Methods for Identifying and Compounds Useful for Increasing the Functional Activity and Cell Surface Expression of CF-Associated Mutant Cystic Fibrosis Transmembrance Conductance Regulator

Abstract

The present invention relates to agents, and methods for identifying compounds, which agents and compounds result in the modulation of cellular trafficking of proteins in particular that of CF-associated mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). In addition, the invention relates to compositions and methods for the use thereof in treating conditions that are characterized by an ER-associated protein misfolding and abnormal cellular trafficking of disease-associated proteins, including cystic fibrosis (CF).

Description

BACKGROUND OF THE INVENTION

[0001] The present invention relates to agents, and methods for identifying compounds, which agents and compounds result in the increased functional activity of CF-associated mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). In addition, the invention relates to compositions and methods for the use thereof in treating conditions that are characterized by a decrease in function of CF-associated mutant CFTR including cystic fibrosis (CF), and other protein misfolding diseases.

[0002] Cystic Fibrosis Transmembrane Conductance Regulator, a member of the ATP-binding cassette (ABC) transporter family, is believed to regulate the chloride channel responsible for cAMP-mediated chloride secretion in epithelial cells. For reviews on cystic fibrosis we refer to Guggino and Stanton, 2006) and Rowe et al., 2005. By its chloride channel function, CFTR plays a key role in chloride secretion and water balance in epithelia throughout the body. CFTR has been identified and sequenced (Riordan et al., 1989). Defects in this gene causing diminished activity and/or expression of CFTR lead to cystic fibrosis. CF is the most common fatal genetic disease in humans affecting approximately one in every 2,500 infants born in the United States of America. In patients with CF, expression of the CF-associated gene in epithelial cells leads to reduced cellular apical chloride conductance, causing an imbalance in ion and fluid transport. It is widely believed that this leads to the abnormal mucus secretion in pancreatic ductules and in the airways that ultimately results in the pulmonary infections and epithelial cell damage typically associated with disease progression in CF. In addition to respiratory problems, CF patients typically suffer from gastrointestinal problems, and pancreatic insufficiency. Males are almost uniformly infertile and fertility is decreased in females.

[0003] Sequence analysis of the CFTR gene of CF chromosomes has revealed a variety of disease-causing mutations. At present, more than 1000 mutations in the CF gene have been identified (http://www.genet.sickkids.on.ca/cftr/ or http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602421), but population studies have indicated that the most common CF mutation, a deletion of the 3 nucleotides that encode phenylalanine at position 508 of the CFTR amino acid sequence, is associated with approximately 70% of the cases of cystic fibrosis. The mutated CFTR protein is referred to as ΔF508.

[0004] It is believed that the deletion of residue 508 in ΔF508-CFTR prevents the nascent protein from folding correctly, resulting in the inability of this mutant protein to exit the endoplasmic reticulum (ER), and traffic to the plasma membrane. As a result, insufficient amounts of the mature protein are present at the plasma membrane and chloride transport within epithelial tissues is significantly reduced (Quinton, 1990). Studies have shown, however, that ΔF508-CFTR, when presented at the plasma membrane is functional as a cAMP-responsive Cl^channel (Denning et al., 1992). Correcting ΔF508-CFTR maturation, allowing exit of ΔF508-CFTR from the ER, or enhancing the activity of ΔF508-CFTR would constitute a mode of action of a novel drug to treat CF.

[0005] In fact, the cellular phenomenon of defective ER processing of ABC transporters, or other proteins, by the ER machinery has been shown to be the underlying basis not only for CF disease, but for a wide range of other isolated and inherited diseases (Ulloa-Aguirre et al., 2004). This means that drugs found for CF treatment may also be effective in the treatment of other diseases.

[0006] No therapy currently exists that restores the function of mutant CFTR. Restoring mutant CFTR function is expected to decrease CF-associated complications, and improve quality of life and expected life-span of CF patients.

[0007] Therefore, there is a clear need for molecules that facilitate the folding, processing and/or migration of the ΔF508-CFTR to the plasma membrane, thereby increasing the density of ΔF508-CFTR in the membrane, and rescuing the function of ΔF508-CFTR (correctors). These correctors may be an inhibitory agent, particularly small molecule drug compounds or biologic drugs, which target a protein regulating the processing of ΔF508-CFTR through the ER. To enable the development of such a drug, there is a need to identify target proteins, that, when antagonized, increase the density and functional performance of ΔF508-CFTR in the plasma membrane.

[0008] An example of such a protein target is syntaxin-8 (STX8), which is involved in trafficking of vesicles and has been shown to bind to the wild-type CFTR (Antonin et al., 2000; Bilan et al., 2004; Thoreau et al., 1999). It has been shown that syntaxin-8 can function as a drug target by correcting CF-associated mutant CFTR function (Fischer et al., 2006). Another positive control is BCAP31 (Lambert et al., 2001). It has been previously demonstrated that down-regulation of BCAP31 by Ad-siRNA allows functional restoration of ΔF508-CFTR (Fischer et al., 2006).

[0009] Therefore, there remains a need to identify further targets which may be of use in the diagnosis, prevention and or treatment of disorders involving ER-associated protein misfolding and in particular diseases characterized by abnormal trafficking of a disease-associated protein. Exemplary conditions include, but are not limited to, Cystic Fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease, Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome and retinitis pimentosa, transthyretin-linked amyloidosis, Alzheimer's disease, prion disease, and inclusion body myositis. In particular the disease is Cystic Fibrosis. As many of the clinical symptoms (e.g. airway obstruction, chronic inflammation, mucus overproduction, enhanced cytokine production) of CF overlap with those of asthma and COPD (Chronic Obstructive Pulmonary Disease), these targets may also be of use in the diagnosis, prevention and or treatment of asthma and COPD.

SUMMARY OF THE INVENTION

[0010] The present invention is based on the discovery that agents which inhibit the expression and/or activity of the TARGETS disclosed herein are able to result in the increased functional activity of CF-associated mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in human airway bronchial epithelial cells. The present invention therefore provides TARGETS which are involved in the pathway involved in cellular trafficking/protein trafficking and/or folding, methods for screening for agents capable of modulating the expression and/or activity of TARGETS and uses of these agents in the prevention and/or treatment of ER-associated protein misfolding diseases, in particular Cystic Fibrosis.

[0011] The present invention relates to a method for identifying compounds that increase the functional activity of CF-associated mutant CFTR, comprising contacting the compound with the identified TARGETS or their protein domain fragments (SEQ ID. NO 30-55) under conditions that allow said TARGETS or their protein domain fragments to bind to the compound, and measuring a compound-polypeptide property related to the increased functional activity of CF-associated mutant CFTR.

[0012] In particular the present invention provides TARGETS which are involved in the pathway involved in cellular trafficking, particularly of CFTR, methods for screening for agents capable of modulating the expression and/or activity of TARGETS and uses of these agents in the prevention and/or treatment of CF. The present invention provides TARGETS which are involved in or otherwise associated with airway epithelial cell function. The present invention provides TARGETS which are involved in inflammation and the inflammatory response, particularly associated with CF and/or in airway epithelial cells. The invention provides uses of agents directed against these targets in CF and other airway diseases involving an inflammatory aspect or component, including asthma and COPD.

[0013] Aspects of the present method include the in vitro assay of compounds using identified TARGETS, and cellular assays wherein identified TARGET inhibition is followed by observing indicators of efficacy, including chloride channel activity. Another aspect of the invention is a method of treatment or prevention of a condition involving a decrease in functional activity of CF-associated mutant CFTR, in a subject suffering or susceptible thereto, by administering a pharmaceutical composition comprising an effective corrector for enhancing the functional activity of CF-associated mutant CFTR.

[0014] The present invention relates to a method for identifying compounds that inhibit the TARGET(s), comprising contacting the compound with the identified TARGETS (SEQ ID NO: 30-55) or their protein domain fragments under conditions wherein the compounds may interact with or influence the TARGET(s), measuring the expression or activity of a protein which is misfolded in an ER-associated protein misfolding disease, and selecting compounds which increase the expression or activity of the protein which is misfolded in the ER-associated protein misfolding disease. In one such method the expression or activity of ΔF508 CFTR, misfolded in the disease CF, is measured. In exemplary further such methods, the expression or activity of fibrillin, misfolded in Marfan syndrome, or of alpha galactosidase, misfolded in Fabry's disease, or of rhodopsin, misfolded in retinitis pigmentosa, or beta-amyloid protein, misfolded in Alzheimer's disease, is/are measured, and compounds which increase the proper expression or activity thereof are selected.

[0015] The present invention relates to a method for identifying compounds that are able to modulate protein folding and trafficking, and particularly ER-associated protein folding and cellular trafficking, comprising contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55 (hereinafter "TARGETS") and fragments thereof, under conditions that allow said polypeptide to bind to said compound, and measuring a compound-polypeptide property related to cellular trafficking of proteins. In a specific embodiment, the present invention relates to a method for identifying compounds that are able to modulate the protein folding, trafficking or activity of the mutant CFTR protein in airway epithelial cells, comprising contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55 (hereinafter "TARGETS") and fragments thereof, under conditions that allow said polypeptide to bind to said compound, and measuring a compound-polypeptide property related to CFTR expression or activity. In a specific embodiment the compound-polypeptide property measured is CFTR-mediated halide flux. In a specific embodiment, the property measured is CFTR expression on the cell surface.

[0016] Aspects of the present method include the in vitro assay of compounds using polypeptide of a TARGET, or fragments thereof, such fragments including the amino acid sequences described by SEQ ID NO: 30-55 and cellular assays wherein TARGET inhibition is followed by observing indicators of efficacy including, for example, TARGET expression levels, TARGET enzymatic activity, CFTR protein levels, CFTR activity, CFTR-mediated halide flux, and/or other assessments of protein folding/trafficking or inflammation and inflammatory response.

[0017] The present invention also relates to

[0018] (1) expression inhibitory agents comprising a polynucleotide selected from the group of an antisense polynucleotide, a ribozyme, and a small interfering RNA (siRNA), wherein said polynucleotide comprises a nucleic acid sequence complementary to, or engineered from, a naturally occurring polynucleotide sequence encoding a TARGET polypeptide said polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID NO: 1-29 and

[0019] (2) pharmaceutical compositions comprising said agent(s), useful in the treatment, or prevention, of a disease characterized by ER-associated protein misfolding, including in particular Cystic Fibrosis.

[0020] Another aspect of the invention is a method of treatment, or prevention of a condition related to a disease characterized by ER-associated protein misfolding, in particular Cystic Fibrosis, in a subject suffering or susceptible thereto, by administering a pharmaceutical composition comprising an effective TARGET-expression inhibiting amount of a expression-inhibitory agent or an effective TARGET activity inhibiting amount of a activity-inhibitory agent.

[0021] A further aspect of the present invention is a method for diagnosis of a disease characterized by ER-associated protein misfolding comprising measurement of indicators of levels of TARGET expression in a subject. In particular the present invention relates to a method for the diagnosis of Cystic Fibrosis.

[0022] Another aspect of this invention relates to the use of agents which inhibit a TARGET as disclosed herein in a therapeutic method, a pharmaceutical composition, and the manufacture of such composition, useful for the treatment of a disease involving protein misfolding. In particular, the present method relates to the use of the agents which inhibit a TARGET in the treatment of a disease characterized by ER-associated protein misfolding, and in particular, a disease characterized by abnormal trafficking of a disease-associated protein. Suitable conditions include, but are not limited to, Cystic Fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, prion disease, and inclusion body myositis. In particular the disease is Cystic Fibrosis.

[0023] Other objects and advantages will become apparent from a consideration of the ensuing description taken in conjunction with the following illustrative drawings.

BRIEF DESCRIPTION OF THE FIGURES

[0024] FIGS. 1A and 1B: Expression of halide-sensitive fluorescent protein YFP

[0025] FIG. 2: YFP halide transport in CFBE cells transduced with ΔF508 CFTR virus and wild type CFTR cells

[0026] FIG. 3: Example of a control plate during Ad-siRNA screening

[0027] FIG. 4: High-throughput screening data on 11,330 Ad-siRNAs in the CFTR-Dependent Halide Flux Assay.

DETAILED DESCRIPTION OF THE INVENTION

[0028] The following terms are intended to have the meanings presented therewith below and are useful in understanding the description and intended scope of the present invention.

[0029] The term `agent` means any molecule, including polypeptides, antibodies, polynucleotides, chemical compounds and small molecules. In particular the term agent includes compounds such as test compounds or drug candidate compounds.

[0030] The term `agonist` refers to a ligand that stimulates the receptor the ligand binds to in the broadest sense.

[0031] The term `assay` means any process used to measure a specific property of a compound. A `screening assay` means a process used to characterize or select compounds based upon their activity from a collection of compounds.

[0032] The term `binding affinity` is a property that describes how strongly two or more compounds associate with each other in a non-covalent relationship. Binding affinities can be characterized qualitatively, (such as `strong`, `weak`, `high`, or `low`) or quantitatively (such as measuring the K_D).

[0033] The term `carrier` means a non-toxic material used in the formulation of pharmaceutical compositions to provide a medium, bulk and/or useable form to a pharmaceutical composition. A carrier may comprise one or more of such materials such as an excipient, stabilizer, or an aqueous pH buffered solution. Examples of physiologically acceptable carriers include aqueous or solid buffer ingredients including phosphate, citrate, and other organic acids; antioxidants including ascorbic acid; low molecular weight (less than about 10 residues) polypeptide; proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and/or nonionic surfactants such as TWEEN®, polyethylene glycol (PEG), and PLURONICS®.

[0034] The term `complex` means the entity created when two or more compounds bind to, contact, or associate with each other.

[0035] The term `compound` is used herein in the context of a `test compound` or a `drug candidate compound` described in connection with the assays of the present invention. As such, these compounds comprise organic or inorganic compounds, derived synthetically, recombinantly, or from natural sources.

[0036] The compounds include inorganic or organic compounds such as polynucleotides, lipids or hormone analogs. Other biopolymeric organic test compounds include peptides comprising from about 2 to about 40 amino acids and larger polypeptides comprising from about 40 to about 500 amino acids, including polypeptide ligands, enzymes, receptors, channels, antibodies or antibody conjugates.

[0037] The term `condition` or `disease` means the overt presentation of symptoms (i.e., illness) or the manifestation of abnormal clinical indicators (for example, biochemical indicators or diagnostic indicators). Alternatively, the term `disease` refers to a genetic or environmental risk of or propensity for developing such symptoms or abnormal clinical indicators.

[0038] The term `contact` or `contacting` means bringing at least two moieties together, whether in an in vitro system or an in vivo system.

[0039] The term `derivatives of a polypeptide` relates to those peptides, oligopeptides, polypeptides, proteins and enzymes that comprise a stretch of contiguous amino acid residues of the polypeptide and that retain a biological activity of the protein, for example, polypeptides that have amino acid mutations compared to the amino acid sequence of a naturally-occurring form of the polypeptide. A derivative may further comprise additional naturally occurring, altered, glycosylated, acylated or non-naturally occurring amino acid residues compared to the amino acid sequence of a naturally occurring form of the polypeptide. It may also contain one or more non-amino acid substituents, or heterologous amino acid substituents, compared to the amino acid sequence of a naturally occurring form of the polypeptide, for example a reporter molecule or other ligand, covalently or non-covalently bound to the amino acid sequence.

[0040] The term `derivatives of a polynucleotide` relates to DNA-molecules, RNA-molecules, and oligonucleotides that comprise a stretch of nucleic acid residues of the polynucleotide, for example, polynucleotides that may have nucleic acid mutations as compared to the nucleic acid sequence of a naturally occurring form of the polynucleotide. A derivative may further comprise nucleic acids with modified backbones such as PNA, polysiloxane, and 2'-O-(2-methoxy)ethyl-phosphorothioate, non-naturally occurring nucleic acid residues, or one or more nucleic acid substituents, such as methyl-, thio-, sulphate, benzoyl-, phenyl-, amino-, propyl-, chloro-, and methanocarbanucleosides, or a reporter molecule to facilitate its detection.

