art. These variants can comprise a nucleotide sequence encoding a protein that is typically 60-70%, 70-80%, 80-90%, 90-95%, 96%, 97%, 98%, or 99% homologous to the nucleotide sequence. Such nucleic acid molecules can readily be identified as being able to hybridize under moderate to stringent conditions, to a nucleotide sequence shown in the Sequence Listing or a fragment thereof.

[0106] As used herein, the term "hybridizes under stringent conditions" is intended to describe conditions for hybridization and washing under which nucleotide sequences encoding a protein at least 60-70% homologous to each other typically remain hybridized to each other. The conditions can be such that sequences at least about 60%, at least about 70%, or at least about 80% or more homologous to each other typically remain hybridized to each other. Such stringent conditions are known to those skilled in the art and can be found in, for example, Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989-2006), 6.3.1-6.3.6. One example of stringent hybridization conditions is hybridization in 6.times. sodium chloride/sodium citrate (SSC) at about 45.degree. C., followed by one or more washes in 0.2.times.SSC, 0.1% SDS at 50-65.degree. C. Examples of moderate to low stringency hybridization conditions are well known in the art.

[0107] Exemplary embodiments of the invention also include kits for detecting the presence of CAT nucleic acid (e.g., DNA or mRNA) in a biological sample. For example, a kit can comprise reagents such as a labeled or labelable nucleic acid and/or other agents capable of detecting CAT nucleic acid in a biological sample; means for determining the amount of CAT nucleic acid in the sample; and means for comparing the amount of CAT nucleic acid in the sample with a standard. The nucleic acid and/or other agent can be packaged in one or more suitable containers. The kit can further comprise instructions for using the kit to detect CAT nucleic acid.

[0108] 5. Vectors and Host Cells

[0109] Exemplary embodiments of the invention also provide vectors containing CAT nucleic acid molecules. The term "vector" refers to a vehicle, such as a nucleic acid molecule, which can transport the CAT nucleic acid molecules. When the vector is a nucleic acid molecule, the CAT nucleic acid molecules are covalently linked to the vector nucleic acid. A vector can be, for example, a plasmid, single or double stranded phage, a single or double stranded RNA or DNA viral vector, or artificial chromosome, such as a BAC, PAC, YAC, OR MAC.

[0110] A vector can be maintained in a host cell as an extrachromosomal element where it replicates and produces additional copies of the CAT nucleic acid molecules. Alternatively, a vector can integrate into a host cell genome and produce additional copies of the CAT nucleic acid molecules when the host cell replicates.

[0111] Exemplary embodiments of the invention provide vectors for maintenance (cloning vectors) and vectors for expression (expression vectors) of the nucleic acid molecules, for example. Expression vectors can express a portion of, or all of, a protein sequence. Vectors can function in prokaryotic or eukaryotic cells or in both (shuttle vectors). Vectors also include insertion vectors, which integrate a nucleic acid molecule into another nucleic acid molecule, such as into the cellular genome (such as to alter in situ expression of a gene and/or gene product). For example, an endogenous protein-coding sequence can be entirely or partially replaced via homologous recombination with a protein-coding sequence containing one or more specifically introduced mutations.

[0112] Expression vectors can contain cis-acting regulatory regions that are operably-linked in the vector to the nucleic acid molecules such that transcription of the nucleic acid molecules is allowed in a host cell. The nucleic acid molecules can be introduced into the host cell with a separate nucleic acid molecule capable of affecting transcription. The separate nucleic acid molecule may provide, for example, a trans-acting factor interacting with the cis-regulatory control region to allow transcription of the nucleic acid molecules from the vector. Alternatively, a trans-acting factor may be supplied by a host cell. Additionally, a trans-acting factor can be produced from a vector itself. It is understood, however, that transcription and/or translation of nucleic acid molecules can occur in cell-free systems.

[0113] Regulatory sequences to which CAT nucleic acid molecules can be operably linked include, for example, promoters for directing mRNA transcription. These include, but are not limited to, the left promoter from bacteriophage, the lac, TRP, and TAC promoters from E. coli, the early and late promoters from SV40, the CMV immediate early promoter, the adenovirus early and late promoters, and retrovirus long-terminal repeats.

[0114] In addition to control regions that promote transcription, expression vectors can also include regions that modulate transcription, such as repressor binding sites and enhancers. Examples include the SV40 enhancer, the cytomegalovirus immediate early enhancer, polyoma enhancer, adenovirus enhancers, and retrovirus LTR enhancers.

[0115] In addition to containing sites for transcription initiation and control, expression vectors can also contain sequences necessary for transcription termination and, in the transcribed region, a ribosome binding site for translation. Other regulatory control elements for expression include initiation and termination codons as well as polyadenylation signals. Numerous regulatory sequences useful in expression vectors are well known in the art (e.g., Sambrook et al., Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001)).

[0116] A variety of expression vectors can be used to express a nucleic acid molecule. Such vectors include chromosomal, episomal, and virus-derived vectors, for example vectors derived from bacterial plasmids, from bacteriophage, from yeast episomes, from yeast chromosomal elements, including yeast artificial chromosomes, from viruses such as baculoviruses, papovaviruses such as SV40, Vaccinia viruses, adenoviruses, poxviruses, pseudorabies viruses, and retroviruses. Vectors may also be derived from combinations of these sources such as those derived from plasmid and bacteriophage genetic elements, e.g. cosmids and phagemids. Appropriate cloning and expression vectors for prokaryotic and eukaryotic hosts are described in Sambrook et al., Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001).

[0117] A regulatory sequence can provide constitutive expression in one or more host cells (e.g., tissue specific) or can provide for inducible expression in one or more cell types such as by temperature, nutrient additive, or exogenous factors such as a hormone or other ligand. A variety of vectors providing for constitutive and inducible expression in prokaryotic and eukaryotic hosts are well known in the art.

[0118] Nucleic acid molecules can be inserted into vector nucleic acid by well-known methodology. For example, the DNA sequence that will ultimately be expressed can be joined to an expression vector by cleaving the DNA sequence and the expression vector with one or more restriction enzymes and then ligating the fragments together. Procedures for restriction enzyme digestion and ligation are well known in the art.

[0119] A vector containing a nucleic acid molecule of interest can be introduced into an appropriate host cell for propagation or expression using well-known techniques. Bacterial cells include, but are not limited to, E. coli, Streptomyces, and Salmonella typhimurium. Eukaryotic cells include, but are not limited to, yeast, insect cells such as Drosophila, animal cells such as COS and CHO cells (e.g., DG44 or CHO-s), and plant cells.

[0120] As described herein, it may be desirable to express a protein as a fusion protein. Accordingly, exemplary embodiments of the invention provide fusion vectors that allow for the production of fusion proteins. Fusion vectors can, for example, increase the expression of a recombinant protein; increase the solubility of a recombinant protein, and/or aid in the purification of a protein such as by acting as a ligand for affinity purification. A proteolytic cleavage site can be introduced at the junction of the fusion moiety so that the desired protein can ultimately be separated from the fusion moiety. Proteolytic enzymes include, but are not limited to, factor Xa, thrombin, and enteroenzyme. Typical fusion expression vectors include pGEX (Smith et al., Gene 67:31-40 (1988)), pMAL (New England Biolabs, Beverly, Mass.) and pRIT5 (Pharmacia, Piscataway, N.J.), which fuse glutathione S-transferase (GST), maltose E binding protein, or protein A, respectively, to a target recombinant protein. Examples of suitable inducible non-fusion E. coli expression vectors include pTrc (Amann et al., Gene 69:301-315 (1988)) and pET 11d (Studier et al., Gene Expression Technology: Methods in Enzymology 185:60-89 (1990)).

[0121] Recombinant protein expression can be maximized in host bacteria by providing a genetic background wherein the host cell has an impaired capacity to proteolytically cleave the recombinant protein (Gottesman, S., Gene Expression Technology: Methods in Enzymology 185, Academic Press, San Diego, Calif. (1990), pp. 119-128). Alternatively, the sequence of a nucleic acid molecule of interest can be altered to provide preferential codon usage for a specific host cell, such as E. coli (Wada et al., Nucleic Acids Res. 20:2111-2118 (1992)).

[0122] CAT nucleic acid molecules can, for example, be expressed by expression vectors in a yeast host. Examples of vectors for expression in yeast (e.g., S. cerevisiae) include pYepSec1 (Baldari, et al., EMBO J. 6:229-234 (1987)), pMFa (Kurjan et al., Cell 30:933-943 (1982)), pJRY88 (Schultz et al., Gene 54:113-123 (1987)), and pYES2 (Invitrogen Corporation, San Diego, Calif.). Nucleic acid molecules can also be expressed in insect cells using, for example, baculovirus expression vectors. Baculovirus vectors available for expression of proteins in cultured insect cells (e.g., Sf 9 cells) include the pAc series (Smith et al., Mol. Cell Biol. 3:2156-2165 (1983)) and the pVL series (Lucklow et al., Virology 170:31-39 (1989)). Nucleic acid molecules can also be expressed in mammalian cells using mammalian expression vectors. Examples of mammalian expression vectors include pCDM8 (Seed, B. Nature 329:840 (1987)), pMT2PC (Kaufman et al., EMBO J. 6:187-195 (1987)), and CHEF (U.S. Pat. No. 5,888,809).

[0123] The expression vectors listed herein are provided by way of example only of well-known vectors available to those of ordinary skill in the art that would be useful to express CAT nucleic acid molecules. The person of ordinary skill in the art would be aware of other vectors suitable for maintenance, propagation, and/or expression of CAT nucleic acid molecules (e.g., Sambrook et al. Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001).

[0124] Exemplary embodiments of the invention also encompasses vectors in which CAT nucleic acid molecules are cloned into a vector in reverse orientation, but operably linked to a regulatory sequence that permits transcription of antisense RNA. Thus, an antisense transcript can be produced to all, or to a portion, of a CAT nucleic acid molecule, including coding and non-coding regions. Expression of this antisense RNA may be subject to each of the parameters described above in relation to expression of the sense RNA (e.g., regulatory sequences, constitutive or inducible expression, tissue-specific expression).

[0125] Exemplary embodiments of the invention provide recombinant host cells containing the vectors described herein. Host cells include, for example, prokaryotic cells, lower eukaryotic cells such as yeast, other eukaryotic cells such as insect cells, and higher eukaryotic cells such as mammalian cells.

[0126] Recombinant host cells can be prepared by introducing vector constructs, such as described herein, into cells by techniques readily available to a person of ordinary skill in the art. These techniques include, but are not limited to, calcium phosphate transfection, DEAE-dextran-mediated transfection, cationic lipid-mediated transfection, electroporation, transduction, infection, lipofection, microinjection, and other techniques such as those found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (2001).

[0127] For example, using techniques such as these, a retroviral or other viral vector can be introduced into mammalian cells. Examples of mammalian cells into which a retroviral vector can be introduced include, but are not limited to, primary mammalian cultures or continuous mammalian cultures, COS cells, NIH3T3, 293 cells (ATCC #CRL 1573), and dendritic cells.

[0128] Host cells can contain more than one vector. Thus, different nucleotide sequences can be introduced on different vectors of the same cell. Similarly, nucleic acid molecules of interest can be introduced either alone or with other unrelated nucleic acid molecules such as those providing trans-acting factors for expression vectors. When more than one vector is introduced into a cell, the vectors can be introduced independently, co-introduced, or joined to the nucleic acid molecule vector.

[0129] Bacteriophage and viral vectors can be introduced into cells as packaged or encapsulated virus by standard procedures for infection and transduction. Viral vectors can be replication-competent or replication-defective. If viral replication is defective, replication can occur in host cells that provide functions that complement the defects.

[0130] Vectors can include selectable markers that enable the selection of a subpopulation of cells that contain the recombinant vector constructs. Markers can be contained in the same vector that contains the nucleic acid molecules of interest or can be on a separate vector. Exemplary markers include tetracycline or ampicillin-resistance genes for prokaryotic host cells, and dihydrofolate reductase or neomycin resistance for eukaryotic host cells. However, any marker that provides selection for a phenotypic trait can be used.

[0131] While mature proteins can be produced in bacteria, yeast, mammalian cells, and other cells under the control of appropriate regulatory sequences, cell-free transcription and translation systems can also be used to produce these proteins using RNA derived from the DNA constructs described herein.

[0132] If secretion of a protein is desired, appropriate secretion signals can be incorporated into a vector. The signal sequence can be endogenous or heterologous to the protein.

[0133] If a protein is not secreted into a medium, the protein can be isolated from a host cell by standard disruption procedures, including freeze/thaw, sonication, mechanical disruption, use of lysing agents, and the like. A protein can then be recovered and purified by well-known purification methods including, for example, ammonium sulfate precipitation, acid extraction, anion or cationic exchange chromatography, phosphocellulose chromatography, hydrophobic-interaction chromatography, affinity chromatography, hydroxylapatite chromatography, lectin chromatography, or high performance liquid chromatography.

[0134] It is also understood that, depending upon the host cell used in recombinant production of a protein, proteins can have various glycosylation patterns or can be non-glycosylated, such as when produced in bacteria. In addition, proteins can include an initial modified methionine in some instances as a result of a host-mediated process.

[0135] Recombinant host cells that express a CAT protein have a variety of uses. For example, such host cells are useful for producing CAT proteins, which can be further purified to produce desired amounts of the protein or fragments thereof. Thus, host cells containing expression vectors are useful for protein production.

[0136] Host cells are also useful for conducting cell-based assays involving a CAT protein or fragments thereof. For example, a recombinant host cell expressing a CAT protein can be used to assay compounds that stimulate or inhibit the protein's function.

[0137] Host cells are also useful for identifying mutant CAT proteins in which the protein's function is affected. Host cells expressing mutant proteins are useful for assaying compounds that have a desired effect on the mutant proteins (e.g., stimulating or inhibiting function), particularly if the mutant proteins naturally occur and give rise to a pathology.

[0138] 6. Diagnosis and Treatment in General

[0139] The following terms, as used in the present specification and claims, are intended to have the meaning as defined below, unless indicated otherwise.

[0140] As used herein, a "biological sample" (or just "sample") can comprise, for example, tissue, blood, sera, cells, cell lines, or biological fluids such as plasma, interstitial fluid, urine, cerebrospinal fluid, and the like. A biological sample is typically, although not necessarily, obtained from an individual by a medical practitioner.

[0141] As used herein, a "subject" can be a mammalian subject or non-mammalian subject, preferably a mammalian subject. A mammalian subject can be a human or non-human, preferably a human. The terms "subject", "individual", and "patient" are used herein interchangeably.

[0142] A "healthy" or "normal" subject or biological sample is a subject or biological sample in which the disease of interest is not detectable, as ascertained by using conventional diagnostic methods (such a biological sample can interchangeably be referred to as a "control" sample).

[0143] As used herein, "disease(s)" include cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target, and associated diseases and pathologies.

[0144] The terms "diagnose" (or "diagnosing", etc.) and "assess" (or "assessing", etc.) are used herein interchangeably. Diagnosing or assessing diseases can include, for example, initially detecting a disease; determining a specific stage, sub-type, or other classification of a disease; prognosing the future course of a disease; monitoring disease progression or remission (e.g., monitoring metastatic spread of a cancer); determining response to a treatment; determining or predicting recurrence of a disease; and/or determining the likelihood of developing a disease in the future.

[0145] "Treat", "treating", or "treatment" of a disease includes: (1) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or (2) relieving the disease, i.e., causing regression of the disease or its clinical symptom(s).

[0146] The term "prophylaxis" is used to distinguish from "treatment," and to encompass both "preventing" and "suppressing." It is not always possible to distinguish between "preventing" and "suppressing," as the ultimate inductive event or events may be unknown, latent, or the patient is not ascertained until well after the occurrence of the event or events. Therefore, the term "protection", as used herein, is meant to include "prophylaxis."

[0147] A "therapeutically effective amount" means the amount of an agent that, when administered to a subject for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" can vary depending on such factors as the agent, the disease and its severity, and the age, weight, etc., of the subject to be treated.

[0148] A "differential level" is a level of a target (e.g., CAT protein or nucleic acid) in a test sample (e.g., disease sample, or drug resistant cells) either above or below the level of the same target in a corresponding control or normal sample (e.g., a control cell line or a biological sample from a healthy individual, or cells responsive/sensitive to a drug).

[0149] Exemplary embodiments of the invention provide methods for treating diseases, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target, comprising administering to a patient a therapeutically effective amount of an antagonist, agonist, or a pharmaceutical composition thereof. Exemplary embodiments of the invention further provide agonists and antagonists to CAT proteins, as well as pharmaceutical compositions that comprise an agonist or antagonist with a suitable carrier such as a pharmaceutically acceptable excipient.

[0150] Exemplary agonists or antagonists include antibodies that specifically bind to a CAT protein. Antibodies can be used alone or in combination with one or more other therapeutic agents (e.g., as an antibody-drug conjugate or a combination therapy). Further examples of molecules that can be used as antagonists include, but are not limited to, small molecules that inhibit the function or abundance level of CAT, and inhibitory nucleic acid molecules such as RNAi or antisense nucleic acid molecules that specifically hybridize to CAT nucleic acid.

[0151] Exemplary embodiments of the invention further encompass novel agents identified by screening assays using CAT, such as the screening assays described herein, as well as methods of using these agents, such as for treatment or diagnostic purposes. For example, an agent identified as described herein (e.g., a CAT-modulating agent, a CAT-specific nucleic acid molecule such as an RNAi or antisense molecule, a CAT-specific antibody, a CAT-specific antibody-drug conjugate, or a CAT-binding partner) can be used in an animal or other model, such as to determine efficacy, toxicity, or side effects of treatment with the agent.

[0152] Modulators of CAT protein activity, such as modulators identified according to the drug screening assays described herein, can be used to treat a subject with a disorder mediated by a CAT, e.g., by treating cells or tissues that express CAT at a differential level. Methods of treatment can include the step of administering a modulator of CAT activity in a pharmaceutical composition to a subject in need of such treatment.

[0153] In certain exemplary embodiments, if decreased expression or activity of a protein is desired, an antibody to the protein or an inhibitor/antagonist and the like, or a pharmaceutical agent containing one or more of these molecules, can be administered to an individual. In other exemplary embodiments, if increased expression or activity of a protein is desired, the protein itself or an agonist/enhancer and the like, or a pharmaceutical agent containing one or more of these molecules, can be administered. Administration can be effected by methods well known in the art and may include delivery by an antibody specifically targeted to the protein. Neutralizing antibodies, which inhibit dimer formation, can be used when decreased expression or activity of a protein is desired.

[0154] Although modulating agents can be administered in a pure or substantially pure form, modulating agents can also be administered as pharmaceutical compositions, formulations, or preparations with a carrier. Exemplary formulations of the invention, such as for human or veterinary use, comprise a suitable active CAT-modulating agent, together with one or more pharmaceutically acceptable carriers and, optionally, other therapeutic ingredients. The carrier(s) are "acceptable" in the sense of being compatible with other ingredients of a formulation and not deleterious to the recipient thereof. The formulations can be presented in unit dosage form and can be prepared by any method known to the skilled artisan.

[0155] Examples of suitable pharmaceutical carriers include proteins such as albumins (e.g., U.S. Pat. No. 4,507,234), peptides and polysaccharides such as aminodextran (e.g., U.S. Pat. No. 4,699,784), and water. A carrier can also bear an agent by noncovalent bonding or by encapsulation, such as within a liposome vesicle (e.g., U.S. Pat. Nos. 4,429,008 and 4,873,088). Carriers specific for radionuclide agents include radiohalogenated small molecules and chelating compounds. For example, U.S. Pat. No. 4,735,792 discloses representative radiohalogenated small molecules and their synthesis. A radionuclide chelate can be formed from chelating compounds that include those containing nitrogen and sulfur atoms as the donor atoms for binding the metal, metal oxide, radionuclide. For example, U.S. Pat. No. 4,673,562 discloses representative chelating compounds and their synthesis.

[0156] Methods of preparing pharmaceutical formulations typically include the step of bringing into association the active ingredient with the carrier, which constitutes one or more accessory ingredients. Formulations can be prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired formulation.

[0157] Formulations suitable for intravenous, intramuscular, subcutaneous, or intraperitoneal administration can comprise sterile aqueous solutions of the active ingredient with solutions, which can be isotonic with the blood of the recipient. Such formulations can be prepared by dissolving solid active ingredient in water containing physiologically compatible substances such as sodium chloride (e.g., 0.1-2.0M), glycine, and the like, and having a buffered pH compatible with physiological conditions to produce an aqueous solution, and rendering the solution sterile. These may be present in unit or multi-dose containers, for example, sealed ampoules or vials.

[0158] Exemplary formulations of the invention can incorporate a stabilizer. Exemplary stabilizers include polyethylene glycol, proteins, saccharides, amino acids, inorganic acids, detergents, and organic acids, which can be used either alone or as admixtures. These stabilizers can be incorporated in an amount of, for example, 0.11-10,000 parts by weight per part by weight of an agent. If two or more stabilizers are to be used, their total amount can be within the range specified above. These stabilizers can be used in aqueous solutions at an appropriate concentration and pH. The specific osmotic pressure of such aqueous solutions can be in the range of 0.1-3.0 osmoles, preferably in the range of 0.8-1.2. The pH of the aqueous solution can be adjusted to be within the range of 5.0-9.0, preferably within the range of 6-8. In formulating an antibody or antibody-drug conjugate, an anti-adsorption agent can be used.

[0159] Additional pharmaceutical methods can be employed to control duration of action. Controlled release can be achieved through the use of polymer to complex or absorb the proteins or their derivatives. Controlled delivery can be achieved by selecting appropriate macromolecules (e.g., polyester, polyamino acids, polyvinyl, pyrrolidone, ethylenevinylacetate, methylcellulose, carboxymethylcellulose, or protamine sulfate) and the concentration of macromolecules as well as the methods of incorporation in order to control release. Another possible method to control the duration of action by controlled-release preparations is to incorporate an anti-CAT antibody into particles of a polymeric material such as polyesters, polyamino acids, hydrogels, poly(lactic acid) or ethylene vinylacetate copolymers. Alternatively, instead of incorporating these agents into polymeric particles, it is possible to entrap these materials in microcapsules prepared, for example, by coacervation techniques or by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly(methylmethacylate) microcapsules, respectively, or in colloidal drug delivery systems, for example, liposomes, albumin microspheres, microemulsions, nanoparticles, and nanocapsules or in macroemulsions.

[0160] When oral preparations are desired, the compositions can be combined with typical carriers, such as lactose, sucrose, starch, talc magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose, glycerin, sodium alginate or gum arabic, among others.

[0161] Any of the therapeutic agents provided herein may be administered in combination with other therapeutic agents. Selection of agents for use in combination therapy can be made by one of ordinary skill in the art according to conventional pharmaceutical principles. A combination of therapeutic agents may act synergistically to affect treatment of a particular disorder at a lower dosage of each agent.

[0162] 7. Methods of Detection and Diagnosis Based on CAT Proteins

[0163] CAT proteins are useful for diagnosing a disease, or predisposition to a disease, particularly diseases in which the protein is over- or under-expressed, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target. The diagnostic methods may be further suitable for monitoring disease progression in patients undergoing treatment, or for testing for reoccurrence of disease in patients who were previously treated for a disease, for example. Accordingly, exemplary embodiments of the invention provide methods for detecting the presence of, or abundance levels of, a CAT protein in a biological sample.

[0164] In vitro techniques for detection of proteins include, but are not limited to, enzyme linked immunosorbent assays (ELISAs), Western blots, immunoprecipitations, and immunofluorescence using a detection reagent, such as an antibody or protein binding agent. Alternatively, a protein can be detected in vivo in a subject by introducing into the subject a labeled antibody (or other types of detection agent) specific for the protein target. For example, an antibody can be labeled with a radioactive marker whose presence and location in a subject can be detected by standard imaging techniques. Particularly useful are methods that detect variants of a protein (e.g., allelic variants or mutations) and methods that detect fragments of a protein in a sample.

[0165] Proteins can be isolated from a biological sample (such as from a patient having a disease) and assayed for the presence of a mutation. A mutation can include, for example, one or more amino acid substitutions, deletions, insertions, rearrangements (such as from aberrant splicing events), or inappropriate post-translational modifications. Examples of analytic methods useful for detecting mutations in a protein include, but are not limited to, altered electrophoretic mobility, altered tryptic peptide digest, altered protein activity in cell-based or cell-free assays, alteration in substrate or antibody-binding patterns, altered isoelectric point, and direct amino acid sequencing.

[0166] Information obtained by detecting a protein can be used, for example, to determine prognosis and appropriate course of treatment for a disease. For example, individuals with a particular CAT expression level or stage of disease may respond differently to a given treatment that individuals lacking CAT expression, or individuals over- or under-expressing CAT. Information obtained from diagnostic methods of the invention can provide for the personalization of diagnosis and treatment.

[0167] In exemplary embodiments, the invention provides methods for diagnosing disease (including, for example, monitoring treatment response or recurrence of disease following treatment) in a subject comprising: determining the abundance level of CAT (e.g., CAT protein or nucleic acid, or protein or nucleic acid fragments thereof) in a test sample from the subject; wherein a difference in the abundance level of CAT relative to the abundance level of CAT in a test sample from a healthy subject, or the level established for a healthy subject, is indicative of disease.

[0168] Exemplary embodiments of the invention provide methods for diagnosing diseases having differential protein expression. For example, normal, control, or standard values (e.g., that represent typical expression levels of a protein in healthy subjects) can be established, such as by combining body fluids, tissues, or cell extracts taken from a normal healthy mammalian or human subject with specific antibodies to a protein under conditions for complex formation. Standard values for complex formation in normal and disease tissues can be established by various methods, such as photometric means. Complex formation, as it is expressed in a test sample, can be compared with the standard values. Deviation from a normal standard and toward a disease standard can provide parameters for disease diagnosis or prognosis while deviation away from a disease standard and toward a normal standard can be used to evaluate treatment efficacy, for example.

[0169] Immunological methods for detecting and measuring complex formation as a measure of protein expression using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include ELISAs, radioimmunoassays (RIAs), flow cytometry (also referred to as fluorescence-activated cell sorting, or FACS), and antibody arrays. Such immunoassays typically involve the measurement of complex formation between a protein and its specific antibody. These assays and their quantitation against purified, labeled standards are well known in the art (Ausubel, supra, unit 10.1-10.6). For example, a two-site, monoclonal-based immunoassay utilizing antibodies reactive to two non-interfering epitopes can be utilized, and competitive binding assay can also be utilized (Pound (1998) Immunochemical Protocols, Humana Press, Totowa N.J.).

[0170] For diagnostic applications, an antibody can be labeled with a detectable moiety (interchangeably referred to as a "label" or "detectable substance"), such as to facilitate detection by various imaging methods. Methods for detection of labels include, but are not limited to, fluorescence, light, confocal, and electron microscopy; magnetic resonance imaging and spectroscopy; fluoroscopy, computed tomography and positron emission tomography. Examples of suitable labels include, but are not limited to, fluorescein, rhodamine, eosin and other fluorophores, radioisotopes, gold, gadolinium and other lanthanides, paramagnetic iron, fluorine-18 and other positron-emitting radionuclides. Additionally, labels may be bi- or multi-functional and be detectable by more than one of the methods listed. Antibodies may be directly or indirectly labeled. Attachment of labels to antibodies includes covalent attachment of a label, incorporation of a label into an antibody, and covalent attachment of a chelating compound for binding of a label, among others well known in the art.

[0171] Numerous detectable moieties are available for labeling antibodies, including, but not limited to, those in the following categories:

[0172] (a) Radioisotopes, such as .sup.36S, .sup.14C, .sup.125I, .sup.3H, and .sup.131I. An antibody can be labeled with a radioisotope using the techniques described in Current Protocols in Immunology, vol 1-2, Coligen et al., Ed., Wiley-Interscience, New York, Pubs. (1991-2006), for example, and radioactivity can be measured using scintillation counting.

[0173] (b) Fluorescent labels such as rare earth chelates (europium chelates) or fluorescein and its derivatives, rhodamine and its derivatives, dansyl, Lissamine, phycoerythrin and Texas Red are available. Fluorescent labels can be conjugated to an antibody using the techniques disclosed in Current Protocols in Immunology, supra, for example. Fluorescence can be quantified using a fluorometer.

[0174] (c) Various enzyme-substrate labels are available (e.g., U.S. Pat. Nos. 4,275,149 and 4,318,980). An enzyme generally catalyzes a chemical alteration of a chromogenic substrate which can be measured using various techniques. For example, an enzyme may catalyze a color change in a substrate, which can be measured spectrophotometrically. Alternatively, an enzyme may alter the fluorescence or chemiluminescence of a substrate. Techniques for quantifying a change in fluorescence are described herein and well known in the art A chemiluminescent substrate becomes electronically excited by a chemical reaction and may then emit light which can be measured (using a chemiluminometer, for example) or donates energy to a fluorescent acceptor. Examples of enzymatic labels include luciferases (e.g., firefly luciferase and bacterial luciferase; U.S. Pat. No. 4,737,456), luciferin, 2,3-dihydrophthalazinediones, malate dehydrogenase, urease, peroxidase such as horseradish peroxidase (HRPO), alkaline phosphatase, .beta.-galactosidase, glucoamylase, lysozyme, saccharide oxidases (e.g., glucose oxidase, galactose oxidase, and glucose-6-phosphate dehydrogenase), heterocyclic oxidases (such as uricase and xanthine oxidase), lactoperoxidase, microperoxidase, and the like. Techniques for conjugating enzymes to antibodies are described in O'Sullivan et al., Methods for the Preparation of Enzyme-Antibody Conjugates for Use in Enzyme Immunoassay, in Methods in Enzyme. (Ed. J. Langone & H. Van Vunakis), Academic press, New York, 73: 147-166 (1981).

[0175] A label can be indirectly conjugated with an antibody. The skilled artisan will be aware of various techniques for achieving this. For example, an antibody can be conjugated with biotin and any of the three broad categories of labels mentioned above can be conjugated with avidin, or vice versa. Biotin binds selectively to avidin and thus, the label can be conjugated with the antibody in this indirect manner. Alternatively, to achieve indirect conjugation of a label with an antibody, an antibody can be conjugated with a small hapten (e.g., digoxin) and one of the different types of labels mentioned above can be conjugated with an anti-hapten antibody (e.g., anti-digoxin antibody). Thus, indirect conjugation of a label with an antibody can be achieved.

[0176] Antibodies can be used to isolate CAT proteins by standard techniques, such as affinity chromatography or immunoprecipitation, and antibodies can facilitate the purification of the natural protein from cells and recombinantly-produced protein expressed in host cells. Biological samples can be tested directly for the presence of a CAT protein by assays (e.g., ELISA or radioimmunoassay) and format (e.g., microwells, dipstick, etc., as described in International Patent Publication WO 93/03367). Alternatively, proteins in a sample can be size separated (e.g., by polyacrylamide gel electrophoresis (PAGE)), in the presence or absence of sodium dodecyl sulfate (SDS), and the presence of a CAT detected by immunoblotting (e.g., Western blotting).

[0177] Antibody binding can also be detected by "sandwich" immunoassays, immunoradiometric assays, gel diffusion precipitation reactions, immunodiffusion assays, in situ immunoassays (e.g., using colloidal gold, enzyme or radioisotope labels, for example), precipitation reactions, agglutination assays (e.g., gel agglutination assays, hemagglutination assays, etc.), complement fixation assays, immunofluorescence assays, protein A assays, and immunoelectrophoresis assays, etc.

[0178] In certain exemplary embodiments, antibody binding can be detected by detecting a label on the primary antibody. In other exemplary embodiments, a primary antibody can be detected by detecting binding of a secondary antibody or reagent to the primary antibody. In further exemplary embodiments, the secondary antibody is labeled. Numerous means are known in the art for detecting binding in an immunoassay and are within the scope of the invention. In some embodiments, an automated detection assay is utilized. Methods for the automation of immunoassays are well known in the art (e.g., U.S. Pat. Nos. 5,885,530: 4,981,785: 6,159,750: and 5,358,691, each of which is herein incorporated by reference). In some embodiments, the analysis and presentation of results are also automated. For example, in some embodiments, software that generates a prognosis based on the presence or absence of one or more antigens can be implemented.

[0179] Competitive binding assays typically rely on the ability of a labeled standard to compete with a test sample for binding with a limited amount of antibody. The amount of antigen in the test sample is inversely proportional to the amount of standard that becomes bound to the antibodies. To facilitate determining the amount of standard that becomes bound, the antibodies generally are insolubilized before or after the competition. As a result, the standard and test sample that are bound to the antibodies can be separated from the standard and test sample that remain unbound.

[0180] Sandwich assays typically involve the use of two antibodies, each capable of binding to a different immunogenic portion, or epitope, of the protein to be detected. In typical sandwich assays, the test sample to be analyzed is bound by a first antibody, which is immobilized on a solid support, and thereafter a second antibody binds to the test sample, thus forming an insoluble three-part complex (e.g., U.S. Pat. No. 4,376,110). The second antibody can itself be labeled with a detectable moiety (direct sandwich assays) or can be measured using an anti-immunoglobulin antibody that is labeled with a detectable moiety (indirect sandwich assay). For example, one type of sandwich assay is an ELISA assay, in which case the detectable moiety is an enzyme.

[0181] Antibodies can also be used for in vivo diagnostic assays. Generally, an antibody can be labeled with a radionuclide (such as .sup.111In, .sup.99Tc, .sup.14C, .sup.131I, .sup.3H, .sup.32P or .sup.35S) so that disease cells or tissues can be localized using immunoscintiography, for example. In certain embodiment, antibodies or fragments thereof bind to the extracellular domains of two or more CAT proteins and the affinity value (Kd) is less than 1.times.10.sup.8 M.

[0182] For immunohistochemistry, a disease tissue sample may be, for example, fresh or frozen or may be embedded in paraffin and fixed with a preservative such as formalin. A fixed or embedded section can be contacted with a labeled primary antibody and secondary antibody, wherein the antibody is used to detect CAT protein expression in situ.

[0183] Antibodies can be used to detect a target protein in situ, in vitro, or in a cell lysate or supernatant in order to evaluate the abundance and pattern of expression. Also, antibodies can be used to assess abnormal tissue distribution or abnormal expression during development or progression of a biological condition. Antibodies against CAT proteins are useful for detecting the presence of the proteins in cells or tissues to determine the pattern of expression of the proteins among various tissues in an organism and over the course of the organism's development.

[0184] Further, antibodies can be used to assess expression in disease states such as in active stages of a disease or in an individual with a predisposition toward disease related to the protein's function. When a disorder is caused by inappropriate tissue distribution, developmental expression, or level of expression of a protein, or expressed/processed form, for example, an antibody can be prepared against the normal protein. If a disorder is characterized by a specific mutation in a protein, antibodies specific for the mutant protein can be used to assay for the presence of the specific mutant protein and to target the mutant protein for therapeutic purposes. Antibodies are also useful as diagnostic tools, as immunological markers for aberrant protein analyzed by electrophoretic mobility, isoelectric point, tryptic peptide digest, and other physical assays known in the art.

[0185] Certain exemplary diagnostic methods of the invention can also include monitoring a treatment modality. Accordingly, where treatment is ultimately aimed at correcting, for example, the function, activity, expression level, tissue distribution, or developmental expression of a protein, antibodies directed against the protein can be used to monitor therapeutic efficacy and to modify a treatment regimen as necessary.

[0186] Additionally, antibodies to a target protein are useful in pharmacogenomic analysis. For example, antibodies prepared against polymorphic proteins can be used to identify individuals that require modified treatment modalities. Moreover, the target proteins and antibodies thereto can be used for clinical trials, such as to identify individuals that should be included (e.g., individuals more likely to respond to a therapy) or excluded (e.g., individuals less likely to respond to a therapy, or individuals more likely to experience harmful side effects from a therapy) from a clinical trial.

[0187] The invention also encompasses kits for using antibodies to detect the presence of a target protein in a biological sample. An exemplary kit can comprise antibodies such as a labeled or labelable antibody and a compound or agent for detecting protein in a biological sample; means for determining the amount of protein in the sample; means for comparing the amount of protein in the sample with a standard; and instructions for use. Such a kit can be configured to detect a single target protein or epitope or can be configured to detect one of a multitude of epitopes, such as in an antibody detection array.

[0188] LC/MS and ICAT

[0189] In certain exemplary embodiments, the invention provides detection or diagnostic methods of a CAT by using LC/MS. Proteins can be prepared from cells by methods known in the art (e.g., Zhang et al., Nature Biotechnology 21(6):660-666 (2003)). The differential expression of proteins in disease and healthy (or drug-resistant and drug-sensitive, for example) samples can be quantitated using mass spectrometry and ICAT (Isotope Coded Affinity Tag) labeling, which is known in the art. ICAT is an isotope label technique that allows for discrimination between two populations of proteins, such as a healthy and a disease sample. Over-expression or under-expression of a CAT protein, as measured by ICAT, can indicate, for example, the likelihood of having or developing a disease or an associated pathology.

[0190] LC/MS spectra can be collected for labeled samples and processed as follows. The raw scans from the LC/MS instrument can be subjected to peak detection and noise reduction software. Filtered peak lists can then be used to detect `features` corresponding to specific peptides from the original sample(s). Features are characterized by their mass/charge ratio, charge, retention time, isotope pattern, and/or intensity, for example.

[0191] The intensity of a peptide present in both healthy and disease samples can be used to calculate the differential expression, or relative abundance, of the peptide. The intensity of a peptide found exclusively in one sample can be used to calculate a theoretical expression ratio for that peptide (singleton). Expression ratios can be calculated for each peptide in an assay or experiment.

[0192] Statistical tests can be performed to assess the robustness of the data and select statistically significant differentials. To ensure the accuracy of data, the following steps can be taken: a) ensure that similar features are detected in all replicates of an experiment; b) assess the distribution of the log ratios of all peptides (a Gaussian is expected); c) calculate the overall pair wise correlations between ICAT LC/MS maps to ensure that the expression ratios for peptides are reproducible across multiple replicates; and d) aggregate multiple experiments in order to compare the expression ratio of a peptide in multiple diseases or disease samples.

[0193] 8. Methods of Treatment Based on CAT Proteins

[0194] a. Antibody Therapy

[0195] Antibodies of the invention can be used for therapeutic purposes. It is contemplated that antibodies of the invention may be used to treat a mammal, preferably a human, with a disease, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target. The antibodies can be delivered alone, in a pharmaceutical composition (such as with a carrier), or conjugated to one or more therapeutic agents, for example.

[0196] Antibodies can be useful for modulating (e.g., agonizing or antagonizing) protein function, such as for therapeutic purposes. Antibodies can also be useful for inhibiting protein function by, for example, blocking the binding of a CAT protein to a binding partner such as a substrate, which can be useful therapeutically. Antibodies can be prepared against, for example, specific portions of a protein that contain domains required for protein function, or against intact protein that is associated with a cell membrane.

[0197] Antibodies of the invention can also be used for enhancing the immune response. The antibodies can be administered in amounts similar to those used for other therapeutic administrations of antibodies. For example, pooled gamma globulin can be administered at a range of about 1 mg to about 100 mg per patient.

[0198] Antibodies reactive with CAT proteins can be administered alone or in conjunction with other therapies, such as anti-cancer therapies, to a mammal afflicted with cancer or other disease. Examples of anti-cancer therapies include, but are not limited to, chemotherapy, radiation therapy, and adoptive immunotherapy therapy with TIL (tumor infiltrating lymphocytes).

[0199] The selection of an antibody subclass for therapy may depend upon the nature of the antigen to be acted upon. For example, an IgM may be preferred in situations where the antigen is highly specific for the diseased target and rarely occurs on normal cells. However, where the disease-associated antigen is also expressed in normal tissues, although at lower levels, the IgG subclass may be preferred. The IgG subclass may be preferred in these instances because the binding of at least two IgG molecules in close proximity is typically required to activate complement, and therefore less complement-mediated damage may occur in normal tissues that express smaller amounts of the antigen and thus bind fewer IgG antibody molecules. Furthermore, IgG molecules, by being smaller, may be more able than IgM molecules to localize to a diseased tissue.

[0200] A mechanism for antibody therapy can be that a therapeutic antibody recognizes a cell surface, secreted, or cytosolic target protein that is expressed (preferably, over-expressed) in a disease cell. By NK cell or complement activation, or conjugation of the antibody with an immunotoxin or radiolabel, the interaction of the antibody with the target protein can abrogate ligand/receptor interaction or activation of apoptosis, for example.

[0201] Potential mechanisms of antibody-mediated cytotoxicity of diseased cells include phagocyte (antibody-dependent cellular cytotoxicity (ADCC)), complement (complement-dependent cytotoxicity (CDC)), naked antibody (receptor cross-linking apoptosis and growth factor inhibition), or targeted payload labeled with a therapeutic agent, such as a radionuclide, immunotoxin, or immunochemotherapeutic or other therapeutic agent.

[0202] In certain exemplary embodiments, an antibody is administered to a nonhuman mammal for the purposes of obtaining preclinical data, for example. Exemplary nonhuman mammals to be treated include nonhuman primates, dogs, cats, rodents, and other mammals in which preclinical studies are performed. Such mammals may be established animal models for a disease or may be used to study toxicity of an antibody of interest, for example. Dose escalation studies may be performed in the mammal, for example.

[0203] An antibody can be administered to an individual by any suitable means, including parenteral, subcutaneous, intraperitoneal, intrapulmonary, and intranasal, and, if desired for local immunomodulatory treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration. In addition, an antibody can be administered by pulse infusion, particularly with declining doses of the antibody. The dosing can be given by injections, such as intravenous or subcutaneous injections, which may depend in part on whether the administration is brief or chronic.

[0204] For the prevention or treatment of a disease, the appropriate dosage of an antibody may depend on the type of disease to be treated, the severity and the course of the disease, whether the antibody is administered for preventive or therapeutic purposes, previous therapy, the patient's clinical history and response to the antibody, and the discretion of the attending physician.

[0205] Depending on the type and severity of disease, about 1 .mu.g/kg to 150 mg/kg (e.g., 0.1-20 mg/kg) of antibody can be an initial candidate dosage for administration to a patient, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage may range from about 1 .mu.g/kg to 100 mg/kg or more, depending on such factors as those mentioned above. An antibody-drug conjugate can be administered from about 1 .mu.g/kg to 50 mg/kg, typically from about 0.1-20 mg/kg, whether, for example, by one or more separate administrations, or by continuous infusion. A typical daily dosage may range from about 0.1 mg/kg to 10 mg/kg, or from about 0.3 mg/kg to about 7.5 mg/kg, depending on such factors as those mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment can be sustained until a desired suppression of disease symptoms occurs. However, other dosage regimens may be useful. Therapy progress can be monitored by conventional techniques and assays.

[0206] Antibody composition can be formulated, dosed, and administered in a manner consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners.

[0207] An antibody may optionally be formulated with, or administered with, one or more therapeutic agents used to prevent or treat the disorder in question. For example, an antibody can be administered as a co-therapy with a standard of care therapeutic for the specific disease being treated.

[0208] b. Other Immunotherapy

[0209] An "immunogenic peptide" is a peptide that comprises an allele-specific motif such that the peptide will bind an MHC allele (HLA in human) and be capable of inducing a CTL (cytotoxic T-lymphocytes) response. Thus, immunogenic peptides are capable of binding to an appropriate class I or II MHC molecule and inducing a cytotoxic T cell or T helper cell response against the antigen from which the immunogenic peptide is derived.

[0210] Peptides derived from a CAT protein can be modified to increase their immunogenicity, such as by enhancing the binding of the peptide to the MHC molecules in which the peptide is presented. The peptide or modified peptide can be conjugated to a carrier molecule to enhance the antigenicity of the peptide. Examples of carrier molecules, include, but are not limited to, human albumin, bovine albumin, lipoprotein and keyhole limpet hemo-cyanin ("Basic and Clinical Immunology" (1991) Stites and Terr (eds) Appleton and Lange, Norwalk Conn., San Mateo, Calif.).

[0211] Further, amino acid sequence variants of a peptide can be prepared, such as by altering the nucleic acid sequence of the DNA which encodes the peptide, or by peptide synthesis. At the genetic level, these variants can be prepared by, for example, site-directed mutagenesis of nucleotides in the DNA encoding the peptide, thereby producing DNA encoding the variant, and thereafter expressing the DNA in recombinant cell culture. The variants can exhibit the same qualitative biological activity as the nonvariant peptide.

[0212] Exemplary embodiments of the invention provide peptides or modified peptides derived from a CAT protein that are differentially expressed in disease. Examples of peptide modifications include, but are not limited to, substitutions, deletions, or additions of one or more amino acids in a given immunogenic peptide sequence, or mutation of existing amino acids within a given immunogenic peptide sequence, or derivatization of existing amino acids within a given immunogenic peptide sequence. Any amino acid in an immunogenic peptide sequence may be modified. In some embodiments, at least one amino acid can be substituted or replaced within the given immunogenic peptide sequence. Any amino acid may be used to substitute or replace a given amino acid within the immunogenic peptide sequence. Modified peptides can include any immunogenic peptide obtained from differentially expressed proteins, which has been modified and exhibits enhanced binding to the MHC molecule with which it associates when presented to a T-cell. These modified peptides can be synthetically or recombinantly produced by conventional methods, for example.

[0213] In certain exemplary embodiments of the invention, the peptides comprise, or consist of, sequences of about 5-30 amino acids in length which are immunogenic (i.e., capable of inducing an immune response when injected into a subject).

[0214] In certain exemplary embodiments, the peptides may be used, for example, to treat T cell-mediated pathologies. The term "T cell-mediated pathologies" refers to any condition in which an inappropriate T cell response is a component of the pathology. The term is intended to encompass both T cell mediated diseases and diseases resulting from unregulated clonal T cell replication.

[0215] Modified (e.g., recombinant) or natural CAT proteins, or fragments thereof, can be used as a vaccine either prophylactically or therapeutically. When provided prophylactically, a vaccine can be provided in advance of any evidence of disease. The prophylactic administration of a disease vaccine may serve to prevent or attenuate a disease in a mammal such as a human.

[0216] An exemplary vaccine formulation can comprise an immunogen that induces an immune response directed against a disease-associated antigen such as a CAT protein. For example, a substantially or partially purified CAT protein or fragments thereof can be administered as a vaccine in a pharmaceutically acceptable carrier. An immunogen can be administered in a pure or substantially pure form, or can be administered as a pharmaceutical composition, formulation, or preparation. Exemplary doses of protein that can be administered are about 0.001 to about 100 mg per patient, or about 0.01 to about 100 mg per patient. Immunization can be repeated as necessary until a sufficient titer of anti-immunogen antibody or immune cells has been obtained.

[0217] Vaccine can be prepared using, for example, recombinant protein or expression vectors comprising a nucleic acid sequence encoding all or part of a CAT protein. Examples of vectors that can be used in vaccines include, but are not limited to, defective retroviral vectors, adenoviral vectors vaccinia viral vectors, fowl pox viral vectors, or other viral vectors (Mulligan, R. C., (1993) Science 260:926-932). The vectors can be introduced into a mammal (e.g., a human) either prior to any evidence of a disease or to mediate regression of a disease in a mammal afflicted with the disease. Examples of methods for administering a viral vector into mammals include, but are not limited to, exposure of cells to the virus ex vivo, or injection of the retrovirus or a producer cell line of the virus into the affected tissue, or intravenous administration of the virus. Alternatively, the vector can be administered locally by direct injection into a disease lesion or topical application in a pharmaceutically acceptable carrier. The quantity of viral vector to be administered can be based on the titer of virus particles. An exemplary range can be about 10.sup.6 to about 10.sup.11 virus particles per mammal.

[0218] After immunization, the efficacy of the vaccine can be assessed by, for example, the production of antibodies or immune cells that recognize the antigen, as assessed by specific lytic activity, specific cytokine production, or disease regression, which can be measured using conventional methods. If the mammal to be immunized is already afflicted with a disease, the vaccine can be administered in conjunction with other therapeutic treatments. Examples of other therapeutic treatments include, but are not limited to, adoptive T cell immunotherapy and coadministration of cytokines or other therapeutic drugs.

[0219] In certain embodiments, mammals, preferably humans, at high risk for disease, especially cancer, are prophylactically treated with vaccines of the invention. Examples include, but are not limited to, individuals with a family history of a disease, individuals who themselves have a history of disease (e.g., cancer that has been previously resected and at risk for reoccurrence), or individuals already afflicted with a disease. When provided therapeutically, a vaccine can be provided to enhance the patient's own immune response to a disease antigen. An exemplary vaccine, which acts as an immunogen, can be a cell, cell lysate from cells transfected with a recombinant expression vector, or a culture supernatant containing the expressed protein, for example. Alternatively, an immunogen can be, for example, a partially or substantially purified recombinant protein, peptide, or analog thereof, or a modified protein, peptide, or analog thereof. The proteins or peptides can be, for example, conjugated with lipoprotein or administered in liposomal form or with adjuvant.

[0220] Vaccination can be carried out using conventional methods. For example, an immunogen can be used in a suitable diluent such as saline or water, or complete or incomplete adjuvants. Further, an immunogen may or may not be bound to a carrier, including carriers to increase the immunogenicity of the immunogen. Examples of carrier molecules include, but are not limited to, bovine serum albumin (BSA), keyhole limpet hemocyanin (KLH), tetanus toxoid, and the like. An immunogen also may be coupled with lipoproteins or administered in liposomal form or with adjuvants. An immunogen can be administered by any route appropriate for antibody production such as intravenous, intraperitoneal, intramuscular, subcutaneous, and the like. An immunogen can be administered once or at periodic intervals until a significant titer of anti-CAT immune cells or anti-CAT antibody is produced. The presence of anti-CAT immune cells can be assessed by measuring the frequency of precursor CTL (cytotoxic T-lymphocytes) against CAT antigen prior to and after immunization by a CTL precursor analysis assay (Coulie et al., 1992, International Journal Of Cancer 50:289-297). An immunoassay can be used to detect antibody in serum.

[0221] The safety of a vaccine can be determined by examining the effect of immunization on the general health of an immunized animal (e.g., weight change, fever, change in appetite or behavior, etc.) and looking for pathological changes during autopsies. After initial testing in animals, a vaccine can be tested in patients having a disease of interest. Conventional methods can be used to evaluate the immune response of a patient to determine the efficiency of the vaccine.

[0222] In certain exemplary embodiments of the invention, a CAT protein or fragments thereof, or a modified CAT protein, can be exposed to dendritic cells cultured in vitro. The cultured dendritic cells provide a means of producing T-cell dependent antigens comprised of dendritic cell-modified antigen or dendritic cells pulsed with antigen, in which the antigen is processed and expressed on the antigen-activated dendritic cell. The antigen-activated dendritic cells or processed dendritic cell antigens can be used as immunogens for vaccines or for the treatment of diseases. The dendritic cells can be exposed to the antigen for sufficient time to allow the antigens to be internalized and presented on the surface of dendritic cells. The resulting dendritic cells or the dendritic cell-processed antigens can then be administered to an individual in need of therapy. Such methods are described in Steinman et al. (WO93/208185) and in Banchereau et al. (EPO Application 0563485A1).

[0223] In certain exemplary embodiments of the invention, T-cells isolated from individuals can be exposed to a CAT protein or fragment thereof, or a modified CAT protein, in vitro and then administered in a therapeutically effective amount to a patient in need of such treatment. Examples of where T-lymphocytes can be isolated include, but are not limited to, peripheral blood cells lymphocytes (PBL), lymph nodes, or tumor infiltrating lymphocytes (TIL). Such lymphocytes can be isolated from the individual to be treated or from a donor by methods known in the art and cultured in vitro (Kawakami et al., 1989, J. Immunol. 142: 2453-3461). Lymphocytes can be cultured in media such as RPMI or RPMI 1640 or AIM V for 1-10 weeks. Viability can be assessed by trypan blue dye exclusion assay. Examples of how these sensitized T-cells can be administered to a mammal include, but are not limited to, intravenously, intraperitoneally, or intralesionally. Parameters that can be assessed to determine the efficacy of these sensitized T-lymphocytes include, but are not limited to, production of immune cells in the mammal being treated or tumor regression. Conventional methods can be used to assess these parameters. Such treatment can be given in conjunction with cytokines or gene-modified cells, for example (Rosenberg et al., 1992, Human Gene Therapy, 3: 75-90; Rosenberg et al., 1992, Human Gene Therapy, 3: 57-73).

[0224] 9. Screening Methods Using CAT Proteins

[0225] Exemplary embodiments of the invention provide methods of screening for agents (interchangeably referred to by such terms as candidate agents, compounds, or candidate compounds) that modulate CAT protein activity (interchangeably referred to as protein function). Examples of candidate agents include, but are not limited to, proteins, peptides, antibodies, nucleic acids (such as antisense and RNAi nucleic acid molecules), and small molecules. Exemplary embodiments of the invention further provide agents identified by these screening methods, and methods of using these agents, such as for treating diseases, especially cancer, particularly the cancers identified in the Figures and section 13 of the Examples for each target.

[0226] Exemplary screening methods can typically comprise the steps of (i) contacting a CAT protein with a candidate agent, and (ii) assaying for CAT protein activity, wherein a change in protein activity in the presence of the agent relative to protein activity in the absence of the agent indicates that the agent modulates CAT protein activity.

[0227] Other exemplary screening methods can determine a candidate agent's ability to modulate CAT expression. Exemplary methods can typically comprise the steps of (i) contacting a candidate agent with a system that is capable of expressing CAT protein or CAT mRNA, and (ii) assaying for the level of CAT protein or CAT mRNA, wherein a change in the level in the presence of the agent relative to the level in the absence of the agent indicates that the agent modulates CAT expression levels.

[0228] Exemplary embodiments of the invention further provide methods to screen for agents that bind to CAT proteins. Exemplary methods can typically comprise the steps of contacting a CAT protein with a test agent and measuring the extent of binding of the agent to the CAT protein.

[0229] CAT proteins can be used to identify agents that modulate activity of a protein in its natural state or an altered form that causes a specific disease or pathology. CAT proteins and appropriate variants and fragments can be used in high-throughput screens to assay candidate compounds for their ability to bind to CAT. These compounds can be further screened against functional CAT proteins to determine the effect of the compound on the protein's activity. Further, these compounds can be tested in animal or invertebrate systems to determine activity/effectiveness. Compounds can be identified that activate (agonist) or inactivate (antagonist) CAT proteins to a desired degree.

[0230] CAT proteins can be used to screen agents for their ability to stimulate or inhibit interaction between a CAT protein and a target molecule that normally interacts with the CAT protein (e.g., a substrate, an extracellular binding ligand, or a component of a signal pathway that a CAT protein normally interacts with such as a cytosolic signal protein). Exemplary assays can include the steps of combining a CAT protein or fragment thereof with a candidate compound under conditions that allow the CAT protein (or fragment thereof) to interact with a target molecule, and detecting the formation of a complex between the CAT protein and the target molecule or detecting the biochemical consequence of the interaction between the CAT protein and the target molecule, such as any of the associated effects of signal transduction (e.g., protein phosphorylation, cAMP turnover, adenylate cyclase activation, etc.). Any of the biological or biochemical functions mediated by a CAT protein can be used as an endpoint assay to identify an agent that modulates CAT activity.

[0231] Candidate compounds or agents include, but are not limited to, 1) peptides such as soluble peptides, including Ig-tailed fusion peptides and members of random peptide libraries (see, e.g., Lam et al., Nature 354:82-84 (1991); Houghten et al., Nature 354:84-86 (1991)) and combinatorial chemistry-derived molecular libraries made of D- and/or L-configuration amino acids; 2) phosphopeptides (e.g., members of random and partially degenerate, directed phosphopeptide libraries, see, e.g., Songyang et al., Cell 72:767-778 (1993)); 3) antibodies (e.g., polyclonal, monoclonal, humanized, anti-idiotypic, chimeric, and single chain antibodies as well as Fab, F(ab').sub.2, Fab expression library fragments, and epitope-binding fragments of antibodies); and 4) small organic and inorganic molecules (e.g., molecules obtained from combinatorial and natural product libraries).

[0232] An exemplary candidate compound or agent is a soluble fragment of a CAT that competes for substrate binding. Other exemplary candidate compounds include mutant CAT proteins or appropriate fragments containing mutations that affect CAT function and thus compete for substrate. Accordingly, a fragment that competes for substrate, for example with a higher affinity, or a fragment that binds substrate but does not allow release, is encompassed by the invention.

[0233] Compounds can also be screened by using chimeric proteins in which any portion of a protein such as an amino terminal extracellular domain, a transmembrane domain (e.g., transmembrane segments or intracellular or extracellular loops), or a carboxy terminal intracellular domain can be replaced in whole or part by heterologous domains or subregions. For example, a substrate-binding region can be used that interacts with a different substrate than the substrate that is recognized by a native target protein. Accordingly, a different set of signal transduction components can be available as an end-point assay for activation, thereby allowing assays to be performed in other than the specific host cell from which a target is derived.

[0234] Competition binding assays can also be used to screen for compounds that interact with a target protein (e.g., binding partners and/or ligands). For example, a test compound can be exposed to a target protein under conditions that allow the test compound to bind or otherwise interact with the target protein. Soluble target protein can also be added to the mixture. If the test compound interacts with the soluble target protein, it can decrease the amount of complex formed or activity of the target protein. This type of assay is particularly useful in instances in which compounds are sought that interact with specific regions of a target protein. Thus, the soluble target protein that competes with the target protein can contain peptide sequences corresponding to the target region of interest.

[0235] To perform cell-free drug screening assays, it may be desirable to immobilize either a CAT protein (or fragment thereof) or a molecule that binds the CAT protein (referred to herein as a "binding partner") to facilitate separation of complexes from uncomplexed forms, as well as to facilitate automation of the assays.

[0236] Techniques for immobilizing proteins on matrices can be utilized in exemplary drug screening assays. In exemplary embodiments, a fusion protein can be provided which adds a domain that allows a protein to be bound to a matrix. For example, glutathione-S-transferase fusion proteins can be adsorbed onto glutathione SEPHAROSE beads (Sigma Chemical, St. Louis, Mo.) or glutathione derivatized microtitre plates, which are then combined with cell lysates (e.g., .sup.35S-labeled) and a candidate compound, and the mixture incubated under conditions conducive to complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the beads can be washed to remove any unbound label, and the matrix immobilized and radiolabel determined directly, or in the supernatant after the complexes are dissociated. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of a binding partner found in the bead fraction quantitated from the gel using standard electrophoretic techniques. For example, either a target protein or a binding partner can be immobilized by conjugation of biotin and streptavidin using techniques well known in the art. Alternatively, antibodies that are reactive with a target protein but do not interfere with binding of the target protein to its binding partner can be derivatized to the wells of a plate, and the target protein trapped in the wells by antibody conjugation. Preparations of a binding partner and a candidate compound can be incubated in target protein-presenting wells and the amount of complex trapped in the well can be quantitated. Methods for detecting such complexes, in addition to those described for GST-immobilized complexes, include immunodetection of complexes using antibodies reactive with a binding partner, or which are reactive with a target protein and compete with the binding partner, as well as target protein-linked assays which rely on detecting an enzymatic activity associated with a binding partner.

[0237] In exemplary embodiments of the invention, a CAT protein can be used as a "bait protein" in a two-hybrid assay or three-hybrid assay (see, e.g., U.S. Pat. No. 5,283,317; Zervos et al. (1993) Cell 72:223-232; Madura et al. (1993) J. Biol. Chem. 268:12046-12054; Bartel et al. (1993) Biotechniques 14:920-924; Iwabuchi et al. (1993) Oncogene 8:1693-1696; and Brent WO94/10300), to identify other proteins, which bind to or interact with a CAT protein and are involved in the protein's activity. The two-hybrid system is based on the modular nature of most transcription factors, which typically consist of separable DNA-binding and activation domains. In exemplary embodiments, the two-hybrid assay can utilize two different DNA constructs. In one construct, a gene that encodes a CAT protein can be fused to a gene encoding the DNA binding domain of a known transcription factor (e.g., GAL-4). In the other construct, a DNA sequence from a library of DNA sequences that encode an unidentified protein ("prey" or "sample") can be fused to a gene that encodes the activation domain of the known transcription factor. If the "bait" and the "prey" proteins are able to interact in vivo, forming a CAT-dependent complex, the DNA-binding and activation domains of the transcription factor are brought into close proximity. This proximity allows transcription of a reporter gene (e.g., LacZ), which can be operably linked to a transcriptional regulatory site responsive to the transcription factor. Expression of the reporter gene can be detected and cell colonies containing the functional transcription factor can be isolated and used to obtain the cloned gene that encodes the protein that interacts with the CAT protein.

[0238] Agents that modulate a CAT protein can be identified using one or more of the above assays, alone or in combination. For example, a cell-based or cell free system can be used for initial identification of agents, and then activity of the agents can be confirmed in an animal or other model system. Such model systems are well known in the art and can readily be employed in this context.

[0239] 10. Diagnosis, Treatment, and Screening Methods Using CAT Nucleic Acid Molecules

[0240] The nucleic acid molecules of the invention are useful, for example, as probes, primers, chemical intermediates, and in biological assays. The nucleic acid molecules are useful as hybridization probes for messenger RNA, transcript/cDNA, and genomic DNA to detect or isolate full-length cDNA and genomic clones encoding a CAT protein, or variants thereof. The nucleic acid molecules are also useful as primers for PCR to amplify any given region of a nucleic acid molecule and are useful to synthesize antisense molecules of desired length and sequence. The nucleic acid molecules are also useful for producing ribozymes corresponding to all, or a part, of the mRNA produced from the nucleic acid molecules described herein.

[0241] The nucleic acid molecules are also useful for constructing recombinant vectors. Exemplary vectors include expression vectors that express a portion of, or all of, a CAT protein. The nucleic acid molecules are also useful for expressing antigenic portions of the proteins. The nucleic acid molecules are also useful for constructing host cells expressing a part, or all, of the proteins. The nucleic acid molecules are also useful for constructing transgenic animals expressing all, or a part, of the proteins.

[0242] A primer or probe can correspond to any sequence along the entire length of a CAT-encoding nucleic acid molecule such as the nucleic acid molecules of SEQ ID NOS:4-6, 10-12, 18-22, 24, 34-42, 45-46, 49-50, 53-55, 60-63, 68-71, and 74-75. Accordingly, a primer or probe can be derived from 5' noncoding regions, coding regions, or 3' noncoding regions, for example.

[0243] Exemplary in vitro techniques for detection of mRNA include Northern hybridizations and in situ hybridizations. Exemplary in vitro techniques for detecting DNA include Southern hybridizations and in situ hybridization. Reverse transcriptase PCR amplification (RT-PCR) and the like can also be used for detecting RNA expression. A specific exemplary method of detection comprises using TaqMan technology (Applied Biosystems, Foster City, Calif.).

[0244] a. Methods of Diagnosis Using Nucleic Acids

[0245] Nucleic acid molecules of the invention are useful, for example, as hybridization probes for determining the presence, level, form, and/or distribution of nucleic acid expression. Exemplary probes can be used to detect the presence of, or to determine levels of, a specific nucleic acid molecule in cells, tissues, and in organisms. Accordingly, probes corresponding to a CAT described herein can be used to assess expression and/or gene copy number in a given cell, tissue, or organism, which can be applied to, for example, diagnosis of disorders involving an increase or decrease in CAT protein expression relative to normal CAT protein expression levels.

[0246] Probes can be used as part of a diagnostic test kit for identifying cells or tissues that express CAT protein differentially, such as by measuring a level of a CAT-encoding nucleic acid (e.g., mRNA or genomic DNA) in a sample of cells from a subject, or determining if a CAT-encoding nucleic acid is mutated.

[0247] Exemplary embodiments of the invention encompass kits for detecting the presence of CAT-encoding nucleic acid (e.g., mRNA or genomic DNA) in a biological sample. For example, an exemplary kit can comprise reagents such as a labeled or labelable nucleic acid or agent capable of detecting CAT nucleic acid in a biological sample; means for determining the amount of CAT nucleic acid in the sample; and means for comparing the amount of CAT nucleic acid in the sample with a standard. The compound or agent can be packaged in a suitable container. The kit can further comprise instructions for using the kit to detect CAT nucleic acid.

[0248] The nucleic acid molecules are useful in diagnostic assays for qualitative changes in CAT nucleic acid expression, and particularly in qualitative changes that lead to pathology. The nucleic acid molecules can be used to detect mutations in CAT genes and gene expression products such as mRNA. The nucleic acid molecules can be used as hybridization probes to detect naturally occurring genetic mutations in a CAT gene and to determine whether a subject with the mutation is at risk for a disorder caused by the mutation. Examples of mutations include deletions, additions, or substitutions of one or more nucleotides in a gene, chromosomal rearrangements (such as inversions or transpositions), and modification of genomic DNA such as aberrant methylation patterns or changes in gene copy number (such as amplification). Detection of a mutated form of a CAT gene associated with a dysfunction can provide a diagnostic tool for an active disease or susceptibility to disease in instances in which the disease results from overexpression, underexpression, or altered expression of a CAT protein, for example.

[0249] Mutations in a CAT gene can be detected at the nucleic acid level by a variety of techniques. For example, genomic DNA, RNA, or cDNA can be analyzed directly or can be amplified (e.g., using PCR) prior to analysis. In certain exemplary embodiments, detection of a mutation involves the use of a probe/primer in a PCR reaction (see, e.g. U.S. Pat. Nos. 4,683,195 and 4,683,202), such as anchor PCR or RACE PCR, or, alternatively, in a ligation chain reaction (LCR) (see, e.g., Landegran et al., Science 241:1077-1080 (1988) and Nakazawa et al., PNAS 91:360-364 (1994)), the latter of which can be particularly useful for detecting point mutations in a gene (see Abravaya et al., Nucleic Acids Res. 23:675-682 (1995)). Exemplary methods such as these can include the steps of collecting a sample of cells from a patient, isolating nucleic acid (e.g., genomic, mRNA, or both) from the cells of the sample, contacting the nucleic acid with one or more primers which specifically hybridize to a target nucleic acid under conditions such that hybridization and amplification of the target nucleic acid (if present) occurs, and detecting the presence or absence of an amplification product, or detecting the size of the amplification product and comparing the length to a control sample. Deletions and insertions can be detected by a change in size of the amplified product compared to a normal genotype. Point mutations can be identified by hybridizing amplified DNA to normal RNA or antisense DNA sequences, for example.

[0250] Alternatively, mutations in a CAT gene can be identified, for example, by alterations in restriction enzyme digestion patterns as determined by gel electrophoresis. Further, sequence-specific ribozymes (U.S. Pat. No. 5,498,531) can be used to identify the presence of specific mutations by development or loss of a ribozyme cleavage site. Perfectly matched sequences can be distinguished from mismatched sequences by nuclease cleavage digestion assays or by differences in melting temperature.

[0251] Sequence changes at specific locations can be assessed by nuclease protection assays such as RNase and 51 protection, or chemical cleavage methods. Furthermore, sequence differences between a mutant CAT gene and a corresponding wild-type gene can be determined by direct DNA sequencing. A variety of automated sequencing procedures can be utilized when performing diagnostic assays (Naeve, C. W., (1995) Biotechniques 19:448), including sequencing by mass spectrometry (e.g., PCT International Publication No. WO 94/16101; Cohen et al., Adv. Chromatogr. 36:127-162 (1996); and Griffin et al., Appl. Biochem. Biotechnol. 38:147-159 (1993)).

[0252] Other methods for detecting mutations in a nucleic acid include methods in which protection from cleavage agents is used to detect mismatched bases in RNA/RNA or RNA/DNA duplexes (Myers et al., Science 230:1242 (1985)); Cotton et al., PNAS 85:4397 (1988); Saleeba et al., Meth. Enzymol. 217:286-295 (1992)), electrophoretic mobility of mutant and wild type nucleic acid is compared (Orita et al., PNAS 86:2766 (1989); Cotton et al., Mutat. Res. 285:125-144 (1993); and Hayashi et al., Genet. Anal. Tech. Appl. 9:73-79 (1992)), and movement of mutant or wild-type fragments in polyacrylamide gels containing a gradient of denaturant is assayed using denaturing gradient gel electrophoresis (DGGE) (Myers et al., Nature 313:495 (1985)). Examples of other techniques for detecting point mutations include selective oligonucleotide hybridization, selective amplification, and selective primer extension.

[0253] b. Methods of Monitoring Treatment and Pharmacogenomic Methods Using Nucleic Acids

[0254] Nucleic acid molecules of the invention are also useful for monitoring the effectiveness of modulating agents on the expression or activity of a CAT gene, such as in clinical trials or in a treatment regimen. For example, the gene expression pattern of a CAT gene can serve as a barometer for the continuing effectiveness of treatment with a compound, particularly with compounds to which a patient can develop resistance. The gene expression pattern can also serve as a marker indicative of a physiological response of the affected cells to the compound. For example, based on monitoring nucleic acid expression, the administration of a compound can be increased or alternative compounds to which the patient has not become resistant can be administered instead. Similarly, if the level of nucleic acid expression falls below a desirable level, administration of the compound can be commensurately decreased.

[0255] The nucleic acid molecules are also useful for testing an individual for a genotype that, while not necessarily causing a disease, nevertheless affects the treatment modality. Thus, the nucleic acid molecules can be used to study the relationship between an individual's genotype and the individual's response to a compound used for treatment (pharmacogenomic relationship). Accordingly, the nucleic acid molecules provided herein can be used to assess the mutation content of a target gene in an individual in order to select an appropriate compound or dosage regimen for treatment. For example, target nucleic acid molecules having genetic variations that affect treatment can provide diagnostic targets that can be used to tailor treatment to an individual. Accordingly, the production of recombinant cells and animals having these genetic variations allows effective clinical design of treatment compounds and dosage regimens, for example.

[0256] c. Methods of Treatment Using Nucleic Acids

[0257] Nucleic acid molecules of the invention are useful to design antisense constructs to control CAT gene expression in cells, tissues, and organisms. An antisense nucleic acid molecule typically blocks translation of mRNA into CAT protein by hybridizing to target mRNA in a sequence-specific manner. Nucleic acid molecules of the invention can also be used to specifically suppress gene expression by methods such as RNA interference (RNAi). RNAi and antisense-based gene suppression are well known in the art (e.g., Science 288:1370-1372, 2000). RNAi typically operates on a post-transcriptional level and is sequence specific. RNAi and antisense nucleic acid molecules are useful for treating diseases, especially cancer. RNAi fragments, particularly double-stranded (ds) RNAi, as well as antisense nucleic acid molecules can also be used to generate loss-of-function phenotypes by suppressing gene expression. Accordingly, exemplary embodiments of the invention provide RNAi and antisense nucleic acid molecules, and methods of using these RNAi and antisense nucleic acid molecules, such as for therapy or for modulating cell function. Nucleic acid molecules may also be produced that are complementary to a region of a gene involved in transcription, such as to hybridize to the gene to prevent transcription.

[0258] Exemplary embodiments of the invention relate to isolated RNA molecules (double-stranded; single-stranded) that are about 17 to about 29 nucleotides (nt) in length, and more particularly about 21 to about 25 nt in length, which mediate RNAi (e.g., degradation of mRNA, and such mRNA may be referred to herein as mRNA to be degraded). With respect to RNAi, the terms RNA, RNA molecule(s), RNA segment(s), and RNA fragment(s) are used interchangeably to refer to RNA that mediates RNAi. These terms include double-stranded RNA, single-stranded RNA, isolated RNA (e.g., partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA), as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution, and/or alteration of one or more nucleotides. Such alterations can include, for example, addition of non-nucleotide material, such as to the end(s) of a 21-25 nt RNA or internally (at one or more nucleotides of the RNA). Nucleotides in exemplary RNA molecules of the invention can also comprise non-standard nucleotides, including non-naturally occurring nucleotides or deoxyribonucleotides. Collectively, all such altered RNAs are referred to as analogs or analogs of naturally-occurring RNA. RNA of 21-25 nt typically need only be sufficiently similar to natural RNA that it has the ability to mediate RNAi. As used herein, the phrase "mediates RNAi" refers to the ability to distinguish which RNAs are to be degraded by RNAi processes. RNA that mediates RNAi directs degradation of particular mRNAs by RNAi processes. Such RNA may include RNAs of various structures, including short hairpin RNA.

[0259] In certain exemplary embodiments, the invention relates to RNA molecules of about 21 to about 25 nt that direct cleavage of specific mRNA to which their sequence corresponds. It is not necessary that there be a perfect correspondence (i.e., match) of the sequences, but the correspondence must be sufficient to enable the RNA to direct RNAi cleavage of the target mRNA (Holen et al., Nucleic Acids Res. 33:4704-4710 (2005)). In an exemplary embodiment, the 21-25 nt RNA molecules of the invention comprise a 3' hydroxyl group.

[0260] Certain exemplary embodiments of the invention relate to 21-25 nt RNAs of specific genes, produced by chemical synthesis or recombinant DNA techniques, that mediate RNAi. As used herein, the term "isolated RNA" includes RNA obtained by any means, including processing or cleavage of dsRNA, production by chemical synthetic methods, and production by recombinant DNA techniques, for example. Exemplary embodiments of the invention further relate to uses of the 21-25 nt RNAs, such as for therapeutic or prophylactic treatment and compositions comprising 21-25 nt RNAs that mediate RNAi, such as pharmaceutical compositions comprising 21-25 nt RNAs and an appropriate carrier.

[0261] Further exemplary embodiments of the invention relate to methods of mediating RNAi of genes of a patient. For example, RNA of about 21 to about 25 nt which targets a specific mRNA to be degraded can be introduced into a patient's cells. The cells can be maintained under conditions allowing degradation of the mRNA, resulting in RNA-mediated interference of the mRNA of the gene in the cells of the patient. Treatment of cancer patients, for example, with RNAi may inhibit the growth and spread of the cancer and reduce tumor size. Treatment of patients using RNAi can also be in combination with other therapies. For example, RNAi can be used in combination with other treatment modalities, such as chemotherapy, radiation therapy, and other treatments. In an exemplary embodiment, a chemotherapy agent is used in combination with RNAi. In a further exemplary embodiment, GEMZAR (gemcitabine HCl) chemotherapy is used with RNAi.

[0262] Treatment of certain diseases by RNAi may require introduction of the RNA into the disease cells. RNA can be directly introduced into a cell, or introduced extracellularly into a cavity, interstitial space, into the circulation of a patient, or introduced orally, for example. Physical methods of introducing nucleic acids, such as injection directly into a cell or extracellular injection into a patient, may also be used. RNA may be introduced into vascular or extravascular circulation, the blood or lymph system, or the cerebrospinal fluid, for example. RNA may be introduced into an embryonic stem cell or another multipotent cell, which may be derived from a patient. Physical methods of introducing nucleic acids include injection of a solution containing the RNA, bombardment by particles covered by the RNA, soaking cells or tissue in a solution of the RNA, or electroporation of cell membranes in the presence of the RNA. A viral construct packaged into a viral particle may be used to introduce an expression construct into a cell, with the construct expressing the RNA. Other methods known in the art for introducing nucleic acids to cells may be used, such as lipid-mediated carrier transport, chemical-mediated transport, and the like. The RNA may be introduced along with components that perform one or more of the following activities: enhance RNA uptake by the cell, promote annealing of the duplex strands, stabilize the annealed strands, or otherwise increase inhibition of the target gene.

[0263] Exemplary RNA of the invention can be used alone or as a component of a kit having at least one reagent for carrying out in vitro or in vivo introduction of the RNA to a cell, tissue/fluid, or patient. Exemplary components of a kit include dsRNA and a vehicle that promotes introduction of the dsRNA. A kit may also include instructions for using the kit.

[0264] Certain exemplary embodiments of the invention provide compositions and methods for cleavage of mRNA by ribozymes having nucleotide sequences complementary to one or more regions in the mRNA, thereby attenuating the translation of the mRNA. Examples of regions in mRNA that can be targeted by ribozymes include coding regions, particularly coding regions corresponding to catalytic or other functional activities of a target protein, such as substrate binding. These compositions and methods may be used to treat a disorder characterized by abnormal or undesired target nucleic acid expression.

[0265] In certain exemplary embodiments, nucleic acid molecules of the invention may be used for gene therapy in individuals having cells that are aberrant in gene expression of a target. For example, recombinant cells that have been engineered ex vivo (which can include an individual's own cells) can be introduced into an individual where the cells produce the desired target protein to thereby treat the individual.

[0266] d. Methods of Screening Using Nucleic Acids

[0267] Nucleic acid expression assays are useful for drug screening to identify compounds that modulate CAT nucleic acid expression.

[0268] Exemplary embodiments of the invention thus provide methods for identifying a compound that can be used to treat a disease associated with differential expression of a CAT gene, especially cancer. Exemplary methods can typically include assaying the ability of a compound to modulate the expression of a target nucleic acid to thereby identify a compound that can be used to treat a disorder characterized by undesired target nucleic acid expression. The assays can be performed in cell-based or cell-free systems. Examples of cell-based assays include cells naturally expressing target nucleic acid or recombinant cells genetically engineered to express specific target nucleic acid sequences.

[0269] Assays for target nucleic acid expression can involve direct assay of target nucleic acid levels, such as mRNA levels, or on collateral compounds involved in a signal pathway. Further, the expression of genes that are up- or down-regulated in response to a signal pathway can also be assayed. In these embodiments, the regulatory regions of these genes can be operably linked to a reporter gene such as luciferase.

[0270] Thus, in exemplary embodiments, modulators of gene expression of a target can be identified in methods wherein a cell is contacted with a candidate agent and the expression of target mRNA determined. The level of expression of target mRNA in the presence of the candidate agent is compared to the level of expression of target mRNA in the absence of the candidate agent. The candidate agent can then be identified as a modulator of target nucleic acid expression based on this comparison and may be used, for example, to treat a disorder characterized by aberrant target nucleic acid expression. When expression of target mRNA is statistically significantly greater in the presence of the candidate agent than in its absence, the candidate agent is identified as a stimulator (agonist) of nucleic acid expression. When nucleic acid expression is statistically significantly less in the presence of the candidate agent than in its absence, the candidate compound is identified as an inhibitor (antagonist) of nucleic acid expression.