[0041] The term `endogenous` shall mean a material that a cell or mammal (as the context dictates) naturally produces. Endogenous in reference to the term `protease`, `kinase`, or G-Protein Coupled Receptor (`GPCR`) shall mean that which is naturally produced by a cell, for example a mammalian cell (for example, not limitation a human cell), or by a mammal (for example, and not limitation, a human). In contrast, the term non-endogenous in this context shall mean that which is not naturally produced by a cell, in particular by a mammalian cell, (for example, not limitation a human cell), or that is not naturally produced by a mammal (for example, and not limitation, a human). Both terms can be utilized to describe both in vivo and in vitro systems. For example, and without limitation, in a screening approach, the endogenous or non-endogenous TARGET may be in reference to an in vitro screening system. As a further example and not limitation, where the genome of a mammal has been manipulated to include a non-endogenous TARGET, screening of a candidate compound by means of an in vivo system is viable.

[0042] The term `expressible nucleic acid` means a nucleic acid coding for a proteinaceous molecule, an RNA molecule, or a DNA molecule.

[0043] The term `expression` comprises both endogenous expression and overexpression by transduction.

[0044] The term `expression inhibitory agent` means a polynucleotide designed to interfere selectively with the transcription, translation and/or expression of a specific polypeptide or protein normally expressed within a cell. More particularly, `expression inhibitory agent` comprises a DNA or RNA molecule that contains a nucleotide sequence identical to or complementary to at least about 15-30, particularly at least 17, sequential nucleotides within the polyribonucleotide sequence coding for a specific polypeptide or protein. Exemplary expression inhibitory molecules include ribozymes, double stranded siRNA molecules, self-complementary single-stranded siRNA molecules, genetic antisense constructs, and synthetic RNA antisense molecules with modified stabilized backbones.

[0045] The term `fragment of a polynucleotide` relates to oligonucleotides that comprise a stretch of contiguous nucleic acid residues that exhibit substantially a similar, but not necessarily identical, activity as the complete sequence. In a particular aspect, `fragment` may refer to a oligonucleotide comprising a nucleic acid sequence of at least 5 nucleic acid residues (preferably, at least 10 nucleic acid residues, at least 15 nucleic acid residues, at least 20 nucleic acid residues, at least 25 nucleic acid residues, at least 40 nucleic acid residues, at least 50 nucleic acid residues, at least 60 nucleic residues, at least 70 nucleic acid residues, at least 80 nucleic acid residues, at least 90 nucleic acid residues, at least 100 nucleic acid residues, at least 125 nucleic acid residues, at least 150 nucleic acid residues, at least 175 nucleic acid residues, at least 200 nucleic acid residues, or at least 250 nucleic acid residues) of the nucleic acid sequence of said complete sequence.

[0046] The term `fragment of a polypeptide` relates to peptides, oligopeptides, polypeptides, proteins, monomers, subunits and enzymes that comprise a stretch of contiguous amino acid residues, and exhibit substantially a similar, but not necessarily identical, functional or expression activity as the complete sequence. In a particular aspect, `fragment` may refer to a peptide or polypeptide comprising an amino acid sequence of at least 5 amino acid residues (preferably, at least 10 amino acid residues, at least 15 amino acid residues, at least 20 amino acid residues, at least 25 amino acid residues, at least 40 amino acid residues, at least 50 amino acid residues, at least 60 amino residues, at least 70 amino acid residues, at least 80 amino acid residues, at least 90 amino acid residues, at least 100 amino acid residues, at least 125 amino acid residues, at least 150 amino acid residues, at least 175 amino acid residues, at least 200 amino acid residues, or at least 250 amino acid residues) of the amino acid sequence of said complete sequence.

[0047] The term `hybridization` means any process by which a strand of nucleic acid binds with a complementary strand through base pairing. The term `hybridization complex` refers to a complex formed between two nucleic acid sequences by virtue of the formation of hydrogen bonds between complementary bases. A hybridization complex may be formed in solution (for example, C₀t or R₀t analysis) or formed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (for example, paper, membranes, filters, chips, pins or glass slides, or any other appropriate substrate to which cells or their nucleic acids have been fixed). The term "stringent conditions" refers to conditions that permit hybridization between polynucleotides and the claimed polynucleotides. Stringent conditions can be defined by salt concentration, the concentration of organic solvent, for example, formamide, temperature, and other conditions well known in the art. In particular, reducing the concentration of salt, increasing the concentration of formamide, or raising the hybridization temperature can increase stringency. The term `standard hybridization conditions` refers to salt and temperature conditions substantially equivalent to 5×SSC and 65° C. for both hybridization and wash. However, one skilled in the art will appreciate that such `standard hybridization conditions` are dependent on particular conditions including the concentration of sodium and magnesium in the buffer, nucleotide sequence length and concentration, percent mismatch, percent formamide, and the like. Also important in the determination of "standard hybridization conditions" is whether the two sequences hybridizing are RNA-RNA, DNA-DNA or RNA-DNA. Such standard hybridization conditions are easily determined by one skilled in the art according to well known formulae, wherein hybridization is typically 10-20^NC below the predicted or determined T_m with washes of higher stringency, if desired.

[0048] The term `inhibit` or `inhibiting`, in relationship to the term `response` means that a response is decreased or prevented in the presence of a compound as opposed to in the absence of the compound.

[0049] The term `inhibition` refers to the reduction, down regulation of a process or the elimination of a stimulus for a process, which results in the absence or minimization of the expression or activity of a protein or polypeptide.

[0050] The term `induction` refers to the inducing, up-regulation, or stimulation of a process, which results in the expression or activity of a protein or polypeptide.

[0051] The term `ligand` means an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.

[0052] The term `pharmaceutically acceptable salts` refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds which inhibit the expression or activity of TARGETS as disclosed herein. These salts can be prepared in situ during the final isolation and purification of compounds useful in the present invention.

[0053] The term `polypeptide` relates to proteins (such as TARGETS), proteinaceous molecules, fragments of proteins, monomers, subunits or portions of polymeric proteins, peptides, oligopeptides and enzymes (such as kinases, proteases, GPCR's etc.).

[0054] The term `polynucleotide` means a polynucleic acid, in single or double stranded form, and in the sense or antisense orientation, complementary polynucleic acids that hybridize to a particular polynucleic acid under stringent conditions, and polynucleotides that are homologous in at least about 60 percent of its base pairs, and more particularly 70 percent of its base pairs are in common, most particularly 90 percent, and in a particular embodiment, 100 percent of its base pairs. The polynucleotides include polyribonucleic acids, polydeoxyribonucleic acids, and synthetic analogues thereof. It also includes nucleic acids with modified backbones such as peptide nucleic acid (PNA), polysiloxane, and 2'-O-(2-methoxy)ethylphosphorothioate. The polynucleotides are described by sequences that vary in length, that range from about 10 to about 5000 bases, particularly about 100 to about 4000 bases, more particularly about 250 to about 2500 bases. One polynucleotide embodiment comprises from about 10 to about 30 bases in length. A particular embodiment of polynucleotide is the polyribonucleotide of from about 17 to about 22 nucleotides, more commonly described as small interfering RNAs (siRNAs). Another particular embodiment are nucleic acids with modified backbones such as peptide nucleic acid (PNA), polysiloxane, and 2'-O-(2-methoxy)ethylphosphorothioate, or including non-naturally occurring nucleic acid residues, or one or more nucleic acid substituents, such as methyl-, thio-, sulphate, benzoyl-, phenyl-, amino-, propyl-, chloro-, and methanocarbanucleosides, or a reporter molecule to facilitate its detection. Polynucleotides herein are selected to be `substantially` complementary to different strands of a particular target DNA sequence. This means that the polynucleotides must be sufficiently complementary to hybridize with their respective strands. Therefore, the polynucleotide sequence need not reflect the exact sequence of the target sequence. For example, a non-complementary nucleotide fragment may be attached to the 5' end of the polynucleotide, with the remainder of the polynucleotide sequence being complementary to the strand. Alternatively, non-complementary bases or longer sequences can be interspersed into the polynucleotide, provided that the polynucleotide sequence has sufficient complementarity with the sequence of the strand to hybridize therewith under stringent conditions or to form the template for the synthesis of an extension product.

[0055] The term `preventing` or `prevention` refers to a reduction in risk of acquiring or developing a disease or disorder (i.e., causing at least one of the clinical symptoms of the disease not to develop) in a subject that may be exposed to a disease-causing agent, or predisposed to the disease in advance of disease onset.

[0056] The term `prophylaxis` is related to and encompassed in the term `prevention`, and refers to a measure or procedure the purpose of which is to prevent, rather than to treat or cure a disease. Non-limiting examples of prophylactic measures may include the administration of vaccines; the administration of low molecular weight heparin to hospital patients at risk for thrombosis due, for example, to immobilization; and the administration of an anti-malarial agent such as chloroquine, in advance of a visit to a geographical region where malaria is endemic or the risk of contracting malaria is high.

[0057] The term `solvate` means a physical association of a compound useful in this invention with one or more solvent molecules. This physical association includes hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. `Solvate` encompasses both solution-phase and isolable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0058] The term `subject` includes humans and other mammals.

[0059] `Therapeutically effective amount` means that amount of a drug, compound, expression inhibitory agent, or pharmaceutical agent that will elicit the biological or medical response of a subject that is being sought by a medical doctor or other clinician. In particular, with regard to increasing the functional activity of CF-associated mutant CFTR, the term "effective amount" is intended to include an effective amount of a compound or agent that will bring about a biologically meaningful increase in CFTR-dependent halide flux.

[0060] The term `treating` or `treatment` of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting the disease or reducing the manifestation, extent or severity of at least one of the clinical symptoms thereof). In another embodiment `treating` or `treatment` refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, `treating` or `treatment` refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discernible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In a further embodiment, `treating` or `treatment` relates to slowing the progression of the disease.

[0061] The term `vectors` also relates to plasmids as well as to viral vectors, such as recombinant viruses, or the nucleic acid encoding the recombinant virus.

[0062] The term `vertebrate cells` means cells derived from animals having vertebral structure, including fish, avian, reptilian, amphibian, marsupial, and mammalian species. Preferred cells are derived from mammalian species, and most preferred cells are human cells. Mammalian cells include feline, canine, bovine, equine, caprine, ovine, porcine and murine, such as mice and rats, and rabbits.

[0063] The term `TARGET` or `TARGETS` means the protein(s) identified in accordance with the assays described herein and determined to be involved in the modulation of a Cystic Fibrosis phenotype. The term TARGET or TARGETS includes and contemplates alternative species forms, isoforms, and variants, such as allelic variants, including as a result of allelic or natural variation in the amino acid sequence, and splice variants, alternate in frame exons, and alternative or premature termination or start sites, including known or recognized isoforms or variants thereof such as indicated in Table 1.

[0064] The term `disease characterized by ER-associated protein misfolding` refers to a disease which involves, results at least in part from, or includes a protein misfolding aspect, particularly wherein a protein is not processed and/or sorted by or through the endoplasmic reticulum (ER) in a proper, efficient, or effective manner, such that it is misprocessed, poorly processed, degraded, or misfolded, resulting in such instances in less protein processed to the cell membrane or other protein location destination, or in processed protein having reduced or altered activity. The term includes, but is not limited to, exemplary diseases selected from Cystic Fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1 antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, prion disease, and inclusion body myositis. Such diseases can be associated with misfolding of proteins, or alternatively folded proteins, including misfolded CFTR (Cystic Fibrosis), misfolded fibrillin (Marfan syndrome), misfolded alpha gatactosidase (Fabry's disease), misfolded beta glucocerebrosidase (Gaucher's disease), misfolded hERG receptor (long QT syndrome), misfolded rhodopsin (retinitis pigmentosa), misfolded or alternatively folded beta amyloid protein (Alzheimer's disease), and misfolded or alternatively folded prion protein (Prion Disease).

Targets

[0065] The present invention is based on the present inventors' discovery that the TARGETS are factors in the translocation of ΔF508 CFTR to the plasma membrane, whereby inhibition of the TARGETS results in an increase in CFTR-mediated halide flux. The TARGETS are factors or protein molecules involved in protein trafficking and/or folding such that their inhibition results in an increased amount of ΔF508 CFTR being trafficked to, expressed, and/or active at the plasma membrane. The TARGETS may also serve a role in inflammation and/or the inflammatory response, particularly in pulmonary epithelial cells. In the present application, the effect of down-regulation of syntaxin-8, which is involved in trafficking of vesicles and has been shown to bind to the wild type CFTR (Antonin et al. 2000; Bilan et al., 2004; Thoreau et al., 1999), or BCAP31, for which down-regulation by Ad-siRNA allows functional restoration of ΔF508 CFTR (Fischer et al., 2006), is used as a positive control in a screen of 11,330 Ad-siRNAs to identify novel TARGETS.

[0066] CFTR is an ion channel. Ion channels are membrane protein complexes and their function is to facilitate the diffusion of ions across biological membranes. Membranes, or phospholipid bilayers, build a hydrophobic, low dielectric barrier to hydrophilic and charged molecules. Ion channels provide a high conducting, hydrophilic pathway across the hydrophobic interior of the membrane. The activity of an ion channel can be measured using classical patch clamping. High-throughput fluorescence-based or tracer-based assays are also widely available to measure ion channel activity. These fluorescent-based assays screen compounds on the basis of their ability to either open or close an ion channel thereby changing the concentration of specific fluorescent dyes across a membrane. In the case of the tracer based assay, the changes in concentration of the tracer within and outside the cell are measured by radioactivity measurement or gas absorption spectrometry.

[0067] The TARGETS listed in Table 1 below were identified herein as involved in the modulation of the migration of ΔF508-CFTR to the plasma membrane, therefore, inhibitors of these TARGETS are able to increase the density of ΔF508-CFTR in the membrane, and rescue the function of ΔF508-CFTR. These TARGETS are proposed to have a general role in modulating the folding of proteins within the ER and their subsequent trafficking to the cell membrane. Therefore these TARGETS are involved in diseases characterized by ER-associated protein misfolding, in particular Cystic Fibrosis.

[0068] Therefore, in one aspect, the present invention relates to a method for assaying for drug candidate compounds that modulate trafficking of a disease-associated protein comprising contacting the compound with a polypeptide comprising an amino acid sequence of SEQ ID NO: 30-55, or fragment thereof, under conditions that allow said polypeptide to bind to the compound, and detecting the formation of a complex between the polypeptide and the compound. In particular said method is used to identify an agent that increases the functional activity of CF-associated mutant CFTR said method. In particular said method may be used to identify drug candidate compounds that promote migration of ΔF508-CFTR to the plasma membrane. One particular means of measuring the complex formation is to determine the binding affinity of said compound to said polypeptide.

[0069] More particularly, the invention relates to a method for identifying an agent or compound that increases the functional activity of CF-associated mutant CFTR said method comprising:

[0070] (a) contacting a population of mammalian cells with one or more compound that exhibits binding affinity for a TARGET polypeptide, or fragment thereof, and

[0071] (b) measuring a compound-polypeptide property related to ΔF508-CFTR activity or expression.

[0072] In a further aspect of the present invention said method is used to identify a compound that increases the activity or expression of CF-associated mutant CFTR by promoting migration or trafficking of ΔF508-CFTR to the plasma membrane.

[0073] In a further aspect, the present invention relates to a method for assaying for drug candidate compounds that modulate trafficking of a disease-associated protein comprising contacting the compound with a polypeptide comprising an amino acid sequence of SEQ ID NO: 30-55, or fragment thereof, under conditions that allow said compound to modulate the activity or expression of the polypeptide, and determining the activity or expression of the polypeptide. In particular said method may be used to identify drug candidate compounds capable of promoting the migration of ΔF508-CFTR to the plasma membrane. One particular means of measuring the activity or expression of the polypeptide is to determine the amount of said polypeptide using a polypeptide binding agent, such as an antibody, or to determine the activity of said polypeptide in a biological or biochemical measure, for instance the amount of phosphorylation of a target of a kinase polypeptide.

[0074] The compound-polypeptide property referred to above is related to the expression and/or activity of the TARGET, and is a measurable phenomenon chosen by the person of ordinary skill in the art. The measurable property may be, for example, the binding affinity of said compound for a peptide domain of the polypeptide TARGET, a property related to the folding or activity of the disease-related protein or the level of any one of a number of biochemical marker levels of CF-associated mutant CFTR activity. In a preferred method, CF-associated mutant CFTR activity is measured by measuring CFTR-dependent halide flux, which can be monitored by using a reporter protein, halide-sensitive fluorescent protein YFP. It has been reported that cells expressing this reporter protein show enhanced fluorescence quenching of YFP by extracellular isomolar iodide solutions in the presence of activated CFTR (Galietta et al., 2001b). Fluorescence quenching is a measure of halide transport--as halide ions cross the plasma membrane, the halide ions interact with halide-sensitive fluorescent protein YFP, and quench the fluorescence of YFP. Fluorescence quenching is measured on a fluorescence plate reader.

[0075] In an additional aspect, the present invention relates to a method for assaying for drug candidate compounds that modulate trafficking of a disease-associated protein, comprising contacting the compound with a nucleic acid encoding a TARGET polypeptide, including a nucleic acid sequence selected from SEQ ID NO: 1-29, or fragment/portion thereof, under conditions that allow said nucleic acid to bind to or otherwise associate with the compound, and detecting the formation of a complex between the nucleic acid and the compound. In particular, said method may be used to identify drug candidate compounds able to promote migration of ΔF508-CFTR to the plasma membrane. One particular means of measuring the complex formation is to determine the binding affinity of said compound to said nucleic acid or the presence of a complex by virtue of resistance to nucleases or by gel mobility assays. Alternatively, complex formation may be determined by inhibition of nucleic acid transcription or translation.

[0076] In a particular embodiment of the invention, the TARGET polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID No: 30-55 as listed in Table 1. In an embodiment of the invention, the nucleic acid capable of encoding the TARGET polypeptide comprises a nucleic acid sequence selected from the group consisting of SEQ ID NO: 1-29 as listed in Table 1. Table 1 provides TARGET exemplary human nucleic acid and protein sequence, including recognized variants or isoforms where more than one accession number and SEQ ID NO: is indicated. Isoforms or variants of the TARGET(S) include nucleic acid or proteins with or utilizing alternate in frame exons, alternative splicing or splice variants, and alternative or premature termination variants.

TABLE-US-00001 TABLE 1 TARGETS TARGET SEQ ID SEQ ID Gene GenBank nucleic NO: GenBank NO: Symbol acid Acc#: DNA protein Acc#: Protein Class UGT3A1 NM_152404 1 NP_689617 30 enzyme UGT3A2 NM_174914 2 NP_777574 31 enzyme PHGDH NM_006623 3 NP_006614 32 enzyme B3GNT3 NM_014256 4 NP_055071 33 enzyme PPIH NM_006347 5 NP_006338 34 enzyme/chaperone CELSR3 NM_001407 6 NP_001398 35 GPCR MC2R NM_000529 7 NP_000520 36 GPCR MAS1L NM_052967 8 NP_443199 37 GPCR LRRK2 NM_198578 9 NP_940980 38 kinase/nucleotide binding NLRP1 NM_001033053 10 NP_001028225 39 kinase/nucleotide NM_014922 11 NP_055737 40 binding NM_033004 12 NP_127497 41 NM_033006 13 NP_127499 42 NM_033007 14 PMS1 NM_000534 15 NP_000525 43 kinase/nucleotide NM_001128143 16 binding NM_001128144 17 MAK NM_005906 18 NP_005897 44 kinase/nucleotide binding CPD NM_001304 19 NP_001295 45 peptidase/peptidase inhibitor CST7 NM_003650 20 NP_003641 46 peptidase/peptidase inhibitor DUSP5 NM_004419 21 NP_004410 47 phosphatase PTPRG NM_002841 22 NP_002832 48 phosphatase/receptor IL6R NM_000565 23 NP_000556 49 receptor NM_181359 24 NP_852004 50 GHR NM_000163 25 NP_000154 51 receptor CSF3 NM_000759 26 NP_000750 52 secreted NM_172219 27 NP_757373 53 NM_172220 28 NP_757374 54 SPNS1 NM_032038 29 NP_114427 55 transporter

[0077] Depending on the choice of the skilled artisan, the present assay method may be designed to function as a series of measurements, each of which is designed to determine whether the drug candidate compound is indeed acting on the TARGET to thereby increase the functional activity of CF-associated mutant CFTR. For example, an assay designed to determine the binding affinity of a compound to the TARGET, or fragment thereof, may be necessary, but not sufficient, to ascertain whether the test compound would be useful for increasing the functional activity of CF-associated mutant CFTR when administered to a subject. Nonetheless, such binding information would be useful in identifying a set of test compounds for use in an assay that would measure a different property, further down the biochemical pathway, such as halide flux, assayed by measuring the quenching of a halide-sensitive fluorescent protein. Such additional assay(s) may be designed to confirm that the test compound, having binding affinity for the TARGET, actually increases the functional activity of CF-associated mutant CFTR.

[0078] Suitable controls should always be in place to insure against false positive readings. In a particular embodiment of the present invention the screening method comprises the additional step of comparing the compound to a suitable control. In one embodiment, the control may be a cell or a sample that has not been in contact with the test compound. In an alternative embodiment, the control may be a cell that does not express the TARGET; for example in one aspect of such an embodiment the test cell may naturally express the TARGET and the control cell may have been contacted with an agent, e.g. an siRNA, which inhibits or prevents expression of the TARGET. Alternatively, in another aspect of such an embodiment, the cell in its native state does not express the TARGET and the test cell has been engineered so as to express the TARGET, so that in this embodiment, the control could be the untransformed native cell. Whilst exemplary controls are described herein, this should not be taken as limiting; it is within the scope of a person of skill in the art to select appropriate controls for the experimental conditions being used.

[0079] The order of taking these measurements is not believed to be critical to the practice of the present invention, which may be practiced in any order. For example, one may first perform a screening assay of a set of compounds for which no information is known respecting the compounds' binding affinity for the TARGET. Alternatively, one may screen a set of compounds identified as having binding affinity for a TARGET protein domain, or a class of compounds identified as being an inhibitor of the TARGET. However, for the present assay to be meaningful to the ultimate use of the drug candidate compounds in diseases characterized by ER-associated protein misfolding a measurement of functional activity or appropriate expression of the relevant protein is necessary. In a specific embodiment the disease is cystic fibrosis and the protein is CF-associated mutant CFTR. In alternative embodiments, the disease is Marfan syndrome and the protein is fibrillin, or the disease is Fabry's disease and the protein is alpha gatactosidase, or the disease is Gaucher's disease and the protein is beta glucocerebrosidase, or the disease is long QT syndrome and the protein is misfolded hERG receptor, or the disease is retinitis pigmentosa and the protein is rhodopsin, or the disease is Alzheimer's disease and the protein is beta-amyloid or the disease is prion disease and the protein is prion protein. Validation studies, including controls, and measurements of binding affinity to the polypeptides of the invention are nonetheless useful in identifying a compound useful in any therapeutic or diagnostic application.

[0080] Analogous approaches based on art-recognized methods and assays may be applicable with respect to the TARGETS and compounds in any of various disease(s) characterized by ER-associated protein misfolding or inflammatory diseases, including airway epithelial cell diseases, asthma, COPD. An assay or assays may be designed to confirm that the test compound, having binding affinity for the TARGET, increases the functional activity and/or alters the protein misfolding or protein trafficking of a protein associated with misfolding disease. In one such method the expression or activity of ΔF508 CFTR, misfolded in the disease CF, is measured. In the case of CF, and in lieu of animal models, chambers with primary human airway epithelial cells (Li et al, 2004) may be utilized in further assessing the TARGETS and/or compounds. In exemplary further such methods, the expression or activity of fibrillin, misfolded in Marfan syndrome, or of alpha galactosidase, misfolded in Fabry disease, or of rhodopsin, misfolded ion retinitis pigmentosa, or beta amyloid protein, misfolded in Alzheimer's disease, is/are measured, and compounds which increase the proper expression or activity thereof are selected. Protein trafficking may be assessed or monitored in art-recognized methods, including in vitro, ex vivo, and animal systems.

[0081] The present assay method may be practiced in vitro, using one or more of the TARGET proteins, or fragments thereof, including monomers, portions or subunits of polymeric proteins, peptides, oligopeptides and enzymatically active portions thereof.

[0082] The binding affinity of the compound with the TARGET or a fragment thereof can be measured by methods known in the art, such as using surface plasmon resonance biosensors (Biacore), by saturation binding analysis with a labeled compound (e.g. Scatchard and Lindmo analysis), by differential UV spectrophotometer, fluorescence polarization assay, Fluorometric Imaging Plate Reader (FLIPR®) system, Fluorescence resonance energy transfer, and Bioluminescence resonance energy transfer. The binding affinity of compounds can also be expressed in dissociation constant (Kd) or as IC₅₀ or EC₅₀. The IC₅₀ represents the concentration of a compound that is required for 50% inhibition of binding of another ligand to the polypeptide. The EC₅₀ represents the concentration required for obtaining 50% of the maximum effect in any assay that measures the TARGET function. The dissociation constant, Kd, is a measure of how well a ligand binds to the polypeptide, it is equivalent to the ligand concentration required to saturate exactly half of the binding-sites on the polypeptide. Compounds with a high affinity binding have low Kd, IC₅₀ and EC₅₀ values, i.e. in the range of 100 nM to 1 pM; a moderate to low affinity binding relates to a high Kd, IC₅₀ and EC₅₀ values, i.e. in the micromolar range.

[0083] The present assay method may also be practiced in a cellular assay. A host cell expressing the TARGET can be a cell with endogenous expression or a cell over-expressing the TARGET e.g. by transduction. When the endogenous expression of the polypeptide is not sufficient to determine a baseline that can easily be measured, one may use host cells that over-express the TARGET. Over-expression has the advantage that the level of the TARGET substrate end products is higher than the activity level by endogenous expression. Accordingly, measuring such levels using presently available techniques is easier. In one such cellular assay, the biological activity of the TARGET may be measured by measuring the functional activity of for instance CF-associated mutant CFTR.

[0084] One embodiment of the present method for identifying a compound that increases CFTR expression and/or activity comprises culturing a population of mammalian cells expressing a TARGET polypeptide, or a functional fragment or derivative thereof; determining a first level of CFTR or ΔF508-CFTR expression at the cell membrane and/or activity of CFTR or ΔF508-CFTR in said population of cells; eventually activating the population of cells; exposing said population of cells to a compound, or a mixture of compounds; determining a second level of CFTR or ΔF508-CFTR expression and/or activity in said population of cells during or after exposure of said population of cells to said compound, or the mixture of said compounds; and identifying the compound(s) that induce ΔF508-CFTR migration to the cell membrane and/or CFTR or ΔF508-CFTR activity.

[0085] As noted above, promotion of disease-related protein trafficking may be determined by measuring the expression and/or activity of the TARGET polypeptide and/or CFTR or ΔF508-CFTR.

[0086] The expression and/or activity of CFTR or ΔF508-CFTR can be determined by methods known in the art such as immunohistochemistry using specific antibodies, or an activity assay as described herein.

[0087] The present inventors identified TARGET genes involved in disease-related protein trafficking by using a `knock-down` library. This type of library is a screen in which siRNA molecules are transduced into cells by recombinant adenoviruses, which siRNA molecules inhibit or repress the expression of a specific gene as well as expression and activity of the corresponding gene product in a cell. Each siRNA in a viral vector corresponds to a specific natural gene. By identifying a siRNA that promotes migration of ΔF508-CFTR to the cell membrane, a direct correlation can be drawn between the specific gene expression and the pathway for rescuing mutant CFTR receptors. The TARGET genes identified using the knock-down library (the protein expression products thereof herein referred to as "TARGET" polypeptides) are then used in the present inventive method for identifying compounds that can be used to correct mutant CFTR expression and/or activity. Indeed, shRNA compounds comprising the sequences listed in Table 2 (SEQ ID NOs: 56-99) inhibit the expression and/or activity of these TARGET genes and promote migration of ΔF508-CFTR in cells, confirming the role of the TARGETS in the protein-trafficking pathway.

TABLE-US-00002 TABLE 2 KD TARGET sequences useful in the practice of the present expression-inhibitory agent invention SEQ ID TARGET NO: Gene SEQ ID Knock- Symbol NO: DNA Sequences Down UGT3A1 or 1, 2 CGCACCTCAAGCCCTATGT; 56 UTG3A2 UGT3A2 2 AACATGGTCCGAGTAGAAG 57 PHGDH 3 AGAGGAGCTGATAGCGGAG; 58 AATGGGAGCGGAAGAAGTT 59 B3GNT3 4 CATCCTGCAGTGGGACTTC; 60 CAACATGGTCTTCTACCTG 61 PPIH 5 GTACAAATGGCTGTCAGTT; 62 TTGAGAATGTTCCCACAGG; 63 ATGGAGATGGTACTGGAGT 64 CELSR3 6 AGGATGCAGCTAACAACAA; 65 ACTGTGCGCGTACACATAA; 66 ATGCTCCACAATTTGTGGC 67 MC2R 7 CATGGGCTATCTCAAGCCA; 68 AACATGGGCTATCTCAAGC 69 MAS1L 8 CAGAACCCAAACCTGGTAT; 70 GCCATATTGTCTCCCTTCT; 71 ACAGCAGCGCCAACCCTAT 72 LRRK2 9 AAGGCTCGCGCTTCTTCTT; 73 CATTGAGACAAGAACAAGC 74 NLRP1 10, 11, AGATGGACTCTACCAAGCC; 75 12, 13, ATTGGGAAGTCAACACTGG 76 14 PMS1 15, 16, CAGATGTTTCCGCAGCTGA; 77 17 CCAGACAATTACCCATGTA 78 MAK 18 ACCTCCAAAGCAACAGAGT; 79 AGTTGTTCCCTGAATCAGT 80 CPD 19 AAGTCCCAGGAAGGAGATT; 81 ACATTCACAGGTCTTTGTG 82 CST7 20 CGAACGACATGTTCTTGTT; 83 CTTGTTCCCAGGACCTTAA 84 DUSP5 21 TGACATTAGCTCCCACTTT; 85 ACTGGGATGGAGGAATCGG 86 PTPRG 22 CCAGGAGTAGGAGGAAAGA; 87 CGGAGCAGCAAGACCATGT 88 IL6R 23, 24 ACAGTCCGGCCGAAGACTT; 89 ACTATTCATGCTACCGGGC; 90 CAACATGGATGGTCAAGGA 91 GHR 25 AGTGAGATGGGAAGCACCA; 92 ATGACATACATGAGGGTAC 93 CSF3 26, 27, TGGAAGAACTGGGAATGGC; 94 28 CTTTGCCACCACCATCTGG; 95 AAGCTCCTGTCCTCCCATC 96 SPNS1 29 CCGCCATCTTCATTGAGGC; 97 ATCTTCTACTTTGCCATTC; 98 ACTACATGGACCGCTTCAC 99

[0088] The present invention further relates to a method for identifying a compound that increases the functional activity of CF-associated mutant CFTR, comprising:

[0089] (a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55;

[0090] (b) determining the binding affinity of the compound to the polypeptide;

[0091] (c) contacting a population of mammalian cells expressing said polypeptide with the compound that exhibits at least a moderate binding affinity; and

[0092] (d) identifying the compound that increases the functional activity of CF-associated mutant CFTR.

[0093] In one aspect, the assay method involves contacting a compound with a polypeptide comprising a fragment of an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55. In one aspect, the assay method includes contacting cells expressing said polypeptide or fragment with the compound that exhibits a binding affinity in the micromolar range. In an aspect, the binding affinity exhibited is at least 10 micromolar. In one aspect, the binding affinity is at least 1 micromolar. In one aspect, the binding affinity is at least 500 nanomolar.