[0271] 11. Arrays and Expression Analysis

[0272] "Array" (interchangeably referred to as "microarray") typically refers to an arrangement of at least one, but more typically at least two, nucleic acid molecules, proteins, or antibodies on a substrate. In certain exemplary arrangements, at least one of the nucleic acid molecules, proteins, or antibodies typically represents a control or standard, and other nucleic acid molecules, proteins, or antibodies are of diagnostic or therapeutic interest. In exemplary embodiments, the arrangement of nucleic acid molecules, proteins, or antibodies on the substrate is such that the size and signal intensity of each labeled complex (e.g., formed between each nucleic acid molecule and a complementary nucleic acid, or between each protein and a ligand or antibody, or between each antibody and a protein to which the antibody specifically binds) is individually distinguishable.

[0273] An "expression profile" is a representation of target expression in a sample. A nucleic acid expression profile can be produced using, for example, arrays, sequencing, hybridization, or amplification technologies for nucleic acids from a sample. A protein expression profile can be produced using, for example, arrays, gel electrophoresis, mass spectrometry, or antibodies (and, optionally, labeling moieties) which specifically bind proteins. Nucleic acids, proteins, or antibodies can be attached to a substrate or provided in solution, and their detection can be based on methods well known in the art.

[0274] A substrate includes, but is not limited to, glass, paper, nylon or other type of membrane, filter, chip, metal, or any other suitable solid or semi-solid (e.g., gel) support.

[0275] Exemplary arrays can be prepared and used according to the methods described in U.S. Pat. No. 5,837,832; PCT application WO95/11995; Lockhart et al., 1996, Nat. Biotech. 14: 1675-1680; Schena et al., 1996; Proc. Natl. Acad. Sci. 93: 10614-10619; and U.S. Pat. No. 5,807,522. Exemplary embodiments of the invention also provide antibody arrays (see, e.g., de Wildt et al. (2000) Nat. Biotechnol. 18:989-94).

[0276] Certain exemplary embodiments of the invention provide a nucleic acid array for assaying target expression, which can be composed of single-stranded nucleic acid molecules, usually either synthetic antisense oligonucleotides or fragments of cDNAs, fixed to a solid support. The oligonucleotides can be, for example, about 6-60 nucleotides in length, about 15-30 nucleotides in length, or about 20-25 nucleotides in length.

[0277] To produce oligonucleotides to a target nucleic acid molecule for an array, the target nucleic acid molecule of interest is typically examined using a computer algorithm to identify oligonucleotides of defined length that are unique to the nucleic acid molecule, have a GC content within a range suitable for hybridization, and lack predicted secondary structure that may interfere with hybridization. In certain instances, it may be desirable to use pairs of oligonucleotides on an array. In exemplary embodiments, the "pairs" can be identical, except for one nucleotide (which can be located in the center of the sequence, for example). The second oligonucleotide in the pair (mismatched by one) serves as a control. Any number of oligonucleotide pairs may be utilized.

[0278] Oligonucleotides can be synthesized on the surface of a substrate, such as by using a light-directed chemical process or by using a chemical coupling procedure and an ink jet application apparatus (e.g., PCT application WO95/251116).

[0279] In some exemplary embodiments, an array can be used to diagnose or monitor the progression of disease, for example, by assaying target expression.

[0280] For example, an oligonucleotide probe specific for a target can be labeled by standard methods and added to a biological sample from a patient under conditions that allow for the formation of hybridization complexes. After an incubation period, the sample can be washed and the amount of label (or signal) associated with hybridization complexes can be quantified and compared with a standard value. If complex formation in the patient sample is significantly altered (higher or lower) in comparison to a normal (e.g., healthy) standard, or is similar to a disease standard, this differential expression can be diagnostic of a disorder.

[0281] By analyzing changes in patterns of target expression, disease may be diagnosed at earlier stages before a patient is symptomatic. In exemplary embodiments of the invention, arrays or target expression analysis methods can be used to formulate a diagnosis or prognosis, to design a treatment regimen, and/or to monitor the efficacy of treatment. For example, a treatment dosage can be established that causes a change in target expression patterns indicative of successful treatment, and target expression patterns associated with the onset of undesirable side effects can be avoided. In further exemplary embodiments, assays of target expression can be repeated on a regular basis to determine if the level of target expression in a patient begins to approximate that which is observed in a normal subject. The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to years, for example.

[0282] Exemplary arrays of the invention can also be used to screen candidate agents, such as to identify agents that produce a target expression profile similar to that caused by known therapeutic agents, with the expectation that agents that cause a similar expression profile of a target may have similar therapeutic effects and/or modes of action on the target.

EXAMPLES

[0283] Exemplary embodiments of the invention are further described in the following examples, which do not limit the scope of the invention.

[0284] 1. Tissue Samples and Cell Lines

[0285] Tissue Processing and Preparation of Single Cell Suspensions from Tissue

[0286] Tissue samples (e.g., normal tissues or disease tissues such as surgically resected neoplastic or metastatic lesions) can be procured from clinical sites and transported in transport buffer. Tissues can be collected as remnant tissues following surgical resection of cancer (or other disease) tissues. Remnant tissues are supplied following processing for pathological diagnosis according to proper standards of patient care. Normal tissue specimens can be normal tissue adjacent to tumors (or other disease tissue) that is collected during tumor resection. Normal tissue from healthy patients not having cancer (or other disease of interest) can also be included, such as to reduce the contribution from pre-neoplastic changes that may exist in normal adjacent tissue. Procurement of tissue samples is carried out in an anonymous manner in compliance with federally mandated ethical and legal guidelines (HIPAA) and in accordance with clinical institution ethical review board and internal institutional review board guidelines.

[0287] Tissue can be crudely minced and incubated for 20-30 minutes with periodic agitation at 37.degree. C. in Enzyme Combination #1 (200 units collagenase, cat# C5894 Sigma; 126 .mu.g DNAse I, cat#D4513 Sigma (in 10 mM Tris/HCl pH7.5); 50 mM NaCl; 10 mM MgCl2; 0.05% elastase, cat# E7885 Sigma) (additionally, hyaluronidase enzyme may also be utilized). D-PBS is added at 3.times. the volume of the enzyme combination, the tissue finely minced, and disassociated cells passed through a 200 .mu.m filter. The cells are washed twice with D-PBS. Red blood cells are lysed with PharMLyse (BD Biosciences) when necessary. Cell number and viability are determined by PI exclusion (GUAVA). Cells at a total cell number greater than 20.times.10.sup.6 are sorted using a high-speed sorter (MoFlo Cytomation) for epithelial cells (EpCAM positive).

[0288] The remaining undigested tissue is incubated for 20-30 minutes with periodic agitation at 37.degree. C. in Enzyme Combination #2 (1.times. Liberase Blendzyme 1, cat#988-417 Roche; 1.times. Liberase Blendzyme 3, cat#814-184 Roche; 0.05% elastase, cat# E7885 Sigma). D-PBS is added at 3.times. the volume of the enzyme combination, and the tissue finely minced until tissue is completely disassociated. The cells are passed through a 200 .mu.m filter, washed twice with D-PBS, and pooled with cells from the Enzyme Combination #1 digestion.

[0289] Cells are passed through a 70 .mu.m filter for single cell suspension, and cell number and viability are determined by PI exclusion (GUAVA). When needed, red blood cells are lysed with PharMLyse (BD Biosciences). Cells are incubated in 20 ml of 1.times. PharMLyse in D-PBS for 30 seconds with gentle agitation and cells pelleted at 300.times.g for 5 minutes at 4.degree. C. Cells are washed once in D-PBS and cell number and viability are recalculated by PI exclusion using the GUAVA. Cells at a total cell number greater than 20.times.10.sup.6 are sorted using a high-speed sorter (MoFlo Cytomation) for epithelial cells (EpCAM positive).

[0290] Single cell suspensions can also be prepared from tissue samples as follows: specimens are washed in DTT for 15 min, digested with Dispase (30-60 min), then filtered twice (380 .mu.m/74 .mu.m) before red blood cells are removed through addition of ACK lysis buffer. Epithelial (EpCAM) and leukocyte (CD45) content and cellular viability (PI exclusion) can be determined through flow cytometry analysis (LSR I, BD Biosciences, San Jose, Calif.).

[0291] The epithelial content of both disease and normal specimens can be enriched through depletion of immune CD45-positive cells by flow cytometry or purification of Epithelial Cell Surface Antigen (ECSA/EpCam)-positive cells by bead capture.

[0292] Bead capture of epithelial cells can be performed using a Dynal CELLection Epithelial Enrich kit (Invitrogen, Carlsbad, Calif.) as follows. Dynal CELLection beads at a concentration of 2.times.10.sup.8 beads are incubated with 1.times.10.sup.8 cells in HBSS with 10% fetal calf serum for 30 minutes at 4.degree. C. Cells and beads are placed in a magnet system Dynal MPC for 2 minutes. Bead/cell complexes are washed in RPMI 1640 media with 1% fetal calf serum. Cells are released from the bead complex with 15 minute incubation with DNase with agitation in RPMI with 1% fetal calf serum.

[0293] DynalBead cell depletion of CD45 cells can be carried out as follows. DynalBead M-450 CD45 beads and cells are incubated at a concentration of 250 .mu.l beads per 2.times.10.sup.7 cells for 30 minutes at 4.degree. C. Bead/cell complexes are washed in DPBS buffer with 2% fetal bovine serum. Cells and beads are placed in a magnet system Dynal MPC for 2 minutes. The supernatant contains EpCAM enriched cells.

[0294] Cell Line Culture

[0295] Cell lines can be obtained from the American Type Culture Collection (ATCC, Manassas, Va.). Cell lines can be grown in a culturing medium that is supplemented as necessary with growth factors and serum, in accordance with the ATCC guidelines for each particular cell line. Cultures are established from frozen stocks in which the cells are suspended in a freezing medium (cell culture medium with 10% DMSO [v/v]) and flash frozen in liquid nitrogen. Frozen stocks prepared in this way are stored in liquid nitrogen vapor. Cell cultures are established by rapidly thawing frozen stocks at 37.degree. C. Thawed stock cultures are slowly transferred to a culture vessel containing a large volume of supplemented culture medium. For maintenance of culture, cells are seeded at 1.times.10.sup.5 cells/per ml in medium and incubated at 37.degree. C. until confluence of cells in the culture vessel exceeds 50% by area. At this time, cells are harvested from the culture vessel using enzymes or EDTA where necessary. The density of harvested, viable cells is estimated by hemocytometry and the culture reseeded as above. A passage of this nature is repeated no more than 25 times, at which point the culture is destroyed and reestablished from frozen stocks as described above.

[0296] Alternatively, cells (e.g., adipocytes such as differentiated subcutaneous or visceral adipocytes) can be obtained from commercial sources, which may provide the cells seeded into T-75 tissue culture flasks. Upon arrival in the laboratory, the media is removed and replaced with DMEM/Ham's F-12 medium (1:1 v/v) supplemented with HEPES pH 7.4, FBS, biotin, pantothenate, human insulin, dexamethasone, penicillin-streptomycin, and Amphotercin B. The cells are cultured for two days and then harvested with versene before enrichment of proteins.

[0297] Alternatively, for secreted protein analysis, cells can be grown under routine tissue culture conditions in 490 cm.sup.2 roller bottles at an initial seeding density of approximately 15 million cells per roller bottle. When the cells reach .about.70-80% confluence, the culturing media is removed, the cells are washed 3 times with D-PBS and once with CD293 protein-free media (Invitrogen cat#11913-019), and the culturing media is replaced with CD293 for generating conditioned media. Cells are incubated for 72 hours in CD293 and the media is collected for analysis, such as mass spectrometry analysis of secreted proteins (30-300 ml). Cell debris is removed from the conditioned media by centrifugation at 300 g for 5 minutes and filtering through a 0.2 micron filter prior to analysis.

[0298] Alternatively, for secreted protein analysis, conditioned media collected from differentiated cells (e.g., visceral or subcutaneous adipocytes), can be obtained (e.g., from a commercial source). Conditioned medium is shipped on dry ice and maintained at -80.degree. C. ahead of protein capture. Cells are isolated from tissue and expanded to passage 2 (P2) to passage 4 (P4) prior to differentiation. Media is changed and cells are grown in conditioned medium for three days prior to harvesting. Enriching for proteins such as secreted proteins can then be carried out.

[0299] 2. Cloning and Expression of Target Proteins

[0300] cDNA Retrieval

[0301] Peptide sequences can be searched using the BLAST algorithm against relevant protein sequence databases to identify the corresponding full-length protein (reference sequence). Each full-length protein sequence can then be searched using the BLAST algorithm against a human cDNA clone collection. For each sequence of interest, clones can be pulled and streaked onto LB/Ampicillin (100 .mu.g/ml) plates. Plasmid DNA is isolated using Qiagen spin mini-prep kit and verified by restriction digest. Subsequently, the isolated plasmid DNA is sequence verified against the reference full-length protein sequence. Sequencing reactions are carried out using Applied Biosystems BigDye Terminator kit followed by ethanol precipitation. Sequence data is collected using the Applied Biosystems 3700 Genetic Analyzer and analyzed by alignment to the reference full-length protein sequence using the Clone Manager alignment tool.

[0302] PCR

[0303] PCR primers are designed to amplify the region encoding the full-length protein and/or any regions of the protein that are of interest for expression (e.g., antigenic or hydrophilic regions as determined by the Clone Manager sequence analysis tool). Primers also contain 5' and 3' overhangs to facilitate cloning (see below). PCR reactions contain 2.5 units Platinum Taq DNA Polymerase High Fidelity (Invitrogen), 50 ng cDNA plasmid template, 1 .mu.M forward and reverse primers, 800 .mu.M dNTP cocktail (Applied Biosystems), and 2 mM MgSO.sub.4. After 20-30 cycles (94.degree. C. for 30 seconds, 55.degree. C. for 1 minute, and 73.degree. C. for 2 minutes), the resulting product is verified by sequence analysis and quantitated by agarose gel electrophoresis.

[0304] Construction of Entry Clones

[0305] PCR products are cloned into an entry vector for use with the Gateway recombination based cloning system (Invitrogen). These vectors include pDonr221, pDonr201, pEntr/D-TOPO, or pEntr/SD/D-TOPO and are used as described in the cloning methods below.

[0306] TOPO Cloning into pEntr/D-TOPO or pEntr/SD/D-TOPO

[0307] For cloning using this method, the forward PCR primer contains a 5' overhang containing the sequence "CACC". PCR products are generated as described above and cloned into the entry vector using the Invitrogen TOPO.RTM. cloning kit. Reactions are typically carried out at room temperature for 10 minutes and subsequently transformed into TOP10 chemically competent cells (Invitrogen, CA). Candidate clones are picked, and plasmid DNA is prepared using a Qiagen spin mini-prep kit and screened by restriction enzyme digestion. Inserts are subsequently sequence-verified as described above.

[0308] Gateway Cloning into pDonr201 or pDonr221

[0309] For cloning using this method, PCR primers contain forward and reverse 5' overhangs. PCR products are generated as described above. Protein-encoding nucleic acid molecules are recombined into the entry vector using the Invitrogen Gateway BP Clonase enzyme mix. Reactions are typically carried out at 25.degree. C. for 1 hour, treated with Proteinase K at 37.degree. C. for 10 minutes, and transformed into Library Efficiency DH5a chemically competent cells (Invitrogen, CA). Candidate clones are picked, plasmid DNA is prepared using a Qiagen spin mini-prep kit, and screened by restriction enzyme digestion. Inserts are subsequently sequence-verified as described above.

[0310] Construction of Expression Clones

[0311] Protein-encoding nucleic acid molecules are transferred from the entry construct into a series of expression vectors using the Gateway LR Clonase enzyme mix. Reactions are typically carried out for 1 hour at 25.degree. C., treated with Proteinase K at 37.degree. C. for 10 minutes, and subsequently transformed into Library Efficiency DH5a chemically competent cells (Invitrogen). Candidate clones are picked, plasmid DNA is prepared using a Qiagen spin mini-prep kit, and screened by restriction enzyme digestion. Expression vectors include, but are not limited to, pDest14, pDest15, pDest17, pDest8, pDest10 and pDest20. These vectors allow expression in systems such as E. coli and recombinant baculovirus. Other vectors not listed here allow expression in yeast, mammalian cells, or in vitro.

[0312] Expression of Recombinant Proteins in E. coli

[0313] Constructs are transformed into one or more of the following host strains: BL21 SI, BL21 AI, (Invitrogen), Origami B (DE3), Origami B (DE3) pLysS, Rosetta (DE3), Rosetta (DE3) pLysS, Rosetta-Gami (DE3), Rosetta-Gami (DE3) pLysS, or Rosetta-Gami B (DE3) pLysS (Novagen). The transformants are grown in LB with or without NaCl and with appropriate antibiotics, at temperatures in the range of 20-37.degree. C., with aeration. Expression is induced with the addition of IPTG (0.03-0.30 mM) or NaCl (75-300 mM) when the cells are in mid-log growth. Growth is continued for one to 24 hours post-induction. Cells are harvested by centrifugation in a Sorvall RC-3C centrifuge in a H6000A rotor for 10 minutes at 3000 rpm at 4.degree. C. Cell pellets are stored at -80.degree. C.

[0314] Expression of Recombinant Proteins Using Baculovirus

[0315] Recombinant proteins are expressed using baculovirus in Sf21 fall army worm ovarian cells. Recombinant baculoviruses are prepared using the Bac-to-Bac system (Invitrogen) per the manufacturer's instructions. Proteins are expressed on the large scale in Sf900II serum-free medium (Invitrogen) in a 10 L bioreactor tank (27.degree. C., 130 rpm, 50% dissolved oxygen for 48 hours).

[0316] 3. Recombinant Protein Purification

[0317] Recombinant proteins can be purified from E. coli and/or insect cells using a variety of standard chromatography methods. Briefly, cells are lysed using sonication or detergents. The insoluble material is pelleted by centrifugation at 10,000.times.g for 15 minutes. The supernatant is applied to an appropriate affinity column. For example, His-tagged proteins are separated using a pre-packed chelating sepharose column (Pharmacia) or GST-tagged proteins are separated using a glutathione sepharose column (Pharmacia). After using the affinity column, proteins are further separated using various techniques, such as ion exchange chromatography (columns from Pharmacia) to separate on the basis of electrical charge or size exclusion chromatography (columns from Tosohaas) to separate on the basis of molecular weight, size, and shape.

[0318] Expression and purification of the protein can also be achieved using either a mammalian cell expression system or an insect cell expression system. The pUB6/V5-His vector system (Invitrogen, CA) can be used to express cDNA in CHO cells. The vector contains the selectable bsd gene, multiple cloning sites, the promoter/enhancer sequence from the human ubiquitin C gene, a C-terminal V5 epitope for antibody detection with anti-V5 antibodies, and a C-terminal polyhistidine (6.times. His) sequence for rapid purification on PROBOND resin (Invitrogen, CA). Transformed cells are selected on media containing blasticidin.

[0319] Spodoptera frugiperda (Sf9) insect cells are infected with recombinant Autographica californica nuclear polyhedrosis virus (baculovirus). The polyhedrin gene is replaced with the cDNA by homologous recombination and the polyhedrin promoter drives cDNA transcription. The protein is synthesized as a fusion protein with 6.times. His which enables purification as described above. Purified proteins can be used to produce antibodies.

[0320] 4. Chemical Synthesis of Proteins

[0321] Proteins or portions thereof can be produced not only by recombinant methods (such as described above), but also by using chemical methods well known in the art. Solid phase peptide synthesis can be carried out in a batchwise or continuous flow process which sequentially adds .alpha.-amino- and side chain-protected amino acid residues to an insoluble polymeric support via a linker group. A linker group such as methylamine-derivatized polyethylene glycol is attached to poly(styrene-co-divinylbenzene) to form the support resin. The amino acid residues are N-a-protected by acid labile Boc (t-butyloxycarbonyl) or base-labile Fmoc (9-fluorenylmethoxycarbonyl) groups. The carboxyl group of the protected amino acid is coupled to the amine of the linker group to anchor the residue to the solid phase support resin. Trifluoroacetic acid or piperidine are used to remove the protecting group in the case of Boc or Fmoc, respectively. Each additional amino acid is added to the anchored residue using a coupling agent or pre-activated amino acid derivative, and the resin is washed. The full-length peptide is synthesized by sequential deprotection, coupling of derivitized amino acids, and washing with dichloromethane and/or N,N-dimethylformamide. The peptide is cleaved between the peptide carboxy terminus and the linker group to yield a peptide acid or amide. (Novabiochem 1997/98 Catalog and Peptide Synthesis Handbook, San Diego Calif. pp. S1-S20).

[0322] Automated synthesis can also be carried out on machines such as the 431A peptide synthesizer (Applied Bio systems, Foster City, Calif.). A protein or portion thereof can be purified by preparative high performance liquid chromatography and its composition confirmed by amino acid analysis or by sequencing (Creighton, 1984, Proteins, Structures and Molecular Properties, W H Freeman, New York N.Y.).

[0323] 5. Antibody Production

[0324] Polyclonal Antibodies

[0325] Polyclonal antibodies against recombinant proteins can be raised in rabbits (Green Mountain Antibodies, Burlington, Vt.). Briefly, two New Zealand rabbits are immunized with 0.1 mg of antigen in complete Freund's adjuvant. Subsequent immunizations are carried out using 0.05 mg of antigen in incomplete Freund's adjuvant at days 14, 21, and 49. Bleeds are collected and screened for recognition of the antigen by solid phase ELISA and Western blot analysis. The IgG fraction is separated by centrifugation at 20,000.times.g for 20 minutes followed by a 50% ammonium sulfate cut. The pelleted protein is resuspended in 5 mM Tris and separated by ion exchange chromatography. Fractions are pooled based on IgG content. Antigen-specific antibody is affinity purified using Pierce AminoLink resin coupled to the appropriate antigen.

[0326] Isolation of Antibody Fragments Directed Against a Protein Target from a Library of scFvs

[0327] Naturally occurring V-genes isolated from human PBLs can be constructed into a library of antibody fragments which contain reactivities against a target protein to which the donor may or may not have been exposed (see, for example, U.S. Pat. No. 5,885,793, incorporated herein by reference in its entirety).

[0328] Rescue of the library: A library of scFvs is constructed from the RNA of human PBLs, as described in PCT publication WO 92/01047. To rescue phage displaying antibody fragments, approximately 10.sup.9 E. coli harboring the phagemid are used to inoculate 50 ml of 2.times.TY containing 1% glucose and 100 .mu.g/ml of ampicillin (2.times.TY-AMP-GLU) and grown to an O.D. of 0.8 with shaking. Five ml of this culture is used to innoculate 50 ml of 2.times.TY-AMP-GLU, 2.times.10.sup.8 TU of delta gene 3 helper (M13 delta gene III, see PCT publication WO 92/01047) are added and the culture incubated at 37.degree. C. for 45 minutes without shaking and then at 37.degree. C. for 45 minutes with shaking. The culture is centrifuged at 4000 rpm. for 10 min. and the pellet resuspended in 2 liters of 2.times.TY containing 100 .mu.g/ml ampicillin and 50 .mu.g/ml kanamycin and grown overnight. Phage are prepared as described in PCT publication WO 92/01047.

[0329] Preparation of M13 delta gene III: M13 delta gene III helper phage does not encode gene III protein, hence the phage(mid) displaying antibody fragments have a greater avidity of binding to antigen. Infectious M13 delta gene III particles are made by growing the helper phage in cells harboring a pUC19 derivative supplying the wild type gene III protein during phage morphogenesis. The culture is incubated for 1 hour at 37.degree. C. without shaking and then for a further hour at 37.degree. C. with shaking. Cells are spun down (IEC-Centra 8,400 rpm for 10 min), resuspended in 300 ml 2.times.TY broth containing 100 .mu.g ampicillin/ml and 25 .mu.g kanamycin/ml (2.times.TY-AMP-KAN) and grown overnight, shaking at 37.degree. C. Phage particles are purified and concentrated from the culture medium by two PEG-precipitations (Sambrook et al., 2001, Molecular Cloning: A Laboratory Manual. 3rd. ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.), resuspended in 2 ml PBS and passed through a 0.45 .mu.m filter (Minisart NML; Sartorius) to give a final concentration of approximately 10.sup.13 transducing units/ml (ampicillin-resistant clones).

[0330] Panning of the library: Immunotubes (Nunc) are coated overnight in PBS with 4 ml of either 100 .mu.g/ml or 10 .mu.g/ml of a protein target of interest. Tubes are blocked with 2% Marvel-PBS for 2 hours at 37.degree. C. and then washed 3 times in PBS. Approximately 10.sup.13 TU of phage is applied to the tube and incubated for 30 minutes at room temperature tumbling on an over-and-under turntable and then left to stand for another 1.5 hours. Tubes are washed 10 times with PBS 0.1% Tween-20 and 10 times with PBS. Phage are eluted by adding 1 ml of 100 mM triethylamine and rotating 15 minutes on an under-and-over turntable after which the solution is immediately neutralized with 0.5 ml of 1.0M Tris-HCl, pH 7.4. Phages are then used to infect 10 ml of mid-log E. coli TG1 by incubating eluted phage with bacteria for 30 minutes at 37.degree. C. The E. coli are then plated on TYE plates containing 1% glucose and 100 .mu.g/ml ampicillin. The resulting bacterial library is then rescued with delta gene 3 helper phage as described above to prepare phage for a subsequent round of selection. This process is then repeated for a total of 4 rounds of affinity purification with tube-washing increased to 20 times with PBS, 0.1% Tween-20 and 20 times with PBS for rounds 3 and 4.

[0331] Characterization of binders: Eluted phage from the 3rd and 4th rounds of selection are used to infect E. coli HB 2151 and soluble scFv is produced (Marks et al., 1991, J. Mol. Biol. 222: 581-597) from single colonies for assay. ELISAs are performed with microtitre plates coated with either 10 .mu.g/ml of the protein target of interest in 50 mM bicarbonate pH 9.6. Clones positive in ELISA are further characterized by PCR fingerprinting (see, e.g., PCT publication WO 92/01047) and then by sequence analysis.

[0332] Monoclonal Antibodies

[0333] a) Materials:

[0334] 1. Complete Media No Sera (CMNS) for washing of the myeloma and spleen cells; Hybridoma medium CM-HAT (Cell Mab (BD), 10% FBS (or HS); 5% Origen HCF (hybridoma cloning factor) containing 4 mM L-glutamine and antibiotics) to be used for plating hybridomas after the fusion.

[0335] 2. Hybridoma medium CM-HT (no aminopterin) (Cell Mab (BD), 10% FBS 5% Origen HCF containing 4 mM L-glutamine and antibiotics) to be used for fusion maintenance is stored in the refrigerator at 4-6.degree. C. The fusions are fed on days 4, 8, and 12, and subsequent passages. Inactivated and pre-filtered commercial fetal bovine serum (FBS) or horse serum (HS) are thawed and stored in the refrigerator at 4.degree. C. and is pretested for myeloma growth from single cells prior to use.

[0336] 3. The L-glutamine (200 mM, 100.times. solution), which is stored at -20.degree. C., is thawed and warmed until completely in solution. The L-glutamine is dispensed into media to supplement growth. L-glutamine is added to 2 mM for myelomas and 4 mM for hybridoma media. Further, the penicillin, streptomycin, amphotericin (antibacterial-antifungal stored at -20.degree. C.) is thawed and added to Cell Mab Media to 1%.

[0337] 4. Myeloma growth media is Cell Mab Media (Cell Mab Media, Quantum Yield, from BD, which is stored in the refrigerator at 4.degree. C. in the dark), to which is added L-glutamine to 2 mM and antibiotic/antimycotic solution to 1% and is called CMNS.

[0338] 5. One bottle of PEG 1500 in Hepes (Roche, N.J.) is prepared.

[0339] 6. 8-Azaguanine is stored as the dried powder supplied by SIGMA at -700.degree. C. until needed. One vial/500 ml of media is reconstituted and the entire contents are added to 500 ml media (e.g., 2 vials/liter).

[0340] 7. Myeloma Media is CM which has 10% FBS (or HS) and 8-Aza (1.times.) stored in the refrigerator at 4.degree. C.

[0341] 8. Clonal cell medium D (Stemcell, Vancouver) contains HAT and methyl cellulose for semi-solid direct cloning from the fusion. This comes in 90 ml bottles with a CoA and is melted at 37.degree. C. in a waterbath in the morning of the day of the fusion. The cap is loosened and the bottle is left in a CO.sub.2 incubator to sufficiently gas the medium D and bring the pH down.

[0342] 9. Hybridoma supplements HT [hypoxanthine, thymidine] to be used in medium for the section of hybridomas and maintenance of hybridomas through the cloning stages, respectively.

[0343] 10. Origen HCF can be obtained directly from Igen and is a cell supernatant produced from a macrophage-like cell-line. It can be thawed and aliqouted to 15 ml tubes at 5 ml per tube and stored frozen at -20.degree. C. Positive hybridomas are fed HCF through the first subcloning and are gradually weaned (individual hybridomas can continue to be supplemented, as needed). This and other additives are typically more effective in promoting new hybridoma growth than conventional feeder layers.

[0344] b) Procedure:

[0345] To generate monoclonal antibodies, mice are immunized with 5-50 .mu.g of antigen, either intra-peritoneally (i.p.) or by intravenous injection in the tail vein (i.v.). The antigen used can be a recombinant target protein of interest, for example. The primary immunization takes place two months prior to the harvesting of splenocytes from the mouse, and the immunization is typically boosted by i.v. injection of 5-50 .mu.g of antigen every two weeks. At least one week prior to the expected fusion date, a fresh vial of myeloma cells is thawed and cultured. Several flasks of different densities can be maintained so that a culture at the optimum density is ensured at the time of fusion. An optimum density can be 3-6.times.10.sup.5 cells/ml, for example. 2-5 days before the scheduled fusion, a final immunization of approximately 5 .mu.g of antigen in PBS is administered (either i.p. or i.v).

[0346] Myeloma cells are washed with 30 ml serum free media by centrifugation at 500 g at 4.degree. C. for 5 minutes. Viable cell density is determined in resuspended cells using hemocytometry and vital stains. Cells resuspended in complete growth medium are stored at 37.degree. C. during the preparation of splenocytes. Meanwhile, to test aminopterin sensitivity, 1.times.10.sup.6 myeloma cells are transferred to a 15 ml conical tube and centrifuged at 500 g at 4.degree. C. for 5 minutes. The resulting pellet is resuspended in 15 ml of HAT media and cells plated at 2 drops/well on a 96-well plate.

[0347] To prepare splenocytes from immunized mice, the animals are euthanised and submerged in 70% ethanol. Under sterile conditions, the spleen is surgically removed and placed in 10 ml of RPMI medium supplemented with 20% fetal calf serum in a petri dish. Cells are extricated from the spleen by infusing the organ with medium >50 times using a 21 g syringe.

[0348] Cells are harvested and washed by centrifugation (at 500 g at 4.degree. C. for 5 minutes) with 30 ml of medium. Cells are resuspended in 10 ml of medium and the density of viable cells determined by hemocytometry using vital stains. The splenocytes are mixed with myeloma cells at a ratio of 5:1 (spleen cells: myeloma cells). Both the myeloma and spleen cells are washed twice more with 30 ml of RPMI-CMNS, and the cells are spun at 800 rpm for 12 minutes.

[0349] Supernatant is removed and cells are resuspended in 5 ml of RPMI-CMNS and are pooled to fill volume to 30 ml and spun down as before. Then, the pellet is broken up by gently tapping on the flow hood surface and resuspending in 1 ml of BMB REG1500 (prewarmed to 37.degree. C.) dropwise with a 1 cc needle over 1 minute.

[0350] RPMI-CMNS to the PEG cells and RPMI-CMNS are added to slowly dilute out the PEG. Cells are centrifuged and diluted in 5 ml of Complete media and 95 ml of Clonacell Medium D (HAT) media (with 5 ml of HCF). The cells are plated out 10 ml per small petri plate.

[0351] Myeloma/HAT control is prepared as follows: dilute about 1000 P3X63 Ag8.653 myeloma cells into 1 ml of medium D and transfer into a single well of a 24-well plate. Plates are placed in an incubator, with two plates inside of a large petri plate, with an additional petri plate full of distilled water, for 10-18 days under 5% CO.sub.2 overlay at 37.degree. C. Clones are picked from semisolid agarose into 96-well plates containing 150-200 .mu.l of CM-HT. Supernatants are screened 4 days later in ELISA, and positive clones are moved up to 24-well plates. Heavy growth requires changing of the media at day 8 (+/-150 ml). The HCF can be further decreased to 0.5% (gradually--2%, then 1%, then 0.5%) in the cloning plates.

[0352] 6. Liquid Chromatography and Mass Spectrometry (LC/MS)

[0353] For LC/MS analysis, proteins are reduced in 2.5 mM DTT for 1 hour at 37.degree. C., and alkylated with ICAT.TM. reagent according to the procedures recommended by the manufacturer (Applied Biosystems, Framingham, Mass.). The reaction is quenched by adding excess DTT. Proteins are digested using sequencing grade modified trypsin overnight at 37.degree. C. followed by desalting using 3 cc Oasis HLB solid phase extraction columns (Waters, Milford, Mass.) and vacuum drying. Cysteine-containing peptides are purified by avidin column (Applied Biosystems, Framingham, Mass.). The peptides are reconstituted in buffer A (0.1% formic acid in water) and separated over a C18 monomeric column (150 mm, 150 .mu.m i.d., Grace Vydac 238EV5, 5 .mu.m) at a flow rate of 1.5 .mu.l/min with a trap column. Peptides are eluted from the column using a gradient, 3%-30% buffer B (0.1% formic acid in 90% acetonitrile) in 215 min, 30%-90% buffer B in 30 min. Eluted peptides are analyzed using an online QSTAR XL system (MDS/Sciex, Toronto, ON). Peptide ion peaks from the map are automatically detected with RESPECT.TM. (PPL Inc., UK).

[0354] The sequence-composition of peptides detected, for example, at higher levels in disease samples (or drug-resistant samples) relative to adjacent normal tissue (or drug-sensitive samples) can be resolved through tandem mass spectrometry and database analysis. For data analysis, peptide ion peaks of LC/MS maps from normal and disease samples can be aligned based on mass to charge ratio (m/z), retention time (Rt), and charge state (z). The list of aligned peptide ions is loaded into Spotfire.TM. (Spotfire Inc. Somerville, Mass.). Intensities can be normalized before further differential analysis between disease and normal samples. Differentially expressed ions are manually verified before LC-MS/MS-based peptide sequencing and database searching for protein/protein identification.

[0355] For intensity normalization and expression analysis, a heat map can be constructed by sorting the rows by the ratio of the mean intensity in the disease samples to the mean intensity of the normal samples. Rows are included if there is at least one MS/MS identification of an ion in the row. The display colors are determined for each row separately by assigning black to the median intensity in the row, green to the lowest intensity in the row, and red to the highest intensity.

[0356] Using a mass spectrometry procedure such as this, a comprehensive analysis of proteins differentially expressed by disease cells (or drug resistant cells, for example) compared with normal cells (or cells responsive/sensitive to a drug, for example) can be carried out.

[0357] 7. mRNA Expression Analysis

[0358] Expression of target mRNA can be quantitated by RT-PCR using TaqMan.RTM. technology. The Taqman.RTM. system couples a 5' fluorogenic nuclease assay with PCR for real-time quantitation. A probe is used to monitor the formation of the amplification product.

[0359] Total RNA can be isolated from disease model cell lines using an RNEasy Kit.RTM. (Qiagen, Valencia, Calif.) with DNase treatment (per the manufacturer's instructions). Normal human tissue RNAs can be acquired from commercial vendors (e.g., Ambion, Austin, Tex.; Stratagene, La Jolla, Calif.; BioChain Institute, Newington, N.H.), as well as RNAs from matched disease/normal tissues.

[0360] Target transcript sequences can be identified for differentially expressed peptides by database searching using a search algorithm such as BLAST. TaqMan.RTM. assays (PCR primer/probe sets) specific for those transcripts can be obtained from Applied Biosystems (AB) as part of the Assays on Demand.TM. product line or by custom design through the AB Assays by Design service. If desired, the assays can be designed to span exon-exon borders so as not to amplify genomic DNA.

[0361] RT-PCR can be accomplished using AmpliTaq Gold.RTM. and MultiScribe.TM. reverse transcriptase in the One Step RT-PCR Master Mix reagent kit (AB) (according to the manufacturer's instructions). Probe and primer concentrations are 250 nM and 900 nM, respectively, in a 15 .mu.l reaction. For each experiment, a master mix of the above components is made and aliquoted into each optical reaction well. Eight nanograms of total RNA is used as template. Quantitative RT-PCR can be performed using the ABI Prism.RTM. 7900HT Sequence Detection System (SDS). The following cycling parameters are used: 48.degree. C. for 30 min. for one cycle; 95.degree. C. for 10 min for one cycle; and 95.degree. C. for 15 sec, 60.degree. C. for 1 min. for 40 cycles.

[0362] SDS software can be utilized to calculate the threshold cycle (C.sub.T) for each reaction, and C.sub.T values are used to quantitate the relative amount of starting template in the reaction. The C.sub.T values for each set of reactions can be averaged for all subsequent calculations

[0363] Data can be analyzed to determine estimated copy number per cell. Gene expression can be quantitated relative to 18S rRNA expression and copy number estimated assuming 5.times.10.sup.6 copies of 18S rRNA per cell. Alternatively, data can be analyzed for fold difference in expression using an endogenous control for normalization and expressed relative to a normal tissue or normal cell line reference. The choice of endogenous control can be determined empirically by testing various candidates against the cell line and tissue RNA panels and selecting the one with the least variation in expression. Relative changes in expression can be quantitated using the 2.sup.-.DELTA..DELTA.CT method (Livak et al., 2001, Methods 25: 402-408; User bulletin #2: ABI Prism 7700 Sequence Detection System). Alternatively, total RNA can be quantitated using a RiboGreen RNA Quantitation Kit according to manufacturer's instructions and the percentage mRNA expression calculated using total RNA for normalization. Percentage knockdown can then be calculated relative to a no addition control.

[0364] 8. Flow Cytometry (FACS) Analysis

[0365] Flow cytometry is interchangeably referred to as fluorescence-activated cell sorting (FACS). Quantitative flow cytometry can be used to compare the level of expression of a protein on disease cells to the level found on normal cells, for example.

[0366] Expression levels of a target protein on primary tissue samples can be quantified using the Quantum Simply Cellular System (Bangs Laboratories, Fishers, Ind.) and a target-specific antibody. Normal adjacent and disease tissues can be processed into single cell suspensions, as described above, which can be stained for various markers (e.g., the epithelial marker EpCam) and the target-specific antibody. At least 0.5.times.10.sup.6 cells are typically used for each analysis. Cells are washed once with Flow Staining Buffer (0.5% BSA, 0.05% NaN3 in D-PBS). To the cells, 20 .mu.l of each target-specific antibody are added. An additional 5 .mu.l of anti-EpCam antibody conjugated to APC can be added when unsorted cells are used. Cells are incubated with antibodies for 30 minutes at 4.degree. C. Cells are washed once with Flow Staining Buffer and either analyzed immediately on an LSR flow cytometry apparatus or fixed in 1% formaldehyde and stored at 4.degree. C. until LSR analysis. Antibodies used to detect a target can be PE-conjugated. PE-conjugated mouse IgG1k can used as an isotype control antibody. Cells are analyzed by flow cytometry and epitope copy number and the percentage of viable epithelial cells positive for target expression can be measured. Cell numbers and viability can be determined by PI exclusion (GUAVA) for cells isolated from both normal and disease tissue. Standard curve and samples can be analyzed on a LSR I (BDBiosciences, San Jose Calif.) flow cytometer. Antibody binding capacity for each lineage population can be calculated using geometric means and linear regression.

[0367] Expression levels of a target protein can be quantified in cell lines with QIFIKIT flow cytometric indirect immunofluorescence assay (Dako A/S) using a primary antibody to the target. Briefly, cells are detached with versene or trypsin and washed once with complete media and then PBS. 5.times.10.sup.5 cells/sample are incubated with saturating concentration (10 .mu.g/ml) of primary antibody for 60 minutes at 4.degree. C. After washes, a FITC-conjugated secondary antibody (1:50 dilution) is added for 45 minutes at 4.degree. C. QIFIKIT standard beads are simultaneously labeled with the secondary antibody. Binding of antibodies is analyzed by flow cytometry and specific antigen density is calculated by subtracting background antibody equivalent from antibody-binding capacity based on a standard curve of log mean fluorescence intensity versus log antigen binding capacity.

[0368] Cells can also be prepared for flow cytometry analysis (as well as other types of analysis) as follows: cells are incubated with 1:100 dilution of BrdU in culturing media for 2-4 hours (BrdU Flow Kit, cat#559619 BD Biosciences). Cells are washed 3 times with D-PBS and disassociated from the flask with versene. Cell numbers and viability can be determined by PI exclusion (GUAVA). Cells are washed once with Flow Staining Buffer (0.5% BSA, 0.05% NaN.sub.3 in D-PBS). Cells are incubated with 400 .mu.l of Cytofix/Cytoperm Buffer (BrdU Flow Kit, BD Biosciences) for 15-30 minutes at 4.degree. C. Cells are washed once with Flow Staining Buffer and resuspended in 400 .mu.l Cytoperm Plus Buffer (BrdU Flow Kit BD Biosciences). Cells are incubated for 10 minutes at 4.degree. C. and washed once with 1.times. Perm/Wash Buffer (BrdU Flow Kit, BD Biosciences). Cells are incubated for 1 hour at 37.degree. C. protected from light in DNAse solution (BrdU Flow Kit, BD Biosciences). Cells are washed once with 1.times. Perm/Wash Buffer and incubated for 20 min at room temperature with anti-BrdU FITC-conjugated antibody (BrdU Flow Kit, BD Biosciences), PE-conjugated active caspase 3 (BD Biosciences cat#550821), and PE mouse IgG2B isotype control. Cells are washed once with 1.times. Perm/Wash Buffer and resuspended in DAPI for LSR flow cytometry analysis.

[0369] 9. Immunohistochemistry (IHC)

[0370] IHC of Tissue Sections

[0371] Paraffin embedded, fixed tissue sections (e.g., from disease tissue samples such as solid tumors or other cancer tissues) can be obtained from a panel of normal tissues as well as tumor (or other disease) samples with matched normal adjacent tissues, along with replicate sections (if desired). For example, for an initial survey of target expression, a panel of common cancer formalin-fixed paraffin-embedded (FFPE) tissue microarrays (TMAs) can be used for analysis, and such TMAs can be obtained from commercial sources (TriStar, Rockville, Md.; USBiomax, Rockville, Md.; Imgenex, San Diego, Calif.; Petagen/Abxis, Seoul, Korea). Sections can be stained with hemotoxylin and eosin and histologically examined to ensure adequate representation of cell types in each tissue section.

[0372] An identical set of tissues can be obtained from frozen sections for use in those instances where it is not possible to generate antibodies that are suitable for fixed sections. Frozen tissues do not require an antigen retrieval step.

[0373] Paraffin Fixed Tissue Sections

[0374] An exemplary protocol for hemotoxylin and eosin staining of paraffin embedded, fixed tissue sections is as follows. Sections are deparaffinized in three changes of xylene or xylene substitute for 2-5 minutes each. Sections are rinsed in two changes of absolute alcohol for 1-2 minutes each, in 95% alcohol for 1 minute, followed by 80% alcohol for 1 minute. Slides are washed in running water and stained in Gill solution 3 hemotoxylin for 3-5 minutes. Following a vigorous wash in running water for 1 minute, sections are stained in Scott's solution for 2 minutes. Sections are washed for 1 minute in running water and then counterstained in eosin solution for 2-3 minutes, depending upon the desired staining intensity. Following a brief wash in 95% alcohol, sections are dehydrated in three changes of absolute alcohol for 1 minute each and three changes of xylene or xylene substitute for 1-2 minutes each. Slides are coverslipped and stored for analysis.

[0375] Optimization of Antibody Staining

[0376] For each antibody, a positive and negative control sample can be generated using data from ICAT analysis of disease cell lines or tissues. Cells can be selected that are known to express low levels of a particular target as determined from the ICAT data, and this cell line can be used as a reference normal control. Similarly, a disease cell line that is determined to over-express the target can also be selected.

[0377] Antigen Retrieval

[0378] Sections are deparaffinized and rehydrated by washing 3 times for 5 minutes in xylene, two times for 5 minutes in 100% ethanol, two times for 5 minutes in 95% ethanol, and once for 5 minutes in 80% ethanol. Sections are then placed in endogenous blocking solution (methanol+2% hydrogen peroxide) and incubated for 20 minutes at room temperature. Sections are rinsed twice for 5 minutes each in deionized water and twice for 5 minutes in phosphate buffered saline (PBS), pH 7.4.

[0379] Alternatively, where necessary, sections are de-parrafinized by High Energy Antigen Retrieval as follows: sections are washed three times for 5 minutes in xylene, two times for 5 minutes in 100% ethanol, two times for 5 minutes in 95% ethanol, and once for 5 minutes in 80% ethanol. Sections are placed in a Coplin jar with dilute antigen retrieval solution (10 mM citrate acid, pH 6). The Coplin jar containing slides is placed in a vessel filled with water and microwaved on high for 2-3 minutes (700 watt oven). Following cooling for 2-3 minutes, steps 3 and 4 are repeated four times (depending on the tissue), followed by cooling for 20 minutes at room temperature. Sections are then rinsed in deionized water (two times for 5 minutes), placed in modified endogenous oxidation blocking solution (PBS+2% hydrogen peroxide), and rinsed for 5 minutes in PBS.

[0380] Alternatively, formalin fixed paraffin embedded tissues can be deparaffinized and processed for antigen retrieval using the EZ-retriever system (BioGenex, San Ramon, Calif.). EZ-antigen Retrieval common solution is used for deparaffinization and EZ-retrieval citrate-based buffer used for antigen retrieval. Samples are pre-blocked with non-serum protein block (Dako A/S, Glostrup, Denmark) for 15 min. Primary antibodies (at 2.5-5.0 .mu.g/ml, for example) are incubated overnight at room temperature. Envision Plus system HRP (Dako A/S) is used for detection with diaminobenzidine (DAB) as substrate for horseradish peroxidase.

[0381] Blocking and Staining

[0382] Sections are blocked with PBS/1% bovine serum albumin (PBA) for 1 hour at room temperature followed by incubation in normal serum diluted in PBA (2%) for 30 minutes at room temperature to reduce non-specific binding of antibody. Incubations are performed in a sealed humidity chamber to prevent air-drying of the tissue sections. The choice of blocking serum is typically the same as the species of the biotinylated secondary antibody. Excess antibody is gently removed by shaking and sections covered with primary antibody diluted in PBA and incubated either at room temperature for 1 hour or overnight at 4.degree. C. (care is taken that the sections do not touch during incubation). Sections are rinsed twice for 5 minutes in PBS, shaking gently. Excess PBS is removed by gently shaking. The sections are covered with diluted biotinylated secondary antibody in PBA and incubated for 30 minutes to 1 hour at room temperature in the humidity chamber. If using a monoclonal primary antibody, addition of 2% rat serum can be used to decrease the background on rat tissue sections. Following incubation, sections are rinsed twice for 5 minutes in PBS, shaking gently. Excess PBS is removed and sections incubated for 1 hour at room temperature in Vectastain ABC reagent (as per kit instructions). The lid of the humidity chamber is secured during all incubations to ensure a moist environment. Sections are rinsed twice for 5 minutes in PBS, shaking gently.

[0383] Developing and Counterstaining

[0384] Sections are incubated for 2 minutes in peroxidase substrate solution that is made up immediately prior to use as follows: 10 mg diaminobenzidine (DAB) dissolved in 10 ml of 50 mM sodium phosphate buffer, pH 7.4; 12.5 microliters 3% CoCl.sub.2/NiCl.sub.2 in deionized water; and 1.25 microliters hydrogen peroxide.

[0385] Slides are rinsed well three times for 10 minutes in deionized water and counterstained with 0.01% Light Green acidified with 0.01% acetic acid for 1-2 minutes, depending on the desired intensity of counterstain.

[0386] Slides are rinsed three times for 5 minutes with deionized water and dehydrated two times for 2 minutes in 95% ethanol; two times for 2 minutes in 100% ethanol; and two times for 2 minutes in xylene. Stained slides are mounted for visualization by microscopy.

[0387] Slides are scored manually using a microscope such as the Zeiss Axiovert 200M microscope (Carl Zeiss Microimaging, Thornwood, N.Y.). Representative images are acquired using 40.times. objective (400.times. magnification).

[0388] IHC Staining of Frozen Tissue Sections

[0389] For IHC staining of frozen tissue sections, fresh tissues are embedded in OCT in plastic mold, without trapping air bubbles surrounding the tissue. Tissues are frozen by setting the mold on top of liquid nitrogen until 70-80% of the block turns white at which point the mold is placed on dry ice. The frozen blocks are stored at -80.degree. C. Blocks are sectioned with a cryostat with care taken to avoid warming to greater than -10.degree. C. Initially, the block is equilibrated in the cryostat for about 5 minutes and 6-10 mm sections are cut sequentially. Sections are allowed to dry for at least 30 minutes at room temperature. Following drying, tissues are stored at 4.degree. C. for short term and -80.degree. C. for long term storage.

[0390] Sections are fixed by immersing in an acetone jar for 1-2 minutes at room temperature, followed by drying at room temperature. Primary antibody is added (diluted in 0.05M Tris-saline [0.05M Tris, 0.15M NaCl, pH 7.4], 2.5% serum) directly to the sections by covering the section dropwise to cover the tissue entirely. Binding is carried out by incubation in a chamber for 1 hour at room temperature. Without letting the sections dry out, the secondary antibody (diluted in Tris-saline/2.5% serum) is added in a similar manner to the primary antibody and incubated as before (at least 45 minutes).

[0391] Following incubation, the sections are washed gently in Tris-saline for 3-5 minutes and then in Tris-saline/2.5% serum for another 3-5 minutes. If a biotinylated primary antibody is used, in place of the secondary antibody incubation, slides are covered with 100 .mu.l of diluted alkaline phosphatase conjugated streptavidin, incubated for 30 minutes at room temperature and washed as above. Sections are incubated with alkaline phosphatase substrate (1 mg/ml Fast Violet; 0.2 mg/ml Napthol AS-MX phosphate in Tris-Saline pH 8.5) for 10-20 minutes until the desired positive staining is achieved at which point the reaction is stopped by washing twice with Tris-saline. Slides are counter-stained with Mayer's hematoxylin for 30 seconds and washed with tap water for 2-5 minutes. Sections are mounted with Mount coverslips and mounting media.

[0392] 10. RNAi Assays in Cell Lines

[0393] RNAi Transfections

[0394] Expression of a target can be knocked down by transfection with small interfering RNA (siRNA) to that target. Synthetic siRNA oligonucleotides can be obtained from Dharmacon (Lafayette, Colo.) or Qiagen (Valencia, Calif.). For siRNA transfection, cells (e.g., disease cells) can be seeded into 96 well tissue culture plates at a density of 2,500 cells per well 24 hours before transfection. Culture medium is removed and 50 .mu.l of reaction mix containing siRNA (final concentration 1 to 100 nM) and 0.4 .mu.l of DharmaFECT4 (Dharmacon, Lafayette, Colo.) diluted in Opti-MEM is added to each well. An equal volume of complete medium follows and the cells are then incubated at 5% CO.sub.2 at 37.degree. C. for 1 to 4 days.

[0395] Alternatively, in the initial screening phase, RNAi can be performed using 100 nM (final) of Smartpools (Dharmacon, Lafayette, Colo.), pool of 4- for Silencing siRNA duplexes (Qiagen, Valencia, Calif.), or non-targeting negative control siRNA (Dharmacon or Qiagen). In the breakout phase, each individual duplex is used at 100 nM (final). In the titration phase, individual duplex is used at 0.1-100 nM (final). Transient transfections are carried out using either Lipofectamine 2000 from Invitrogen (Carlsbad, Calif.) or GeneSilencer from Gene Therapy Systems (San Diego, Calif.) (see below). One day after transfections, total RNA is isolated using the RNeasy 96 Kit (Qiagen) according to manufacturer's instructions and expression of mRNA is quantitated using TaqMan technology. Apoptosis and cell proliferation assays can be performed daily using Apop-one homogeneous caspase-3/7 kit and Alamar Blue or CellTiter 96 AQueous One Solution Cell Proliferation Assays (see below).

[0396] RNAi Transfections--Lipofectamine 2000 and GeneSilencer

[0397] Transient RNAi transfections can be carried out using Lipofectamine 2000 (Invitrogen, Carlsbad, Calif.) or GeneSilencer (Gene Therapy Systems, San Diego, Calif.), such as on sub-confluent disease cell lines, as described elsewhere (Elbashir et al., 2001, Nature 411: 494-498; Caplen et al., 2001, Proc Natl Acad Sci USA 98: 9742-9747; Sharp, 2001, Genes and Development 15: 485-490). Synthetic RNA to a gene of interest or non-targeting negative control siRNA are transfected using Lipofectamine 2000 or GeneSilencer according to manufacturer's instructions. Cells are plated in 96-well plates in antibiotic-free medium. The next day, the transfection reagent and siRNA are prepared for transfections as follows.

[0398] 0.1-100 nM siRNA is resuspended in 20-25 .mu.l serum-free media in each well (with Plus for Lipofectamine 2000) and incubated at room temperature for 15 minutes. 0.1-1 .mu.l of Lipofectamine 2000 or 1-1.5 .mu.l of GeneSilencer is also resuspended in serum-free medium to a final volume of 20-25 .mu.l per well. After incubation, the diluted siRNA and either the Lipofectamine 2000 or the GeneSilencer are combined and incubated for 15 minutes (Lipofectamine 2000) or 5-20 minutes (GeneSilencer) at room temperature. Media is then removed from the cells and the combined siRNA-Lipofectamine 2000 reagent or siRNA-GeneSilencer reagent is added to a final volume of 50 .mu.l per well. After further incubation at 37.degree. C. for 4 hours, 50 .mu.l serum-containing medium is added back to the cells. 1-4 days after transfection, expression of mRNA can be quantitated by RT-PCR using TaqMan technology, and protein expression levels can be measured by flow cytometry. Apoptosis and proliferation assays can be performed daily using Apop-one homogeneous caspase-3/7 kit and Alamar Blue or CellTiter 96 AQueous One Solution Cell Proliferation Assays (see below).

[0399] mRNA and Protein Knockdowns

[0400] Knockdown of target mRNA levels can be monitored by Q-PCR one day after siRNA transfection by using a TaqMan.RTM. assay (Applied Biosystems, Foster City, Calif.). RT-PCR is accomplished in a one-step reaction by using M-MLV reverse transcriptase (Promega, Madison, Wis.) and AmpliTaq Gold.RTM. (ABI) and analyzed on the ABI Prism.RTM. 7900HT Sequence Detection System (ABI). Relative gene expression can be quantitated by the .DELTA..DELTA.Ct method (User Bulletin #2, ABI) with 18S rRNA serving as the endogenous control.

[0401] Protein knockdown can be monitored by FACS four days after transfection by using an antibody to the target. The samples can be run on a LSR flow cytometer (BD Biosciences, San Jose, Calif.) and live cells monitored by using PI exclusion (50 .mu.g/ml PI, 2.5 units/ml RNase A, 0.1% Triton X-100 in D-PBS). The data can be analyzed using CellQuest software.

[0402] Cell Proliferation--Alamar Blue

[0403] Cell growth can be assessed four days after transfection by adding a 1:10 dilution of Alamar blue reagent (Invitrogen, Carlsbad, Calif. or Biosource, Camarillo, Calif.) and incubated for 2 hours at 37.degree. C. Analysis can be performed on a Spectrafluor Plus (Tecan, Durham, N.C.) set at excitation wavelength of 530 nm and emission wavelength of 595 nm.

[0404] Cell Proliferation--MTS

[0405] Alternatively, cell proliferation assays can be performed using a CellTiter 96 AQueous One Solution Cell Proliferation Assay kit (Promega, Madison, Wis.). 20 .mu.l of CellTiter 96 AQueous One Solution is added to 1000 of culture medium. The plates are then incubated for 1-4 hours at 37.degree. C. in a humidified 5% CO.sub.2 incubator. After incubation, the change in absorbance is read at 490 nm.

[0406] Apoptosis

[0407] Apoptosis assays can be performed using the Apop-one homogeneous caspase-3/7 kit (Promega, Madison, Wis.). Briefly, the caspase-3/7 substrate is thawed to room temperature and diluted 1:100 with buffer. The diluted substrate is then added 1:1 to cells, control, or blank. The plates are then placed on a plate shaker for 30 minutes to 18 hours at 300-500 rpm. The fluorescence of each well is then measured using an excitation wavelength of 485+/-20 nm and an emission wavelength of 530+/-25 nm.

[0408] 11. Antibody Assays in Cell Lines

[0409] Cytotoxicity Assays

[0410] Cytotoxicity can be measured using a Resazurin (Sigma, Mo.) dye reduction assay (McMillian et al., 2002, Cell Biol. Toxicol. 18:157-173). Briefly, cells are plated at 1,000-5,500 cells/well in 96 well plates, allowed to attach to the plates for 18 hours before addition of fresh media with or without antibody. After 96-144 hours of exposure to antibody, resazurin is added to cells to a final concentration of 50 Cells are incubated for 2-6 hours depending on dye conversion of cell lines, and dye reduction is measured on a Fusion HT fluorescent plate reader (Packard Instruments, Meridien, Conn.) with excitation and emission wavelengths of 530 nm and 590 nm, respectively. The IC.sub.50 value is defined here as the drug concentration that results in 50% reduction in growth or viability as compared with untreated control cultures.

[0411] Assays for Antibody-Dependent Cellular Cytotoxicity

[0412] Antibody-dependent cellular cytotoxicity (ADCC) assays can be carried out as follows. Cultured disease cells (e.g., tumor cells) are labeled with 100 .mu.Ci .sup.51Cr for 1 hour (Livingston et al., 1997, Cancer Immunol. Immunother. 43, 324-330). After being washed three times with culture medium, cells are resuspended at 10.sup.5/ml, and 100 .mu.l/well are plated onto 96-well round-bottom plates. A range of antibody concentrations are applied to the wells, including an isotype control together with donor peripheral blood mononuclear cells that are plated at a 100:1 and 50:1 ratio. After an 18 hour incubation at 37.degree. C., supernatant (30 .mu.l/well) is harvested and transferred onto Lumaplate 96 (Packard), dried, and read in a Packard Top-Count NXT .gamma. counter. Spontaneous release is determined by cpm of disease cells incubated with medium and maximum release by cpm of disease cells plus 1% Triton X-100 (Sigma). Specific lysis is defined as: % specific lysis=[(experimental release-spontaneous release)/(maximum release-spontaneous release)].times.100. The percent ADCC is expressed as peak specific lysis postimmune subtracted by preimmune percent specific lysis. A doubling of the ADCC to >20% can typically be considered significant.

[0413] Assays for Complement Dependent Cytotoxicity

[0414] Chromium release assays to assess complement dependent cytotoxicity (CDC) can be carried out as follows (Dickler et al., 1999, Clin. Cancer Res. 5, 2773-2779). Cultured disease cells (e.g., tumor cells) are washed in FCS-free media two times, resuspended in 500 .mu.l of media, and incubated with 100 .mu.Ci .sup.51Cr per 10 million cells for 2 hours at 37.degree. C. The cells are then shaken every 15 min for 2 hours, washed 3 times in media to achieve a concentration of approximately 20,000 cells/well, and then plated in round-bottom plates. The plates contain either 50 .mu.l cells plus 50 .mu.l monoclonal antibody, 50 .mu.l cells plus serum (pre- and post-therapy), or 50 .mu.l cells plus mouse serum as a control. The plates are incubated in a cold room on a shaker for 45 min. Human complement of a 1:5 dilution (resuspended in 1 ml of ice-cold water and diluted with 3% human serum albumin) is added to each well at a volume of 100 Control wells include those for maximum release of isotope in 10% Triton X-100 (Sigma) and for spontaneous release in the absence of complement with medium alone. The plates are incubated for 2 hours at 37.degree. C., centrifuged for 3 min, and then 100 .mu.l of supernatant is removed for radioactivity counting. The percentage of specific lysis is calculated as follows: % cytotoxicity=[(experimental release-spontaneous release)/(maximum release-spontaneous release)].times.100. A doubling of the CDC to >20% can typically be considered significant.

[0415] Cell Proliferation Assays

[0416] To measure cell proliferation, cells can be plated, grown and treated as for the cytotoxicity assay (above) in 96 well plates. After 96-144 hours of treatment, 0.5 .mu.Ci/well .sup.3H-Thymidine (PerkinElmer, 6.7 Ci/mmol) is added to cells and incubated for 4-6 hours at 37.degree. C., 5% CO.sub.2 in an incubator. To lyse cells, plates are frozen overnight at -20.degree. C. and then cell lysates are harvested using FilterMate (Packard Instrument, Meridien, Conn.) into 96 well filter plates. Radioactivity associated with cells is measured on a TopCount (Packard) scintillation counter.

[0417] Other cell assays (e.g., proliferation assays such as Alamar blue and MTS, and apoptosis assays) can be carried out using antibodies, as described above for RNAi.

[0418] Testing of Function-Blocking Antibodies

[0419] For testing of function-blocking antibodies, sub-confluent disease cell lines are serum-starved overnight. The next day, serum-containing media is added back to the cells in the presence of 5-50 ng/ml of function-blocking antibodies. After 2 or 5 days incubation at 37.degree. C. 5% CO.sub.2, antibody binding is examined by flow cytometry, and apoptosis and proliferation are measured.

[0420] Cell Invasion

[0421] Cell invasion assays can be performed using a 96-well cell invasion assay kit (Chemicon). After the cell invasion chamber plates are adjusted to room temperature, 100 .mu.l serum-free media is added to the interior of the inserts. 1-2 hours later, cell suspensions of 1.times.10.sup.6 cells/ml are prepared. Media is then carefully removed from the inserts and 100 .mu.l of prepared cells are added into the insert +/-0 to 50 ng function blocking antibodies. The cells are pre-incubated for 15 minutes at 37.degree. C. before 150 .mu.l of media containing 10% FBS is added to the lower chamber. The cells are then incubated for 48 hours at 37.degree. C. After incubation, the cells from the top side of the insert are discarded and the invasion chamber plates are then placed on a new 96-well feeder tray containing 150 .mu.l of pre-warmed cell detachment solution in the wells. The plates are incubated for 30 minutes at 37.degree. C. and are periodically shaken. Lysis buffer/dye solution (4 .mu.l CyQuant Dye/300 .mu.l 4.times. lysis buffer) is prepared and added to each well of dissociation buffer/cells on feeder tray. The plates are incubated for 15 minutes at room temperature before 150 .mu.l is transferred to a new 96-well plate. Fluorescence of invading cells is then read at 480 nm excitation and 520 nm emission.

[0422] Receptor Internalization

[0423] For quantification of receptor internalization, ELISA assays can be performed essentially as described by Daunt et al. (Daunt et al., 1997, Mol. Pharmacol. 51, 711-720). Cell lines are plated at 6.times.10.sup.5 cells per in a 24-well tissue culture dishes that have previously been coated with 0.1 mg/ml poly-L-lysine. The next day, the cells are washed once with PBS and incubated in DMEM at 37.degree. C. for several minutes. Agonist to the cell surface target of interest is then added to the wells at a pre-determined concentration in prewarmed DMEM. The cells are then incubated for various times at 37.degree. C. and reactions are stopped by removing the media and fixing the cells in 3.7% formaldehyde/TBS for 5 min at room temperature. The cells are then washed three times with TBS and nonspecific binding blocked with TBS containing 1% BSA for 45 min at room temperature. The first antibody is added at a pre-determined dilution in TBS/BSA for 1 hr at room temperature. Three washes with TBS follow, and cells are briefly reblocked for 15 min at room temperature. Incubation with goat anti-mouse conjugated alkaline phosphatase (Bio-Rad) diluted 1:1000 in TBS/BSA is carried out for 1 hr at room temperature. The cells are washed three times with TBS and a colorimetric alkaline phosphatase substrate is added. When the adequate color change is reached, 100 .mu.l samples are taken for colorimetric readings.

[0424] 12. Treatment with Antibodies

[0425] Treatment of Disease Cells with Monoclonal Antibodies.

[0426] Disease cells (e.g., cancer cells), or cells such as NIH 3T3 cells that express a target of interest, are seeded at a density of 4.times.10.sup.4 cells per well in 96-well microtiter plates and allowed to adhere for 2 hours. The cells are then treated with different concentrations of monoclonal antibody (Mab) specific for the protein target of interest, or irrelevant isotype matched (e.g., anti-rHuIFN-gamma) Mab, at 0.05, 0.5 or 5.0 .mu.g/ml. After a 72 hour incubation, the cell monolayers are stained with crystal violet dye for determination of relative percent viability (RPV) compared to control (untreated) cells. Each treatment group can have replicates. Cell growth inhibition is monitored.

[0427] In Vivo Treatment with Monoclonal Antibodies.

[0428] NIH 3T3 cells transfected with either an expression plasmid that expresses the target of interest or a neo-DHFR vector are injected into nu/nu (athymic) mice subcutaneously at a dose of 10.sup.6 cells in 0.1 ml of phosphate-buffered saline. On days 0, 1, 5, and every 4 days thereafter, 100 .mu.g (0.1 ml in PBS) of a Mab specific for the protein target of interest, or an irrelevant Mab, of the IgA2 subclass is injected intraperitoneally. Disease progression (e.g., tumor occurrence and size) can be monitored for a one month period of treatment, for example.

[0429] 13. Specific Examples of Results from Experimental Validation

[0430] Exemplary results of experimental validation studies for each target are provided in the Figures and are set forth below:

TMPRSS4

[0431] A TMPRSS4 peptide was observed by mass-spec as over expressed in a pancreatic cancer cell line.

[0432] IHC indicated over-expression of TMPRSS4 in multiple tumor types, as follows: kidney (over-expressed in 100% of tumors evaluated); brain, glioblastoma (85%); lung, adenocarcinoma (70%); melanoma, lymph node (60%); liver (50%); pancreas (43%); lung, squamous (40%); pancreas, metastatic (33%); and colon (20%). TMPRSS4 was expressed in 8/10 lung tumor specimens evaluated, and TMPRSS4 was over-expressed by two pathology grades in 70% of the lung tumor samples evaluated. TMPRSS4 was expressed in 7/10 pancreatic tumor specimens evaluated, and TMPRSS4 was over-expressed by two pathology grades in 40% of the pancreatic tumor samples evaluated. TMPRSS4 was expressed in 10/10 kidney tumor specimens evaluated, and TMPRSS4 was over-expressed by two pathology grades in 100% of the renal tumor samples evaluated.

[0433] RNAi knockdown of TMPRSS4 inhibits proliferation in H1299 (lung) and AGS (gastric) cancer cell lines, as well as other cancer cell lines.

[0434] TMPRSS4 mRNA levels over-expressed in lung and pancreas tumor tissues.

SLC5A6

[0435] SLC5A6 peptides were identified by mass-spec as overexpressed in 6 breast cancer cell-lines (3.1-8.2 fold over-expressed), 5 colon tumor tissues (4.3-15.9 fold), and 1 gastric cancer cell line (4.8 fold).

[0436] IHC indicates over-expression of SLC5A6 in multiple tumor types, as follows: 100% renal (i.e., over-expressed in 100% of tumors evaluated), 90% breast, 70% lung (squamous), 63% liver, 60% lung (adenocarcinoma), 50% metastatic pancreas, 30% colon, and 20% ovary (FIG. 1). IHC confirmed expression of SLC5A6 in 6 out of 10 gastric tumor specimens, 9 out of 10 breast tumor specimens, 2 out of 10 colon tumor specimens, 10 out of 10 kidney tumors specimens, 4 out of 8 liver tumor specimens, 7 out of 10 lung carcinoma specimens, 2 out of 10 ovary tumor specimens, 2 out of 8 pancreatic tumor specimens, and 7 out of 10 lung carcinoma specimens.

[0437] SLC5A6 mRNA overexpression observed in colorectal, lung, and kidney tumor tissue (FIG. 2).

[0438] Knockdown of SLC5A6 mRNA inhibits proliferation of pancreatic cancer cells (MPANC-96 cell line) (30%) and gastric cancer cells (NCI-N87 cells) (39%), as well as other cancer cells and spheroid cells (cancer stem cells) (data not shown).

ITGB6

[0439] ITGB6 peptides were observed by mass spec as over-expressed in pancreatic, lung, breast, and gastric tumor cell lines, and in breast cancer conditioned medium, as well as in a colon cancer stem cell line. Degree of ITGB6 over-expression was as follows: 3-21 fold over-expressed in pancreatic cell lines, 15-20 fold in lung cell lines, 5-100 fold in breast cell lines, 12 fold in a gastric cell line, 9 fold in a breast cell line conditioned medium, and 4 fold in a colon cancer stem cell line.

[0440] IHC indicates over-expression of ITGB6 in multiple tumor types, as follows: pancreas, metastatic (over-expressed in 67% of tumors evaluated); pharyngeal (60%); pancreas (57%); lung NSC (50%); skin melanoma (40%); melanoma, lymph node (40%); liver (38%); breast (30%); and lung, squamous (10%). As indicated by IHC, ITGB6 was expressed in 4 out of 7 pancreatic tumor specimens, in 5 out of 10 lung tumor specimens, and in 3 out of 10 breast tumor specimens.

[0441] ITGB6 mRNA over-expression was observed in pancreatic tumor tissue.

[0442] Knockdown of ITGB6 mRNA inhibits proliferation in the following cancer cells: gastric (47%), pancreas (52 and 52%), lung (50%), colon (64 and 84%), liver (42%), cancer stem cells (51%), and endothelial cells (31%).

[0443] Knockdown of ITGB6 induced apoptosis in the following cancer cells: gastric (1.7 fold), pancreas (1.7 and 1.9 fold), lung (2.8 fold), colon (3.6 fold), breast (1.5 fold), kidney (2.7 and 4.6 fold), liver (1.9 fold), and endothelial cells (3.1 fold).

[0444] Knockdown of ITGB6 mRNA in combination with Gemzar increases apoptosis in Calu-1 lung cancer cells.

GLG1

[0445] GLG1 peptides were observed by mass spec as over-expressed in 4 breast cell lines, 1 breast tumor tissue, 2 colon cell lines, 10 colon tumor tissues, 3 lung cell lines, 6 lung tumor tissues, 2 pancreatic cell lines, 3 gastric cell lines and 1 gastric tumor tissue. GLG1 was over-expressed by 2.2-9.2 fold in breast cell lines and tissues, 2.1-100 fold in colon cell lines and tissues, 4.6 fold in kidney tissue, 2.4-100 fold in lung cell lines and tissues, 2.7-100 fold in pancreatic cell lines, 5-7.9 fold in stomach lines, and 20.9 fold in stomach tissue.

[0446] IHC confirmed the mass spec results and indicated expression of GLG1 in multiple tumor types, as follows: 80% melanoma (over-expressed in 80% of melanoma tumors evaluated); 50% melanoma, lymph nodes; 43% pancreas; 30% lung (squamous); and 17% non-Hodgkin's lymphoma.

[0447] mRNA over-expression observed in pancreatic tumor tissues.

[0448] Further ectopic expression of non-cell surface targets in tumor cell populations (for example, A549 lung cancer cell line vs. Beas-2B non-cancer lung cell line) showed that GLG1 is overexpressed in the tumor cell line.

[0449] Knockdown of GLG1 mRNA inhibits proliferation in multiple cancer cells, including SNU-475 kidney cancer cells.

KIAA0152

[0450] A KIAA0152 peptide was identified by mass spec as over-expressed (by 7-fold) in colon tumor tissue.

[0451] As indicated by IHC, KIAA0152 was overexpressed in multiple tumor types, as follows: brain, glioblastoma (over-expressed in 100% of tumors evaluated); pancreas (57%); liver (38%); pancreas, metastatic (33%); and bladder (30%). As indicated by IHC, KIAA0152 was expressed in 6 out of 7 pancreatic tumor specimens, in 8 out of 10 melanoma specimens, in 6 out of 6 glioblastoma specimens, in 10 out of 10 colon tumor specimens, in 9 out of 10 lung tumor specimens, and in 7 out of 10 prostate tumor specimens.

[0452] Over-expression of KIAA0152 was confirmed by FACS in primary and lymph node metastatic colon tumor tissues.

[0453] Elevated KIAA0152 mRNA expression was observed in colon tumors by TaqMan, which correlated with elevated protein expression observed by mass-spec and IHC.

[0454] KIAA0152 mRNA knockdown inhibits proliferation in the following cancer cell lines: colon (91% and 82%), lung (64% and 28%), pancreas (53%), melanoma (44%), gastric (35%), and liver.

[0455] Expression of KIAA0152 was observed by FACS in the following cancer cell lines: breast (MDA MB 231 and MCF-7 cell lines), colon (HCT116 cell line), pancreas (BXPC3 cell line), and prostate (LnCAP and RWPE-2 cell lines). Expression of KIAA0152 was also observed in hormone-dependent and refractory prostate xenografts (LnCAP cell line--LnCAP hormone-dependent xenograft and LnCAP hormone-independent xenograft).

[0456] KIAA0152 is under-expressed in 3D spheroid cells (cancer stem cells) derived from kidney and lung cancer cell lines (ACHN kidney cell line and H1299 lung cell line).

Matriptase (ST14)

[0457] Matriptase peptides were identified by mass spec as over-expressed in breast, pancreatic, gastric, colon, and melanoma cancer cell lines, and in conditioned medium from lung and breast tumor cell lines. The degree of matriptase over-expression was as follows: 4.5-46.1 fold in breast cancer cell lines, 5.8 fold in breast conditioned medium, 4.7-17.7 fold in gastric cancer cell lines, 4.3 fold in lung conditioned medium, and 5.4-7.1 fold in pancreatic cancer cell lines.

[0458] IHC indicates over expression of matriptase in multiple tumors types, as follows: non-Hodgkins lymphoma ("NHL") (lymph node) (over-expressed in 83% of tumors evaluated), colon (70%), ovary (60%), pancreas (38%), and lung (squamous) (20%). IHC indicated expression of matriptase in 7 out of 10 lung tumor specimens that were evaluated, in 5 out of 6 NHL tumor specimens, in 6 out of 10 ovary tumor specimens, in 7 out of 10 colon tumor specimens, and in 4 out of 8 pancreatic tumor specimens.

[0459] Over-expression of matriptase mRNA was observed in pancreatic, lung, and ovarian tumor tissues, as well as breast tumor tissues.

[0460] Knockdown of matriptase mRNA leads to inhibition of proliferation in pancreatic (38-53%), lung (31-35%), colon (47-75%), and gastric (50%) cancer cell lines.

AADACL1

[0461] AADACL1 peptides were observed by mass spec as over-expressed in colon tumor tissues and in breast, colon, pancreatic, and prostate cancer cell lines. The degree of AADACL1 over-expression was as follows: 2.3 fold in breast cancer cell line, 3 fold in colon cancer cell line, 4.4-13.3 fold in colon tumor tissues, 2.2-5.7 fold in pancreatic cancer cell line, and 5.5-12.1 fold in prostate cancer cell line.

[0462] IHC indicates over-expression of AADACL1 in multiple tumor types, as follows: pancreas (over-expressed in 100% of tumors evaluated); melanoma, lymph node (80%); melanoma (80%); metastatic pancreas (75%); colon (60%); and non-Hodgkin's lymphoma (NHL) (33%). AADACL1 was expressed in 6 out of 6 pancreatic tumor specimens, in 8 out of 10 melanoma specimens, in 8 out of 10 melanoma lymph node specimens, in 6 out of 10 colon carcinoma specimens, and in 2 out of 6 NHL tumor specimens.

[0463] AADACL1 mRNA over-expression was observed in pancreatic tumor tissues and pancreatic tumor cell lines.

Podocalyxin

[0464] Podocalyxin peptides were observed by mass spec as over-expressed in breast and lung tumor tissue samples and in breast, esophageal, hepatocellular, liver, lung, ovarian, prostate, melanoma, and gastric cancer cell lines. Podocalyxin peptides were also observed in conditioned medium collected from colon tumor cell lines. Degree of podocalyxin over-expression, as measured by mass spec, was as follows: 3.9-100 fold in breast tumor tissues, 3.4-36.6 fold in breast cancer cell lines, 10.3-10.6 fold in esophageal cancer cell line, 27.3-60.7 fold in gastric cancer cell lines, 21.3-44.7 fold in gastric tumor tissues, 8.4-8.6 fold in ovarian cancer cell lines, 12.8-13.1 fold in lung cancer cell lines, 3.5-100 fold in lung tumor tissues, 7.2-12.6 fold in melanoma cell lines, 8.8-12.6 fold in prostate cancer cell lines, 7.8-20.5 fold in liver cancer cell lines, and 3.4-11.8 fold in conditioned medium from colon cancer cells.

[0465] IHC confirms expression of podocalyxin in colon, lung, gastric, and breast tumor samples. IHC indicates that podocalyxin is over-expressed in multiple tumor types, as follows: pancreatic (over-expressed in 40% of tumors evaluated), ovarian (20%), breast (10%), and colon (10%). As measured by IHC, podocalyxin was expressed in 4 out of 10 pancreatic tumor specimens and in 2 out of 10 ovary tumor specimens.

[0466] RNAi knockdown of podocalyxin mediates a decrease in proliferation and induction of apoptosis in lung cancer cells.

[0467] mRNA analysis confirms elevated expression of podocalyxin in pancreatic tumor tissues.

[0468] Cell surface expression of podocalyxin was confirmed by FACS in lung and breast cancer cell lines.

[0469] Podocalyxin siRNA is synergistic with EGFR siRNA.