[0094] The assay method may be based on the particular expression or activity of the TARGET polypeptide, including but not limited to an enzyme activity. Thus, assays for the enzyme TARGETs identified as SEQ ID NOs: 30-34 may be based on enzymatic activity or enzyme expression. Assays for the peptidease/protease or peptidase inhibitor/protease inhibitor TARGETs identified as SEQ ID NOs: 45-46 may be based on protease activity or expression. Assays for the kinase TARGETs identified as SEQ ID NOs: 38-44 may be based on kinase activity or expression, including but not limited to phosphorylation of a kinase target. Assays for the phosphatase TARGETs identified as SEQ ID NOs: 47-48 may be based on phosphatase activity or expression, including but not limited to dephosphorylation of a phosphatase target. Assays for the GPCR and receptor TARGETs identified as SEQ ID NO: 35-37, 48-51 may be based on GPCR activity or expression, including downstream mediators or activators. Assays for the secreted TARGETs identified as SEQ ID NOs: 52-54 may utilize activity or expression in soluble culture media or secreted activity. Assays for the transporter TARGET identified as SEQ ID NOs: 55 may use techniques well known to those of skill in the art including classical patch clamping, high-throughput fluorescence based or tracer based assays which measure the ability of a compound to open or close an ion channel thereby changing the concentration of fluorescent dyes or tracers across a membrane or within a cell. The measurable phenomenon, activity or property may be selected or chosen by the skilled artisan. The person of ordinary skill in the art may select from any of a number of assay formats, systems or design one using his knowledge and expertise in the art.

[0095] Table 1 lists the TARGETS identified using applicants' knock-down library in the CFTR assay described below, including the class of polypeptides identified. TARGETS have been identified in polypeptide classes including kinase, protease, enzyme, GPCR, phosphodiesterase and phosphatase, for instance. Specific methods to determine the activity of a kinase by measuring the phosphorylation of a substrate by the kinase, which measurements are performed in the presence or absence of a compound, are well known in the art.

[0096] Specific methods to determine the inhibition by a compound by measuring the cleavage of the substrate by the polypeptide, which is a protease, are well known in the art. Classically, substrates are used in which a fluorescent group is linked to a quencher through a peptide sequence that is a substrate that can be cleaved by the target protease. Cleavage of the linker separates the fluorescent group and quencher, giving rise to an increase in fluorescence.

[0097] G-protein coupled receptors (GPCR) are capable of activating an effector protein, resulting in changes in second messenger levels in the cell. The activity of a GPCR can be measured by measuring the activity level of such second messengers. Two important and useful second messengers in the cell are cyclic AMP (cAMP) and Ca²+. The activity levels can be measured by methods known to persons skilled in the art, either directly by ELISA or radioactive technologies or by using substrates that generate a fluorescent or luminescent signal when contacted with Ca²+ or indirectly by reporter gene analysis. The activity level of the one or more secondary messengers may typically be determined with a reporter gene controlled by a promoter, wherein the promoter is responsive to the second messenger. Promoters known and used in the art for such purposes are the cyclic-AMP responsive promoter that is responsive for the cyclic-AMP levels in the cell, and the NF-AT responsive promoter that is sensitive to cytoplasmic Ca²+-levels in the cell. The reporter gene typically has a gene product that is easily detectable. The reporter gene can either be stably infected or transiently transfected in the host cell. Useful reporter genes are alkaline phosphatase, enhanced green fluorescent protein, destabilized green fluorescent protein, luciferase and β-galactosidase.

[0098] It should be understood that the cells expressing the polypeptides, may be cells naturally expressing the polypeptides, or the cells may be transfected to express the polypeptides, as described above. Also, the cells may be transduced to overexpress the polypeptide, or may be transfected to express a non-endogenous form of the polypeptide, which can be differentially assayed or assessed.

[0099] In one particular embodiment the methods of the present invention further comprise the step of contacting the population of cells with an agonist of the polypeptide. This is useful in methods wherein the expression of the polypeptide in a certain chosen population of cells is too low for a proper detection of its activity. By using an agonist the polypeptide may be triggered, enabling a proper read-out if the compound inhibits the polypeptide. Similar considerations apply to the measurement of the activity of CFTR. In a particular embodiment, the cells used in the present method are mammalian lung epithelial cells. The lung epithelial cells, in the assay contemplated, may be activated (e.g. by cytokines).

[0100] A method for identifying a compound that modulates trafficking of a disease-associated protein, comprising:

[0101] (a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55, and fragments thereof; and

[0102] (b) measuring a compound-polypeptide property related to protein trafficking.

[0103] In one embodiment of the present invention the method relates to identifying a compound that promotes migration of ΔF508-CFTR to the plasma membrane.

[0104] In one embodiment of the present invention the compound-polypeptide property related to protein trafficking is binding affinity.

[0105] In one embodiment of the present invention the compound-polypeptide property related to protein trafficking is increased activity of ΔF508-CFTR or CFTR.

[0106] In one embodiment of the present invention the compound-polypeptide property related to protein trafficking is the activity of said polypeptide. In particular, in one embodiment the compound inhibits the activity of said polypeptide.

[0107] In one embodiment of the present invention the compound-polypeptide property related to protein trafficking is the expression of said polypeptide. In particular, in one embodiment the compound inhibits the expression of said polypeptide.

[0108] The present invention further relates to a method for identifying a compound that modulates trafficking of a protein misfolding disease-related protein, wherein said compound exhibits at least a moderate binding affinity to an amino acid selected from the group of SEQ ID NOS: 30-55, said method comprising:

[0109] a) contacting a compound with a population of mammalian cells expressing a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOS: 30-55, wherein the cells also express the protein misfolding disease-related protein;

[0110] b) determining the activity or expression of the protein misfolding disease-related protein; and

[0111] d) identifying the compound that modulates protein trafficking as the compound which alters the activity or expression of the protein misfolding disease-related protein.

[0112] In one such method, the compound exhibits a binding affinity to an amino acid selected from the group of SEQ ID NOS: 30-55 of at least 10 micromolar. In one aspect, the binding affinity is at least 1 micromolar. In one aspect, the binding affinity is at least 500 nanomolar.

[0113] The present invention further relates to a method for identifying a compound that modulates trafficking of a disease-related protein, said method comprising:

[0114] a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55;

[0115] b) determining the binding affinity of the compound to the polypeptide;

[0116] c) contacting a population of mammalian cells expressing said polypeptide with the compound that exhibits a binding affinity of at least 10 micromolar; and

[0117] d) identifying the compound that modulates protein trafficking.

[0118] The present invention further relates to a method for identifying a compound that modulates trafficking of a disease-related protein said method comprising:

[0119] a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55;

[0120] b) determining the ability of the compound inhibit the expression or activity of the polypeptide;

[0121] c) contacting a population of mammalian cells expressing said polypeptide with the compound that significantly inhibits the expression or activity of the polypeptide; and

[0122] d) identifying the compound that modulates protein trafficking.

[0123] In a particular aspect of the present invention the methods described above include the additional step of comparing the compound to be tested to a control, where the control is a population of cells that have not been contacted with the test compound.

[0124] In a particular aspect of the present invention the methods described above include the additional step of comparing the compound to be tested to a control, where the control is a population of cells that do not express said polypeptide.

[0125] For high-throughput purposes, libraries of compounds may be used such as antibody fragment libraries, peptide phage display libraries, peptide libraries (e.g. LOPAP®, Sigma Aldrich), lipid libraries (BioMol), synthetic compound libraries (e.g. LOPAC®, Sigma Aldrich, BioFocus DPI) or natural compound libraries (Specs, TimTec, BioFocus DPI).

[0126] Preferred drug candidate compounds are low molecular weight compounds. Low molecular weight compounds, i.e. with a molecular weight of 500 Dalton or less, are likely to have good absorption and permeation in biological systems and are consequently more likely to be successful drug candidates than compounds with a molecular weight above 500 Dalton (Lipinski et al. (1997)). Peptides comprise another preferred class of drug candidate compounds. Peptides may be excellent drug candidates and there are multiple examples of commercially valuable peptides such as fertility hormones and platelet aggregation inhibitors. Natural compounds are another preferred class of drug candidate compound. Such compounds are found in and extracted from natural sources, and which may thereafter be synthesized. The lipids are another preferred class of drug candidate compound.

[0127] Another preferred class of drug candidate compounds is an antibody. The present invention also provides antibodies directed against the TARGETS. These antibodies may be endogenously produced to bind to the TARGETS within the cell, or added to the tissue to bind to the TARGET polypeptide present outside the cell. These antibodies may be monoclonal antibodies or polyclonal antibodies. The present invention includes chimeric, single chain, and humanized antibodies, as well as FAb fragments and the products of a FAb expression library, and Fv fragments and the products of an Fv expression library.

[0128] In certain embodiments, polyclonal antibodies may be used in the practice of the invention. The skilled artisan knows methods of preparing polyclonal antibodies. Polyclonal antibodies can be raised in a mammal, for example, by one or more injections of an immunizing agent and, if desired, an adjuvant. Typically, the immunizing agent and/or adjuvant will be injected in the mammal by multiple subcutaneous or intraperitoneal injections. Antibodies may also be generated against the intact TARGET protein or polypeptide, or against a fragment, derivatives including conjugates, or other epitope of the TARGET protein or polypeptide, such as the TARGET embedded in a cellular membrane, or a library of antibody variable regions, such as a phage display library.

[0129] It may be useful to conjugate the immunizing agent to a protein known to be immunogenic in the mammal being immunized. Examples of such immunogenic proteins include but are not limited to keyhole limpet hemocyanin, serum albumin, bovine thyroglobulin, and soybean trypsin inhibitor. Examples of adjuvants that may be employed include Freund's complete adjuvant and MPL-TDM adjuvant (monophosphoryl Lipid A, synthetic trehalose dicorynomycolate). One skilled in the art without undue experimentation may select the immunization protocol.

[0130] In some embodiments, the antibodies may be monoclonal antibodies. Monoclonal antibodies may be prepared using methods known in the art. The monoclonal antibodies of the present invention may be "humanized" to prevent the host from mounting an immune response to the antibodies. A "humanized antibody" is one in which the complementarity determining regions (CDRs) and/or other portions of the light and/or heavy variable domain framework are derived from a non-human immunoglobulin, but the remaining portions of the molecule are derived from one or more human immunoglobulins. Humanized antibodies also include antibodies characterized by a humanized heavy chain associated with a donor or acceptor unmodified light chain or a chimeric light chain, or vice versa. The humanization of antibodies may be accomplished by methods known in the art (see, e.g. Mark and Padlan, (1994) "Chapter 4. Humanization of Monoclonal Antibodies", The Handbook of Experimental Pharmacology Vol. 113, Springer-Verlag, New York). Transgenic animals may be used to express humanized antibodies.

[0131] Human antibodies can also be produced using various techniques known in the art, including phage display libraries (Hoogenboom and Winter, (1991) J. Mol. Biol. 227:381-8; Marks et al. (1991) J. Mol. Biol. 222:581-97). The techniques of Cole, et al. and Boerner, et al. are also available for the preparation of human monoclonal antibodies (Cole, et al. (1985) Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77; Boerner, et al (1991) J. Immunol., 147(1):86-95).

[0132] Techniques known in the art for the production of single chain antibodies can be adapted to produce single chain antibodies to the TARGETS. The antibodies may be monovalent antibodies. Methods for preparing monovalent antibodies are well known in the art. For example, one method involves recombinant expression of immunoglobulin light chain and modified heavy chain. The heavy chain is truncated generally at any point in the Fc region so as to prevent heavy chain cross-linking. Alternatively, the relevant cysteine residues are substituted with another amino acid residue or are deleted so as to prevent cross-linking.

[0133] Bispecific antibodies are monoclonal, preferably human or humanized, antibodies that have binding specificities for at least two different antigens and preferably for a cell-surface protein or receptor or receptor subunit. In the present case, one of the binding specificities is for one domain of the TARGET; the other one is for another domain of the TARGET.

[0134] Methods for making bispecific antibodies are known in the art. Traditionally, the recombinant production of bispecific antibodies is based on the co-expression of two immunoglobulin heavy-chain/light-chain pairs, where the two heavy chains have different specificities (Milstein and Cuello (1983) Nature 305:537-9). Because of the random assortment of immunoglobulin heavy and light chains, these hybridomas (quadromas) produce a potential mixture of ten different antibody molecules, of which only one has the correct bispecific structure. Affinity chromatography steps usually accomplish the purification of the correct molecule. Similar procedures are disclosed in Trauneeker, et al. (1991) EMBO J. 10:3655-9.

[0135] According to another preferred embodiment, the assay method uses a drug candidate compound identified as having a binding affinity for the TARGET, and/or has already been identified as having down-regulating activity such as antagonist activity for the TARGET.

[0136] The present invention further relates to a method for increasing functional activity of CF-associated mutant CFTR comprising contacting said cells with an expression inhibitory agent comprising a polynucleotide sequence that complements at least about 15 to about 30, particularly at least 17 to about 30, most particularly at least 17 to about 25 contiguous nucleotides of a nucleotide sequence encoding a polypeptide TARGET or portion thereof including the nucleotide sequences selected from the group consisting of SEQ ID NO: 1-29.

[0137] Another aspect of the present invention relates to a method for increasing the functional activity of CF-associated mutant CFTR, comprising by contacting said cell with an expression-inhibiting agent that inhibits the translation in the cell of a polyribonucleotide encoding the TARGET. A particular embodiment relates to a composition comprising a polynucleotide including at least one antisense strand that functions to pair the agent with the TARGET mRNA, and thereby down-regulate or block the expression of the TARGET. The inhibitory agent preferably comprises antisense polynucleotide, a ribozyme, and a small interfering RNA (siRNA), wherein said agent comprises a nucleic acid sequence complementary to, or engineered from, a naturally-occurring polynucleotide sequence encoding a portion of a polypeptide comprising the amino acid sequence SEQ ID NO: 30-55. In a preferred embodiment the expression-inhibiting agent is complementary to a polynucleotide sequence consisting of SEQ ID NO: 1-29. In a preferred embodiment, the nucleotide sequence is complementary to a polynucleotide comprising a sequence selected from the group SEQ ID NO: 56-99. In another preferred embodiment the expression-inhibiting agent is complementary to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 56-99.

[0138] An embodiment of the present invention relates to a method wherein the expression-inhibiting agent is selected from the group consisting of antisense RNA, antisense oligodeoxynucleotide (ODN), a ribozyme that cleaves the polyribonucleotide coding for SEQ ID NO: 30-55, a small interfering RNA (siRNA, preferably shRNA,) that is sufficiently complementary to a portion of the polyribonucleotide coding for SEQ ID NO: 30-55, such that the siRNA, preferably shRNA, interferes with the translation of the TARGET polyribonucleotide to the TARGET polypeptide. Preferably the expression-inhibiting agent is an antisense RNA, ribozyme, antisense oligodeoxynucleotide, or siRNA, preferably shRNA, complementary to a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-29. In a preferred embodiment, the nucleotide sequence is complementary to a polynucleotide comprising a sequence selected from the group SEQ ID NO: 56-99. In another preferred embodiment, the nucleotide sequence is complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 56-99.

[0139] The down regulation of gene expression using antisense nucleic acids can be achieved at the translational or transcriptional level. Antisense nucleic acids of the invention are preferably nucleic acid fragments capable of specifically hybridizing with all or part of a nucleic acid encoding the TARGET or the corresponding messenger RNA. In addition, antisense nucleic acids may be designed which decrease expression of the nucleic acid sequence capable of encoding the TARGET by inhibiting splicing of its primary transcript. Any length of antisense sequence is suitable for practice of the invention so long as it is capable of down-regulating or blocking expression of a nucleic acid coding for the TARGETS. Preferably, the antisense sequence is at least about 17 nucleotides in length. The preparation and use of antisense nucleic acids, DNA encoding antisense RNAs and the use of oligo and genetic antisense is known in the art.