CD90 (Thy1)

[0470] CD90 peptides were observed by mass spec as over-expressed in colon, lung, breast, kidney, and stomach tumor tissues, in liver, lung, and skin tumor cell lines, in kidney and colon tumor endothelium, and in adipose tissue. Degree of CD90 over-expression, as measured by mass spec, was as follows: 3-70 fold in 6 kidney tumor endothelia, 15-74 fold in colon tumor derived endothelial cell line, 4-10 fold in 2 breast tumor tissues, 4-14 fold in 4 colon tumor tissues, 3-6 fold in 2 kidney tumor tissues, 4-22 fold in 3 lung tumor tissues, 6 fold in 1 stomach tumor tissue, 7-13 fold in 2 liver tumor cell lines, 5-48 fold in 2 lung tumor cell lines, 37-153 fold in 1 skin cell line, and 66 fold in 1 adipose tissue.

[0471] IHC indicated over-expression of CD90 in multiple tumor types, as follows: pancreas (over-expressed in 38% of tumors evaluated), liver (25%), prostate (20%), skin (melanoma) (20%), gastric (20%), breast (20%), bladder (20%), and non-Hodgkin's Lymphoma (17%). IHC confirms expression of CD90 in 2 out of 10 melanoma specimens that were evaluated, in 3 out of 8 pancreatic tumor specimens, in 2 out of 10 breast carcinoma specimens, in 2 out of 10 gastric tumor specimens, in 2 out of 10 prostate tumor specimens, and in 5 out of 10 kidney tumor specimens.

[0472] CD90 is over-expressed in tumor endothelium, as indicated by IHC, including kidney, pancreas, and lung tumor endothelium.

[0473] CD90 is over-expressed in colorectal tumor tissues, as indicated by QFACS. FACS also indicates that CD90 is over-expressed in kidney tumors.

[0474] CD90 is expressed by kidney tumor endothelial cells and lung tumor tissue endothelial cells.

[0475] mRNA analysis shows marked over-expression of CD90 in pancreas, lung, stomach and colon tumor tissues, and in kidney tumor tissue endothelial cells.

[0476] Knockdown of CD90 mRNA inhibits proliferation in cancer cell lines, particularly in kidney (61%), melanoma (43%) and colon (38%) cancer cell lines.

ISGF4

[0477] ISGF4 peptides were identified by mass spectrometry as over-expression in 3 breast cancer cell lines, 1 kidney cancer cell line, 3 liver cancer cell lines, 4 lung cancer cell lines, 2 prostate cancer cell lines, 3 melanoma cell lines, and 1 gastric cancer cell line. The magnitude of ISGF4 overexpression, as indicated by mass spec, was as follows: 26.9-100 fold overexpression in breast cell lines, 3.6-fold in a kidney cell line, 4-7.4 fold in liver cell lines, 4.9-377.6 fold in lung cell lines, 7.5-73.4 fold in prostate cell lines, 5.1-13.9 fold in melanoma cell lines, and 11.2-fold in gastric cell line.

[0478] ISGF4 is over-expressed in multiple tumor types, as indicated by IHC, as follows: 100% kidney (over-expressed in 100% of kidney tumors evaluated), 80% ovary, 60% bladder, 50% lung (NSC), 50% lung (Squamous), 50% liver, 50% stomach, 33% metastatic pancreatic, 30% colon, 20% prostate, and 10% breast. As indicated by IHC, ISGF4 was expressed in 10 out of 10 kidney tumor specimens, 6 out of 10 lung tumor specimens, and 9 out of 10 ovarian tumor specimens that were evaluated.

[0479] Over-expression of ISGF4 mRNA was observed in breast tumor tissues.

[0480] Knockdown of ISGF4 mRNA inhibited proliferation in multiple types of cancer cells, particularly in lung, kidney, gastric, and prostate cancer cells, as well as other types of cancer.

[0481] Both mass spec and mRNA analysis of ISGF4 in lung cancer cell lines indicates an increase in ISGF4 expression in lung cancer cell lines that are increasingly resistant to the drug cisplatin. Thus, increased ISGF4 expression correlates with increased resistance to cisplatin in lung cancer cells.

DB83

[0482] DB83 peptides were identified by mass-spec as over-expressed in 7 lung tumor tissues, 1 breast tumor tissue and 1 colon cancer cell line. DB83 peptides were over-expressed 4.6-100 fold in lung tissues, 2.6 fold in breast tumor tissue, 3.6 fold in colon cancer cell line.

[0483] DB83 is over-expressed, as indicated by IHC, in multiple tumor types as follows: 100% renal (over-expressed in 100% of kidney tumors evaluated), 80% lung (adenocarcinoma), 80% melanoma, 66% glioblastoma, 50% lung (squamous), 33% metastatic pancreas, 29% pancreas, 20% colon.

[0484] Mass-spec cross tissue analysis of DB83 reveals elevated levels of DB83 in lung tumors.

[0485] DB83 is expressed on the cell surface of colon cancer cells (HCT116 and HT29 cells), as indicated by FACS.

[0486] Over-expression of DB83 mRNA was observed in kidney, breast, colon and lung tumors.

[0487] Knockdown of DB83 mRNA inhibits proliferation and induces apoptosis in multiple types of cancer cells, such as in ACHN kidney cancer cells and SK--N--SH neuroblastoma cancer cells. Knockdown of DB83 mRNA induces apoptosis in HT29 colon cancer cells and inhibits proliferation in Calu-1 lung cancer cells.

[0488] RNAi knockdown of DB83 inhibits proliferation in the following cancer cell lines: in NCI-N87 gastric cells by 39%, in ASPC-1 pancreatic cells by 30%, in HCT116 colon cells by 36%, and in Calu-1 lung cells by 20%.

[0489] RNAi knockdown of DB83 induces apoptosis in the following cancer cell lines: in HT29 and HCT116 colon cells by 3.2 and 2.4 fold, in Calu-1 lung cells by 1.9 fold, and in ACHN kidney cells by 3.2 fold.

[0490] All publications and patents mentioned in the above specification are herein incorporated by reference. Various modifications and variations of the described methods and compositions of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific exemplary embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the above-described modes for carrying out the invention, which are obvious to those skilled in the field of molecular biology or related fields, are intended to be within the scope of the following claims.

Sequence CWU 1

1

831435PRTHomo sapiens 1Met Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val Lys Pro1 5 10 15 Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val Gly Ile 20 25 30 Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile Val Val 35 40 45 Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys Gly Gln 50 55 60 Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu Leu Asp65 70 75 80 Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe Pro Glu 85 90 95 Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr Leu Gln 100 105 110 Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe Asp Asn 115 120 125 Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln Met Gly Tyr Ser 130 135 140 Ser Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro Asp Gln Asp Leu145 150 155 160 Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met Arg Asn 165 170 175 Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His Cys Leu 180 185 190 Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Val Glu Glu 195 200 205 Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr Asp Lys 210 215 220 Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val Leu Thr225 230 235 240 Ala Ala His Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp Lys Val 245 250 255 Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala Val Ala 260 265 270 Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp Asn Asp 275 280 285 Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly Thr Val 290 295 300 Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro Ala Thr305 310 315 320 Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly Gly Lys 325 330 335 Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp Ser Thr 340 345 350 Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val Thr Glu Lys Met 355 360 365 Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr Cys Gln Gly Asp 370 375 380 Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp His Val Val Gly385 390 395 400 Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser Thr Pro Gly Val 405 410 415 Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr Asn Val Trp Lys 420 425 430 Ala Glu Leu 435 2437PRTHomo sapiens 2Met Leu Gln Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val1 5 10 15 Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val 20 25 30 Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile 35 40 45 Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys 50 55 60 Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu65 70 75 80 Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe 85 90 95 Pro Glu Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr 100 105 110 Leu Gln Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe 115 120 125 Asp Asn Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln Met Gly 130 135 140 Tyr Ser Ser Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro Asp Gln145 150 155 160 Asp Leu Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met 165 170 175 Arg Asn Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His 180 185 190 Cys Leu Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Gly 195 200 205 Glu Glu Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr 210 215 220 Asp Lys Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val225 230 235 240 Leu Thr Ala Ala His Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp 245 250 255 Lys Val Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala 260 265 270 Val Ala Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp 275 280 285 Asn Asp Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly 290 295 300 Thr Val Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro305 310 315 320 Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly 325 330 335 Gly Lys Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp 340 345 350 Ser Thr Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val Thr Glu 355 360 365 Lys Met Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr Cys Gln 370 375 380 Gly Asp Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp His Val385 390 395 400 Val Gly Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser Thr Pro 405 410 415 Gly Val Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr Asn Val 420 425 430 Trp Lys Ala Glu Leu 435 3437PRTHomo sapiens 3Met Val Ser Asp Pro Asp Ser Asp Gln Pro Leu Asn Ser Leu Asp Val1 5 10 15 Lys Pro Leu Arg Lys Pro Arg Ile Pro Met Glu Thr Phe Arg Lys Val 20 25 30 Gly Ile Pro Ile Ile Ile Ala Leu Leu Ser Leu Ala Ser Ile Ile Ile 35 40 45 Val Val Val Leu Ile Lys Val Ile Leu Asp Lys Tyr Tyr Phe Leu Cys 50 55 60 Gly Gln Pro Leu His Phe Ile Pro Arg Lys Gln Leu Cys Asp Gly Glu65 70 75 80 Leu Asp Cys Pro Leu Gly Glu Asp Glu Glu His Cys Val Lys Ser Phe 85 90 95 Pro Glu Gly Pro Ala Val Ala Val Arg Leu Ser Lys Asp Arg Ser Thr 100 105 110 Leu Gln Val Leu Asp Ser Ala Thr Gly Asn Trp Phe Ser Ala Cys Phe 115 120 125 Asp Asn Phe Thr Glu Ala Leu Ala Glu Thr Ala Cys Arg Gln Met Gly 130 135 140 Tyr Ser Ser Lys Pro Thr Phe Arg Ala Val Glu Ile Gly Pro Asp Gln145 150 155 160 Asp Leu Asp Val Val Glu Ile Thr Glu Asn Ser Gln Glu Leu Arg Met 165 170 175 Arg Asn Ser Ser Gly Pro Cys Leu Ser Gly Ser Leu Val Ser Leu His 180 185 190 Cys Leu Ala Cys Gly Lys Ser Leu Lys Thr Pro Arg Val Val Gly Val 195 200 205 Glu Glu Ala Ser Val Asp Ser Trp Pro Trp Gln Val Ser Ile Gln Tyr 210 215 220 Asp Lys Gln His Val Cys Gly Gly Ser Ile Leu Asp Pro His Trp Val225 230 235 240 Leu Thr Ala Ala His Cys Phe Arg Lys His Thr Asp Val Phe Asn Trp 245 250 255 Lys Val Arg Ala Gly Ser Asp Lys Leu Gly Ser Phe Pro Ser Leu Ala 260 265 270 Val Ala Lys Ile Ile Ile Ile Glu Phe Asn Pro Met Tyr Pro Lys Asp 275 280 285 Asn Asp Ile Ala Leu Met Lys Leu Gln Phe Pro Leu Thr Phe Ser Gly 290 295 300 Thr Val Arg Pro Ile Cys Leu Pro Phe Phe Asp Glu Glu Leu Thr Pro305 310 315 320 Ala Thr Pro Leu Trp Ile Ile Gly Trp Gly Phe Thr Lys Gln Asn Gly 325 330 335 Gly Lys Met Ser Asp Ile Leu Leu Gln Ala Ser Val Gln Val Ile Asp 340 345 350 Ser Thr Arg Cys Asn Ala Asp Asp Ala Tyr Gln Gly Glu Val Thr Glu 355 360 365 Lys Met Met Cys Ala Gly Ile Pro Glu Gly Gly Val Asp Thr Cys Gln 370 375 380 Gly Asp Ser Gly Gly Pro Leu Met Tyr Gln Ser Asp Gln Trp His Val385 390 395 400 Val Gly Ile Val Ser Trp Gly Tyr Gly Cys Gly Gly Pro Ser Thr Pro 405 410 415 Gly Val Tyr Thr Lys Val Ser Ala Tyr Leu Asn Trp Ile Tyr Asn Val 420 425 430 Trp Lys Ala Glu Leu 435 42590DNAHomo sapiens 4actcctggaa tacacagaga gaggcagcag cttgctcagc ggacaaggat gctgggcgtg 60agggaccaag gcctgccctg cactcgggcc tcctccagcc agtgctgacc agggacttct 120gacctgctgg ccagccagga cctgtgtggg gaggccctcc tgctgccttg gggtgacaat 180ctcagctcca ggctacaggg agaccgggag gatcacagag ccagcatgga tcctgacagt 240gatcaacctc tgaacagcct cgatgtcaaa cccctgcgca aaccccgtat ccccatggag 300accttcagaa aggtggggat ccccatcatc atagcactac tgagcctggc gagtatcatc 360attgtggttg tcctcatcaa ggtgattctg gataaatact acttcctctg cgggcagcct 420ctccacttca tcccgaggaa gcagctgtgt gacggagagc tggactgtcc cttgggggag 480gacgaggagc actgtgtcaa gagcttcccc gaagggcctg cagtggcagt ccgcctctcc 540aaggaccgat ccacactgca ggtgctggac tcggccacag ggaactggtt ctctgcctgt 600ttcgacaact tcacagaagc tctcgctgag acagcctgta ggcagatggg ctacagcagc 660aaacccactt tcagagctgt ggagattggc ccagaccagg atctggatgt tgttgaaatc 720acagaaaaca gccaggagct tcgcatgcgg aactcaagtg ggccctgtct ctcaggctcc 780ctggtctccc tgcactgtct tgcctgtggg aagagcctga agaccccccg tgtggtgggt 840gtggaggagg cctctgtgga ttcttggcct tggcaggtca gcatccagta cgacaaacag 900cacgtctgtg gagggagcat cctggacccc cactgggtcc tcacggcagc ccactgcttc 960aggaaacata ccgatgtgtt caactggaag gtgcgggcag gctcagacaa actgggcagc 1020ttcccatccc tggctgtggc caagatcatc atcattgaat tcaaccccat gtaccccaaa 1080gacaatgaca tcgccctcat gaagctgcag ttcccactca ctttctcagg cacagtcagg 1140cccatctgtc tgcccttctt tgatgaggag ctcactccag ccaccccact ctggatcatt 1200ggatggggct ttacgaagca gaatggaggg aagatgtctg acatactgct gcaggcgtca 1260gtccaggtca ttgacagcac acggtgcaat gcagacgatg cgtaccaggg ggaagtcacc 1320gagaagatga tgtgtgcagg catcccggaa gggggtgtgg acacctgcca gggtgacagt 1380ggtgggcccc tgatgtacca atctgaccag tggcatgtgg tgggcatcgt tagttggggc 1440tatggctgcg ggggcccgag caccccagga gtatacacca aggtctcagc ctatctcaac 1500tggatctaca atgtctggaa ggctgagctg taatgctgct gcccctttgc agtgctggga 1560gccgcttcct tcctgccctg cccacctggg gatcccccaa agtcagacac agagcaagag 1620tccccttggg tacacccctc tgcccacagc ctcagcattt cttggagcag caaagggcct 1680caattcctat aagagaccct cgcagcccag aggcgcccag aggaagtcag cagccctagc 1740tcggccacac ttggtgctcc cagcatccca gggagagaca cagcccactg aacaaggtct 1800caggggtatt gctaagccaa gaaggaactt tcccacacta ctgaatggaa gcaggctgtc 1860ttgtaaaagc ccagatcact gtgggctgga gaggagaagg aaagggtctg cgccagccct 1920gtccgtcttc acccatcccc aagcctacta gagcaagaaa ccagttgtaa tataaaatgc 1980actgccctac tgttggtatg actaccgtta cctactgttg tcattgttat tacagctatg 2040gccactatta ttaaagagct gtgtaacatc tctggcatag gctagctgga atgcttgata 2100agaactgagc tgggatgatt gaactttcat tctttggctt ggggagaaaa gaagtcctgg 2160ggaagcaatt gagtctcaaa gtagaggcag gggaaaaaag agttagggag accagatctg 2220ctgagtggca gcaagagtga gctgcagatt acagaaacca gggtgagcaa gtttgagtcc 2280cacacagggc cttctccctt tgcctctttc cctccctccc tgcctgtgat aatcagccag 2340gagccaggga taacctatga cttgggaaag agatgagtta ggcagtcaag ggtgacattc 2400aatcagggat ccacaagtgg ctggaaagaa atgctggtcc tgtgtcctaa ctttttccgc 2460ctggagagcc ctcagtgtgg cttcttacat ttaaaaaaca aaaaggatca gctgccaggt 2520gtgaggcagt ccccaagctg agttgtgagg atgtaagcat gaataagtcc ctgcactcaa 2580aatggtcaaa 259052021DNAHomo sapiens 5ctgcactcgg gcctcctcca gccagtgctg accagggact tctgacctgc tggcagccag 60gacctgtgtg gggaggccct cctgctgcct tggggtgaca atctcagctc caggctacag 120ggagaccggg aggatcacag agccagcatg ttacaggatc ctgacagtga tcaacctctg 180aacagcctcg atgtcaaacc cctgcgcaaa ccccgtatcc ccatggagac cttcagaaag 240gtggggatcc ccatcatcat agcactactg agcctggcga gtatcatcat tgtggttgtc 300ctcatcaagg tgattctgga taaatactac ttcctctgcg ggcagcctct ccacttcatc 360ccgaggaagc agctgtgtga cggagagctg gactgtccct tgggggagga cgaggagcac 420tgtgtcaaga gcttccccga agggcctgca gtggcagtcc gcctctccaa ggaccgatcc 480acactgcagg tgctggactc ggccacaggg aactggttct ctgcctgttt cgacaacttc 540acagaagctc tcgctgagac agcctgtagg cagatgggct acagcagcaa acccactttc 600agagctgtgg agattggccc agaccaggat ctggatgttg ttgaaatcac agaaaacagc 660caggagcttc gcatgcggaa ctcaagtggg ccctgtctct caggctccct ggtctccctg 720cactgtcttg cctgtgggaa gagcttgaag accccccgtg tggtgggtgg ggaggaggcc 780tctgtggatt cttggccttg gcaggtcagc atccagtacg acaaacagca cgtctgtgga 840gggagcatcc tggaccccca ctgggtcctc acggcagccc actgcttcag gaaacatacc 900gatgtgttca actggaaggt gcgggcaggc tcagacaaac tgggcagctt cccatccctg 960gctgtggcca agatcatcat cattgaattc aaccccatgt accccaaaga caatgacatc 1020gccctcatga agctgcagtt cccactcact ttctcaggca cagtcaggcc catctgtctg 1080cccttctttg atgaggagct cactccagcc accccactct ggatcattgg atggggcttt 1140acgaagcaga atggagggaa gatgtctgac atactgctgc aggcgtcagt ccaggtcatt 1200gacagcacac ggtgcaatgc agacgatgcg taccaggggg aagtcaccga gaagatgatg 1260tgtgcaggca tcccggaagg gggtgtggac acctgccagg gtgacagtgg tgggcccctg 1320atgtaccaat ctgaccagtg gcatgtggtg ggcatcgtta gttggggcta tggctgcggg 1380ggcccgagca ccccaggagt atacaccaag gtctcagcct atctcaactg gatctacaat 1440gtctggaagg ctgagctgta atgctgctgc ccctttgcag tgctgggagc cgcttccttc 1500ctgccctgcc cacctgggga tcccccaaag tcagacacag agcaagagtc cccttgggta 1560cacccctctg cccacagcct cagcatttct tggagcagca aagggcctca attcctgtaa 1620gagaccctcg cagcccagag gcgcccagag gaagtcagca gccctagctc ggccacactt 1680ggtgctccca gcatcccagg gagagacaca gcccactgaa caaggtctca ggggtattgc 1740taagccaaga aggaactttc ccacactact gaatggaagc aggctgtctt gtaaaagccc 1800agatcactgt gggctggaga ggagaaggaa agggtctgcg ccagccctgt ccgtcttcac 1860ccatccccaa gcctactaga gcaagaaacc agttgtaata taaaatgcac tgccctactg 1920ttggtatgac taccgttacc tactgttgtc attgttatta cagctatggc cactattatt 1980aaagagctgt gtaacatctc tggaaaaaaa aaaaaaaaaa a 202162627DNAHomo sapiens 6ttttaatcaa gctgcccaaa gtcccccaat cactcctgga atacacagag agaggcagca 60gcttgctcag cggacaagga tgctgggcgt gagggaccaa ggcctgccct gcactcgggc 120ctcctccagc cagtgctgac cagggacttc tgacctgctg gccagccagg acctgtgtgg 180ggaggccctc ctgctgcctt ggggtgacaa tctcagctcc aggctacagg gagaccggga 240ggatcacaga gccagcatgg tgagtgatcc tgacagtgat caacctctga acagcctcga 300tgtcaaaccc ctgcgcaaac cccgtatccc catggagacc ttcagaaagg tggggatccc 360catcatcata gcactactga gcctggcgag tatcatcatt gtggttgtcc tcatcaaggt 420gattctggat aaatactact tcctctgcgg gcagcctctc cacttcatcc cgaggaagca 480gctgtgtgac ggagagctgg actgtccctt gggggaggac gaggagcact gtgtcaagag 540cttccccgaa gggcctgcag tggcagtccg cctctccaag gaccgatcca cactgcaggt 600gctggactcg gccacaggga actggttctc tgcctgtttc gacaacttca cagaagctct 660cgctgagaca gcctgtaggc agatgggcta cagcagcaaa cccactttca gagctgtgga 720gattggccca gaccaggatc tggatgttgt tgaaatcaca gaaaacagcc aggagcttcg 780catgcggaac tcaagtgggc cctgtctctc aggctccctg gtctccctgc actgtcttgc 840ctgtgggaag agcctgaaga ccccccgtgt ggtgggtgtg gaggaggcct ctgtggattc 900ttggccttgg caggtcagca tccagtacga caaacagcac gtctgtggag ggagcatcct 960ggacccccac tgggtcctca cggcagccca ctgcttcagg aaacataccg atgtgttcaa 1020ctggaaggtg cgggcaggct cagacaaact gggcagcttc ccatccctgg ctgtggccaa 1080gatcatcatc attgaattca accccatgta ccccaaagac aatgacatcg ccctcatgaa 1140gctgcagttc ccactcactt tctcaggcac agtcaggccc atctgtctgc ccttctttga 1200tgaggagctc actccagcca ccccactctg gatcattgga tggggcttta cgaagcagaa 1260tggagggaag atgtctgaca tactgctgca ggcgtcagtc caggtcattg acagcacacg 1320gtgcaatgca gacgatgcgt accaggggga agtcaccgag aagatgatgt gtgcaggcat 1380cccggaaggg ggtgtggaca cctgccaggg tgacagtggt gggcccctga tgtaccaatc 1440tgaccagtgg catgtggtgg gcatcgttag ttggggctat ggctgcgggg gcccgagcac 1500cccaggagta tacaccaagg tctcagccta tctcaactgg atctacaatg tctggaaggc 1560tgagctgtaa tgctgctgcc cctttgcagt gctgggagcc gcttccttcc tgccctgccc 1620acctggggat cccccaaagt cagacacaga gcaagagtcc ccttgggtac acccctctgc 1680ccacagcctc agcatttctt ggagcagcaa agggcctcaa ttcctataag agaccctcgc 1740agcccagagg cgcccagagg

aagtcagcag ccctagctcg gccacacttg gtgctcccag 1800catcccaggg agagacacag cccactgaac aaggtctcag gggtattgct aagccaagaa 1860ggaactttcc cacactactg aatggaagca ggctgtcttg taaaagccca gatcactgtg 1920ggctggagag gagaaggaaa gggtctgcgc cagccctgtc cgtcttcacc catccccaag 1980cctactagag caagaaacca gttgtaatat aaaatgcact gccctactgt tggtatgact 2040accgttacct actgttgtca ttgttattac agctatggcc actattatta aagagctgtg 2100taacatctct ggcataggct agctggaatg cttgataaga actgagctgg gatgattgaa 2160ctttcattct ttggcttggg gagaaaagaa gtcctgggga agcaattgag tctcaaagta 2220gaggcagggg aaaaaagagt tagggagacc agatctgctg agtggcagca agagtgagct 2280gcagattaca gaaaccaggg tgagcaagtt tgagtcccac acagggcctt ctccctttgc 2340ctctttccct ccctccctgc ctgtgataat cagccaggag ccagggataa cctatgactt 2400gggaaagaga tgagttaggc agtcaagggt gacattcaat cagggatcca caagtggctg 2460gaaagaaatg ctggtcctgt gtcctaactt tttccgcctg gagagccctc agtgtggctt 2520cttacattta aaaaacaaaa aggatcagct gccaggtgtg aggcagtccc caagctgagt 2580tgtgaggatg taagcatgaa taagtccctg cactcaaaat ggtcaaa 26277635PRTHomo sapiens 7Met Ser Val Gly Val Ser Thr Ser Ala Pro Leu Ser Pro Thr Ser Gly1 5 10 15 Thr Ser Val Gly Met Ser Thr Phe Ser Ile Met Asp Tyr Val Val Phe 20 25 30 Val Leu Leu Leu Val Leu Ser Leu Ala Ile Gly Leu Tyr His Ala Cys 35 40 45 Arg Gly Trp Gly Arg His Thr Val Gly Glu Leu Leu Met Ala Asp Arg 50 55 60 Lys Met Gly Cys Leu Pro Val Ala Leu Ser Leu Leu Ala Thr Phe Gln65 70 75 80 Ser Ala Val Ala Ile Leu Gly Val Pro Ser Glu Ile Tyr Arg Phe Gly 85 90 95 Thr Gln Tyr Trp Phe Leu Gly Cys Cys Tyr Phe Leu Gly Leu Leu Ile 100 105 110 Pro Ala His Ile Phe Ile Pro Val Phe Tyr Arg Leu His Leu Thr Ser 115 120 125 Ala Tyr Glu Tyr Leu Glu Leu Arg Phe Asn Lys Thr Val Arg Val Cys 130 135 140 Gly Thr Val Thr Phe Ile Phe Gln Met Val Ile Tyr Met Gly Val Val145 150 155 160 Leu Tyr Ala Pro Ser Leu Ala Leu Asn Ala Val Thr Gly Phe Asp Leu 165 170 175 Trp Leu Ser Val Leu Ala Leu Gly Ile Val Cys Thr Val Tyr Thr Ala 180 185 190 Leu Gly Gly Leu Lys Ala Val Ile Trp Thr Asp Val Phe Gln Thr Leu 195 200 205 Val Met Phe Leu Gly Gln Leu Ala Val Ile Ile Val Gly Ser Ala Lys 210 215 220 Val Gly Gly Leu Gly Arg Val Trp Ala Val Ala Ser Gln His Gly Arg225 230 235 240 Ile Ser Gly Phe Glu Leu Asp Pro Asp Pro Phe Val Arg His Thr Phe 245 250 255 Trp Thr Leu Ala Phe Gly Gly Val Phe Met Met Leu Ser Leu Tyr Gly 260 265 270 Val Asn Gln Ala Gln Val Gln Arg Tyr Leu Ser Ser Arg Thr Glu Lys 275 280 285 Ala Ala Val Leu Ser Cys Tyr Ala Val Phe Pro Phe Gln Gln Val Ser 290 295 300 Leu Cys Val Gly Cys Leu Ile Gly Leu Val Met Phe Ala Tyr Tyr Gln305 310 315 320 Glu Tyr Pro Met Ser Ile Gln Gln Ala Gln Ala Ala Pro Asp Gln Phe 325 330 335 Val Leu Tyr Phe Val Met Asp Leu Leu Lys Gly Leu Pro Gly Leu Pro 340 345 350 Gly Leu Phe Ile Ala Cys Leu Phe Ser Gly Ser Leu Ser Thr Ile Ser 355 360 365 Ser Ala Phe Asn Ser Leu Ala Thr Val Thr Met Glu Asp Leu Ile Arg 370 375 380 Pro Trp Phe Pro Glu Phe Ser Glu Ala Arg Ala Ile Met Leu Ser Arg385 390 395 400 Gly Leu Ala Phe Gly Tyr Gly Leu Leu Cys Leu Gly Met Ala Tyr Ile 405 410 415 Ser Ser Gln Met Gly Pro Val Leu Gln Ala Ala Ile Ser Ile Phe Gly 420 425 430 Met Val Gly Gly Pro Leu Leu Gly Leu Phe Cys Leu Gly Met Phe Phe 435 440 445 Pro Cys Ala Asn Pro Pro Gly Ala Val Val Gly Leu Leu Ala Gly Leu 450 455 460 Val Met Ala Phe Trp Ile Gly Ile Gly Ser Ile Val Thr Ser Met Gly465 470 475 480 Ser Ser Met Pro Pro Ser Pro Ser Asn Gly Ser Ser Phe Ser Leu Pro 485 490 495 Thr Asn Leu Thr Val Ala Thr Val Thr Thr Leu Met Pro Leu Thr Thr 500 505 510 Phe Ser Lys Pro Thr Gly Leu Gln Arg Phe Tyr Ser Leu Ser Tyr Leu 515 520 525 Trp Tyr Ser Ala His Asn Ser Thr Thr Val Ile Val Val Gly Leu Ile 530 535 540 Val Ser Leu Leu Thr Gly Arg Met Arg Gly Arg Ser Leu Asn Pro Ala545 550 555 560 Thr Ile Tyr Pro Val Leu Pro Lys Leu Leu Ser Leu Leu Pro Leu Ser 565 570 575 Cys Gln Lys Arg Leu His Cys Arg Ser Tyr Gly Gln Asp His Leu Asp 580 585 590 Thr Gly Leu Phe Pro Glu Lys Pro Arg Asn Gly Val Leu Gly Asp Ser 595 600 605 Arg Asp Lys Glu Ala Met Ala Leu Asp Gly Thr Ala Tyr Gln Gly Ser 610 615 620 Ser Ser Thr Cys Ile Leu Gln Glu Thr Ser Leu625 630 635 8257PRTHomo sapiens 8Met Glu Asp Leu Ile Arg Pro Trp Phe Pro Glu Phe Ser Glu Ala Arg1 5 10 15 Ala Ile Met Leu Ser Arg Gly Leu Ala Phe Gly Tyr Gly Leu Leu Cys 20 25 30 Leu Gly Met Ala Tyr Ile Ser Ser Gln Met Gly Pro Val Leu Gln Ala 35 40 45 Ala Ile Ser Ile Phe Gly Met Val Gly Gly Pro Leu Leu Gly Leu Phe 50 55 60 Cys Leu Gly Met Phe Phe Pro Cys Ala Asn Pro Pro Gly Ala Val Val65 70 75 80 Gly Leu Leu Ala Gly Leu Val Met Ala Phe Trp Ile Gly Ile Gly Ser 85 90 95 Ile Val Thr Ser Met Gly Phe Ser Met Pro Pro Ser Pro Ser Asn Gly 100 105 110 Ser Ser Phe Ser Leu Pro Thr Asn Leu Thr Val Ala Thr Val Thr Thr 115 120 125 Leu Met Pro Leu Thr Thr Phe Ser Lys Pro Thr Gly Leu Gln Arg Phe 130 135 140 Tyr Ser Leu Ser Tyr Leu Trp Tyr Ser Ala His Asn Ser Thr Thr Val145 150 155 160 Ile Val Val Gly Leu Ile Val Ser Leu Leu Thr Gly Arg Met Arg Gly 165 170 175 Arg Ser Leu Asn Pro Ala Thr Ile Tyr Pro Val Leu Pro Lys Leu Leu 180 185 190 Ser Leu Leu Pro Leu Ser Cys Gln Lys Arg Leu His Cys Arg Ser Tyr 195 200 205 Gly Gln Asp His Leu Asp Thr Gly Leu Phe Pro Glu Lys Pro Arg Asn 210 215 220 Gly Val Leu Gly Asp Ser Arg Asp Lys Glu Ala Met Ala Leu Asp Gly225 230 235 240 Thr Ala Tyr Gln Gly Ser Ser Ser Thr Cys Ile Leu Gln Glu Thr Ser 245 250 255 Leu 9635PRTHomo sapiens 9Met Ser Val Gly Val Ser Thr Ser Ala Pro Leu Ser Pro Thr Ser Gly1 5 10 15 Thr Ser Val Gly Met Ser Thr Phe Ser Ile Met Asp Tyr Val Val Phe 20 25 30 Val Leu Leu Leu Val Leu Ser Leu Ala Ile Gly Leu Tyr His Ala Cys 35 40 45 Arg Gly Trp Gly Arg His Thr Val Gly Glu Leu Leu Met Ala Asp Arg 50 55 60 Lys Met Gly Cys Leu Pro Val Ala Leu Ser Leu Leu Ala Thr Phe Gln65 70 75 80 Ser Ala Val Ala Ile Leu Gly Val Pro Ser Glu Ile Tyr Arg Phe Gly 85 90 95 Thr Gln Tyr Trp Phe Leu Gly Cys Cys Tyr Phe Leu Gly Leu Leu Ile 100 105 110 Pro Ala His Ile Phe Ile Pro Val Phe Tyr Arg Leu His Leu Thr Ser 115 120 125 Ala Tyr Glu Tyr Leu Glu Leu Arg Phe Asn Lys Thr Val Arg Val Cys 130 135 140 Gly Thr Val Thr Phe Ile Phe Gln Met Val Ile Tyr Met Gly Val Val145 150 155 160 Leu Tyr Ala Pro Ser Leu Ala Leu Asn Ala Val Thr Gly Phe Asp Leu 165 170 175 Trp Leu Ser Val Leu Ala Leu Gly Ile Val Cys Thr Val Tyr Thr Ala 180 185 190 Leu Gly Gly Leu Lys Ala Val Ile Trp Thr Asp Val Phe Gln Thr Leu 195 200 205 Val Met Phe Leu Gly Gln Leu Ala Val Ile Ile Val Gly Ser Ala Lys 210 215 220 Val Gly Gly Leu Gly Arg Val Trp Ala Val Ala Ser Gln His Gly Arg225 230 235 240 Ile Ser Gly Phe Glu Leu Asp Pro Asp Pro Phe Val Arg His Thr Phe 245 250 255 Trp Thr Leu Ala Phe Gly Gly Val Phe Met Met Leu Ser Leu Tyr Gly 260 265 270 Val Asn Gln Ala Gln Val Gln Arg Tyr Leu Ser Ser Arg Thr Glu Lys 275 280 285 Ala Ala Val Leu Ser Cys Tyr Ala Val Phe Pro Phe Gln Gln Val Ser 290 295 300 Leu Cys Val Gly Cys Leu Ile Gly Leu Val Met Phe Ala Tyr Tyr Gln305 310 315 320 Glu Tyr Pro Met Ser Ile Gln Gln Ala Gln Ala Ala Pro Asp Gln Phe 325 330 335 Val Leu Tyr Phe Val Met Asp Leu Leu Lys Gly Leu Pro Gly Leu Pro 340 345 350 Gly Leu Phe Ile Ala Cys Leu Phe Ser Gly Ser Leu Ser Thr Ile Ser 355 360 365 Ser Ala Phe Asn Ser Leu Ala Thr Val Thr Met Glu Asp Leu Ile Arg 370 375 380 Pro Trp Phe Pro Glu Phe Ser Glu Ala Arg Ala Ile Met Leu Ser Arg385 390 395 400 Gly Leu Ala Phe Gly Tyr Gly Leu Leu Cys Leu Gly Met Ala Tyr Ile 405 410 415 Ser Ser Gln Met Gly Pro Val Leu Gln Ala Ala Ile Ser Ile Phe Gly 420 425 430 Met Val Gly Gly Pro Leu Leu Gly Leu Phe Cys Leu Gly Met Phe Phe 435 440 445 Pro Cys Ala Asn Pro Pro Gly Ala Val Val Gly Leu Leu Ala Gly Leu 450 455 460 Val Met Ala Phe Trp Ile Gly Ile Gly Ser Ile Val Thr Ser Met Gly465 470 475 480 Phe Ser Met Pro Pro Ser Pro Ser Asn Gly Ser Ser Phe Ser Leu Pro 485 490 495 Thr Asn Leu Thr Val Ala Thr Val Thr Thr Leu Met Pro Leu Thr Thr 500 505 510 Phe Ser Lys Pro Thr Gly Leu Gln Arg Phe Tyr Ser Leu Ser Tyr Leu 515 520 525 Trp Tyr Ser Ala His Asn Ser Thr Thr Val Ile Val Val Gly Leu Ile 530 535 540 Val Ser Leu Leu Thr Gly Arg Met Arg Gly Arg Ser Leu Asn Pro Ala545 550 555 560 Thr Ile Tyr Pro Val Leu Pro Lys Leu Leu Ser Leu Leu Pro Leu Ser 565 570 575 Cys Gln Lys Arg Leu His Cys Arg Ser Tyr Gly Gln Asp His Leu Asp 580 585 590 Thr Gly Leu Phe Pro Glu Lys Pro Arg Asn Gly Val Leu Gly Asp Ser 595 600 605 Arg Asp Lys Glu Ala Met Ala Leu Asp Gly Thr Ala Tyr Gln Gly Ser 610 615 620 Ser Ser Thr Cys Ile Leu Gln Glu Thr Ser Leu625 630 635 103031DNAHomo sapiens 10atatcgcaca gggaaggtcc tcatctctga agatcactat tcgaacttat ttattatgct 60ttctgcagag acttctcaat ctgacagccc tagtttggcg cggtgtaaaa cgaccgcagg 120aaaagggagc gatgttgatc tcaggaagca caaagggacc ttcctagctc tgactgaacc 180acggagctca ccctggacag tatcactccg tggaggaaga ctgtgagact gtggctggaa 240gccagattgt agccacacat ccgcccctgc cctaccccag agccctggag cagcaactgg 300ctgcagatca cagacacagt gaggatatga gtgtaggggt gagcacctca gcccctcttt 360ccccaacctc gggcacaagc gtgggcatgt ctaccttctc catcatggac tatgtggtgt 420tcgtcctgct gctggttctc tctcttgcca ttgggctcta ccatgcttgt cgtggctggg 480gccggcatac tgttggtgag ctgctgatgg cggaccgcaa aatgggctgc cttccggtgg 540cactgtccct gctggccacc ttccagtcag ccgtggccat cctgggtgtg ccgtcagaga 600tctaccgatt tgggacccaa tattggttcc tgggctgctg ctactttctg gggctgctga 660tacctgcaca catcttcatc cccgttttct accgcctgca tctcaccagt gcctatgagt 720acctggagct tcgattcaat aaaactgtgc gagtgtgtgg aactgtgacc ttcatctttc 780agatggtgat ctacatggga gttgtgctct atgctccgtc attggctctc aatgcagtga 840ctggctttga tctgtggctg tccgtgctgg ccctgggcat tgtctgtacc gtctatacag 900ctctgggtgg gctgaaggcc gtcatctgga cagatgtgtt ccagacactg gtcatgttcc 960tcgggcagct ggcagttatc atcgtggggt cagccaaggt gggcggcttg gggcgtgtgt 1020gggccgtggc ttcccagcac ggccgcatct ctgggtttga gctggatcca gacccctttg 1080tgcggcacac cttctggacc ttggccttcg ggggtgtctt catgatgctc tccttatacg 1140gggtgaacca ggctcaggtg cagcggtacc tcagttcccg cacggagaag gctgctgtgc 1200tctcctgtta tgcagtgttc cccttccagc aggtgtccct ctgcgtgggc tgcctcattg 1260gcctggtcat gttcgcgtat taccaggagt atcccatgag cattcagcag gctcaggcag 1320ccccagacca gttcgtcctg tactttgtga tggatctcct gaagggcctg ccaggcctgc 1380cagggctctt cattgcctgc ctcttcagcg gctctctcag cactatatcc tctgctttta 1440attcattggc aactgttacg atggaagacc tgattcgacc ttggttccct gagttctctg 1500aagcccgggc catcatgctt tccagaggcc ttgcctttgg ctatgggctg ctttgtctag 1560gaatggccta tatttcctcc cagatgggac ctgtgctgca ggcagcaatc agcatctttg 1620gcatggttgg gggaccgctg ctgggactct tctgccttgg aatgttcttt ccatgtgcta 1680accctcctgg tgctgttgtg ggcctgttgg ctgggctcgt catggccttc tggattggca 1740tcgggagcat cgtgaccagc atgggcttca gcatgccacc ctctccctct aatgggtcca 1800gcttctccct gcccaccaat ctaaccgttg ccactgtgac cacactgatg cccttgacta 1860ccttctccaa gcccacaggg ctgcagcggt tctattcctt gtcttactta tggtacagtg 1920ctcacaactc caccacagtg attgtggtgg gcctgattgt cagtctactc actgggagaa 1980tgcgaggccg gtccctgaac cctgcaacca tttacccagt gttgccaaag ctcctgtccc 2040tccttccgtt gtcctgtcag aagcggctcc actgcaggag ctacggccag gaccacctcg 2100acactggcct gtttcctgag aagccgagga atggtgtgct gggggacagc agagacaagg 2160aggccatggc cctggatggc acagcctatc aggggagcag ctccacctgc atcctccagg 2220agacctccct gtgatgttga ctcaggaccc cgcctctgtc ctcacttgtg ttctgcaggg 2280acaggcctgg atgatctagc tcataccaaa ggaccttgtt ctgagaggtt cttgcctgca 2340ggagaagctg tcacatctca agcatgtgag gcaccgtttt tctcgtcgct tgccaatctg 2400ttttttaaag gatcaggctc gtagggagca ggatcatgcc agaaataggg atggaagtgc 2460atcctctggg aaaaagataa tggcttctga ttcaacatag ccatagtcct ttgaagtaag 2520tggctagaaa cagcactctg gttataattg ccccagggcc tgattcagga ctgactctcc 2580accataaaac tggaagctgc ttcccctgta gtccccattt cagtaccagt tctgccagcc 2640acagtgagcc cctattatta ctttcagatt gtctgtgaca ctcaagcccc tctcattttt 2700atctgtctac ctccattctg aagagggagg ttttggtgtc cctggtcctc tgggaataga 2760agatccattt gtctttgtgt agagcaagca cgttttccac ctcactgtct ccatcctcca 2820cctctgagat ggacacttaa gagacggggc aaatgtggat ccaagaaacc agggccatga 2880ccaggtccac tgtggagcag ccatctatct acctgactcc tgagccaggc tgccgtggtg 2940tcatttctgt catccgtgct ctgtttcctt ttggagtttc ttctccacat tatctttgtt 3000cctggggaat aaaaactacc attggaccta g 3031113031DNAHomo sapiens 11atatcgcaca gggaaggtcc tcatctctga agatcactat tcgaacttat ttattatgct 60ttctgcagag acttctcaat ctgacagccc tagtttggcg cggtgtaaaa cgaccgcagg 120aaaagggagc gatgttgatc tcaggaagca caaagggacc ttcctagctc tgactgaacc 180acggagctca ccctggacag tatcactccg tggaggaaga ctgtgagact gtggctggaa 240gccagattgt agccacacat ccgcccctgc cctaccccag agccctggag cagcaactgg 300ctgcagatca cagacacagt gaggatatga gtgtaggggt gagcacctca gcccctcttt 360ccccaacctc gggcacaagc gtgggcatgt ctaccttctc catcatggac tatgtggtgt 420tcgtcctgct gctggttctc tctcttgcca ttgggctcta ccatgcttgt cgtggctggg 480gccggcatac tgttggtgag ctgctgatgg cggaccgcaa aatgggctgc cttccggtgg 540cactgtccct gctggccacc ttccagtcag ccgtggccat cctgggtgtg ccgtcagaga 600tctaccgatt tgggacccaa tattggttcc tgggctgctg ctactttctg gggctgctga 660tacctgcaca catcttcatc cccgttttct accgcctgca tctcaccagt gcctatgagt 720acctggagct tcgattcaat aaaactgtgc gagtgtgtgg aactgtgacc ttcatctttc 780agatggtgat ctacatggga gttgtgctct atgctccgtc attggctctc aatgcagtga 840ctggctttga tctgtggctg tccgtgctgg ccctgggcat tgtctgtacc gtctatacag 900ctctgggtgg gctgaaggcc gtcatctgga cagatgtgtt ccagacactg gtcatgttcc 960tcgggcagct ggcagttatc atcgtggggt cagccaaggt gggcggcttg gggcgtgtgt 1020gggccgtggc ttcccagcac ggccgcatct ctgggtttga gctggatcca gacccctttg 1080tgcggcacac

cttctggacc ttggccttcg ggggtgtctt catgatgctc tccttatacg 1140gggtgaacca ggctcaggtg cagcggtacc tcagttcccg cacggagaag gctgctgtgc 1200tctcctgtta tgcagtgttc cccttccagc aggtgtccct ctgcgtgggc tgcctcattg 1260gcctggtcat gttcgcgtat taccaggagt atcccatgag cattcagcag gctcaggcag 1320ccccagacca gttcgtcctg tactttgtga tggatctcct gaagggcctg ccaggcctgc 1380cagggctctt cattgcctgc ctcttcagcg gctctctcag cactatatcc tctgctttta 1440attcattggc aactgttacg atggaagacc tgattcgacc ttggttccct gagttctctg 1500aagcccgggc catcatgctt tccagaggcc ttgcctttgg ctatgggctg ctttgtctag 1560gaatggccta tatttcctcc cagatgggac ctgtgctgca ggcagcaatc agcatctttg 1620gcatggttgg gggaccgctg ctgggactct tctgccttgg aatgttcttt ccatgtgcta 1680accctcctgg tgctgttgtg ggcctgttgg ctgggctcgt catggccttc tggattggca 1740tcgggagcat cgtgaccagc atgggcttca gcatgccacc ctctccctct aatgggtcca 1800gcttctccct gcccaccaat ctaaccgttg ccactgtgac cacactgatg cccttgacta 1860ccttctccaa gcccacaggg ctgcagcggt tctattcctt gtcttactta tggtacagtg 1920ctcacaactc caccacagtg attgtggtgg gcctgattgt cagtctactc actgggagaa 1980tgcgaggccg gtccctgaac cctgcaacca tttacccagt gttgccaaag ctcctgtccc 2040tccttccgtt gtcctgtcag aagcggctcc actgcaggag ctacggccag gaccacctcg 2100acactggcct gtttcctgag aagccgagga atggtgtgct gggggacagc agagacaagg 2160aggccatggc cctggatggc acagcctatc aggggagcag ctccacctgc atcctccagg 2220agacctccct gtgatgttga ctcaggaccc cgcctctgtc ctcacttgtg ttctgcaggg 2280acaggcctgg atgatctagc tcataccaaa ggaccttgtt ctgagaggtt cttgcctgca 2340ggagaagctg tcacatctca agcatgtgag gcaccgtttt tctcgtcgct tgccaatctg 2400ttttttaaag gatcaggctc gtagggagca ggatcatgcc agaaataggg atggaagtgc 2460atcctctggg aaaaagataa tggcttctga ttcaacatag ccatagtcct ttgaagtaag 2520tggctagaaa cagcactctg gttataattg ccccagggcc tgattcagga ctgactctcc 2580accataaaac tggaagctgc ttcccctgta gtccccattt cagtaccagt tctgccagcc 2640acagtgagcc cctattatta ctttcagatt gtctgtgaca ctcaagcccc tctcattttt 2700atctgtctac ctccattctg aagagggagg ttttggtgtc cctggtcctc tgggaataga 2760agatccattt gtctttgtgt agagcaagca cgttttccac ctcactgtct ccatcctcca 2820cctctgagat ggacacttaa gagacggggc aaatgtggat ccaagaaacc agggccatga 2880ccaggtccac tgtggagcag ccatctatct acctgactcc tgagccaggc tgccgtggtg 2940tcatttctgt catccgtgct ctgtttcctt ttggagtttc ttctccacat tatctttgtt 3000cctggggaat aaaaactacc attggaccta g 3031123031DNAHomo sapiens 12atatcgcaca gggaaggtcc tcatctctga agatcactat tcgaacttat ttattatgct 60ttctgcagag acttctcaat ctgacagccc tagtttggcg cggtgtaaaa cgaccgcagg 120aaaagggagc gatgttgatc tcaggaagca caaagggacc ttcctagctc tgactgaacc 180acggagctca ccctggacag tatcactccg tggaggaaga ctgtgagact gtggctggaa 240gccagattgt agccacacat ccgcccctgc cctaccccag agccctggag cagcaactgg 300ctgcagatca cagacacagt gaggatatga gtgtaggggt gagcacctca gcccctcttt 360ccccaacctc gggcacaagc gtgggcatgt ctaccttctc catcatggac tatgtggtgt 420tcgtcctgct gctggttctc tctcttgcca ttgggctcta ccatgcttgt cgtggctggg 480gccggcatac tgttggtgag ctgctgatgg cggaccgcaa aatgggctgc cttccggtgg 540cactgtccct gctggccacc ttccagtcag ccgtggccat cctgggtgtg ccgtcagaga 600tctaccgatt tgggacccaa tattggttcc tgggctgctg ctactttctg gggctgctga 660tacctgcaca catcttcatc cccgttttct accgcctgca tctcaccagt gcctatgagt 720acctggagct tcgattcaat aaaactgtgc gagtgtgtgg aactgtgacc ttcatctttc 780agatggtgat ctacatggga gttgtgctct atgctccgtc attggctctc aatgcagtga 840ctggctttga tctgtggctg tccgtgctgg ccctgggcat tgtctgtacc gtctatacag 900ctctgggtgg gctgaaggcc gtcatctgga cagatgtgtt ccagacactg gtcatgttcc 960tcgggcagct ggcagttatc atcgtggggt cagccaaggt gggcggcttg gggcgtgtgt 1020gggccgtggc ttcccagcac ggccgcatct ctgggtttga gctggatcca gacccctttg 1080tgcggcacac cttctggacc ttggccttcg ggggtgtctt catgatgctc tccttatacg 1140gggtgaacca ggctcaggtg cagcggtacc tcagttcccg cacggagaag gctgctgtgc 1200tctcctgtta tgcagtgttc cccttccagc aggtgtccct ctgcgtgggc tgcctcattg 1260gcctggtcat gttcgcgtat taccaggagt atcccatgag cattcagcag gctcaggcag 1320ccccagacca gttcgtcctg tactttgtga tggatctcct gaagggcctg ccaggcctgc 1380cagggctctt cattgcctgc ctcttcagcg gctctctcag cactatatcc tctgctttta 1440attcattggc aactgttacg atggaagacc tgattcgacc ttggttccct gagttctctg 1500aagcccgggc catcatgctt tccagaggcc ttgcctttgg ctatgggctg ctttgtctag 1560gaatggccta tatttcctcc cagatgggac ctgtgctgca ggcagcaatc agcatctttg 1620gcatggttgg gggaccgctg ctgggactct tctgccttgg aatgttcttt ccatgtgcta 1680accctcctgg tgctgttgtg ggcctgttgg ctgggctcgt catggccttc tggattggca 1740tcgggagcat cgtgaccagc atgggcttca gcatgccacc ctctccctct aatgggtcca 1800gcttctccct gcccaccaat ctaaccgttg ccactgtgac cacactgatg cccttgacta 1860ccttctccaa gcccacaggg ctgcagcggt tctattcctt gtcttactta tggtacagtg 1920ctcacaactc caccacagtg attgtggtgg gcctgattgt cagtctactc actgggagaa 1980tgcgaggccg gtccctgaac cctgcaacca tttacccagt gttgccaaag ctcctgtccc 2040tccttccgtt gtcctgtcag aagcggctcc actgcaggag ctacggccag gaccacctcg 2100acactggcct gtttcctgag aagccgagga atggtgtgct gggggacagc agagacaagg 2160aggccatggc cctggatggc acagcctatc aggggagcag ctccacctgc atcctccagg 2220agacctccct gtgatgttga ctcaggaccc cgcctctgtc ctcacttgtg ttctgcaggg 2280acaggcctgg atgatctagc tcataccaaa ggaccttgtt ctgagaggtt cttgcctgca 2340ggagaagctg tcacatctca agcatgtgag gcaccgtttt tctcgtcgct tgccaatctg 2400ttttttaaag gatcaggctc gtagggagca ggatcatgcc agaaataggg atggaagtgc 2460atcctctggg aaaaagataa tggcttctga ttcaacatag ccatagtcct ttgaagtaag 2520tggctagaaa cagcactctg gttataattg ccccagggcc tgattcagga ctgactctcc 2580accataaaac tggaagctgc ttcccctgta gtccccattt cagtaccagt tctgccagcc 2640acagtgagcc cctattatta ctttcagatt gtctgtgaca ctcaagcccc tctcattttt 2700atctgtctac ctccattctg aagagggagg ttttggtgtc cctggtcctc tgggaataga 2760agatccattt gtctttgtgt agagcaagca cgttttccac ctcactgtct ccatcctcca 2820cctctgagat ggacacttaa gagacggggc aaatgtggat ccaagaaacc agggccatga 2880ccaggtccac tgtggagcag ccatctatct acctgactcc tgagccaggc tgccgtggtg 2940tcatttctgt catccgtgct ctgtttcctt ttggagtttc ttctccacat tatctttgtt 3000cctggggaat aaaaactacc attggaccta g 303113414PRTHomo sapiens 13Met Ala Ser Val Val Leu Pro Ser Gly Ser Gln Cys Ala Ala Ala Ala1 5 10 15 Ala Ala Ala Ala Pro Pro Gly Leu Arg Leu Arg Leu Leu Leu Leu Leu 20 25 30 Phe Ser Ala Ala Ala Leu Ile Pro Thr Gly Asp Gly Gln Asn Leu Phe 35 40 45 Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala Thr Ile Ser Cys 50 55 60 Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu Leu Asn Pro Asn65 70 75 80 Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu Lys Asp Ser Arg 85 90 95 Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys Val Ser Leu Thr 100 105 110 Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys Gln Leu Tyr Thr 115 120 125 Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val Leu Val Pro Pro 130 135 140 Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala Val Glu Gly Glu145 150 155 160 Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys Pro Ala Thr Thr 165 170 175 Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly Lys Ser Glu Val 180 185 190 Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln Leu Met Leu Lys 195 200 205 Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys Gln Val Glu His 210 215 220 Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr Leu Glu Val Gln225 230 235 240 Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro Leu Gln Gly Leu 245 250 255 Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu Ala Ile Gly Lys 260 265 270 Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp Asp Glu Met Pro 275 280 285 Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile Asn Asn Leu Asn 290 295 300 Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser Asn Ile Val Gly305 310 315 320 Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp Ser Arg Ala Gly 325 330 335 Glu Glu Gly Ser Ile Arg Ala Val Asp His Ala Val Ile Gly Gly Val 340 345 350 Val Ala Val Val Val Phe Ala Met Leu Cys Leu Leu Ile Ile Leu Gly 355 360 365 Arg Tyr Phe Ala Arg His Lys Gly Thr Tyr Phe Thr His Glu Ala Lys 370 375 380 Gly Ala Asp Asp Ala Ala Asp Ala Asp Thr Ala Ile Ile Asn Ala Glu385 390 395 400 Gly Gly Gln Asn Asn Ser Glu Glu Lys Lys Glu Tyr Phe Ile 405 410 14442PRTHomo sapiens 14Met Ala Ser Val Val Leu Pro Ser Gly Ser Gln Cys Ala Ala Ala Ala1 5 10 15 Ala Ala Ala Ala Pro Pro Gly Leu Arg Leu Arg Leu Leu Leu Leu Leu 20 25 30 Phe Ser Ala Ala Ala Leu Ile Pro Thr Gly Asp Gly Gln Asn Leu Phe 35 40 45 Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala Thr Ile Ser Cys 50 55 60 Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu Leu Asn Pro Asn65 70 75 80 Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu Lys Asp Ser Arg 85 90 95 Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys Val Ser Leu Thr 100 105 110 Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys Gln Leu Tyr Thr 115 120 125 Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val Leu Val Pro Pro 130 135 140 Arg Asn Leu Met Ile Asp Ile Gln Arg Asp Thr Ala Val Glu Gly Glu145 150 155 160 Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys Pro Ala Thr Thr 165 170 175 Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly Lys Ser Glu Val 180 185 190 Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln Leu Met Leu Lys 195 200 205 Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys Gln Val Glu His 210 215 220 Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr Leu Glu Val Gln225 230 235 240 Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro Leu Gln Gly Leu 245 250 255 Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu Ala Ile Gly Lys 260 265 270 Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp Asp Glu Met Pro 275 280 285 Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile Asn Asn Leu Asn 290 295 300 Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser Asn Ile Val Gly305 310 315 320 Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp Pro Pro Thr Thr 325 330 335 Ile Pro Pro Pro Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr Thr 340 345 350 Thr Ile Leu Thr Ile Ile Thr Asp Ser Arg Ala Gly Glu Glu Gly Ser 355 360 365 Ile Arg Ala Val Asp His Ala Val Ile Gly Gly Val Val Ala Val Val 370 375 380 Val Phe Ala Met Leu Cys Leu Leu Ile Ile Leu Gly Arg Tyr Phe Ala385 390 395 400 Arg His Lys Gly Thr Tyr Phe Thr His Glu Ala Lys Gly Ala Asp Asp 405 410 415 Ala Ala Asp Ala Asp Thr Ala Ile Ile Asn Ala Glu Gly Gly Gln Asn 420 425 430 Asn Ser Glu Glu Lys Lys Glu Tyr Phe Ile 435 440 15333PRTHomo sapiens 15Met Ala Ser Val Val Leu Pro Ser Gly Ser Gln Cys Ala Ala Ala Ala1 5 10 15 Ala Ala Ala Ala Pro Pro Gly Leu Arg Leu Arg Leu Leu Leu Leu Leu 20 25 30 Phe Ser Ala Ala Ala Leu Ile Pro Thr Gly Asp Gly Gln Asn Leu Phe 35 40 45 Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala Thr Ile Ser Cys 50 55 60 Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu Leu Asn Pro Asn65 70 75 80 Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu Lys Asp Ser Arg 85 90 95 Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys Val Ser Leu Thr 100 105 110 Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys Gln Leu Tyr Thr 115 120 125 Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val Leu Val Pro Pro 130 135 140 Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala Val Glu Gly Glu145 150 155 160 Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys Pro Ala Thr Thr 165 170 175 Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly Lys Ser Glu Val 180 185 190 Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln Leu Met Leu Lys 195 200 205 Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys Gln Val Glu His 210 215 220 Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr Leu Glu Val Gln225 230 235 240 Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro Leu Gln Gly Leu 245 250 255 Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu Ala Ile Gly Lys 260 265 270 Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp Asp Glu Met Pro 275 280 285 Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile Asn Asn Leu Asn 290 295 300 Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser Asn Ile Val Gly305 310 315 320 Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Gly Thr 325 330 16443PRTHomo sapiens 16Met Ala Ser Val Val Leu Pro Ser Gly Ser Gln Cys Ala Ala Ala Ala1 5 10 15 Ala Ala Ala Ala Pro Pro Gly Leu Arg Leu Arg Leu Leu Leu Leu Leu 20 25 30 Phe Ser Ala Ala Ala Leu Ile Pro Thr Gly Asp Gly Gln Asn Leu Phe 35 40 45 Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala Thr Ile Ser Cys 50 55 60 Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu Leu Asn Pro Asn65 70 75 80 Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu Lys Asp Ser Arg 85 90 95 Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys Val Ser Leu Thr 100 105 110 Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys Gln Leu Tyr Thr 115 120 125 Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val Leu Val Pro Pro 130 135 140 Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala Val Glu Gly Glu145 150 155 160 Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys Pro Ala Thr Thr 165 170 175 Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly Lys Ser Glu Val 180 185 190 Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln Leu Met Leu Lys 195 200 205 Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys Gln Val Glu His 210 215 220 Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr Leu Glu Val Gln225 230 235 240 Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro Leu Gln Gly Leu 245 250 255 Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu Ala Ile Gly Lys 260 265 270 Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp Asp Glu Met Pro 275 280 285 Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile Asn Asn Leu Asn 290 295 300 Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser Asn Ile Val Gly305 310 315 320 Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp Thr Thr Ala Thr 325 330

335 Thr Glu Pro Ala Val His Gly Leu Thr Gln Leu Pro Asn Ser Ala Glu 340 345 350 Glu Leu Asp Ser Glu Asp Leu Ser Asp Ser Arg Ala Gly Glu Glu Gly 355 360 365 Ser Ile Arg Ala Val Asp His Ala Val Ile Gly Gly Val Val Ala Val 370 375 380 Val Val Phe Ala Met Leu Cys Leu Leu Ile Ile Leu Gly Arg Tyr Phe385 390 395 400 Ala Arg His Lys Gly Thr Tyr Phe Thr His Glu Ala Lys Gly Ala Asp 405 410 415 Asp Ala Ala Asp Ala Asp Thr Ala Ile Ile Asn Ala Glu Gly Gly Gln 420 425 430 Asn Asn Ser Glu Glu Lys Lys Glu Tyr Phe Ile 435 440 17425PRTHomo sapiens 17Met Ala Ser Val Val Leu Pro Ser Gly Ser Gln Cys Ala Ala Ala Ala1 5 10 15 Ala Ala Ala Ala Pro Pro Gly Leu Arg Leu Arg Leu Leu Leu Leu Leu 20 25 30 Phe Ser Ala Ala Ala Leu Ile Pro Thr Gly Asp Gly Gln Asn Leu Phe 35 40 45 Thr Lys Asp Val Thr Val Ile Glu Gly Glu Val Ala Thr Ile Ser Cys 50 55 60 Gln Val Asn Lys Ser Asp Asp Ser Val Ile Gln Leu Leu Asn Pro Asn65 70 75 80 Arg Gln Thr Ile Tyr Phe Arg Asp Phe Arg Pro Leu Lys Asp Ser Arg 85 90 95 Phe Gln Leu Leu Asn Phe Ser Ser Ser Glu Leu Lys Val Ser Leu Thr 100 105 110 Asn Val Ser Ile Ser Asp Glu Gly Arg Tyr Phe Cys Gln Leu Tyr Thr 115 120 125 Asp Pro Pro Gln Glu Ser Tyr Thr Thr Ile Thr Val Leu Val Pro Pro 130 135 140 Arg Asn Leu Met Ile Asp Ile Gln Lys Asp Thr Ala Val Glu Gly Glu145 150 155 160 Glu Ile Glu Val Asn Cys Thr Ala Met Ala Ser Lys Pro Ala Thr Thr 165 170 175 Ile Arg Trp Phe Lys Gly Asn Thr Glu Leu Lys Gly Lys Ser Glu Val 180 185 190 Glu Glu Trp Ser Asp Met Tyr Thr Val Thr Ser Gln Leu Met Leu Lys 195 200 205 Val His Lys Glu Asp Asp Gly Val Pro Val Ile Cys Gln Val Glu His 210 215 220 Pro Ala Val Thr Gly Asn Leu Gln Thr Gln Arg Tyr Leu Glu Val Gln225 230 235 240 Tyr Lys Pro Gln Val His Ile Gln Met Thr Tyr Pro Leu Gln Gly Leu 245 250 255 Thr Arg Glu Gly Asp Ala Leu Glu Leu Thr Cys Glu Ala Ile Gly Lys 260 265 270 Pro Gln Pro Val Met Val Thr Trp Val Arg Val Asp Asp Glu Met Pro 275 280 285 Gln His Ala Val Leu Ser Gly Pro Asn Leu Phe Ile Asn Asn Leu Asn 290 295 300 Lys Thr Asp Asn Gly Thr Tyr Arg Cys Glu Ala Ser Asn Ile Val Gly305 310 315 320 Lys Ala His Ser Asp Tyr Met Leu Tyr Val Tyr Asp Thr Thr Ala Thr 325 330 335 Thr Glu Pro Ala Val His Asp Ser Arg Ala Gly Glu Glu Gly Ser Ile 340 345 350 Arg Ala Val Asp His Ala Val Ile Gly Gly Val Val Ala Val Val Val 355 360 365 Phe Ala Met Leu Cys Leu Leu Ile Ile Leu Gly Arg Tyr Phe Ala Arg 370 375 380 His Lys Gly Thr Tyr Phe Thr His Glu Ala Lys Gly Ala Asp Asp Ala385 390 395 400 Ala Asp Ala Asp Thr Ala Ile Ile Asn Ala Glu Gly Gly Gln Asn Asn 405 410 415 Ser Glu Glu Lys Lys Glu Tyr Phe Ile 420 425 182940DNAHomo sapiens 18cgccgaacgc cagcgccagg gggcggggtg ggggagggag cgaggccctc cgagagccgg 60gttgggctcg cggcgctgtg attggtctgc ccggactccg cctccagcgc atgtcattag 120catctcatta gctgtccgct cgggctccgg aggcagccaa cgccgccagt ctgaggcagg 180tgcccgacat ggcgagtgta gtgctgccga gcggatccca gtgtgcggcg gcagcggcgg 240cggcggcgcc tcccgggctc cggctccggc ttctgctgtt gctcttctcc gccgcggcac 300tgatccccac aggtgatggg cagaatctgt ttacgaaaga cgtgacagtg atcgagggag 360aggttgcgac catcagttgc caagtcaata agagtgacga ctctgtgatt cagctactga 420atcccaacag gcagaccatt tatttcaggg acttcaggcc tttgaaggac agcaggtttc 480agttgctgaa tttttctagc agtgaactca aagtatcatt gacaaacgtc tcaatttctg 540atgaaggaag atacttttgc cagctctata ccgatccccc acaggaaagt tacaccacca 600tcacagtcct ggtcccacca cgtaatctga tgatcgatat ccagaaagac actgcggtgg 660aaggtgagga gattgaagtc aactgcactg ctatggccag caagccagcc acgactatca 720ggtggttcaa agggaacaca gagctaaaag gcaaatcgga ggtggaagag tggtcagaca 780tgtacactgt gaccagtcag ctgatgctga aggtgcacaa ggaggacgat ggggtcccag 840tgatctgcca ggtggagcac cctgcggtca ctggaaacct gcagacccag cggtatctag 900aagtacagta taagcctcaa gtgcacattc agatgactta tcctctacaa ggcttaaccc 960gggaagggga cgcgcttgag ttaacatgtg aagccatcgg gaagccccag cctgtgatgg 1020taacttgggt gagagtcgat gatgaaatgc ctcaacacgc cgtactgtct gggcccaacc 1080tgttcatcaa taacctaaac aaaacagata atggtacata ccgctgtgaa gcttcaaaca 1140tagtggggaa agctcactcg gattatatgc tgtatgtata cgacacaacg gcgacgacag 1200aaccagcagt tcacgattcc cgagcaggtg aagaaggctc gatcagggca gtggatcatg 1260ccgtgatcgg tggcgtcgtg gcggtggtgg tgttcgccat gctgtgcttg ctcatcattc 1320tggggcgcta ttttgccaga cataaaggta catacttcac tcatgaagcc aaaggagccg 1380atgacgcagc agacgcagac acagctataa tcaatgcaga aggaggacag aacaactccg 1440aagaaaagaa agagtacttc atctagatca gcctttttgt ttcaatgagg tgtccaactg 1500gccctattta gatgataaag agacagtgat attggaactt gcgagaaatt cgtgtgtttt 1560tttatgaatg ggtggaaagg tgtgagactg ggaaggcttg ggatttgctg tgtaaaaaaa 1620aaaaaaatgt tctttggaaa gtacactctg ctgtttgaca cctctttttt cgtttgtttg 1680tttgtttaat ttttatttct tcctaccaag tcaaacttgg atacttggat ttagtttcag 1740tagattgcag aaaattctgt gccttgtttt ttgtttgttt gttgcgttcc tttcttttcc 1800ccctttgtgc acatttattt cctccctcta ccccaatttc ggattttttc caaaatctcc 1860cattttggaa tttgcctgct gggattcctt agactctttt ccttcccttt tctgttctag 1920ttttttactt ttgtttattt ttatggtaac tgctttctgt tccaaattca gtttcataaa 1980aggagaacca gcacagctta gatttcatag ttcagaattt agtgtatcca taatgcattc 2040ttctctgttg tcgtaaagat ttgggtgaac aaacaatgaa aactctttgc tgctgcccat 2100gtttcaaata cttagagcag tgaagactag aaaattagac tgtgattcag aaaatgttct 2160gtttgctgtg gaactacatt actgtacagg gttatctgca agtgaggtgt gtcacaatga 2220gattgaattt cactgtcttt aattctgtat ctgtagacgg ctcagtatag ataccctacg 2280ctgtccagaa aggtttgggg cagaaaggac tcctcctttt tccatgccct aaacagacct 2340gacaggtgag gtctgttcct tttatataag tggacaaatt ttgagttgcc acaggagggg 2400aagtagggag gggggaaata cagttctgct ctggttgttt ctgttccaaa tgattccatc 2460cacctttccc aatcggcctt acttctcact aatttgtagg aaaaagcaag ttcgtctgtt 2520gtgcgaatga ctgaatggga cagagttgat tttttttttt tttcctttgt gcttagttag 2580gaaggcagta ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat 2640ttccaactcg aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga 2700ggtacaaaag aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga 2760taggtcagag cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact 2820caaatgtgag tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag 2880ccatagtgca tagctactaa aatcagtgac cttgaacata tcttagatgg ggagcctcgg 2940193512DNAHomo sapiens 19gacatggcga gtgtagtgct gccgagcgga tcccagtgtg cggcggcagc ggcggcggcg 60gcgcctcccg ggctccggct ccggcttctg ctgttgctct tctccgccgc ggcactgatc 120cccacaggtg atgggcagaa tctgtttacg aaagacgtga cagtgatcga gggagaggtt 180gcgaccatca gttgccaagt caataagagt gacgactctg tgattcagct actgaatccc 240aacaggcaga ccatttattt cagggacttc aggcctttga aggacagcag gtttcagttg 300ctgaattttt ctagcagtga actcaaagta tcattgacaa acgtctcaat ttctgatgaa 360ggaagatact tttgccagct ctataccgat cccccacagg aaagttacac caccatcaca 420gtcctggtcc caccacgtaa tctgatgatc gatatccaga gagacactgc ggtggaaggt 480gaggagattg aagtcaactg cactgctatg gccagcaagc cagccacgac tatcaggtgg 540ttcaaaggga acacagagct aaaaggcaaa tcggaggtgg aagagtggtc agacatgtac 600actgtgacca gtcagctgat gctgaaggtg cacaaggagg acgatggggt cccagtgatc 660tgccaggtgg agcaccctgc ggtcactgga aacctgcaga cccagcggta tctagaagta 720cagtataagc cacaagtgca cattcagatg acttatcctc tacaaggctt aacccgggaa 780ggggacgcgc ttgagttaac atgtgaagcc atcgggaagc cccagcctgt gatggtaact 840tgggtgagag tcgatgatga aatgcctcaa cacgccgtac tgtctgggcc caacctgttc 900atcaataacc taaacaaaac agataatggt acataccgct gtgaagcttc aaacatagtg 960gggaaagctc actcggatta tatgctgtat gtatacgatc cccccacaac tatccctcct 1020cccacaacaa ccaccaccac caccaccacc accaccacca ccatccttac catcatcaca 1080gattcccgag caggtgaaga aggctcgatc agggcagtgg atcatgccgt gatcggtggc 1140gtcgtggcgg tggtggtgtt cgccatgctg tgcttgctca tcattctggg gcgctatttt 1200gccagacata aaggtacata cttcactcat gaagccaaag gagccgatga cgcagcagac 1260gcagacacag ctataatcaa tgcagaagga ggacagaaca actccgaaga aaagaaagag 1320tacttcatct agatcagcct ttttgtttca atgaggtgtc caactggccc tatttagatg 1380ataaagagac agtgatattg gaacttgcga gaaattcgtg tgttttttta tgaatgggtg 1440gaaaggtgtg agactgggaa ggcttgggat ttgctgtgta aaaaaaaaaa aaaatgttct 1500ttggaaagta cactctgctg tttgacacct cttttttcgt ttgtttgttt gtttaatttt 1560tatttcttcc taccaagtca aacttggata cttggattta gtttcagtag attgcagaaa 1620attctgtgcc ttgttttttg tttgtttgtt gcgttccttt cttttccccc tttgtgcaca 1680tttatttcct ccctctaccc caatttcgga ttttttccaa aatctcccat tttggaattt 1740gcctgctggg attccttaga ctcttttcct tcccttttct gttctagttt tttacttttg 1800tttattttta tggtaactgc tttctgttcc aaattcagtt tcataaaagg agaaccagca 1860cagcttagga tttcatagtt cagaatttag tgtatccata atgcattctt ctctgttgtc 1920gtaaagattt gggtgaacaa acaatgaaaa ctctttgctg ctgcccatgt ttcaaatact 1980tagagcagtg aagactagaa aattagactg tgattcagaa aatgttctgt ttgctgtgga 2040actacattac tgtacagggt tatctgcaag tgaggtgtgt cacaatgaga ttgaatttca 2100ctgtctttaa ttctgtatct gtagacggct cagtatagat accctacgct gtccagaaag 2160gtttggggca gaaaggactc ctcctttttc catgccctaa acagacctga caggtgaggt 2220ctgttccttt tatataagtg gacaaatttt gagttgccac aggaggggaa gtagggaggg 2280gggaaataca gttctgctct ggttgtttct gttccaaatg attccatcca cctttcccaa 2340tcggccttac ttctcactaa tttgtaggaa aaagcaagtt cgtctgttgt gcgaatgact 2400gaatgggaca gagttgattt tttttttttt tttcctttgt gcttagttag gaaggcagta 2460ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat ttccaactcg 2520aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga ggtacaaaag 2580aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga taggtcagag 2640cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact caaatgtgag 2700tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag ccttaagaac 2760catctgccaa aaattactga tcctcgcatg atggcagcca tagtgcatag ctactaaaat 2820cagtgacctt gaacatatct tagatgggga gcctcgggaa aaggtagagg agtcacgtta 2880ccatttacat gttttaaaga aagaagtgtg gggattttca ctgaaacgtc taggaaatct 2940agaagtagtc ctgaaggaca gaaactaaac tcttaccata tgtttggtaa gactccagac 3000tccagctaac agtccctatg gaaagatggc atcaaaaaag atagatctat atatatatat 3060aaatatatat tctattacat tttcagtgag taattttgga ttttgcaagg tgcattttta 3120ctattgttac attatgtgga aaacttatgc tgatttattt aagggggaaa aagtgtcaac 3180tctttgttat ttgaaaacat gtttattttt cttgtcttta ttttaacctt tgatagaacc 3240attgcaatat gggggccttt tgggaacgga ctggtatgta aaagaaaatc cattatcgag 3300cagcatttta tttacccctc ccctatccct aggcacttaa ccaagacaaa aagccacaat 3360gaacatccct ttttcaatga attttataat ctgcagctct attccgagcc cttagcaccc 3420attccgacca tagtataatc atatcaaagg gtgagaatca tttagcatgt tgttgaaagg 3480ttttttttca gttgttcttt ttagaaaaaa ag 3512202940DNAHomo sapiens 20cgccgaacgc cagcgccagg gggcggggtg ggggagggag cgaggccctc cgagagccgg 60gttgggctcg cggcgctgtg attggtctgc ccggactccg cctccagcgc atgtcattag 120catctcatta gctgtccgct cgggctccgg aggcagccaa cgccgccagt ctgaggcagg 180tgcccgacat ggcgagtgta gtgctgccga gcggatccca gtgtgcggcg gcagcggcgg 240cggcggcgcc tcccgggctc cggctccggc ttctgctgtt gctcttctcc gccgcggcac 300tgatccccac aggtgatggg cagaatctgt ttacgaaaga cgtgacagtg atcgagggag 360aggttgcgac catcagttgc caagtcaata agagtgacga ctctgtgatt cagctactga 420atcccaacag gcagaccatt tatttcaggg acttcaggcc tttgaaggac agcaggtttc 480agttgctgaa tttttctagc agtgaactca aagtatcatt gacaaacgtc tcaatttctg 540atgaaggaag atacttttgc cagctctata ccgatccccc acaggaaagt tacaccacca 600tcacagtcct ggtcccacca cgtaatctga tgatcgatat ccagaaagac actgcggtgg 660aaggtgagga gattgaagtc aactgcactg ctatggccag caagccagcc acgactatca 720ggtggttcaa agggaacaca gagctaaaag gcaaatcgga ggtggaagag tggtcagaca 780tgtacactgt gaccagtcag ctgatgctga aggtgcacaa ggaggacgat ggggtcccag 840tgatctgcca ggtggagcac cctgcggtca ctggaaacct gcagacccag cggtatctag 900aagtacagta taagcctcaa gtgcacattc agatgactta tcctctacaa ggcttaaccc 960gggaagggga cgcgcttgag ttaacatgtg aagccatcgg gaagccccag cctgtgatgg 1020taacttgggt gagagtcgat gatgaaatgc ctcaacacgc cgtactgtct gggcccaacc 1080tgttcatcaa taacctaaac aaaacagata atggtacata ccgctgtgaa gcttcaaaca 1140tagtggggaa agctcactcg gattatatgc tgtatgtata cgacacaacg gcgacgacag 1200aaccagcagt tcacgattcc cgagcaggtg aagaaggctc gatcagggca gtggatcatg 1260ccgtgatcgg tggcgtcgtg gcggtggtgg tgttcgccat gctgtgcttg ctcatcattc 1320tggggcgcta ttttgccaga cataaaggta catacttcac tcatgaagcc aaaggagccg 1380atgacgcagc agacgcagac acagctataa tcaatgcaga aggaggacag aacaactccg 1440aagaaaagaa agagtacttc atctagatca gcctttttgt ttcaatgagg tgtccaactg 1500gccctattta gatgataaag agacagtgat attggaactt gcgagaaatt cgtgtgtttt 1560tttatgaatg ggtggaaagg tgtgagactg ggaaggcttg ggatttgctg tgtaaaaaaa 1620aaaaaaatgt tctttggaaa gtacactctg ctgtttgaca cctctttttt cgtttgtttg 1680tttgtttaat ttttatttct tcctaccaag tcaaacttgg atacttggat ttagtttcag 1740tagattgcag aaaattctgt gccttgtttt ttgtttgttt gttgcgttcc tttcttttcc 1800ccctttgtgc acatttattt cctccctcta ccccaatttc ggattttttc caaaatctcc 1860cattttggaa tttgcctgct gggattcctt agactctttt ccttcccttt tctgttctag 1920ttttttactt ttgtttattt ttatggtaac tgctttctgt tccaaattca gtttcataaa 1980aggagaacca gcacagctta gatttcatag ttcagaattt agtgtatcca taatgcattc 2040ttctctgttg tcgtaaagat ttgggtgaac aaacaatgaa aactctttgc tgctgcccat 2100gtttcaaata cttagagcag tgaagactag aaaattagac tgtgattcag aaaatgttct 2160gtttgctgtg gaactacatt actgtacagg gttatctgca agtgaggtgt gtcacaatga 2220gattgaattt cactgtcttt aattctgtat ctgtagacgg ctcagtatag ataccctacg 2280ctgtccagaa aggtttgggg cagaaaggac tcctcctttt tccatgccct aaacagacct 2340gacaggtgag gtctgttcct tttatataag tggacaaatt ttgagttgcc acaggagggg 2400aagtagggag gggggaaata cagttctgct ctggttgttt ctgttccaaa tgattccatc 2460cacctttccc aatcggcctt acttctcact aatttgtagg aaaaagcaag ttcgtctgtt 2520gtgcgaatga ctgaatggga cagagttgat tttttttttt tttcctttgt gcttagttag 2580gaaggcagta ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat 2640ttccaactcg aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga 2700ggtacaaaag aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga 2760taggtcagag cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact 2820caaatgtgag tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag 2880ccatagtgca tagctactaa aatcagtgac cttgaacata tcttagatgg ggagcctcgg 2940212940DNAHomo sapiens 21cgccgaacgc cagcgccagg gggcggggtg ggggagggag cgaggccctc cgagagccgg 60gttgggctcg cggcgctgtg attggtctgc ccggactccg cctccagcgc atgtcattag 120catctcatta gctgtccgct cgggctccgg aggcagccaa cgccgccagt ctgaggcagg 180tgcccgacat ggcgagtgta gtgctgccga gcggatccca gtgtgcggcg gcagcggcgg 240cggcggcgcc tcccgggctc cggctccggc ttctgctgtt gctcttctcc gccgcggcac 300tgatccccac aggtgatggg cagaatctgt ttacgaaaga cgtgacagtg atcgagggag 360aggttgcgac catcagttgc caagtcaata agagtgacga ctctgtgatt cagctactga 420atcccaacag gcagaccatt tatttcaggg acttcaggcc tttgaaggac agcaggtttc 480agttgctgaa tttttctagc agtgaactca aagtatcatt gacaaacgtc tcaatttctg 540atgaaggaag atacttttgc cagctctata ccgatccccc acaggaaagt tacaccacca 600tcacagtcct ggtcccacca cgtaatctga tgatcgatat ccagaaagac actgcggtgg 660aaggtgagga gattgaagtc aactgcactg ctatggccag caagccagcc acgactatca 720ggtggttcaa agggaacaca gagctaaaag gcaaatcgga ggtggaagag tggtcagaca 780tgtacactgt gaccagtcag ctgatgctga aggtgcacaa ggaggacgat ggggtcccag 840tgatctgcca ggtggagcac cctgcggtca ctggaaacct gcagacccag cggtatctag 900aagtacagta taagcctcaa gtgcacattc agatgactta tcctctacaa ggcttaaccc 960gggaagggga cgcgcttgag ttaacatgtg aagccatcgg gaagccccag cctgtgatgg 1020taacttgggt gagagtcgat gatgaaatgc ctcaacacgc cgtactgtct gggcccaacc 1080tgttcatcaa taacctaaac aaaacagata atggtacata ccgctgtgaa gcttcaaaca 1140tagtggggaa agctcactcg gattatatgc tgtatgtata cgacacaacg gcgacgacag 1200aaccagcagt tcacgattcc cgagcaggtg aagaaggctc gatcagggca gtggatcatg 1260ccgtgatcgg tggcgtcgtg gcggtggtgg tgttcgccat gctgtgcttg ctcatcattc 1320tggggcgcta ttttgccaga cataaaggta catacttcac tcatgaagcc aaaggagccg 1380atgacgcagc agacgcagac acagctataa tcaatgcaga aggaggacag aacaactccg 1440aagaaaagaa agagtacttc atctagatca gcctttttgt ttcaatgagg tgtccaactg 1500gccctattta gatgataaag agacagtgat attggaactt gcgagaaatt cgtgtgtttt 1560tttatgaatg ggtggaaagg tgtgagactg ggaaggcttg ggatttgctg tgtaaaaaaa 1620aaaaaaatgt tctttggaaa gtacactctg ctgtttgaca cctctttttt cgtttgtttg 1680tttgtttaat ttttatttct tcctaccaag tcaaacttgg atacttggat ttagtttcag 1740tagattgcag aaaattctgt gccttgtttt ttgtttgttt gttgcgttcc tttcttttcc 1800ccctttgtgc acatttattt cctccctcta ccccaatttc ggattttttc caaaatctcc 1860cattttggaa tttgcctgct gggattcctt agactctttt ccttcccttt tctgttctag 1920ttttttactt ttgtttattt ttatggtaac tgctttctgt tccaaattca gtttcataaa 1980aggagaacca gcacagctta gatttcatag ttcagaattt agtgtatcca taatgcattc 2040ttctctgttg tcgtaaagat ttgggtgaac aaacaatgaa

aactctttgc tgctgcccat 2100gtttcaaata cttagagcag tgaagactag aaaattagac tgtgattcag aaaatgttct 2160gtttgctgtg gaactacatt actgtacagg gttatctgca agtgaggtgt gtcacaatga 2220gattgaattt cactgtcttt aattctgtat ctgtagacgg ctcagtatag ataccctacg 2280ctgtccagaa aggtttgggg cagaaaggac tcctcctttt tccatgccct aaacagacct 2340gacaggtgag gtctgttcct tttatataag tggacaaatt ttgagttgcc acaggagggg 2400aagtagggag gggggaaata cagttctgct ctggttgttt ctgttccaaa tgattccatc 2460cacctttccc aatcggcctt acttctcact aatttgtagg aaaaagcaag ttcgtctgtt 2520gtgcgaatga ctgaatggga cagagttgat tttttttttt tttcctttgt gcttagttag 2580gaaggcagta ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat 2640ttccaactcg aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga 2700ggtacaaaag aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga 2760taggtcagag cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact 2820caaatgtgag tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag 2880ccatagtgca tagctactaa aatcagtgac cttgaacata tcttagatgg ggagcctcgg 2940222940DNAHomo sapiens 22cgccgaacgc cagcgccagg gggcggggtg ggggagggag cgaggccctc cgagagccgg 60gttgggctcg cggcgctgtg attggtctgc ccggactccg cctccagcgc atgtcattag 120catctcatta gctgtccgct cgggctccgg aggcagccaa cgccgccagt ctgaggcagg 180tgcccgacat ggcgagtgta gtgctgccga gcggatccca gtgtgcggcg gcagcggcgg 240cggcggcgcc tcccgggctc cggctccggc ttctgctgtt gctcttctcc gccgcggcac 300tgatccccac aggtgatggg cagaatctgt ttacgaaaga cgtgacagtg atcgagggag 360aggttgcgac catcagttgc caagtcaata agagtgacga ctctgtgatt cagctactga 420atcccaacag gcagaccatt tatttcaggg acttcaggcc tttgaaggac agcaggtttc 480agttgctgaa tttttctagc agtgaactca aagtatcatt gacaaacgtc tcaatttctg 540atgaaggaag atacttttgc cagctctata ccgatccccc acaggaaagt tacaccacca 600tcacagtcct ggtcccacca cgtaatctga tgatcgatat ccagaaagac actgcggtgg 660aaggtgagga gattgaagtc aactgcactg ctatggccag caagccagcc acgactatca 720ggtggttcaa agggaacaca gagctaaaag gcaaatcgga ggtggaagag tggtcagaca 780tgtacactgt gaccagtcag ctgatgctga aggtgcacaa ggaggacgat ggggtcccag 840tgatctgcca ggtggagcac cctgcggtca ctggaaacct gcagacccag cggtatctag 900aagtacagta taagcctcaa gtgcacattc agatgactta tcctctacaa ggcttaaccc 960gggaagggga cgcgcttgag ttaacatgtg aagccatcgg gaagccccag cctgtgatgg 1020taacttgggt gagagtcgat gatgaaatgc ctcaacacgc cgtactgtct gggcccaacc 1080tgttcatcaa taacctaaac aaaacagata atggtacata ccgctgtgaa gcttcaaaca 1140tagtggggaa agctcactcg gattatatgc tgtatgtata cgacacaacg gcgacgacag 1200aaccagcagt tcacgattcc cgagcaggtg aagaaggctc gatcagggca gtggatcatg 1260ccgtgatcgg tggcgtcgtg gcggtggtgg tgttcgccat gctgtgcttg ctcatcattc 1320tggggcgcta ttttgccaga cataaaggta catacttcac tcatgaagcc aaaggagccg 1380atgacgcagc agacgcagac acagctataa tcaatgcaga aggaggacag aacaactccg 1440aagaaaagaa agagtacttc atctagatca gcctttttgt ttcaatgagg tgtccaactg 1500gccctattta gatgataaag agacagtgat attggaactt gcgagaaatt cgtgtgtttt 1560tttatgaatg ggtggaaagg tgtgagactg ggaaggcttg ggatttgctg tgtaaaaaaa 1620aaaaaaatgt tctttggaaa gtacactctg ctgtttgaca cctctttttt cgtttgtttg 1680tttgtttaat ttttatttct tcctaccaag tcaaacttgg atacttggat ttagtttcag 1740tagattgcag aaaattctgt gccttgtttt ttgtttgttt gttgcgttcc tttcttttcc 1800ccctttgtgc acatttattt cctccctcta ccccaatttc ggattttttc caaaatctcc 1860cattttggaa tttgcctgct gggattcctt agactctttt ccttcccttt tctgttctag 1920ttttttactt ttgtttattt ttatggtaac tgctttctgt tccaaattca gtttcataaa 1980aggagaacca gcacagctta gatttcatag ttcagaattt agtgtatcca taatgcattc 2040ttctctgttg tcgtaaagat ttgggtgaac aaacaatgaa aactctttgc tgctgcccat 2100gtttcaaata cttagagcag tgaagactag aaaattagac tgtgattcag aaaatgttct 2160gtttgctgtg gaactacatt actgtacagg gttatctgca agtgaggtgt gtcacaatga 2220gattgaattt cactgtcttt aattctgtat ctgtagacgg ctcagtatag ataccctacg 2280ctgtccagaa aggtttgggg cagaaaggac tcctcctttt tccatgccct aaacagacct 2340gacaggtgag gtctgttcct tttatataag tggacaaatt ttgagttgcc acaggagggg 2400aagtagggag gggggaaata cagttctgct ctggttgttt ctgttccaaa tgattccatc 2460cacctttccc aatcggcctt acttctcact aatttgtagg aaaaagcaag ttcgtctgtt 2520gtgcgaatga ctgaatggga cagagttgat tttttttttt tttcctttgt gcttagttag 2580gaaggcagta ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat 2640ttccaactcg aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga 2700ggtacaaaag aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga 2760taggtcagag cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact 2820caaatgtgag tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag 2880ccatagtgca tagctactaa aatcagtgac cttgaacata tcttagatgg ggagcctcgg 294023788PRTHomo sapiens 23Met Gly Ile Glu Leu Leu Cys Leu Phe Phe Leu Phe Leu Gly Arg Asn1 5 10 15 Asp His Val Gln Gly Gly Cys Ala Leu Gly Gly Ala Glu Thr Cys Glu 20 25 30 Asp Cys Leu Leu Ile Gly Pro Gln Cys Ala Trp Cys Ala Gln Glu Asn 35 40 45 Phe Thr His Pro Ser Gly Val Gly Glu Arg Cys Asp Thr Pro Ala Asn 50 55 60 Leu Leu Ala Lys Gly Cys Gln Leu Asn Phe Ile Glu Asn Pro Val Ser65 70 75 80 Gln Val Glu Ile Leu Lys Asn Lys Pro Leu Ser Val Gly Arg Gln Lys 85 90 95 Asn Ser Ser Asp Ile Val Gln Ile Ala Pro Gln Ser Leu Ile Leu Lys 100 105 110 Leu Arg Pro Gly Gly Ala Gln Thr Leu Gln Val His Val Arg Gln Thr 115 120 125 Glu Asp Tyr Pro Val Asp Leu Tyr Tyr Leu Met Asp Leu Ser Ala Ser 130 135 140 Met Asp Asp Asp Leu Asn Thr Ile Lys Glu Leu Gly Ser Arg Leu Ser145 150 155 160 Lys Glu Met Ser Lys Leu Thr Ser Asn Phe Arg Leu Gly Phe Gly Ser 165 170 175 Phe Val Glu Lys Pro Val Ser Pro Phe Val Lys Thr Thr Pro Glu Glu 180 185 190 Ile Ala Asn Pro Cys Ser Ser Ile Pro Tyr Phe Cys Leu Pro Thr Phe 195 200 205 Gly Phe Lys His Ile Leu Pro Leu Thr Asn Asp Ala Glu Arg Phe Asn 210 215 220 Glu Ile Val Lys Asn Gln Lys Ile Ser Ala Asn Ile Asp Thr Pro Glu225 230 235 240 Gly Gly Phe Asp Ala Ile Met Gln Ala Ala Val Cys Lys Glu Lys Ile 245 250 255 Gly Trp Arg Asn Asp Ser Leu His Leu Leu Val Phe Val Ser Asp Ala 260 265 270 Asp Ser His Phe Gly Met Asp Ser Lys Leu Ala Gly Ile Val Ile Pro 275 280 285 Asn Asp Gly Leu Cys His Leu Asp Ser Lys Asn Glu Tyr Ser Met Ser 290 295 300 Thr Val Leu Glu Tyr Pro Thr Ile Gly Gln Leu Ile Asp Lys Leu Val305 310 315 320 Gln Asn Asn Val Leu Leu Ile Phe Ala Val Thr Gln Glu Gln Val His 325 330 335 Leu Tyr Glu Asn Tyr Ala Lys Leu Ile Pro Gly Ala Thr Val Gly Leu 340 345 350 Leu Gln Lys Asp Ser Gly Asn Ile Leu Gln Leu Ile Ile Ser Ala Tyr 355 360 365 Glu Glu Leu Arg Ser Glu Val Glu Leu Glu Val Leu Gly Asp Thr Glu 370 375 380 Gly Leu Asn Leu Ser Phe Thr Ala Ile Cys Asn Asn Gly Thr Leu Phe385 390 395 400 Gln His Gln Lys Lys Cys Ser His Met Lys Val Gly Asp Thr Ala Ser 405 410 415 Phe Ser Val Thr Val Asn Ile Pro His Cys Glu Arg Arg Ser Arg His 420 425 430 Ile Ile Ile Lys Pro Val Gly Leu Gly Asp Ala Leu Glu Leu Leu Val 435 440 445 Ser Pro Glu Cys Asn Cys Asp Cys Gln Lys Glu Val Glu Val Asn Ser 450 455 460 Ser Lys Cys His His Gly Asn Gly Ser Phe Gln Cys Gly Val Cys Ala465 470 475 480 Cys His Pro Gly His Met Gly Pro Arg Cys Glu Cys Gly Glu Asp Met 485 490 495 Leu Ser Thr Asp Ser Cys Lys Glu Ala Pro Asp His Pro Ser Cys Ser 500 505 510 Gly Arg Gly Asp Cys Tyr Cys Gly Gln Cys Ile Cys His Leu Ser Pro 515 520 525 Tyr Gly Asn Ile Tyr Gly Pro Tyr Cys Gln Cys Asp Asn Phe Ser Cys 530 535 540 Val Arg His Lys Gly Leu Leu Cys Gly Gly Asn Gly Asp Cys Asp Cys545 550 555 560 Gly Glu Cys Val Cys Arg Ser Gly Trp Thr Gly Glu Tyr Cys Asn Cys 565 570 575 Thr Thr Ser Thr Asp Ser Cys Val Ser Glu Asp Gly Val Leu Cys Ser 580 585 590 Gly Arg Gly Asp Cys Val Cys Gly Lys Cys Val Cys Thr Asn Pro Gly 595 600 605 Ala Ser Gly Pro Thr Cys Glu Arg Cys Pro Thr Cys Gly Asp Pro Cys 610 615 620 Asn Ser Lys Arg Ser Cys Ile Glu Cys His Leu Ser Ala Ala Gly Gln625 630 635 640 Ala Arg Glu Glu Cys Val Asp Lys Cys Lys Leu Ala Gly Ala Thr Ile 645 650 655 Ser Glu Glu Glu Asp Phe Ser Lys Asp Gly Ser Val Ser Cys Ser Leu 660 665 670 Gln Gly Glu Asn Glu Cys Leu Ile Thr Phe Leu Ile Thr Thr Asp Asn 675 680 685 Glu Gly Lys Thr Ile Ile His Ser Ile Asn Glu Lys Asp Cys Pro Lys 690 695 700 Pro Pro Asn Ile Pro Met Ile Met Leu Gly Val Ser Leu Ala Ile Leu705 710 715 720 Leu Ile Gly Val Val Leu Leu Cys Ile Trp Lys Leu Leu Val Ser Phe 725 730 735 His Asp Arg Lys Glu Val Ala Lys Phe Glu Ala Glu Arg Ser Lys Ala 740 745 750 Lys Trp Gln Thr Gly Thr Asn Pro Leu Tyr Arg Gly Ser Thr Ser Thr 755 760 765 Phe Lys Asn Val Thr Tyr Lys His Arg Glu Lys Gln Lys Val Asp Leu 770 775 780 Ser Thr Asp Cys785 242932DNAHomo sapiens 24cacagcaaga actgaaacga atggggattg aactgctttg cctgttcttt ctatttctag 60gaaggaatga tcacgtacaa ggtggctgtg ccctgggagg tgcagaaacc tgtgaagact 120gcctgcttat tggacctcag tgtgcctggt gtgctcagga gaattttact catccatctg 180gagttggcga aaggtgtgat accccagcaa accttttagc taaaggatgt caattaaact 240tcatcgaaaa ccctgtctcc caagtagaaa tacttaaaaa taagcctctc agtgtaggca 300gacagaaaaa tagttctgac attgttcaga ttgcgcctca aagcttgatc cttaagttga 360gaccaggtgg tgcgcagact ctgcaggtgc atgtccgcca gactgaggac tacccggtgg 420atttgtatta cctcatggac ctctccgcct ccatggatga cgacctcaac acaataaagg 480agctgggctc ccggctttcc aaagagatgt ctaaattaac cagcaacttt agactgggct 540tcggatcttt tgtggaaaaa cctgtatccc cttttgtgaa aacaacacca gaagaaattg 600ccaacccttg cagtagtatt ccatacttct gtttacctac atttggattc aagcacattt 660tgccattgac aaatgatgct gaaagattca atgaaattgt gaagaatcag aaaatttctg 720ctaatattga cacacccgaa ggtggatttg atgcaattat gcaagctgct gtgtgtaagg 780aaaaaattgg ctggcggaat gactccctcc acctcctggt ctttgtgagt gatgctgatt 840ctcattttgg aatggacagc aaactagcag gcatcgtcat tcctaatgac gggctctgtc 900acttggacag caagaatgaa tactccatgt caactgtctt ggaatatcca acaattggac 960aactcattga taaactggta caaaacaacg tgttattgat cttcgctgta acccaagaac 1020aagttcattt atatgagaat tacgcaaaac ttattcctgg agctacagta ggtctacttc 1080agaaggactc cggaaacatt ctccagctga tcatctcagc ttatgaagaa ctgcggtctg 1140aggtggaact ggaagtatta ggagacactg aaggactcaa cttgtcattt acagccatct 1200gtaacaacgg taccctcttc caacaccaaa agaaatgctc tcacatgaaa gtgggagaca 1260cagcttcctt cagcgtgact gtgaatatcc cacactgcga gagaagaagc aggcacatta 1320tcataaagcc tgtggggctg ggggatgccc tggaattact tgtcagccca gaatgcaact 1380gcgactgtca gaaagaagtg gaagtgaaca gctccaaatg tcaccacggg aacggctctt 1440tccagtgtgg ggtgtgtgcc tgccaccctg gccacatggg gcctcgctgt gagtgtggcg 1500aggacatgct gagcacagat tcctgcaagg aggccccaga tcatccctcc tgcagcggaa 1560ggggtgactg ctactgtggg cagtgtatct gccacttgtc tccctatgga aacatttatg 1620ggccttattg ccagtgtgac aatttctcct gcgtgagaca caaagggctg ctctgcggag 1680gtaacggcga ctgtgactgt ggtgaatgtg tgtgcaggag cggctggact ggcgagtact 1740gcaactgcac caccagcacg gactcctgcg tctctgaaga tggagtgctc tgcagcgggc 1800gcggggactg tgtttgtggc aagtgtgttt gcacaaaccc tggagcctca ggaccaacct 1860gtgaacgatg tcctacctgt ggtgacccct gtaactctaa acggagctgc attgagtgcc 1920acctgtcagc agctggccaa gcccgagaag aatgtgtgga caagtgcaaa ctagctggtg 1980cgaccatcag tgaagaagaa gatttctcaa aggatggttc tgtttcctgc tctctgcaag 2040gagaaaatga atgtcttatt acattcctaa taactacaga taatgagggg aaaaccatca 2100ttcacagcat caatgaaaaa gattgtccga agcctccaaa cattcccatg atcatgttag 2160gggtttccct ggctattctt ctcatcgggg ttgtcctact gtgcatctgg aagctactgg 2220tgtcatttca tgatcgtaaa gaagttgcca aatttgaagc agaacgatca aaagccaagt 2280ggcaaacggg aaccaatcca ctctacagag gatccacaag tacttttaaa aatgtaactt 2340ataaacacag ggaaaaacaa aaggtagacc tttccacaga ttgctagaac tactttatgc 2400atgaaaaaag tctgtttcac tgatatgaaa tgttaatgca ctatttaatt tttttctctt 2460tgttgcttca aaatgaggtt ggtttaagat aataatagga catctgcaga taagtcatcc 2520tctacatgaa ggtgacagac tgttggcagt ttcaaaataa tcaagaagag aaatatcctt 2580agcaaagaga tgactttggg gatcatttga ggaatactaa ctctgttgca ttaatgcttc 2640aaaaaatcat caaatgattc atgggggcct gatttgcatt tgaaaaatgt ttgaaattag 2700agtctcattt gtttcaggaa tgcagctacc tgagtttttt gtctcggcaa agtcacaaag 2760cccatatact cacattgtgt gtctatactt gccaattaat tctaaacttg taggaaatat 2820gccctctctt aaaggagaat tttttttaaa tctctgagaa atgagattct gagtttattt 2880cagctaaaag gttgcaattc ttctgaagat atctcaaata taaggttgaa ag 2932251179PRTHomo sapiens 25Met Ala Ala Cys Gly Arg Val Arg Arg Met Phe Arg Leu Ser Ala Ala1 5 10 15 Leu His Leu Leu Leu Leu Phe Ala Ala Gly Ala Glu Lys Leu Pro Gly 20 25 30 Gln Gly Val His Ser Gln Gly Gln Gly Pro Gly Ala Asn Phe Val Ser 35 40 45 Phe Val Gly Gln Ala Gly Gly Gly Gly Pro Ala Gly Gln Gln Leu Pro 50 55 60 Gln Leu Pro Gln Ser Ser Gln Leu Gln Gln Gln Gln Gln Gln Gln Gln65 70 75 80 Gln Gln Gln Gln Pro Gln Pro Pro Gln Pro Pro Phe Pro Ala Gly Gly 85 90 95 Pro Pro Ala Arg Arg Gly Gly Ala Gly Ala Gly Gly Gly Trp Lys Leu 100 105 110 Ala Glu Glu Glu Ser Cys Arg Glu Asp Val Thr Arg Val Cys Pro Lys 115 120 125 His Thr Trp Ser Asn Asn Leu Ala Val Leu Glu Cys Leu Gln Asp Val 130 135 140 Arg Glu Pro Glu Asn Glu Ile Ser Ser Asp Cys Asn His Leu Leu Trp145 150 155 160 Asn Tyr Lys Leu Asn Leu Thr Thr Asp Pro Lys Phe Glu Ser Val Ala 165 170 175 Arg Glu Val Cys Lys Ser Thr Ile Thr Glu Ile Lys Glu Cys Ala Asp 180 185 190 Glu Pro Val Gly Lys Gly Tyr Met Val Ser Cys Leu Val Asp His Arg 195 200 205 Gly Asn Ile Thr Glu Tyr Gln Cys His Gln Tyr Ile Thr Lys Met Thr 210 215 220 Ala Ile Ile Phe Ser Asp Tyr Arg Leu Ile Cys Gly Phe Met Asp Asp225 230 235 240 Cys Lys Asn Asp Ile Asn Ile Leu Lys Cys Gly Ser Ile Arg Leu Gly 245 250 255 Glu Lys Asp Ala His Ser Gln Gly Glu Val Val Ser Cys Leu Glu Lys 260 265 270 Gly Leu Val Lys Glu Ala Glu Glu Arg Glu Pro Lys Ile Gln Val Ser 275 280 285 Glu Leu Cys Lys Lys Ala Ile Leu Arg Val Ala Glu Leu Ser Ser Asp 290 295 300 Asp Phe His Leu Asp Arg His Leu Tyr Phe Ala Cys Arg Asp Asp Arg305 310 315 320 Glu Arg Phe Cys Glu Asn Thr Gln Ala Gly Glu Gly Arg Val Tyr Lys 325 330 335 Cys Leu Phe Asn His Lys Phe Glu Glu Ser Met Ser Glu Lys Cys Arg 340 345 350 Glu Ala Leu Thr Thr Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val 355 360 365 Ser Tyr Ser Leu Ala Lys Ser Cys Lys Ser Asp Leu Lys Lys Tyr Arg 370 375 380 Cys Asn Val Glu Asn Leu Pro Arg Ser Arg Glu Ala Arg Leu Ser Tyr385 390 395 400 Leu Leu Met Cys Leu Glu Ser Ala Val His Arg Gly Arg Gln Val Ser 405 410 415 Ser Glu Cys Gln Gly Glu Met Leu Asp Tyr Arg Arg Met Leu Met Glu 420 425 430 Asp Phe Ser Leu Ser Pro Glu Ile Ile Leu Ser Cys Arg Gly Glu Ile 435 440 445 Glu His His Cys Ser Gly Leu His Arg Lys Gly Arg Thr Leu His Cys 450 455 460 Leu Met Lys Val Val Arg Gly Glu Lys Gly Asn Leu Gly Met Asn Cys465 470

475 480 Gln Gln Ala Leu Gln Thr Leu Ile Gln Glu Thr Asp Pro Gly Ala Asp 485 490 495 Tyr Arg Ile Asp Arg Ala Leu Asn Glu Ala Cys Glu Ser Val Ile Gln 500 505 510 Thr Ala Cys Lys His Ile Arg Ser Gly Asp Pro Met Ile Leu Ser Cys 515 520 525 Leu Met Glu His Leu Tyr Thr Glu Lys Met Val Glu Asp Cys Glu His 530 535 540 Arg Leu Leu Glu Leu Gln Tyr Phe Ile Ser Arg Asp Trp Lys Leu Asp545 550 555 560 Pro Val Leu Tyr Arg Lys Cys Gln Gly Asp Ala Ser Arg Leu Cys His 565 570 575 Thr His Gly Trp Asn Glu Thr Ser Glu Phe Met Pro Gln Gly Ala Val 580 585 590 Phe Ser Cys Leu Tyr Arg His Ala Tyr Arg Thr Glu Glu Gln Gly Arg 595 600 605 Arg Leu Ser Arg Glu Cys Arg Ala Glu Val Gln Arg Ile Leu His Gln 610 615 620 Arg Ala Met Asp Val Lys Leu Asp Pro Ala Leu Gln Asp Lys Cys Leu625 630 635 640 Ile Asp Leu Gly Lys Trp Cys Ser Glu Lys Thr Glu Thr Gly Gln Glu 645 650 655 Leu Glu Cys Leu Gln Asp His Leu Asp Asp Leu Val Val Glu Cys Arg 660 665 670 Asp Ile Val Gly Asn Leu Thr Glu Leu Glu Ser Glu Asp Ile Gln Ile 675 680 685 Glu Ala Leu Leu Met Arg Ala Cys Glu Pro Ile Ile Gln Asn Phe Cys 690 695 700 His Asp Val Ala Asp Asn Gln Ile Asp Ser Gly Asp Leu Met Glu Cys705 710 715 720 Leu Ile Gln Asn Lys His Gln Lys Asp Met Asn Glu Lys Cys Ala Ile 725 730 735 Gly Val Thr His Phe Gln Leu Val Gln Met Lys Asp Phe Arg Phe Ser 740 745 750 Tyr Lys Phe Lys Met Ala Cys Lys Glu Asp Val Leu Lys Leu Cys Pro 755 760 765 Asn Ile Lys Lys Lys Val Asp Val Val Ile Cys Leu Ser Thr Thr Val 770 775 780 Arg Asn Asp Thr Leu Gln Glu Ala Lys Glu His Arg Val Ser Leu Lys785 790 795 800 Cys Arg Arg Gln Leu Arg Val Glu Glu Leu Glu Met Thr Glu Asp Ile 805 810 815 Arg Leu Glu Pro Asp Leu Tyr Glu Ala Cys Lys Ser Asp Ile Lys Asn 820 825 830 Phe Cys Ser Ala Val Gln Tyr Gly Asn Ala Gln Ile Ile Glu Cys Leu 835 840 845 Lys Glu Asn Lys Lys Gln Leu Ser Thr Arg Cys His Gln Lys Val Phe 850 855 860 Lys Leu Gln Glu Thr Glu Met Met Asp Pro Glu Leu Asp Tyr Thr Leu865 870 875 880 Met Arg Val Cys Lys Gln Met Ile Lys Arg Phe Cys Pro Glu Ala Asp 885 890 895 Ser Lys Thr Met Leu Gln Cys Leu Lys Gln Asn Lys Asn Ser Glu Leu 900 905 910 Met Asp Pro Lys Cys Lys Gln Met Ile Thr Lys Arg Gln Ile Thr Gln 915 920 925 Asn Thr Asp Tyr Arg Leu Asn Pro Met Leu Arg Lys Ala Cys Lys Ala 930 935 940 Asp Ile Pro Lys Phe Cys His Gly Ile Leu Thr Lys Ala Lys Asp Asp945 950 955 960 Ser Glu Leu Glu Gly Gln Val Ile Ser Cys Leu Lys Leu Arg Tyr Ala 965 970 975 Asp Gln Arg Leu Ser Ser Asp Cys Glu Asp Gln Ile Arg Ile Ile Ile 980 985 990 Gln Glu Ser Ala Leu Asp Tyr Arg Leu Asp Pro Gln Leu Gln Leu His 995 1000 1005 Cys Ser Asp Glu Ile Ser Ser Leu Cys Ala Glu Glu Ala Ala Ala Gln 1010 1015 1020 Glu Gln Thr Gly Gln Val Glu Glu Cys Leu Lys Val Asn Leu Leu Lys1025 1030 1035 1040Ile Lys Thr Glu Leu Cys Lys Lys Glu Val Leu Asn Met Leu Lys Glu 1045 1050 1055 Ser Lys Ala Asp Ile Phe Val Asp Pro Val Leu His Thr Ala Cys Ala 1060 1065 1070 Leu Asp Ile Lys His His Cys Ala Ala Ile Thr Pro Gly Arg Gly Arg 1075 1080 1085 Gln Met Ser Cys Leu Met Glu Ala Leu Glu Asp Lys Arg Val Arg Leu 1090 1095 1100 Gln Pro Glu Cys Lys Lys Arg Leu Asn Asp Arg Ile Glu Met Trp Ser1105 1110 1115 1120Tyr Ala Ala Lys Val Ala Pro Ala Asp Gly Phe Ser Asp Leu Ala Met 1125 1130 1135 Gln Val Met Thr Ser Pro Ser Lys Asn Tyr Ile Leu Ser Val Ile Ser 1140 1145 1150 Gly Ser Ile Cys Ile Leu Phe Leu Ile Gly Leu Met Cys Gly Arg Ile 1155 1160 1165 Thr Lys Arg Val Thr Arg Glu Leu Lys Asp Arg 1170 1175 26756PRTHomo sapiens 26Met Ser Arg Pro Gly Thr Ala Thr Pro Ala Leu Ala Leu Val Leu Leu1 5 10 15 Ala Val Thr Leu Ala Gly Val Gly Ala Gln Gly Ala Ala Leu Glu Asp 20 25 30 Pro Asp Tyr Tyr Gly Gln Glu Ile Trp Ser Arg Glu Pro Tyr Tyr Ala 35 40 45 Arg Pro Glu Pro Glu Leu Glu Thr Phe Ser Pro Pro Leu Pro Ala Gly 50 55 60 Pro Gly Glu Glu Trp Glu Arg Arg Pro Gln Glu Pro Arg Pro Pro Lys65 70 75 80 Arg Ala Thr Lys Pro Lys Lys Ala Pro Lys Arg Glu Lys Ser Ala Pro 85 90 95 Glu Pro Pro Pro Pro Gly Lys His Ser Asn Lys Lys Val Met Arg Thr 100 105 110 Lys Ser Ser Glu Lys Ala Ala Asn Asp Asp His Ser Val Arg Val Ala 115 120 125 Arg Glu Asp Val Arg Glu Ser Cys Pro Pro Leu Gly Leu Glu Thr Leu 130 135 140 Lys Ile Thr Asp Phe Gln Leu His Ala Ser Thr Val Lys Arg Tyr Gly145 150 155 160 Leu Gly Ala His Arg Gly Arg Leu Asn Ile Gln Ala Gly Ile Asn Glu 165 170 175 Asn Asp Phe Tyr Asp Gly Ala Trp Cys Ala Gly Arg Asn Asp Leu Gln 180 185 190 Gln Trp Ile Glu Val Asp Ala Arg Arg Leu Thr Arg Phe Thr Gly Val 195 200 205 Ile Thr Gln Gly Arg Asn Ser Leu Trp Leu Ser Asp Trp Val Thr Ser 210 215 220 Tyr Lys Val Met Val Ser Asn Asp Ser His Thr Trp Val Thr Val Lys225 230 235 240 Asn Gly Ser Gly Asp Met Ile Phe Glu Gly Asn Ser Glu Lys Glu Ile 245 250 255 Pro Val Leu Asn Glu Leu Pro Val Pro Met Val Ala Arg Tyr Ile Arg 260 265 270 Ile Asn Pro Gln Ser Trp Phe Asp Asn Gly Ser Ile Cys Met Arg Met 275 280 285 Glu Ile Leu Gly Cys Pro Leu Pro Asp Pro Asn Asn Tyr Tyr His Arg 290 295 300 Arg Asn Glu Met Thr Thr Thr Asp Asp Leu Asp Phe Lys His His Asn305 310 315 320 Tyr Lys Glu Met Arg Gln Leu Met Lys Val Val Asn Glu Met Cys Pro 325 330 335 Asn Ile Thr Arg Ile Tyr Asn Ile Gly Lys Ser His Gln Gly Leu Lys 340 345 350 Leu Tyr Ala Val Glu Ile Ser Asp His Pro Gly Glu His Glu Val Gly 355 360 365 Glu Pro Glu Phe His Tyr Ile Ala Gly Ala His Gly Asn Glu Val Leu 370 375 380 Gly Arg Glu Leu Leu Leu Leu Leu Val Gln Phe Val Cys Gln Glu Tyr385 390 395 400 Leu Ala Arg Asn Ala Arg Ile Val His Leu Val Glu Glu Thr Arg Ile 405 410 415 His Val Leu Pro Ser Leu Asn Pro Asp Gly Tyr Glu Lys Ala Tyr Glu 420 425 430 Gly Gly Ser Glu Leu Gly Gly Trp Ser Leu Gly Arg Trp Thr His Asp 435 440 445 Gly Ile Asp Ile Asn Asn Asn Phe Pro Asp Leu Asn Thr Leu Leu Trp 450 455 460 Glu Ala Glu Asp Arg Gln Asn Val Pro Arg Lys Val Pro Asn His Tyr465 470 475 480 Ile Ala Ile Pro Glu Trp Phe Leu Ser Glu Asn Ala Thr Val Ala Ala 485 490 495 Glu Thr Arg Ala Val Ile Ala Trp Met Glu Lys Ile Pro Phe Val Leu 500 505 510 Gly Gly Asn Leu Gln Gly Gly Glu Leu Val Val Ala Tyr Pro Tyr Asp 515 520 525 Leu Val Arg Ser Pro Trp Lys Thr Gln Glu His Thr Pro Thr Pro Asp 530 535 540 Asp His Val Phe Arg Trp Leu Ala Tyr Ser Tyr Ala Ser Thr His Arg545 550 555 560 Leu Met Thr Asp Ala Arg Arg Arg Val Cys His Thr Glu Asp Phe Gln 565 570 575 Lys Glu Glu Gly Thr Val Asn Gly Ala Ser Trp His Thr Val Ala Gly 580 585 590 Ser Leu Asn Asp Phe Ser Tyr Leu His Thr Asn Cys Phe Glu Leu Ser 595 600 605 Ile Tyr Val Gly Cys Asp Lys Tyr Pro His Glu Ser Gln Leu Pro Glu 610 615 620 Glu Trp Glu Asn Asn Arg Glu Ser Leu Ile Val Phe Met Glu Gln Val625 630 635 640 His Arg Gly Ile Lys Gly Leu Val Arg Asp Ser His Gly Lys Gly Ile 645 650 655 Pro Asn Ala Ile Ile Ser Val Glu Gly Ile Asn His Asp Ile Arg Thr 660 665 670 Ala Asn Asp Gly Asp Tyr Trp Arg Leu Leu Asn Pro Gly Glu Tyr Val 675 680 685 Val Thr Ala Lys Ala Glu Gly Phe Thr Ala Ser Thr Lys Asn Cys Met 690 695 700 Val Gly Tyr Asp Met Gly Ala Thr Arg Cys Asp Phe Thr Leu Ser Lys705 710 715 720 Thr Asn Met Ala Arg Ile Arg Glu Ile Met Glu Lys Phe Gly Lys Gln 725 730 735 Pro Val Ser Leu Pro Ala Arg Arg Leu Lys Leu Arg Gly Arg Lys Arg 740 745 750 Arg Gln Arg Gly 755 271203PRTHomo sapiens 27Met Ala Ala Cys Gly Arg Val Arg Arg Met Phe Arg Leu Ser Ala Ala1 5 10 15 Leu His Leu Leu Leu Leu Phe Ala Ala Gly Ala Glu Lys Leu Pro Gly 20 25 30 Gln Gly Val His Ser Gln Gly Gln Gly Pro Gly Ala Asn Phe Val Ser 35 40 45 Phe Val Gly Gln Ala Gly Gly Gly Gly Pro Ala Gly Gln Gln Leu Pro 50 55 60 Gln Leu Pro Gln Ser Ser Gln Leu Gln Gln Gln Gln Gln Gln Gln Gln65 70 75 80 Gln Gln Gln Gln Pro Gln Pro Pro Gln Pro Pro Phe Pro Ala Gly Gly 85 90 95 Pro Pro Ala Arg Arg Gly Gly Ala Gly Ala Gly Gly Gly Trp Lys Leu 100 105 110 Ala Glu Glu Glu Ser Cys Arg Glu Asp Val Thr Arg Val Cys Pro Lys 115 120 125 His Thr Trp Ser Asn Asn Leu Ala Val Leu Glu Cys Leu Gln Asp Val 130 135 140 Arg Glu Pro Glu Asn Glu Ile Ser Ser Asp Cys Asn His Leu Leu Trp145 150 155 160 Asn Tyr Lys Leu Asn Leu Thr Thr Asp Pro Lys Phe Glu Ser Val Ala 165 170 175 Arg Glu Val Cys Lys Ser Thr Ile Thr Glu Ile Lys Glu Cys Ala Asp 180 185 190 Glu Pro Val Gly Lys Gly Tyr Met Val Ser Cys Leu Val Asp His Arg 195 200 205 Gly Asn Ile Thr Glu Tyr Gln Cys His Gln Tyr Ile Thr Lys Met Thr 210 215 220 Ala Ile Ile Phe Ser Asp Tyr Arg Leu Ile Cys Gly Phe Met Asp Asp225 230 235 240 Cys Lys Asn Asp Ile Asn Ile Leu Lys Cys Gly Ser Ile Arg Leu Gly 245 250 255 Glu Lys Asp Ala His Ser Gln Gly Glu Val Val Ser Cys Leu Glu Lys 260 265 270 Gly Leu Val Lys Glu Ala Glu Glu Arg Glu Pro Lys Ile Gln Val Ser 275 280 285 Glu Leu Cys Lys Lys Ala Ile Leu Arg Val Ala Glu Leu Ser Ser Asp 290 295 300 Asp Phe His Leu Asp Arg His Leu Tyr Phe Ala Cys Arg Asp Asp Arg305 310 315 320 Glu Arg Phe Cys Glu Asn Thr Gln Ala Gly Glu Gly Arg Val Tyr Lys 325 330 335 Cys Leu Phe Asn His Lys Phe Glu Glu Ser Met Ser Glu Lys Cys Arg 340 345 350 Glu Ala Leu Thr Thr Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val 355 360 365 Ser Tyr Ser Leu Ala Lys Ser Cys Lys Ser Asp Leu Lys Lys Tyr Arg 370 375 380 Cys Asn Val Glu Asn Leu Pro Arg Ser Arg Glu Ala Arg Leu Ser Tyr385 390 395 400 Leu Leu Met Cys Leu Glu Ser Ala Val His Arg Gly Arg Gln Val Ser 405 410 415 Ser Glu Cys Gln Gly Glu Met Leu Asp Tyr Arg Arg Met Leu Met Glu 420 425 430 Asp Phe Ser Leu Ser Pro Glu Ile Ile Leu Ser Cys Arg Gly Glu Ile 435 440 445 Glu His His Cys Ser Gly Leu His Arg Lys Gly Arg Thr Leu His Cys 450 455 460 Leu Met Lys Val Val Arg Gly Glu Lys Gly Asn Leu Gly Met Asn Cys465 470 475 480 Gln Gln Ala Leu Gln Thr Leu Ile Gln Glu Thr Asp Pro Gly Ala Asp 485 490 495 Tyr Arg Ile Asp Arg Ala Leu Asn Glu Ala Cys Glu Ser Val Ile Gln 500 505 510 Thr Ala Cys Lys His Ile Arg Ser Gly Asp Pro Met Ile Leu Ser Cys 515 520 525 Leu Met Glu His Leu Tyr Thr Glu Lys Met Val Glu Asp Cys Glu His 530 535 540 Arg Leu Leu Glu Leu Gln Tyr Phe Ile Ser Arg Asp Trp Lys Leu Asp545 550 555 560 Pro Val Leu Tyr Arg Lys Cys Gln Gly Asp Ala Ser Arg Leu Cys His 565 570 575 Thr His Gly Trp Asn Glu Thr Ser Glu Phe Met Pro Gln Gly Ala Val 580 585 590 Phe Ser Cys Leu Tyr Arg His Ala Tyr Arg Thr Glu Glu Gln Gly Arg 595 600 605 Arg Leu Ser Arg Glu Cys Arg Ala Glu Val Gln Arg Ile Leu His Gln 610 615 620 Arg Ala Met Asp Val Lys Leu Asp Pro Ala Leu Gln Asp Lys Cys Leu625 630 635 640 Ile Asp Leu Gly Lys Trp Cys Ser Glu Lys Thr Glu Thr Gly Gln Glu 645 650 655 Leu Glu Cys Leu Gln Asp His Leu Asp Asp Leu Val Val Glu Cys Arg 660 665 670 Asp Ile Val Gly Asn Leu Thr Glu Leu Glu Ser Glu Asp Ile Gln Ile 675 680 685 Glu Ala Leu Leu Met Arg Ala Cys Glu Pro Ile Ile Gln Asn Phe Cys 690 695 700 His Asp Val Ala Asp Asn Gln Ile Asp Ser Gly Asp Leu Met Glu Cys705 710 715 720 Leu Ile Gln Asn Lys His Gln Lys Asp Met Asn Glu Lys Cys Ala Ile 725 730 735 Gly Val Thr His Phe Gln Leu Val Gln Met Lys Asp Phe Arg Phe Ser 740 745 750 Tyr Lys Phe Lys Met Ala Cys Lys Glu Asp Val Leu Lys Leu Cys Pro 755 760 765 Asn Ile Lys Lys Lys Val Asp Val Val Ile Cys Leu Ser Thr Thr Val 770 775 780 Arg Asn Asp Thr Leu Gln Glu Ala Lys Glu His Arg Val Ser Leu Lys785 790 795 800 Cys Arg Arg Gln Leu Arg Val Glu Glu Leu Glu Met Thr Glu Asp Ile 805 810 815 Arg Leu Glu Pro Asp Leu Tyr Glu Ala Cys Lys Ser Asp Ile Lys Asn 820 825 830 Phe Cys Ser Ala Val Gln Tyr Gly Asn Ala Gln Ile Ile Glu Cys Leu 835 840 845 Lys Glu Asn Lys Lys Gln Leu Ser

Thr Arg Cys His Gln Lys Val Phe 850 855 860 Lys Leu Gln Glu Thr Glu Met Met Asp Pro Glu Leu Asp Tyr Thr Leu865 870 875 880 Met Arg Val Cys Lys Gln Met Ile Lys Arg Phe Cys Pro Glu Ala Asp 885 890 895 Ser Lys Thr Met Leu Gln Cys Leu Lys Gln Asn Lys Asn Ser Glu Leu 900 905 910 Met Asp Pro Lys Cys Lys Gln Met Ile Thr Lys Arg Gln Ile Thr Gln 915 920 925 Asn Thr Asp Tyr Arg Leu Asn Pro Met Leu Arg Lys Ala Cys Lys Ala 930 935 940 Asp Ile Pro Lys Phe Cys His Gly Ile Leu Thr Lys Ala Lys Asp Asp945 950 955 960 Ser Glu Leu Glu Gly Gln Val Ile Ser Cys Leu Lys Leu Arg Tyr Ala 965 970 975 Asp Gln Arg Leu Ser Ser Asp Cys Glu Asp Gln Ile Arg Ile Ile Ile 980 985 990 Gln Glu Ser Ala Leu Asp Tyr Arg Leu Asp Pro Gln Leu Gln Leu His 995 1000 1005 Cys Ser Asp Glu Ile Ser Ser Leu Cys Ala Glu Glu Ala Ala Ala Gln 1010 1015 1020 Glu Gln Thr Gly Gln Val Glu Glu Cys Leu Lys Val Asn Leu Leu Lys1025 1030 1035 1040Ile Lys Thr Glu Leu Cys Lys Lys Glu Val Leu Asn Met Leu Lys Glu 1045 1050 1055 Ser Lys Ala Asp Ile Phe Val Asp Pro Val Leu His Thr Ala Cys Ala 1060 1065 1070 Leu Asp Ile Lys His His Cys Ala Ala Ile Thr Pro Gly Arg Gly Arg 1075 1080 1085 Gln Met Ser Cys Leu Met Glu Ala Leu Glu Asp Lys Arg Val Arg Leu 1090 1095 1100 Gln Pro Glu Cys Lys Lys Arg Leu Asn Asp Arg Ile Glu Met Trp Ser1105 1110 1115 1120Tyr Ala Ala Lys Val Ala Pro Ala Asp Gly Phe Ser Asp Leu Ala Met 1125 1130 1135 Gln Val Met Thr Ser Pro Ser Lys Asn Tyr Ile Leu Ser Val Ile Ser 1140 1145 1150 Gly Ser Ile Cys Ile Leu Phe Leu Ile Gly Leu Met Cys Gly Arg Ile 1155 1160 1165 Thr Lys Arg Val Thr Arg Glu Leu Lys Asp Arg Leu Gln Tyr Arg Ser 1170 1175 1180 Glu Thr Met Ala Tyr Lys Gly Leu Val Trp Ser Gln Asp Val Thr Gly1185 1190 1195 1200Ser Pro Ala281177PRTHomo sapiens 28Met Ala Ala Cys Gly Arg Val Arg Arg Met Phe Arg Leu Ser Ala Ala1 5 10 15 Leu His Leu Leu Leu Leu Phe Ala Ala Gly Gly Arg Asn Ser Pro Ala 20 25 30 Arg Ala Ser His Ser Gln Gly Gln Gly Pro Gly Ala Asn Phe Val Ser 35 40 45 Phe Val Gly Gln Ala Gly Gly Gly Gly Pro Ala Gly Gln Gln Leu Pro 50 55 60 Gln Leu Pro Gln Ser Ser Gln Leu Gln Gln Gln Gln Gln Gln Gln Gln65 70 75 80 Gln Gln Gln Gln Pro Gln Pro Pro Gln Pro Pro Phe Pro Ala Gly Gly 85 90 95 Pro Pro Arg Arg Gly Gly Ala Gly Ala Gly Gly Gly Trp Lys Leu Ala 100 105 110 Glu Glu Glu Ser Cys Arg Glu Asp Val Thr Arg Val Cys Pro Lys His 115 120 125 Thr Trp Ser Asn Asn Leu Ala Val Leu Glu Cys Leu Gln Asp Val Arg 130 135 140 Glu Pro Glu Asn Glu Ile Ser Ser Asp Cys Asn His Leu Leu Trp Asn145 150 155 160 Tyr Lys Leu Asn Leu Thr Thr Asp Pro Lys Phe Glu Ser Val Ala Arg 165 170 175 Glu Val Cys Lys Ser Thr Ile Thr Glu Ile Lys Glu Cys Ala Asp Glu 180 185 190 Pro Val Gly Lys Gly Tyr Met Val Ser Cys Leu Val Asp His Arg Gly 195 200 205 Asn Ile Thr Glu Tyr Gln Cys His Gln Tyr Ile Thr Lys Met Thr Ala 210 215 220 Ile Ile Phe Ser Asp Tyr Arg Leu Ile Cys Gly Phe Met Asp Asp Cys225 230 235 240 Lys Asn Asp Ile Asn Ile Leu Lys Cys Gly Ser Ile Arg Leu Gly Glu 245 250 255 Lys Asp Ala His Ser Gln Gly Glu Val Val Ser Cys Leu Glu Lys Gly 260 265 270 Leu Val Lys Glu Ala Glu Glu Arg Glu Pro Lys Ile Gln Val Ser Glu 275 280 285 Leu Cys Lys Lys Ala Ile Leu Arg Val Ala Glu Leu Ser Ser Asp Asp 290 295 300 Phe His Leu Asp Arg His Leu Tyr Phe Ala Cys Arg Asp Asp Arg Glu305 310 315 320 Arg Phe Cys Glu Asn Thr Gln Ala Gly Glu Gly Arg Val Tyr Lys Cys 325 330 335 Leu Phe Asn His Lys Phe Glu Glu Ser Met Ser Glu Lys Cys Arg Glu 340 345 350 Ala Leu Thr Thr Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val Ser 355 360 365 Tyr Ser Leu Ala Lys Ser Cys Lys Ser Asp Leu Lys Lys Tyr Arg Cys 370 375 380 Asn Val Glu Asn Leu Pro Arg Ser Arg Glu Ala Arg Leu Ser Tyr Leu385 390 395 400 Leu Met Cys Leu Glu Ser Ala Val His Arg Gly Arg Gln Val Ser Ser 405 410 415 Glu Cys Gln Gly Glu Met Leu Asp Tyr Arg Arg Met Leu Met Glu Asp 420 425 430 Phe Ser Leu Ser Pro Glu Ile Ile Leu Ser Cys Arg Gly Glu Ile Glu 435 440 445 His His Cys Ser Gly Leu His Arg Lys Gly Arg Thr Leu His Cys Leu 450 455 460 Met Lys Val Val Arg Gly Glu Lys Gly Asn Leu Gly Met Asn Cys Gln465 470 475 480 Gln Ala Leu Gln Thr Leu Ile Gln Glu Thr Asp Pro Gly Ala Asp Tyr 485 490 495 Arg Ile Asp Arg Ala Leu Asn Glu Ala Cys Glu Ser Val Ile Gln Thr 500 505 510 Ala Cys Lys His Ile Arg Ser Gly Asp Pro Met Ile Ser Ser Cys Leu 515 520 525 Met Glu His Leu Tyr Thr Glu Lys Met Val Glu Asp Cys Glu His Arg 530 535 540 Leu Leu Glu Leu Gln Tyr Phe Ile Ser Arg Asp Trp Lys Leu Asp Pro545 550 555 560 Val Leu Tyr Arg Lys Cys Gln Gly Asp Ala Ser Arg Leu Cys His Thr 565 570 575 His Gly Trp Asn Glu Thr Ser Glu Phe Met Pro Gln Gly Ala Val Phe 580 585 590 Ser Cys Leu Tyr Arg His Ala Tyr Arg Thr Glu Glu Gln Gly Arg Arg 595 600 605 Leu Ser Arg Glu Cys Arg Ala Glu Val Gln Arg Ile Leu His Gln Arg 610 615 620 Ala Met Asp Val Lys Leu Asp Pro Ala Leu Gln Asp Lys Cys Leu Ile625 630 635 640 Asp Leu Gly Lys Trp Cys Ser Glu Lys Thr Glu Thr Gly Gln Glu Leu 645 650 655 Glu Cys Leu Gln Asp His Leu Asp Asp Leu Val Val Glu Cys Arg Asp 660 665 670 Ile Val Gly Asn Leu Thr Glu Leu Glu Ser Glu Asp Ile Gln Ile Glu 675 680 685 Ala Leu Leu Met Arg Ala Cys Glu Pro Ile Ile Gln Thr Phe Cys His 690 695 700 Asp Ala Asp Asn Gln Ile Asp Ser Gly Asp Leu Met Glu Cys Leu Ile705 710 715 720 Gln Asn Lys His Gln Lys Asp Met Asn Glu Lys Cys Ala Ile Gly Val 725 730 735 Thr His Phe Gln Leu Val Gln Met Lys Asp Phe Arg Phe Ser Tyr Lys 740 745 750 Phe Lys Met Ala Cys Lys Glu Asp Val Leu Lys Leu Cys Pro Asn Ile 755 760 765 Lys Lys Lys Val Asp Val Val Ile Cys Leu Ser Thr Thr Val Arg Asn 770 775 780 Asp Thr Leu Gln Glu Ala Lys Glu His Arg Val Ser Leu Lys Cys Arg785 790 795 800 Arg Gln Leu Arg Val Glu Glu Leu Glu Met Thr Glu Asp Ile Arg Leu 805 810 815 Glu Pro Asp Leu Tyr Glu Ala Cys Lys Ser Asp Ile Lys Asn Phe Cys 820 825 830 Ser Ala Val Gln Tyr Gly Asn Ala Gln Ile Ile Glu Cys Leu Lys Glu 835 840 845 Asn Lys Lys Gln Leu Ser Thr Arg Cys His Gln Lys Val Phe Lys Leu 850 855 860 Gln Glu Thr Glu Met Met Asp Pro Glu Leu Asp Tyr Thr Leu Met Arg865 870 875 880 Val Cys Lys Gln Met Ile Lys Arg Phe Cys Pro Glu Ala Asp Ser Lys 885 890 895 Thr Met Leu Gln Cys Leu Lys Gln Asn Lys Asn Ser Glu Leu Met Asp 900 905 910 Pro Lys Cys Lys Gln Met Ile Thr Lys Arg Gln Ile Thr Gln Asn Thr 915 920 925 Asp Tyr Arg Leu Asn Pro Met Leu Arg Lys Ala Cys Lys Ala Asp Ile 930 935 940 Pro Lys Phe Cys His Gly Ile Leu Thr Lys Ala Lys Asp Asp Ser Glu945 950 955 960 Leu Glu Gly Gln Val Ile Ser Cys Leu Lys Leu Arg Tyr Ala Asp Gln 965 970 975 Arg Leu Ser Ser Asp Cys Glu Asp Gln Ile Arg Ile Ile Ile Gln Glu 980 985 990 Ser Ala Leu Asp Tyr Arg Leu Asp Pro Gln Leu Gln Leu His Cys Ser 995 1000 1005 Asp Glu Ile Ser Ser Leu Cys Ala Glu Glu Ala Ala Ala Gln Glu Gln 1010 1015 1020 Thr Gly Gln Val Glu Glu Cys Leu Lys Val Asn Leu Leu Lys Ile Lys1025 1030 1035 1040Thr Glu Leu Cys Lys Lys Glu Val Leu Asn Met Leu Lys Glu Ser Lys 1045 1050 1055 Ala Asp Ile Phe Val Asp Pro Val Leu His Thr Ala Cys Ala Leu Asp 1060 1065 1070 Ile Lys His His Cys Ala Ala Leu Thr Pro Gly Arg Gly Arg Gln Met 1075 1080 1085 Ser Cys Leu Met Glu Ala Leu Glu Asp Lys Arg Val Arg Leu Gln Pro 1090 1095 1100 Glu Cys Lys Lys Arg Leu Asn Asp Arg Ile Glu Met Trp Ser Tyr Ala1105 1110 1115 1120Ala Lys Val Ala Pro Ala Asp Gly Phe Ser Asp Leu Ala Met Gln Val 1125 1130 1135 Met Thr Ser Pro Ser Lys Asn Tyr Ile Leu Ser Val Ile Ser Gly Ser 1140 1145 1150 Ile Cys Ile Leu Phe Leu Ile Gly Leu Met Cys Gly Arg Ile Thr Lys 1155 1160 1165 Arg Val Thr Arg Glu Leu Lys Asp Arg 1170 1175 29442PRTHomo sapiens 29Met Ser Ala Ala Gln Gly Trp Asp Arg Asn Arg Arg Arg Gly Gly Gly1 5 10 15 Ala Ala Gly Ala Gly Gly Gly Gly Ser Gly Ala Gly Gly Gly Ser Gly 20 25 30 Gly Ser Gly Gly Arg Gly Thr Gly Gln Leu Asn Arg Phe Val Gln Leu 35 40 45 Ser Gly Arg Pro His Leu Pro Gly Lys Lys Lys Ile Arg Trp Asp Pro 50 55 60 Val Arg Arg Arg Phe Ile Gln Ser Cys Pro Ile Ile Arg Ile Pro Asn65 70 75 80 Arg Phe Leu Arg Gly His Arg Pro Pro Pro Ala Arg Ser Gly His Arg 85 90 95 Cys Val Ala Asp Asn Thr Asn Leu Tyr Val Phe Gly Gly Tyr Asn Pro 100 105 110 Asp Tyr Asp Glu Ser Gly Gly Pro Asp Asn Glu Asp Tyr Pro Leu Phe 115 120 125 Arg Glu Leu Trp Arg Tyr His Phe Ala Thr Gly Val Trp His Gln Met 130 135 140 Gly Thr Asp Gly Tyr Met Pro Arg Glu Leu Ala Ser Met Ser Leu Val145 150 155 160 Leu His Gly Asn Asn Leu Leu Val Phe Gly Gly Thr Gly Ile Pro Phe 165 170 175 Gly Glu Ser Asn Gly Asn Asp Val His Val Cys Asn Val Lys Tyr Lys 180 185 190 Arg Trp Ala Leu Leu Ser Cys Arg Gly Lys Lys Pro Ser Arg Ile Tyr 195 200 205 Gly Gln Ala Met Ala Ile Ile Asn Gly Ser Leu Tyr Val Phe Gly Gly 210 215 220 Thr Thr Gly Tyr Ile Tyr Ser Thr Asp Leu His Lys Leu Asp Leu Asn225 230 235 240 Thr Arg Glu Trp Thr Gln Leu Lys Pro Asn Asn Leu Ser Cys Asp Leu 245 250 255 Pro Glu Glu Arg Tyr Arg His Glu Ile Ala His Asp Gly Gln Arg Ile 260 265 270 Tyr Ile Leu Gly Gly Gly Thr Ser Trp Thr Ala Tyr Ser Leu Asn Lys 275 280 285 Ile His Ala Tyr Asn Leu Glu Thr Asn Ala Trp Glu Glu Ile Ala Thr 290 295 300 Lys Pro His Glu Lys Ile Gly Phe Pro Ala Ala Arg Arg Cys His Ser305 310 315 320 Cys Val Gln Ile Lys Asn Asp Val Phe Ile Cys Gly Gly Tyr Asn Gly 325 330 335 Glu Val Ile Leu Gly Asp Ile Trp Lys Leu Asn Leu Gln Thr Phe Gln 340 345 350 Trp Val Lys Leu Pro Ala Thr Met Pro Glu Pro Val Tyr Phe His Cys 355 360 365 Ala Ala Val Thr Pro Ala Gly Cys Met Tyr Ile His Gly Gly Val Val 370 375 380 Asn Ile His Glu Asn Lys Arg Thr Gly Ser Leu Phe Lys Ile Trp Leu385 390 395 400 Val Val Pro Ser Leu Leu Glu Leu Ala Trp Glu Lys Leu Leu Ala Ala 405 410 415 Phe Pro Asn Leu Ala Asn Leu Ser Arg Thr Gln Leu Leu His Leu Gly 420 425 430 Leu Thr Gln Gly Leu Ile Glu Arg Leu Lys 435 440 30698PRTHomo sapiens 30Met Ala Ala Cys Gly Arg Val Arg Arg Met Phe Arg Leu Ser Ala Ala1 5 10 15 Leu His Leu Leu Leu Leu Phe Ala Ala Gly Ala Glu Lys Leu Pro Gly 20 25 30 Gln Gly Val His Ser Gln Gly Gln Gly Pro Gly Ala Asn Phe Val Ser 35 40 45 Phe Val Gly Gln Ala Gly Gly Gly Gly Pro Ala Gly Gln Gln Leu Pro 50 55 60 Gln Leu Pro Gln Ser Ser Gln Leu Gln Gln Gln Gln Gln Gln Gln Gln65 70 75 80 Gln Gln Gln Gln Pro Gln Pro Pro Gln Pro Pro Phe Pro Ala Gly Gly 85 90 95 Pro Pro Ala Arg Arg Gly Gly Ala Gly Ala Gly Gly Gly Trp Lys Leu 100 105 110 Ala Glu Glu Glu Ser Cys Arg Glu Asp Val Thr Arg Val Cys Pro Lys 115 120 125 His Thr Trp Ser Asn Asn Leu Ala Val Leu Glu Cys Leu Gln Asp Val 130 135 140 Arg Glu Pro Glu Asn Glu Ile Ser Ser Asp Cys Asn His Leu Leu Trp145 150 155 160 Asn Tyr Lys Leu Asn Leu Thr Thr Asp Pro Lys Phe Glu Ser Val Ala 165 170 175 Arg Glu Val Cys Lys Ser Thr Ile Thr Glu Ile Lys Glu Cys Ala Asp 180 185 190 Glu Pro Val Gly Lys Gly Tyr Met Val Ser Cys Leu Val Asp His Arg 195 200 205 Gly Asn Ile Thr Glu Tyr Gln Cys His Gln Tyr Ile Thr Lys Met Thr 210 215 220 Ala Ile Ile Phe Ser Asp Tyr Arg Leu Ile Cys Gly Phe Met Asp Asp225 230 235 240 Cys Lys Asn Asp Ile Asn Ile Leu Lys Cys Gly Ser Ile Arg Leu Gly 245 250 255 Glu Lys Asp Ala His Ser Gln Gly Glu Val Val Ser Cys Leu Glu Lys 260 265 270 Gly Leu Val Lys Glu Ala Glu Glu Arg Glu Pro Lys Ile Gln Val Ser 275 280 285 Glu Leu Cys Lys Lys Ala Ile Leu Arg Val Ala Glu Leu Ser Ser Asp 290 295 300 Asp Phe His Leu Asp Arg His Leu Tyr Phe Ala Cys Arg Asp Asp Arg305 310 315 320 Glu Arg Phe Cys Glu Asn Thr Gln Ala Gly Glu Gly Arg Val Tyr Lys 325 330

335 Cys Leu Phe Asn His Lys Phe Glu Glu Ser Met Ser Glu Lys Cys Arg 340 345 350 Glu Ala Leu Thr Thr Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val 355 360 365 Ser Tyr Ser Leu Ala Lys Ser Cys Lys Ser Asp Leu Lys Lys Tyr Arg 370 375 380 Cys Asn Val Glu Asn Leu Pro Arg Ser Arg Glu Ala Arg Leu Ser Tyr385 390 395 400 Leu Leu Met Cys Leu Glu Ser Ala Val His Arg Gly Arg Gln Val Ser 405 410 415 Ser Glu Cys Gln Gly Glu Met Leu Asp Tyr Arg Arg Met Leu Met Glu 420 425 430 Asp Phe Ser Leu Ser Pro Glu Ile Ile Leu Ser Cys Arg Gly Glu Ile 435 440 445 Glu His His Cys Ser Gly Leu His Arg Lys Gly Arg Thr Leu His Cys 450 455 460 Leu Met Lys Val Val Arg Gly Glu Lys Gly Asn Leu Gly Met Asn Cys465 470 475 480 Gln Gln Ala Leu Gln Thr Leu Ile Gln Glu Thr Asp Pro Gly Ala Asp 485 490 495 Tyr Arg Ile Asp Arg Ala Leu Asn Glu Ala Cys Glu Ser Val Ile Gln 500 505 510 Thr Ala Cys Lys His Ile Arg Ser Gly Asp Pro Met Ile Leu Ser Cys 515 520 525 Leu Met Glu His Leu Tyr Thr Glu Lys Met Val Glu Asp Cys Glu His 530 535 540 Arg Leu Leu Glu Leu Gln Tyr Phe Ile Ser Arg Asp Trp Lys Leu Asp545 550 555 560 Pro Val Leu Tyr Arg Lys Cys Gln Gly Asp Ala Ser Arg Leu Cys His 565 570 575 Thr His Gly Trp Asn Glu Thr Ser Glu Phe Met Pro Gln Gly Ala Val 580 585 590 Phe Ser Cys Leu Tyr Arg His Ala Tyr Arg Thr Glu Glu Gln Gly Arg 595 600 605 Arg Leu Ser Arg Glu Cys Arg Ala Glu Val Gln Arg Ile Leu His Gln 610 615 620 Arg Ala Met Asp Val Lys Leu Asp Pro Ala Leu Gln Asp Lys Cys Leu625 630 635 640 Ile Asp Leu Gly Lys Trp Cys Ser Glu Lys Thr Glu Thr Gly Gln Glu 645 650 655 Leu Glu Cys Leu Gln Asp His Leu Asp Asp Leu Val Val Glu Cys Arg 660 665 670 Asp Ile Val Gly Asn Leu Thr Glu Leu Glu Ser Glu Ala Glu Arg Glu 675 680 685 Tyr Val Phe Lys Asn Leu Pro Phe Lys Val 690 695 31299PRTHomo sapiens 31Met Gly Thr Asp Gly Tyr Met Pro Arg Glu Leu Ala Ser Met Ser Leu1 5 10 15 Val Leu His Gly Asn Asn Leu Leu Val Phe Gly Gly Thr Gly Ile Pro 20 25 30 Phe Gly Glu Ser Asn Gly Asn Asp Val His Val Cys Asn Val Lys Tyr 35 40 45 Lys Arg Trp Ala Leu Leu Ser Cys Arg Gly Lys Lys Pro Ser Arg Ile 50 55 60 Tyr Gly Gln Ala Met Ala Ile Ile Asn Gly Ser Leu Tyr Val Phe Gly65 70 75 80 Gly Thr Thr Gly Tyr Ile Tyr Ser Thr Asp Leu His Lys Leu Asp Leu 85 90 95 Asn Thr Arg Glu Trp Thr Gln Leu Lys Pro Asn Asn Leu Ser Cys Asp 100 105 110 Leu Pro Glu Glu Arg Tyr Arg His Glu Ile Ala His Asp Gly Gln Arg 115 120 125 Ile Tyr Ile Leu Gly Gly Gly Thr Ser Trp Thr Ala Tyr Ser Leu Asn 130 135 140 Lys Ile His Ala Tyr Asn Leu Glu Thr Asn Ala Trp Glu Glu Ile Ala145 150 155 160 Thr Lys Pro His Glu Lys Ile Gly Phe Pro Ala Ala Arg Arg Cys His 165 170 175 Ser Cys Val Gln Ile Lys Asn Asp Val Phe Ile Cys Gly Gly Tyr Asn 180 185 190 Gly Glu Val Ile Leu Gly Asp Ile Trp Lys Leu Asn Leu Gln Thr Phe 195 200 205 Gln Trp Val Lys Leu Pro Ala Thr Met Pro Glu Pro Val Tyr Phe His 210 215 220 Cys Ala Ala Val Thr Pro Ala Gly Cys Met Tyr Ile His Gly Gly Val225 230 235 240 Val Asn Ile His Glu Asn Lys Arg Thr Gly Ser Leu Phe Lys Ile Trp 245 250 255 Leu Val Val Pro Ser Leu Leu Glu Leu Ala Trp Glu Lys Leu Leu Ala 260 265 270 Ala Phe Pro Asn Leu Ala Asn Leu Ser Arg Thr Gln Leu Leu His Leu 275 280 285 Gly Leu Thr Gln Gly Leu Ile Glu Arg Leu Lys 290 295 32906PRTHomo sapiens 32Met Thr Ser His Lys Ser Gly Arg Asp Gln Arg His Val Thr Gln Ser1 5 10 15 Gly Cys Asn Arg Lys Phe Lys Cys Thr Glu Cys Gly Lys Ala Phe Lys 20 25 30 Tyr Lys His His Leu Lys Glu His Leu Arg Ile His Ser Gly Glu Lys 35 40 45 Pro Tyr Glu Cys Pro Asn Cys Lys Lys Arg Phe Ser His Ser Gly Ser 50 55 60 Tyr Ser Ser His Ile Ser Ser Lys Lys Cys Ile Ser Leu Ile Pro Val65 70 75 80 Asn Gly Arg Pro Arg Thr Gly Leu Lys Thr Ser Gln Cys Ser Ser Pro 85 90 95 Ser Leu Ser Ala Ser Pro Gly Ser Pro Thr Arg Pro Gln Ile Arg Gln 100 105 110 Lys Ile Glu Asn Lys Pro Leu Gln Glu Gln Leu Ser Val Asn Gln Ile 115 120 125 Lys Thr Glu Pro Val Asp Tyr Glu Phe Lys Pro Ile Val Val Ala Ser 130 135 140 Gly Ile Asn Cys Ser Thr Pro Leu Gln Asn Gly Val Phe Thr Gly Gly145 150 155 160 Gly Pro Leu Gln Ala Thr Ser Ser Pro Gln Gly Met Val Gln Ala Val 165 170 175 Val Leu Pro Thr Val Gly Leu Val Ser Pro Ile Ser Ile Asn Leu Ser 180 185 190 Asp Ile Gln Asn Val Leu Lys Val Ala Val Asp Gly Asn Val Ile Arg 195 200 205 Gln Val Leu Glu Asn Asn Gln Ala Asn Leu Ala Ser Lys Glu Gln Glu 210 215 220 Thr Ile Asn Ala Ser Pro Ile Gln Gln Gly Gly His Ser Val Ile Ser225 230 235 240 Ala Ile Ser Leu Pro Leu Val Asp Gln Asp Gly Thr Thr Lys Ile Ile 245 250 255 Ile Asn Tyr Ser Leu Glu Gln Pro Ser Gln Leu Gln Val Val Pro Gln 260 265 270 Asn Leu Lys Lys Glu Asn Pro Val Ala Thr Asn Ser Cys Lys Ser Glu 275 280 285 Lys Leu Pro Glu Asp Leu Thr Val Lys Ser Glu Lys Asp Lys Ser Phe 290 295 300 Glu Gly Gly Val Asn Asp Ser Thr Cys Leu Leu Cys Asp Asp Cys Pro305 310 315 320 Gly Asp Ile Asn Ala Leu Pro Glu Leu Lys His Tyr Asp Leu Lys Gln 325 330 335 Pro Thr Gln Pro Pro Pro Leu Pro Ala Ala Glu Ala Glu Lys Pro Glu 340 345 350 Ser Ser Val Ser Ser Ala Thr Gly Asp Gly Asn Leu Ser Pro Ser Gln 355 360 365 Pro Pro Leu Lys Asn Leu Leu Ser Leu Leu Lys Ala Tyr Tyr Ala Leu 370 375 380 Asn Ala Gln Pro Ser Ala Glu Glu Leu Ser Lys Ile Ala Asp Ser Val385 390 395 400 Asn Leu Pro Leu Asp Val Val Lys Lys Trp Phe Glu Lys Met Gln Ala 405 410 415 Gly Gln Ile Ser Val Gln Ser Ser Glu Pro Ser Ser Pro Glu Pro Gly 420 425 430 Lys Val Asn Ile Pro Ala Lys Asn Asn Asp Gln Pro Gln Ser Ala Asn 435 440 445 Ala Asn Glu Pro Gln Asp Ser Thr Val Asn Leu Gln Ser Pro Leu Lys 450 455 460 Met Thr Asn Ser Pro Val Leu Pro Val Gly Ser Thr Thr Asn Gly Ser465 470 475 480 Arg Ser Ser Thr Pro Ser Pro Ser Pro Leu Asn Leu Ser Ser Ser Arg 485 490 495 Asn Thr Gln Gly Tyr Leu Tyr Thr Ala Glu Gly Ala Gln Glu Glu Pro 500 505 510 Gln Val Glu Pro Leu Asp Leu Ser Leu Pro Lys Gln Gln Gly Glu Leu 515 520 525 Leu Glu Arg Ser Thr Ile Thr Ser Val Tyr Gln Asn Ser Val Tyr Ser 530 535 540 Val Gln Glu Glu Pro Leu Asn Leu Ser Cys Ala Lys Lys Glu Pro Gln545 550 555 560 Lys Asp Ser Cys Val Thr Asp Ser Glu Pro Val Val Asn Val Ile Pro 565 570 575 Pro Ser Ala Asn Pro Ile Asn Ile Ala Ile Pro Thr Val Thr Ala Gln 580 585 590 Leu Pro Thr Ile Val Ala Ile Ala Asp Gln Asn Ser Val Pro Cys Leu 595 600 605 Arg Ala Leu Ala Ala Asn Lys Gln Thr Ile Leu Ile Pro Gln Val Ala 610 615 620 Tyr Thr Tyr Ser Thr Thr Val Ser Pro Ala Val Gln Glu Pro Pro Leu625 630 635 640 Lys Val Ile Gln Pro Asn Gly Asn Gln Asp Glu Arg Gln Asp Thr Ser 645 650 655 Ser Glu Gly Val Ser Asn Val Glu Asp Gln Asn Asp Ser Asp Ser Thr 660 665 670 Pro Pro Lys Lys Lys Met Arg Lys Thr Glu Asn Gly Met Tyr Ala Cys 675 680 685 Asp Leu Cys Asp Lys Ile Phe Gln Lys Ser Ser Ser Leu Leu Arg His 690 695 700 Lys Tyr Glu His Thr Gly Lys Arg Pro His Glu Cys Gly Ile Cys Lys705 710 715 720 Lys Ala Phe Lys His Lys His His Leu Ile Glu His Met Arg Leu His 725 730 735 Ser Gly Glu Lys Pro Tyr Gln Cys Asp Lys Cys Gly Lys Arg Phe Ser 740 745 750 His Ser Gly Ser Tyr Ser Gln His Met Asn His Arg Tyr Ser Tyr Cys 755 760 765 Lys Arg Glu Ala Glu Glu Arg Asp Ser Thr Glu Gln Glu Glu Ala Gly 770 775 780 Pro Glu Ile Leu Ser Asn Glu His Val Gly Ala Arg Ala Ser Pro Ser785 790 795 800 Gln Gly Asp Ser Asp Glu Arg Glu Ser Leu Thr Arg Glu Glu Asp Glu 805 810 815 Asp Ser Glu Lys Glu Glu Glu Glu Glu Asp Lys Glu Met Glu Glu Leu 820 825 830 Gln Glu Glu Lys Glu Cys Glu Lys Pro Gln Gly Asp Glu Glu Glu Glu 835 840 845 Glu Glu Glu Glu Glu Val Glu Glu Glu Glu Val Glu Glu Ala Glu Asn 850 855 860 Glu Gly Glu Glu Ala Lys Thr Glu Gly Leu Met Lys Asp Asp Arg Ala865 870 875 880 Glu Ser Gln Ala Ser Ser Leu Gly Gln Lys Val Gly Glu Ser Ser Glu 885 890 895 Gln Val Ser Glu Glu Lys Thr Asn Glu Ala 900 905 331179PRTHomo sapiens 33Met Ala Ala Cys Gly Arg Val Arg Arg Met Phe Arg Leu Ser Ala Ala1 5 10 15 Leu His Leu Leu Leu Leu Phe Ala Ala Gly Ala Glu Lys Leu Pro Gly 20 25 30 His Gly Val His Ser Gln Gly Gln Gly Pro Gly Ala Asn Phe Val Ser 35 40 45 Phe Val Gly Gln Ala Gly Gly Gly Gly Pro Ala Gly Gln Gln Leu Pro 50 55 60 Gln Leu Leu Gln Ser Ser Gln Leu Gln Gln Gln Gln Gln Gln Gln Gln65 70 75 80 Gln Gln Gln Gln Leu Gln Pro Pro Gln Pro Pro Phe Pro Ala Gly Gly 85 90 95 Pro Pro Ala Arg Arg Gly Gly Ala Gly Ala Gly Gly Gly Trp Lys Leu 100 105 110 Ala Glu Glu Glu Ser Cys Arg Glu Asp Val Thr Arg Val Cys Pro Lys 115 120 125 His Thr Trp Ser Asn Asn Leu Ala Val Leu Glu Cys Leu Gln Asp Val 130 135 140 Arg Glu Pro Glu Asn Glu Ile Ser Ser Asp Cys Asn His Leu Leu Trp145 150 155 160 Asn Tyr Lys Leu Asn Leu Thr Thr Asp Pro Lys Phe Glu Ser Val Ala 165 170 175 Arg Glu Val Cys Lys Ser Thr Ile Thr Glu Ile Lys Glu Cys Ala Asp 180 185 190 Glu Pro Val Gly Lys Gly Tyr Met Val Ser Cys Leu Val Asp His Arg 195 200 205 Gly Asn Ile Thr Glu Tyr Gln Cys His Gln Tyr Ile Thr Lys Met Thr 210 215 220 Ala Ile Ile Phe Ser Asp Tyr Arg Leu Ile Cys Gly Phe Met Asp Asp225 230 235 240 Cys Lys Asn Asp Ile Asn Ile Leu Lys Cys Gly Ser Ile Arg Leu Gly 245 250 255 Glu Lys Asp Ala His Ser Gln Gly Glu Val Val Ser Cys Leu Glu Lys 260 265 270 Gly Leu Val Lys Glu Ala Glu Glu Arg Glu Pro Lys Ile Gln Val Ser 275 280 285 Glu Leu Cys Lys Lys Ala Ile Leu Arg Val Ala Glu Leu Ser Ser Asp 290 295 300 Asp Phe His Leu Asp Arg His Leu Tyr Phe Ala Cys Arg Asp Asp Arg305 310 315 320 Glu Arg Phe Cys Glu Asn Thr Gln Ala Gly Glu Gly Arg Val Tyr Lys 325 330 335 Cys Leu Phe Asn His Lys Phe Glu Glu Ser Met Ser Glu Lys Cys Arg 340 345 350 Glu Ala Leu Thr Thr Arg Gln Lys Leu Ile Ala Gln Asp Tyr Lys Val 355 360 365 Ser Tyr Ser Leu Ala Lys Ser Cys Lys Ser Asp Leu Lys Lys Tyr Arg 370 375 380 Cys Asn Val Glu Asn Leu Pro Arg Ser Arg Glu Ala Arg Leu Ser Tyr385 390 395 400 Leu Leu Met Cys Leu Glu Ser Ala Val His Arg Gly Arg Gln Val Ser 405 410 415 Ser Glu Cys Gln Gly Glu Met Leu Asp Tyr Arg Arg Met Leu Met Glu 420 425 430 Asp Phe Ser Leu Ser Pro Glu Ile Ile Leu Ser Cys Arg Gly Glu Ile 435 440 445 Glu His His Cys Ser Gly Leu His Arg Lys Gly Arg Thr Leu His Cys 450 455 460 Leu Met Lys Val Val Arg Gly Glu Lys Gly Asn Leu Gly Met Asn Cys465 470 475 480 Gln Gln Ala Leu Gln Thr Leu Ile Gln Glu Thr Asp Pro Gly Ala Asp 485 490 495 Tyr Arg Ile Asp Arg Ala Leu Asn Glu Ala Cys Glu Ser Val Ile Gln 500 505 510 Thr Ala Cys Lys His Ile Arg Ser Gly Asp Pro Met Ile Leu Ser Cys 515 520 525 Leu Met Glu His Leu Tyr Thr Glu Lys Met Val Glu Asp Cys Glu His 530 535 540 Arg Leu Leu Glu Leu Gln Tyr Phe Ile Ser Arg Asp Trp Lys Leu Asp545 550 555 560 Pro Val Leu Tyr Arg Lys Cys Gln Gly Asp Ala Ser Arg Leu Cys His 565 570 575 Thr His Gly Trp Asn Glu Thr Ser Glu Phe Met Pro Gln Gly Ala Val 580 585 590 Phe Ser Cys Leu Tyr Arg His Ala Tyr Arg Thr Glu Glu Gln Gly Arg 595 600 605 Arg Leu Ser Arg Glu Cys Arg Ala Glu Val Gln Arg Ile Leu His Gln 610 615 620 Arg Ala Met Asp Val Lys Leu Asp Pro Ala Leu Gln Asp Lys Cys Leu625 630 635 640 Ile Asp Leu Gly Lys Trp Cys Ser Glu Lys Thr Glu Thr Gly Gln Glu 645 650 655 Leu Glu Cys Leu Gln Asp His Leu Asp Asp Leu Val Val Glu Cys Arg 660 665 670 Asp Ile Val Gly Asn Leu Thr Glu Leu Glu Ser Glu Asp Ile Gln Ile 675 680 685 Glu Ala Leu Leu Met Arg Ala Cys Glu Pro Ile Ile Gln Asn Phe Cys 690 695 700 His Asp Val Ala Asp Asn Gln Ile Asp Ser Gly Asp Leu Met Glu Cys705 710 715 720 Leu Ile Gln Asn Lys His Gln Lys Asp Met Asn Glu Lys Cys Ala Ile 725 730 735 Gly Val Thr His Phe Gln Leu Val Gln Met