[0140] One embodiment of expression-inhibitory agent is a nucleic acid that is antisense to a nucleic acid selected from the group consisting of SEQ ID NO: 1-29. For example, an antisense nucleic acid (e.g. DNA) may be introduced into cells in vitro, or administered to a subject in vivo, as gene therapy to inhibit cellular expression of a nucleic acid selected from the group consisting of SEQ ID NO: 1-29. Antisense oligonucleotides preferably comprise a sequence containing from about 15 to about 100 nucleotides and more preferably the antisense oligonucleotides comprise from about 17 to about 30, most particularly at least 17 to about 25. Antisense nucleic acids may be prepared from about 10 to about 30 contiguous nucleotides complementary to a nucleic acid sequence selected from the sequences of SEQ ID NO: 1-29.

[0141] The skilled artisan can readily utilize any of several strategies to facilitate and simplify the selection process for antisense nucleic acids and oligonucleotides effective in inhibition of TARGET OPG expression. Predictions of the binding energy or calculation of thermodynamic indices between an oligonucleotide and a complementary sequence in an mRNA molecule may be utilized (Chiang et al. (1991) J. Biol. Chem. 266:18162-18171; Stull et al. (1992) Nucl. Acids Res. 20:3501-3508). Antisense oligonucleotides may be selected on the basis of secondary structure (Wickstrom et al (1991) in Prospects for Antisense Nucleic Acid Therapy of Cancer and AIDS, Wickstrom, ed., Wiley-Liss, Inc., New York, pp. 7-24; Lima et al. (1992) Biochem. 31:12055-12061). Schmidt and Thompson (U.S. Pat. No. 6,416,951) describe a method for identifying a functional antisense agent comprising hybridizing an RNA with an oligonucleotide and measuring in real time the kinetics of hybridization by hybridizing in the presence of an intercalation dye or incorporating a label and measuring the spectroscopic properties of the dye or the label's signal in the presence of unlabelled oligonucleotide. In addition, any of a variety of computer programs may be utilized which predict suitable antisense oligonucleotide sequences or antisense targets utilizing various criteria recognized by the skilled artisan, including for example the absence of self-complementarity, the absence hairpin loops, the absence of stable homodimer and duplex formation (stability being assessed by predicted energy in kcal/mol). Examples of such computer programs are readily available and known to the skilled artisan and include the OLIGO 4 or OLIGO 6 program (Molecular Biology Insights, Inc., Cascade, Colo.) and the Oligo Tech program (Oligo Therapeutics Inc., Wilsonville, Oreg.). In addition, antisense oligonucleotides suitable in the present invention may be identified by screening an oligonucleotide library, or a library of nucleic acid molecules, under hybridization conditions and selecting for those which hybridize to the target RNA or nucleic acid (see for example U.S. Pat. No. 6,500,615). Mishra and Toulme have also developed a selection procedure based on selective amplification of oligonucleotides that bind target (Mishra et al (1994) Life Sciences 317:977-982). Oligonucleotides may also be selected by their ability to mediate cleavage of target RNA by RNAse H, by selection and characterization of the cleavage fragments (Ho et al (1996) Nucl Acids Res 24:1901-1907; Ho et al (1998) Nature Biotechnology 16:59-630). Generation and targeting of oligonucleotides to GGGA motifs of RNA molecules has also been described (U.S. Pat. No. 6,277,981).

[0142] The antisense nucleic acids are preferably oligonucleotides and may consist entirely of deoxyribo-nucleotides, modified deoxyribonucleotides, or some combination of both. The antisense nucleic acids can be synthetic oligonucleotides. The oligonucleotides may be chemically modified, if desired, to improve stability and/or selectivity. Since oligonucleotides are susceptible to degradation by intracellular nucleases, the modifications can include, for example, the use of a sulfur group to replace the free oxygen of the phosphodiester bond. This modification is called a phosphorothioate linkage. Phosphorothioate antisense oligonucleotides are water soluble, polyanionic, and resistant to endogenous nucleases. In addition, when a phosphorothioate antisense oligonucleotide hybridizes to its target site, the RNA-DNA duplex activates the endogenous enzyme ribonuclease (RNase) H, which cleaves the mRNA component of the hybrid molecule. Oligonucleotides may also contain one or more substituted sugar moieties. Particular oligonucleotides comprise one of the following at the 2' position: OH, SH, SCH₃, F, OCN, heterocycloalkyl; heterocycloalkaryl; aminoalkylamino; polyalkylamino; substituted silyl; an RNA cleaving group; a reporter group; an intercalator; a group for improving the pharmacokinetic properties of an oligonucleotide; or a group for improving the pharmacodynamic properties of an oligonucleotide and other substituents having similar properties. Similar modifications may also be made at other positions on the oligonucleotide, particularly the 3' position of the sugar on the 3' terminal nucleotide and the 5' position of 5' terminal nucleotide.

[0143] In addition, antisense oligonucleotides with phosphoramidite and polyamide (peptide) linkages can be synthesized. These molecules should be very resistant to nuclease degradation. Furthermore, chemical groups can be added to the 2' carbon of the sugar moiety and the 5 carbon (C-5) of pyrimidines to enhance stability and facilitate the binding of the antisense oligonucleotide to its target site. Modifications may include 2'-deoxy, O-pentoxy, O-propoxy, O-methoxy, fluoro, methoxyethoxy phosphorothioates, modified bases, as well as other modifications known to those of skill in the art.

[0144] Another type of expression-inhibitory agent that can reduce the level of the TARGETS is the ribozyme. Ribozymes are catalytic RNA molecules (RNA enzymes) that have separate catalytic and substrate binding domains. The substrate binding sequence combines by nucleotide complementarity and, possibly, non-hydrogen bond interactions with its target sequence. The catalytic portion cleaves the target RNA at a specific site. The substrate domain of a ribozyme can be engineered to direct it to a specified mRNA sequence. The ribozyme recognizes and then binds a target mRNA through complementary base pairing. Once it is bound to the correct target site, the ribozyme acts enzymatically to cut the target mRNA. Cleavage of the mRNA by a ribozyme destroys its ability to direct synthesis of the corresponding polypeptide. Once the ribozyme has cleaved its target sequence, it is released and can repeatedly bind and cleave at other mRNAs.

[0145] Ribozyme forms include a hammerhead motif, a hairpin motif, a hepatitis delta virus, group I intron or RNaseP RNA (in association with an RNA guide sequence) motif or Neurospora VS RNA motif. Ribozymes possessing a hammerhead or hairpin structure are readily prepared since these catalytic RNA molecules can be expressed within cells from eukaryotic promoters (Chen, et al. (1992) Nucleic Acids Res. 20:4581-9). A ribozyme of the present invention can be expressed in eukaryotic cells from the appropriate DNA vector. If desired, the activity of the ribozyme may be augmented by its release from the primary transcript by a second ribozyme (Ventura, et al. (1993) Nucleic Acids Res. 21:3249-55).

[0146] Ribozymes may be chemically synthesized by combining an oligodeoxyribonucleotide with a ribozyme catalytic domain (20 nucleotides) flanked by sequences that hybridize to the target mRNA after transcription. The oligodeoxyribonucleotide is amplified by using the substrate binding sequences as primers. The amplification product is cloned into a eukaryotic expression vector.

[0147] Ribozymes are expressed from transcription units inserted into DNA, RNA, or viral vectors. Transcription of the ribozyme sequences are driven from a promoter for eukaryotic RNA polymerase I (pol (I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters will be expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type will depend on nearby gene regulatory sequences. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Gao and Huang, (1993) Nucleic Acids Res. 21:2867-72). It has been demonstrated that ribozymes expressed from these promoters can function in mammalian cells (Kashani-Sabet, et al. (1992) Antisense Res. Dev. 2:3-15).

[0148] A particularly preferred inhibitory agent is a small interfering RNA (siRNA, preferably shRNA). siRNA, preferably shRNA, mediate the post-transcriptional process of gene silencing by double stranded RNA (dsRNA) that is homologous in sequence to the silenced RNA. siRNA according to the present invention comprises a sense strand of 15-30, particularly 17-30, most particularly 17-25 nucleotides complementary or homologous to a contiguous 17-25 nucleotide sequence of a sequence selected from the group consisting of SEQ ID NO: 1-29, and an antisense strand of 17-23 nucleotides complementary to the sense strand. Exemplary sequences are described as sequences complementary to SEQ ID NO: 56-99. The most preferred siRNA comprises sense and anti-sense strands that are 100 percent complementary to each other and the target polynucleotide sequence. Preferably the siRNA further comprises a loop region linking the sense and the antisense strand.

[0149] A self-complementing single stranded siRNA molecule polynucleotide according to the present invention comprises a sense portion and an antisense portion connected by a loop region linker. Preferably, the loop region sequence is 4-30 nucleotides long, more preferably 5-15 nucleotides long and most preferably 12 nucleotides long. In a most particular embodiment the linker sequence is UUGCUAUA or GUUUGCUAUAAC (SEQ ID NO: 100). Self-complementary single stranded siRNAs form hairpin loops and are more stable than ordinary dsRNA. In addition, they are more easily produced from vectors.

[0150] Analogous to antisense RNA, the siRNA can be modified to confirm resistance to nucleolytic degradation, or to enhance activity, or to enhance cellular distribution, or to enhance cellular uptake, such modifications may consist of modified internucleoside linkages, modified nucleic acid bases, modified sugars and/or chemical linkage the siRNA to one or more moieties or conjugates. The nucleotide sequences are selected according to siRNA designing rules that give an improved reduction of the TARGET sequences compared to nucleotide sequences that do not comply with these siRNA designing rules (For a discussion of these rules and examples of the preparation of siRNA, WO 2004/094636, and US 2003/0198627, are hereby incorporated by reference).

[0151] The present invention also relates to compositions, and methods using said compositions, comprising a DNA expression vector capable of expressing a polynucleotide capable of increasing functional activity of CF-associated mutant CFTR and described hereinabove as an expression inhibition agent.

[0152] A particular aspect of these compositions and methods relates to the down-regulation or blocking of the expression of the TARGET by the induced expression of a polynucleotide encoding an intracellular binding protein that is capable of selectively interacting with the TARGET. An intracellular binding protein includes any protein capable of selectively interacting, or binding, with the polypeptide in the cell in which it is expressed and neutralizing the function of the polypeptide. Preferably, the intracellular binding protein is a neutralizing antibody or a fragment of a neutralizing antibody having binding affinity to an epitope of a TARGET selected from the group consisting of SEQ ID NO: 30-55. More preferably, the intracellular binding protein is a single chain antibody.

[0153] A particular embodiment of this composition comprises the expression-inhibiting agent selected from the group consisting of antisense RNA, antisense oligodeoxynucleotide (ODN), a ribozyme that cleaves the polyribonucleotide coding for a TARGET selected from the group consisting of SEQ ID NO: 30-55, and a small interfering RNA (siRNA) that is sufficiently homologous to a portion of the polyribonucleotide coding for a TARGET selected from the group consisting of SEQ ID NO: 30-55, such that the siRNA interferes with the translation of the TARGET polyribonucleotide to the TARGET polypeptide.

[0154] The polynucleotide expressing the expression-inhibiting agent, or a polynucleotide expressing the TARGET polypeptide in cells, is particularly included within a vector. The polynucleic acid is operably linked to signals enabling expression of the nucleic acid sequence and is introduced into a cell utilizing, preferably, recombinant vector constructs, which will express the antisense nucleic acid once the vector is introduced into the cell. A variety of viral-based systems are available, including adenoviral, retroviral, adeno-associated viral, lentiviral, herpes simplex viral or a sendaiviral vector systems, and all may be used to introduce and express polynucleotide sequence for the expression-inhibiting agents or the polynucleotide expressing the TARGET polypeptide in the target cells.

[0155] Particularly, the viral vectors used in the methods of the present invention are replication defective. Such replication defective vectors will usually pack at least one region that is necessary for the replication of the virus in the infected cell. These regions can either be eliminated (in whole or in part), or be rendered non-functional by any technique known to a person skilled in the art. These techniques include the total removal, substitution, partial deletion or addition of one or more bases to an essential (for replication) region. Such techniques may be performed in vitro (on the isolated DNA) or in situ, using the techniques of genetic manipulation or by treatment with mutagenic agents. Preferably, the replication defective virus retains the sequences of its genome, which are necessary for encapsidating, the viral particles.

[0156] In a preferred embodiment, the viral element is derived from an adenovirus. Preferably, the vehicle includes an adenoviral vector packaged into an adenoviral capsid, or a functional part, derivative, and/or analogue thereof. Adenovirus biology is also comparatively well known on the molecular level. Many tools for adenoviral vectors have been and continue to be developed, thus making an adenoviral capsid a preferred vehicle for incorporating in a library of the invention. An adenovirus is capable of infecting a wide variety of cells. However, different adenoviral serotypes have different preferences for cells. To combine and widen the target cell population that an adenoviral capsid of the invention can enter in a preferred embodiment, the vehicle includes adenoviral fiber proteins from at least two adenoviruses. Preferred adenoviral fiber protein sequences are serotype 17, 45 and 51. Techniques or construction and expression of these chimeric vectors are disclosed in US 2003/0180258 and US 2004/0071660, hereby incorporated by reference.

[0157] In a preferred embodiment, the nucleic acid derived from an adenovirus includes the nucleic acid encoding an adenoviral late protein or a functional part, derivative, and/or analogue thereof. An adenoviral late protein, for instance an adenoviral fiber protein, may be favorably used to target the vehicle to a certain cell or to induce enhanced delivery of the vehicle to the cell. Preferably, the nucleic acid derived from an adenovirus encodes for essentially all adenoviral late proteins, enabling the formation of entire adenoviral capsids or functional parts, analogues, and/or derivatives thereof. Preferably, the nucleic acid derived from an adenovirus includes the nucleic acid encoding adenovirus E2A or a functional part, derivative, and/or analogue thereof. Preferably, the nucleic acid derived from an adenovirus includes the nucleic acid encoding at least one E4-region protein or a functional part, derivative, and/or analogue thereof, which facilitates, at least in part, replication of an adenoviral derived nucleic acid in a cell. The adenoviral vectors used in the examples of this application are exemplary of the vectors useful in the present method of treatment invention.

[0158] Certain embodiments of the present invention use retroviral vector systems. Retroviruses are integrating viruses that infect dividing cells, and their construction is known in the art. Retroviral vectors can be constructed from different types of retrovirus, such as, MoMuLV ("murine Moloney leukemia virus") MSV ("murine Moloney sarcoma virus"), HaSV ("Harvey sarcoma virus"); SNV ("spleen necrosis virus"); RSV ("Rous sarcoma virus") and Friend virus. Lentiviral vector systems may also be used in the practice of the present invention.

[0159] In other embodiments of the present invention, adeno-associated viruses ("AAV") are utilized. The AAV viruses are DNA viruses of relatively small size that integrate, in a stable and site-specific manner, into the genome of the infected cells. They are able to infect a wide spectrum of cells without inducing any effects on cellular growth, morphology or differentiation, and they do not appear to be involved in human pathologies.

[0160] In the vector construction, the polynucleotide agents of the present invention may be linked to one or more regulatory regions. Selection of the appropriate regulatory region or regions is a routine matter, within the level of ordinary skill in the art. Regulatory regions include promoters, and may include enhancers, suppressors, etc.