Lys Asp Phe Arg Phe Ser 740 745 750 Tyr Lys Phe Lys Met Ala Cys Lys Glu Asp Val Leu Lys Leu Cys Pro 755 760 765 Asn Ile Lys Lys Lys Val Asp Val Val Ile Cys Leu Ser Thr Thr Val 770 775 780 Arg Asn Asp Thr Leu Gln Glu Ala Lys Glu His Arg Val Ser Leu Lys785 790 795 800 Cys Arg Arg Gln Leu Arg Val Glu Glu Leu Glu Met Thr Glu Asp Ile 805 810 815 Arg Leu Glu Pro Asp Leu Tyr Glu Ala Cys Lys Ser Asp Ile Lys Asn 820 825 830 Phe Cys Ser Ala Val Gln Tyr Gly Asn Ala Gln Ile Ile Glu Cys Leu 835 840 845 Lys Glu Asn Lys Lys Gln Leu Ser Thr Arg Cys His Gln Lys Val Phe 850 855 860 Lys Leu Gln Glu Thr Glu Met Met Asp Pro Glu Leu Asp Tyr Thr Leu865 870 875 880 Met Arg Val Cys Lys Gln Met Ile Lys Arg Phe Cys Pro Glu Ala Asp 885 890 895 Ser Lys Thr Met Leu Gln Cys Leu Lys Gln Asn Lys Asn Ser Glu Leu 900 905 910 Met Asp Pro Lys Cys Lys Gln Met Ile Thr Lys Arg Gln Ile Thr Gln 915 920 925 Asn Thr Asp Tyr Arg Leu Asn Pro Met Leu Arg Lys Ala Cys Lys Ala 930 935 940 Asp Ile Pro Lys Phe Cys His Gly Ile Leu Thr Lys Ala Lys Asp Asp945 950 955 960 Ser Glu Leu Glu Gly Gln Val Ile Ser Cys Leu Lys Leu Arg Tyr Ala 965 970 975 Asp Gln Arg Leu Ser Ser Asp Cys Glu Asp Gln Ile Arg Ile Ile Ile 980 985 990 Gln Glu Ser Ala Leu Asp Tyr Arg Leu Asp Pro Gln Leu Gln Leu His 995 1000 1005 Cys Ser Asp Glu Ile Ser Ser Leu Cys Ala Glu Glu Ala Ala Ala Gln 1010 1015 1020 Glu Gln Thr Gly Gln Val Glu Glu Cys Leu Lys Val Asn Leu Leu Lys1025 1030 1035 1040Ile Lys Thr Glu Leu Cys Lys Lys Glu Val Leu Asn Met Leu Lys Glu 1045 1050 1055 Ser Lys Ala Asp Ile Phe Val Asp Pro Val Leu His Thr Ala Cys Ala 1060 1065 1070 Leu Asp Ile Lys His His Cys Ala Ala Ile Thr Pro Gly Arg Gly Arg 1075 1080 1085 Gln Met Ser Cys Leu Met Glu Ala Leu Glu Asp Lys Arg Val Arg Leu 1090 1095 1100 Gln Pro Glu Cys Lys Lys Arg Leu Asn Asp Arg Ile Glu Met Trp Ser1105 1110 1115 1120Tyr Ala Ala Lys Val Ala Pro Ala Asp Gly Phe Ser Asp Leu Ala Met 1125 1130 1135 Gln Val Met Thr Ser Pro Ser Lys Asn Tyr Ile Leu Ser Val Ile Ser 1140 1145 1150 Gly Ser Ile Cys Ile Leu Phe Leu Ile Gly Leu Met Cys Gly Arg Ile 1155 1160 1165 Thr Lys Arg Val Thr Arg Glu Leu Lys Asp Arg 1170 1175 345191DNAHomo sapiens 34ggcgagtgcg tcgagctcgc cgcggactca agatggcggc gtgtggacgt gtacggagga 60tgttccgctt gtcggcggcg ctgcatctgc tgctgctatt cgcggccggg gccgagaaac 120tccccggcca gggcgtccac agccagggcc agggtcccgg ggccaacttt gtgtccttcg 180tagggcaggc cggaggcggc ggcccggcgg gtcagcagct gccccagctg cctcagtcat 240cgcagcttca gcagcaacag cagcagcagc aacagcaaca gcagcctcag ccgccgcagc 300cgcctttccc ggcgggtggg cctccggccc ggcggggagg agcgggggct ggtgggggct 360ggaagctggc ggaggaagag tcctgcaggg aggacgtgac ccgcgtgtgc cctaagcaca 420cctggagcaa caacctggcg gtgctcgagt gcctgcagga tgtgagggag cctgaaaatg 480aaatttcttc agactgcaat catttgttgt ggaattataa gctgaaccta actacagatc 540ccaaatttga atctgtggcc agagaggttt gcaaatctac tataacagag attaaagaat 600gtgctgatga accggttgga aaaggttaca tggtttcctg cttggtggat caccgaggca 660acatcactga gtatcagtgt caccagtaca ttaccaagat gacggccatc atttttagtg 720attaccgttt aatctgtggc ttcatggatg actgcaaaaa tgacatcaac attctgaaat 780gtggcagtat tcggcttgga gaaaaggatg cacattcaca aggtgaggtg gtatcatgct 840tggagaaagg cctggtgaaa gaagcagaag aaagagaacc caagattcaa gtttctgaac 900tctgcaagaa agccattctc cgggtggctg agctgtcatc ggatgacttt cacttagacc 960ggcatttata ttttgcttgc cgagatgatc gggagcgttt ttgtgaaaat acacaagctg 1020gtgagggcag agtgtataag tgcctcttta accataaatt tgaagaatcc atgagtgaaa 1080agtgtcgaga agcacttaca acccgccaaa agctgattgc ccaggattat aaagtcagtt 1140attcattggc caaatcctgt aaaagtgact tgaagaaata ccggtgcaat gtggaaaacc 1200ttccgcgatc gcgtgaagcc aggctctcct acttgttaat gtgcctggag tcagctgtac 1260acagagggcg acaagtcagc agtgagtgcc agggggagat gctggattac cgacgcatgt 1320tgatggaaga cttttctctg agccctgaga tcatcctaag ctgtcggggg gagattgaac 1380accattgttc cggattacat cgaaaagggc ggaccctaca ctgtctgatg aaagtagttc 1440gaggggagaa ggggaacctt ggaatgaact gccagcaggc gcttcaaaca ctgattcagg 1500agactgaccc tggtgcagat taccgcattg atcgagcttt gaatgaagct tgtgaatctg 1560taatccagac agcctgcaaa catataagat ctggagaccc aatgatcttg tcgtgcctga 1620tggaacattt atacacagag aagatggtag aagactgtga acaccgtctc ttagagctgc 1680agtatttcat ctcccgggat tggaagctgg accctgtcct gtaccgcaag tgccagggag 1740acgcttctcg tctttgccac acccacggtt ggaatgagac cagtgaattt atgcctcagg 1800gagctgtgtt ctcttgttta tacagacacg cctaccgcac tgaggaacag ggaaggaggc 1860tctcacggga gtgccgagct gaagtccaaa ggatcctaca ccagcgtgcc atggatgtca 1920agctggatcc tgccctccag gataagtgcc tgattgatct gggaaaatgg tgcagtgaga 1980aaacagagac tggacaggag ctggagtgcc ttcaggacca tctggatgac ttggtggtgg 2040agtgtagaga tatagttggc aacctcactg agttagaatc agaggatatt caaatagaag 2100ccttgctgat gagagcctgt gagcccataa ttcagaactt ctgccacgat gtggcagata 2160accagataga ctctggggac ctgatggagt gtctgataca gaacaaacac cagaaggaca 2220tgaacgagaa gtgtgccatc ggagttaccc acttccagct ggtgcagatg aaggattttc 2280ggttttctta caagtttaaa atggcctgca aggaggacgt gttgaagctt tgcccaaaca 2340taaaaaagaa ggtggacgtg gtgatctgcc tgagcacgac cgtgcgcaat gacactctgc 2400aggaagccaa ggagcacagg gtgtccctga agtgccgcag gcagctccgt gtggaggagc 2460tggagatgac ggaggacatc cgcttggagc cagatctata cgaagcctgc aagagtgaca 2520tcaaaaactt ctgttccgct gtgcaatatg gcaacgctca gattatcgaa tgtctgaaag 2580aaaacaagaa gcagctaagc acccgctgcc accaaaaagt atttaagctg caggagacag 2640agatgatgga cccagagcta gactacaccc tcatgagggt ctgcaagcag atgataaaga 2700ggttctgtcc ggaagcagat tctaaaacca tgttgcagtg cttgaagcaa aataaaaaca 2760gtgaattgat ggatcccaaa tgcaaacaga tgataaccaa gcgccagatc acccagaaca 2820cagattaccg cttaaacccc atgttaagaa aagcctgtaa agctgacatt cctaaattct 2880gtcacggtat cctgactaag gccaaggatg attcagaatt agaaggacaa gtcatctctt 2940gcctgaagct gagatatgct gaccagcgcc tgtcttcaga ctgtgaagac cagatccgaa 3000tcattatcca ggagtccgcc ctggactacc gcctggatcc tcagctccag ctgcactgct 3060cagacgagat ctccagtcta tgtgctgaag aagcagcagc ccaagagcag acaggtcagg 3120tggaggagtg cctcaaggtc aacctgctca agatcaaaac agaattgtgt aaaaaggaag 3180tgctaaacat gctgaaggaa agcaaagcag acatctttgt tgacccggta cttcatactg 3240cttgtgccct ggacattaaa caccactgcg cagccatcac ccctggccgc gggcgtcaaa 3300tgtcctgtct catggaagca ctggaggata agcgggtgag gttacagccc gagtgcaaaa 3360agcgcctcaa tgaccggatt gagatgtgga gttacgcagc aaaggtggcc ccagcagatg 3420gcttctctga tcttgccatg caagtaatga cgtctccatc taagaactac attctctctg 3480tgatcagtgg gagcatctgt atattgttcc tgattggcct gatgtgtgga cggatcacca 3540agcgagtgac acgagagctc aaggacaggt agagccacct tgaccaccaa aggaactacc 3600tatccagtgc ccagtttgta cagccctctt gtatagcatc cccactcacc tcgctcttct 3660cagaagtgac accaaccccg tgttagagca ttagcagatg tccactgcgt tgtcccatcc 3720agcctccact cgtgtccatg gtgtcctcct cctcctcacc gtgcagcagc agcagctggt 3780cgctggggtt actgcctttg tttggcaaac ttgggtttac ctgcctgtag acaagtctct 3840ctcataccaa cagaacttcc ggtacttcca gaaccaactc acctgacctg caactcaaag 3900gcttttttaa gaaaaccacc aaaaaaaaaa atttttttaa agaaaaaaat gtatatagta 3960acgcatctcc tccaggcttg atttgggcaa tggggttatg tctttcatat gactgtgtaa 4020aacaaagaca ggacttggag gggaagcaca ccacccagtg tgccatgact gaggtgtctc 4080gttcatctct cagaagcacc ttggggcctc gccagggccg tggtcttcac cgaggcgtgg 4140gtgggcagcc gttccccagg ctgtgtgggg tcctgctttc ttctgctgag acagtgacgc 4200tttccagttt ccaccctaat cagccactgc tggtcacagc cccacagcca tgggtatttc 4260tgtggtctcc tcgcttcatt gaagcaaagc atgagccttc ctagacaagg gcagctgggg 4320aggggaaggg accggaagtt tgtgaagttg aacagtccat ccatctgcac tgagaggctg 4380gatcctgagt cccggggcag caggatccca ggaaccttcc tcctccaggg cagcacagga 4440ctcagccatg tctggaccgg ccctgctgag gctacagtca ctctggaagc tctgcgcttc 4500atcaggaggc aggactgtgg cgggaggggt ccttgaagat gggtgtgggg agcagtgggt 4560caggaagtgg gagccagagg tttgactcac tttgctttat ttttcaggct acaatacagg 4620tcagagacaa tggcttataa aggtttagtg tggtctcagg atgtgacagg cagtccagcc 4680tgacctttct gcacactcca gacaaacttc ccagacaagc tcctttgtgc ctctacgtgg 4740agagggtgtg gaaagttatc acattaaaag atggaggatt tgctctgttt tttttctttc 4800tgtccatttg ctgcgtgtac ccactctagt aggcattggc taaatgttgt attttggcga 4860ttcatcaacc tttgcagaat atgggcttta tagaagcaat attcttggcc atcccgcctc 4920attcctccag tgtggagatg acaagtctgg gtgtgagagg gaggggtccg ggcatcatgg 4980ttcagcgtgg cactcctttg gttgagtttg gggcatgaga tcacagtggc tgcacaagag 5040agcagtgtgt acagtaggag agacatttat gtaatatata ttttattaac ctgttagatg 5100tccacaaagt attataaatc acgtgcctaa aactgtccat gtagaccaag gcctgccctc 5160ggcgcccccc actcttgcct ctgctctgca c 5191353556DNAHomo sapiens 35cgggccggtc acacgcgcag ccagccggcc gccctcccgc gcccaagcgc gccgctctag 60ctgtgccctg cgcccttgcc ccgcgccagc ttctgcgccc gcagcccgcc cggcgccccc 120ggtgaccgtg accctgccct gggcgcgggg cggagcaggc atgtcccgcc cggggaccgc 180taccccagcg ctggccctgg tgctcctggc agtgaccctg gccggggtcg gagcccaggg 240cgcagccctc gaggaccctg attattacgg gcaggagatc tggagccggg agccctacta 300cgcgcgcccg gagcccgagc tcgagacctt ctctccgccg ctgcctgcgg ggcccgggga 360ggagtgggag cggcgcccgc aggagcccag gccgcccaag agggccacca agcccaagaa 420agctcccaag agggagaagt cggctccgga gccgcctcca ccaggtaaac acagcaacaa 480aaaagttatg agaaccaaga gctctgagaa ggctgccaac gatgatcaca gtgtccgtgt 540ggcccgtgaa gatgtcagag agagttgccc acctcttggt ctggaaacct taaaaatcac 600agacttccag ctccatgcct ccacggtgaa gcgctatggc ctgggggcac atcgagggag 660actcaacatc caggcgggca ttaatgaaaa tgatttttat gacggagcgt ggtgcgcggg 720aagaaatgac ctccagcagt ggattgaagt ggatgctcgg cgcctgacca gattcactgg 780tgtcatcact caagggagga actccctctg gctgagtgac tgggtgacat cctataaggt 840catggtgagc aatgacagcc acacgtgggt cactgttaag aatggatctg gagacatgat 900atttgaggga aacagtgaga aggagatccc tgttctcaat gagctacccg tccccatggt 960ggcccgctac atccgcataa accctcagtc ctggtttgat aatgggagca tctgcatgag 1020aatggagatc ctgggctgcc cactgccaga tcctaataat tattatcacc gccggaacga 1080gatgaccacc actgatgacc tggattttaa gcaccacaat tataaggaaa tgcgccagtt 1140gatgaaagtt gtgaatgaaa tgtgtcccaa tatcaccaga atttacaaca ttggaaaaag 1200ccaccagggc ctgaagctgt atgctgtgga gatctcagat caccctgggg agcatgaagt 1260cggtgagccc gagttccact acatcgcggg ggcccacggc aatgaggtgc tgggccggga 1320gctgctgctg ctgctggtgc agttcgtgtg tcaggagtac ttggcccgga atgcgcgcat 1380cgtccacctg gtggaggaga cgcggattca cgtcctcccc tccctcaacc ccgatggcta 1440cgagaaggcc tatgaagggg gctcggagct gggaggctgg tccctgggac gctggaccca 1500cgatggaatt gacatcaaca acaactttcc tgatttaaac acgctgctct gggaggcaga 1560ggatcgacag aatgtcccca ggaaagttcc caatcactat attgcaatcc ctgagtggtt 1620tctgtcggaa aatgccacgg tggctgccga gaccagagca gtcatagcct ggatggaaaa 1680aatccctttt gtgctgggcg gcaacctgca gggcggcgag ctggtggtgg cgtaccccta 1740cgacctggtg cggtccccct ggaagacgca ggaacacacc cccacccccg acgaccacgt 1800gttccgctgg ctggcctact cctatgcctc cacacaccgc ctcatgacag acgcccggag 1860gagggtgtgc cacacggagg acttccagaa ggaggagggc actgtcaatg gggcctcctg 1920gcacaccgtc gctggaagtc tgaacgattt cagctacctt catacaaact gcttcgaact 1980gtccatctac gtgggctgtg ataaataccc acatgagagc cagctgcccg aggagtggga 2040gaataaccgg gaatctctga tcgtgttcat ggagcaggtt catcgtggca ttaaaggctt 2100ggtgagagat tcacatggaa aaggaatccc aaacgccatt atctccgtag aaggcattaa 2160ccatgacatc cgaacagcca acgatgggga ttactggcgc ctcctgaacc ctggagagta 2220tgtggtcaca gcaaaggccg aaggtttcac tgcatccacc aagaactgta tggttggcta 2280tgacatgggg gccacaaggt gtgacttcac acttagcaaa accaacatgg ccaggatccg 2340agagatcatg gagaagtttg ggaagcagcc cgtcagcctg ccagccaggc ggctgaagct 2400gcgggggcgg aagagacgac agcgtgggtg accctcctgg gcccttgaga ctcgtctggg 2460acccatgcaa attaaaccaa cctggtagta gctccatagt ggactcactc actgttgttt 2520cctctgtaat tcaagaagtg cctggaagag agggtgcatt gtgaggcagg tcccaaaagg 2580gaaggctgga ggctgaggct gttttctttt ctttgttccc atttatccaa ataacttgga 2640cagagcagca gagaaaagct gatgggagtg agagaactca gcaagccaac ctgggaatca 2700gagagagaag gagaaggagg ggagcctgtc cgttcagagc ctctggctgc atagaaaagg 2760attctggtgc ttcccctgtt tgcgtggcag caagggttcc acgtgcattt gcaatttgca 2820cagctaaaat tgcagcattt ccccagctgg gctgtcccaa atgttaccat ttgagatgct 2880cccaggcgtc ctaagagaat ccaccctctc tggccctggg acattgcaag ctgctacaaa 2940taaattctgt gttcttttga caatagcgtc attgccaagt gcacatcagt gagcctcttg 3000aatctgttta gtctcctttt tcaacaaagg agtgtgttca gaaaaggaga gagaggctga 3060gatcattcag gagtttgttg ggcagcaagc atggagcttc ttgcacaaat tctgggtcca 3120taaacaaccc ccaaagtccc tgctgatcca gtagccctgg aggttcccca ggtagggaga 3180gccagaggtg ccagccttcc tgaagggcca gaaaatttag cctggatctc ctcttttacc 3240tgctaggact ggaaagagcc agaagtgggg tggcctgaag ccctctctct gcttgaggta 3300ttgcccctgt gtggaattga gtgctcatgg gttggcctca tatcagcctg ggagttattt 3360ttgatatgta gaatgccaga tcttccagat taggctaaat gtaatgaaaa cctcttagga 3420ttatctgtgg agcatcagtt tgggaagaat tattgaatta tcttgcaaga aaaaagtatg 3480tctcactttt tgttaatgtt gctgcctcat tgacctggga aaaatgaaaa aaaaaaataa 3540agcaaatggt aagacc 3556365191DNAHomo sapiens 36ggcgagtgcg tcgagctcgc cgcggactca agatggcggc gtgtggacgt gtacggagga 60tgttccgctt gtcggcggcg ctgcatctgc tgctgctatt cgcggccggg gccgagaaac 120tccccggcca gggcgtccac agccagggcc agggtcccgg ggccaacttt gtgtccttcg 180tagggcaggc cggaggcggc ggcccggcgg gtcagcagct gccccagctg cctcagtcat 240cgcagcttca gcagcaacag cagcagcagc aacagcaaca gcagcctcag ccgccgcagc 300cgcctttccc ggcgggtggg cctccggccc ggcggggagg agcgggggct ggtgggggct 360ggaagctggc ggaggaagag tcctgcaggg aggacgtgac ccgcgtgtgc cctaagcaca 420cctggagcaa caacctggcg gtgctcgagt gcctgcagga tgtgagggag cctgaaaatg 480aaatttcttc agactgcaat catttgttgt ggaattataa gctgaaccta actacagatc 540ccaaatttga atctgtggcc agagaggttt gcaaatctac tataacagag attaaagaat 600gtgctgatga accggttgga aaaggttaca tggtttcctg cttggtggat caccgaggca 660acatcactga gtatcagtgt caccagtaca ttaccaagat gacggccatc atttttagtg 720attaccgttt aatctgtggc ttcatggatg actgcaaaaa tgacatcaac attctgaaat 780gtggcagtat tcggcttgga gaaaaggatg cacattcaca aggtgaggtg gtatcatgct 840tggagaaagg cctggtgaaa gaagcagaag aaagagaacc caagattcaa gtttctgaac 900tctgcaagaa agccattctc cgggtggctg agctgtcatc ggatgacttt cacttagacc 960ggcatttata ttttgcttgc cgagatgatc gggagcgttt ttgtgaaaat acacaagctg 1020gtgagggcag agtgtataag tgcctcttta accataaatt tgaagaatcc atgagtgaaa 1080agtgtcgaga agcacttaca acccgccaaa agctgattgc ccaggattat aaagtcagtt 1140attcattggc caaatcctgt aaaagtgact tgaagaaata ccggtgcaat gtggaaaacc 1200ttccgcgatc gcgtgaagcc aggctctcct acttgttaat gtgcctggag tcagctgtac 1260acagagggcg acaagtcagc agtgagtgcc agggggagat gctggattac cgacgcatgt 1320tgatggaaga cttttctctg agccctgaga tcatcctaag ctgtcggggg gagattgaac 1380accattgttc cggattacat cgaaaagggc ggaccctaca ctgtctgatg aaagtagttc 1440gaggggagaa ggggaacctt ggaatgaact gccagcaggc gcttcaaaca ctgattcagg 1500agactgaccc tggtgcagat taccgcattg atcgagcttt gaatgaagct tgtgaatctg 1560taatccagac agcctgcaaa catataagat ctggagaccc aatgatcttg tcgtgcctga 1620tggaacattt atacacagag aagatggtag aagactgtga acaccgtctc ttagagctgc 1680agtatttcat ctcccgggat tggaagctgg accctgtcct gtaccgcaag tgccagggag 1740acgcttctcg tctttgccac acccacggtt ggaatgagac cagtgaattt atgcctcagg 1800gagctgtgtt ctcttgttta tacagacacg cctaccgcac tgaggaacag ggaaggaggc 1860tctcacggga gtgccgagct gaagtccaaa ggatcctaca ccagcgtgcc atggatgtca 1920agctggatcc tgccctccag gataagtgcc tgattgatct gggaaaatgg tgcagtgaga 1980aaacagagac tggacaggag ctggagtgcc ttcaggacca tctggatgac ttggtggtgg 2040agtgtagaga tatagttggc aacctcactg agttagaatc agaggatatt caaatagaag 2100ccttgctgat gagagcctgt gagcccataa ttcagaactt ctgccacgat gtggcagata 2160accagataga ctctggggac ctgatggagt gtctgataca gaacaaacac cagaaggaca 2220tgaacgagaa gtgtgccatc ggagttaccc acttccagct ggtgcagatg aaggattttc 2280ggttttctta caagtttaaa atggcctgca aggaggacgt gttgaagctt tgcccaaaca 2340taaaaaagaa ggtggacgtg gtgatctgcc tgagcacgac cgtgcgcaat gacactctgc 2400aggaagccaa ggagcacagg gtgtccctga agtgccgcag gcagctccgt gtggaggagc 2460tggagatgac ggaggacatc cgcttggagc cagatctata cgaagcctgc aagagtgaca 2520tcaaaaactt ctgttccgct gtgcaatatg gcaacgctca gattatcgaa tgtctgaaag 2580aaaacaagaa gcagctaagc acccgctgcc accaaaaagt atttaagctg caggagacag 2640agatgatgga cccagagcta gactacaccc tcatgagggt ctgcaagcag atgataaaga 2700ggttctgtcc ggaagcagat tctaaaacca tgttgcagtg cttgaagcaa aataaaaaca 2760gtgaattgat ggatcccaaa tgcaaacaga tgataaccaa gcgccagatc acccagaaca 2820cagattaccg cttaaacccc atgttaagaa aagcctgtaa agctgacatt cctaaattct 2880gtcacggtat cctgactaag gccaaggatg attcagaatt agaaggacaa gtcatctctt 2940gcctgaagct gagatatgct gaccagcgcc tgtcttcaga ctgtgaagac cagatccgaa 3000tcattatcca ggagtccgcc ctggactacc gcctggatcc tcagctccag ctgcactgct 3060cagacgagat ctccagtcta tgtgctgaag aagcagcagc ccaagagcag acaggtcagg 3120tggaggagtg cctcaaggtc aacctgctca agatcaaaac agaattgtgt aaaaaggaag 3180tgctaaacat gctgaaggaa agcaaagcag acatctttgt tgacccggta cttcatactg 3240cttgtgccct ggacattaaa caccactgcg cagccatcac ccctggccgc gggcgtcaaa 3300tgtcctgtct catggaagca

ctggaggata agcgggtgag gttacagccc gagtgcaaaa 3360agcgcctcaa tgaccggatt gagatgtgga gttacgcagc aaaggtggcc ccagcagatg 3420gcttctctga tcttgccatg caagtaatga cgtctccatc taagaactac attctctctg 3480tgatcagtgg gagcatctgt atattgttcc tgattggcct gatgtgtgga cggatcacca 3540agcgagtgac acgagagctc aaggacaggt agagccacct tgaccaccaa aggaactacc 3600tatccagtgc ccagtttgta cagccctctt gtatagcatc cccactcacc tcgctcttct 3660cagaagtgac accaaccccg tgttagagca ttagcagatg tccactgcgt tgtcccatcc 3720agcctccact cgtgtccatg gtgtcctcct cctcctcacc gtgcagcagc agcagctggt 3780cgctggggtt actgcctttg tttggcaaac ttgggtttac ctgcctgtag acaagtctct 3840ctcataccaa cagaacttcc ggtacttcca gaaccaactc acctgacctg caactcaaag 3900gcttttttaa gaaaaccacc aaaaaaaaaa atttttttaa agaaaaaaat gtatatagta 3960acgcatctcc tccaggcttg atttgggcaa tggggttatg tctttcatat gactgtgtaa 4020aacaaagaca ggacttggag gggaagcaca ccacccagtg tgccatgact gaggtgtctc 4080gttcatctct cagaagcacc ttggggcctc gccagggccg tggtcttcac cgaggcgtgg 4140gtgggcagcc gttccccagg ctgtgtgggg tcctgctttc ttctgctgag acagtgacgc 4200tttccagttt ccaccctaat cagccactgc tggtcacagc cccacagcca tgggtatttc 4260tgtggtctcc tcgcttcatt gaagcaaagc atgagccttc ctagacaagg gcagctgggg 4320aggggaaggg accggaagtt tgtgaagttg aacagtccat ccatctgcac tgagaggctg 4380gatcctgagt cccggggcag caggatccca ggaaccttcc tcctccaggg cagcacagga 4440ctcagccatg tctggaccgg ccctgctgag gctacagtca ctctggaagc tctgcgcttc 4500atcaggaggc aggactgtgg cgggaggggt ccttgaagat gggtgtgggg agcagtgggt 4560caggaagtgg gagccagagg tttgactcac tttgctttat ttttcaggct acaatacagg 4620tcagagacaa tggcttataa aggtttagtg tggtctcagg atgtgacagg cagtccagcc 4680tgacctttct gcacactcca gacaaacttc ccagacaagc tcctttgtgc ctctacgtgg 4740agagggtgtg gaaagttatc acattaaaag atggaggatt tgctctgttt tttttctttc 4800tgtccatttg ctgcgtgtac ccactctagt aggcattggc taaatgttgt attttggcga 4860ttcatcaacc tttgcagaat atgggcttta tagaagcaat attcttggcc atcccgcctc 4920attcctccag tgtggagatg acaagtctgg gtgtgagagg gaggggtccg ggcatcatgg 4980ttcagcgtgg cactcctttg gttgagtttg gggcatgaga tcacagtggc tgcacaagag 5040agcagtgtgt acagtaggag agacatttat gtaatatata ttttattaac ctgttagatg 5100tccacaaagt attataaatc acgtgcctaa aactgtccat gtagaccaag gcctgccctc 5160ggcgcccccc actcttgcct ctgctctgca c 5191375191DNAHomo sapiens 37ggcgagtgcg tcgagctcgc cgcggactca agatggcggc gtgtggacgt gtacggagga 60tgttccgctt gtcggcggcg ctgcatctgc tgctgctatt cgcggccggg gccgagaaac 120tccccggcca gggcgtccac agccagggcc agggtcccgg ggccaacttt gtgtccttcg 180tagggcaggc cggaggcggc ggcccggcgg gtcagcagct gccccagctg cctcagtcat 240cgcagcttca gcagcaacag cagcagcagc aacagcaaca gcagcctcag ccgccgcagc 300cgcctttccc ggcgggtggg cctccggccc ggcggggagg agcgggggct ggtgggggct 360ggaagctggc ggaggaagag tcctgcaggg aggacgtgac ccgcgtgtgc cctaagcaca 420cctggagcaa caacctggcg gtgctcgagt gcctgcagga tgtgagggag cctgaaaatg 480aaatttcttc agactgcaat catttgttgt ggaattataa gctgaaccta actacagatc 540ccaaatttga atctgtggcc agagaggttt gcaaatctac tataacagag attaaagaat 600gtgctgatga accggttgga aaaggttaca tggtttcctg cttggtggat caccgaggca 660acatcactga gtatcagtgt caccagtaca ttaccaagat gacggccatc atttttagtg 720attaccgttt aatctgtggc ttcatggatg actgcaaaaa tgacatcaac attctgaaat 780gtggcagtat tcggcttgga gaaaaggatg cacattcaca aggtgaggtg gtatcatgct 840tggagaaagg cctggtgaaa gaagcagaag aaagagaacc caagattcaa gtttctgaac 900tctgcaagaa agccattctc cgggtggctg agctgtcatc ggatgacttt cacttagacc 960ggcatttata ttttgcttgc cgagatgatc gggagcgttt ttgtgaaaat acacaagctg 1020gtgagggcag agtgtataag tgcctcttta accataaatt tgaagaatcc atgagtgaaa 1080agtgtcgaga agcacttaca acccgccaaa agctgattgc ccaggattat aaagtcagtt 1140attcattggc caaatcctgt aaaagtgact tgaagaaata ccggtgcaat gtggaaaacc 1200ttccgcgatc gcgtgaagcc aggctctcct acttgttaat gtgcctggag tcagctgtac 1260acagagggcg acaagtcagc agtgagtgcc agggggagat gctggattac cgacgcatgt 1320tgatggaaga cttttctctg agccctgaga tcatcctaag ctgtcggggg gagattgaac 1380accattgttc cggattacat cgaaaagggc ggaccctaca ctgtctgatg aaagtagttc 1440gaggggagaa ggggaacctt ggaatgaact gccagcaggc gcttcaaaca ctgattcagg 1500agactgaccc tggtgcagat taccgcattg atcgagcttt gaatgaagct tgtgaatctg 1560taatccagac agcctgcaaa catataagat ctggagaccc aatgatcttg tcgtgcctga 1620tggaacattt atacacagag aagatggtag aagactgtga acaccgtctc ttagagctgc 1680agtatttcat ctcccgggat tggaagctgg accctgtcct gtaccgcaag tgccagggag 1740acgcttctcg tctttgccac acccacggtt ggaatgagac cagtgaattt atgcctcagg 1800gagctgtgtt ctcttgttta tacagacacg cctaccgcac tgaggaacag ggaaggaggc 1860tctcacggga gtgccgagct gaagtccaaa ggatcctaca ccagcgtgcc atggatgtca 1920agctggatcc tgccctccag gataagtgcc tgattgatct gggaaaatgg tgcagtgaga 1980aaacagagac tggacaggag ctggagtgcc ttcaggacca tctggatgac ttggtggtgg 2040agtgtagaga tatagttggc aacctcactg agttagaatc agaggatatt caaatagaag 2100ccttgctgat gagagcctgt gagcccataa ttcagaactt ctgccacgat gtggcagata 2160accagataga ctctggggac ctgatggagt gtctgataca gaacaaacac cagaaggaca 2220tgaacgagaa gtgtgccatc ggagttaccc acttccagct ggtgcagatg aaggattttc 2280ggttttctta caagtttaaa atggcctgca aggaggacgt gttgaagctt tgcccaaaca 2340taaaaaagaa ggtggacgtg gtgatctgcc tgagcacgac cgtgcgcaat gacactctgc 2400aggaagccaa ggagcacagg gtgtccctga agtgccgcag gcagctccgt gtggaggagc 2460tggagatgac ggaggacatc cgcttggagc cagatctata cgaagcctgc aagagtgaca 2520tcaaaaactt ctgttccgct gtgcaatatg gcaacgctca gattatcgaa tgtctgaaag 2580aaaacaagaa gcagctaagc acccgctgcc accaaaaagt atttaagctg caggagacag 2640agatgatgga cccagagcta gactacaccc tcatgagggt ctgcaagcag atgataaaga 2700ggttctgtcc ggaagcagat tctaaaacca tgttgcagtg cttgaagcaa aataaaaaca 2760gtgaattgat ggatcccaaa tgcaaacaga tgataaccaa gcgccagatc acccagaaca 2820cagattaccg cttaaacccc atgttaagaa aagcctgtaa agctgacatt cctaaattct 2880gtcacggtat cctgactaag gccaaggatg attcagaatt agaaggacaa gtcatctctt 2940gcctgaagct gagatatgct gaccagcgcc tgtcttcaga ctgtgaagac cagatccgaa 3000tcattatcca ggagtccgcc ctggactacc gcctggatcc tcagctccag ctgcactgct 3060cagacgagat ctccagtcta tgtgctgaag aagcagcagc ccaagagcag acaggtcagg 3120tggaggagtg cctcaaggtc aacctgctca agatcaaaac agaattgtgt aaaaaggaag 3180tgctaaacat gctgaaggaa agcaaagcag acatctttgt tgacccggta cttcatactg 3240cttgtgccct ggacattaaa caccactgcg cagccatcac ccctggccgc gggcgtcaaa 3300tgtcctgtct catggaagca ctggaggata agcgggtgag gttacagccc gagtgcaaaa 3360agcgcctcaa tgaccggatt gagatgtgga gttacgcagc aaaggtggcc ccagcagatg 3420gcttctctga tcttgccatg caagtaatga cgtctccatc taagaactac attctctctg 3480tgatcagtgg gagcatctgt atattgttcc tgattggcct gatgtgtgga cggatcacca 3540agcgagtgac acgagagctc aaggacaggt agagccacct tgaccaccaa aggaactacc 3600tatccagtgc ccagtttgta cagccctctt gtatagcatc cccactcacc tcgctcttct 3660cagaagtgac accaaccccg tgttagagca ttagcagatg tccactgcgt tgtcccatcc 3720agcctccact cgtgtccatg gtgtcctcct cctcctcacc gtgcagcagc agcagctggt 3780cgctggggtt actgcctttg tttggcaaac ttgggtttac ctgcctgtag acaagtctct 3840ctcataccaa cagaacttcc ggtacttcca gaaccaactc acctgacctg caactcaaag 3900gcttttttaa gaaaaccacc aaaaaaaaaa atttttttaa agaaaaaaat gtatatagta 3960acgcatctcc tccaggcttg atttgggcaa tggggttatg tctttcatat gactgtgtaa 4020aacaaagaca ggacttggag gggaagcaca ccacccagtg tgccatgact gaggtgtctc 4080gttcatctct cagaagcacc ttggggcctc gccagggccg tggtcttcac cgaggcgtgg 4140gtgggcagcc gttccccagg ctgtgtgggg tcctgctttc ttctgctgag acagtgacgc 4200tttccagttt ccaccctaat cagccactgc tggtcacagc cccacagcca tgggtatttc 4260tgtggtctcc tcgcttcatt gaagcaaagc atgagccttc ctagacaagg gcagctgggg 4320aggggaaggg accggaagtt tgtgaagttg aacagtccat ccatctgcac tgagaggctg 4380gatcctgagt cccggggcag caggatccca ggaaccttcc tcctccaggg cagcacagga 4440ctcagccatg tctggaccgg ccctgctgag gctacagtca ctctggaagc tctgcgcttc 4500atcaggaggc aggactgtgg cgggaggggt ccttgaagat gggtgtgggg agcagtgggt 4560caggaagtgg gagccagagg tttgactcac tttgctttat ttttcaggct acaatacagg 4620tcagagacaa tggcttataa aggtttagtg tggtctcagg atgtgacagg cagtccagcc 4680tgacctttct gcacactcca gacaaacttc ccagacaagc tcctttgtgc ctctacgtgg 4740agagggtgtg gaaagttatc acattaaaag atggaggatt tgctctgttt tttttctttc 4800tgtccatttg ctgcgtgtac ccactctagt aggcattggc taaatgttgt attttggcga 4860ttcatcaacc tttgcagaat atgggcttta tagaagcaat attcttggcc atcccgcctc 4920attcctccag tgtggagatg acaagtctgg gtgtgagagg gaggggtccg ggcatcatgg 4980ttcagcgtgg cactcctttg gttgagtttg gggcatgaga tcacagtggc tgcacaagag 5040agcagtgtgt acagtaggag agacatttat gtaatatata ttttattaac ctgttagatg 5100tccacaaagt attataaatc acgtgcctaa aactgtccat gtagaccaag gcctgccctc 5160ggcgcccccc actcttgcct ctgctctgca c 5191386437DNAHomo sapiens 38agtcattggt ctctggtggg accgggcgct gcccccttcc cctgtctcct gggtctctgg 60aggagcccag gaaggaggct ccgctggttc cgctgggtca ggcgctgacg ggaccgggct 120gcggcaatcg ttagcgggtc atgtcggccg cccagggctg ggacaggaac cgccggaggg 180gaggaggcgc cgccggcgct ggtggcggag gtagcggggc cggcgggggc agtgggggca 240gcgggggtcg ggggactggc cagctcaacc gcttcgtgca actctccggg cggccgcacc 300tgccaggtaa gaagaaaata cgatgggacc cagttaggag gcgcttcatt cagtcctgtc 360ccatcataag gatccctaac aggtttttga gaggccacag acctccacca gcacgaagtg 420gacatcgttg tgtggcagat aataccaacc tatatgtgtt tggaggttat aacccagatt 480atgatgaatc gggagggcct gataatgaag actatcctct cttcagggaa ctctggaggt 540atcattttgc tacaggagta tggcaccaga tgggcacaga tggctacatg ccccgggaat 600tggcatctat gtcacttgtg ctgcatggaa acaacctgtt agtatttgga ggtacgggca 660tcccatttgg agagagcaac ggcaatgacg tccatgtgtg taatgtgaag tataagagat 720gggctttgct cagctgtcgg gggaagaaac ccagtcgtat atatggacag gctatggcca 780tcatcaatgg ctccctttat gtctttggag gtacaaccgg ctatatttac agcacagacc 840tgcacaagtt agatctcaat accagagagt ggacacaact gaaaccaaac aacctatcct 900gtgatctacc agaagagaga taccgacatg aaattgcaca tgacgggcag aggatttaca 960tcttgggagg tggtacttcc tggacagcat attccttaaa caagatccat gcatacaacc 1020ttgaaacgaa tgcctgggag gaaattgcaa caaaacccca tgaaaaaata ggctttcctg 1080cagcccgaag gtgtcacagt tgtgttcaaa taaaaaatga tgtatttatt tgtgggggct 1140ataatggaga ggtgatcctg ggagatatct ggaagttgaa tctgcagact ttccaatggg 1200tgaagctccc agctaccatg ccagagccag tttattttca ctgtgcagct gttacaccag 1260ctggttgcat gtacattcat ggaggagtgg tgaacatcca tgaaaacaaa cggactgggt 1320cattgtttaa gatctggctg gtggtaccta gcctgctgga actggcatgg gagaagctgc 1380ttgcggcctt ccctaacctt gcaaacctct cccgaacaca acttctgcac cttggactca 1440cacagggact catcgaacgc ttgaaatgag gatttctgga ctgttcattg atactggaaa 1500tgttaattta aagagactcc tttatttatg ggcagtgtag aatgtgctac aaagaggatt 1560ggttaccctg atcaaggcct tatttagaaa atacatcaga tgcctttctg taaattggtt 1620tttcagttta tggacatctc actttcccac gtgcttcctt ctttgcttct gttcctcctg 1680acccattaca tgcacatgta ctcacatact ccctcttcct tctcgatgga gttaagggaa 1740agcctgaaag taccttaata atgttattaa tcaagacaga ttccttttta aaggaattct 1800gaatagttcc atgtcataca atattctaga aattaaaaca tcatcaacat aaagaaaaat 1860gaaattaaaa aatttttaca tctagcaaca gcaacaacca caaatttagg ggaagctgag 1920aaggctaacc ttgggaatct tgcaggttat acttaaacct agatgtttaa cttagtgttt 1980tcaagatgtg tctaactgag tagtagctgg gtctgatggc agcagtgctt gccatcttgt 2040tgcacagata actcaaacct accctttggc tttgaaggaa ggttaagcag cccagcaact 2100cttggttagt gatttctttc tcatcctcat ggtgccagca gtggttagag ttggtttgtc 2160aaaagactta cgtgtgtgtc gtggtcgtgc tctttgttgt tgctcttaga aattatggca 2220ccaagaatgt ttcaaacgga aaaacttgtg gtggccaaag ttcttcattc tggcagtttt 2280gaaactctct tatgcttatt aatggtttta aatatctctt tgacttcttc atggggaatt 2340gtagacccta agtatgtggt gtaaatgcca tgtaacatga acacaagctc ccgagggagg 2400ccagagaaga gccaggcaga gaaaacctgc atcctctggg cttgttaact tggcttccac 2460tcgggctgtg gtctttggct atcatcttgg ccatttcctt ttgagaactt gtttcttttc 2520taatctctgg gccaggtacc tgccattttc tcaggcagtt ggtccttgat ttttccctta 2580gcttgttgcc ttcttttccg tctgctttaa tgtgcatggt gctgtgaata attgtctagt 2640aattggatac aaggtcttgg gggtaaagcc acaggtcatc cttcctgaag aaccaagtat 2700catttaaaaa ctagcatgag gaaggaatga aactgagtag cattcatttt gtgtgtgtga 2760aattttagtt ctggtttgtt tgatttgttt tttttttaat tctaaaaaga atgacataaa 2820ttttcactcg ctttgccatc tggctgctag gggagctgag caagaggctc accatgcgca 2880tgtgtaagcc gcaggtgtac tcaaggtgct gaaggcgtgc aaggggcagc gctggtcctc 2940ccggggccaa ctcacagcag gagactcgca tgggagagtt ggaacacatc tttcctttaa 3000gtgcctcttt tttcacctag cttttaaagt tattctttgt ccttcatctc agaagggatc 3060tctttagctt atgtgtggat ttaaaatgac ctttgagcta cggttaaaaa gctaccatct 3120ggtgttcagt tctgggaaag agaaaaccgt agcctccaga catgctcctg atttctaggc 3180cttatcatac catcccctct gtgatgggtt gagttcatgg agcctgtatt ctgggaagtc 3240ttataataac cacgcacctg tgaacgtggg tcctttctgg ggagtgagga atgtgggaga 3300gaggcagaaa aaggagcagc tcctctaggg gcccatcctc ccacatcttg ccattaccag 3360tctgtgtagc acttaacctc ctgccaccac tgccaggctt gctcctccgt tctctcccag 3420agcaagtcag tctgagcagc tccattagtc caaaacagag ctttgctgca tgacttcagc 3480ctggcctctg gatatttggt ggaaatatat tctaaattga acaagccagg ctgtccaggg 3540tggcaagagg atttttgacc tggatttata cagggaccaa agactgaatg ctcagcctct 3600gtgcttagac tttcatggtc cttaggatag aagtgagtct ctagccctgc tacaccagag 3660agctgaagag agatgtggtc tggttccatc catacttgct ggcatccttt gttaagcctt 3720ctgagggcag tcttctttga ggtagacctt ggaggcctga catcgaagac ctgtgtgttt 3780tattttcata aaagtatata tccttggtct aaagtgtctt cttttaatat aacactagta 3840aaaatgacat ggtatgacca gcactgagtg ctatagaacc acacatgtgt acatgttctg 3900gatgccaaat gagactgtgt gtaaatgact aagtgtagat aactagaaat tagatagggg 3960tcatcaggcg tttcggtata cctataacca gcactcggaa ttcctgacac tgtttacttg 4020atttaggaaa gtttatgcct gctgcttctc tgcctctttg aggtactccc agccgtctta 4080ctacagtcct gtaaatttaa gtgcaatata tagaaacata tggatatata cagattatat 4140atagggtgta actataaagc aggtagacta cttttttgca tcttggggaa gtgagctcat 4200tactttaggt tcaaattatg ccaagaattt tagatgtgat cagctggctt aagccaactc 4260atgtcatgat aaagctggat tttcaagtcc atgttttctt actccaactc ttagagactc 4320attgttcctt aggtttgtta gagttgagat tttttttctc cctgtcatct ttgtactctc 4380tcatgtttgc atgtcttaca ttttgttgcc ggagaacaag gaagtccatc tgtaaggagt 4440ttcctaaacg gagaattaaa acctagtatt taacactaac cattctccta tgtatatact 4500aatttatctg ggaatgtaat actttattaa atgaagaaaa tgatgctttc ttcatttaat 4560attttccaca tcctggaaaa actataaact gacacagaat agattgaaat cttaactggg 4620gctaaacaaa accctttcca ttggcagaat ctcctttttt cagggccata atgacatgat 4680gtaaaaattt gctttaaacc attcatgccc ttaaatagct agattttaaa gcataataag 4740catattaaca tttttaagca aaagatacgt taacagtgac ctttggttat ccacagtagc 4800aagagtaaag cacagatcat tgaaatccat agataatcag tgaatcaact ttcctaccaa 4860acaatagatt catttacatt tctttttcct ccctatcctt tcctgtaagc acctgttttt 4920ccatggaatg gggttaatga gtaggtagaa aaggaaaagg aataatcagt aggagctgac 4980aaccagtgac catataagca gctgattgcc tgtaattagt caggctgaac aattagagtt 5040gaatgctgaa attaggaacc acaggtggta atcctgagta gatgtagctc ttcagcgtca 5100tctcctgccc tgagctccag gccatctctc taaccaccaa agaactctta gtacctacgg 5160gaaggaaaag ctgtgtgcga cacagaggaa actccattat ttgaacacat ttctttggct 5220cttgacaaat acttgctttt cctctaatct tgcaagagct atggctcttc tattttccaa 5280tcacacagct tggcatgtag gaaaggttga atgatcctct aagactgtgt tggtcttcgt 5340attctgtaaa acccattttt tttttgtggt cttacagatg tttagaaagt ggcacaggtt 5400actgaattgt ctacctgcca gcattctgat atagcacaaa aagctatttt cctttatttt 5460ttgtattatt ttttattttt ctggcattga gctctagggt ggatgagggt ttatggtcct 5520ctgatcataa gctccattct aaaaactggt cactgttagc tgaaattgct ttggttcccc 5580aaatgccttg gaactccaga cgcacccgca gggcctgagg taggcttcat agagttctag 5640gacttccgtg tgcgttgcca ccagatcctg cccagcaatg gcctttccct tctaaggtca 5700ttagattcag ccaaaagcga cctcttctct agtccggtgt tacgaacaga agttctgagt 5760tgtgctacaa aagtagttcc atctttttgg tgtaattttc atgtttttaa tttgaaaaaa 5820aaaaaaaaaa aaaacaactt tttataagtt ttttaagggc cctgcttagt cagtgtacag 5880ggtggagtca gaggcagttt tcagaaaaaa acaaaaaaca aaaaaaattt caccaagcgg 5940tagtaattgt tgttttacta gttatacatt tagaatataa aggaggcatc agaaaacaca 6000ctctctaaag ccacttcctt gtgcacagag tctgcacagg gagagcacag gcatctccct 6060ggaaaagcac ctgccaatga cgaatttcat ggaagaacct aggcaagaaa ggaagcctct 6120ttctgagaca cagtctctga gaggtgagcc tagctttgct cttcctacag ggtatgcttg 6180ggccatacac aatgctcgcc ttactttaaa gctattttgc cacagtcctg ttaaatagtg 6240tggacgtcct tttgcagtct ggtgtgcatg ccatatgatc aggacagctt ttccacttta 6300ctcggtttcc tacaagcaag taggaaatac agtgaattta ccctaaaatg tccaatctgt 6360atttatgtac cttgtcagtg ttttgctgtt ggttttctaa aacaatctga tcaataaatc 6420ttatccaaat caatttg 6437395191DNAHomo sapiens 39ggcgagtgcg tcgagctcgc cgcggactca agatggcggc gtgtggacgt gtacggagga 60tgttccgctt gtcggcggcg ctgcatctgc tgctgctatt cgcggccggg gccgagaaac 120tccccggcca gggcgtccac agccagggcc agggtcccgg ggccaacttt gtgtccttcg 180tagggcaggc cggaggcggc ggcccggcgg gtcagcagct gccccagctg cctcagtcat 240cgcagcttca gcagcaacag cagcagcagc aacagcaaca gcagcctcag ccgccgcagc 300cgcctttccc ggcgggtggg cctccggccc ggcggggagg agcgggggct ggtgggggct 360ggaagctggc ggaggaagag tcctgcaggg aggacgtgac ccgcgtgtgc cctaagcaca 420cctggagcaa caacctggcg gtgctcgagt gcctgcagga tgtgagggag cctgaaaatg 480aaatttcttc agactgcaat catttgttgt ggaattataa gctgaaccta actacagatc 540ccaaatttga atctgtggcc agagaggttt gcaaatctac tataacagag attaaagaat 600gtgctgatga accggttgga aaaggttaca tggtttcctg cttggtggat caccgaggca 660acatcactga gtatcagtgt caccagtaca ttaccaagat gacggccatc atttttagtg 720attaccgttt aatctgtggc ttcatggatg actgcaaaaa tgacatcaac attctgaaat 780gtggcagtat tcggcttgga gaaaaggatg cacattcaca aggtgaggtg gtatcatgct 840tggagaaagg cctggtgaaa gaagcagaag aaagagaacc caagattcaa gtttctgaac 900tctgcaagaa agccattctc cgggtggctg agctgtcatc ggatgacttt cacttagacc 960ggcatttata ttttgcttgc cgagatgatc gggagcgttt ttgtgaaaat acacaagctg 1020gtgagggcag agtgtataag tgcctcttta accataaatt tgaagaatcc atgagtgaaa 1080agtgtcgaga agcacttaca acccgccaaa agctgattgc ccaggattat aaagtcagtt 1140attcattggc caaatcctgt aaaagtgact tgaagaaata ccggtgcaat gtggaaaacc 1200ttccgcgatc gcgtgaagcc aggctctcct acttgttaat gtgcctggag tcagctgtac 1260acagagggcg acaagtcagc agtgagtgcc agggggagat gctggattac cgacgcatgt 1320tgatggaaga cttttctctg agccctgaga tcatcctaag ctgtcggggg gagattgaac 1380accattgttc cggattacat

cgaaaagggc ggaccctaca ctgtctgatg aaagtagttc 1440gaggggagaa ggggaacctt ggaatgaact gccagcaggc gcttcaaaca ctgattcagg 1500agactgaccc tggtgcagat taccgcattg atcgagcttt gaatgaagct tgtgaatctg 1560taatccagac agcctgcaaa catataagat ctggagaccc aatgatcttg tcgtgcctga 1620tggaacattt atacacagag aagatggtag aagactgtga acaccgtctc ttagagctgc 1680agtatttcat ctcccgggat tggaagctgg accctgtcct gtaccgcaag tgccagggag 1740acgcttctcg tctttgccac acccacggtt ggaatgagac cagtgaattt atgcctcagg 1800gagctgtgtt ctcttgttta tacagacacg cctaccgcac tgaggaacag ggaaggaggc 1860tctcacggga gtgccgagct gaagtccaaa ggatcctaca ccagcgtgcc atggatgtca 1920agctggatcc tgccctccag gataagtgcc tgattgatct gggaaaatgg tgcagtgaga 1980aaacagagac tggacaggag ctggagtgcc ttcaggacca tctggatgac ttggtggtgg 2040agtgtagaga tatagttggc aacctcactg agttagaatc agaggatatt caaatagaag 2100ccttgctgat gagagcctgt gagcccataa ttcagaactt ctgccacgat gtggcagata 2160accagataga ctctggggac ctgatggagt gtctgataca gaacaaacac cagaaggaca 2220tgaacgagaa gtgtgccatc ggagttaccc acttccagct ggtgcagatg aaggattttc 2280ggttttctta caagtttaaa atggcctgca aggaggacgt gttgaagctt tgcccaaaca 2340taaaaaagaa ggtggacgtg gtgatctgcc tgagcacgac cgtgcgcaat gacactctgc 2400aggaagccaa ggagcacagg gtgtccctga agtgccgcag gcagctccgt gtggaggagc 2460tggagatgac ggaggacatc cgcttggagc cagatctata cgaagcctgc aagagtgaca 2520tcaaaaactt ctgttccgct gtgcaatatg gcaacgctca gattatcgaa tgtctgaaag 2580aaaacaagaa gcagctaagc acccgctgcc accaaaaagt atttaagctg caggagacag 2640agatgatgga cccagagcta gactacaccc tcatgagggt ctgcaagcag atgataaaga 2700ggttctgtcc ggaagcagat tctaaaacca tgttgcagtg cttgaagcaa aataaaaaca 2760gtgaattgat ggatcccaaa tgcaaacaga tgataaccaa gcgccagatc acccagaaca 2820cagattaccg cttaaacccc atgttaagaa aagcctgtaa agctgacatt cctaaattct 2880gtcacggtat cctgactaag gccaaggatg attcagaatt agaaggacaa gtcatctctt 2940gcctgaagct gagatatgct gaccagcgcc tgtcttcaga ctgtgaagac cagatccgaa 3000tcattatcca ggagtccgcc ctggactacc gcctggatcc tcagctccag ctgcactgct 3060cagacgagat ctccagtcta tgtgctgaag aagcagcagc ccaagagcag acaggtcagg 3120tggaggagtg cctcaaggtc aacctgctca agatcaaaac agaattgtgt aaaaaggaag 3180tgctaaacat gctgaaggaa agcaaagcag acatctttgt tgacccggta cttcatactg 3240cttgtgccct ggacattaaa caccactgcg cagccatcac ccctggccgc gggcgtcaaa 3300tgtcctgtct catggaagca ctggaggata agcgggtgag gttacagccc gagtgcaaaa 3360agcgcctcaa tgaccggatt gagatgtgga gttacgcagc aaaggtggcc ccagcagatg 3420gcttctctga tcttgccatg caagtaatga cgtctccatc taagaactac attctctctg 3480tgatcagtgg gagcatctgt atattgttcc tgattggcct gatgtgtgga cggatcacca 3540agcgagtgac acgagagctc aaggacaggt agagccacct tgaccaccaa aggaactacc 3600tatccagtgc ccagtttgta cagccctctt gtatagcatc cccactcacc tcgctcttct 3660cagaagtgac accaaccccg tgttagagca ttagcagatg tccactgcgt tgtcccatcc 3720agcctccact cgtgtccatg gtgtcctcct cctcctcacc gtgcagcagc agcagctggt 3780cgctggggtt actgcctttg tttggcaaac ttgggtttac ctgcctgtag acaagtctct 3840ctcataccaa cagaacttcc ggtacttcca gaaccaactc acctgacctg caactcaaag 3900gcttttttaa gaaaaccacc aaaaaaaaaa atttttttaa agaaaaaaat gtatatagta 3960acgcatctcc tccaggcttg atttgggcaa tggggttatg tctttcatat gactgtgtaa 4020aacaaagaca ggacttggag gggaagcaca ccacccagtg tgccatgact gaggtgtctc 4080gttcatctct cagaagcacc ttggggcctc gccagggccg tggtcttcac cgaggcgtgg 4140gtgggcagcc gttccccagg ctgtgtgggg tcctgctttc ttctgctgag acagtgacgc 4200tttccagttt ccaccctaat cagccactgc tggtcacagc cccacagcca tgggtatttc 4260tgtggtctcc tcgcttcatt gaagcaaagc atgagccttc ctagacaagg gcagctgggg 4320aggggaaggg accggaagtt tgtgaagttg aacagtccat ccatctgcac tgagaggctg 4380gatcctgagt cccggggcag caggatccca ggaaccttcc tcctccaggg cagcacagga 4440ctcagccatg tctggaccgg ccctgctgag gctacagtca ctctggaagc tctgcgcttc 4500atcaggaggc aggactgtgg cgggaggggt ccttgaagat gggtgtgggg agcagtgggt 4560caggaagtgg gagccagagg tttgactcac tttgctttat ttttcaggct acaatacagg 4620tcagagacaa tggcttataa aggtttagtg tggtctcagg atgtgacagg cagtccagcc 4680tgacctttct gcacactcca gacaaacttc ccagacaagc tcctttgtgc ctctacgtgg 4740agagggtgtg gaaagttatc acattaaaag atggaggatt tgctctgttt tttttctttc 4800tgtccatttg ctgcgtgtac ccactctagt aggcattggc taaatgttgt attttggcga 4860ttcatcaacc tttgcagaat atgggcttta tagaagcaat attcttggcc atcccgcctc 4920attcctccag tgtggagatg acaagtctgg gtgtgagagg gaggggtccg ggcatcatgg 4980ttcagcgtgg cactcctttg gttgagtttg gggcatgaga tcacagtggc tgcacaagag 5040agcagtgtgt acagtaggag agacatttat gtaatatata ttttattaac ctgttagatg 5100tccacaaagt attataaatc acgtgcctaa aactgtccat gtagaccaag gcctgccctc 5160ggcgcccccc actcttgcct ctgctctgca c 5191406090DNAHomo sapiens 40cagctcaacc gcttcgtgca actctccggg cggccgcacc tgccaggcca cagacctcca 60ccagcacgaa gtggacatcg ttgtgtggca gataatacca acctatatgt gtttggaggt 120tataacccag attatgatga atcgggaggg cctgataatg aagactatcc tctcttcagg 180gaactctgga ggtatcattt tgctacagga gtatggcacc agatgggcac agatggctac 240atgccccggg aattggcatc tatgtcactt gtgctgcatg gaaacaacct gttagtattt 300ggaggtacgg gcatcccatt tggagagagc aacggcaatg acgtccatgt gtgtaatgtg 360aagtataaga gatgggcttt gctcagctgt cgggggaaga aacccagtcg tatatatgga 420caggctatgg ccatcatcaa tggctccctt tatgtctttg gaggtacaac cggctatatt 480tacagcacag acctgcacaa gttagatctc aataccagag agtggacaca actgaaacca 540aacaacctat cctgtgatct accagaagag agataccgac atgaaattgc acatgacggg 600cagaggattt acatcttggg aggtggtact tcctggacag catattcctt aaacaagatc 660catgcataca accttgaaac gaatgcctgg gaggaaattg caacaaaacc ccatgaaaaa 720ataggctttc ctgcagcccg aaggtgtcac agttgtgttc aaataaaaaa tgatgtattt 780atttgtgggg gctataatgg agaggtgatc ctgggagata tctggaagtt gaatctgcag 840actttccaat gggtgaagct cccagctacc atgccagagc cagtttattt tcactgtgca 900gctgttacac cagctggttg catgtacatt catggaggag tggtgaacat ccatgaaaac 960aaacggactg ggtcattgtt taagatctgg ctggtggtac ctagcctgct ggaactggca 1020tgggagaagc tgcttgcggc cttccctaac cttgcaaacc tctcccgaac acaacttctg 1080caccttggac tcacacaggg actcatcgaa cgcttgaaat gaggatttct ggactgttca 1140ttgatactgg aaatgttaat ttaaagagac tcctttattt atgggcagtg tagaatgtgc 1200tacaaagagg attggttacc ctgatcaagg ccttatttag aaaatacatc agatgccttt 1260ctgtaaattg gtttttcagt ttatggacat ctcactttcc cacgtgcttc cttctttgct 1320tctgttcctc ctgacccatt acatgcacat gtactcacat actccctctt ccttctcgat 1380ggagttaagg gaaagcctga aagtacctta ataatgttat taatcaagac agattccttt 1440ttaaaggaat tctgaatagt tccatgtcat acaatattct agaaattaaa acatcatcaa 1500cataaagaaa aatgaaatta aaaaattttt acatctagca acagcaacaa ccacaaattt 1560aggggaagct gagaaggcta accttgggaa tcttgcaggt tatacttaaa cctagatgtt 1620taacttagtg ttttcaagat gtgtctaact gagtagtagc tgggtctgat ggcagcagtg 1680cttgccatct tgttgcacag ataactcaaa cctacccttt ggctttgaag gaaggttaag 1740cagcccagca actcttggtt agtgatttct ttctcatcct catggtgcca gcagtggtta 1800gagttggttt gtcaaaagac ttacgtgtgt gtcgtggtcg tgctctttgt tgttgctctt 1860agaaattatg gcaccaagaa tgtttcaaac ggaaaaactt gtggtggcca aagttcttca 1920ttctggcagt tttgaaactc tcttatgctt attaatggtt ttaaatatct ctttgacttc 1980ttcatgggga attgtagacc ctaagtatgt ggtgtaaatg ccatgtaaca tgaacacaag 2040ctcccgaggg aggccagaga agagccaggc agagaaaacc tgcatcctct gggcttgtta 2100acttggcttc cactcgggct gtggtctttg gctatcatct tggccatttc cttttgagaa 2160cttgtttctt ttctaatctc tgggccaggt acctgccatt ttctcaggca gttggtcctt 2220gatttttccc ttagcttgtt gccttctttt ccgtctgctt taatgtgcat ggtgctgtga 2280ataattgtct agtaattgga tacaaggtct tgggggtaaa gccacaggtc atccttcctg 2340aagaaccaag tatcatttaa aaactagcat gaggaaggaa tgaaactgag tagcattcat 2400tttgtgtgtg tgaaatttta gttctggttt gtttgatttg tttttttttt aattctaaaa 2460agaatgacat aaattttcac tcgctttgcc atctggctgc taggggagct gagcaagagg 2520ctcaccatgc gcatgtgtaa gccgcaggtg tactcaaggt gctgaaggcg tgcaaggggc 2580agcgctggtc ctcccggggc caactcacag caggagactc gcatgggaga gttggaacac 2640atctttcctt taagtgcctc ttttttcacc tagcttttaa agttattctt tgtccttcat 2700ctcagaaggg atctctttag cttatgtgtg gatttaaaat gacctttgag ctacggttaa 2760aaagctacca tctggtgttc agttctggga aagagaaaac cgtagcctcc agacatgctc 2820ctgatttcta ggccttatca taccatcccc tctgtgatgg gttgagttca tggagcctgt 2880attctgggaa gtcttataat aaccacgcac ctgtgaacgt gggtcctttc tggggagtga 2940ggaatgtggg agagaggcag aaaaaggagc agctcctcta ggggcccatc ctcccacatc 3000ttgccattac cagtctgtgt agcacttaac ctcctgccac cactgccagg cttgctcctc 3060cgttctctcc cagagcaagt cagtctgagc agctccatta gtccaaaaca gagctttgct 3120gcatgacttc agcctggcct ctggatattt ggtggaaata tattctaaat tgaacaagcc 3180aggctgtcca gggtggcaag aggatttttg acctggattt atacagggac caaagactga 3240atgctcagcc tctgtgctta gactttcatg gtccttagga tagaagtgag tctctagccc 3300tgctacacca gagagctgaa gagagatgtg gtctggttcc atccatactt gctggcatcc 3360tttgttaagc cttctgaggg cagtcttctt tgaggtagac cttggaggcc tgacatcgaa 3420gacctgtgtg ttttattttc ataaaagtat atatccttgg tctaaagtgt cttcttttaa 3480tataacacta gtaaaaatga catggtatga ccagcactga gtgctataga accacacatg 3540tgtacatgtt ctggatgcca aatgagactg tgtgtaaatg actaagtgta gataactaga 3600aattagatag gggtcatcag gcgtttcggt atacctataa ccagcactcg gaattcctga 3660cactgtttac ttgatttagg aaagtttatg cctgctgctt ctctgcctct ttgaggtact 3720cccagccgtc ttactacagt cctgtaaatt taagtgcaat atatagaaac atatggatat 3780atacagatta tatatagggt gtaactataa agcaggtaga ctactttttt gcatcttggg 3840gaagtgagct cattacttta ggttcaaatt atgccaagaa ttttagatgt gatcagctgg 3900cttaagccaa ctcatgtcat gataaagctg gattttcaag tccatgtttt cttactccaa 3960ctcttagaga ctcattgttc cttaggtttg ttagagttga gatttttttt ctccctgtca 4020tctttgtact ctctcatgtt tgcatgtctt acattttgtt gccggagaac aaggaagtcc 4080atctgtaagg agtttcctaa acggagaatt aaaacctagt atttaacact aaccattctc 4140ctatgtatat actaatttat ctgggaatgt aatactttat taaatgaaga aaatgatgct 4200ttcttcattt aatattttcc acatcctgga aaaactataa actgacacag aatagattga 4260aatcttaact ggggctaaac aaaacccttt ccattggcag aatctccttt tttcagggcc 4320ataatgacat gatgtaaaaa tttgctttaa accattcatg cccttaaata gctagatttt 4380aaagcataat aagcatatta acatttttaa gcaaaagata cgttaacagt gacctttggt 4440tatccacagt agcaagagta aagcacagat cattgaaatc catagataat cagtgaatca 4500actttcctac caaacaatag attcatttac atttcttttt cctccctatc ctttcctgta 4560agcacctgtt tttccatgga atggggttaa tgagtaggta gaaaaggaaa aggaataatc 4620agtaggagct gacaaccagt gaccatataa gcagctgatt gcctgtaatt agtcaggctg 4680aacaattaga gttgaatgct gaaattagga accacaggtg gtaatcctga gtagatgtag 4740ctcttcagcg tcatctcctg ccctgagctc caggccatct ctctaaccac caaagaactc 4800ttagtaccta cgggaaggaa aagctgtgtg cgacacagag gaaactccat tatttgaaca 4860catttctttg gctcttgaca aatacttgct tttcctctaa tcttgcaaga gctatggctc 4920ttctattttc caatcacaca gcttggcatg taggaaaggt tgaatgatcc tctaagactg 4980tgttggtctt cgtattctgt aaaacccatt ttttttttgt ggtcttacag atgtttagaa 5040agtggcacag gttactgaat tgtctacctg ccagcattct gatatagcac aaaaagctat 5100tttcctttat tttttgtatt attttttatt tttctggcat tgagctctag ggtggatgag 5160ggtttatggt cctctgatca taagctccat tctaaaaact ggtcactgtt agctgaaatt 5220gctttggttc cccaaatgcc ttggaactcc agacgcaccc gcagggcctg aggtaggctt 5280catagagttc taggacttcc gtgtgcgttg ccaccagatc ctgcccagca atggcctttc 5340ccttctaagg tcattagatt cagccaaaag cgacctcttc tctagtccgg tgttacgaac 5400agaagttctg agttgtgcta caaaagtagt tccatctttt tggtgtaatt ttcatgtttt 5460taatttgaaa aaaaaaaaaa aaaaaaacaa ctttttataa gttttttaag ggccctgctt 5520agtcagtgta cagggtggag tcagaggcag ttttcagaaa aaaacaaaaa acaaaaaaaa 5580tttcaccaag cggtagtaat tgttgtttta ctagttatac atttagaata taaaggaggc 5640atcagaaaac acactctcta aagccacttc cttgtgcaca gagtctgcac agggagagca 5700caggcatctc cctggaaaag cacctgccaa tgacgaattt catggaagaa cctaggcaag 5760aaaggaagcc tctttctgag acacagtctc tgagaggtga gcctagcttt gctcttccta 5820cagggtatgc ttgggccata cacaatgctc gccttacttt aaagctattt tgccacagtc 5880ctgttaaata gtgtggacgt ccttttgcag tctggtgtgc atgccatatg atcaggacag 5940cttttccact ttactcggtt tcctacaagc aagtaggaaa tacagtgaat ttaccctaaa 6000atgtccaatc tgtatttatg taccttgtca gtgttttgct gttggttttc taaaacaatc 6060tgatcaataa atcttatcca aatcaatttg 6090415753DNAHomo sapiens 41atcatggcgg atggccccag gtgtaagcgc agaaagcagg cgaacccgcg gcgcaataac 60gttacaaatt ataatactgt ggtagaaaca aattcagatt cagatgatga agacaaactg 120catattgtgg aagaagaaag tgttacagat gcagctgact gtgaaggtgt accagaggat 180gacctgccaa cagaccagac agtgttacca gggaggagca gtgaaagaga agggaatgct 240aagaactgct gggaggatga cagaaaggaa gggcaagaaa tcctggggcc tgaagctcag 300gcagatgaag caggatgtac agtaaaagat gatgaatgcg agtcagatgc agaaaatgag 360caaaaccatg atcctaatgt tgaagagttt ctacaacaac aagacactgc tgtcattttt 420cctgaggcac ctgaagagga ccagaggcag ggcacaccag aagccagtgg tcatgatgaa 480aatggaacac cagatgcatt ttcacaatta ctcacctgtc catattgtga tagaggctat 540aaacgcttta cctctctgaa agaacacatt aaatatcgtc atgaaaagaa tgaagataac 600tttagttgct ccctgtgcag ttacaccttt gcatacagaa cccaacttga acgtcacatg 660acatcacata aatcaggaag agatcaaaga catgtgacgc agtctgggtg taatcgtaaa 720ttcaaatgca ctgagtgtgg aaaagctttc aaatacaaac atcacctaaa agagcactta 780agaattcaca gtggagagaa gccatatgaa tgcccaaact gcaagaaacg cttttcccat 840tctggctcct atagctcaca cataagcagt aagaaatgta tcagcttgat acctgtgaat 900gggcgaccaa gaacaggact caagacatct cagtgttctt caccgtctct ttcagcatca 960ccaggcagtc ccacacgacc acagatacgg caaaagatag agaataaacc ccttcaagaa 1020caactttctg ttaaccaaat taaaactgaa cctgtggatt atgaattcaa acccatagtg 1080gttgcttcag gaatcaactg ttcaacccct ttacaaaatg gggttttcac tggtggtggc 1140ccattacagg caaccagttc tcctcagggc atggtgcaag ctgttgttct gccaacagtt 1200ggtttggtgt ctcccataag tatcaattta agtgatattc agaatgtact taaagtggcg 1260gtagatggta atgtaataag gcaagtgttg gagaataatc aagccaatct tgcatccaaa 1320gaacaagaaa caatcaatgc ttcacccata caacaaggtg gccattctgt tatttcagcc 1380atcagtcttc ctttggttga tcaagatgga acaaccaaaa ttatcatcaa ctacagtctt 1440gagcagccta gccaacttca agttgttcct caaaatttaa aaaaagaaaa tccagtcgct 1500acaaacagtt gtaaaagtga aaagttacca gaagatctta ctgttaagtc tgagaaggac 1560aaaagctttg aagggggggt gaatgatagc acttgtcttc tgtgtgatga ttgtccagga 1620gatattaatg cacttccaga attaaagcac tatgacctaa agcagcctac tcagcctcct 1680ccactccctg cagcagaagc tgagaagcct gagtcctctg tttcatcagc tactggagat 1740ggcaatttgt ctcctagtca gccaccttta aagaacctct tgtctctcct aaaagcatat 1800tatgctttga atgcacaacc aagtgcagaa gagctctcaa aaattgctga ttcagtaaac 1860ctaccactgg atgtagtaaa aaagtggttt gaaaagatgc aagctggaca gatttcagtg 1920cagtcttctg aaccatcttc tcctgaacca ggcaaagtaa atatccctgc caagaacaat 1980gatcagcctc aatctgcaaa tgcaaatgaa ccccaggaca gcacagtaaa tctacaaagt 2040cctttgaaga tgactaactc cccagtttta ccagtgggat caaccaccaa tggttccaga 2100agtagtacac catccccatc acctctaaac ctttcctcat ccagaaatac acagggttac 2160ttgtacacag ctgagggtgc acaagaagag ccacaagtag aacctcttga tctttcacta 2220ccaaagcaac agggagaatt attagaaagg tcaactatca ctagtgttta ccagaacagt 2280gtttattctg tccaggaaga acccttgaac ttgtcttgcg caaaaaagga gccacaaaag 2340gacagttgtg ttacagactc agaaccagtt gtaaatgtaa tcccaccaag tgccaacccc 2400ataaatatcg ctatacctac agtcactgcc cagttaccca caatcgtggc cattgctgac 2460cagaacagtg ttccatgctt aagagcgcta gctgccaata agcaaacgat tctgattccc 2520caggtggcat acacctactc aactacggtc agccctgcag tccaagaacc acccttgaaa 2580gtgatccagc caaatggaaa tcaggatgaa agacaagata ctagctcaga aggagtatca 2640aatgtagagg atcagaatga ctctgattct acaccgccca aaaagaaaat gcggaagaca 2700gaaaatggaa tgtatgcttg tgatttgtgt gacaagatat tccaaaagag tagttcatta 2760ttgagacata aatatgaaca cacaggtaaa agacctcatg agtgtggaat ctgtaaaaag 2820gcatttaaac acaaacatca tttgattgaa cacatgcgat tacattctgg agaaaagccc 2880tatcaatgtg acaaatgtgg aaagcgcttc tcacactctg ggtcttattc tcaacacatg 2940aatcatcgct actcctactg taagagagaa gcggaagaac gtgacagcac agagcaggaa 3000gaggcagggc ctgaaatcct ctcgaatgag cacgtgggtg ccagggcgtc tccctcacag 3060ggcgactcgg acgagagaga gagtttgaca agggaagagg atgaagacag tgaaaaagag 3120gaagaggagg aggataaaga gatggaagaa ttgcaggaag aaaaagaatg tgaaaaacca 3180caaggggatg aggaagagga ggaggaggag gaagaagtgg aagaagaaga ggtagaagag 3240gcagagaatg agggagaaga agcaaaaact gaaggtctga tgaaggatga cagggctgaa 3300agtcaagcaa gcagcttagg acaaaaagta ggcgagagta gtgagcaagt gtctgaagaa 3360aagacaaatg aagcctaatc gtttttctag aaggaaaata aattctaatt gataatgaat 3420ttcgttcaat attatccttg cttttcatgg aaacacagta acctgtatgc tgtgattcct 3480gttcactact gtgtaaagta aaaactaaaa aaatacaaaa tacaaaacac acacacacac 3540acacacacac acacacacac acacacaaaa taaatccggg tgtgcctgaa cctcagacct 3600agtaattttt catgcagttt tcaaagttag gaacaagttt gtaacatgca gcagattaga 3660aaaccttaat gactcagaga gcaacaatac aagaggttaa aggaagctga ttaattagat 3720atgcatctgg cattgtttta tcttatcagt attatcactc ttatgttggt ttattcttaa 3780gctgtacaat tgggagaaat tttataattt tttattggta aacatatgct aaatccgctt 3840cagtatttta ttatgttttt taaaatgtga gaacttctgc actacaaaat tcccttcaca 3900gagaagtata atgtagttcc aacccgtgct aactaccttt tataaattca gtctagaagg 3960tagtaatttc taatatttag atgtcttagt agagcgtatt atcatttaaa gtgtattgtt 4020agccttaaga aagcagctga tagaagaact gaagtttctt actcacgtgg tttaaaatgg 4080agttcaaaag attgccattg agttctgatt gcagggacta acaatgttaa tctgataagg 4140acagcaaaat catcagaatc agtgtttgtg attgtgtttg aatatgtggt aacatatgaa 4200ggatatgaca tgaagctttg tatctccttt ggccttaagc aagacctgtg tgctgtaagt 4260gccatttctc agtattttca aggctctaac ccgccttcat ccaatgtgtg gcctacaata 4320actagcattt gttgatttgt ctcttgtatc aaaattccca aataaaactt aaaaccactg 4380actctgtcag agaaactgaa acactgggac atttcatcct tcaattcctc ggtattgatt 4440ttatgttgat tgattttcag aatttctcta cagaaacgaa agggaaattt tctaatctgc 4500tttatccatg tacttgcatt tcagacatgg acatgctatt gttatttggc tcataactgt 4560ttccaaatgt tagttattat ggacccaatt tattaacaac attagctgat ttttacctat 4620cagtattatt ttatttcttt tagtttatag atctgtgcaa catttttgta ctgtatgtct 4680tcaaacctgg cagtattaat acccttctta ctgacatatg tacttttagt tttagaaaac 4740ttttatattt atgtgtctta tttttatatt tctttattta ttacacagtg tagtgtataa 4800tactgtagtt tgtattaata caataatata ttttagtatg aaaatttgga aagttgataa 4860gatttaaagt agagatgcaa ttggttctcc tgcattgaga tttgatttaa cagtgttatg 4920ttaacattta tacttgcctt ggactgtaga acagaactta aatgggaatg tattagtttt 4980acaactacaa tcaagtcatt ttacctttac ccagttttta atataaaact taaattttga 5040aattcactgt gtgactaata gcatgatgct ctgcagtttt

attaagaaat cagcctaacc 5100atacaactct catttcctta gtaagccaaa ttaggattaa cttctataaa cagtgttggg 5160aacaatgttt aacattttgt gccaatttgt tcctgtattc atgtatgtaa gttacagatc 5220tgactcttca tttttaagtt ccttgttaca tcatggtcat tttctagttt tttaccagac 5280tcccatctca caataaaatg catcaacaag cctgaactgc tgtcattctt ttcatcatta 5340tcagtatttt ctttggaaaa ctgtgaaatg gggtacattg tcatcctgca tttgattcat 5400cttgagctga atttgggtaa cactaaatgt tttagacatt ctccactaaa ttatggattt 5460tcttgtggct aaatgtttct ggagaggtca gagttgacaa aacctcttca caggttgctc 5520cttcttcctg aaatccttaa tcctccgcat ttcatgcttc aggtcatttc agggaagcct 5580gggtttagat gcctttctga ctctcagctc ctgcacttct gtcatcatac ctctgatact 5640attatttata ttccttcccc actaggaaca ggaaccacat ttgtcatagt cactctcaca 5700ttcctcactg cctaacaggg tgcctggcat aagttgggac aacagatatt tgt 5753423901DNAHomo sapiens 42aagatggcgg cgtgtggacg tgtacggagg atgttccgct tgtcggcggc gctgcatctg 60ctgctgctat tcgcggccgg ggccgagaaa ctccccggcc atggcgtcca cagccagggc 120cagggtcccg gggccaactt tgtgtccttc gtagggcagg ccggaggcgg cggcccggcg 180ggtcagcagc tgccccagct gcttcagtca tcgcagcttc agcagcaaca gcagcagcag 240caacagcaac agcagcttca gccgccgcag ccgcctttcc cggcgggtgg gcctccggcc 300cggcggggag gagcgggggc tggtgggggc tggaagctgg cggaggaaga gtcctgcagg 360gaggacgtga cccgcgtgtg ccctaagcac acctggagca acaacctggc ggtgctcgag 420tgcctgcagg atgtgaggga gcctgaaaat gaaatttctt cagactgcaa tcatttgttg 480tggaattata agctgaacct aactacagat cccaaatttg aatctgtggc cagagaggtt 540tgcaaatcta ctataacaga gattaaagaa tgtgctgatg aaccggttgg aaaaggttac 600atggtttcct gcttagtgga tcaccgaggc aacatcactg agtatcagtg tcaccagtac 660attaccaaga tgacggccat catttttagt gattaccgtt taatctgtgg cttcatggat 720gactgcaaaa atgacatcaa cattctgaaa tgtggcagta ttcggcttgg agaaaaggat 780gcacattcac aaggtgaggt ggtatcatgc ttggagaaag gcctggtgaa agaagcagaa 840gaaagagaac ccaagattca agtttctgaa ctctgcaaga aagccattct ccgggtggct 900gagctgtcat cggatgactt tcacttagac cggcatttat attttgcttg ccgagatgat 960cgggagcgtt tttgtgaaaa tacacaagct ggtgagggca gagtgtataa gtgcctcttt 1020aaccataaat ttgaagaatc catgagtgaa aagtgtcgag aagcacttac aacccgccaa 1080aagctgattg cccaggatta taaagtcagt tattcattgg ccaaatcctg taaaagtgac 1140ttgaagaaat accggtgcaa tgtggaaaac cttccgcgat cgcgtgaagc caggctctcc 1200tacttgttaa tgtgcctgga gtcagctgta cacagagggc gacaagtcag cagtgagtgc 1260cagggggaga tgctggatta ccgacgcatg ttgatggaag acttttctct gagccctgag 1320atcatcctaa gctgtcgggg ggagattgaa caccattgtt ccggattaca tcgaaaaggg 1380cggaccctac actgtctgat gaaagtagtt cgaggggaga aggggaacct tggaatgaac 1440tgccagcagg cgcttcaaac actgattcag gagactgacc ctggtgcaga ttaccgcatt 1500gatcgagctt tgaatgaagc ttgtgaatct gtaatccaga cagcctgcaa acatataaga 1560tctggagacc caatgatctt gtcgtgcctg atggaacatt tatacacaga gaagatggta 1620gaagactgtg aacaccgtct cttagagctg cagtatttca tctcccggga ttggaagctg 1680gaccctgtcc tgtaccgcaa gtgccaggga gacgcttctc gtctttgcca cacccacggt 1740tggaatgaga ccagtgaatt tatgcctcag ggagctgtgt tctcttgttt atacagacac 1800gcctaccgca ctgaggaaca gggaaggagg ctctcacggg agtgccgagc tgaagtccaa 1860aggatcctac accagcgtgc catggatgtc aagctggatc ctgccctcca ggataagtgc 1920ctgattgatc tgggaaaatg gtgcagtgag aaaacagaga ctggacagga gctggagtgc 1980cttcaggacc atctggatga cttggtggtg gagtgtagag atatagttgg caacctcact 2040gagttagaat cagaggatat tcaaatagaa gccttgctga tgagagcctg tgagcccata 2100attcagaact tctgccacga tgtggcagat aaccagatag actctgggga cctgatggag 2160tgtctgatac agaacaaaca ccagaaggac atgaacgaga agtgtgccat cggagttacc 2220cacttccagc tggtgcagat gaaggatttt cggttttctt acaagtttaa aatggcctgc 2280aaggaggacg tgttgaagct ttgcccaaac ataaaaaaga aggtggacgt ggtgatctgc 2340ctgagcacga ccgtgcgcaa tgacactctg caggaagcca aggagcacag ggtgtccctg 2400aagtgccgca ggcagctccg tgtggaggag ctggagatga cggaggacat ccgcttggag 2460ccagatctat acgaagcctg caagagtgac atcaaaaact tctgttccgc tgtgcaatat 2520ggcaacgctc agattatcga atgtctgaaa gaaaacaaga agcagctaag cacccgctgc 2580caccaaaaag tatttaagct gcaggagaca gagatgatgg acccagagct agactacacc 2640ctcatgaggg tctgcaagca gatgataaag aggttctgtc cggaagcaga ttctaaaacc 2700atgttgcagt gcttgaagca aaataaaaac agtgaattga tggatcccaa atgcaaacag 2760atgataacca agcgccagat cacccagaac acagattacc gcttaaaccc catgttaaga 2820aaagcctgta aagctgacat tcctaaattc tgtcacggta tcctgactaa ggccaaggat 2880gattcagaat tagaaggaca agtcatctct tgcctgaagc tgagatatgc tgaccagcgc 2940ctgtcttcag actgtgaaga ccagatccga atcattatcc aggagtccgc cctggactac 3000cgcctggatc ctcagctcca gctgcactgc tcagacgaga tctccagtct atgtgctgaa 3060gaagcagcag cccaagagca gacaggtcag gtggaggagt gcctcaaggt caacctgctc 3120aagatcaaaa cagaattgtg taaaaaggaa gtgctaaaca tgctgaagga aagcaaagca 3180gacatctttg ttgacccggt acttcatact gcttgtgccc tggacattaa acaccactgc 3240gcagccatca cccctggccg cgggcgtcaa atgtcctgtc tcatggaagc actggaggat 3300aagcgggtga ggttacagcc cgagtgcaaa aagcgcctca atgaccggat tgagatgtgg 3360agttacgcag caaaggtggc cccagcagat ggcttctctg atcttgccat gcaagtaatg 3420acgtctccat ctaagaacta cattctctct gtgatcagtg ggagcatctg tatattgttc 3480ctgattggcc tgatgtgtgg acggatcacc aagcgagtga cacgagagct caaggacagg 3540tagagccacc ttgaccacca aaggaactac ctatccagtg cccagtttgt acagccctct 3600tgtatagcat ccccactcac ctcgctcttc tcagaagtga caccaacccc gtgttagagc 3660attagcagat gtccactgcg ttgtcccatc cagcctccac tcgtgtccat ggtgtcctcc 3720tcctcctcac cgtgcagcag cagcagctgg tcgctggggt tactgccttt gtttggcaaa 3780cttgggttta cctgcctgta gacaagtctc tctcatacca acagaacttc cggtacttcc 3840agaaccaact cacctgacct gcaactcaaa ggctttttta agaaaaccac caaaaaaaaa 3900a 390143247PRTHomo sapiens 43Met Ala Asp Thr Thr Pro Ser Gly Pro Gln Gly Ala Gly Ala Val Gln1 5 10 15 Phe Met Met Thr Asn Lys Leu Asp Thr Ala Met Trp Leu Ser Arg Leu 20 25 30 Phe Thr Val Tyr Cys Ser Ala Leu Phe Val Leu Pro Leu Leu Gly Leu 35 40 45 His Glu Ala Ala Ser Phe Tyr Gln Arg Ala Leu Leu Ala Asn Ala Leu 50 55 60 Thr Ser Ala Leu Arg Leu His Gln Arg Leu Pro His Phe Gln Leu Ser65 70 75 80 Arg Ala Phe Leu Ala Gln Ala Leu Leu Glu Asp Ser Cys His Tyr Leu 85 90 95 Leu Tyr Ser Leu Ile Phe Val Asn Ser Tyr Pro Val Thr Met Ser Ile 100 105 110 Phe Pro Val Leu Leu Phe Ser Leu Leu His Ala Ala Thr Tyr Thr Lys 115 120 125 Lys Val Leu Asp Ala Arg Gly Ser Asn Ser Leu Pro Leu Leu Arg Ser 130 135 140 Val Leu Asp Lys Leu Ser Ala Asn Gln Gln Asn Ile Leu Lys Phe Ile145 150 155 160 Ala Cys Asn Glu Ile Phe Leu Met Pro Ala Thr Val Phe Met Leu Phe 165 170 175 Ser Gly Gln Gly Ser Leu Leu Gln Pro Phe Ile Tyr Tyr Arg Phe Leu 180 185 190 Thr Leu Arg Tyr Ser Ser Arg Arg Asn Pro Tyr Cys Arg Thr Leu Phe 195 200 205 Asn Glu Leu Arg Ile Val Val Glu His Ile Ile Met Lys Pro Ala Cys 210 215 220 Pro Leu Phe Val Arg Arg Leu Cys Leu Gln Ser Ile Ala Phe Ile Ser225 230 235 240 Arg Leu Ala Pro Thr Val Pro 245 44247PRTHomo sapiens 44Met Ala Asp Thr Thr Pro Asn Gly Pro Gln Gly Ala Gly Ala Val Gln1 5 10 15 Phe Met Met Thr Asn Lys Leu Asp Thr Ala Met Trp Leu Ser Arg Leu 20 25 30 Phe Thr Val Tyr Cys Ser Ala Leu Phe Val Leu Pro Leu Leu Gly Leu 35 40 45 His Glu Ala Ala Ser Phe Tyr Gln Arg Ala Leu Leu Ala Asn Ala Leu 50 55 60 Thr Ser Ala Leu Arg Leu His Gln Arg Leu Pro His Phe Gln Leu Ser65 70 75 80 Arg Ala Phe Leu Ala Gln Ala Leu Leu Glu Asp Ser Cys His Tyr Leu 85 90 95 Leu Tyr Ser Leu Ile Phe Val Asn Ser Tyr Pro Val Thr Met Ser Ile 100 105 110 Phe Pro Val Leu Leu Phe Ser Leu Leu His Ala Ala Thr Tyr Thr Lys 115 120 125 Lys Val Leu Asp Ala Arg Gly Ser Asn Ser Leu Pro Leu Leu Arg Ser 130 135 140 Val Leu Asp Lys Leu Ser Ala Asn Gln Gln Asn Ile Leu Lys Phe Ile145 150 155 160 Ala Cys Asn Glu Ile Phe Leu Met Pro Ala Thr Val Phe Met Leu Phe 165 170 175 Ser Gly Gln Gly Ser Leu Leu Gln Pro Phe Ile Tyr Tyr Arg Phe Leu 180 185 190 Thr Leu Arg Tyr Ser Ser Arg Arg Asn Pro Tyr Cys Arg Thr Leu Phe 195 200 205 Asn Glu Leu Arg Ile Val Val Glu His Ile Ile Met Lys Pro Ala Cys 210 215 220 Pro Leu Phe Val Arg Arg Leu Cys Leu Gln Ser Ile Ala Phe Ile Ser225 230 235 240 Arg Leu Ala Pro Thr Val Pro 245 451780DNAHomo sapiens 45gtaggttggc tctttagggc ttcaccccga agctccacct tcgctcccgt ctttctggaa 60acaccgcttt gatctcggcg gtgcgggaca ggtacctccc ggctgctgcg ggtgccctgg 120atccagtcgg ctgcaccaga cgctagtgtg agcccccatg gcagatacga ccccgaacgg 180cccccaaggg gcgggcgctg tgcaattcat gatgaccaat aaactggaca cggcaatgtg 240gctttctcgc ttgttcacag tttactgctc tgctctgttt gttctgcctc ttcttgggtt 300gcatgaagca gcaagctttt accaacgtgc tttgctggca aatgctctta ccagtgctct 360gaggctgcat caaagattac cacacttcca gttaagcaga gcattcctgg cccaggcttt 420gttagaggac agctgccact acctgttgta ttcactcatc tttgtaaatt cctatccagt 480tacaatgagt atcttcccag tcttgttatt ctctttgctt catgctgcca catatacgaa 540aaaggtcctt gacgcaaggg gctcaaatag tttacctctg ctgagatctg tcttggacaa 600attaagtgct aatcaacaaa atattctgaa attcattgct tgcaatgaaa tattcctgat 660gcctgcgaca gtttttatgc tttttagtgg tcaaggaagt ttgctccaac cttttatata 720ctatagattt cttacccttc gatattcgtc tcgaagaaac ccatattgtc ggaccttatt 780taatgaactg aggattgttg ttgaacacat aataatgaaa cctgcttgcc cactgtttgt 840gagaagactt tgtctccaga gcattgcctt tataagcaga ttggcaccaa cagttccata 900gtttaacatc tagttaagct acaaatatag tataagcatt attagcagct ggtacttctg 960ctaggggttg taaattccag gtgttacact gacctcaatc caatttacat aatttacata 1020aatgcatctc ggtggaaaaa taatcatttt cttggcatgt taaatcaagc ttaaaaagtt 1080ttgagaaaat tttactgtgc tgtgttgcta atggttaaag aagtctgtat ctagtgataa 1140atataccagt ttttttaaaa agatgctgtt gtgcctatat catgaagtac attaatttct 1200catgtaaaaa aaatagctct aaaatttcag tattctacca ttcagtaatt ttggttaatg 1260attttaacac ttctcagtgt atttaatttc aaattgtttt tttaattggt tttatgctgc 1320tttgttagga cagatgtgtt ttgaatgtac cattataaga agaattctat gtatcttaaa 1380ctatgatctt ctaaaatttt atttccgtaa gtacttctgt ggccttgagt attttttaaa 1440aggctcaact gtaagcctct tagccagttg gataaatatt tggggtcacc tagccattga 1500aagcagaaag cagtagtgac acagctttcc cttcaaagag ccattgagaa acatttctca 1560aacaggaaat ccttctttta ctaatgtgga catatagatt attcgtatta tagtttgtag 1620aactacctag ttcagaatct tgactgccag ttttcttggt ttcttaggct tgaattttca 1680tagacaattg caacagttta gatgcctttt gaaaggaatg taatgaagat tcagcatctg 1740actatatgtg tgtctatcct gaaataataa tggagagtat 1780461780DNAHomo sapiens 46gtaggttggc tctttagggc ttcaccccga agctccacct tcgctcccgt ctttctggaa 60acaccgcttt gatctcggcg gtgcgggaca ggtacctccc ggctgctgcg ggtgccctgg 120atccagtcgg ctgcaccaga cgctagtgtg agcccccatg gcagatacga ccccgaacgg 180cccccaaggg gcgggcgctg tgcaattcat gatgaccaat aaactggaca cggcaatgtg 240gctttctcgc ttgttcacag tttactgctc tgctctgttt gttctgcctc ttcttgggtt 300gcatgaagca gcaagctttt accaacgtgc tttgctggca aatgctctta ccagtgctct 360gaggctgcat caaagattac cacacttcca gttaagcaga gcattcctgg cccaggcttt 420gttagaggac agctgccact acctgttgta ttcactcatc tttgtaaatt cctatccagt 480tacaatgagt atcttcccag tcttgttatt ctctttgctt catgctgcca catatacgaa 540aaaggtcctt gacgcaaggg gctcaaatag tttacctctg ctgagatctg tcttggacaa 600attaagtgct aatcaacaaa atattctgaa attcattgct tgcaatgaaa tattcctgat 660gcctgcgaca gtttttatgc tttttagtgg tcaaggaagt ttgctccaac cttttatata 720ctatagattt cttacccttc gatattcgtc tcgaagaaac ccatattgtc ggaccttatt 780taatgaactg aggattgttg ttgaacacat aataatgaaa cctgcttgcc cactgtttgt 840gagaagactt tgtctccaga gcattgcctt tataagcaga ttggcaccaa cagttccata 900gtttaacatc tagttaagct acaaatatag tataagcatt attagcagct ggtacttctg 960ctaggggttg taaattccag gtgttacact gacctcaatc caatttacat aatttacata 1020aatgcatctc ggtggaaaaa taatcatttt cttggcatgt taaatcaagc ttaaaaagtt 1080ttgagaaaat tttactgtgc tgtgttgcta atggttaaag aagtctgtat ctagtgataa 1140atataccagt ttttttaaaa agatgctgtt gtgcctatat catgaagtac attaatttct 1200catgtaaaaa aaatagctct aaaatttcag tattctacca ttcagtaatt ttggttaatg 1260attttaacac ttctcagtgt atttaatttc aaattgtttt tttaattggt tttatgctgc 1320tttgttagga cagatgtgtt ttgaatgtac cattataaga agaattctat gtatcttaaa 1380ctatgatctt ctaaaatttt atttccgtaa gtacttctgt ggccttgagt attttttaaa 1440aggctcaact gtaagcctct tagccagttg gataaatatt tggggtcacc tagccattga 1500aagcagaaag cagtagtgac acagctttcc cttcaaagag ccattgagaa acatttctca 1560aacaggaaat ccttctttta ctaatgtgga catatagatt attcgtatta tagtttgtag 1620aactacctag ttcagaatct tgactgccag ttttcttggt ttcttaggct tgaattttca 1680tagacaattg caacagttta gatgcctttt gaaaggaatg taatgaagat tcagcatctg 1740actatatgtg tgtctatcct gaaataataa tggagagtat 178047363PRTHomo sapiens 47Met Leu Gly Ala Trp Ala Val Glu Gly Thr Ala Val Ala Leu Leu Arg1 5 10 15 Leu Leu Leu Leu Leu Leu Pro Pro Ala Ile Arg Gly Pro Gly Leu Gly 20 25 30 Val Ala Gly Val Ala Gly Ala Ala Gly Ala Gly Leu Pro Glu Ser Val 35 40 45 Ile Trp Ala Val Asn Ala Gly Gly Glu Ala His Val Asp Val His Gly 50 55 60 Ile His Phe Arg Lys Asp Pro Leu Glu Gly Arg Val Gly Arg Ala Ser65 70 75 80 Asp Tyr Gly Met Lys Leu Pro Ile Leu Arg Ser Asn Pro Glu Asp Gln 85 90 95 Ile Leu Tyr Gln Thr Glu Arg Tyr Asn Glu Glu Thr Phe Gly Tyr Glu 100 105 110 Val Pro Ile Lys Glu Glu Gly Asp Tyr Val Leu Val Leu Lys Phe Ala 115 120 125 Glu Val Tyr Phe Ala Gln Ser Gln Gln Lys Val Phe Asp Val Arg Leu 130 135 140 Asn Gly His Val Val Val Lys Asp Leu Asp Ile Phe Asp Arg Val Gly145 150 155 160 His Ser Thr Ala His Asp Glu Ile Ile Pro Met Ser Ile Arg Lys Gly 165 170 175 Lys Leu Ser Val Gln Gly Glu Val Ser Thr Phe Thr Gly Lys Leu Tyr 180 185 190 Ile Glu Phe Val Lys Gly Tyr Tyr Asp Asn Pro Lys Val Cys Ala Leu 195 200 205 Tyr Ile Met Ala Gly Thr Val Asp Asp Val Pro Lys Leu Gln Pro His 210 215 220 Pro Gly Leu Glu Lys Lys Glu Glu Glu Glu Glu Glu Glu Glu Tyr Asp225 230 235 240 Glu Gly Ser Asn Leu Lys Lys Gln Thr Asn Lys Asn Arg Val Gln Ser 245 250 255 Gly Pro Arg Thr Pro Asn Pro Tyr Ala Ser Asp Asn Ser Ser Leu Met 260 265 270 Phe Pro Ile Leu Val Ala Phe Gly Val Phe Ile Pro Thr Leu Phe Cys 275 280 285 Leu Cys Arg Leu Ala Gly Trp Val Cys Phe Gly Leu Ser Pro Ser Val 290 295 300 Ala Pro Glu Glu Gly Glu Thr Glu Ala Arg Gln Ser Asp Ser Thr Leu305 310 315 320 Lys Gln Asn Arg Lys His Pro Gly Thr Val Gln Lys Ser Gln Lys Lys 325 330 335 Ser Ala Ser Leu Arg Trp Lys Asp Ile Ile Asn Asp Gln Arg Ala Phe 340 345 350 Ser Leu Ser Val Gln Thr Lys Thr Leu Cys Ile 355 360 48292PRTHomo sapiens 48Met Leu Gly Ala Trp Ala Val Glu Gly Thr Ala Val Ala Leu Leu Arg1 5 10 15 Leu Leu Leu Leu Leu Leu Pro Pro Ala Ile Arg Gly Pro Gly Leu Gly 20 25 30 Val Ala Gly Val Ala Gly Ala Ala Gly Ala Gly Leu Pro Glu Ser Val 35 40 45 Ile Trp Ala Val Asn Ala Gly Gly Glu Ala His Val Asp Val His Gly 50 55 60 Ile His Phe Arg Lys Asp Pro Leu Glu Gly Arg Val Gly Arg Ala Ser65 70 75 80 Asp Tyr Gly Met Lys Leu Pro Ile Leu Arg Ser Asn Pro Glu Asp Gln 85 90 95 Ile Leu Tyr Gln Thr Glu Arg Tyr Asn Glu Glu Thr Phe Gly Tyr Glu 100 105 110 Val Pro Ile Lys Glu Glu Gly Asp Tyr Val Leu Val Leu Lys Phe Ala 115 120 125 Glu Val Tyr Phe Ala Gln Ser Gln Gln Lys Val Phe Asp Val Arg Leu 130 135 140 Asn Gly His Val Val Val Lys Asp Leu Asp Ile Phe Asp Arg Val Gly145 150 155 160 His Ser Thr Ala His Asp Glu Ile Ile Pro Met

Ser Ile Arg Lys Gly 165 170 175 Lys Leu Ser Val Gln Gly Glu Val Ser Thr Phe Thr Gly Lys Leu Tyr 180 185 190 Ile Glu Phe Val Lys Gly Tyr Tyr Asp Asn Pro Lys Val Cys Ala Leu 195 200 205 Tyr Ile Met Ala Gly Thr Val Asp Asp Val Pro Lys Leu Gln Pro His 210 215 220 Pro Gly Leu Glu Lys Lys Glu Glu Glu Glu Glu Glu Glu Glu Tyr Asp225 230 235 240 Glu Gly Ser Asn Leu Lys Lys Gln Thr Asn Lys Asn Arg Val Gln Ser 245 250 255 Gly Pro Arg Thr Pro Asn Pro Tyr Ala Ser Asp Asn Ser Ser Leu Met 260 265 270 Phe Pro Ile Leu Val Ala Phe Gly Val Phe Ile Pro Thr Leu Phe Cys 275 280 285 Leu Cys Arg Leu 290 491800DNAHomo sapiens 49gtggctgaga agaaggaggc ctgagagcga catgtccccg gcggctcagg cggagcggcc 60cgtggcgctg tttttctgag tccggggtgg cctggcagcc ggccgaggac gagggtcggc 120gggggctgcc cccgtggtgg tggccgccat gctgggagcc tgggcggttg agggaaccgc 180tgtggcgctc ctgcgactgc tgctgctgct gctgccgccg gcgatccggg gacccgggct 240cggcgtggcc ggcgtggccg gcgcggcggg ggccgggctg cccgagagcg tcatttgggc 300ggtcaacgcg ggtggagagg cgcatgtgga cgtgcacggg atccacttcc gcaaggaccc 360tttggaaggc cgggtgggcc gagcctcaga ctatggcatg aaactgccaa tcctgcgttc 420caaccctgag gaccagatcc tgtatcaaac tgagcggtac aatgaggaga cctttggcta 480cgaagtgccc atcaaagagg agggggacta cgtgctggtc ttgaaatttg cagaggtcta 540ctttgcacag tcccagcaaa aggtatttga tgtacgattg aatggccacg tcgtggtgaa 600ggacttggat atctttgatc gtgttgggca tagcacagct cacgatgaaa ttatacctat 660gagcatcaga aaggggaagc tgagtgtcca gggggaggtg tccaccttca cagggaaact 720ctacattgag tttgtcaagg ggtactatga caatcccaag gtctgtgcac tctacatcat 780ggctgggaca gtggatgatg taccaaagct tcagcctcat ccgggattgg agaagaaaga 840agaggaagaa gaagaagaag aatatgatga agggtctaat ctcaaaaaac agaccaataa 900gaaccgggtg cagtcaggcc cccgcacacc caacccctat gcctcggaca acagcagcct 960catgtttccc atcctggtgg ccttcggagt cttcattcca accctcttct gcctctgccg 1020gttggcagga tgggtatgct ttgggctttc tccttctgtg gccccggagg aaggagagac 1080tgaggcaagg caaagtgata gtacactgaa gcagaaccgg aaacacccag gaactgttca 1140gaaatctcag aagaaatctg cttctcttcg atggaaagat ataattaacg atcaaagagc 1200tttttctctt tcagtccaaa ctaagactct ctgtatttaa atctctctgg ggcaagaggg 1260ctagatttcc tcattttgtt atgagactag attggtacca gtagatcagc tgcctagcga 1320gggcaggttt cttctttgca tctgtgtggc ttgcttccag tctggcctgt cctttccagc 1380tgccttttgt ctagcctgct atggggggcc agattatctt gataagagca ggtgatttgg 1440ggactagctg ggttggcagg aaaagagcag gatggatctc ttgggacagg ttcccccagg 1500agtataaaca caaggagcca ggattgtgct gtctattttg agcttcagtg ctttatttca 1560gtatgaggaa aaacaacaac aaactgaagt gcgctttccg tcctttcaaa ggacaactgt 1620cgggaaggga gagccgagtt gcgaggtagg aggggagcac tggcagggag agacattctt 1680gactcctctc ttccctggtg tgttgtgatc cagggcaggc aaggaccagc tgcccattct 1740gagcccaggg cagcctcttc aaccattatt ggtctaacct ggcttgtcag gaaaccaagc 1800506340DNAHomo sapines 50gtggctgaga agaaggaggc ctgagagcga catgtccccg gcggctcagg cggagcggcc 60cgtggcgctg tttttctgag tccggggtgg cctggcagcc ggccgaggac gagggtcggc 120gggggctgcc cccgtggtgg tggccgccat gctgggagcc tgggcggttg agggaaccgc 180tgtggcgctc ctgcgactgc tgctgctgct gctgccgccg gcgatccggg gacccgggct 240cggcgtggcc ggcgtggccg gcgcggcggg ggccgggctg cccgagagcg tcatttgggc 300ggtcaacgcg ggtggagagg cgcatgtgga cgtgcacggg atccacttcc gcaaggaccc 360tttggaaggc cgggtgggcc gagcctcaga ctatggcatg aaactgccaa tcctgcgttc 420caaccctgag gaccagatcc tgtatcaaac tgagcggtac aatgaggaga cctttggcta 480cgaagtgccc atcaaagagg agggggacta cgtgctggtc ttgaaatttg cagaggtcta 540ctttgcacag tcccagcaaa aggtatttga tgtacgattg aatggccacg tcgtggtgaa 600ggacttggat atctttgatc gtgttgggca tagcacagct cacgatgaaa ttatacctat 660gagcatcaga aaggggaagc tgagtgtcca gggggaggtg tccaccttca cagggaaact 720ctacattgag tttgtcaagg ggtactatga caatcccaag gtctgtgcac tctacatcat 780ggctgggaca gtggatgatg taccaaagct tcagcctcat ccgggattgg agaagaaaga 840agaggaagaa gaagaagaag aatatgatga agggtctaat ctcaaaaaac agaccaataa 900gaaccgggtg cagtcaggcc cccgcacacc caacccctat gcctcggaca acagcagcct 960catgtttccc atcctggtgg ccttcggagt cttcattcca accctcttct gcctctgccg 1020gttgtgagaa caaatgacta tcctgaacag ggtggagggg tgtgggaaag aaaccagcca 1080tattggtttt ggtttctgta tttttcacaa tgattaatga acaaaaacaa agagaaaaaa 1140acacacatca attaaaggag acaaaaagag gcagagcgag tagagagcag ccctcattca 1200ccacctggtc ccagacgtgc ttcagtcctc gtcctctctt tgtggctggc tcccagcctt 1260ctctttcctc ttgaggatac ttagggtaaa ctggatcctt cctgctcaag gatcctcatt 1320tgtataccta gtggaaagga ctctgaactc agaggagtca ctgttccttt ttttaggtta 1380gaaattaaca gcagggaaat gccatcttat tacctgagac gaccagcact gggagttagg 1440tacggtctga agttatgtct agataagact tcagacgtcc tgggattgaa agaatgtgtg 1500tgaaggggta gaatttgtgc ggtaaagact taaaaaaaaa agtagggaga ttaaaaaaaa 1560agaaagaaaa tgcttcctta tctggaagcc tttctggatt aatccagtga tggtcccacc 1620tttagtgttt gagctttgtc attgcttgtc tccctggcat gtgccagtta tagactgtcc 1680agcatccaag acgtttcggt tatgtcgggt cctcagatcg cctctgactt gttaccacaa 1740caaatcattt tgatttcagt gcctgttggg gacttgattt cttctcagtt ttgtttgttt 1800gtttgtttcc ttaatctggc tcatttgaaa tttcttctcc ctctcaacca tcccactaag 1860ttatagccaa gaagggaagg agacacgggg atttggggtt ctctgcttga atgtcttctc 1920ctttaccacc tcaccttgtt ggtacctccc tccctggatc tctgagccag cagccaggag 1980gacctgaccc agcagttctt tactggcccc tttgtagggc cttgctgcca gggggcaggg 2040atgctttcca gcctgcagca acagaacact tgaccttaaa agtctcttct ggtctttgga 2100ttagaaaagg cttatgttag catagcttaa gagcaacctc agagatttga gccctactaa 2160gtgactgacc actgtttaga gtgtctggta tctgatgttc atttattccc atgttcttgt 2220gtgtcacagt tcagccagtt ttggtttatg cctagagcta cttcaaggaa ctagactaat 2280tagctatata ggcccagcga tgcttcttat tgatcttaat agtatgcccc tccttcccct 2340gtcctttcat ttctctatcc aagtagcagt caggttcttg gtgtgatggg actgaaagaa 2400ttccagtcag ccagagcctt ggcagctctg aagctaacct tagcatctaa gtgtcgatct 2460tgaattccct gaaaaaattt ctataggaaa tgaagcttcc ctggtcccct cctttctggc 2520cattgtcatc catttcccag ttagggcaac aatgaaggag gacccagcca agctagaagg 2580aattttgtgg atgggagaca gcaggattag cttcagcttg ggctggagca gtcaatatag 2640gatctcaggc caggcccgct tttctagaat gtgtttaatt ttgagtttgc tttattagat 2700atgtttttta agagctctgt atatttgaac tgctccttat gtgacaaaat aggtagctct 2760tgggctcatg tcctgggttt tggctcttta atgattactc caggccagca tttagtcgtt 2820tgagaattgt agcctgttgt tttcgctgtg acttgggtct cagtgctagg gtattgagtc 2880aggcagctgg agggttgtgg cccgaggctg cagtcagagg tatacttccc atagtgcttc 2940acacagctcc cctgcttcta aaggataagg tactgtagcc ttggtcctgg ggaccacctg 3000cctggggcag tggacatcct aactaaacag gcttctggca gtagctttgg ttcctatccc 3060atcgaaattc cccaaagccc tgggccactg ccattgggtt agtcaagatg aaggaggagg 3120actggctgcc tccattttgc cttgtttgtt agtttgcctg ggtctgtctg aggaaggagg 3180gggtcccgcc ttccacctca acacatccct tcagtgactc agagtctcag aaggaaaccc 3240tgactcctgg ggccatttcc taatggtact gtaagccaag cagctttgct tctgcctctg 3300tttccaagcc cacccttttc ccctgagctc agggttaggg atgggcgctt tcctctctgg 3360ttgtgaacga aaggaaggaa catctttcta tggctaacaa aaactaaagg ggaagtgagg 3420aaacaggaag aagtatggtg ggggctgggg tagactcccc tggagccaag cctatccagc 3480taacaagagc tccctggggc tggtcacagc tggctcatga tgctgaactt gaaagttttt 3540ttgtttttgt ttttgttttg tggctcctcc aagatatagg tacatgaagt ttaggttaaa 3600ggggtgggat tctttatttt tatttttgta ttgtatgtgt caagaattac tctgttgttc 3660accttttgct ttttgcactg tttgttctct tatctgtatt ttgagcttag tgctaggact 3720gagaggctgc accataggga atgtatggga gatggtgagg ggtgccagtg aggggtgcgt 3780ggaggagagg cctgggctcc tctactggat ctacactctg tcccaggttt ttagatccca 3840ctgagcccag ctgactgaaa acaaggacag tcagggtgaa acttcttttg ccagaagtgt 3900ggcctgagtt gaatttctgg gaggatgacg cagatgtctg ctgcagagct gggctgagag 3960ttctgcagtc tagctctgac ttaggtcagg ggcctgttgg tctctcattg gacgtttttg 4020ggtctcactc atgcttactg aaacattgtg ccaagaaact ctgtgggatt tgtgtccctt 4080aaaccagact cacttttctg aaaaatctcc attgttgagg agaggctgct caatcgacac 4140cccgagttct catgactggg aagatagttt tcttcaggtg tcaatggcgt tagactccca 4200ggaagactag ccctgcccac agggccacct gttggtttga gagcgtgttc gtgttctctt 4260gccctccctg cctaagagct actgggatca cgttagcggg catttaggct ttgatgagag 4320ggcacagttt gagttaggtt tacctccccc tttctgtgcc tgggaactgt ttggtccagc 4380tttagaactg tggttttgac ttccttatct cttgggagaa gcttctgttt taaggaattt 4440ctcttccttc ttctcctgcc tctagcctct cctggaaagg cctggatatg gtttctaaaa 4500tctcagctga gaacttcaga aaacagcagc agtattttcc ttttcctagt gctaaaatcc 4560ctttccctag aaattggctc accttgggaa acccagggaa agaatcagca ggttctctgc 4620cctccctagg ggttggggaa ggacccaccc cggtcagcac agtgcctttt cctctcctgc 4680tctgagccag ggtggggcat tccctctaga ttcaggtttg ggcaggggtc ctatagtccc 4740tgccatgggg ctgcttccct gtcccttccc tcccctttgc tggcctactc tggcataatt 4800caagtgtctt cttgccttgg ggatccttag tggcatcaaa tggcaacatg gaatattgtc 4860ctccatgccc ctccagaagg acctaggaga gtaggtgagc tttccaaagt gagagacgaa 4920tctttctttc tttttttttt taaagggcag gatgggtatg ctttgggctt tctccttctg 4980tggccccgga ggaaggagag actgaggcaa ggcaaagtga tagtacactg aagcagaacc 5040ggaaacaccc aggaactgtt cagaaatctc agaagaaatc tgcttctctt cgatggaaag 5100atataattaa cgatcaaaga gctctaagaa aattgcaaag aagccttaat gttcaagctt 5160tagaaagatc agagcaattt ttctctttca gtccaaacta agactctctg tatttaaatc 5220tctctggggc aagagggcta gatttcctca ttttgttatg agactagatt ggtaccagta 5280gatcagctgc ctagcgaggg caggtttctt ctttgcatct gtgtggcttg cttccagtct 5340ggcctgtcct ttccagctgc cttttgtcta gcctgctatg gggggccaga ttatcttgat 5400aagagcaggt gatttgggga ctagctgggt tggcaggaaa agagcaggat ggatctcttg 5460ggacaggttc ccccaggagt ataaacacaa ggagccagga ttgtgctggc agccaaggaa 5520acagtagtgc ctgtttgagt tggcagagag ggccttggca cctcttgcat ccaggcagtc 5580ttgtgagatg ggggcacata gcactgggga aagcagaact ccattctcac ctctattttg 5640agcttcagtg ctttatttca gtatgaggaa aaacaacaac aaactgaagt gcgctttccg 5700tcctttcaaa ggacaactgt cgggaaggga gagccgagtt gcgaggtagg aggggagcac 5760tggcagggag agacattctt gactcctctc ttccctggtg tgttgtgatc cagggaatga 5820aaagaaattt gaccctggat tggttctctc cttggactta aggaatctta ccttttcctt 5880ccacaaagtt ctcccaggca aggaccagct gcccattctg agcccagggc agcctcttca 5940accattattg gtctaacctg gcttgtcagg aaaccaagcc cacccttcca cattgggcct 6000ggctgctcta ttctgtacca agtactggag aaaaagcatc aagttcttag cccttgtagc 6060ttctacccta gtttcccatc ctctctctgt ggaggccaaa ccaactcttt gccagcagcc 6120acaacatgca ttgacagcgg cacagtgaga tataactgat gggctttgaa cctggttggc 6180cggggaagct gtaggggtgg atagagctgg ctttccttct gggctgtctc catctgaccc 6240taccccttcc atgtcccacc ccactcccac caaaaagtac aaaatcagga tgtttttcac 6300tgtccattgc tttgtgtttt aataaacaat ttgcagtgac 634051855PRTHomo sapiens 51Met Gly Ser Asp Arg Ala Arg Lys Gly Gly Gly Gly Pro Lys Asp Phe1 5 10 15 Gly Ala Gly Leu Lys Tyr Asn Ser Arg His Glu Lys Val Asn Gly Leu 20 25 30 Glu Glu Gly Val Glu Phe Leu Pro Val Asn Asn Val Lys Lys Val Glu 35 40 45 Lys His Gly Pro Gly Arg Trp Val Val Leu Ala Ala Val Leu Ile Gly 50 55 60 Leu Leu Leu Val Leu Leu Gly Ile Gly Phe Leu Val Trp His Leu Gln65 70 75 80 Tyr Arg Asp Val Arg Val Gln Lys Val Phe Asn Gly Tyr Met Arg Ile 85 90 95 Thr Asn Glu Asn Phe Val Asp Ala Tyr Glu Asn Ser Asn Ser Thr Glu 100 105 110 Phe Val Ser Leu Ala Ser Lys Val Lys Asp Ala Leu Lys Leu Leu Tyr 115 120 125 Ser Gly Val Pro Phe Leu Gly Pro Tyr His Lys Glu Ser Ala Val Thr 130 135 140 Ala Phe Ser Glu Gly Ser Val Ile Ala Tyr Tyr Trp Ser Glu Phe Ser145 150 155 160 Ile Pro Gln His Leu Val Glu Glu Ala Glu Arg Val Met Ala Glu Glu 165 170 175 Arg Val Val Met Leu Pro Pro Arg Ala Arg Ser Leu Lys Ser Phe Val 180 185 190 Val Thr Ser Val Val Ala Phe Pro Thr Asp Ser Lys Thr Val Gln Arg 195 200 205 Thr Gln Asp Asn Ser Cys Ser Phe Gly Leu His Ala Arg Gly Val Glu 210 215 220 Leu Met Arg Phe Thr Thr Pro Gly Phe Pro Asp Ser Pro Tyr Pro Ala225 230 235 240 His Ala Arg Cys Gln Trp Ala Leu Arg Gly Asp Ala Asp Ser Val Leu 245 250 255 Ser Leu Thr Phe Arg Ser Phe Asp Leu Ala Ser Cys Asp Glu Arg Gly 260 265 270 Ser Asp Leu Val Thr Val Tyr Asn Thr Leu Ser Pro Met Glu Pro His 275 280 285 Ala Leu Val Gln Leu Cys Gly Thr Tyr Pro Pro Ser Tyr Asn Leu Thr 290 295 300 Phe His Ser Ser Gln Asn Val Leu Leu Ile Thr Leu Ile Thr Asn Thr305 310 315 320 Glu Arg Arg His Pro Gly Phe Glu Ala Thr Phe Phe Gln Leu Pro Arg 325 330 335 Met Ser Ser Cys Gly Gly Arg Leu Arg Lys Ala Gln Gly Thr Phe Asn 340 345 350 Ser Pro Tyr Tyr Pro Gly His Tyr Pro Pro Asn Ile Asp Cys Thr Trp 355 360 365 Asn Ile Glu Val Pro Asn Asn Gln His Val Lys Val Arg Phe Lys Phe 370 375 380 Phe Tyr Leu Leu Glu Pro Gly Val Pro Ala Gly Thr Cys Pro Lys Asp385 390 395 400 Tyr Val Glu Ile Asn Gly Glu Lys Tyr Cys Gly Glu Arg Ser Gln Phe 405 410 415 Val Val Thr Ser Asn Ser Asn Lys Ile Thr Val Arg Phe His Ser Asp 420 425 430 Gln Ser Tyr Thr Asp Thr Gly Phe Leu Ala Glu Tyr Leu Ser Tyr Asp 435 440 445 Ser Ser Asp Pro Cys Pro Gly Gln Phe Thr Cys Arg Thr Gly Arg Cys 450 455 460 Ile Arg Lys Glu Leu Arg Cys Asp Gly Trp Ala Asp Cys Thr Asp His465 470 475 480 Ser Asp Glu Leu Asn Cys Ser Cys Asp Ala Gly His Gln Phe Thr Cys 485 490 495 Lys Asn Lys Phe Cys Lys Pro Leu Phe Trp Val Cys Asp Ser Val Asn 500 505 510 Asp Cys Gly Asp Asn Ser Asp Glu Gln Gly Cys Ser Cys Pro Ala Gln 515 520 525 Thr Phe Arg Cys Ser Asn Gly Lys Cys Leu Ser Lys Ser Gln Gln Cys 530 535 540 Asn Gly Lys Asp Asp Cys Gly Asp Gly Ser Asp Glu Ala Ser Cys Pro545 550 555 560 Lys Val Asn Val Val Thr Cys Thr Lys His Thr Tyr Arg Cys Leu Asn 565 570 575 Gly Leu Cys Leu Ser Lys Gly Asn Pro Glu Cys Asp Gly Lys Glu Asp 580 585 590 Cys Ser Asp Gly Ser Asp Glu Lys Asp Cys Asp Cys Gly Leu Arg Ser 595 600 605 Phe Thr Arg Gln Ala Arg Val Val Gly Gly Thr Asp Ala Asp Glu Gly 610 615 620 Glu Trp Pro Trp Gln Val Ser Leu His Ala Leu Gly Gln Gly His Ile625 630 635 640 Cys Gly Ala Ser Leu Ile Ser Pro Asn Trp Leu Val Ser Ala Ala His 645 650 655 Cys Tyr Ile Asp Asp Arg Gly Phe Arg Tyr Ser Asp Pro Thr Gln Trp 660 665 670 Thr Ala Phe Leu Gly Leu His Asp Gln Ser Gln Arg Ser Ala Pro Gly 675 680 685 Val Gln Glu Arg Arg Leu Lys Arg Ile Ile Ser His Pro Phe Phe Asn 690 695 700 Asp Phe Thr Phe Asp Tyr Asp Ile Ala Leu Leu Glu Leu Glu Lys Pro705 710 715 720 Ala Glu Tyr Ser Ser Met Val Arg Pro Ile Cys Leu Pro Asp Ala Ser 725 730 735 His Val Phe Pro Ala Gly Lys Ala Ile Trp Val Thr Gly Trp Gly His 740 745 750 Thr Gln Tyr Gly Gly Thr Gly Ala Leu Ile Leu Gln Lys Gly Glu Ile 755 760 765 Arg Val Ile Asn Gln Thr Thr Cys Glu Asn Leu Leu Pro Gln Gln Ile 770 775 780 Thr Pro Arg Met Met Cys Val Gly Phe Leu Ser Gly Gly Val Asp Ser785 790 795 800 Cys Gln Gly Asp Ser Gly Gly Pro Leu Ser Ser Val Glu Ala Asp Gly 805 810 815 Arg Ile Phe Gln Ala Gly Val Val Ser Trp Gly Asp Gly Cys Ala Gln 820 825 830 Arg Asn Lys Pro Gly Val Tyr Thr Arg Leu Pro Leu Phe Arg Asp Trp 835 840 845 Ile Lys Glu Asn Thr Gly Val 850 855 52422PRTHomo sapiens 52Ser Tyr Thr Asp Thr Gly Phe Leu Ala Glu Tyr Leu Ser Tyr Asp Ser1 5 10 15 Ser Asp Pro Cys Pro Gly Gln Phe Thr Cys Arg Thr Gly Arg Cys Ile 20 25 30 Arg Lys Glu Leu Arg Cys Asp Gly Trp Ala Asp Cys Thr Asp His Ser 35 40 45 Asp Glu Leu Asn Cys Ser Cys Asp Ala Gly His Gln Phe Thr Cys Lys 50 55 60 Asn Lys Phe Cys Lys Pro Leu Phe

Trp Val Cys Asp Ser Val Asn Asp65 70 75 80 Cys Gly Asp Asn Ser Asp Glu Gln Gly Cys Ser Cys Pro Ala Gln Thr 85 90 95 Phe Arg Cys Ser Asn Gly Lys Cys Leu Ser Lys Ser Gln Gln Cys Asn 100 105 110 Gly Lys Asp Asp Cys Gly Asp Gly Ser Asp Glu Ala Ser Cys Pro Lys 115 120 125 Val Asn Val Val Thr Cys Thr Lys His Thr Tyr Arg Cys Leu Asn Gly 130 135 140 Leu Cys Leu Ser Lys Gly Asn Pro Glu Cys Asp Gly Lys Glu Asp Cys145 150 155 160 Ser Asp Gly Ser Asp Glu Lys Asp Cys Asp Cys Gly Leu Arg Ser Phe 165 170 175 Thr Arg Gln Ala Arg Val Val Gly Gly Thr Asp Ala Asp Glu Gly Glu 180 185 190 Trp Pro Trp Gln Val Ser Leu His Ala Leu Gly Gln Gly His Ile Cys 195 200 205 Gly Ala Ser Leu Ile Ser Pro Asn Trp Leu Val Ser Ala Ala His Cys 210 215 220 Tyr Ile Asp Asp Arg Gly Phe Arg Tyr Ser Asp Pro Thr Gln Trp Thr225 230 235 240 Ala Phe Leu Gly Leu His Asp Gln Ser Gln Arg Ser Ala Pro Gly Val 245 250 255 Gln Glu Arg Arg Leu Lys Arg Ile Ile Ser His Pro Phe Phe Asn Asp 260 265 270 Phe Thr Phe Asp Tyr Asp Ile Ala Leu Leu Glu Leu Glu Lys Pro Ala 275 280 285 Glu Tyr Ser Ser Met Val Arg Pro Ile Cys Leu Pro Asp Ala Ser His 290 295 300 Val Phe Pro Ala Gly Lys Ala Ile Trp Val Thr Gly Trp Gly His Thr305 310 315 320 Gln Tyr Gly Gly Thr Gly Ala Leu Ile Leu Gln Lys Gly Glu Ile Arg 325 330 335 Val Ile Asn Gln Thr Thr Cys Glu Asn Leu Leu Pro Gln Gln Ile Thr 340 345 350 Pro Arg Met Met Cys Val Gly Phe Leu Ser Gly Gly Val Asp Ser Cys 355 360 365 Gln Gly Asp Ser Gly Gly Pro Leu Ser Ser Val Glu Ala Asp Gly Arg 370 375 380 Ile Phe Gln Ala Gly Val Val Ser Trp Gly Asp Gly Cys Ala Gln Arg385 390 395 400 Asn Lys Pro Gly Val Tyr Thr Arg Leu Pro Leu Phe Arg Asp Trp Ile 405 410 415 Lys Glu Asn Thr Gly Val 420 533120DNAHomo sapiens 53cgaggatcct gagacccgcg agcggcctcg gggaccatgg ggagcgatcg ggcccgcaag 60ggcggagggg gcccgaagga cttcggcgcg ggactcaagt acaactcccg gcacgagaaa 120gtgaatggct tggaggaagg cgtggagttc ctgccagtca acaacgtcaa gaaggtggaa 180aagcatggcc cggggcgctg ggtggtgctg gcagccgtgc tgatcggcct cctcttggtc 240ttgctgggga tcggcttcct ggtgtggcat ttgcagtacc gggacgtgcg tgtccagaag 300gtcttcaatg gctacatgag gatcacaaat gagaattttg tggatgccta cgagaactcc 360aactccactg agtttgtaag cctggccagc aaggtgaagg acgcgctgaa gctgctgtac 420agcggagtcc cattcctggg cccctaccac aaggagtcgg ctgtgacggc cttcagcgag 480ggcagcgtca tcgcctacta ctggtctgag ttcagcatcc cgcagcacct ggtggaggag 540gccgagcgcg tcatggccga ggagcgcgta gtcatgctgc ccccgcgggc gcgctccctg 600aagtcctttg tggtcacctc agtggtggct ttccccacgg actccaaaac agtacagagg 660acccaggaca acagctgcag ctttggcctg cacgcccgcg gtgtggagct gatgcgcttc 720accacgcccg gcttccctga cagcccctac cccgctcatg cccgctgcca gtgggccctg 780cggggggacg ccgactcagt gctgagcctc accttccgca gctttgacct tgcgtcctgc 840gacgagcgcg gcagcgacct ggtgacggtg tacaacaccc tgagccccat ggagccccac 900gccctggtgc agttgtgtgg cacctaccct ccctcctaca acctgacctt ccactcctcc 960cagaacgtcc tgctcatcac actgataacc aacactgagc ggcggcatcc cggctttgag 1020gccaccttct tccagctgcc taggatgagc agctgtggag gccgcttacg taaagcccag 1080gggacattca acagccccta ctacccaggc cactacccac ccaacattga ctgcacatgg 1140aacattgagg tgcccaacaa ccagcatgtg aaggtgcgct tcaaattctt ctacctgctg 1200gagcccggcg tgcctgcggg cacctgcccc aaggactacg tggagatcaa tggggagaaa 1260tactgcggag agaggtccca gttcgtcgtc accagcaaca gcaacaagat cacagttcgc 1320ttccactcag atcagtccta caccgacacc ggcttcttag ctgaatacct ctcctacgac 1380tccagtgacc catgcccggg gcagttcacg tgccgcacgg ggcggtgtat ccggaaggag 1440ctgcgctgtg atggctgggc cgactgcacc gaccacagcg atgagctcaa ctgcagttgc 1500gacgccggcc accagttcac gtgcaagaac aagttctgca agcccctctt ctgggtctgc 1560gacagtgtga acgactgcgg agacaacagc gacgagcagg ggtgcagttg tccggcccag 1620accttcaggt gttccaatgg gaagtgcctc tcgaaaagcc agcagtgcaa tgggaaggac 1680gactgtgggg acgggtccga cgaggcctcc tgccccaagg tgaacgtcgt cacttgtacc 1740aaacacacct accgctgcct caatgggctc tgcttgagca agggcaaccc tgagtgtgac 1800gggaaggagg actgtagcga cggctcagat gagaaggact gcgactgtgg gctgcggtca 1860ttcacgagac aggctcgtgt tgttgggggc acggatgcgg atgagggcga gtggccctgg 1920caggtaagcc tgcatgctct gggccagggc cacatctgcg gtgcttccct catctctccc 1980aactggctgg tctctgccgc acactgctac atcgatgaca gaggattcag gtactcagac 2040cccacgcagt ggacggcctt cctgggcttg cacgaccaga gccagcgcag cgcccctggg 2100gtgcaggagc gcaggctcaa gcgcatcatc tcccacccct tcttcaatga cttcaccttc 2160gactatgaca tcgcgctgct ggagctggag aaaccggcag agtacagctc catggtgcgg 2220cccatctgcc tgccggacgc ctcccatgtc ttccctgccg gcaaggccat ctgggtcacg 2280ggctggggac acacccagta tggaggcact ggcgcgctga tcctgcaaaa gggtgagatc 2340cgcgtcatca accagaccac ctgcgagaac ctcctgccgc agcagatcac gccgcgcatg 2400atgtgcgtgg gcttcctcag cggcggcgtg gactcctgcc agggtgattc cgggggaccc 2460ctgtccagcg tggaggcgga tgggcggatc ttccaggccg gtgtggtgag ctggggagac 2520ggctgcgctc agaggaacaa gccaggcgtg tacacaaggc tccctctgtt tcgggactgg 2580atcaaagaga acactggggt ataggggccg gggcacccaa gatgtgtaca cctgcggggc 2640cacccatcgt ccaccccagt gtgcacgcct gcaggctgga gactggaccg ctgactgcac 2700cagcgccccc agaacataca ctgtgaactc aatctccagg gctccaaatc tgcctagaaa 2760acctctcgct tcctcagcct ccaaagtgga gctgggaggt agaaggggag gacactggtg 2820gttctactga cccaactggg ggcaaaggtt tgaagacaca gcctcccccg ccagccccaa 2880gctgggccga ggcgcgtttg tgtatatctg cctcccctgt ctgtaaggag cagcgggaac 2940ggagcttcgg ggcctcctca gtgaaggtgg tggggctgcc ggatctgggc tgtggggccc 3000ttgggccacg ctcttgagga agcccaggct cggaggaccc tggaaaacag acgggtctga 3060gactgaaatt gttttaccag ctcccagggt ggacttcagt gtgtgtattt gtgtaaatga 3120543305DNAHomo sapiens 54agcggagctg cagccggaga aagaggaaga gggagagaga gcgcgccagg gcgagggcac 60cgccgccggt cgggcgcgct gggcctgccc ggaatcccgc cgcctgcgcc ccgcgccccg 120cgccctgcgg gccatgggag ccggccgccg gcagggacga cgcctgtgag acccgcgagc 180ggcctcgggg accatgggga gcgatcgggc ccgcaagggc ggagggggcc cgaaggactt 240cggcgcggga ctcaagtaca actcccggca cgagaaagtg aatggcttgg aggaaggcgt 300ggagttcctg ccagtcaaca acgtcaagaa ggtggaaaag catggcccgg ggcgctgggt 360ggtgctggca gccgtgctga tcggcctcct cttggtcttg ctggggatcg gcttcctggt 420gtggcatttg cagtaccggg acgtgcgtgt ccagaaggtc ttcaatggct acatgaggat 480cacaaatgag aattttgtgg atgcctacga gaactccaac tccactgagt ttgtaagcct 540ggccagcaag gtgaaggacg cgctgaagct gctgtacagc ggagtcccat tcctgggccc 600ctaccacaag gagtcggctg tgacggcctt cagcgagggc agcgtcatcg cctactactg 660gtctgagttc agcatcccgc agcacctggt ggaggaggcc gagcgcgtca tggccgagga 720gcgcgtagtc atgctgcccc cgcgggcgcg ctccctgaag tcctttgtgg tcacctcagt 780ggtggctttc cccacggact ccaaaacagt acagaggacc caggacaaca gctgcagctt 840tggcctgcac gcccgcggtg tggagctgat gcgcttcacc acgcccggct tccctgacag 900cccctacccc gctcatgccc gctgccagtg ggccctgcgg ggggacgccg actcagtgct 960gagcctcacc ttccgcagct ttgaccttgc gtcctgcgac gagcgcggca gcgacctggt 1020gacggtgtac aacaccctga gccccatgga gccccacgcc ctggtgcagt tgtgtggcac 1080ctaccctccc tcctacaacc tgaccttcca ctcctcccag aacgtcctgc tcatcacact 1140gataaccaac actgagcggc ggcatcccgg ctttgaggcc accttcttcc agctgcctag 1200gatgagcagc tgtggaggcc gcttacgtaa agcccagggg acattcaaca gcccctacta 1260cccaggccac tacccaccca acattgactg cacatggaac attgaggtgc ccaacaacca 1320gcatgtgaag gtgcgcttca aattcttcta cctgctggag cccggcgtgc ctgcgggcac 1380ctgccccaag gactacgtgg agatcaatgg ggagaaatac tgcggagaga ggtcccagtt 1440cgtcgtcacc agcaacagca acaagatcac agttcgcttc cactcagatc agtcctacac 1500cgacaccggc ttcttagctg aatacctctc ctacgactcc agtgacccat gcccggggca 1560gttcacgtgc cgcacggggc ggtgtatccg gaaggagctg cgctgtgatg gctgggccga 1620ctgcaccgac cacagcgatg agctcaactg cagttgcgac gccggccacc agttcacgtg 1680caagaacaag ttctgcaagc ccctcttctg ggtctgcgac agtgtgaacg actgcggaga 1740caacagcgac gagcaggggt gcagttgtcc ggcccagacc ttcaggtgtt ccaatgggaa 1800gtgcctctcg aaaagccagc agtgcaatgg gaaggacgac tgtggggacg ggtccgacga 1860ggcctcctgc cccaaggtga acgtcgtcac ttgtaccaaa cacacctacc gctgcctcaa 1920tgggctctgc ttgagcaagg gcaaccctga gtgtgacggg aaggaggact gtagcgacgg 1980ctcagatgag aaggactgcg actgtgggct gcggtcattc acgagacagg ctcgtgttgt 2040tgggggcacg gatgcggatg agggcgagtg gccctggcag gtaagcctgc atgctctggg 2100ccagggccac atctgcggtg cttccctcat ctctcccaac tggctggtct ctgccgcaca 2160ctgctacatc gatgacagag gattcaggta ctcagacccc acgcagtgga cggccttcct 2220gggcttgcac gaccagagcc agcgcagcgc ccctggggtg caggagcgca ggctcaagcg 2280catcatctcc caccccttct tcaatgactt caccttcgac tatgacatcg cgctgctgga 2340gctggagaaa ccggcagagt acagctccat ggtgcggccc atctgcctgc cggacgcctc 2400ccatgtcttc cctgccggca aggccatctg ggtcacgggc tggggacaca cccagtatgg 2460aggcactggc gcgctgatcc tgcaaaaggg tgagatccgc gtcatcaacc agaccacctg 2520cgagaacctc ctgccgcagc agatcacgcc gcgcatgatg tgcgtgggct tcctcagcgg 2580cggcgtggac tcctgccagg gtgattccgg gggacccctg tccagcgtgg aggcggatgg 2640gcggatcttc caggccggtg tggtgagctg gggagacggc tgcgctcaga ggaacaagcc 2700aggcgtgtac acaaggctcc ctctgtttcg ggactggatc aaagagaaca ctggggtata 2760ggggccgggg ccacccaaat gtgtacacct gcggggccac ccatcgtcca ccccagtgtg 2820cacgcctgca ggctggagac tggaccgctg actgcaccag cgcccccaga acatacactg 2880tgaactcaat ctccagggct ccaaatctgc ctagaaaacc tctcgcttcc tcagcctcca 2940aagtggagct gggaggtaga aggggaggac actggtggtt ctactgaccc aactgggggc 3000aaaggtttga agacacagcc tcccccgcca gccccaagct gggccgaggc gcgtttgtgt 3060atatctgcct cccctgtctg taaggagcag cgggaacgga gcttcggagc ctcctcagtg 3120aaggtggtgg ggctgccgga tctgggctgt ggggcccttg ggccacgctc ttgaggaagc 3180ccaggctcgg aggaccctgg aaaacagacg ggtctgagac tgaaattgtt ttaccagctc 3240ccagggtgga cttcagtgtg tgtatttgtg taaatgagta aaacatttta tttcttttta 3300ggtaa 3305553305DNAHomo sapiens 55agcggagctg cagccggaga aagaggaaga gggagagaga gcgcgccagg gcgagggcac 60cgccgccggt cgggcgcgct gggcctgccc ggaatcccgc cgcctgcgcc ccgcgccccg 120cgccctgcgg gccatgggag ccggccgccg gcagggacga cgcctgtgag acccgcgagc 180ggcctcgggg accatgggga gcgatcgggc ccgcaagggc ggagggggcc cgaaggactt 240cggcgcggga ctcaagtaca actcccggca cgagaaagtg aatggcttgg aggaaggcgt 300ggagttcctg ccagtcaaca acgtcaagaa ggtggaaaag catggcccgg ggcgctgggt 360ggtgctggca gccgtgctga tcggcctcct cttggtcttg ctggggatcg gcttcctggt 420gtggcatttg cagtaccggg acgtgcgtgt ccagaaggtc ttcaatggct acatgaggat 480cacaaatgag aattttgtgg atgcctacga gaactccaac tccactgagt ttgtaagcct 540ggccagcaag gtgaaggacg cgctgaagct gctgtacagc ggagtcccat tcctgggccc 600ctaccacaag gagtcggctg tgacggcctt cagcgagggc agcgtcatcg cctactactg 660gtctgagttc agcatcccgc agcacctggt ggaggaggcc gagcgcgtca tggccgagga 720gcgcgtagtc atgctgcccc cgcgggcgcg ctccctgaag tcctttgtgg tcacctcagt 780ggtggctttc cccacggact ccaaaacagt acagaggacc caggacaaca gctgcagctt 840tggcctgcac gcccgcggtg tggagctgat gcgcttcacc acgcccggct tccctgacag 900cccctacccc gctcatgccc gctgccagtg ggccctgcgg ggggacgccg actcagtgct 960gagcctcacc ttccgcagct ttgaccttgc gtcctgcgac gagcgcggca gcgacctggt 1020gacggtgtac aacaccctga gccccatgga gccccacgcc ctggtgcagt tgtgtggcac 1080ctaccctccc tcctacaacc tgaccttcca ctcctcccag aacgtcctgc tcatcacact 1140gataaccaac actgagcggc ggcatcccgg ctttgaggcc accttcttcc agctgcctag 1200gatgagcagc tgtggaggcc gcttacgtaa agcccagggg acattcaaca gcccctacta 1260cccaggccac tacccaccca acattgactg cacatggaac attgaggtgc ccaacaacca 1320gcatgtgaag gtgcgcttca aattcttcta cctgctggag cccggcgtgc ctgcgggcac 1380ctgccccaag gactacgtgg agatcaatgg ggagaaatac tgcggagaga ggtcccagtt 1440cgtcgtcacc agcaacagca acaagatcac agttcgcttc cactcagatc agtcctacac 1500cgacaccggc ttcttagctg aatacctctc ctacgactcc agtgacccat gcccggggca 1560gttcacgtgc cgcacggggc ggtgtatccg gaaggagctg cgctgtgatg gctgggccga 1620ctgcaccgac cacagcgatg agctcaactg cagttgcgac gccggccacc agttcacgtg 1680caagaacaag ttctgcaagc ccctcttctg ggtctgcgac agtgtgaacg actgcggaga 1740caacagcgac gagcaggggt gcagttgtcc ggcccagacc ttcaggtgtt ccaatgggaa 1800gtgcctctcg aaaagccagc agtgcaatgg gaaggacgac tgtggggacg ggtccgacga 1860ggcctcctgc cccaaggtga acgtcgtcac ttgtaccaaa cacacctacc gctgcctcaa 1920tgggctctgc ttgagcaagg gcaaccctga gtgtgacggg aaggaggact gtagcgacgg 1980ctcagatgag aaggactgcg actgtgggct gcggtcattc acgagacagg ctcgtgttgt 2040tgggggcacg gatgcggatg agggcgagtg gccctggcag gtaagcctgc atgctctggg 2100ccagggccac atctgcggtg cttccctcat ctctcccaac tggctggtct ctgccgcaca 2160ctgctacatc gatgacagag gattcaggta ctcagacccc acgcagtgga cggccttcct 2220gggcttgcac gaccagagcc agcgcagcgc ccctggggtg caggagcgca ggctcaagcg 2280catcatctcc caccccttct tcaatgactt caccttcgac tatgacatcg cgctgctgga 2340gctggagaaa ccggcagagt acagctccat ggtgcggccc atctgcctgc cggacgcctc 2400ccatgtcttc cctgccggca aggccatctg ggtcacgggc tggggacaca cccagtatgg 2460aggcactggc gcgctgatcc tgcaaaaggg tgagatccgc gtcatcaacc agaccacctg 2520cgagaacctc ctgccgcagc agatcacgcc gcgcatgatg tgcgtgggct tcctcagcgg 2580cggcgtggac tcctgccagg gtgattccgg gggacccctg tccagcgtgg aggcggatgg 2640gcggatcttc caggccggtg tggtgagctg gggagacggc tgcgctcaga ggaacaagcc 2700aggcgtgtac acaaggctcc ctctgtttcg ggactggatc aaagagaaca ctggggtata 2760ggggccgggg ccacccaaat gtgtacacct gcggggccac ccatcgtcca ccccagtgtg 2820cacgcctgca ggctggagac tggaccgctg actgcaccag cgcccccaga acatacactg 2880tgaactcaat ctccagggct ccaaatctgc ctagaaaacc tctcgcttcc tcagcctcca 2940aagtggagct gggaggtaga aggggaggac actggtggtt ctactgaccc aactgggggc 3000aaaggtttga agacacagcc tcccccgcca gccccaagct gggccgaggc gcgtttgtgt 3060atatctgcct cccctgtctg taaggagcag cgggaacgga gcttcggagc ctcctcagtg 3120aaggtggtgg ggctgccgga tctgggctgt ggggcccttg ggccacgctc ttgaggaagc 3180ccaggctcgg aggaccctgg aaaacagacg ggtctgagac tgaaattgtt ttaccagctc 3240ccagggtgga cttcagtgtg tgtatttgtg taaatgagta aaacatttta tttcttttta 3300ggtaa 330556408PRTHomo sapiens 56Met Arg Ser Ser Cys Val Leu Leu Thr Ala Leu Val Ala Leu Ala Ala1 5 10 15 Tyr Tyr Val Tyr Ile Pro Leu Pro Gly Ser Val Ser Asp Pro Trp Lys 20 25 30 Leu Met Leu Leu Asp Ala Thr Phe Arg Gly Ala Gln Gln Val Ser Asn 35 40 45 Leu Ile His Tyr Leu Gly Leu Ser His His Leu Leu Ala Leu Asn Phe 50 55 60 Ile Ile Val Ser Phe Gly Lys Lys Ser Ala Trp Ser Ser Ala Lys Val65 70 75 80 Lys Val Thr Asp Thr Asp Phe Asp Gly Val Glu Val Arg Val Phe Glu 85 90 95 Gly Pro Pro Lys Pro Glu Glu Pro Leu Lys Arg Ser Val Val Tyr Ile 100 105 110 His Gly Gly Gly Trp Ala Leu Ala Ser Ala Lys Ile Arg Tyr Tyr Asp 115 120 125 Glu Leu Cys Thr Ala Met Ala Glu Glu Leu Asn Ala Val Ile Val Ser 130 135 140 Ile Glu Tyr Arg Leu Val Pro Lys Val Tyr Phe Pro Glu Gln Ile His145 150 155 160 Asp Val Val Arg Ala Thr Lys Tyr Phe Leu Lys Pro Glu Val Leu Gln 165 170 175 Lys Tyr Met Val Asp Pro Gly Arg Ile Cys Ile Ser Gly Asp Ser Ala 180 185 190 Gly Gly Asn Leu Ala Ala Ala Leu Gly Gln Gln Phe Thr Gln Asp Ala 195 200 205 Ser Leu Lys Asn Lys Leu Lys Leu Gln Ala Leu Ile Tyr Pro Val Leu 210 215 220 Gln Ala Leu Asp Phe Asn Thr Pro Ser Tyr Gln Gln Asn Val Asn Thr225 230 235 240 Pro Ile Leu Pro Arg Tyr Val Met Val Lys Tyr Trp Val Asp Tyr Phe 245 250 255 Lys Gly Asn Tyr Asp Phe Val Gln Ala Met Ile Val Asn Asn His Thr 260 265 270 Ser Leu Asp Val Glu Glu Ala Ala Ala Val Arg Ala Arg Leu Asn Trp 275 280 285 Thr Ser Leu Leu Pro Ala Ser Phe Thr Lys Asn Tyr Lys Pro Val Val 290 295 300 Gln Thr Thr Gly Asn Ala Arg Ile Val Gln Glu Leu Pro Gln Leu Leu305 310 315 320 Asp Ala Arg Ser Ala Pro Leu Ile Ala Asp Gln Ala Val Leu Gln Leu 325 330 335 Leu Pro Lys Thr Tyr Ile Met Thr Cys Glu His Asp Val Leu Arg Asp 340 345 350 Asp Gly Ile Met Tyr Ala Lys Arg Leu Glu Ser Ala Gly Val Glu Val 355 360 365 Thr Leu Asp His Phe Glu Asp Gly Phe His Gly Cys Met Ile Phe Thr 370 375 380 Ser Trp Pro Thr Asn Phe Ser Val Gly Ile Arg Thr Arg Asn Ser Tyr385 390 395 400 Ile Lys Trp Leu Asp Gln Asn Leu 405 57440PRTHomo sapiens 57Met Ser Ser Cys Arg Gly Gln Lys Val Ala Gly Gly Leu Arg Val Val1 5 10 15 Ser Pro Phe Pro Leu Cys Gln Pro Ala Gly Glu Pro Ser