[0161] Promoters that may be used in the expression vectors of the present invention include both constitutive promoters and regulated (inducible) promoters. The promoters may be prokaryotic or eukaryotic depending on the host. Among the prokaryotic (including bacteriophage) promoters useful for practice of this invention are lac, lacZ, T3, T7, lambda P_r, P₁, and trp promoters. Among the eukaryotic (including viral) promoters useful for practice of this invention are ubiquitous promoters (e.g. HPRT, vimentin, actin, tubulin), intermediate filament promoters (e.g. desmin, neurofilaments, keratin, GFAP), therapeutic gene promoters (e.g. MDR type, CFTR, factor VIII), tissue-specific promoters (e.g. actin promoter in smooth muscle cells, or Flt and Flk promoters active in endothelial cells), including animal transcriptional control regions, which exhibit tissue specificity and have been utilized in transgenic animals: elastase I gene control region which is active in pancreatic acinar cells (Swift, et al. (1984) Cell 38:639-46; Ornitz, et al. (1986) Cold Spring Harbor Symp. Quant. Biol. 50:399-409; MacDonald, (1987) Hepatology 7:425-515); insulin gene control region which is active in pancreatic beta cells (Hanahan, (1985) Nature 315:115-22), immunoglobulin gene control region which is active in lymphoid cells (Grosschedl, et al. (1984) Cell 38:647-58; Adames, et al. (1985) Nature 318:533-8; Alexander, et al. (1987) Mol. Cell. Biol. 7:1436-44), mouse mammary tumor virus control region which is active in testicular, breast, lymphoid and mast cells (Leder, et al. (1986) Cell 45:485-95), albumin gene control region which is active in liver (Pinkert, et al. (1987) Genes and Devel. 1:268-76), alpha-fetoprotein gene control region which is active in liver (Krumlauf, et al. (1985) Mol. Cell. Biol., 5:1639-48; Hammer, et al. (1987) Science 235:53-8), alpha 1-antitrypsin gene control region which is active in the liver (Kelsey, et al. (1987) Genes and Devel., 1: 161-71), beta-globin gene control region which is active in myeloid cells (Mogram, et al. (1985) Nature 315:338-40; Kollias, et al. (1986) Cell 46:89-94), myelin basic protein gene control region which is active in oligodendrocyte cells in the brain (Readhead, et al. (1987) Cell 48:703-12), myosin light chain-2 gene control region which is active in skeletal muscle (Sani, (1985) Nature 314.283-6), and gonadotropic releasing hormone gene control region which is active in the hypothalamus (Mason, et al. (1986) Science 234:1372-8).

[0162] Other promoters which may be used in the practice of the invention include promoters which are preferentially activated in dividing cells, promoters which respond to a stimulus (e.g. steroid hormone receptor, retinoic acid receptor), tetracycline-regulated transcriptional modulators, cytomegalovirus immediate-early, retroviral LTR, metallothionein, SV-40, E1a, and MLP promoters. Further promoters which may be of use in the practice of the invention include promoters which are active and/or expressed in lung cells, or in epithelial cells, particularly in airway or brochial epithelial cells.

[0163] Additional vector systems include the non-viral systems that facilitate introduction of polynucleotide agents into a patient. For example, a DNA vector encoding a desired sequence can be introduced in vivo by lipofection. Synthetic cationic lipids designed to limit the difficulties encountered with liposome-mediated transfection can be used to prepare liposomes for in vivo transfection of a gene encoding a marker (Feigner, et. al. (1987) Proc. Natl. Acad. Sci. USA 84:7413-7); see Mackey, et al. (1988) Proc. Natl. Acad. Sci. USA 85:8027-31; Ulmer, et al. (1993) Science 259:1745-8). The use of cationic lipids may promote encapsulation of negatively charged nucleic acids, and also promote fusion with negatively charged cell membranes (Feigner and Ringold, (1989) Nature 337:387-8). Particularly useful lipid compounds and compositions for transfer of nucleic acids are described in International Patent Publications WO 95/18863 and WO 96/17823, and in U.S. Pat. No. 5,459,127. The use of lipofection to introduce exogenous genes into the specific organs in vivo has certain practical advantages and directing transfection to particular cell types would be particularly advantageous in a tissue with cellular heterogeneity, for example, pancreas, liver, kidney, and the brain. Lipids may be chemically coupled to other molecules for the purpose of targeting. Targeted peptides, e.g., hormones or neurotransmitters, and proteins for example, antibodies, or non-peptide molecules could be coupled to liposomes chemically. Other molecules are also useful for facilitating transfection of a nucleic acid in vivo, for example, a cationic oligopeptide (e.g., International Patent Publication WO 95/21931), peptides derived from DNA binding proteins (e.g., International Patent Publication WO 96/25508), or a cationic polymer (e.g., International Patent Publication WO 95/21931).

[0164] It is also possible to introduce a DNA vector in vivo as a naked DNA plasmid (see U.S. Pat. Nos. 5,693,622, 5,589,466 and 5,580,859). Naked DNA vectors for therapeutic purposes can be introduced into the desired host cells by methods known in the art, e.g., transfection, electroporation, microinjection, transduction, cell fusion, DEAE dextran, calcium phosphate precipitation, use of a gene gun, or use of a DNA vector transporter (see, e.g., Wilson, et al. (1992) J. Biol. Chem. 267:963-7; Wu and Wu, (1988) J. Biol. Chem. 263:14621-4; Hartmut, et al. Canadian Patent Application No. 2,012,311, filed Mar. 15, 1990; Williams, et al (1991). Proc. Natl. Acad. Sci. USA 88:2726-30). Receptor-mediated DNA delivery approaches can also be used (Curie), et al. (1992) Hum. Gene Ther. 3:147-54; Wu and Wu, (1987) J. Biol. Chem. 262:4429-32).

[0165] The present invention also provides biologically compatible, CF-associated mutant CFTR inducing compositions comprising an effective amount of one or more compounds identified as TARGET inhibitors, and/or the expression-inhibiting agents as described hereinabove.

[0166] A biologically compatible composition is a composition, that may be solid, liquid, gel, or other form, in which the compound, polynucleotide, vector, and antibody of the invention is maintained in an active form, e.g., in a form able to effect a biological activity. For example, a compound of the invention would have inverse agonist or antagonist activity on the TARGET; a nucleic acid would be able to replicate, translate a message, or hybridize to a complementary mRNA of the TARGET; a vector would be able to transfect a target cell and express the antisense, antibody, ribozyme or siRNA as described hereinabove; an antibody would bind a the TARGET polypeptide domain.

[0167] A particular biologically compatible composition is an aqueous solution that is buffered using, e.g., Tris, phosphate, or HEPES buffer, containing salt ions. Usually the concentration of salt ions will be similar to physiological levels. Biologically compatible solutions may include stabilizing agents and preservatives. In a more preferred embodiment, the biocompatible composition is a pharmaceutically acceptable composition. Such compositions can be formulated for administration by topical, oral, parenteral, intranasal, subcutaneous, and intraocular, routes. Parenteral administration is meant to include intravenous injection, intramuscular injection, intra-arterial injection or infusion techniques. The composition may be administered parenterally in dosage unit formulations containing standard, well-known non-toxic physiologically acceptable carriers, adjuvants and vehicles as desired.

[0168] A particular embodiment of the present composition invention is a pharmaceutical composition comprising a therapeutically effective amount of an expression-inhibiting agent as described hereinabove, in admixture with a pharmaceutically acceptable carrier. Another preferred embodiment is a pharmaceutical composition for the treatment or prevention of a disease involving a decrease in functional activity of CF-associated mutant CFTR, or a susceptibility to the condition, comprising an effective amount of the TARGET antagonist or inverse agonist, its pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof in admixture with a pharmaceutically acceptable carrier.

[0169] Pharmaceutical compositions for oral administration can be formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration. Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for ingestion by the patient. Pharmaceutical compositions for oral use can be prepared by combining active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are carbohydrate or protein fillers, such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, or other plants; cellulose, such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethyl-cellulose; gums including arabic and tragacanth; and proteins such as gelatin and collagen. If desired, disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid, or a salt thereof, such as sodium alginate. Dragee cores may be used in conjunction with suitable coatings, such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinyl-pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, i.e., dosage.

[0170] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating, such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with filler or binders, such as lactose or starches, lubricants, such as talc or magnesium stearate, and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid, or liquid polyethylene glycol with or without stabilizers.

[0171] Preferred sterile injectable preparations can be a solution or suspension in a non-toxic parenterally acceptable solvent or diluent. Examples of pharmaceutically acceptable carriers are saline, buffered saline, isotonic saline (e.g. monosodium or disodium phosphate, sodium, potassium; calcium or magnesium chloride, or mixtures of such salts), Ringer's solution, dextrose, water, sterile water, glycerol, ethanol, and combinations thereof 1,3-butanediol and sterile fixed oils are conveniently employed as solvents or suspending media. Any bland fixed oil can be employed including synthetic mono- or di-glycerides. Fatty acids such as oleic acid also find use in the preparation of injectables.

[0172] The agents or compositions of the invention may be combined for administration with or embedded in polymeric carrier(s), biodegradable or biomimetic matrices or in a scaffold. The carrier, matrix or scaffold may be of any material that will allow composition to be incorporated and expressed and will be compatible with the addition of cells or in the presence of cells. Particularly, the carrier matrix or scaffold is predominantly non-immunogenic and is biodegradable. Examples of biodegradable materials include, but are not limited to, polyglycolic acid (PGA), polylactic acid (PLA), hyaluronic acid, catgut suture material, gelatin, cellulose, nitrocellulose, collagen, albumin, fibrin, alginate, cotton, or other naturally-occurring biodegradable materials. It may be preferable to sterilize the matrix or scaffold material prior to administration or implantation, e.g., by treatment with ethylene oxide or by gamma irradiation or irradiation with an electron beam. In addition, a number of other materials may be used to form the scaffold or framework structure, including but not limited to: nylon (polyamides), dacron (polyesters), polystyrene, polypropylene, polyacrylates, polyvinyl compounds (e.g., polyvinylchloride), polycarbonate (PVC), polytetrafluorethylene (PTFE, teflon), thermanox (TPX), polymers of hydroxy acids such as polylactic acid (PLA), polyglycolic acid (PGA), and polylactic acid-glycolic acid (PLGA), polyorthoesters, polyanhydrides, polyphosphazenes, and a variety of polyhydroxyalkanoates, and combinations thereof. Matrices suitable include a polymeric mesh or sponge and a polymeric hydrogel. In the particular embodiment, the matrix is biodegradable over a time period of less than a year, more particularly less than six months, most particularly over two to ten weeks. The polymer composition, as well as method of manufacture, can be used to determine the rate of degradation. For example, mixing increasing amounts of polylactic acid with polyglycolic acid decreases the degradation time. Meshes of polyglycolic acid that can be used can be obtained commercially, for instance, from surgical supply companies (e.g., Ethicon, N.J.). In general, these polymers are at least partially soluble in aqueous solutions, such as water, buffered salt solutions, or aqueous alcohol solutions, that have charged side groups, or a monovalent ionic salt thereof.

[0173] The composition medium can also be a hydrogel, which is prepared from any biocompatible or non-cytotoxic homo- or hetero-polymer, such as a hydrophilic polyacrylic acid polymer that can act as a drug absorbing sponge. Certain of them, such as, in particular, those obtained from ethylene and/or propylene oxide are commercially available. A hydrogel can be deposited directly onto the surface of the tissue to be treated, for example during surgical intervention.

[0174] Embodiments of pharmaceutical compositions of the present invention comprise a replication defective recombinant viral vector encoding the polynucleotide inhibitory agent of the present invention and a transfection enhancer, such as poloxamer. An example of a poloxamer is Poloxamer 407, which is commercially available (BASF, Parsippany, N.J.) and is a non-toxic, biocompatible polyol. A poloxamer impregnated with recombinant viruses may be deposited directly on the surface of the tissue to be treated, for example during a surgical intervention. Poloxamer possesses essentially the same advantages as hydrogel while having a lower viscosity.

[0175] The active expression-inhibiting agents may also be entrapped in microcapsules prepared, for example, by interfacial polymerization, for example, hydroxymethylcellulose or gelatin-microcapsules and poly-(methylmethacylate) microcapsules, respectively, in colloidal drug delivery systems (for example, liposomes, albumin microspheres, microemulsions, nano-particles and nanocapsules) or in macroemulsions. Such techniques are disclosed in Remington's Pharmaceutical Sciences (1980) 16th edition, Osol, A. Ed.

[0176] Sustained-release preparations may be prepared. Suitable examples of sustained-release preparations include semi-permeable matrices of solid hydrophobic polymers containing the antibody, which matrices are in the form of shaped articles, e.g. films, or microcapsules. Examples of sustained-release matrices include polyesters, hydrogels (for example, poly(2-hydroxyethyl-methacrylate), or poly(vinylalcohol)), polylactides (U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid and gamma-ethyl-L-glutamate, non-degradable ethylene-vinyl acetate, degradable lactic acid-glycolic acid copolymers such as the LUPRON DEPOT® (injectable microspheres composed of lactic acid-glycolic acid copolymer and leuprolide acetate), and poly-D-(-)-3-hydroxybutyric acid. While polymers such as ethylene-vinyl acetate and lactic acid-glycolic acid enable release of molecules for over 100 days, certain hydrogels release proteins for shorter time periods. When encapsulated antibodies remain in the body for a long time, they may denature or aggregate as a result of exposure to moisture at 37° C., resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be devised for stabilization depending on the mechanism involved. For example, if the aggregation mechanism is discovered to be intermolecular S--S bond formation through thio-disulfide interchange, stabilization may be achieved by modifying sulfhydryl residues, lyophilizing from acidic solutions, controlling moisture content, using appropriate additives, and developing specific polymer matrix compositions.

[0177] As defined above, therapeutically effective dose means that amount of protein, polynucleotide, peptide, or its antibodies, agonists or antagonists, which ameliorate the symptoms or condition. Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED₅₀ (the dose therapeutically effective in 50% of the population) and LD₅₀ (the dose lethal to 50% of the population). The dose ratio of toxic to therapeutic effects is the therapeutic index, and it can be expressed as the ratio, LD₅₀/ED₅₀. Pharmaceutical compositions that exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used in formulating a range of dosage for human use. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED₅₀ with little or no toxicity. The dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration.

[0178] For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays or in animal models, usually mice, rabbits, dogs, or pigs. The animal model is also used to achieve a desirable concentration range and route of administration. Such information can then be used to determine useful doses and routes for administration in humans. The exact dosage is chosen by the individual physician in view of the patient to be treated. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Additional factors which may be taken into account include the severity of the disease state, age, weight and gender of the patient; diet, desired duration of treatment, method of administration, time and frequency of administration, drug combination(s), reaction sensitivities, and tolerance/response to therapy. Long acting pharmaceutical compositions might be administered every 3 to 4 days, every week, or once every two weeks depending on half-life and clearance rate of the particular formulation.

[0179] The pharmaceutical compositions according to this invention may be administered to a subject by a variety of methods. They may be added directly to target tissues, complexed with cationic lipids, packaged within liposomes, or delivered to target cells by other methods known in the art. Localized administration to the desired tissues may be done by direct injection, transdermal absorption, catheter, infusion pump or stent. The DNA, DNA/vehicle complexes, or the recombinant virus particles are locally administered to the site of treatment. Alternative routes of delivery include, but are not limited to, intravenous injection, intramuscular injection, subcutaneous injection, aerosol inhalation, oral (tablet or pill form), topical, systemic, ocular, intraperitoneal and/or intrathecal delivery. Examples of ribozyme delivery and administration are provided in Sullivan et al. WO 94/02595.

[0180] Antibodies according to the invention may be delivered as a bolus only, infused over time or both administered as a bolus and infused over time. Those skilled in the art may employ different formulations for polynucleotides than for proteins. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.

[0181] As discussed hereinabove, recombinant viruses may be used to introduce DNA encoding polynucleotide agents useful in the present invention. Recombinant viruses according to the invention are generally formulated and administered in the form of doses of between about 10⁴ and about 10¹⁴ pfu. In the case of AAVs and adenoviruses, doses of from about 10⁶ to about 10¹¹ pfu are preferably used. The term pfu ("plaque-forming unit") corresponds to the infective power of a suspension of virions and is determined by infecting an appropriate cell culture and measuring the number of plaques formed. The techniques for determining the pfu titre of a viral solution are well documented in the prior art.

[0182] In one aspect the present invention provides methods of preventing and/or treating disorders involving ER-associated protein misfolding, said methods comprising administering to a subject a therapeutically effective amount of an agent as disclosed herein. In a particular embodiment, the agent is selected from an expression-inhibiting agent and an antibody.