Gln Gly Lys 20 25 30 Met Arg Ser Ser Cys Val Leu Leu Thr Ala Leu Val Ala Leu Ala Ala 35 40 45 Tyr Tyr Val Tyr Ile Pro Leu Pro Gly Ser Val Ser Asp Pro Trp Lys 50 55 60 Leu Met Leu Leu Asp Ala Thr Phe Arg Gly Ala Gln Gln Val Ser Asn65 70 75 80 Leu Ile His Tyr Leu Gly Leu Ser His His Leu Leu Ala Leu Asn Phe 85 90 95 Ile Ile Val Ser Phe Gly Lys Lys Ser Ala Trp Ser Ser Ala Gln Val 100 105 110 Lys Val Thr Asp Thr Asp Phe Asp Gly Val Glu Val Arg Val Phe Glu 115 120 125 Gly Pro Pro Lys Pro Glu Glu Pro Leu Lys Arg Ser Val Val Tyr Ile 130 135 140 His Gly Gly Gly Trp Ala Leu Ala Ser Ala Lys Ile Arg Tyr Tyr Asp145 150 155 160 Glu Leu Cys Thr Ala Met Ala Glu Glu Leu Asn Ala Val Ile Val Ser 165 170 175 Ile Glu Tyr Arg Leu Val Pro Lys Val Tyr Phe Pro Glu Gln Ile His 180 185 190 Asp Val Val Arg Ala Thr Lys Tyr Phe Leu Lys Pro Glu Val Leu Gln 195 200 205 Lys Tyr Met Val Asp Pro Gly Arg Ile Cys Ile Ser Gly Asp Ser Ala 210 215 220 Gly Gly Asn Leu Ala Ala Ala Leu Gly Gln Gln Phe Thr Gln Asp Ala225 230 235 240 Ser Leu Lys Asn Lys Leu Lys Leu Gln Ala Leu Ile Tyr Pro Val Leu 245 250 255 Gln Ala Leu Asp Phe Asn Thr Pro Ser Tyr Gln Gln Asn Val Asn Thr 260 265 270 Pro Ile Leu Pro Arg Tyr Val Met Val Lys Tyr Trp Val Asp Tyr Phe 275 280 285 Lys Gly Asn Tyr Asp Phe Val Gln Ala Met Ile Val Asn Asn His Thr 290 295 300 Ser Leu Asp Val Glu Glu Ala Ala Ala Val Arg Ala Arg Leu Asn Trp305 310 315 320 Thr Ser Leu Leu Pro Ala Ser Phe Thr Lys Asn Tyr Lys Pro Val Val 325 330 335 Gln Thr Thr Gly Asn Ala Arg Ile Val Gln Glu Leu Pro Gln Leu Leu 340 345 350 Asp Ala Arg Ser Ala Pro Leu Ile Ala Asp Gln Ala Val Leu Gln Leu 355 360 365 Leu Pro Lys Thr Tyr Ile Leu Thr Cys Glu His Asp Val Leu Arg Asp 370 375 380 Asp Gly Ile Met Tyr Ala Lys Arg Leu Glu Ser Ala Gly Val Glu Val385 390 395 400 Thr Leu Asp His Phe Glu Asp Gly Phe His Gly Cys Met Ile Phe Thr 405 410 415 Ser Trp Pro Thr Asn Phe Ser Val Gly Ile Arg Thr Arg Asn Ser Tyr 420 425 430 Ile Lys Trp Leu Asp Gln Asn Leu 435 440 58408PRTHomo sapiens 58Met Arg Ser Ser Cys Val Leu Leu Thr Ala Leu Val Ala Leu Ala Ala1 5 10 15 Tyr Tyr Val Tyr Ile Pro Leu Pro Gly Ser Val Ser Asp Pro Trp Lys 20 25 30 Leu Met Leu Leu Asp Ala Thr Phe Arg Gly Ala Gln Gln Val Ser Asn 35 40 45 Leu Ile His Tyr Leu Gly Leu Ser His His Leu Leu Ala Leu Asn Phe 50 55 60 Ile Ile Val Ser Phe Gly Lys Lys Ser Ala Trp Ser Ser Ala Gln Val65 70 75 80 Lys Val Thr Asp Thr Asp Phe Asp Gly Val Glu Val Arg Val Phe Glu 85 90 95 Gly Pro Pro Lys Pro Glu Glu Pro Leu Lys Arg Ser Val Val Tyr Ile 100 105 110 His Gly Gly Gly Trp Ala Leu Ala Ser Ala Lys Ile Arg Tyr Tyr Asp 115 120 125 Glu Leu Cys Thr Ala Met Ala Glu Glu Leu Asn Ala Val Ile Val Ser 130 135 140 Ile Glu Tyr Arg Leu Val Pro Lys Val Tyr Phe Pro Glu Gln Ile His145 150 155 160 Asp Val Val Arg Ala Thr Lys Tyr Phe Leu Lys Pro Glu Val Leu Gln 165 170 175 Lys Tyr Met Val Asp Pro Gly Arg Ile Cys Ile Ser Gly Asp Ser Ala 180 185 190 Gly Gly Asn Leu Ala Ala Ala Leu Gly Gln Gln Phe Thr Gln Asp Ala 195 200 205 Ser Leu Lys Asn Lys Leu Lys Leu Gln Ala Leu Ile Tyr Pro Val Leu 210 215 220 Gln Ala Leu Asp Phe Asn Thr Pro Ser Tyr Gln Gln Asn Val Asn Thr225 230 235 240 Pro Ile Leu Pro Arg Tyr Val Met Val Lys Tyr Trp Val Asp Tyr Phe 245 250 255 Lys Gly Asn Tyr Asp Phe Val Gln Ala Met Ile Val Asn Asn His Thr 260 265 270 Ser Leu Asp Val Glu Glu Ala Ala Ala Val Arg Ala Arg Leu Asn Trp 275 280 285 Thr Ser Leu Leu Pro Ala Ser Phe Thr Lys Asn Tyr Lys Pro Val Val 290 295 300 Gln Thr Thr Gly Asn Ala Arg Ile Val Gln Glu Leu Pro Gln Leu Leu305 310 315 320 Asp Ala Arg Ser Ala Pro Leu Ile Ala Asp Gln Ala Val Leu Gln Leu 325 330 335 Leu Pro Lys Thr Tyr Ile Leu Thr Cys Glu His Asp Val Leu Arg Asp 340 345 350 Asp Gly Ile Met Tyr Ala Lys Arg Leu Glu Ser Ala Gly Val Glu Val 355 360 365 Thr Leu Asp His Phe Glu Asp Gly Phe His Gly Cys Met Ile Phe Thr 370 375 380 Ser Trp Pro Thr Asn Phe Ser Val Gly Ile Arg Thr Arg Asn Ser Tyr385 390 395 400 Ile Lys Trp Leu Asp Gln Asn Leu 405 59430PRTHomo sapiens 59Gly Gly Leu Arg Val Val Ser Pro Phe Pro Leu Cys Gln Pro Ala Gly1 5 10 15 Glu Pro Ser Arg Gly Lys Met Arg Ser Ser Cys Val Leu Leu Thr Ala 20 25 30 Leu Val Ala Leu Ala Thr Tyr Tyr Val Tyr Ile Pro Leu Pro Gly Ser 35 40 45 Val Ser Asp Pro Trp Lys Leu Met Leu Leu Asp Ala Thr Phe Arg Gly 50 55 60 Ala Gln Gln Val Ser Asn Leu Ile His Tyr Leu Gly Leu Ser His His65 70 75 80 Leu Leu Ala Leu Asn Phe Ile Ile Val Ser Phe Gly Lys Lys Ser Ala 85 90 95 Trp Ser Ser Ala Gln Val Lys Val Thr Asp Thr Asp Phe Asp Gly Val 100 105 110 Glu Val Arg Val Phe Glu Gly Pro Pro Lys Pro Glu Glu Pro Leu Lys 115 120 125 Arg Ser Val Val Tyr Ile His Gly Gly Gly Trp Ala Leu Ala Ser Ala 130 135 140 Lys Ile Arg Tyr Tyr Asp Glu Leu Cys Thr Ala Met Ala Glu Glu Leu145 150 155 160 Asn Ala Val Ile Val Ser Ile Glu Tyr Arg Leu Val Pro Lys Val Tyr 165 170 175 Phe Pro Glu Gln Ile His Asp Val Val Arg Ala Thr Lys Tyr Phe Leu 180 185 190 Lys Pro Glu Val Leu Gln Lys Tyr Met Val Asp Pro Gly Arg Ile Cys 195 200 205 Ile Ser Gly Asp Ser Ala Gly Gly Asn Leu Ala Ala Ala Leu Gly Gln 210 215 220 Gln Phe Thr Gln Asp Ala Ser Leu Lys Asn Lys Leu Lys Leu Gln Ala225 230 235 240 Leu Ile Tyr Pro Val Leu Gln Ala Leu Asp Phe Asn Thr Pro Ser Tyr 245 250 255 Gln Gln Asn Val Asn Thr Pro Ile Leu Pro Arg Tyr Val Met Val Lys 260 265 270 Tyr Trp Val Asp Tyr Phe Lys Gly Asn Tyr Asp Phe Val Gln Ala Met 275 280 285 Ile Val Asn Asn His Thr Ser Leu Asp Val Glu Glu Ala Ala Ala Val 290 295 300 Arg Ala Arg Leu Asn Trp Thr Ser Leu Leu Pro Ala Ser Phe Thr Lys305 310 315 320 Asn Tyr Lys Pro Val Val Gln Thr Thr Gly Asn Ala Arg Ile Val Gln 325 330 335 Glu Leu Pro Gln Leu Leu Asp Ala Arg Ser Ala Pro Leu Ile Ala Asp 340 345 350 Gln Ala Val Leu Gln Leu Leu Pro Lys Thr Tyr Ile Leu Thr Cys Glu 355 360 365 His Asp Val Leu Arg Asp Asp Gly Ile Met Tyr Ala Lys Arg Leu Glu 370 375 380 Ser Ala Gly Val Glu Val Thr Leu Asp His Phe Glu Asp Gly Phe His385 390 395 400 Gly Cys Met Ile Phe Thr Ser Trp Pro Thr Asn Phe Ser Val Gly Ile 405 410 415 Arg Thr Arg Asn Ser Tyr Ile Lys Trp Leu Asp Gln Asn Leu 420 425 430 604339DNAHomo sapiens 60atgcagtaca aaccagtgtc ctccagagtc cgctgtgcct acggccagag cagcgacaga 60gccttcctca aacctgtagt gactgccaca ctttgcaagg acaccgtaga gggggcatgt 120ccgcgctcca acttcctccc gacgcagcct ctgattggct cctgggctta taagaaacgc 180gtgaatgagc agctgccgcg ggcagaaagt tgccggaggt ctccgggtgg tatcgccctt 240tcctctttgc cagcccgctg gcgagccgag ccagggcaag atgaggtcgt cctgtgtcct 300gctcaccgcc ctggtggcgc tggccgccta ttacgtctac atcccgctgc ctggctccgt 360gtccgacccc tggaagctga tgctgctgga cgccactttc cggggtgcac agcaagtgag 420taacctgatc cactacctgg gactgagcca tcacctgctg gcactgaatt ttatcattgt 480ttcttttggc aaaaaaagcg cgtggtcttc tgcccaagtg aaggtgaccg acacagactt 540tgatggtgtg gaagtcagag tgtttgaagg ccctccgaag cccgaagagc cactgaaacg 600cagcgtcgtt tatatccacg gaggaggctg ggccttggca agtgcaaaaa tcaggtatta 660tgatgagctg tgtacagcaa tggctgagga attgaatgct gtcattgttt ccattgaata 720caggctagtt ccaaaggttt attttcctga gcaaattcat gatgttgtac gggccacaaa 780gtatttcctg aagccagaag tcttacagaa gtatatggtt gatccaggca gaatttgcat 840ttctggtgac agtgctggtg gaaatctggc tgctgccctt ggacaacagt ttactcaaga 900tgccagccta aaaaataagc tcaaactaca agctttaatt tatccagttc ttcaagcttt 960agattttaac acaccatctt atcagcaaaa tgtgaacacc ccaatcctgc cccgctatgt 1020catggtgaag tattgggtgg actacttcaa aggcaactat gactttgtgc aggcaatgat 1080cgttaacaat cacacttcac ttgatgtgga agaggctgct gctgtcaggg cccgtctaaa 1140ctggacatcc ctcttgcctg catccttcac aaagaactac aagcctgttg tacagaccac 1200aggcaatgcc aggattgtcc aggagcttcc tcagttgctg gatgcccgct ccgccccact 1260cattgcagac caggcagtgc tgcagctcct cccaaagacc tacattctga cgtgtgagca 1320tgatgtcctc agagacgatg gcatcatgta tgccaagcgt ttggagagtg ccggtgtgga 1380ggtgaccctg gatcactttg aggatggctt tcacggatgt atgattttca ctagctggcc 1440caccaacttc tcagtgggaa tccggactag gaatagttac atcaagtggc tagatcaaaa 1500cctgtaaagg agcaaaactt ccagaagcct cgagcccctc ttgacctcct acacctgctt 1560tggaaagaca tgcacttttt agttgactaa ttcttcctcc cattcccctc tacttgcgag 1620ttatggaatt tctattccat aactgaagtc tttatgataa cctaattttt aaaaatgaat 1680ttgactaact taagtgcaaa acatgtaaat ttggttccca gagtgggcca atctctctgt 1740tcttgttatc ttagccaact atactgatac ctacagctac agaaagcagg actaggaact 1800ggaaataact ttgggtcctg ccttcattag gacgttcttt ttagaagcag ttcttccagc 1860tctggatcat agagtgacct ttaataagtt aaaaaaacga ggactcctta attctgctag 1920agttaacctt gagttcagag cagtattaaa tgcgtgcact ttcaggtcag tactggggac 1980caagtaccct ctggtctttt gtgaatggat ggttttgttt cctatgggaa ttttggcaaa 2040ggttttctgg aaagaacaag tttctcaaag gactttcttc ctctagaatg ttcattttat 2100gagatcgcta tctgtaagtc cagttggatt acaggaatac ttgaaagtta ctttctacca 2160ctattagaaa atatgaagtc gcatgcactg gatatctata tatcattagg tttttgttgt 2220gtttttggtt atgctgtccc ccttctcctt ggggagatat ttgggagcaa acttatttag 2280atttagagta aacttttcat tatagagcaa gtaaaaacag acaaatgaaa caacctagtg 2340tttcacataa aaatacttct gacataaagt accaagagca gtgtgaatat acttggcata 2400gtcaaaaaag aaaatacatt taatattagt tcaaaattgt taaaaatacc tttagaaggt 2460ctagtctatt attgaaaact caattttttc acttatatgg ctttaaaatg gagctatttt 2520gctacaatat aatgtattgt ttattttttt aagttattta atgttaatat acatagctag 2580acttaaggtt tttcagaaag atgtccataa taaatattaa aaacaatggt attttttaaa 2640aaactgcctt agggttttaa aaccttccct acagttataa ccacgtgtaa ttttgtggaa 2700atgatataac agctattaat actactataa cataggcata aatattttcg tgtttatatg 2760catatacaag ttaaaataat tagaaactat gactgcgcct agtaaagtca tctaggttta 2820tagttcagta gcttaggcaa ggcacacact gctcatctcc gctttttagg gtcagaggaa 2880cacaagctca tgttctgagt gaagggcgta cactggcacc tggtgttgcc tagatccccc 2940atctcctcct tccagccagg tctggaagtt tcaacagccc aagcttaact tcatgtaaag 3000tcttcactgc cagtgggaac atctttgaca caacaagaca ctccaattgt gatttgagtt 3060gaggatctct gcctgccttc ctgccgtcct tccttcttcc ccgatccatg ctacttttag 3120gggctgcgga gagcagcagc agagctgagt aatgatacag ggcaccacgg agagaaagta 3180gaaccatttc actcctggga agatggggta tttcccactt ccagcaacga aataacaaat 3240gaaaagttgc atacttattg atgtattgta tgagccagta gcattttatg tacaaaacag 3300aagtcaatgc aacagtatgt atgtgtgcct gtgtgtgtat aaaaataacc attgaagcta 3360acttgctaat gtacttaggc aagccacttc ccatctctgg gcctcgtctt tcctccctct 3420aaaatcaaag agctgaatta tgtgatcctt gaggtctctt ccacttataa taccaactgt 3480cttgtcagac tggcaaatta tattggcctc tccttatgtg gtggtttttt tggtaggtca 3540tagttcctta tacacagaca cctgcatcat cgaaggtctt tttttcctaa aaaaaaaaaa 3600tgggatttta gttcttattc tgtgataact atcctcctca tataatacta ttctttttga 3660caccatttga aggaaccaat atttggacct tattttgagg ttgtctgtct cgaagaaaaa 3720gaaaataaaa tgtataggca gggttccttc aattggcatt ttccccagaa ttgtgagcca 3780aagcctatag taattgcaga cagcaaatga ttccggatct ctaaaaggct ctctcagatg 3840aaaagggagt aaaggaaaaa agaggtcaac cactgtttct gataatgtac ttgagtttca 3900ttgttctttt agtttgtatt cttataaaaa atgtttacac tctgcagatt gatttttttt 3960ttttagtact gtggctttct tttcctattt tatgaaaaaa atgataatct ttttgtaaaa 4020ttgtctgtga aatataaaca ttaatatata aagaaaaacc ttgaagtgct gtatagtgaa 4080gtataaatta atgttttatt gatttgtgaa gaatttaaga ctattatata attatcttgg 4140tggatctatt ttatgcatga ccttttaacc tttgactttg cttatttccc actacgaagg 4200ggaaggtaga ttttatgaat gattttaata gcaaatatat tttataaagt gaaaatccag 4260tgtggaggta gcaaagcatc tatctattct gaatcatgtt tggaaataaa attgctccat 4320ctgggaatgt gctttcatt 4339614339DNAHomo sapiens 61atgcagtaca aaccagtgtc ctccagagtc cgctgtgcct acggccagag cagcgacaga 60gccttcctca aacctgtagt gactgccaca ctttgcaagg acaccgtaga gggggcatgt 120ccgcgctcca acttcctccc gacgcagcct ctgattggct cctgggctta taagaaacgc 180gtgaatgagc agctgccgcg ggcagaaagt tgccggaggt ctccgggtgg tatcgccctt 240tcctctttgc cagcccgctg gcgagccgag ccagggcaag atgaggtcgt cctgtgtcct 300gctcaccgcc ctggtggcgc tggccgccta ttacgtctac atcccgctgc ctggctccgt 360gtccgacccc tggaagctga tgctgctgga cgccactttc cggggtgcac agcaagtgag 420taacctgatc cactacctgg gactgagcca tcacctgctg gcactgaatt ttatcattgt 480ttcttttggc aaaaaaagcg cgtggtcttc tgcccaagtg aaggtgaccg acacagactt 540tgatggtgtg gaagtcagag tgtttgaagg ccctccgaag cccgaagagc cactgaaacg 600cagcgtcgtt tatatccacg gaggaggctg ggccttggca agtgcaaaaa tcaggtatta 660tgatgagctg tgtacagcaa tggctgagga attgaatgct gtcattgttt ccattgaata 720caggctagtt ccaaaggttt attttcctga gcaaattcat gatgttgtac gggccacaaa 780gtatttcctg aagccagaag tcttacagaa gtatatggtt gatccaggca gaatttgcat 840ttctggtgac agtgctggtg gaaatctggc tgctgccctt ggacaacagt ttactcaaga 900tgccagccta aaaaataagc tcaaactaca agctttaatt tatccagttc ttcaagcttt 960agattttaac acaccatctt atcagcaaaa tgtgaacacc ccaatcctgc cccgctatgt 1020catggtgaag tattgggtgg actacttcaa aggcaactat gactttgtgc aggcaatgat 1080cgttaacaat cacacttcac ttgatgtgga agaggctgct gctgtcaggg cccgtctaaa 1140ctggacatcc ctcttgcctg catccttcac aaagaactac aagcctgttg tacagaccac 1200aggcaatgcc aggattgtcc aggagcttcc tcagttgctg gatgcccgct ccgccccact 1260cattgcagac caggcagtgc tgcagctcct cccaaagacc tacattctga cgtgtgagca 1320tgatgtcctc agagacgatg gcatcatgta tgccaagcgt ttggagagtg ccggtgtgga 1380ggtgaccctg gatcactttg aggatggctt tcacggatgt atgattttca ctagctggcc 1440caccaacttc tcagtgggaa tccggactag gaatagttac atcaagtggc tagatcaaaa 1500cctgtaaagg agcaaaactt ccagaagcct cgagcccctc ttgacctcct acacctgctt 1560tggaaagaca tgcacttttt agttgactaa ttcttcctcc cattcccctc tacttgcgag 1620ttatggaatt tctattccat aactgaagtc tttatgataa cctaattttt aaaaatgaat 1680ttgactaact taagtgcaaa acatgtaaat ttggttccca gagtgggcca atctctctgt 1740tcttgttatc ttagccaact atactgatac ctacagctac agaaagcagg actaggaact 1800ggaaataact ttgggtcctg ccttcattag gacgttcttt ttagaagcag ttcttccagc 1860tctggatcat agagtgacct ttaataagtt aaaaaaacga ggactcctta attctgctag 1920agttaacctt gagttcagag cagtattaaa tgcgtgcact ttcaggtcag tactggggac 1980caagtaccct ctggtctttt gtgaatggat ggttttgttt cctatgggaa ttttggcaaa 2040ggttttctgg aaagaacaag tttctcaaag gactttcttc ctctagaatg ttcattttat 2100gagatcgcta tctgtaagtc cagttggatt acaggaatac ttgaaagtta ctttctacca 2160ctattagaaa atatgaagtc gcatgcactg gatatctata tatcattagg tttttgttgt 2220gtttttggtt atgctgtccc ccttctcctt ggggagatat ttgggagcaa acttatttag 2280atttagagta aacttttcat tatagagcaa gtaaaaacag acaaatgaaa caacctagtg 2340tttcacataa aaatacttct gacataaagt accaagagca gtgtgaatat acttggcata 2400gtcaaaaaag aaaatacatt

taatattagt tcaaaattgt taaaaatacc tttagaaggt 2460ctagtctatt attgaaaact caattttttc acttatatgg ctttaaaatg gagctatttt 2520gctacaatat aatgtattgt ttattttttt aagttattta atgttaatat acatagctag 2580acttaaggtt tttcagaaag atgtccataa taaatattaa aaacaatggt attttttaaa 2640aaactgcctt agggttttaa aaccttccct acagttataa ccacgtgtaa ttttgtggaa 2700atgatataac agctattaat actactataa cataggcata aatattttcg tgtttatatg 2760catatacaag ttaaaataat tagaaactat gactgcgcct agtaaagtca tctaggttta 2820tagttcagta gcttaggcaa ggcacacact gctcatctcc gctttttagg gtcagaggaa 2880cacaagctca tgttctgagt gaagggcgta cactggcacc tggtgttgcc tagatccccc 2940atctcctcct tccagccagg tctggaagtt tcaacagccc aagcttaact tcatgtaaag 3000tcttcactgc cagtgggaac atctttgaca caacaagaca ctccaattgt gatttgagtt 3060gaggatctct gcctgccttc ctgccgtcct tccttcttcc ccgatccatg ctacttttag 3120gggctgcgga gagcagcagc agagctgagt aatgatacag ggcaccacgg agagaaagta 3180gaaccatttc actcctggga agatggggta tttcccactt ccagcaacga aataacaaat 3240gaaaagttgc atacttattg atgtattgta tgagccagta gcattttatg tacaaaacag 3300aagtcaatgc aacagtatgt atgtgtgcct gtgtgtgtat aaaaataacc attgaagcta 3360acttgctaat gtacttaggc aagccacttc ccatctctgg gcctcgtctt tcctccctct 3420aaaatcaaag agctgaatta tgtgatcctt gaggtctctt ccacttataa taccaactgt 3480cttgtcagac tggcaaatta tattggcctc tccttatgtg gtggtttttt tggtaggtca 3540tagttcctta tacacagaca cctgcatcat cgaaggtctt tttttcctaa aaaaaaaaaa 3600tgggatttta gttcttattc tgtgataact atcctcctca tataatacta ttctttttga 3660caccatttga aggaaccaat atttggacct tattttgagg ttgtctgtct cgaagaaaaa 3720gaaaataaaa tgtataggca gggttccttc aattggcatt ttccccagaa ttgtgagcca 3780aagcctatag taattgcaga cagcaaatga ttccggatct ctaaaaggct ctctcagatg 3840aaaagggagt aaaggaaaaa agaggtcaac cactgtttct gataatgtac ttgagtttca 3900ttgttctttt agtttgtatt cttataaaaa atgtttacac tctgcagatt gatttttttt 3960ttttagtact gtggctttct tttcctattt tatgaaaaaa atgataatct ttttgtaaaa 4020ttgtctgtga aatataaaca ttaatatata aagaaaaacc ttgaagtgct gtatagtgaa 4080gtataaatta atgttttatt gatttgtgaa gaatttaaga ctattatata attatcttgg 4140tggatctatt ttatgcatga ccttttaacc tttgactttg cttatttccc actacgaagg 4200ggaaggtaga ttttatgaat gattttaata gcaaatatat tttataaagt gaaaatccag 4260tgtggaggta gcaaagcatc tatctattct gaatcatgtt tggaaataaa attgctccat 4320ctgggaatgt gctttcatt 4339624339DNAHomo sapiens 62atgcagtaca aaccagtgtc ctccagagtc cgctgtgcct acggccagag cagcgacaga 60gccttcctca aacctgtagt gactgccaca ctttgcaagg acaccgtaga gggggcatgt 120ccgcgctcca acttcctccc gacgcagcct ctgattggct cctgggctta taagaaacgc 180gtgaatgagc agctgccgcg ggcagaaagt tgccggaggt ctccgggtgg tatcgccctt 240tcctctttgc cagcccgctg gcgagccgag ccagggcaag atgaggtcgt cctgtgtcct 300gctcaccgcc ctggtggcgc tggccgccta ttacgtctac atcccgctgc ctggctccgt 360gtccgacccc tggaagctga tgctgctgga cgccactttc cggggtgcac agcaagtgag 420taacctgatc cactacctgg gactgagcca tcacctgctg gcactgaatt ttatcattgt 480ttcttttggc aaaaaaagcg cgtggtcttc tgcccaagtg aaggtgaccg acacagactt 540tgatggtgtg gaagtcagag tgtttgaagg ccctccgaag cccgaagagc cactgaaacg 600cagcgtcgtt tatatccacg gaggaggctg ggccttggca agtgcaaaaa tcaggtatta 660tgatgagctg tgtacagcaa tggctgagga attgaatgct gtcattgttt ccattgaata 720caggctagtt ccaaaggttt attttcctga gcaaattcat gatgttgtac gggccacaaa 780gtatttcctg aagccagaag tcttacagaa gtatatggtt gatccaggca gaatttgcat 840ttctggtgac agtgctggtg gaaatctggc tgctgccctt ggacaacagt ttactcaaga 900tgccagccta aaaaataagc tcaaactaca agctttaatt tatccagttc ttcaagcttt 960agattttaac acaccatctt atcagcaaaa tgtgaacacc ccaatcctgc cccgctatgt 1020catggtgaag tattgggtgg actacttcaa aggcaactat gactttgtgc aggcaatgat 1080cgttaacaat cacacttcac ttgatgtgga agaggctgct gctgtcaggg cccgtctaaa 1140ctggacatcc ctcttgcctg catccttcac aaagaactac aagcctgttg tacagaccac 1200aggcaatgcc aggattgtcc aggagcttcc tcagttgctg gatgcccgct ccgccccact 1260cattgcagac caggcagtgc tgcagctcct cccaaagacc tacattctga cgtgtgagca 1320tgatgtcctc agagacgatg gcatcatgta tgccaagcgt ttggagagtg ccggtgtgga 1380ggtgaccctg gatcactttg aggatggctt tcacggatgt atgattttca ctagctggcc 1440caccaacttc tcagtgggaa tccggactag gaatagttac atcaagtggc tagatcaaaa 1500cctgtaaagg agcaaaactt ccagaagcct cgagcccctc ttgacctcct acacctgctt 1560tggaaagaca tgcacttttt agttgactaa ttcttcctcc cattcccctc tacttgcgag 1620ttatggaatt tctattccat aactgaagtc tttatgataa cctaattttt aaaaatgaat 1680ttgactaact taagtgcaaa acatgtaaat ttggttccca gagtgggcca atctctctgt 1740tcttgttatc ttagccaact atactgatac ctacagctac agaaagcagg actaggaact 1800ggaaataact ttgggtcctg ccttcattag gacgttcttt ttagaagcag ttcttccagc 1860tctggatcat agagtgacct ttaataagtt aaaaaaacga ggactcctta attctgctag 1920agttaacctt gagttcagag cagtattaaa tgcgtgcact ttcaggtcag tactggggac 1980caagtaccct ctggtctttt gtgaatggat ggttttgttt cctatgggaa ttttggcaaa 2040ggttttctgg aaagaacaag tttctcaaag gactttcttc ctctagaatg ttcattttat 2100gagatcgcta tctgtaagtc cagttggatt acaggaatac ttgaaagtta ctttctacca 2160ctattagaaa atatgaagtc gcatgcactg gatatctata tatcattagg tttttgttgt 2220gtttttggtt atgctgtccc ccttctcctt ggggagatat ttgggagcaa acttatttag 2280atttagagta aacttttcat tatagagcaa gtaaaaacag acaaatgaaa caacctagtg 2340tttcacataa aaatacttct gacataaagt accaagagca gtgtgaatat acttggcata 2400gtcaaaaaag aaaatacatt taatattagt tcaaaattgt taaaaatacc tttagaaggt 2460ctagtctatt attgaaaact caattttttc acttatatgg ctttaaaatg gagctatttt 2520gctacaatat aatgtattgt ttattttttt aagttattta atgttaatat acatagctag 2580acttaaggtt tttcagaaag atgtccataa taaatattaa aaacaatggt attttttaaa 2640aaactgcctt agggttttaa aaccttccct acagttataa ccacgtgtaa ttttgtggaa 2700atgatataac agctattaat actactataa cataggcata aatattttcg tgtttatatg 2760catatacaag ttaaaataat tagaaactat gactgcgcct agtaaagtca tctaggttta 2820tagttcagta gcttaggcaa ggcacacact gctcatctcc gctttttagg gtcagaggaa 2880cacaagctca tgttctgagt gaagggcgta cactggcacc tggtgttgcc tagatccccc 2940atctcctcct tccagccagg tctggaagtt tcaacagccc aagcttaact tcatgtaaag 3000tcttcactgc cagtgggaac atctttgaca caacaagaca ctccaattgt gatttgagtt 3060gaggatctct gcctgccttc ctgccgtcct tccttcttcc ccgatccatg ctacttttag 3120gggctgcgga gagcagcagc agagctgagt aatgatacag ggcaccacgg agagaaagta 3180gaaccatttc actcctggga agatggggta tttcccactt ccagcaacga aataacaaat 3240gaaaagttgc atacttattg atgtattgta tgagccagta gcattttatg tacaaaacag 3300aagtcaatgc aacagtatgt atgtgtgcct gtgtgtgtat aaaaataacc attgaagcta 3360acttgctaat gtacttaggc aagccacttc ccatctctgg gcctcgtctt tcctccctct 3420aaaatcaaag agctgaatta tgtgatcctt gaggtctctt ccacttataa taccaactgt 3480cttgtcagac tggcaaatta tattggcctc tccttatgtg gtggtttttt tggtaggtca 3540tagttcctta tacacagaca cctgcatcat cgaaggtctt tttttcctaa aaaaaaaaaa 3600tgggatttta gttcttattc tgtgataact atcctcctca tataatacta ttctttttga 3660caccatttga aggaaccaat atttggacct tattttgagg ttgtctgtct cgaagaaaaa 3720gaaaataaaa tgtataggca gggttccttc aattggcatt ttccccagaa ttgtgagcca 3780aagcctatag taattgcaga cagcaaatga ttccggatct ctaaaaggct ctctcagatg 3840aaaagggagt aaaggaaaaa agaggtcaac cactgtttct gataatgtac ttgagtttca 3900ttgttctttt agtttgtatt cttataaaaa atgtttacac tctgcagatt gatttttttt 3960ttttagtact gtggctttct tttcctattt tatgaaaaaa atgataatct ttttgtaaaa 4020ttgtctgtga aatataaaca ttaatatata aagaaaaacc ttgaagtgct gtatagtgaa 4080gtataaatta atgttttatt gatttgtgaa gaatttaaga ctattatata attatcttgg 4140tggatctatt ttatgcatga ccttttaacc tttgactttg cttatttccc actacgaagg 4200ggaaggtaga ttttatgaat gattttaata gcaaatatat tttataaagt gaaaatccag 4260tgtggaggta gcaaagcatc tatctattct gaatcatgtt tggaaataaa attgctccat 4320ctgggaatgt gctttcatt 4339634116DNAHomo sapiens 63cggaggtctc cgggtggtat cgccctttcc tctttgccag cccgctggcg agccgagccg 60gggcaagatg aggtcgtcct gtgtcctgct caccgccctg gtggcgctgg ccacctatta 120cgtctacatc ccgctgcctg gctccgtgtc cgacccctgg aagctgatgc tgctggacgc 180cactttccgg ggtgcacagc aagtgagtaa cctgatccac tacctgggac tgagccatca 240cctgctggca ctgaatttta tcattgtttc ttttggcaaa aaaagcgcgt ggtcttctgc 300ccaagtgaag gtgaccgaca cagactttga tggtgtggaa gtcagagtgt ttgaaggccc 360tccgaagccc gaagagccac tgaaacgcag cgtcgtttat atccacggag gaggctgggc 420cttggcaagt gcaaaaatca ggtattatga tgagctgtgt acagcaatgg ctgaggaatt 480gaatgctgtc attgtttcca ttgaatacag gctagttcca aaggtttatt ttcctgagca 540aattcatgat gttgtacggg ccacaaagta tttcctgaag ccagaagtct tacagaagta 600tatggttgat ccaggcagaa tttgcatttc tggtgacagt gctggtggaa atctggctgc 660tgcccttgga caacagttta ctcaagatgc cagcctaaaa aataagctca aactacaagc 720tttaatttat ccagttcttc aagctttaga ttttaacaca ccatcttatc agcaaaatgt 780gaacacccca atcctgcccc gctatgtcat ggtgaagtat tgggtggact acttcaaagg 840caactatgac tttgtgcagg caatgatcgt taacaatcac acttcacttg atgtggaaga 900ggctgctgct gtcagggccc gtctaaactg gacatccctc ttgcctgcat ccttcacaaa 960gaactacaag cctgttgtac agaccacagg caatgccagg attgtccagg agcttcctca 1020gttgctggat gcccgctccg ccccactcat tgcagaccag gcagtgctgc agctcctccc 1080aaagacctac attctgacgt gtgagcatga tgtcctcaga gacgatggca tcatgtatgc 1140caagcgtttg gagagtgccg gtgtggaggt gaccctggat cactttgagg atggctttca 1200cggatgtatg attttcacta gctggcccac caacttctca gtgggaatcc ggactaggaa 1260tagttacatc aagtggctag atcaaaacct gtaaaggagc aaaacttcca gaagcctcga 1320gcccctcttg acctcctaca cctgctttgg aaagacatgc actttttagt tgactaattc 1380ttcctcccat tcccctctac ttgcgagtta tggaatttct attccataac tgaagtcttt 1440atgataacct aatttttaaa aatgaatttg actaacttaa gtgcaaaaca tgtaaatttg 1500gttcccagag tgggccaatc tctctgttct tgttatctta gccaactata ctcataccta 1560cagctacaga aagcaggact aggaactgga aataactttg ggtcctgcct tcattaggac 1620gttcttttta gaagcagttc ttccagctct ggatcataga gtgaccttta ataagttaaa 1680aaaacgagga ctccttaatt ctgctagagt taaccttgag ttcagagcag tattaaatgc 1740gtgcactttc aggtcagtac tggggaccaa gtaccctctg gtcttttgtg aatggatggt 1800tttgtttcct atgggaattt tggcaaaggt tttctggaaa gaacaagttt ctcaaaggac 1860tttcttcctc tagaatgttc attttatgag atcgctatct gtaagtccag ttggattaca 1920ggaatacttg aaagttactt tctaccacta ttagaaaata tgaagtcgca tgcactggat 1980atctatatat cattaggttt ttgttgtgtt tttggttatg ctgtccccct tctccttggg 2040gagatatttg ggagcaaact tatttagatt tagagtaaac ttttcattat agagcaagta 2100aaaacagaca aatgaaacaa cctagtgttt cacataaaaa tacttctgac ataaagtacc 2160aagagcagtg tgaatatact tggcatagtc aaaaaagaaa atacatttaa tattagttaa 2220aaattgttaa aaataccttt agaaggtcta gtctattatt gaaaactcaa ttttttcact 2280tatatggctt taaaatggag ctattttgct acaatataat gtattgttta tttttttaag 2340ttatttaatg ttaatataca tagctagact taaggttttt cagaaagatg tccataataa 2400atattaaaaa caatggtatt tttaaaaaaa ctgccttagg gttttaaaac cttccctaca 2460gttataacca cgtgtaattt tgtggaaatg atataacagc tattaatact actataacat 2520aggcataaat attttcgtgt ttatatgcat atacaagtta aaataattag aaactatgac 2580tgcgcctagt aaagtcatct aggtttatag ttcagtagct taggcaaggc acacactgct 2640catctccgct ttttagggtc agaggaacac aagctcatgt tctgagtgaa gggcgtacac 2700tggcacctgg tgttgcctag atcccccatc tcctccttcc agccaggtct ggaagtttca 2760acagcccaag cttaacttca tgtaaagtct tcactgccag tgggaacatc tttgacacaa 2820caagacactc caattgtgat ttgagttgag gatctctgcc tgccttcctg ccgtccttcc 2880ttcttccccg atccatgcta cttttagggg ctgcggagag cagcagcaga gctgagtaat 2940gatacagggc accacggaga gaaagtagaa ccatttcact cctgggaaga tggggtattt 3000cccacttcca gcaacgaaat aacaaatgaa aagttgcata cttattgatg tattgtatga 3060gccagtagca ttttatgtac aaaacagaag tcaatgcaac agtatgtatg tgtgcctgtg 3120tgtgtataaa aataaccatt gaagctaact tgctaatgta cttaggcaag ccacttccca 3180tctctgggcc tcgtctttcc tccctctaaa atcaaagagc tgaattatgt gatccttgag 3240gtctcttcca cttataatac caactgtctt gtcagactgg caaattatat tggcctctcc 3300ttatgtggtg gtttttttgg taggtcatag ttccttatac acggacacct gcatcatcga 3360aggtcttttt ttcctaaaaa aaaaaaatgg gattttagtt cttattctgt gataactatc 3420ctcctcatat aatactattc tttttgacac catttgaagg aaccaatatt tggaccttat 3480tttgaggttg tctgtctcga agaaaaagaa aataaaatgt ataggcaggg ttccttcaat 3540tggcattttc cccagaattg tgagccaaag cctatagtaa ttgcagacag caaatgattc 3600cggatctcta aaaggctctc tcagatgaaa agggagtaaa ggaaaaaaga gggaggtcaa 3660ccactgtttc tgataatgta cttgagtttc attgttcttt tagtttgtat tcttataaaa 3720aatgtttaca ctctgcagat tgattttttt tttttagtac tgtggctttc ttttcctatt 3780ttatgaaaaa aatgataatc tttttgtaaa attgtctgtg aaatataaac attaatatat 3840aaagaaaaac cttgaagtgc tgtatagtga agtataaatt aatgttttat tgatttgtga 3900agaatttaag actattatat aattatcttg gtggatctat tttatgcatg accttttaac 3960ctttgacttt gcttatttcc cactacgaag gggaaggtag attttatgaa tgattttaat 4020agcaaatata ttttataaag tgaaaatcca gtgtggaggt agcaaagcat ctatctattc 4080tgaatcatgt ttggaaataa aattgctcca tctggg 411664526PRTHomo sapiens 64Met Arg Cys Ala Leu Ala Leu Ser Ala Leu Leu Leu Leu Leu Ser Thr1 5 10 15 Pro Pro Leu Leu Pro Ser Ser Pro Ser Pro Ser Pro Ser Pro Ser Gln 20 25 30 Asn Ala Thr Gln Thr Thr Thr Asp Ser Ser Asn Lys Thr Ala Pro Thr 35 40 45 Pro Ala Ser Ser Val Thr Ile Met Ala Thr Asp Thr Ala Gln Gln Ser 50 55 60 Thr Val Pro Thr Ser Lys Ala Asn Glu Ile Leu Ala Ser Val Lys Ala65 70 75 80 Thr Thr Leu Gly Val Ser Ser Asp Ser Pro Gly Thr Thr Thr Leu Ala 85 90 95 Gln Gln Val Ser Gly Pro Val Asn Thr Thr Val Ala Arg Gly Gly Gly 100 105 110 Ser Gly Asn Pro Thr Thr Thr Ile Glu Ser Pro Lys Ser Thr Lys Ser 115 120 125 Ala Asp Thr Thr Thr Val Ala Thr Ser Thr Ala Thr Ala Lys Pro Asn 130 135 140 Thr Thr Ser Ser Gln Asn Gly Ala Glu Asp Thr Thr Asn Ser Gly Gly145 150 155 160 Lys Ser Ser His Ser Val Thr Thr Asp Leu Thr Ser Thr Lys Ala Glu 165 170 175 His Leu Thr Thr Pro His Pro Thr Ser Pro Leu Ser Pro Arg Gln Pro 180 185 190 Thr Ser Thr His Pro Val Ala Thr Pro Thr Ser Ser Gly His Asp His 195 200 205 Leu Met Lys Ile Ser Ser Ser Ser Ser Thr Val Ala Ile Pro Gly Tyr 210 215 220 Thr Phe Thr Ser Pro Gly Met Thr Thr Thr Leu Pro Ser Ser Val Ile225 230 235 240 Ser Gln Arg Thr Gln Gln Thr Ser Ser Gln Met Pro Ala Ser Ser Thr 245 250 255 Ala Pro Ser Ser Gln Glu Thr Val Gln Pro Thr Ser Pro Ala Thr Ala 260 265 270 Leu Arg Thr Pro Thr Leu Pro Glu Thr Met Ser Ser Ser Pro Thr Ala 275 280 285 Ala Ser Thr Thr His Arg Tyr Pro Lys Thr Pro Ser Pro Thr Val Ala 290 295 300 His Glu Ser Asn Trp Ala Lys Cys Glu Asp Leu Glu Thr Gln Thr Gln305 310 315 320 Ser Glu Lys Gln Leu Val Leu Asn Leu Thr Gly Asn Thr Leu Cys Ala 325 330 335 Gly Gly Ala Ser Asp Glu Lys Leu Ile Ser Leu Ile Cys Arg Ala Val 340 345 350 Lys Ala Thr Phe Asn Pro Ala Gln Asp Lys Cys Gly Ile Arg Leu Ala 355 360 365 Ser Val Pro Gly Ser Gln Thr Val Val Val Lys Glu Ile Thr Ile His 370 375 380 Thr Lys Leu Pro Ala Lys Asp Val Tyr Glu Arg Leu Lys Asp Lys Trp385 390 395 400 Asp Glu Leu Lys Glu Ala Gly Val Ser Asp Met Lys Leu Gly Asp Gln 405 410 415 Gly Pro Pro Glu Glu Ala Glu Asp Arg Phe Ser Met Pro Leu Ile Ile 420 425 430 Thr Ile Val Cys Met Ala Ser Phe Leu Leu Leu Val Ala Ala Leu Tyr 435 440 445 Gly Cys Cys His Gln Arg Leu Ser Gln Arg Lys Asp Gln Gln Arg Leu 450 455 460 Thr Glu Glu Leu Gln Thr Val Glu Asn Gly Tyr His Asp Asn Pro Thr465 470 475 480 Leu Glu Val Met Glu Thr Ser Ser Glu Met Gln Glu Lys Lys Val Val 485 490 495 Ser Leu Asn Gly Glu Leu Gly Asp Ser Trp Ile Val Pro Leu Asp Asn 500 505 510 Leu Thr Lys Asp Asp Leu Asp Glu Glu Glu Asp Thr His Leu 515 520 525 65528PRTHomo sapiens 65Met Arg Cys Ala Leu Ala Leu Ser Ala Leu Leu Leu Leu Leu Ser Thr1 5 10 15 Pro Pro Leu Leu Pro Ser Ser Pro Ser Pro Ser Pro Ser Pro Ser Pro 20 25 30 Ser Gln Asn Ala Thr Gln Thr Thr Thr Asp Ser Ser Asn Lys Thr Ala 35 40 45 Pro Thr Pro Ala Ser Ser Val Thr Ile Met Ala Thr Asp Thr Ala Gln 50 55 60 Gln Ser Thr Val Pro Thr Ser Lys Ala Asn Glu Ile Leu Ala Ser Val65 70 75 80 Lys Ala Thr Thr Leu Gly Val Ser Ser Asp Ser Pro Gly Thr Thr Thr 85 90 95 Leu Ala Gln Gln Val Ser Gly Pro Val Asn Thr Thr Val Ala Arg Gly 100 105 110 Gly Gly Ser Gly Asn Pro Thr Thr Thr Ile Glu Ser Pro Lys Ser Thr 115 120 125 Lys Ser Ala Asp Thr Thr Thr Val Ala Thr Ser Thr Ala Thr Ala Lys 130 135 140 Pro Asn Thr Thr Ser Ser Gln Asn Gly Ala Glu Asp Thr Thr Asn Ser145 150 155 160 Gly Gly Lys Ser Ser His Ser Val Thr Thr Asp

Leu Thr Ser Thr Lys 165 170 175 Ala Glu His Leu Thr Thr Pro His Pro Thr Ser Pro Leu Ser Pro Arg 180 185 190 Gln Pro Thr Leu Thr His Pro Val Ala Thr Pro Thr Ser Ser Gly His 195 200 205 Asp His Leu Met Lys Ile Ser Ser Ser Ser Ser Thr Val Ala Ile Pro 210 215 220 Gly Tyr Thr Phe Thr Ser Pro Gly Met Thr Thr Thr Leu Pro Ser Ser225 230 235 240 Val Ile Ser Gln Arg Thr Gln Gln Thr Ser Ser Gln Met Pro Ala Ser 245 250 255 Ser Thr Ala Pro Ser Ser Gln Glu Thr Val Gln Pro Thr Ser Pro Ala 260 265 270 Thr Ala Leu Arg Thr Pro Thr Leu Pro Glu Thr Met Ser Ser Ser Pro 275 280 285 Thr Ala Ala Ser Thr Thr His Arg Tyr Pro Lys Thr Pro Ser Pro Thr 290 295 300 Val Ala His Glu Ser Asn Trp Ala Lys Cys Glu Asp Leu Glu Thr Gln305 310 315 320 Thr Gln Ser Glu Lys Gln Leu Val Leu Asn Leu Thr Gly Asn Thr Leu 325 330 335 Cys Ala Gly Gly Ala Ser Asp Glu Lys Leu Ile Ser Leu Ile Cys Arg 340 345 350 Ala Val Lys Ala Thr Phe Asn Pro Ala Gln Asp Lys Cys Gly Ile Arg 355 360 365 Leu Ala Ser Val Pro Gly Ser Gln Thr Val Val Val Lys Glu Ile Thr 370 375 380 Ile His Thr Lys Leu Pro Ala Lys Asp Val Tyr Glu Arg Leu Lys Asp385 390 395 400 Lys Trp Asp Glu Leu Lys Glu Ala Gly Val Ser Asp Met Lys Leu Gly 405 410 415 Asp Gln Gly Pro Pro Glu Glu Ala Glu Asp Arg Phe Ser Met Pro Leu 420 425 430 Ile Ile Thr Ile Val Cys Met Ala Ser Phe Leu Leu Leu Val Ala Ala 435 440 445 Leu Tyr Gly Cys Cys His Gln Arg Leu Ser Gln Arg Lys Asp Gln Gln 450 455 460 Arg Leu Thr Glu Glu Leu Gln Thr Val Glu Asn Gly Tyr His Asp Asn465 470 475 480 Pro Thr Leu Glu Val Met Glu Thr Ser Ser Glu Met Gln Glu Lys Lys 485 490 495 Val Val Ser Leu Asn Gly Glu Leu Gly Asp Ser Trp Ile Val Pro Leu 500 505 510 Asp Asn Leu Thr Lys Asp Asp Leu Asp Glu Glu Glu Asp Thr His Leu 515 520 525 66573PRTHomo sapiens 66Met Cys Gly Ile Phe Ala Tyr Leu Asn Tyr His Val Pro Arg Thr Arg1 5 10 15 Arg Glu Ile Pro Gly Asp Pro Asn Gln Arg Pro Gln Arg Leu Glu Tyr 20 25 30 Arg Ala His Asp Gly Leu Gly Val Gly Phe Asp Gly Gly Asn Asp Lys 35 40 45 Asp Trp Glu Ala Asn Ala Cys Lys Ile Gln Leu Ile Lys Lys Lys Gly 50 55 60 Lys Val Lys Ala Leu Asp Glu Glu Val His Lys Gln Gln Asp Met Asp65 70 75 80 Leu Asp Ile Glu Phe Asp Val His Leu Gly Ile Ala His Thr Arg Trp 85 90 95 Ala Thr His Gly Glu Pro Ser Pro Val Asn Ser His Pro Gln Arg Ser 100 105 110 Asp Lys Asn Asn Glu Phe Ile Val Ile His Asn Gly Ile Ile Thr Asn 115 120 125 Tyr Lys Asp Leu Lys Lys Phe Leu Glu Ser Lys Gly Tyr Asp Phe Glu 130 135 140 Ser Glu Thr Asp Thr Glu Thr Ile Ala Lys Leu Val Lys Tyr Met Tyr145 150 155 160 Asp Asn Arg Glu Ser Gln Asp Thr Ser Phe Thr Thr Leu Val Glu Arg 165 170 175 Val Ile Gln Gln Leu Glu Gly Ala Phe Ala Leu Val Phe Lys Ser Val 180 185 190 His Phe Pro Gly Gln Ala Val Gly Thr Arg Arg Gly Ser Pro Leu Leu 195 200 205 Ile Gly Val Arg Ser Glu His Lys Leu Ser Thr Asp His Ile Pro Ile 210 215 220 Leu Tyr Arg Thr Gly Lys Asp Lys Lys Gly Ser Cys Asn Leu Ser Arg225 230 235 240 Val Asp Ser Thr Thr Cys Leu Phe Pro Val Glu Glu Lys Ala Val Glu 245 250 255 Tyr Tyr Phe Ala Ser Asp Ala Ser Ala Val Ile Glu His Thr Asn Arg 260 265 270 Val Ile Phe Leu Glu Asp Asp Asp Val Ala Ala Val Val Asp Gly Arg 275 280 285 Leu Ser Ile His Arg Ile Lys Arg Thr Ala Gly Asp His Pro Gly Arg 290 295 300 Ala Val Gln Thr Leu Gln Met Glu Leu Gln Gln Ile Met Lys Gly Asn305 310 315 320 Phe Ser Ser Phe Met Gln Lys Glu Ile Phe Glu Gln Pro Glu Ser Val 325 330 335 Val Asn Thr Met Arg Gly Arg Val Asn Phe Asp Asp Tyr Thr Val Asn 340 345 350 Leu Gly Gly Leu Lys Asp His Ile Lys Glu Ile Gln Arg Cys Arg Arg 355 360 365 Leu Ile Leu Ile Ala Cys Gly Thr Ser Tyr His Ala Gly Val Ala Thr 370 375 380 Arg Gln Val Leu Glu Glu Leu Thr Glu Leu Pro Val Met Val Glu Leu385 390 395 400 Ala Ser Asp Phe Leu Asp Arg Asn Thr Pro Val Phe Arg Asp Asp Val 405 410 415 Cys Phe Phe Leu Ser Gln Ser Gly Glu Thr Ala Asp Thr Leu Met Gly 420 425 430 Leu Arg Tyr Cys Lys Glu Arg Gly Ala Leu Thr Val Gly Ile Thr Asn 435 440 445 Thr Val Gly Ser Ser Ile Ser Arg Glu Thr Asp Cys Gly Val His Ile 450 455 460 Asn Ala Gly Pro Glu Ile Gly Val Ala Ser Thr Lys Ala Tyr Thr Ser465 470 475 480 Gln Phe Val Ser Leu Val Met Phe Ala Leu Met Met Cys Asp Asp Arg 485 490 495 Ile Ser Met Gln Glu Arg Arg Lys Glu Ile Met Leu Gly Leu Lys Arg 500 505 510 Leu Pro Asp Leu Ile Lys Glu Val Leu Ser Met Asp Asp Glu Ile Gln 515 520 525 Lys Leu Ala Thr Glu Leu Tyr His Gln Lys Ser Val Leu Ile Met Gly 530 535 540 Arg Gly Tyr His Tyr Ala Thr Cys Leu Glu Gly Ala Leu Lys Ile Lys545 550 555 560 Glu Ile Thr Tyr Met His Ser Glu Gly Ile Leu Leu Cys 565 570 67518PRTHomo sapiens 67Met Arg Cys Ala Leu Ala Leu Ser Ala Leu Leu Leu Leu Leu Ser Thr1 5 10 15 Pro Pro Ser Pro Ser Pro Ser Gln Asn Ala Thr Gln Thr Thr Thr Asp 20 25 30 Ser Ser Asn Lys Thr Ala Pro Thr Pro Ala Ser Ser Val Thr Ile Met 35 40 45 Ala Thr Asp Thr Ala Gln Gln Ser Thr Val Pro Thr Ser Lys Ala Asn 50 55 60 Glu Ile Leu Ala Ser Val Lys Ala Thr Thr Leu Gly Val Ser Ser Asp65 70 75 80 Ser Pro Gly Thr Thr Thr Leu Ala Gln Gln Val Ser Gly Pro Val Asn 85 90 95 Thr Thr Val Ala Arg Gly Gly Gly Ser Gly Asn Pro Thr Thr Thr Ile 100 105 110 Glu Ser Pro Lys Ser Thr Lys Ser Ala Asp Thr Thr Thr Val Ala Thr 115 120 125 Ser Thr Ala Thr Ala Lys Pro Asn Thr Thr Ser Ser Gln Asn Gly Ala 130 135 140 Glu Asp Thr Thr Asn Ser Gly Gly Lys Ser Ser His Ser Val Thr Thr145 150 155 160 Asp Leu Thr Ser Thr Lys Ala Glu His Leu Thr Thr Pro His Pro Thr 165 170 175 Ser Pro Leu Ser Pro Arg Gln Pro Thr Ser Thr His Pro Val Ala Thr 180 185 190 Pro Thr Ser Ser Gly His Asp His Leu Met Lys Ile Ser Ser Ser Ser 195 200 205 Ser Thr Val Ala Ile Pro Gly Tyr Thr Phe Ala Ser Pro Gly Met Thr 210 215 220 Thr Thr Leu Pro Ser Ser Val Ile Ser Gln Arg Thr Gln Gln Thr Ser225 230 235 240 Ser Gln Met Pro Ala Ser Ser Thr Ala Pro Ser Ser Gln Glu Thr Val 245 250 255 Gln Pro Thr Ser Pro Ala Thr Ala Leu Arg Thr Pro Thr Leu Pro Glu 260 265 270 Thr Met Ser Ser Ser Pro Thr Ala Ala Ser Thr Thr His Arg Tyr Pro 275 280 285 Lys Thr Pro Ser Pro Thr Val Ala His Glu Ser Asn Trp Ala Lys Cys 290 295 300 Glu Asp Leu Glu Thr Gln Thr Gln Ser Glu Lys Gln Leu Val Leu Asn305 310 315 320 Leu Thr Gly Asn Thr Leu Cys Ala Gly Gly Ala Ser Asp Glu Lys Leu 325 330 335 Ile Ser Leu Ile Cys Arg Ala Val Lys Ala Thr Phe Asn Pro Ala Gln 340 345 350 Asp Lys Cys Gly Ile Arg Leu Ala Ser Val Pro Gly Ser Gln Thr Val 355 360 365 Val Val Lys Glu Ile Thr Ile His Thr Lys Leu Pro Ala Lys Asp Val 370 375 380 Tyr Glu Arg Leu Lys Asp Lys Trp Asp Glu Leu Lys Glu Ala Gly Val385 390 395 400 Ser Asp Met Lys Leu Gly Asp Gln Gly Pro Pro Glu Glu Ala Glu Asp 405 410 415 Arg Phe Ser Met Pro Leu Ile Ile Thr Ile Val Cys Met Ala Ser Phe 420 425 430 Leu Leu Leu Val Ala Ala Leu Tyr Gly Cys Cys His Gln Arg Leu Ser 435 440 445 Gln Arg Lys Asp Gln Gln Arg Leu Thr Glu Glu Leu Gln Thr Val Glu 450 455 460 Asn Gly Tyr His Asp Asn Pro Thr Leu Glu Val Met Glu Thr Ser Ser465 470 475 480 Glu Met Gln Glu Lys Lys Val Val Ser Leu Asn Gly Glu Leu Gly Asp 485 490 495 Ser Trp Ile Val Pro Leu Asp Asn Leu Thr Lys Asp Asp Leu Asp Glu 500 505 510 Glu Glu Asp Thr His Leu 515 685880DNAHomo sapiens 68agacgccgcc caggacgcag ccgccgccgc cgccgctcct ctgccactgg ctctgcgccc 60cagcccggct ctgctgcagc ggcagggagg aagagccgcc gcagcgcgac tcgggagccc 120cgggccacag cctggcctcc ggagccaccc acaggcctcc ccgggcggcg cccacgctcc 180taccgcccgg acgcgcggat cctccgccgg caccgcagcc acctgctccc ggcccagagg 240cgacgacacg atgcgctgcg cgctggcgct ctcggcgctg ctgctactgt tgtcaacgcc 300gccgctgctg ccgtcgtcgc cgtcgccgtc gccgtcgccc tcccagaatg caacccagac 360tactacggac tcatctaaca aaacagcacc gactccagca tccagtgtca ccatcatggc 420tacagataca gcccagcaga gcacagtccc cacttccaag gccaacgaaa tcttggcctc 480ggtcaaggcg accacccttg gtgtatccag tgactcaccg gggactacaa ccctggctca 540gcaagtctca ggcccagtca acactaccgt ggctagagga ggcggctcag gcaaccctac 600taccaccatc gagagcccca agagcacaaa aagtgcagac accactacag ttgcaacctc 660cacagccaca gctaaaccta acaccacaag cagccagaat ggagcagaag atacaacaaa 720ctctgggggg aaaagcagcc acagtgtgac cacagacctc acatccacta aggcagaaca 780tctgacgacc cctcacccta caagtccact tagcccccga caacccactt cgacgcatcc 840tgtggccacc ccaacaagct cgggacatga ccatcttatg aaaatttcaa gcagttcaag 900cactgtggct atccctggct acaccttcac aagcccgggg atgaccacca ccctaccgtc 960atcggttatc tcgcaaagaa ctcaacagac ctccagtcag atgccagcca gctctacggc 1020cccttcctcc caggagacag tgcagcccac gagcccggca acggcattga gaacacctac 1080cctgccagag accatgagct ccagccccac agcagcatca actacccacc gataccccaa 1140aacaccttct cccactgtgg ctcatgagag taactgggca aagtgtgagg atcttgagac 1200acagacacag agtgagaagc agctcgtcct gaacctcaca ggaaacaccc tctgtgcagg 1260gggcgcttcg gatgagaaat tgatctcact gatatgccga gcagtcaaag ccaccttcaa 1320cccggcccaa gataagtgcg gcatacggct ggcatctgtt ccaggaagtc agaccgtggt 1380cgtcaaagaa atcactattc acactaagct ccctgccaag gatgtgtacg agcggctgaa 1440ggacaaatgg gatgaactaa aggaggcagg ggtcagtgac atgaagctag gggaccaggg 1500gccaccggag gaggccgagg accgcttcag catgcccctc atcatcacca tcgtctgcat 1560ggcatcattc ctgctcctcg tggcggccct ctatggctgc tgccaccagc gcctctccca 1620gaggaaggac cagcagcggc taacagagga gctgcagaca gtggagaatg gttaccatga 1680caacccaaca ctggaagtga tggagacctc ttctgagatg caggagaaga aggtggtcag 1740cctcaacggg gagctggggg acagctggat cgtccctctg gacaacctga ccaaggacga 1800cctggatgag gaggaagaca cacacctcta gtccggtctg ccggtggcct ccagcagcac 1860cacagagctc cagaccaacc accccaagtg ccgtttggat ggggaaggga aagactgggg 1920agggagagtg aactccgagg ggtgtcccct cccaatcccc ccagggcctt aatttttccc 1980ttttcaacct gaacaaatca cattctgtcc agattcctct tgtaaaataa cccactagtg 2040cctgagctca gtgctgctgg atgatgaggg agatcaagaa aaagccacgt aagggacttt 2100atagatgaac tagtggaatc ccttcattct gcagtgagat tgccgagacc tgaagagggt 2160aagtgacttg cccaaggtca gagccacttg gtgacagagc caggatgaga acaaagattc 2220catttgcacc atgccacact gctgtgttca catgtgcctt ccgtccagag cagtcccggg 2280caggggtgaa actccagcag gtggctgggc tggaaaggag ggcagggcta catcctggct 2340cggtgggatc tgacgacctg aaagtccagc tcccaagttt tccttctcct accccagcct 2400cgtgtaccca tcttcccacc ctctatgttc ttacccctcc ctacactcag tgtttgttcc 2460cacttactct gtcctggggc ctctgggatt agcacaggtt attcataacc ttgaacccct 2520tgttctggat tcggattttc tcacatttgc ttcgtgagat gggggcttaa cccacacagg 2580tctccgtgcg tgaaccaggt ctgcttaggg gacctgcgtg caggtgagga gagaagggga 2640cactcgagtc caggctggta tctcagggca gctgatgagg ggtcagcagg aacactggcc 2700cattgcccct ggcactcctt gcagaggcca cccacgatct tctttgggct tccatttcca 2760ccagggacta aaatctgctg tagctagtga gagcagcgtg ttccttttgt tgttcactgc 2820tcagctgatg ggagtgattc cctgagaccc agtatgaaag agcagtggct gcaggagagg 2880ccttcccggg gccccccatc agcgatgtgt cttcagagac aatccattaa agcagccagg 2940aaggacaggc tttcccctgt atatcatagg aaactcaggg acatttcaag ttgctgagag 3000ttttgttata gttgttttct aacccagccc tccactgcca aaggccaaaa gctcagacag 3060ttggcagacg tccagttagc tcatctcact cactctgatt ctcctgtgcc acaggaaaag 3120agggcctgga aagcgcagtg catgctgggt gcatgaaggg cagcctgggg gacagactgt 3180tgtgggaacg tcccactgtc ctggcctgga gctaggcctt gctgttcctc ttctctgtga 3240gcctagtggg gctgctgcgg ttctcttgca gtttctggtg gcatctcagg ggaacacaaa 3300gctatgtcta ttccccaata taggactttt atgggctcgg cagttagctg ccatgtagaa 3360ggctcctaag cagtgggcat ggtgaggttt catctgattg agaaggggga atcctgtgtg 3420gaatgttgaa ctttcgccat ggtctccatc gttctgggcg taaattccct gggatcaagt 3480aggaaaatgg gcagaactgc ttaggggaat gaaattgcca tttttcgggt gaaacgccac 3540acctccaggg tcttaagagt caggctccgg ctgtagtagc tctgatgaaa taggctatcc 3600actcgggatg gcttactttt taaaagggta gggggagggg ctggggaaga tctgtcctgc 3660accatctgcc taattccttc ctcacagtct gtagccatct gatatcctag gggaaaagga 3720aggccagggg ttcacatagg gccccagcga gtttcccagg agttagaggg atgcgaggct 3780aacaagttcc aaaaacatct gccccgatgc tctagtgttt ggaggtgggc aggatggaga 3840acagtgcctg tttgggggaa aacaggaaat cttgttaggc ttgagtgagg tgtttgcttc 3900cttcttgccc agcgctgggt tctctccacc cagtaggttt tctgttgtgg tcccgtggga 3960gaggccagac tggattattc ctcctttgct gatcctgggt cacacttcac cagccagggc 4020ttttgacgga gacagcaaat aggcctctgc aaatcaatca aaggctgcaa ccctatggcc 4080tcttggagac agatgatgac tggcaaggac tagagagcag gagtgcctgg ccaggtcggt 4140cctgactctc ctgactctcc atcgctctgt ccaaggagaa cccggagagg ctctgggctg 4200attcagaggt tactgcttta tattcgtcca aactgtgtta gtctaggctt aggacagctt 4260cagaatctga caccttgcct tgctcttgcc accaggacac ctatgtcaac aggccaaaca 4320gccatgcatc tataaaggtc atcatcttct gccaccttta ctgggttcta aatgctctct 4380gataattcag agagcattgg gtctgggaag aggtaagagg aacactagaa gctcagcatg 4440acttaaacag gttgtagcaa agacagttta tcatcagctc tttcagtggt aaactgtggt 4500ttccccaagc tgcacaggag gccagaaacc acaagtatga tgactaggaa gcctactgtc 4560atgagagtgg ggagacaggc agcaaagctt atgaaggagg tacagaatat tctttgcgtt 4620gtaagacaga atacgggttt aatctagtct aggcaccaga tttttttccc gcttgataag 4680gaaagctagc agaaagttta tttaaaccac ttcttgagct ttatcttttt tgacaatata 4740ctggagaaac tttgaagaac aagttcaaac tgatacatat acacatattt ttttgataat 4800gtaaatacag tgaccatgtt aacctaccct gcactgcttt aagtgaacat actttgaaaa 4860agcattatgt tagctgagtg atggccaagt tttttctctg gacagtaatg taaatgtctt 4920actggaaatg acaagttttt gcttgatttt tttttttaaa caaaaaatga aatataacaa 4980gacaaactta tgataaagta tttgtcttgt agatcaggtg ttttgttttg tttttttaat 5040tttaaaatgc aaccctgccc cctccccagc aaagtcacag ctccatttca gtaaaggttg 5100gagtcaatat gctctggttg gcaggcaacc ctgtagtcat ggagaaaggt atttcaagat 5160ctagtccaat ctttttctag agaaaaagat aatctgaagc tcacaaagat gaagtgactt 5220cctcaaaatc acatggttca ggacagaaac aagattaaaa cctggatcca cagactgtgc 5280gcctcagaag gaataatcgg taaattaaga attgctactc gaaggtgcca gaatgacaca 5340aaggacagaa ttcctttccc agttgttacc ctagcaaggc tagggagggc atgaacacaa 5400acataagaac tggtcttcta cactttctct gaatcattta ggtttaagat gtaagtgaac 5460aattctttct ttctgccaag aaacaaagtt ttggatgagc ttttatatat ggaacttact 5520ccaacaggac

tgagggacca aggaaacatg atgggggagg cagagagggc aagagtaaaa 5580ctgtagcata gcttttgtca cggtcactag ctgatccctc aggtctgctg caaacacagc 5640atggaggaca cagatgactc tttggtgttg gtctttttgt ctgcagtgaa tgttcaacag 5700tttgcccagg aactggggga tcatatatgt cttagtggac aggggtctga agtacactgg 5760aatttactga gaaacttgtt tgtaaaaact atagttaata attattgcat tttcttacaa 5820aaatatattt tggaaaattg tatactgtca attaaagtgt ttttgtgtaa actggttcaa 5880695880DNAHomo sapiens 69agacgccgcc caggacgcag ccgccgccgc cgccgctcct ctgccactgg ctctgcgccc 60cagcccggct ctgctgcagc ggcagggagg aagagccgcc gcagcgcgac tcgggagccc 120cgggccacag cctggcctcc ggagccaccc acaggcctcc ccgggcggcg cccacgctcc 180taccgcccgg acgcgcggat cctccgccgg caccgcagcc acctgctccc ggcccagagg 240cgacgacacg atgcgctgcg cgctggcgct ctcggcgctg ctgctactgt tgtcaacgcc 300gccgctgctg ccgtcgtcgc cgtcgccgtc gccgtcgccc tcccagaatg caacccagac 360tactacggac tcatctaaca aaacagcacc gactccagca tccagtgtca ccatcatggc 420tacagataca gcccagcaga gcacagtccc cacttccaag gccaacgaaa tcttggcctc 480ggtcaaggcg accacccttg gtgtatccag tgactcaccg gggactacaa ccctggctca 540gcaagtctca ggcccagtca acactaccgt ggctagagga ggcggctcag gcaaccctac 600taccaccatc gagagcccca agagcacaaa aagtgcagac accactacag ttgcaacctc 660cacagccaca gctaaaccta acaccacaag cagccagaat ggagcagaag atacaacaaa 720ctctgggggg aaaagcagcc acagtgtgac cacagacctc acatccacta aggcagaaca 780tctgacgacc cctcacccta caagtccact tagcccccga caacccactt cgacgcatcc 840tgtggccacc ccaacaagct cgggacatga ccatcttatg aaaatttcaa gcagttcaag 900cactgtggct atccctggct acaccttcac aagcccgggg atgaccacca ccctaccgtc 960atcggttatc tcgcaaagaa ctcaacagac ctccagtcag atgccagcca gctctacggc 1020cccttcctcc caggagacag tgcagcccac gagcccggca acggcattga gaacacctac 1080cctgccagag accatgagct ccagccccac agcagcatca actacccacc gataccccaa 1140aacaccttct cccactgtgg ctcatgagag taactgggca aagtgtgagg atcttgagac 1200acagacacag agtgagaagc agctcgtcct gaacctcaca ggaaacaccc tctgtgcagg 1260gggcgcttcg gatgagaaat tgatctcact gatatgccga gcagtcaaag ccaccttcaa 1320cccggcccaa gataagtgcg gcatacggct ggcatctgtt ccaggaagtc agaccgtggt 1380cgtcaaagaa atcactattc acactaagct ccctgccaag gatgtgtacg agcggctgaa 1440ggacaaatgg gatgaactaa aggaggcagg ggtcagtgac atgaagctag gggaccaggg 1500gccaccggag gaggccgagg accgcttcag catgcccctc atcatcacca tcgtctgcat 1560ggcatcattc ctgctcctcg tggcggccct ctatggctgc tgccaccagc gcctctccca 1620gaggaaggac cagcagcggc taacagagga gctgcagaca gtggagaatg gttaccatga 1680caacccaaca ctggaagtga tggagacctc ttctgagatg caggagaaga aggtggtcag 1740cctcaacggg gagctggggg acagctggat cgtccctctg gacaacctga ccaaggacga 1800cctggatgag gaggaagaca cacacctcta gtccggtctg ccggtggcct ccagcagcac 1860cacagagctc cagaccaacc accccaagtg ccgtttggat ggggaaggga aagactgggg 1920agggagagtg aactccgagg ggtgtcccct cccaatcccc ccagggcctt aatttttccc 1980ttttcaacct gaacaaatca cattctgtcc agattcctct tgtaaaataa cccactagtg 2040cctgagctca gtgctgctgg atgatgaggg agatcaagaa aaagccacgt aagggacttt 2100atagatgaac tagtggaatc ccttcattct gcagtgagat tgccgagacc tgaagagggt 2160aagtgacttg cccaaggtca gagccacttg gtgacagagc caggatgaga acaaagattc 2220catttgcacc atgccacact gctgtgttca catgtgcctt ccgtccagag cagtcccggg 2280caggggtgaa actccagcag gtggctgggc tggaaaggag ggcagggcta catcctggct 2340cggtgggatc tgacgacctg aaagtccagc tcccaagttt tccttctcct accccagcct 2400cgtgtaccca tcttcccacc ctctatgttc ttacccctcc ctacactcag tgtttgttcc 2460cacttactct gtcctggggc ctctgggatt agcacaggtt attcataacc ttgaacccct 2520tgttctggat tcggattttc tcacatttgc ttcgtgagat gggggcttaa cccacacagg 2580tctccgtgcg tgaaccaggt ctgcttaggg gacctgcgtg caggtgagga gagaagggga 2640cactcgagtc caggctggta tctcagggca gctgatgagg ggtcagcagg aacactggcc 2700cattgcccct ggcactcctt gcagaggcca cccacgatct tctttgggct tccatttcca 2760ccagggacta aaatctgctg tagctagtga gagcagcgtg ttccttttgt tgttcactgc 2820tcagctgatg ggagtgattc cctgagaccc agtatgaaag agcagtggct gcaggagagg 2880ccttcccggg gccccccatc agcgatgtgt cttcagagac aatccattaa agcagccagg 2940aaggacaggc tttcccctgt atatcatagg aaactcaggg acatttcaag ttgctgagag 3000ttttgttata gttgttttct aacccagccc tccactgcca aaggccaaaa gctcagacag 3060ttggcagacg tccagttagc tcatctcact cactctgatt ctcctgtgcc acaggaaaag 3120agggcctgga aagcgcagtg catgctgggt gcatgaaggg cagcctgggg gacagactgt 3180tgtgggaacg tcccactgtc ctggcctgga gctaggcctt gctgttcctc ttctctgtga 3240gcctagtggg gctgctgcgg ttctcttgca gtttctggtg gcatctcagg ggaacacaaa 3300gctatgtcta ttccccaata taggactttt atgggctcgg cagttagctg ccatgtagaa 3360ggctcctaag cagtgggcat ggtgaggttt catctgattg agaaggggga atcctgtgtg 3420gaatgttgaa ctttcgccat ggtctccatc gttctgggcg taaattccct gggatcaagt 3480aggaaaatgg gcagaactgc ttaggggaat gaaattgcca tttttcgggt gaaacgccac 3540acctccaggg tcttaagagt caggctccgg ctgtagtagc tctgatgaaa taggctatcc 3600actcgggatg gcttactttt taaaagggta gggggagggg ctggggaaga tctgtcctgc 3660accatctgcc taattccttc ctcacagtct gtagccatct gatatcctag gggaaaagga 3720aggccagggg ttcacatagg gccccagcga gtttcccagg agttagaggg atgcgaggct 3780aacaagttcc aaaaacatct gccccgatgc tctagtgttt ggaggtgggc aggatggaga 3840acagtgcctg tttgggggaa aacaggaaat cttgttaggc ttgagtgagg tgtttgcttc 3900cttcttgccc agcgctgggt tctctccacc cagtaggttt tctgttgtgg tcccgtggga 3960gaggccagac tggattattc ctcctttgct gatcctgggt cacacttcac cagccagggc 4020ttttgacgga gacagcaaat aggcctctgc aaatcaatca aaggctgcaa ccctatggcc 4080tcttggagac agatgatgac tggcaaggac tagagagcag gagtgcctgg ccaggtcggt 4140cctgactctc ctgactctcc atcgctctgt ccaaggagaa cccggagagg ctctgggctg 4200attcagaggt tactgcttta tattcgtcca aactgtgtta gtctaggctt aggacagctt 4260cagaatctga caccttgcct tgctcttgcc accaggacac ctatgtcaac aggccaaaca 4320gccatgcatc tataaaggtc atcatcttct gccaccttta ctgggttcta aatgctctct 4380gataattcag agagcattgg gtctgggaag aggtaagagg aacactagaa gctcagcatg 4440acttaaacag gttgtagcaa agacagttta tcatcagctc tttcagtggt aaactgtggt 4500ttccccaagc tgcacaggag gccagaaacc acaagtatga tgactaggaa gcctactgtc 4560atgagagtgg ggagacaggc agcaaagctt atgaaggagg tacagaatat tctttgcgtt 4620gtaagacaga atacgggttt aatctagtct aggcaccaga tttttttccc gcttgataag 4680gaaagctagc agaaagttta tttaaaccac ttcttgagct ttatcttttt tgacaatata 4740ctggagaaac tttgaagaac aagttcaaac tgatacatat acacatattt ttttgataat 4800gtaaatacag tgaccatgtt aacctaccct gcactgcttt aagtgaacat actttgaaaa 4860agcattatgt tagctgagtg atggccaagt tttttctctg gacagtaatg taaatgtctt 4920actggaaatg acaagttttt gcttgatttt tttttttaaa caaaaaatga aatataacaa 4980gacaaactta tgataaagta tttgtcttgt agatcaggtg ttttgttttg tttttttaat 5040tttaaaatgc aaccctgccc cctccccagc aaagtcacag ctccatttca gtaaaggttg 5100gagtcaatat gctctggttg gcaggcaacc ctgtagtcat ggagaaaggt atttcaagat 5160ctagtccaat ctttttctag agaaaaagat aatctgaagc tcacaaagat gaagtgactt 5220cctcaaaatc acatggttca ggacagaaac aagattaaaa cctggatcca cagactgtgc 5280gcctcagaag gaataatcgg taaattaaga attgctactc gaaggtgcca gaatgacaca 5340aaggacagaa ttcctttccc agttgttacc ctagcaaggc tagggagggc atgaacacaa 5400acataagaac tggtcttcta cactttctct gaatcattta ggtttaagat gtaagtgaac 5460aattctttct ttctgccaag aaacaaagtt ttggatgagc ttttatatat ggaacttact 5520ccaacaggac tgagggacca aggaaacatg atgggggagg cagagagggc aagagtaaaa 5580ctgtagcata gcttttgtca cggtcactag ctgatccctc aggtctgctg caaacacagc 5640atggaggaca cagatgactc tttggtgttg gtctttttgt ctgcagtgaa tgttcaacag 5700tttgcccagg aactggggga tcatatatgt cttagtggac aggggtctga agtacactgg 5760aatttactga gaaacttgtt tgtaaaaact atagttaata attattgcat tttcttacaa 5820aaatatattt tggaaaattg tatactgtca attaaagtgt ttttgtgtaa actggttcaa 5880704734DNAHomo sapiens 70cctggcctcg cgggccgtgt ctccggcatc atgtgtggta tatttgctta cttaaactac 60catgttcctc gaacgagacg agaaattcct ggagacccta atcaaaggcc tcagagactg 120gagtacagag ctcatgatgg tttaggtgtg ggatttgatg gaggcaatga taaagattgg 180gaagccaatg cctgcaaaat ccagcttatt aagaagaaag gaaaagttaa ggcactggat 240gaagaagttc acaagcaaca agatatggat ttggatatag aatttgatgt acaccttgga 300atagctcata cccgttgggc aacacatgga gaacccagtc ctgtcaatag ccacccccag 360cgctctgata aaaataatga atttatcgtt attcacaatg gaatcatcac caactacaaa 420gacttgaaaa agtttttgga aagcaaaggc tatgacttcg aatctgaaac agacacagag 480acaattgcca agctcgttaa gtatatgtat gacaatcggg aaagtcaaga taccagcttt 540actaccttgg tggagagagt tatccaacaa ttggaaggtg cttttgcact tgtgtttaaa 600agtgttcatt ttcccgggca agcagttggc acaaggcgag gtagccctct gttgattggt 660gtacggagtg aacataaact ttctactgat cacattccta tactctacag aacaggcaaa 720gacaagaaag gaagctgcaa tctctctcgt gtggacagca caacctgcct tttcccggtg 780gaagaaaaag cagtggagta ttactttgct tctgatgcaa gtgctgtcat agaacacacc 840aatcgcgtca tctttctgga agatgatgat gttgcagcag tagtggatgg acgtctttct 900atccatcgaa ttaaacgaac tgcaggagat caccccggac gagctgtgca aacactccag 960atggaactcc agcagatcat gaagggcaac ttcagttcat ttatgcagaa ggaaatattt 1020gagcagccag agtctgtcgt gaacacaatg agaggaagag tcaactttga tgactatact 1080gtgaatttgg gtggtttgaa ggatcacata aaggagatcc agagatgccg gcgtttgatt 1140cttattgctt gtggaacaag ttaccatgct ggtgtagcaa cacgtcaagt tcttgaggag 1200ctgactgagt tgcctgtgat ggtggaacta gcaagtgact tcctggacag aaacacacca 1260gtctttcgag atgatgtttg ctttttcctt agtcaatcag gtgagacagc agatactttg 1320atgggtcttc gttactgtaa ggagagagga gctttaactg tggggatcac aaacacagtt 1380ggcagttcca tatcacggga gacagattgt ggagttcata ttaatgctgg tcctgagatt 1440ggtgtggcca gtacaaaggc ttataccagc cagtttgtat cccttgtgat gtttgccctt 1500atgatgtgtg atgatcggat ctccatgcaa gaaagacgca aagagatcat gcttggattg 1560aaacggctgc ctgatttgat taaggaagta ctgagcatgg atgacgaaat tcagaaacta 1620gcaacagaac tttatcatca gaagtcagtt ctgataatgg gacgaggcta tcattatgct 1680acttgtcttg aaggggcact gaaaatcaaa gaaattactt atatgcactc tgaaggcatc 1740cttctgtgct gagaggctat gatgttgatt tcccacggaa tcttgccaaa tctgtgactg 1800tagagtgagg aatatctata caaaatgtac gaaactgtat gattaagcaa cacaagacac 1860cttttgtatt taaaaccttg atttaaaata tcaccccttg aagccttttt ttagtaaatc 1920cttatttata tatcagttat aattattcca ctcaatatgt gatttttgtg aagttacctc 1980ttacattttc ccagtaattt gtggaggact ttgaataatg gaatctatat tggaatctgt 2040atcagaaaga ttctagctat tattttcttt aaagaatgct gggtgttgca tttctggacc 2100ctccacttca atctgagaag acaatatgtt tctaaaaatt ggtacttgtt tcaccatact 2160tcattcagac cagtgaaaga gtagtgcatt taattggagt atctaaagcc agtggcagtg 2220tatgctcata cttggacagt tagggaaggg tttgccaagt tttaagagaa gatgtgattt 2280attttgaaat ttgtttctgt tttgttttta aatcaaactg taaaacttaa aactgaaaaa 2340ttttattggt aggatttata tctaagtttg gttagcctta gtttctcaga cttgttgtct 2400attatctgta ggtggaagaa atttaggaag cgaaatatta cagtagtgca ttggtgggtc 2460tcaatcctta acatatttgc acaattttat agcacaaact ttaaattcaa gctgctttgg 2520acaactgaca atatgatttt aaatttgaag atgggatgtg tacatgttgg gtatcctact 2580actttgtgtt ttcatctcct aaaagtggtt tttatttcct tgtatctgta gtcttttatt 2640ttttaaatga ctgctgaatg acatatttta tcttgttctt taaaatcaca acacagagct 2700gctattaaat taatattgat atattcagta ttctcttcaa ctttgtcacg aggaagaatt 2760tcctgtagtt aattttaact ttccttcatt acattgttgc ataaaactag tcccttagtg 2820ccagtttgga agttacttgc aattgtttgg aagatttgca ggtcgctgac ctcatcattt 2880cactctaagt atatgtggta ggctaagctc agaaaaaggt atgtatgctt tacactgata 2940ggcaccaaat ttagtattgt atcctaagta tttttcctct tctgtatttt ctgtgctcta 3000cccctgaaat atatttagga ataaagaaga tataaataaa gtgatattgg ggtatgttca 3060gcttgtaagt gtcagaaatg gaagttgaca atttggatta aaatatttaa agtagaatgt 3120tattatttga tacccccaaa attgtgagta ataatttctt aatggagctt ttctggccag 3180atcttcaggg ctataggaga gtgtgtttgt ttttggtgaa gtccttcttt ttcaaaggtt 3240tttactttta aattgtgaag ataagctatt tagcacaatt atttaagtaa gctgtttttt 3300cctttctttt ctttcttttc ttgttttaac ttctgggtga ggttaagatt ttctaatagt 3360tattgttgtt gccagagaag catagaattc tgcttgtgtc ttagggttag agaaagattt 3420gttatatttt gaggtaattt ggaaggactt tcatacatgg tgactagaaa cctgatcttt 3480ttaagaataa aatagggtca ctatttacat tatatataat atatggctat tatagctata 3540ttaatctact ttaattgttt ctaagattat tttgtgtaag tcagctagcg tgtgtatagt 3600gtcatttctt atgttttgta tattaacgtt ttacaaacac aatttgtgtg ggtttgtagc 3660atttcttata gtttaaagta tgattcagca ttctaagtta aaactaatat gtgaagtcag 3720tcattagtct gcataatctc tgtctccctc tgtgtgtgtc tttctataaa gcacatgtgt 3780acacacacac acacaaatat actgaaagct agggtaagtt ctaaactgaa tatcaaaaac 3840caaaatcaag aacaaagaag tgatattttc caaacaaaca tggattctct gccgggtgca 3900gtggctcagc ctgtaatacc agcctccact ttgggagtct gaggtgggag tattgcttga 3960gctcaagagt tggagaacat gctgggatta caggcatgag tcaccgtgtc ctgcccagac 4020atatcaaatt tgacaggtat tgtataccct ttggatcttt aggaattaat ttttgcctct 4080gtcactcagc tttgtatatt ttgaaatgga gataagtata gggaggtctt ggaaggaaaa 4140ttgccagaat tcccaaacca tgtaacactc attgagaatt ccagatccat tatatctaaa 4200gggcaagtga aggaaacagt attgtgaact gggtataact ccttggttct taactagtac 4260attcttaatc tgtgagaccc aaaggttgat aaacaataat ttaagattgt acagtactct 4320aaacgtctgc aaaggtctag atgttatcag tatcactagt ttttatttct gccagtagct 4380cccttttagg ttacattgtt gtcctctttc cagtgtcgca tctgtcattg gtttttcact 4440atggcaagtt cattaaaaag cttgctccat tgttatcttc aagtaatgcc cataaggaga 4500tggaagatat ctgagacaat taaggcttta gcttctaggc aagagaaata acgttgcatt 4560aaatttcaag tttctttctg ctagacttga atgtgtctag ccactctaat ttatgggggc 4620ttttggtttt ttcctattgt actttgtatg tagaattgtt ttgaaatatc aagcatattt 4680actttgaatt tgaactcttt cttaattttg tatttatcct ttgaataaaa tgta 4734715880DNAHomo sapiens 71agacgccgcc caggacgcag ccgccgccgc cgccgctcct ctgccactgg ctctgcgccc 60cagcccggct ctgctgcagc ggcagggagg aagagccgcc gcagcgcgac tcgggagccc 120cgggccacag cctggcctcc ggagccaccc acaggcctcc ccgggcggcg cccacgctcc 180taccgcccgg acgcgcggat cctccgccgg caccgcagcc acctgctccc ggcccagagg 240cgacgacacg atgcgctgcg cgctggcgct ctcggcgctg ctgctactgt tgtcaacgcc 300gccgctgctg ccgtcgtcgc cgtcgccgtc gccgtcgccc tcccagaatg caacccagac 360tactacggac tcatctaaca aaacagcacc gactccagca tccagtgtca ccatcatggc 420tacagataca gcccagcaga gcacagtccc cacttccaag gccaacgaaa tcttggcctc 480ggtcaaggcg accacccttg gtgtatccag tgactcaccg gggactacaa ccctggctca 540gcaagtctca ggcccagtca acactaccgt ggctagagga ggcggctcag gcaaccctac 600taccaccatc gagagcccca agagcacaaa aagtgcagac accactacag ttgcaacctc 660cacagccaca gctaaaccta acaccacaag cagccagaat ggagcagaag atacaacaaa 720ctctgggggg aaaagcagcc acagtgtgac cacagacctc acatccacta aggcagaaca 780tctgacgacc cctcacccta caagtccact tagcccccga caacccactt cgacgcatcc 840tgtggccacc ccaacaagct cgggacatga ccatcttatg aaaatttcaa gcagttcaag 900cactgtggct atccctggct acaccttcac aagcccgggg atgaccacca ccctaccgtc 960atcggttatc tcgcaaagaa ctcaacagac ctccagtcag atgccagcca gctctacggc 1020cccttcctcc caggagacag tgcagcccac gagcccggca acggcattga gaacacctac 1080cctgccagag accatgagct ccagccccac agcagcatca actacccacc gataccccaa 1140aacaccttct cccactgtgg ctcatgagag taactgggca aagtgtgagg atcttgagac 1200acagacacag agtgagaagc agctcgtcct gaacctcaca ggaaacaccc tctgtgcagg 1260gggcgcttcg gatgagaaat tgatctcact gatatgccga gcagtcaaag ccaccttcaa 1320cccggcccaa gataagtgcg gcatacggct ggcatctgtt ccaggaagtc agaccgtggt 1380cgtcaaagaa atcactattc acactaagct ccctgccaag gatgtgtacg agcggctgaa 1440ggacaaatgg gatgaactaa aggaggcagg ggtcagtgac atgaagctag gggaccaggg 1500gccaccggag gaggccgagg accgcttcag catgcccctc atcatcacca tcgtctgcat 1560ggcatcattc ctgctcctcg tggcggccct ctatggctgc tgccaccagc gcctctccca 1620gaggaaggac cagcagcggc taacagagga gctgcagaca gtggagaatg gttaccatga 1680caacccaaca ctggaagtga tggagacctc ttctgagatg caggagaaga aggtggtcag 1740cctcaacggg gagctggggg acagctggat cgtccctctg gacaacctga ccaaggacga 1800cctggatgag gaggaagaca cacacctcta gtccggtctg ccggtggcct ccagcagcac 1860cacagagctc cagaccaacc accccaagtg ccgtttggat ggggaaggga aagactgggg 1920agggagagtg aactccgagg ggtgtcccct cccaatcccc ccagggcctt aatttttccc 1980ttttcaacct gaacaaatca cattctgtcc agattcctct tgtaaaataa cccactagtg 2040cctgagctca gtgctgctgg atgatgaggg agatcaagaa aaagccacgt aagggacttt 2100atagatgaac tagtggaatc ccttcattct gcagtgagat tgccgagacc tgaagagggt 2160aagtgacttg cccaaggtca gagccacttg gtgacagagc caggatgaga acaaagattc 2220catttgcacc atgccacact gctgtgttca catgtgcctt ccgtccagag cagtcccggg 2280caggggtgaa actccagcag gtggctgggc tggaaaggag ggcagggcta catcctggct 2340cggtgggatc tgacgacctg aaagtccagc tcccaagttt tccttctcct accccagcct 2400cgtgtaccca tcttcccacc ctctatgttc ttacccctcc ctacactcag tgtttgttcc 2460cacttactct gtcctggggc ctctgggatt agcacaggtt attcataacc ttgaacccct 2520tgttctggat tcggattttc tcacatttgc ttcgtgagat gggggcttaa cccacacagg 2580tctccgtgcg tgaaccaggt ctgcttaggg gacctgcgtg caggtgagga gagaagggga 2640cactcgagtc caggctggta tctcagggca gctgatgagg ggtcagcagg aacactggcc 2700cattgcccct ggcactcctt gcagaggcca cccacgatct tctttgggct tccatttcca 2760ccagggacta aaatctgctg tagctagtga gagcagcgtg ttccttttgt tgttcactgc 2820tcagctgatg ggagtgattc cctgagaccc agtatgaaag agcagtggct gcaggagagg 2880ccttcccggg gccccccatc agcgatgtgt cttcagagac aatccattaa agcagccagg 2940aaggacaggc tttcccctgt atatcatagg aaactcaggg acatttcaag ttgctgagag 3000ttttgttata gttgttttct aacccagccc tccactgcca aaggccaaaa gctcagacag 3060ttggcagacg tccagttagc tcatctcact cactctgatt ctcctgtgcc acaggaaaag 3120agggcctgga aagcgcagtg catgctgggt gcatgaaggg cagcctgggg gacagactgt 3180tgtgggaacg tcccactgtc ctggcctgga gctaggcctt gctgttcctc ttctctgtga 3240gcctagtggg gctgctgcgg ttctcttgca gtttctggtg gcatctcagg ggaacacaaa 3300gctatgtcta ttccccaata taggactttt atgggctcgg cagttagctg ccatgtagaa 3360ggctcctaag cagtgggcat ggtgaggttt catctgattg agaaggggga atcctgtgtg 3420gaatgttgaa ctttcgccat ggtctccatc gttctgggcg taaattccct gggatcaagt 3480aggaaaatgg gcagaactgc ttaggggaat gaaattgcca tttttcgggt gaaacgccac 3540acctccaggg tcttaagagt caggctccgg ctgtagtagc tctgatgaaa taggctatcc 3600actcgggatg gcttactttt taaaagggta gggggagggg ctggggaaga tctgtcctgc 3660accatctgcc taattccttc ctcacagtct gtagccatct gatatcctag gggaaaagga 3720aggccagggg ttcacatagg gccccagcga gtttcccagg agttagaggg atgcgaggct 3780aacaagttcc aaaaacatct gccccgatgc tctagtgttt ggaggtgggc aggatggaga 3840acagtgcctg tttgggggaa aacaggaaat cttgttaggc ttgagtgagg tgtttgcttc 3900cttcttgccc agcgctgggt tctctccacc cagtaggttt tctgttgtgg tcccgtggga 3960gaggccagac tggattattc ctcctttgct gatcctgggt cacacttcac cagccagggc

4020ttttgacgga gacagcaaat aggcctctgc aaatcaatca aaggctgcaa ccctatggcc 4080tcttggagac agatgatgac tggcaaggac tagagagcag gagtgcctgg ccaggtcggt 4140cctgactctc ctgactctcc atcgctctgt ccaaggagaa cccggagagg ctctgggctg 4200attcagaggt tactgcttta tattcgtcca aactgtgtta gtctaggctt aggacagctt 4260cagaatctga caccttgcct tgctcttgcc accaggacac ctatgtcaac aggccaaaca 4320gccatgcatc tataaaggtc atcatcttct gccaccttta ctgggttcta aatgctctct 4380gataattcag agagcattgg gtctgggaag aggtaagagg aacactagaa gctcagcatg 4440acttaaacag gttgtagcaa agacagttta tcatcagctc tttcagtggt aaactgtggt 4500ttccccaagc tgcacaggag gccagaaacc acaagtatga tgactaggaa gcctactgtc 4560atgagagtgg ggagacaggc agcaaagctt atgaaggagg tacagaatat tctttgcgtt 4620gtaagacaga atacgggttt aatctagtct aggcaccaga tttttttccc gcttgataag 4680gaaagctagc agaaagttta tttaaaccac ttcttgagct ttatcttttt tgacaatata 4740ctggagaaac tttgaagaac aagttcaaac tgatacatat acacatattt ttttgataat 4800gtaaatacag tgaccatgtt aacctaccct gcactgcttt aagtgaacat actttgaaaa 4860agcattatgt tagctgagtg atggccaagt tttttctctg gacagtaatg taaatgtctt 4920actggaaatg acaagttttt gcttgatttt tttttttaaa caaaaaatga aatataacaa 4980gacaaactta tgataaagta tttgtcttgt agatcaggtg ttttgttttg tttttttaat 5040tttaaaatgc aaccctgccc cctccccagc aaagtcacag ctccatttca gtaaaggttg 5100gagtcaatat gctctggttg gcaggcaacc ctgtagtcat ggagaaaggt atttcaagat 5160ctagtccaat ctttttctag agaaaaagat aatctgaagc tcacaaagat gaagtgactt 5220cctcaaaatc acatggttca ggacagaaac aagattaaaa cctggatcca cagactgtgc 5280gcctcagaag gaataatcgg taaattaaga attgctactc gaaggtgcca gaatgacaca 5340aaggacagaa ttcctttccc agttgttacc ctagcaaggc tagggagggc atgaacacaa 5400acataagaac tggtcttcta cactttctct gaatcattta ggtttaagat gtaagtgaac 5460aattctttct ttctgccaag aaacaaagtt ttggatgagc ttttatatat ggaacttact 5520ccaacaggac tgagggacca aggaaacatg atgggggagg cagagagggc aagagtaaaa 5580ctgtagcata gcttttgtca cggtcactag ctgatccctc aggtctgctg caaacacagc 5640atggaggaca cagatgactc tttggtgttg gtctttttgt ctgcagtgaa tgttcaacag 5700tttgcccagg aactggggga tcatatatgt cttagtggac aggggtctga agtacactgg 5760aatttactga gaaacttgtt tgtaaaaact atagttaata attattgcat tttcttacaa 5820aaatatattt tggaaaattg tatactgtca attaaagtgt ttttgtgtaa actggttcaa 588072160PRTHomo sapiens 72Met Tyr Pro Ala Leu Leu Asn Ile Leu Asn Leu Ile Leu Gln Val Ser1 5 10 15 Arg Gly Gln Lys Val Thr Ser Leu Thr Ala Cys Leu Val Asp Gln Ser 20 25 30 Leu Arg Leu Asp Cys Arg His Glu Asn Thr Ser Ser Ser Pro Ile Gln 35 40 45 Tyr Glu Phe Ser Leu Thr Arg Glu Thr Lys Lys His Val Leu Phe Gly 50 55 60 Thr Val Gly Val Pro Glu His Thr Tyr Arg Ser Arg Thr Asn Phe Thr65 70 75 80 Ser Lys Tyr Asn Met Lys Val Leu Tyr Leu Ser Ala Phe Thr Ser Lys 85 90 95 Asp Glu Gly Thr Tyr Thr Cys Ala Leu His His Ser Gly His Ser Pro 100 105 110 Pro Ile Ser Ser Gln Asn Val Thr Val Leu Arg Asp Lys Leu Val Lys 115 120 125 Cys Glu Gly Ile Ser Leu Leu Ala Gln Asn Thr Ser Trp Leu Leu Leu 130 135 140 Leu Leu Leu Ser Leu Ser Leu Leu Gln Ala Thr Asp Phe Met Ser Leu145 150 155 160 73161PRTHomo sapiens 73Met Asn Leu Ala Ile Ser Ile Ala Leu Leu Leu Thr Val Leu Gln Val1 5 10 15 Ser Arg Gly Gln Lys Val Thr Ser Leu Thr Ala Cys Leu Val Asp Gln 20 25 30 Ser Leu Arg Leu Asp Cys Arg His Glu Asn Thr Ser Ser Ser Pro Ile 35 40 45 Gln Tyr Glu Phe Ser Leu Thr Arg Glu Thr Lys Lys His Val Leu Phe 50 55 60 Gly Thr Val Gly Val Pro Glu His Thr Tyr Arg Ser Arg Thr Asn Phe65 70 75 80 Thr Ser Lys Tyr Asn Met Lys Val Leu Tyr Leu Ser Ala Phe Thr Ser 85 90 95 Lys Asp Glu Gly Thr Tyr Thr Cys Ala Leu His His Ser Gly His Ser 100 105 110 Pro Pro Ile Ser Ser Gln Asn Val Thr Val Leu Arg Asp Lys Leu Val 115 120 125 Lys Cys Glu Gly Ile Ser Leu Leu Ala Gln Asn Thr Ser Trp Leu Leu 130 135 140 Leu Leu Leu Leu Ser Leu Ser Leu Leu Gln Ala Thr Asp Phe Met Ser145 150 155 160 Leu741527DNAHomo sapiens 74ccggtgaaaa ctgcgggctc cgagctgggt gcagcaaccg gaggcggcgg cgcgtctgga 60ggaggctgca gcagcggaag accccagtcc agatccagga ctgagatccc agaaccatga 120acctggccat cagcatcgct ctcctgctaa cagtcttgca ggtctcccga gggcagaagg 180tgaccagcct aacggcctgc ctagtggacc agagccttcg tctggactgc cgccatgaga 240ataccagcag ttcacccatc cagtacgagt tcagcctgac ccgtgagaca aagaagcacg 300tgctctttgg cactgtgggg gtgcctgagc acacataccg ctcccgaacc aacttcacca 360gcaaatacaa catgaaggtc ctctacttat ccgccttcac tagcaaggac gagggcacct 420acacgtgtgc actccaccac tctggccatt ccccacccat ctcctcccag aacgtcacag 480tgctcagaga caaactggtc aagtgtgagg gcatcagcct gctggctcag aacacctcgt 540ggctgctgct gctcctgctc tccctctccc tcctccaggc cacggatttc atgtccctgt 600gactggtggg gcccatggag gagacaggaa gcctcaagtt ccagtgcaga gatcctactt 660ctctgagtca gctgaccccc tccccccaat ccctcaaacc ttgaggagaa gtggggaccc 720cacccctcat caggagttcc agtgctgcat gcgattatct acccacgtcc acgcggccac 780ctcaccctct ccgcacacct ctggctgtct ttttgtactt tttgttccag agctgcttct 840gtctggttta tttaggtttt atccttcctt ttctttgaga gttcgtgaag agggaagcca 900ggattgggga cctgatggag agtgagagca tgtgaggggt agtgggatgg tggggtacca 960gccactggag gggtcatcct tgcccatcgg gaccagaaac ctgggagaga cttggatgag 1020gagtggttgg gctgtgcctg ggcctagcac ggacatggtc tgtcctgaca gcactcctcg 1080gcaggcatgg ctggtgcctg aagaccccag atgtgagggc accaccaaga atttgtggcc 1140taccttgtga gggagagaac tgagcatctc cagcattctc agccacaacc aaaaaaaaat 1200aaaaagggca gccctcctta ccactgtgga agtccctcag aggccttggg gcatgaccca 1260gtgaagatgc aggtttgacc aggaaagcag cgctagtgga gggttggaga aggaggtaaa 1320ggatgagggt tcatcatccc tccctgcccc cgcttcgctg gggtctccac gggtgaggct 1380ggggaacgcc acctcttcct cttccctgac ttctccccaa ccacttagta gcaacgctac 1440cccaggggct aatgactgca cactgggctt cttttcagaa tgaccctaac gagacacatt 1500tgcccaaata aacgaacatc ccatgtc 1527751527DNAHomo sapiens 75ccggtgaaaa ctgcgggctc cgagctgggt gcagcaaccg gaggcggcgg cgcgtctgga 60ggaggctgca gcagcggaag accccagtcc agatccagga ctgagatccc agaaccatga 120acctggccat cagcatcgct ctcctgctaa cagtcttgca ggtctcccga gggcagaagg 180tgaccagcct aacggcctgc ctagtggacc agagccttcg tctggactgc cgccatgaga 240ataccagcag ttcacccatc cagtacgagt tcagcctgac ccgtgagaca aagaagcacg 300tgctctttgg cactgtgggg gtgcctgagc acacataccg ctcccgaacc aacttcacca 360gcaaatacaa catgaaggtc ctctacttat ccgccttcac tagcaaggac gagggcacct 420acacgtgtgc actccaccac tctggccatt ccccacccat ctcctcccag aacgtcacag 480tgctcagaga caaactggtc aagtgtgagg gcatcagcct gctggctcag aacacctcgt 540ggctgctgct gctcctgctc tccctctccc tcctccaggc cacggatttc atgtccctgt 600gactggtggg gcccatggag gagacaggaa gcctcaagtt ccagtgcaga gatcctactt 660ctctgagtca gctgaccccc tccccccaat ccctcaaacc ttgaggagaa gtggggaccc 720cacccctcat caggagttcc agtgctgcat gcgattatct acccacgtcc acgcggccac 780ctcaccctct ccgcacacct ctggctgtct ttttgtactt tttgttccag agctgcttct 840gtctggttta tttaggtttt atccttcctt ttctttgaga gttcgtgaag agggaagcca 900ggattgggga cctgatggag agtgagagca tgtgaggggt agtgggatgg tggggtacca 960gccactggag gggtcatcct tgcccatcgg gaccagaaac ctgggagaga cttggatgag 1020gagtggttgg gctgtgcctg ggcctagcac ggacatggtc tgtcctgaca gcactcctcg 1080gcaggcatgg ctggtgcctg aagaccccag atgtgagggc accaccaaga atttgtggcc 1140taccttgtga gggagagaac tgagcatctc cagcattctc agccacaacc aaaaaaaaat 1200aaaaagggca gccctcctta ccactgtgga agtccctcag aggccttggg gcatgaccca 1260gtgaagatgc aggtttgacc aggaaagcag cgctagtgga gggttggaga aggaggtaaa 1320ggatgagggt tcatcatccc tccctgcccc cgcttcgctg gggtctccac gggtgaggct 1380ggggaacgcc acctcttcct cttccctgac ttctccccaa ccacttagta gcaacgctac 1440cccaggggct aatgactgca cactgggctt cttttcagaa tgaccctaac gagacacatt 1500tgcccaaata aacgaacatc ccatgtc 1527762124DNAHomo sapiens 76aatcaagctg cccaaagtcc cccaatcact cctggaatac acagagagag gcagcagctt 60gctcagcgga caaggatgct gggcgtgagg gaccaaggcc tgccctgcac tcgggcctcc 120tccagccagt gctgaccagg gacttctgac ctgctggcca gccaggacct gtgtggggag 180gccctcctgc tgccttgggg tgacaatctc agctccaggc tacagggaga ccgggaggat 240cacagagcca gcatgttaca ggatcctgac agtgatcaac ctctgaacag cctcgatgtc 300aaacccctgc gcaaaccccg tatccccatg gagaccttca gaaaggtggg gatccccatc 360atcatagcac tactgagcct ggcgagtatc atcattgtgg ttgtcctcat caaggtgatt 420ctggataaat actacttcct ctgcgggcag cctctccact tcatcccgag gaagcagctg 480tgtgacggag agctggactg tcccttgggg gaggacgagg agcactgtgt caagagcttc 540cccgaagggc ctgcagtggc agtccgcctc tccaaggacc gatccacact gcaggtgctg 600gactcggcca cagggaactg gttctctgcc tgtttcgaca acttcacaga agctctcgct 660gagacagcct gtaggcagat gggctacagc agcaaaccca ctttcagagc tgtggagatt 720ggcccagacc aggatctgga tgttgttgaa atcacagaaa acagccagga gcttcgcatg 780cggaactcaa gtgggccctg tctctcaggc tccctggtct ccctgcactg tcttgcctgt 840gggaagagcc tgaagacccc ccgtgtggtg ggtggggagg aggcctctgt ggattcttgg 900ccttggcagg tcagcatcca gtacgacaaa cagcacgtct gtggagggag catcctggac 960ccccactggg tcctcacggc agcccactgc ttcaggaaac ataccgatgt gttcaactgg 1020aaggtgcggg caggctcaga caaactgggc agcttcccat ccctggctgt ggccaagatc 1080atcatcattg aattcaaccc catgtacccc aaagacaatg acatcgccct catgaagctg 1140cagttcccac tcactttctc aggcacagtc aggcccatct gtctgccctt ctttgatgag 1200gagctcactc cagccacccc actctggatc attggatggg gctttacgaa gcagaatgga 1260gggaagatgt ctgacatact gctgcaggcg tcagtccagg tcattgacag cacacggtgc 1320aatgcagacg atgcgtacca gggggaagtc accgagaaga tgatgtgtgc aggcatcccg 1380gaagggggtg tggacacctg ccagggtgac agtggtgggc ccctgatgta ccaatctgac 1440cagtggcatg tggtgggcat cgttagctgg ggctatggct gcgggggccc gagcacccca 1500ggagtataca ccaaggtctc agcctatctc aactggatct acaatgtctg gaaggctgag 1560ctgtaatgct gctgcccctt tgcagtgctg ggagccgctt ccttcctgcc ctgcccacct 1620ggggatcccc caaagtcaga cacagagcaa gagtcccctt gggtacaccc ctctgcccac 1680agcctcagca tttcttggag cagcaaaggg cctcaattcc tgtaagagac cctcgcagcc 1740cagaggcgcc cagaggaagt cagcagccct agctcggcca cacttggtgc tcccagcatc 1800ccagggagag acacagccca ctgaacaagg tctcaggggt attgctaagc caagaaggaa 1860ctttcccaca ctactgaatg gaagcaggct gtcttgtaaa agcccagatc actgtgggct 1920ggagaggaga aggaaagggt ctgcgccagc cctgtccgtc ttcacccatc cccaagccta 1980ctagagcaag aaaccagttg taatataaaa tgcactgccc tactgttggt atgactaccg 2040ttacctactg ttgtcattgt tattacagct atggccacta ttattaaaga gctgtgtaac 2100atctctggaa aaaaaaaaaa aaaa 2124773162DNAHomo sapiens 77gcgccctagc cctctttcgg ggatactggc cgaccccctc ttccttttcc cctttagtga 60aggcctcccc cgtcgccgcg cggcttcccg gagccgactg cagactccct cagcccggtg 120ttccccgcgt ccggacgccg aggtcgcggc ttcgcagaaa ctcgggcccc tccatccgcc 180ctcagaaaag ggagcgatgt tgatctcagg aagcacaaag ggaccttcct agctctgact 240gaaccacgga gctcaccctg gacagtatca ctccgtggag gaagactgtg agactgtggc 300tggaagccag attgtagcca cacatccgcc cctgccctac cccagagccc tggagcagca 360actggctgca gatcacagac acagtgagga tatgagtgta ggggtgagca cctcagcccc 420tctttcccca acctcgggca caagcgtggg catgtctacc ttctccatca tggactatgt 480ggtgttcgtc ctgctgctgg ttctctctct tgccattggg ctctaccatg cttgtcgtgg 540ctggggccgg catactgttg gtgagctgct gatggcggac cgcaaaatgg gctgccttcc 600ggtggcactg tccctgctgg ccaccttcca gtcagccgtg gccatcctgg gtgtgccgtc 660agagatctac cgatttggga cccaatattg gttcctgggc tgctgctact ttctggggct 720gctgatacct gcacacatct tcatccccgt tttctaccgc ctgcatctca ccagtgccta 780tgagtacctg gagcttcgat tcaataaaac tgtgcgagtg tgtggaactg tgaccttcat 840ctttcagatg gtgatctaca tgggagttgt gctctatgct ccgtcattgg ctctcaatgc 900agtgactggc tttgatctgt ggctgtccgt gctggccctg ggcattgtct gtaccgtcta 960tacagctctg ggtgggctga aggccgtcat ctggacagat gtgttccaga cactggtcat 1020gttcctcggg cagctggcag ttatcatcgt ggggtcagcc aaggtgggcg gcttggggcg 1080tgtgtgggcc gtggcttccc agcacggccg catctctggg tttgagctgg atccagaccc 1140ctttgtgcgg cacaccttct ggaccttggc cttcgggggt gtcttcatga tgctctcctt 1200atacggggtg aaccaggctc aggtgcagcg gtacctcagt tcccgcacgg agaaggctgc 1260tgtgctctcc tgttatgcag tgttcccctt ccagcaggtg tccctctgcg tgggctgcct 1320cattggcctg gtcatgttcg cgtattacca ggagtatccc atgagcattc agcaggctca 1380ggcagcccca gaccagttcg tcctgtactt tgtgatggat ctcctgaagg gcctgccagg 1440cctgccaggg ctcttcattg cctgcctctt cagcggctct ctcagcacta tatcctctgc 1500ttttaattca ttggcaactg ttacgatgga agacctgatt cgaccttggt tccctgagtt 1560ctctgaagcc cgggccatca tgctttccag aggccttgcc tttggctatg ggctgctttg 1620tctaggaatg gcctatattt cctcccagat gggacctgtg ctgcaggcag caatcagcat 1680ctttggcatg gttgggggac cgctgctggg actcttctgc cttggaatgt tctttccatg 1740tgctaaccct cctggtgctg ttgtgggcct gttggctggg ctcgtcatgg ccttctggat 1800tggcatcggg agcatcgtga ccagcatggg cttcagcatg ccaccctctc cctctaatgg 1860gtccagcttc tccctgccca ccaatctaac cgttgccact gtgaccacac tgatgccctt 1920gactaccttc tccaagccca cagggctgca gcggttctat tccttgtctt acttatggta 1980cagtgctcac aactccacca cagtgattgt ggtgggcctg attgtcagtc tactcactgg 2040gagaatgcga ggccggtccc tgaaccctgc aaccatttac ccagtgttgc caaagctcct 2100gtccctcctt ccgttgtcct gtcagaagcg gctccactgc aggagctacg gccaggacca 2160cctcgacact ggcctgtttc ctgagaagcc gaggaatggt gtgctggggg acagcagaga 2220caaggaggcc atggccctgg atggcacagc ctatcagggg agcagctcca cctgcatcct 2280ccaggagacc tccctgtgat gttgactcag gaccccgcct ctgtcctcac tgtgccaggc 2340catagccaga ggccaccctg tagtacaggg atgagtcttg gtgtgttctg cagggacagg 2400cctggatgat ctagctcata ccaaaggacc ttgttctgag aggttcttgc ctgcaggaga 2460agctgtcaca tctcaagcat gtgaggcacc gtttttctcg tcgcttgcca atctgttttt 2520taaaggatca ggctcgtagg gagcaggatc atgccagaaa tagggatgga agtgcatcct 2580ctgggaaaaa gataatggct tctgattcaa catagccata gtcctttgaa gtaagtggct 2640agaaacagca ctctggttat aattgcccca gggcctgatt caggactgac tctccaccat 2700aaaactggaa gctgcttccc ctgtagtccc catttcagta ccagttctgc cagccacagt 2760gagcccctat tattactttc agattgtctg tgacactcaa gcccctctca tttttatctg 2820tctacctcca ttctgaagag ggaggttttg gtgtccctgg tcctctggga atagaagatc 2880catttgtctt tgtgtagagc aagcacgttt tccacctcac tgtctccatc ctccacctct 2940gagatggaca cttaagagac ggggcaaatg tggatccaag aaaccagggc catgaccagg 3000tccactgtgg agcagccatc tatctacctg actcctgagc caggctgccg tggtgtcatt 3060tctgtcatcc gtgctctgtt tccttttgga gtttcttctc cacattatct ttgttcctgg 3120ggaataaaaa ctaccattgg acctaaaaaa aaaaaaaaaa aa 3162783779DNAHomo sapiens 78gcgtcgagct cgccgcggac tcaagatggc ggcgtgtgga cgtgtacgga ggatgttccg 60cttgtcggcg gcgctgcatc tgctgctgct attcgcggcc ggggccgaga aactccccgg 120ccagggcgtc cacagccagg gccagggtcc cggggccaac tttgtgtcct tcgtagggca 180ggccggaggc ggcggcccgg cgggtcagca gctgccccag ctgcctcagt catcgcagct 240tcagcagcaa cagcagcagc agcaacagca acagcagcct cagccgccgc agccgccttt 300cccggcgggt gggcctccgg cccggcgggg aggagcgggg gctggtgggg gctggaagct 360ggcggaggaa gagtcctgca gggaggacgt gacccgcgtg tgccctaagc acacctggag 420caacaacctg gcggtgctcg agtgcctgca ggatgtgagg gagcctgaaa atgaaatttc 480ttcagactgc aatcatttgt tgtggaatta taagctgaac ctaactacag atcccaaatt 540tgaatctgtg gccagagagg tttgcaaatc tactataaca gagattaaag aatgtgctga 600tgaaccggtt ggaaaaggtt acatggtttc ctgcttggtg gatcaccgag gcaacatcac 660tgagtatcag tgtcaccagt acattaccaa gatgacggcc atcattttta gtgattaccg 720tttaatctgt ggcttcatgg atgactgcaa aaatgacatc aacattctga aatgtggcag 780tattcggctt ggagaaaagg atgcacattc acaaggtgag gtggtatcat gcttggagaa 840aggcctggtg aaagaagcag aagaaagaga acccaagatt caagtttctg aactctgcaa 900gaaagccatt ctccgggtgg ctgagctgtc atcggatgac tttcacttag accggcattt 960atattttgct tgccgagatg atcgggagcg tttttgtgaa aatacacaag ctggtgaggg 1020cagagtgtat aagtgcctct ttaaccataa atttgaagaa tccatgagtg aaaagtgtcg 1080agaagcactt acaacccgcc aaaagctgat tgcccaggat tataaagtca gttattcatt 1140ggccaaatcc tgtaaaagtg acttgaagaa ataccggtgc aatgtggaaa accttccgcg 1200atcgcgtgaa gccaggctct cctacttgtt aatgtgcctg gagtcagctg tacacagagg 1260gcgacaagtc agcagtgagt gccaggggga gatgctggat taccgacgca tgttgatgga 1320agacttttct ctgagccctg agatcatcct aagctgtcgg ggggagattg aacaccattg 1380ttccggatta catcgaaaag ggcggaccct acactgtctg atgaaagtag ttcgagggga 1440gaaggggaac cttggaatga actgccagca ggcgcttcaa acactgattc aggagactga 1500ccctggtgca gattaccgca ttgatcgagc tttgaatgaa gcttgtgaat ctgtaatcca 1560gacagcctgc aaacatataa gatctggaga cccaatgatc ttgtcgtgcc tgatggaaca 1620tttatacaca gagaagatgg tagaagactg tgaacaccgt ctcttagagc tgcagtattt 1680catctcccgg gattggaagc tggaccctgt cctgtaccgc aagtgccagg gagacgcttc 1740tcgtctttgc cacacccacg gttggaatga gaccagtgaa tttatgcctc agggagctgt 1800gttctcttgt ttatacagac acgcctaccg cactgaggaa cagggaagga ggctctcacg 1860ggagtgccga gctgaagtcc aaaggatcct acaccagcgt gccatggatg tcaagctgga 1920tcctgccctc caggataagt gcctgattga tctgggaaaa tggtgcagtg agaaaacaga 1980gactggacag gagctggagt gccttcagga ccatctggat gacttggtgg tggagtgtag 2040agatatagtt ggcaacctca ctgagttaga atcagaggat attcaaatag aagccttgct 2100gatgagagcc tgtgagccca taattcagaa cttctgccac gatgtggcag ataaccagat 2160agactctggg gacctgatgg agtgtctgat acagaacaaa caccagaagg acatgaacga 2220gaagtgtgcc atcggagtta cccacttcca gctggtgcag atgaaggatt ttcggttttc 2280ttacaagttt aaaatggcct gcaaggagga cgtgttgaag ctttgcccaa acataaaaaa 2340gaaggtggac gtggtgatct gcctgagcac gaccgtgcgc aatgacactc tgcaggaagc 2400caaggagcac agggtgtccc tgaagtgccg caggcagctc cgtgtggagg agctggagat 2460gacggaggac atccgcttgg agccagatct atacgaagcc

tgcaagagtg acatcaaaaa 2520cttctgttcc gctgtgcaat atggcaacgc tcagattatc gaatgtctga aagaaaacaa 2580gaagcagcta agcacccgct gccaccaaaa agtatttaag ctgcaggaga cagagatgat 2640ggacccagag ctagactaca ccctcatgag ggtctgcaag cagatgataa agaggttctg 2700tccggaagca gattctaaaa ccatgttgca gtgcttgaag caaaataaaa acagtgaatt 2760gatggatccc aaatgcaaac agatgataac caagcgccag atcacccaga acacagatta 2820ccgcttaaac cccatgttaa gaaaagcctg taaagctgac attcctaaat tctgtcacgg 2880tatcctgact aaggccaagg atgattcaga attagaagga caagtcatct cttgcctgaa 2940gctgagatat gctgaccagc gcctgtcttc agactgtgaa gaccagatcc gaatcattat 3000ccaggagtcc gccctggact accgcctgga tcctcagctc cagctgcact gctcagacga 3060gatctccagt ctatgtgctg aagaagcagc agcccaagag cagacaggtc aggtggagga 3120gtgcctcaag gtcaacctgc tcaagatcaa aacagaattg tgtaaaaagg aagtgctaaa 3180catgctgaag gaaagcaaag cagacatctt tgttgacccg gtacttcata ctgcttgtgc 3240cctggacatt aaacaccact gcgcagccat cacccctggc cgcgggcgtc aaatgtcctg 3300tctcatggaa gcactggagg ataagcgggt gaggttacag cccgagtgca aaaagcgcct 3360caatgaccgg attgagatgt ggagttacgc agcaaaggtg gccccagcag atggcttctc 3420tgatcttgcc atgcaagtaa tgacgtctcc atctaagaac tacattctct ctgtgatcag 3480tgggagcatc tgtatattgt tcctgattgg cctgatgtgt ggacggatca ccaagcgagt 3540gacacgagag ctcaaggaca ggctacaata caggtcagag acaatggctt ataaaggttt 3600agtgtggtct caggatgtga caggcagtcc agcctgacct ttctgcacac tccagacaaa 3660cttcccagac aagctccttt gtgcctctac gtggagaggg tgtggaaagt tatcacatta 3720aaagatggag gatttaaaaa aaaaaaaaaa aaaaaaaaaa aaagaaaaaa aaaaaaaaa 3779796367DNAHomo sapiens 79cccgtggctg agaagaagga ggcctgagag cgacatgtcc ccggcggctc aggcggagcg 60gcccgtggcg ctgtttttct gagtccgggg tggcctggca gccggccgag gacgagggtc 120ggcgggggct gcccccgtgg tggtggccgc catgctggga gcctgggcgg ttgagggaac 180cgctgtggcg ctcctgcgac tgctgctgct gctgctgccg ccggcgatcc ggggacccgg 240gctcggcgtg gccggcgtgg ccggcgcggc gggggccggg ctgcccgaga gcgtcatttg 300ggcggtcaac gcgggtggag aggcgcatgt ggacgtgcac gggatccact tccgcaagga 360ccctttggaa ggccgggtgg gccgagcctc agactatggc atgaaactgc caatcctgcg 420ttccaaccct gaggaccaga tcctgtatca aactgagcgg tacaatgagg agacctttgg 480ctacgaagtg cccatcaaag aggaggggga ctacgtgctg gtcttgaaat ttgcagaggt 540ctactttgca cagtcccagc aaaaggtatt tgatgtacga ttgaatggcc acgtcgtggt 600gaaggacttg gatatctttg atcgtgttgg gcatagcaca gctcacgatg aaattatacc 660tatgagcatc agaaagggga agctgagtgt ccagggggag gtgtccacct tcacagggaa 720actctacatt gagtttgtca aggggtacta tgacaatccc aaggtctgtg cactctacat 780catggctggg acagtggatg atgtaccaaa gcttcagcct catccgggat tggagaagaa 840agaagaggaa gaagaagaag aagaatatga tgaagggtct aatctcaaaa aacagaccaa 900taagaaccgg gtgcagtcag gcccccgcac acccaacccc tatgcctcgg acaacagcag 960cctcatgttt cccatcctgg tggccttcgg agtcttcatt ccaaccctct tctgcctctg 1020ccggttgtga gaacaaatga ctatcctgaa cagggtggag gggtgtggga aagaaaccag 1080ccatattggt tttggtttct gtatttttca caatgattaa tgaacaaaaa caaagagaaa 1140aaaacacaca tcaattaaag gagacaaaaa gaggcagagc gagtagagag cagccctcat 1200tcaccacctg gtcccagacg tgcttcagtc ctcgtcctct ctttgtggct ggctcccagc 1260cttctctttc ctcttgagga tacttagggt aaactggatc cttcctgctc aaggatcctc 1320atttgtatac ctagtggaaa ggactctgaa ctcagaggag tcactgttcc tttttttagg 1380ttagaaatta acagcaggga aatgccatct tattacctga gacgaccagc actgggagtt 1440aggtacggtc tgaagttatg tctagataag acttcagacg tcctgggatt gaaagaatgt 1500gtgtgaaggg gtagaatttg tgcggtaaag acttaaaaaa aaaagtaggg agattaaaaa 1560aaaagaaaga aaatgcttcc ttatctggaa gcctttctgg attaatccag tgatggtccc 1620acctttagtg tttgagcttt gtcattgctt gtctccctgg catgtgccag ttatagactg 1680tccagcatcc aagacgtttc ggttatgtcg ggtcctcaga tcgcctctga cttgttacca 1740caacaaatca ttttgatttc agtgcctgtt ggggacttga tttcttctca gttttgtttg 1800tttgtttgtt tccttaatct ggctcatttg aaatttcttc tccctctcaa ccatcccact 1860aagttatagc caagaaggga aggagacacg gggatttggg gttctctgct tgaatgtctt 1920ctcctttacc acctcacctt gttggtacct ccctccctgg atctctgagc cagcagccag 1980gaggacctga cccagcagtt ctttactggc ccctttgtag ggccttgctg ccagggggca 2040gggatgcttt ccagcctgca gcaacagaac acttgacctt aaaagtctct tctggtcttt 2100ggattagaaa aggcttatgt tagcatagct taagagcaac ctcagagact tgagccctac 2160taagtgactg accactgttt agagtgtctg gtatctgatg ttcatttatt cccatgttct 2220tgtgtgtcac agttcagcca gttttggttt atgcctagag ctacttcaag gaactagact 2280aattagctat ataggcccag cgatgcttct tattgatctt aatagtatgc ccctccttcc 2340cctgtccttt catttctcta tccaagtagc agtcaggttc ttggtgtgat gggactgaaa 2400gaattccagt cagccagagc cttggcagct ctgaagctaa ccttagcatc taagtgtcga 2460tcttgaattc cctgaaaaaa tttctatagg aaatgaagct tccctggtcc cctcctttct 2520ggccattgtc atccatttcc cagttagggc aacaatgaag gaggacccag ccaagctaga 2580aggaattttg tggatgggag acagcaggat tagcttcagc ttgggctgga gcagtcaata 2640taggatctca ggccaggccc gcttttctag aatgtgttta attttgagtt tgctttatta 2700gatatgtttt ttaagagctc tgtatatttg aactgctcct tatgtgacaa aataggtagc 2760tcttgggctc atgtcctggg ttttggctct ttaatgatta ctccaggcca gcatttagtc 2820gtttgagaat tgtagcctgt tgttttcgct gtgacttggg tctcagtgct agggtattga 2880gtcaggcagc tggagggttg tggcccgagg ctgcagtcag aggtatactt cccatagtgc 2940ttcacacagc tcccctgctt ctaaaggata aggtactgta gccttggtcc tggggaccac 3000ctgcctgggg cagtggacat cctaactaaa caggcttctg gcagtagctt tggttcctat 3060cccatcgaaa ttccccaaag ccctgggcca ctgccattgg gttagtcaag atgaaggagg 3120aggactggct gcctccattt tgccttgttt gttagtttgc ctgggtctgt ctgaggaagg 3180agggggtccc gccttccacc tcaacacatc ccttcagtga ctcagagtct cagaaggaaa 3240ccctgactcc tggggccatt tcctaatggt actgtaagcc aagcagcttt gcttctgcct 3300ctgtttccaa gcccaccctt ttcccctgag ctcagggtta gggatgggcg ctttcctctc 3360tggttgtgaa cgaaaggaag gaacatcttt ctatggctaa caaaaactaa aggggaagtg 3420aggaaacagg aagaagtatg gtgggggctg gggtagactc ccctggagcc aagcctatcc 3480agctaacaag agctccctgg ggctggtcac agctggctca tgatgctgaa cttgaaagtt 3540tttttgtttt tgtttttgtt ttgtggctcc tccaagatat aggtacatga agtttaggtt 3600aaaggggtgg gattctttat ttttattttt gtattgtatg tgtcaagaat tactctgttg 3660ttcacctttt gctttttgca ctgtttgttc tcttatctgt attttgagct tagtgctagg 3720actgagaggc tgcaccatag ggaatgtatg ggagatggtg aggggtgcca gtgaggggtg 3780cgtggaggag aggcctgggc tcctctactg gatctacact ctgtcccagg tttttagatc 3840ccactgagcc cagctgactg aaaacaagga cagtcagggt gaaacttctt ttgccagaag 3900tgtggcctga gttgaatttc tgggaggatg acgcagatgt ctgctgcaga gctgggctga 3960gagttctgca gtctagctct gacttaggtc aggggcctgt tggtctctca ttggacgttt 4020ttgggtctca ctcatgctta ctgaaacatt gtgccaagaa actctgtggg atttgtgtcc 4080cttaaaccag actcactttt ctgaaaaatc tccattgttg aggagaggct gctcaatcga 4140caccccgagt tctcatgact gggaagatag ttttcttcag gtgtcaatgg cgttagactc 4200ccaggaagac tagccctgcc cacagggcca cctgttggtt tgagagcgtg ttcgtgttct 4260cttgccctcc ctgcctaaga gctactggga tcacgttagc gggcatttag gctttgatga 4320gagggcacag tttgagttag gtttacctcc ccctttctgt gcctgggaac tgtttggtcc 4380agctttagaa ctgtggtttt gacttcctta tctcttggga gaagcttctg ttttaaggaa 4440tttctcttcc ttcttctcct gcctctagcc tctcctggaa aggcctggat atggtttcta 4500aaatctcagc tgagaacttc agaaaacagc agcagtattt tccttttcct agtgctaaaa 4560tccctttccc tagaaattgg ctcaccttgg gaaacccagg gaaagaatca gcaggttctc 4620tgccctccct aggggttggg gaaggaccca ccccggtcag cacagtgcct tttcctctcc 4680tgctctgagc cagggtgggg cattccctct agattcaggt ttgggcaggg gtcctatagt 4740ccctgccatg gggctgcttc cctgtccctt ccctcccctt tgctggccta ctctggcata 4800attcaagtgt cttcttgcct tggggatcct tagtggcatc aaatggcaac atggaatatt 4860gtcctccatg cccctccaga aggacctagg agagtaggtg agctttccaa agtgagagac 4920gaatctttct ttcttttttt ttttaaaggg caggatgggt atgctttggg ctttctcctt 4980ctgtggcccc ggaggaagga gagactgagg caaggcaaag tgatagtaca ctgaagcaga 5040accggaaaca cccaggaact gttcagaaat ctcagaagaa atctgcttct cttcgatgga 5100aagatataat taacgatcaa agagctctaa gaaaattgca aagaagcctt aatgttcaag 5160ctttagaaag atcagagcaa tttttctctt tcagtccaaa ctaagactct ctgtatttaa 5220atctctctgg ggcaagaggg ctagatttcc tcattttgtt atgagactag attggtacca 5280gtagatcagc tgcctagcga gggcaggttt cttctttgca tctgtgtggc ttgcttccag 5340tctggcctgt cctttccagc tgccttttgt ctagcctgct atggggggcc agattatctt 5400gataagagca ggtgatttgg ggactagctg ggttggcagg aaaagagcag gatggatctc 5460ttgggacagg ttcccccagg agtataaaca caaggagcca ggattgtgct ggcagccaag 5520gaaacagtag tgcctgtttg agttggcaga gagggccttg gcacctcttg catccaggca 5580gtcttgtgag atgggggcac atagcactgg ggaaagcaga actccattct cacctctatt 5640ttgagcttca gtgctttatt tcagtatgag gaaaaacaac aacaaactga agtgcgcttt 5700ccgtcctttc aaaggacaac tgtcgggaag ggagagccga gttgcgaggt aggaggggag 5760cactggcagg gagagacatt cttgactcct ctcttccctg gtgtgttgtg atccagggaa 5820tgaaaagaaa tttgaccctg gattggttct ctccttggac ttaaggaatc ttaccttttc 5880cttccacaaa gttctcccag gcaaggacca gctgcccatt ctgagcccag ggcagcctct 5940tcaaccatta ttggtctaac ctggcttgtc aggaaaccaa gcccaccctt ccacattggg 6000cctggctgct ctattctgta ccaagtactg gagaaaaagc atcaagttct tagcccttgt 6060agcttctacc ctagtttccc atcctctctc tgtggaggcc aaaccaactc tttgccagca 6120gccacaacat gcattgacag cggcacagtg agatataact gatgggcttt gaacctggtt 6180ggccggggaa gctgtagggg tggatagagc tggctttcct tctgggctgt ctccatctga 6240ccctacccct tccatgtccc accccactcc caccaaaaag tacaaaatca ggatgttttt 6300cactgtccat tgctttgtgt tttaataaac aatttgcagt gacactctga aaaaaaaaaa 6360aaaaaaa 6367803319DNAHomo sapiens 80agcggagctg cagccggaga aagaggaaga gggagagaga gcgcgccagg gcgagggcac 60cgccgccggt cgggcgcgct gggcctgccc ggaatcccgc cgcctgcgcc ccgcgccccg 120cgccctgcgg gccatgggag ccggccgccg gcagggacga cgcctgtgag acccgcgagc 180ggcctcgggg accatgggga gcgatcgggc ccgcaagggc ggagggggcc cgaaggactt 240cggcgcggga ctcaagtaca actcccggca cgagaaagtg aatggcttgg aggaaggcgt 300ggagttcctg ccagtcaaca acgtcaagaa ggtggaaaag catggcccgg ggcgctgggt 360ggtgctggca gccgtgctga tcggcctcct cttggtcttg ctggggatcg gcttcctggt 420gtggcatttg cagtaccggg acgtgcgtgt ccagaaggtc ttcaatggct acatgaggat 480cacaaatgag aattttgtgg atgcctacga gaactccaac tccactgagt ttgtaagcct 540ggccagcaag gtgaaggacg cgctgaagct gctgtacagc ggagtcccat tcctgggccc 600ctaccacaag gagtcggctg tgacggcctt cagcgagggc agcgtcatcg cctactactg 660gtctgagttc agcatcccgc agcacctggt ggaggaggcc gagcgcgtca tggccgagga 720gcgcgtagtc atgctgcccc cgcgggcgcg ctccctgaag tcctttgtgg tcacctcagt 780ggtggctttc cccacggact ccaaaacagt acagaggacc caggacaaca gctgcagctt 840tggcctgcac gcccgcggtg tggagctgat gcgcttcacc acgcccggct tccctgacag 900cccctacccc gctcatgccc gctgccagtg ggccctgcgg ggggacgccg actcagtgct 960gagcctcacc ttccgcagct ttgaccttgc gtcctgcgac gagcgcggca gcgacctggt 1020gacggtgtac aacaccctga gccccatgga gccccacgcc ctggtgcagt tgtgtggcac 1080ctaccctccc tcctacaacc tgaccttcca ctcctcccag aacgtcctgc tcatcacact 1140gataaccaac actgagcggc ggcatcccgg ctttgaggcc accttcttcc agctgcctag 1200gatgagcagc tgtggaggcc gcttacgtaa agcccagggg acattcaaca gcccctacta 1260cccaggccac tacccaccca acattgactg cacatggaac attgaggtgc ccaacaacca 1320gcatgtgaag gtgcgcttca aattcttcta cctgctggag cccggcgtgc ctgcgggcac 1380ctgccccaag gactacgtgg agatcaacgg ggagaaatac tgcggagaga ggtcccagtt 1440cgtcgtcacc agcaacagca acaagatcac agttcgcttc cactcagatc agtcctacac 1500cgacaccggc ttcttagctg aatacctctc ctacgactcc agtgacccat gcccggggca 1560gttcacgtgc cgcacggggc ggtgtatccg gaaggagctg cgctgtgatg gctgggccga 1620ctgcaccgac cacagcgatg agctcaactg cagttgcgac gccggccacc agttcacgtg 1680caagaacaag ttctgcaagc ccctcttctg ggtctgcgac agtgtgaacg actgcggaga 1740caacagcgac gagcaggggt gcagttgtcc ggcccagacc ttcaggtgtt ccaatgggaa 1800gtgcctctcg aaaagccagc agtgcaatgg gaaggacgac tgtggggacg ggtccgacga 1860ggcctcctgc cccaaggtga acgtcgtcac ttgtaccaaa cacacctacc gctgcctcaa 1920tgggctctgc ttgagcaagg gcaaccctga gtgtgacggg aaggaggact gtagcgacgg 1980ctcagatgag aaggactgcg actgtgggct gcggtcattc acgagacagg ctcgtgttgt 2040tgggggcacg gatgcggatg agggcgagtg gccctggcag gtaagcctgc atgctctggg 2100ccagggccac atctgcggtg cttccctcat ctctcccaac tggctggtct ctgccgcaca 2160ctgctacatc gatgacagag gattcaggta ctcagacccc acgcagtgga cggccttcct 2220gggcttgcac gaccagagcc agcgcagcgc ccctggggtg caggagcgca ggctcaagcg 2280catcatctcc caccccttct tcaatgactt caccttcgac tatgacatcg cgctgctgga 2340gctggagaaa ccggcagagt acagctccat ggtgcggccc atctgcctgc cggacgcctc 2400ccatgtcttc cctgccggca aggccatctg ggtcacgggc tggggacaca cccagtatgg 2460aggcactggc gcgctgatcc tgcaaaaggg tgagatccgc gtcatcaacc agaccacctg 2520cgagaacctc ctgccgcagc agatcacgcc gcgcatgatg tgcgtgggct tcctcagcgg 2580cggcgtggac tcctgccagg gtgattccgg gggacccctg tccagcgtgg aggcggatgg 2640gcggatcttc caggccggtg tggtgagctg gggagacggc tgcgctcaga ggaacaagcc 2700aggcgtgtac acaaggctcc ctctgtttcg ggactggatc aaagagaaca ctggggtata 2760ggggccgggg ccacccaaat gtgtacacct gcggggccac ccatcgtcca ccccagtgtg 2820cacgcctgca ggctggagac tggaccgctg actgcaccag cgcccccaga acatacactg 2880tgaactcaat ctccagggct ccaaatctgc ctagaaaacc tctcgcttcc tcagcctcca 2940aagtggagct gggaggtaga aggggaggac actggtggtt ctactgaccc aactgggggc 3000aaaggtttga agacacagcc tcccccgcca gccccaagct gggccgaggc gcgtttgtgc 3060atatctgcct cccctgtctc taaggagcag cgggaacgga gcttcggggc ctcctcagtg 3120aaggtggtgg ggctgccgga tctgggctgt ggggcccttg ggccacgctc ttgaggaagc 3180ccaggctcgg aggaccctgg aaaacagacg ggtctgagac tgaaattgtt ttaccagctc 3240ccagggtgga cttcagtgtg tgtatttgtg taaatgagta aaacatttta tttcttttta 3300aaaaaaaaaa aaaaaaaaa 3319815903DNAHomo sapiens 81agacgccgcc caggacgcag ccgccgccgc cgccgctcct ctgccactgg ctctgcgccc 60cagcccggct ctgctgcagc ggcagggagg aagagccgcc gcagcgcgac tcgggagccc 120cgggccacag cctggcctcc ggagccaccc acaggcctcc ccgggcggcg cccacgctcc 180taccgcccgg acgcgcggat cctccgccgg caccgcagcc acctgctccc ggcccagagg 240cgacgacacg atgcgctgcg cgctggcgct ctcggcgctg ctgctactgt tgtcaacgcc 300gccgctgctg ccgtcgtcgc cgtcgccgtc gccgtcgccc tcccagaatg caacccagac 360tactacggac tcatctaaca aaacagcacc gactccagca tccagtgtca ccatcatggc 420tacagataca gcccagcaga gcacagtccc cacttccaag gccaacgaaa tcttggcctc 480ggtcaaggcg accacccttg gtgtatccag tgactcaccg gggactacaa ccctggctca 540gcaagtctca ggcccagtca acactaccgt ggctagagga ggcggctcag gcaaccctac 600taccaccatc gagagcccca agagcacaaa aagtgcagac accactacag ttgcaacctc 660cacagccaca gctaaaccta acaccacaag cagccagaat ggagcagaag atacaacaaa 720ctctgggggg aaaagcagcc acagtgtgac cacagacctc acatccacta aggcagaaca 780tctgacgacc cctcacccta caagtccact tagcccccga caacccactt cgacgcatcc 840tgtggccacc ccaacaagct cgggacatga ccatcttatg aaaatttcaa gcagttcaag 900cactgtggct atccctggct acaccttcac aagcccgggg atgaccacca ccctaccgtc 960atcggttatc tcgcaaagaa ctcaacagac ctccagtcag atgccagcca gctctacggc 1020cccttcctcc caggagacag tgcagcccac gagcccggca acggcattga gaacacctac 1080cctgccagag accatgagct ccagccccac agcagcatca actacccacc gataccccaa 1140aacaccttct cccactgtgg ctcatgagag taactgggca aagtgtgagg atcttgagac 1200acagacacag agtgagaagc agctcgtcct gaacctcaca ggaaacaccc tctgtgcagg 1260gggcgcttcg gatgagaaat tgatctcact gatatgccga gcagtcaaag ccaccttcaa 1320cccggcccaa gataagtgcg gcatacggct ggcatctgtt ccaggaagtc agaccgtggt 1380cgtcaaagaa atcactattc acactaagct ccctgccaag gatgtgtacg agcggctgaa 1440ggacaaatgg gatgaactaa aggaggcagg ggtcagtgac atgaagctag gggaccaggg 1500gccaccggag gaggccgagg accgcttcag catgcccctc atcatcacca tcgtctgcat 1560ggcatcattc ctgctcctcg tggcggccct ctatggctgc tgccaccagc gcctctccca 1620gaggaaggac cagcagcggc taacagagga gctgcagaca gtggagaatg gttaccatga 1680caacccaaca ctggaagtga tggagacctc ttctgagatg caggagaaga aggtggtcag 1740cctcaacggg gagctggggg acagctggat cgtccctctg gacaacctga ccaaggacga 1800cctggatgag gaggaagaca cacacctcta gtccggtctg ccggtggcct ccagcagcac 1860cacagagctc cagaccaacc accccaagtg ccgtttggat ggggaaggga aagactgggg 1920agggagagtg aactccgagg ggtgtcccct cccaatcccc ccagggcctt aatttttccc 1980ttttcaacct gaacaaatca cattctgtcc agattcctct tgtaaaataa cccactagtg 2040cctgagctca gtgctgctgg atgatgaggg agatcaagaa aaagccacgt aagggacttt 2100atagatgaac tagtggaatc ccttcattct gcagtgagat tgccgagacc tgaagagggt 2160aagtgacttg cccaaggtca gagccacttg gtgacagagc caggatgaga acaaagattc 2220catttgcacc atgccacact gctgtgttca catgtgcctt ccgtccagag cagtcccggg 2280caggggtgaa actccagcag gtggctgggc tggaaaggag ggcagggcta catcctggct 2340cggtgggatc tgacgacctg aaagtccagc tcccaagttt tccttctcct accccagcct 2400cgtgtaccca tcttcccacc ctctatgttc ttacccctcc ctacactcag tgtttgttcc 2460cacttactct gtcctggggc ctctgggatt agcacaggtt attcataacc ttgaacccct 2520tgttctggat tcggattttc tcacatttgc ttcgtgagat gggggcttaa cccacacagg 2580tctccgtgcg tgaaccaggt ctgcttaggg gacctgcgtg caggtgagga gagaagggga 2640cactcgagtc caggctggta tctcagggca gctgatgagg ggtcagcagg aacactggcc 2700cattgcccct ggcactcctt gcagaggcca cccacgatct tctttgggct tccatttcca 2760ccagggacta aaatctgctg tagctagtga gagcagcgtg ttccttttgt tgttcactgc 2820tcagctgatg ggagtgattc cctgagaccc agtatgaaag agcagtggct gcaggagagg 2880ccttcccggg gccccccatc agcgatgtgt cttcagagac aatccattaa agcagccagg 2940aaggacaggc tttcccctgt atatcatagg aaactcaggg acatttcaag ttgctgagag 3000ttttgttata gttgttttct aacccagccc tccactgcca aaggccaaaa gctcagacag 3060ttggcagacg tccagttagc tcatctcact cactctgatt ctcctgtgcc acaggaaaag 3120agggcctgga aagcgcagtg catgctgggt gcatgaaggg cagcctgggg gacagactgt 3180tgtgggaacg tcccactgtc ctggcctgga gctaggcctt gctgttcctc ttctctgtga 3240gcctagtggg gctgctgcgg ttctcttgca gtttctggtg gcatctcagg ggaacacaaa 3300gctatgtcta ttccccaata taggactttt atgggctcgg cagttagctg ccatgtagaa 3360ggctcctaag cagtgggcat ggtgaggttt catctgattg agaaggggga atcctgtgtg 3420gaatgttgaa ctttcgccat ggtctccatc gttctgggcg taaattccct gggatcaagt 3480aggaaaatgg gcagaactgc ttaggggaat gaaattgcca tttttcgggt gaaacgccac 3540acctccaggg tcttaagagt caggctccgg ctgtagtagc tctgatgaaa taggctatcc 3600actcgggatg gcttactttt taaaagggta gggggagggg ctggggaaga tctgtcctgc 3660accatctgcc taattccttc ctcacagtct gtagccatct gatatcctag gggaaaagga 3720aggccagggg ttcacatagg gccccagcga gtttcccagg agttagaggg atgcgaggct 3780aacaagttcc aaaaacatct gccccgatgc tctagtgttt ggaggtgggc aggatggaga 3840acagtgcctg tttgggggaa aacaggaaat cttgttaggc ttgagtgagg tgtttgcttc 3900cttcttgccc agcgctgggt tctctccacc cagtaggttt

tctgttgtgg tcccgtggga 3960gaggccagac tggattattc ctcctttgct gatcctgggt cacacttcac cagccagggc 4020ttttgacgga gacagcaaat aggcctctgc aaatcaatca aaggctgcaa ccctatggcc 4080tcttggagac agatgatgac tggcaaggac tagagagcag gagtgcctgg ccaggtcggt 4140cctgactctc ctgactctcc atcgctctgt ccaaggagaa cccggagagg ctctgggctg 4200attcagaggt tactgcttta tattcgtcca aactgtgtta gtctaggctt aggacagctt 4260cagaatctga caccttgcct tgctcttgcc accaggacac ctatgtcaac aggccaaaca 4320gccatgcatc tataaaggtc atcatcttct gccaccttta ctgggttcta aatgctctct 4380gataattcag agagcattgg gtctgggaag aggtaagagg aacactagaa gctcagcatg 4440acttaaacag gttgtagcaa agacagttta tcatcagctc tttcagtggt aaactgtggt 4500ttccccaagc tgcacaggag gccagaaacc acaagtatga tgactaggaa gcctactgtc 4560atgagagtgg ggagacaggc agcaaagctt atgaaggagg tacagaatat tctttgcgtt 4620gtaagacaga atacgggttt aatctagtct aggcaccaga tttttttccc gcttgataag 4680gaaagctagc agaaagttta tttaaaccac ttcttgagct ttatcttttt tgacaatata 4740ctggagaaac tttgaagaac aagttcaaac tgatacatat acacatattt ttttgataat 4800gtaaatacag tgaccatgtt aacctaccct gcactgcttt aagtgaacat actttgaaaa 4860agcattatgt tagctgagtg atggccaagt tttttctctg gacaggaatg taaatgtctt 4920actggaaatg acaagttttt gcttgatttt tttttttaaa caaaaaatga aatataacaa 4980gacaaactta tgataaagta tttgtcttgt agatcaggtg ttttgttttg tttttttaat 5040tttaaaatgc aaccctgccc cctccccagc aaagtcacag ctccatttca gtaaaggttg 5100gagtcaatat gctctggttg gcaggcaacc ctgtagtcat ggagaaaggt atttcaagat 5160ctagtccaat ctttttctag agaaaaagat aatctgaagc tcacaaagat gaagtgactt 5220cctcaaaatc acatggttca ggacagaaac aagattaaaa cctggatcca cagactgtgc 5280gcctcagaag gaataatcgg taaattaaga attgctactc gaaggtgcca gaatgacaca 5340aaggacagaa ttcctttccc agttgttacc ctagcaaggc tagggagggc atgaacacaa 5400acataagaac tggtcttcta cactttctct gaatcattta ggtttaagat gtaagtgaac 5460aattctttct ttctgccaag aaacaaagtt ttggatgagc ttttatatat ggaacttact 5520ccaacaggac tgagggacca aggaaacatg atgggggagg cagagagggc aagagtaaaa 5580ctgtagcata gcttttgtca cggtcactag ctgatccctc aggtctgctg caaacacagc 5640atggaggaca cagatgactc tttggtgttg gtctttttgt ctgcagtgaa tgttcaacag 5700tttgcccagg aactggggga tcatatatgt cttagtggac aggggtctga agtacactgg 5760aatttactga gaaacttgtt tgtaaaaact atagttaata attattgcat tttcttacaa 5820aaatatattt tggaaaattg tatactgtca attaaagtgt ttttgtgtaa actggttcaa 5880aaaaaaaaaa aaaaaaaaaa aaa 5903821791DNAHomo sapiens 82ggaggctgca gcagcggaag accccagtcc agatccagga ctgagatccc agaaccatga 60acctggccat cagcatcgct ctcctgctaa cagtcttgca ggtctcccga gggcagaagg 120tgaccagcct aacggcctgc ctagtggacc agagccttcg tctggactgc cgccatgaga 180ataccagcag ttcacccatc cagtacgagt tcagcctgac ccgtgagaca aagaagcacg 240tgctctttgg cactgtgggg gtgcctgagc acacataccg ctcccgaacc aacttcacca 300gcaaatacaa catgaaggtc ctctacttat ccgccttcac tagcaaggac gagggcacct 360acacgtgtgc actccaccac tctggccatt ccccacccat ctcctcccag aacgtcacag 420tgctcagaga caaactggtc aagtgtgagg gcatcagcct gctggctcag aacacctcgt 480ggctgctgct gctcctgctc tccctctccc tcctccaggc cacggatttc atgtccctgt 540gactggtggg gcccatggag gagacaggaa gcctcaagtt ccagtgcaga gatcctactt 600ctctgagtca gctgaccccc tccccgcaat ccctcaaacc ttgaggagaa gtggggaccc 660cacccctcat caggagttcc agtgctgcat gcgattatct acccacgtcc acgcggccac 720ctcaccctct ccgcacacct ctggctgtct ttttgtactt tttgttccag agctgcttct 780gtctggttta tttaggtttt atccttcctt ttctttgaga gttcgtgaag agggaagcca 840ggattgggga cctgatggag agtgagagca tgtgaggggt agtgggatgg tggggtacca 900gccactggag gggtcatcct tgcccatcgg gaccagaaac ctgggagaga cttggatgag 960gagtggttgg gctgtgcctg ggcctagcac ggacatggtc tgtcctgaca gcactcctcg 1020gcaggcatgg ctggtgcctg aagaccccag atgtgagggc accaccaaga atttgtggcc 1080taccttgtga gggagagaac tgagcatctc cagcattctc agccacaacc aaaaaaaaat 1140aaaaagggca gccctcctta ccactgtgga agtccctcag aggccttggg gcatgaccca 1200gtgaagatgc aggtttgacc aggaaagcag cgctagtgga gggttggaga aggaggtaag 1260gatgagggtt catcatccct ccctgcctaa ggaagctaaa agcatggccc tgctgcccct 1320ccctgcctcc acccacagtg gagagggcta caaaggagga caagaccctc tcaggctgtc 1380ccaagctccc aagagcttcc agagctctga cccacagcct ccaagtcagg tggggtggag 1440tcccagagct gcacagggtt tggcccaagt ttctaaggga ggcacttcct cccctcgccc 1500atcagtgcca gcccctgctg gctggtgcct gagcccctca gacagccccc tgccccgcag 1560gcctgccttc tcagggactt ctgcggggcc tgaggcaagc catggagtga gacccaggag 1620ccggacactt ctcaggaaat ggcttttccc aacccccagc ccccacccgg tggttcttcc 1680tgttctgtga ctgtgtatag tgccaccaca gcttatggca tctcattgag gacaaagaaa 1740actgcacaat aaaaccaagc ctctggaatc taaaaaaaaa aaaaaaaaaa a 1791833512DNAHomo sapiens 83gacatggcga gtgtagtgct gccgagcgga tcccagtgtg cggcggcagc ggcggcggcg 60gcgcctcccg ggctccggct ccggcttctg ctgttgctct tctccgccgc ggcactgatc 120cccacaggtg atgggcagaa tctgtttacg aaagacgtga cagtgatcga gggagaggtt 180gcgaccatca gttgccaagt caataagagt gacgactctg tgattcagct actgaatccc 240aacaggcaga ccatttattt cagggacttc aggcctttga aggacagcag gtttcagttg 300ctgaattttt ctagcagtga actcaaagta tcattgacaa acgtctcaat ttctgatgaa 360ggaagatact tttgccagct ctataccgat cccccacagg aaagttacac caccatcaca 420gtcctggtcc caccacgtaa tctgatgatc gatatccaga gagacactgc ggtggaaggt 480gaggagattg aagtcaactg cactgctatg gccagcaagc cagccacgac tatcaggtgg 540ttcaaaggga acacagagct aaaaggcaaa tcggaggtgg aagagtggtc agacatgtac 600actgtgacca gtcagctgat gctgaaggtg cacaaggagg acgatggggt cccagtgatc 660tgccaggtgg agcaccctgc ggtcactgga aacctgcaga cccagcggta tctagaagta 720cagtataagc cacaagtgca cattcagatg acttatcctc tacaaggctt aacccgggaa 780ggggacgcgc ttgagttaac atgtgaagcc atcgggaagc cccagcctgt gatggtaact 840tgggtgagag tcgatgatga aatgcctcaa cacgccgtac tgtctgggcc caacctgttc 900atcaataacc taaacaaaac agataatggt acataccgct gtgaagcttc aaacatagtg 960gggaaagctc actcggatta tatgctgtat gtatacgatc cccccacaac tatccctcct 1020cccacaacaa ccaccaccac caccaccacc accaccacca ccatccttac catcatcaca 1080gattcccgag caggtgaaga aggctcgatc agggcagtgg atcatgccgt gatcggtggc 1140gtcgtggcgg tggtggtgtt cgccatgctg tgcttgctca tcattctggg gcgctatttt 1200gccagacata aaggtacata cttcactcat gaagccaaag gagccgatga cgcagcagac 1260gcagacacag ctataatcaa tgcagaagga ggacagaaca actccgaaga aaagaaagag 1320tacttcatct agatcagcct ttttgtttca atgaggtgtc caactggccc tatttagatg 1380ataaagagac agtgatattg gaacttgcga gaaattcgtg tgttttttta tgaatgggtg 1440gaaaggtgtg agactgggaa ggcttgggat ttgctgtgta aaaaaaaaaa aaaatgttct 1500ttggaaagta cactctgctg tttgacacct cttttttcgt ttgtttgttt gtttaatttt 1560tatttcttcc taccaagtca aacttggata cttggattta gtttcagtag attgcagaaa 1620attctgtgcc ttgttttttg tttgtttgtt gcgttccttt cttttccccc tttgtgcaca 1680tttatttcct ccctctaccc caatttcgga ttttttccaa aatctcccat tttggaattt 1740gcctgctggg attccttaga ctcttttcct tcccttttct gttctagttt tttacttttg 1800tttattttta tggtaactgc tttctgttcc aaattcagtt tcataaaagg agaaccagca 1860cagcttagga tttcatagtt cagaatttag tgtatccata atgcattctt ctctgttgtc 1920gtaaagattt gggtgaacaa acaatgaaaa ctctttgctg ctgcccatgt ttcaaatact 1980tagagcagtg aagactagaa aattagactg tgattcagaa aatgttctgt ttgctgtgga 2040actacattac tgtacagggt tatctgcaag tgaggtgtgt cacaatgaga ttgaatttca 2100ctgtctttaa ttctgtatct gtagacggct cagtatagat accctacgct gtccagaaag 2160gtttggggca gaaaggactc ctcctttttc catgccctaa acagacctga caggtgaggt 2220ctgttccttt tatataagtg gacaaatttt gagttgccac aggaggggaa gtagggaggg 2280gggaaataca gttctgctct ggttgtttct gttccaaatg attccatcca cctttcccaa 2340tcggccttac ttctcactaa tttgtaggaa aaagcaagtt cgtctgttgt gcgaatgact 2400gaatgggaca gagttgattt tttttttttt tttcctttgt gcttagttag gaaggcagta 2460ggatgtggcc tgcatgtact gtatattaca gatatttgtc atgctgggat ttccaactcg 2520aatctgtgtg aaactttcat tccttcagat ttggcttgac aaaggcagga ggtacaaaag 2580aagggctggt attgttctca cactggtctg ctgtcgctct cagttctcga taggtcagag 2640cagaggtgga aaaacagcat gtacggattt tcagttactt aatcaaaact caaatgtgag 2700tgtttttatc tttttacctt tcatacacta gccttggcct ctttcctcag ccttaagaac 2760catctgccaa aaattactga tcctcgcatg atggcagcca tagtgcatag ctactaaaat 2820cagtgacctt gaacatatct tagatgggga gcctcgggaa aaggtagagg agtcacgtta 2880ccatttacat gttttaaaga aagaagtgtg gggattttca ctgaaacgtc taggaaatct 2940agaagtagtc ctgaaggaca gaaactaaac tcttaccata tgtttggtaa gactccagac 3000tccagctaac agtccctatg gaaagatggc atcaaaaaag atagatctat atatatatat 3060aaatatatat tctattacat tttcagtgag taattttgga ttttgcaagg tgcattttta 3120ctattgttac attatgtgga aaacttatgc tgatttattt aagggggaaa aagtgtcaac 3180tctttgttat ttgaaaacat gtttattttt cttgtcttta ttttaacctt tgatagaacc 3240attgcaatat gggggccttt tgggaacgga ctggtatgta aaagaaaatc cattatcgag 3300cagcatttta tttacccctc ccctatccct aggcacttaa ccaagacaaa aagccacaat 3360gaacatccct ttttcaatga attttataat ctgcagctct attccgagcc cttagcaccc 3420attccgacca tagtataatc atatcaaagg gtgagaatca tttagcatgt tgttgaaagg 3480ttttttttca gttgttcttt ttagaaaaaa ag 3512

Claims

1. An isolated protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73.

2. A composition comprising the protein of claim 1 and a pharmaceutically acceptable carrier.

3. An isolated nucleic acid molecule comprising a nucleotide sequence selected from the group consisting of: a) SEQ ID NOS:4-6, 10-12, 18-22, 24, 34-42, 45-46, 49-50, 53-55, 60-63, 68-71, and 74-75; b) nucleotide sequences that encode a protein comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73; and c) nucleotide sequences that are completely complementary to the nucleotide sequences of a) or b).

4. An isolated RNAi or antisense nucleic acid molecule that selectively binds to the nucleic acid molecule of claim 3.

5. An isolated antibody that selectively binds to the protein of claim 1.

6. The antibody of claim 5, wherein the antibody is at least one of a monoclonal, polyclonal, fully human, humanized, chimeric, single-chain, or anti-idiotypic antibody.

7. A cell line, hybridoma, phage, or transgenic organism that produces the antibody of claim 5.

8. The antibody of claim 5, wherein the antibody is coupled to a composition selected from the group consisting of detectable substances and therapeutic agents.

9. A composition comprising the antibody of claim 5 and a pharmaceutically acceptable carrier.

10. An isolated antibody fragment of the antibody of claim 5, wherein the antibody fragment comprises a fragment selected from the group consisting of: a) an Fab fragment; b) an F(ab').sub.2 fragment; and c) an Fv fragment.

11. A method of modulating cell proliferation or apoptosis, the method comprising contacting a cell with the antibody of claim 5.

12. The method of claim 11, wherein the method comprises either inhibiting proliferation of cancer cells or stimulating apoptosis of cancer cells.

13. A method of modulating cell proliferation or apoptosis, the method comprising contacting a cell with the RNAi or antisense nucleic acid molecule of claim 4.

14. A method of detecting the protein of claim 1 in a sample, the method comprising contacting the sample with an isolated antibody that selectively binds to the protein and determining whether the antibody binds to the protein.

15. A method of detecting the nucleic acid molecule of claim 3 in a sample, the method comprising contacting the sample with an oligonucleotide that specifically hybridizes to the nucleic acid molecule and determining whether the oligonucleotide binds to the nucleic acid molecule.

16. A method of diagnosing, prognosing, or determining risk of cancer in a subject, the method comprising detecting at least one molecule in a sample, wherein the presence or abundance of the molecule is indicative of cancer, and wherein the molecule is selected from the group consisting of: a) proteins comprising an amino acid sequence selected from the group consisting of SEQ ID NOS:1-3, 7-9, 13-17, 23, 25-33, 43-44, 47-48, 51-52, 56-59, 64-67, and 72-73; b) antibodies that selectively bind to the protein of a); c) nucleic acid molecules comprising a nucleotide sequence selected from the group consisting of SEQ ID NOS:4-6, 10-12, 18-22, 24, 34-42, 45-46, 49-50, 53-55, 60-63, 68-71, and 74-75 and nucleotide sequences that encode the protein of a); and d) nucleic acid molecules comprising a nucleotide sequence that is completely complementary to the nucleic acid molecule of c).

17. A method of treating cancer, the method comprising administering a therapeutically effective amount of the antibody of claim 5 to a subject.

18. A method of screening agents, the method comprising contacting the protein of claim 1 or a cell that expresses the protein with an agent, and assaying for whether the agent binds to the protein or modulates the function, activity, or expression of the protein.

19. A composition comprising the agent identified by the method of claim 18 and a pharmaceutically acceptable carrier.

20. A method of determining or predicting the effectiveness of a treatment or selecting a treatment for administration to a subject having cancer, the method comprising detecting the presence, abundance, or activity of the protein of claim 1 in a sample and determining or predicting the effectiveness of the treatment or selecting the treatment for administration based on the presence, abundance, or activity of the protein.