[0183] In a further aspect the present invention provides a method of preventing and/or treating a disease characterized by abnormal trafficking of a disease associated protein, said method comprising administering to a subject a therapeutically effective amount of an agent as disclosed herein. In a particular embodiment, the agent is selected from an expression-inhibiting agent and an antibody.

[0184] In a particular aspect, the present invention provides a method of preventing and/or treating Cystic Fibrosis, said method comprising administering to a subject a therapeutically effective amount of an agent as disclosed herein. In a particular embodiment, the agent is selected from an expression-inhibiting agent and an antibody.

[0185] A further aspect of the invention relates to a method of treating or preventing a disease involving a decrease in CF-associated mutant CFTR function, comprising administering to said subject a therapeutically effective amount of an agent as disclosed herein. In a particular embodiment, the agent is selected from an expression-inhibiting agent and an antibody.

[0186] The invention also relates to the use of an agent as described above for the preparation of a medicament for treating or preventing a disease involving ER-associated protein misfolding. In a particular embodiment, the disease is characterised by abnormal trafficking of a disease-associated protein. In a particular embodiment of the present invention the disease is selected from Cystic Fibrosis, Parkinson's Disease, Gaucher's Disease, Nephrogenic diabetes insipidus, Emphysema and Liver Disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, Hypogonadotropic hypogonadism, Hyperinsulinemic hypoglycemia, beta-Galactosidosis, Wilson disease, Long QT syndrome, Retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's Disease, Prion disease, and inclusion body myositis. In a further embodiment of the present invention the disease is cystic fibrosis.

[0187] The invention also relates to the use of an agent as described above for the preparation of a medicament for treating or preventing an airway epithelial or brochial inflammatory disease, including asthma or COPD.

[0188] The present invention also provides a method of treating and/or preventing a disease involving ER-associated protein misfolding said method comprising administering, to a subject suffering from, or susceptible to, a disease involving ER-associated protein misfolding, a pharmaceutical composition or compound as described herein, particularly a therapeutically effective amount of an agent which inhibits the expression or activity of a TARGET as identified herein. In one embodiment, the disease is characterized by abnormal trafficking of a disease-associated protein. In a further embodiment the disease is selected from cystic fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's Disease, Prion disease, and inclusion body myositis. In a further embodiment of the present invention the disease is cystic fibrosis.

[0189] The present invention also provides a method of treating and/or preventing asthma and COPD said method comprising administering, to a subject suffering from or susceptible to, asthma and COPD a pharmaceutical composition or an agent as described herein.

[0190] The invention also relates to an agent or a pharmaceutical composition as described above for use in the treatment and/or prevention of a disease involving ER-associated protein misfolding. In a particular embodiment, the disease is characterised by abnormal trafficking of a disease-associated protein. In a particular embodiment of the present invention the disease is selected from cystic fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, Prion disease, and inclusion body myositis. In a further embodiment of the present invention the disease is cystic fibrosis.

[0191] The invention also relates to an agent or a pharmaceutical composition as described above for use in the treatment and/or prevention of an airway epithelial or brochial inflammatory disease, including asthma or COPD.

[0192] Administration of the agent or pharmaceutical composition of the present invention to the subject patient includes both self-administration and administration by another person. The patient may be in need of treatment for an existing disease or medical condition, or may desire prophylactic treatment to prevent or reduce the risk for diseases and medical conditions characterized by ER-associated protein misfolding. The agent of the present invention may be delivered to the subject patient orally, transdermally, via inhalation, injection, nasally, rectally or via a sustained release formulation.

[0193] Still another aspect of the invention relates to a method for diagnosing a pathological condition involving ER-associated protein misfolding, comprising determining the amount of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55 in a biological sample, and comparing the amount with the amount of the polypeptide in a healthy subject, wherein an increase of the amount of polypeptide compared to the healthy subject is indicative of the presence of the pathological condition. In one embodiment, the disease is characterized by abnormal trafficking of a disease-associated protein. In a further embodiment the disease is selected from cystic fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, Prion disease, and inclusion body myositis. In a particular embodiment, said method may be used to diagnose a decrease in CF-associated mutant CFTR functionality or a susceptibility to the condition in a subject. In a further embodiment of the present invention the disease is cystic fibrosis.

[0194] Still another aspect of the invention relates to a method for diagnosing a pathological condition involving ER-associated protein misfolding, comprising determining the activity of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 30-55 in a biological sample, and comparing the activity with the activity of the polypeptide in a healthy subject, wherein an increase of the activity of polypeptide compared to the healthy subject is indicative of the presence of the pathological condition. In one embodiment, the disease is characterized by abnormal trafficking of a disease-associated protein. In an embodiment, the disease is characterized by abnormal folding of a disease-associated protein. In an embodiment, the disease is characterized by misfolding and degradation of a disease-associated protein. In a further embodiment the disease is selected from cystic fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, Prion disease, and inclusion body myositis. In a particular embodiment, said method may be used to diagnose a decrease in CF-associated mutant CFTR functionality or a susceptibility to the condition in a subject. In a further embodiment of the present invention the disease is cystic fibrosis.

[0195] Still another aspect of the invention relates to a method for diagnosing a pathological condition involving ER-associated protein misfolding, comprising determining the nucleic acid sequence of at least one of the genes of SEQ ID NO: 1-29 within the genomic DNA of a subject; comparing the sequence with the nucleic acid sequence obtained from a database and/or a healthy subject; and identifying any difference(s) related to the onset or prevalence of the pathological conditions disclosed herein.

[0196] The polypeptides or the polynucleotides of the present invention employed in the methods described herein may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. To perform the methods it is feasible to immobilize either the polypeptide of the present invention or the compound to facilitate separation of complexes from uncomplexed forms of the polypeptide, as well as to accommodate automation of the assay. Interaction (e.g., binding of) of the polypeptide of the present invention with a compound can be accomplished in any vessel suitable for containing the reactants. Examples of such vessels include microtitre plates, test tubes, and microcentrifuge tubes. In one embodiment, a fusion protein can be provided which adds a domain that allows the polypeptide to be bound to a matrix. For example, the polypeptide of the present invention can be "His" tagged, and subsequently adsorbed onto Ni-NTA microtitre plates, or ProtA fusions with the polypeptides of the present invention can be adsorbed to IgG, which are then combined with the cell lysates (e.g., .sup.(35)S-labelled) and the candidate compound, and the mixture incubated under conditions favorable for complex formation (e.g., at physiological conditions for salt and pH). Following incubation, the plates are washed to remove any unbound label, and the matrix is immobilized. The amount of radioactivity can be determined directly, or in the supernatant after dissociation of the complexes. Alternatively, the complexes can be dissociated from the matrix, separated by SDS-PAGE, and the level of the protein binding to the protein of the present invention quantitated from the gel using standard electrophoretic techniques.

[0197] Other techniques for immobilizing protein on matrices can also be used in the method of identifying compounds. For example, either the polypeptide of the present invention or the compound can be immobilized utilizing conjugation of biotin and streptavidin. Biotinylated protein molecules of the present invention can be prepared from biotin-NHS (N-hydroxy-succinimide) using techniques well known in the art (e.g., biotinylation kit, Pierce Chemicals, Rockford, Ill.), and immobilized in the wells of streptavidin-coated 96 well plates (Pierce Chemical). Alternatively, antibodies reactive with the polypeptides of the present invention but which do not interfere with binding of the polypeptide to the compound can be derivatized to the wells of the plate, and the polypeptide of the present invention can be trapped in the wells by antibody conjugation. As described above, preparations of a labeled candidate compound are incubated in the wells of the plate presenting the polypeptide of the present invention, and the amount of complex trapped in the well can be quantitated.

[0198] The polynucleotides encoding the TARGET polypeptides are identified as SEQ ID NO: 1-29. The present inventors show herein that transfection of mammalian cells with Ad-siRNAs targeting these genes increases the functional activity of CF-associated mutant CFTR.

[0199] The invention is further illustrated in the following figures and examples.

EXPERIMENTAL SECTION

Example 1

Development of a High-Throughput Screening Method for CFTR-Dependent Halide Flux

1.1 Principal of the Assay

[0200] Cystic Fibrosis Transmembrane Conductance Regulator (CFTR), by its chloride channel function, plays a key role in chloride secretion and water balance in epithelia throughout the body. Other halides such as iodide also make use of CFTR. Accordingly, an assay to monitor CFTR-halide flux by using a reporter protein, halide-sensitive fluorescent protein YFP, is developed to measure the functional activity of CFTR. Cells expressing this reporter protein show enhanced fluorescence quenching of YFP by extracellular isomolar iodide solutions in the presence of activated CFTR. This is caused by the increased flux of iodide across the plasma membrane by CFTR. The fluorescence quenching is measured on a fluorescence plate reader.

1.2 Development of the Assay

[0201] Human lung epithelial cells are isolated from a ΔF508-CFTR patient, obtained after informed consent. These cells are stably transfected with ΔF508-CFTR expression plasmids and are named CFBE41o-cells (Gruenert et al., 2004). This is a preferred cell model because it is of human origin and derived from the primary organ suffering from the effect of the CF-associated mutations. Targets identified in human model systems are commonly considered to have lower attrition as compared to targets identified in models from different species, which have naturally diverged from humans during evolution. CFBE41o-cells are cultured on tissue culture grade plastic, coated with 0.1 mg/mL bovine serum albumin (BSA), 0.03 mg/mL bovine collagen type 1 and 0.01 mg/mL human fibronectin. CFBE41o-cells are cultured in MEM containing 10% Fetal Bovine Serum, 2 mM glutamine, 100 IU/mL penicilline, 0.1 mg/ml streptomycine sulfate and 0.5 mg/mL hygromycin B at 37° C., 5% CO₂ in a humidified chamber. For high-throughput screening, 96-well plates are seeded with 1,000 cells per well.

[0202] As discussed above, measuring halide channel activity in cells expressing CFTR represents the preferred method for measuring the functional activity of CF-associated mutant CFTR. Halide channel activity is measured using the reporter, halide-sensitive fluorescent protein YFP (Galietta et al., 2001a).

[0203] To efficiently express the halide-sensitive fluorescent protein YFP in CFBE41o-cells, the reporter cDNA is synthesized and cloned in adenoviral adapter plasmids. dE1/dE2A (deleted for adenoviral genes E1 and E2A) adenoviruses are generated from these adapter plasmids by co-transfection of the helper plasmid pWEAd5AflII-rITR.dE2A in PER.E2A packaging cells, as described in WO99/64582.

[0204] In order to specifically assess the activity of ΔF508-CFTR, this protein is expressed, or as a positive control, the wild-type CFTR is expressed, from adenoviral vectors. ΔF508-CFTR cDNA or the wild-type CFTR cDNA (GenBank accession number NM_--000492) (SEQ ID NO: 101) is cloned in adenoviral adapter plasmids to produce adenoviral vectors.

[0205] To determine the optimal conditions for adenoviral transduction, several conditions for the expression of the YFP halide reporter are tested. An experiment is performed where increasing amounts of adenoviral vectors as defined by virus particles per cell (VPU) are used to transduce CFBE41o-cells. VPU is determined by quantitative PCR, and is defined as adenoviral particles per ml according to (Ma et al., 2001). Three days after transduction of the fluorescent halide reporter, transduction efficiency is measured using fluorescent activated cell sorting (FACS) (Becton Dickinson FACScalibur) with excitation at 488 nm. The outcome of such an experiment is shown in FIGS. 1A and 1B. In this experiment, CFBE41o-cells are transduced with increasing VPU of adenovirus without a cDNA (empty), enhanced Green Fluorescent Protein (eGFP) as a positive control, and the YFP halide-sensitive fluorescent protein (YFP). Three days after transduction, cells are detached with trypsin, fixed and analysed with FACS (10,000 cells are counted).

[0206] As can be seen in FIGS. 1A and 1B, adenovirus without a cDNA represents the background fluorescence in the cells (2.14% at VPU 500 and 2.85% at VPU 2000). eGFP transduction results in 93.3% and 97.4% positive cells at VPU 500 and VPU 2000 respectively. YFP transduction results in 84.2% and 93.4% positive cells at VPU 500 and VPU 2000 respectively. YFP transduction at VPU 2000 results in significantly stronger fluorescent signal compared to VPU 500 (62.6 versus 27.5 respectively). Thus, transduction with the adenoviral YFP reporter at VPU 2000 is the preferred method.

Example 2

Validation of the CFTR-Dependent Halide Flux Assay

[0207] In this example, it is shown that the halide-sensitive reporter expressed in CFBE41o-cells can monitor functional activity of CFTR. CFBE41o-cells are transduced with the YFP fluorescent halide reporter adenoviral vector at a VPU of 2000 viral particles per cell, together with adenoviral vectors expressing ΔF508-CFTR, or as a positive control the wild-type CFTR. Three days after transduction, wells are washed two times with phosphate-buffered saline (PBS: 137 mM NaCl, 2.7 mM KCl, 10 mM Na₂HPO₄, 1.76 mM KH₂PO₄ at pH 7.4), and incubated in 40 microliter of PBS containing 10 microM forskolin and 100 microM genistein for 5 minutes Forskolin and genistein have been shown to activate CFTR activity (Hwang et al., 1997), and are used here to pre-activate any existing CFTR. Plates are read in a fluorescent plate reader, equipped with injectors for the delivery of reagents to the well (Perkin-Elmer Envision 2102). Each well is read for 2 seconds at 485/530 nm (excitation/emission) prior to the addition of 110 microliter iodide-containing buffer (137 mM NaI, 2.7 mM KCl, 10 mM Na₂HPO₄, 1.76 mM KH₂PO₄ at pH 7.4). Fluorescent reading is continued for an additional 12 sec, sampling every 200 msec.

[0208] FIG. 2 shows results of such an experiment. Injection of PBS does not quench YFP fluorescence in ΔF508-CFTR expressing cells. In contrast, injection of iodide results in a slow quenching of fluorescence, where the slope of the curve indicates the rate of halide flux. A minimal increase in halide flux is observed after pre-incubation with forskolin and genistein, indicating that ΔF508-CFTR is activated by this combination. Furthermore, a much stronger increase in YFP fluorescence quenching is observed when the wild-type CFTR protein is expressed. These results confirm that this assay measures CFTR-dependent halide flux, and that the ΔF508-CFTR has reduced activity compared to the wild-type protein. Thus, quenching of YFP in the presence of ΔF508-CFTR is a specific measure of CFTR activity and can be used to identify correctors of defect ΔF508 CFTR activity in a high throughput screen.

Example 3

Screening of 11330 "Ad-siRNAs" in the CFTR-Dependent Halide Flux Assay

[0209] The CFTR-Dependent Halide Flux Assay, the development of which is described in Example 1, has been screened against an arrayed collection of 11,330 different recombinant adenoviruses mediating the expression of shRNAs in CFBE41o-cells. These shRNAs cause a reduction in expression levels of genes that contain homologous sequences by a mechanism known as RNA interference (RNAi). The 11330 Ad-siRNAs contained in the arrayed collection target 5046 different transcripts. On average, every transcript is targeted by 2 to 3 independent Ad-siRNAs. The screening assay followed the following time-course: CFBE41o-cells were seeded at 1000 cells per well in 96-well plates (transparent bottom, black sides). One day after seeding, an aliquot of the Ad-siRNA was applied to each well. Four days after seeding, each well received an aliquot of adenovirus expressing ΔF508-CFTR and an aliquot of adenovirus expressing YFP. Seven days after seeding, the YFP assay was performed as described in Example 2.

[0210] For every batch of Ad-siRNA plates, control plates were screened that contain control viruses that are produced under the same conditions as the SilenceSelect® adenoviral collection. The viruses include sets of negative control viruses (N1 (Ad5-empty_KD)), N2 (Ad5-empty_KD), N3 (no virus)), together with positive control viruses (P1 (Ad5-STX8_v5_KD)), P2 (Ad5-STX8_v5_KD), P3 (Ad5-BCAP31_v3_KD), P4 (Ad5-BCAP31_v3_KD)), P5 (Ad5-CFTR_v5_KI)). Every well of a virus plate contains 150 μL of virus crude lysate. A representative example of the performance of a plate tested with the screening protocol described above is shown in FIG. 3. In this figure, the calculated relative 12 sec endpoint of iodide-mediated quenching of the YFP reporter detected upon performing the assay for every recombinant adenovirus on the plate is shown (as defined by the average of the last three data-points divided by the average of the pre-injection baseline fluorescence).

[0211] For analysis of the screening of 11,330 Ad-siRNAs, data from the fluorescent plate reader is exported and analyzed using perl scripts and the R statistical package as follows:

[0212] 1) Mean baseline fluorescence (prior to iodide injection) is calculated (YFP expression level).

[0213] 2) Data are normalized against the baseline (set at 1).

[0214] 3) Wells are excluded when more than 10% of the data points are above baseline.

[0215] 4) Based on the input parameters, the curve fit is performed using the R statistics program for analysis. It will include the baseline at t=tinj, and use the rest of the data points until t=14 s.

[0216] 5) The exponential decay (y=a*e-bx+c) curve fit requires initial values for variables. Therefore, the script loops through different combinations of initial values, until it finds the optimal curve fit.

[0217] 6) The slope at t=tinj is returned by determining the derivative of the function (initial slope).

[0218] 7) The average of the three last data points (t=14 sec) is determined and calculated relative to baseline (end-point). This value ranges from 1 (no quenching) to 0 (complete quenching of YFP).

[0219] Identification of hits was performed both on the calculated 12-sec endpoint and the calculated initial slope. These values were expressed in fold standard deviation of the samples on the 96-well plate relative to the mean of the samples on the 96-well plate. When either of these values exceeds the cutoff value (defined as 1.5 fold the standard deviation below the sample mean), a Ad-siRNA virus is marked as a hit. An overview of the screening data is shown in FIG. 4, with hits below -1.5. The screen of 11,330 Ad-siRNAs procedure yielded 753 hits.

Example 4

Rescreen of the Primary Hits Using Independent Repropagation Material

[0220] To confirm the results of the identified Ad-siRNA in the CFTR-Dependent Halide Flux Assay, the following approach may be taken: the Ad-siRNA hits are repropagated using PerC6 cells (Crucell, Leiden, The Netherlands) at a 96-well plate level, followed by retesting in the CFTR-Dependent Halide Flux Assay. First, tubes containing the crude lysates of the identified hit Ad-siRNA's samples are picked from the SilenceSelect® collection and rearranged in 96 well plates together with negative/positive controls. As the tubes are labeled with a barcode (Screenmates®, Matrix technologies), quality checks are performed on the rearranged plates. To propagate the rearranged hit viruses, 40,000 PerC6.E2A cells are seeded in 200 microL of DMEM containing 10% non-heat inactivated FBS into each well of a 96 well plate and incubated overnight at 39° C. in a humidified incubator at 10% CO₂. Subsequently, 2 microL of crude lysate from the hit Ad-siRNA's rearranged in the 96 well plates as indicated above is added to the PerC6.E2A cells using a 96 well dispenser. The plates may then be incubated at 34° C. in a humidified incubator at 10% CO₂ for 5 to 10 days. After this period, the repropagation plates are frozen at -20° C., provided that complete CPE (cytopathic effect) could be seen. The propagated Ad-siRNAs are rescreened in the CFTR-Dependent Halide Flux Assay.

[0221] Data analysis for each of the rescreen is performed as follows. For every plate the average and standard deviation is calculated for the negative controls and may be used to convert each data point into a "cutoff value" that indicates the difference between the sample and the average of all negatives in terms of standard deviation of all negatives. Threshold settings for the rescreen were -2 fold standard deviation from the mean of the negative controls. At this cut-off, 315 Ad-siRNAs are again positive in the CFTR-Dependent Halide Flux Assay. Data for the TARGETs of the present invention are shown in Table 3 below, the halide flux is expressed as the fold stdev from the mean of the negative controls.

TABLE-US-00003 TABLE 3 Efficacy of the restoration of CFTR-dependent halide flux in CFBE41o- relevant to the present expression-inhibitory agent invention Forskolin-Genistein TARGET induced halide flux Gene Symbol SEQ ID NO: DNA in CFBE41o- UGT3A2 2 -5.485 PHGDH 3 -6.495 B3GNT3 4 -4.495 PPIH 5 -11.49 CELSR3 6 -2.16 MC2R 7 -9.81 MAS1L 8 -3.93 LRRK2 9 -5.865 NLRP1 10, 11, 12, 13, 14 -7.195 PMS1 15, 16, 17 -5.065 MAK 18 -4.645 CPD 19 -7.04 CST7 20 -3.87 DUSP5 21 -3.39 PTPRG 22 -4.41 IL6R 23, 24 -5.595 GHR 25 -4.425 CSF3 26, 27, 28 -6.36 SPNS1 29 -7.025 STX8_v5 positive control -6.9963 BCAP31_v3 positive control -5.45241 wild-type CFTR_v5 positive control -25.1772

[0222] A quality control of target Ad-siRNAs is performed as follows: Target Ad-siRNAs are propagated using derivatives of PERC6.E2A cells (Crucell, Leiden, The Netherlands) in 96-well plates, followed by sequencing the siRNAs encoded by the target Ad-siRNA viruses. PERC6.E2A cells are seeded in 96 well plates at a density of 40,000 cells/well in 180 μL PER.E2A medium. Cells are then incubated overnight at 39° C. in a 10% CO₂ humidified incubator. One day later, cells are infected with 1 μL of crude cell lysate from SilenceSelect® stocks containing target Ad-siRNAs. Cells are incubated further at 34° C., 10% CO₂ until appearance of cytopathic effect (as revealed by the swelling and rounding up of the cells, typically 7 days post infection). The supernatant is collected, and the virus crude lysate is treated with proteinase K by adding to 4 μL Lysis buffer (1× Expand High Fidelity buffer with MgCl2 (Roche Molecular Biochemicals, Cat. No 1332465) supplemented with 1 mg/mL proteinase K (Roche Molecular Biochemicals, Cat No 745 723) and 0.45% Tween-20 (Roche Molecular Biochemicals, Cat No 1335465) to 12 μL crude lysate in sterile PCR tubes. These tubes are incubated at 55° C. for 2 hours followed by a 15 minutes inactivation step at 95° C. For the PCR reaction, 1 μL lysate is added to a PCR master mix composed of 5 μL 10× Expand High Fidelity buffer with MgCl₂, 0.5 μL at of dNTP mix (10 mM for each dNTP), 1 μL of "Forward primer" (10 mM stock, sequence: 5' CCG TTT ACG TGG AGA CTC GCC 3' (SEQ. ID NO: 102), 1 μL of "Reverse Primer" (10 mM stock, sequence: 5' CCC CCA CCT TAT ATA TAT TCT TTC C 3') (SEQ. ID NO: 103), 0.2 μL of Expand High Fidelity DNA polymerase (3.5 U/μL, Roche Molecular Biochemicals) and 41.3 μL of H2O. PCR is performed in a PE Biosystems GeneAmp PCR system 9700 as follows: the PCR mixture (50 μL in total) is incubated at 95° C. for 5 minutes; each cycle runs at 95° C. for 15 sec., 55° C. for 30 sec., 68° C. for 4 minutes, and is repeated for 35 cycles. A final incubation at 68° C. is performed for 7 minutes. For sequencing analysis, the siRNA constructs expressed by the target adenoviruses are amplified by PCR using primers complementary to vector sequences flanking the SapI site of the pIPspAdapt6-U6 plasmid. The sequence of the PCR fragments is determined and compared with the expected sequence. All sequences are found to be identical to the expected sequence.

Example 5

Analysis of the Expression Levels for Certain Targets Identified in Human Primary Bronchial Epithelial Cells and Human Lung

[0223] Expression levels for certain identified targets are determined in different isolates of lung epithelial cells as follows.

[0224] Microarray data from human lung large airway epithelia, non-smoker, non-COPD (Carolan et al., 2006) is downloaded from the NCBI website (http://www.ncbi.nlm.nih gov/entrez/query.fcgi?db=gds&term=GSE5060 [Accession]&cmd=search) and analyzed for expression of the HITS. Hits expressed in each of the samples present on these arrays (p<0.05) are considered expressed. All other hits are subsequently analyzed using real-time gene expression analysis as follows.

[0225] Two RNA samples from human total lung (either adult or fetal) are obtained from a commercial supplier (Stratagene). These samples will be referred to as "human lung".

[0226] Cultured primary bronchial epithelial cell isolates are obtained from Cell Applications Inc. (#502-05a, cryopreserved at first passage), from the University of Genova (Galieta lab, Genove, Italy) or from cultured CFBE41o-cells (human lung epithelial cells stably transfected with ΔF508-CFTR expression plasmids as described above) are utilized. Total RNA is extracted using the "RNAeasy Total RNA Isolation kit" (Qiagen).

[0227] The concentration of RNA in each sample is fluorimetrically quantified. A similar amount of RNA from each preparation is reverse transcribed into first strand cDNA with the "Taqman reverse transcription kit" from Applied Biosystems. Briefly, 300 ng RNA is included per 50 μL reaction mix containing 125 pmol of random hexamers, 25 U Rnase inhibitor, 62.5 U Multiscribe reverse transcriptase, 5 mM MgCl₂ and 0.5 mM of each dNTP. The reaction mixture is incubated at 25° C. for 10 minutes, followed by 30 minutes incubation at 48° C. and heat inactivation (5 minutes 95° C.) of the reverse transcriptase in a thermocycler (Dyad, MJ Research). Reactions are immediately chilled to 4° C. at the end of the program. To avoid multiple freeze/thaw cycles of the obtained cDNA, the different samples are pooled in 96-well plates, aliquoted and stored at -20° C.

[0228] Real-time PCR reactions are performed and monitored using the "ABI PRISM 7000 Sequence Detection System Instrument" (Applied Biosystems). Pre-designed, gene-specific Taqman probe and primer sets for quantitative gene expression are purchased from Applied Biosystems as part of the "Assays on Demand" Gene expression products. These commercially available kits are quality checked by the supplier and allow quantitative determination of the amount of target cDNA in the sample. The "Assays on Demand" gene expression products are used according to the protocol delivered by the supplier. The PCR mixture consisted of 1×"Taqman Universal PCR Mastermix no AmpErase UNG" and 1× "Taqman Gene Expression Assay on Demand mix" and 5 uL of the retro-transcription reaction product (1-40 ng of RNA converted into cDNA) in a total volume of 25 uL. After an initial denaturation step at 95° C. for 10 minutes, the cDNA products are amplified with 40 cycles consisting of 95° C. for 15 sec, and 60° C. for 1 minute. To normalize for variability in the initial quantities of cDNA between different samples, amplification reactions with the same cDNA are performed for the housekeeping gene GAPDH using the pre-developed "Assays on demand" primer set and Taqman probe mix and "Taqman Universal PCR Mastermix" (all Applied Biosystems) according to the manufacturer's instructions. Threshold cycle values (Ct), for example, the cycle number at which the amount of amplified gene of interest reached a fixed threshold are determined for each sample. A HIT is considered as expressed if the Ct value obtained for this hit is lower than 35 in at least one of the available human lung isolate and at least one of the cultured human bronchial epithelial (HBE) samples. This analysis of 315 hits yielded 210 genes expressed in bronchial epithelium.

TABLE-US-00004 TABLE 4 Expression of the targets in lung epithelial tissue TARGET lung HBE CFBE Gene SEQ ID microarray Q-PCR Q-PCR Q-PCR Symbol NO: DNA (p-value) (Ct) (Ct) (Ct) UGT3A2 2 N/A 37.255 38.18667 33.89 PHGDH 3 0.030273 N/A N/A N/A B3GNT3 4 0.00415 N/A N/A N/A PPIH 5 0.00415 N/A N/A N/A CELSR3 6 0.081337 32.895 32.03 29.14 MC2R 7 0.466064 35.565 40 31.695 MAS1L 8 0.760937 33.2125 40 30.605 LRRK2 9 0.303711 27.435 33.435 35.35 NLRP1 10, 11, 12, 0.888428 28.195 27.60667 27.97 13, 14 PMS1 15, 16, 17 0.000244 N/A N/A N/A MAK 18 0.000244 N/A N/A N/A CPD 19 0.000244 N/A N/A N/A CST7 20 0.533936 26.355 40 31.32 DUSP5 21 0.000244 N/A N/A N/A PTPRG 22 0.030273 N/A N/A N/A IL6R 23, 24 0.00415 N/A N/A N/A GHR 25 0.001953 N/A N/A N/A CSF3 26, 27, 28 0.544587 31.705 30.01 37.66 SPNS1 29 0.018555 N/A N/A N/A

Example 6

"On Target Analysis" Using KD Viruses

[0229] To strengthen the validation of a hit, it is helpful to recapitulate its effect using a completely independent siRNA targeting the same target gene through a different sequence. This analysis is called the "on target analysis". In practice, this was done by designing multiple new shRNA oligonucleotides against the target using a specialised algorithm previously described, and incorporating these into adenoviruses, according to WO 03/020931. After virus production, these viruses were arrayed in 96 well plates, together with positive and negative control viruses. On average, 6 new independent Ad-siRNA's have been produced for a set of targets. One independent repropagation of these virus plates was then performed as described above for the rescreen in Example 4. The plates produced in this repropagation was tested in biological duplicate in the YFP assay at 3 MOIS according to the protocol described (Example 2). Ad-siRNA's mediating an increase in the quenching of the YFP reporter above the set cutoff value in at least 1 were nominated as hits scoring in the "on target analysis". The cutoff value in these experiments was defined as the average over the negative controls+2 times the standard deviation over the negative controls. Through this exercise, 141 hits were identified with at least two active shRNAs (range: 2-6, average: 2.46). These hits are considered "on target", and proceeded to the next validation experiment.

Example 7

Analysis of the Cell-Surface Expression of ΔF508 CFTR

[0230] A further validation of the correction of ΔF508 CFTR is the expression of this protein on the cell surface as measured by cell-surface biotinylation (Prince et al., 1994). This analysis allows a more quantitative measurement of the levels of restoration of cell-surface expressed ΔF508 CFTR, as well as the glycosylation status of the ΔF508 CFTR protein (Cheng et al., 1990). A preferred effect of a HIT would be increased cell-surface expression of ΔF508 CFTR, and especially "band C" (Cheng et al., 1990), fully glycosylated ΔF508 CFTR. The assay to measure cell surface expression of ΔF508-CFTR is performed in the following fashion: CFBE41o-cells are seeded in 60 mm cell culture dishes coated with 0.1 mg/mL bovine serum albumin (BSA), 0.03 mg/mL bovine collagen type 1 and 0.01 mg/mL human fibronectin. CFBE41o-cells are cultured in MEM containing 10% Fetal Bovine Serum, 2 mM glutamine, 100 IU/mL penicillin, 0.1 mg/mL streptomycine sulfate and 0.5 mg/mL hygromycin B at 37° C., 5% CO₂ in a humidified chamber. One day after seeding, an aliquot of the Ad-siRNA is applied to each well. Four days after seeding, each well receives an aliquot of adenovirus expressing ΔF508-CFTR. Seven days after seeding, the cell cultures are exposed to 10 microM forskolin and 100 microM genistein for 15 min at 37° C. The cells are washed three times in PBS pH 8 to which 1 mM MgCl₂ and 0.1 mM CaCl₂ are added at 0° C., and 1.5 ml of 0.5 mg/mL sulfo-NHS-SS-biotin (Pierce #21328) diluted in PBS pH 8 supplemented with 1 mM MgCl₂ and 0.1 mM CaCl₂ is added to the cell cultures. The cell culture dishes are gently rocked for 30 min at 4° C. Cell cultures are washed three times in PBS containing 1% bovine serum albumin at 0° C. and one with PBS at 0° C. Cells are scraped from the plastic in PBS at 0° C. and transferred to 1.5 mL Eppendorf tubes. The cells are harvested by centrifugation at 4° C., 20,000 g for 1 min. Cells are lysed in 270 microl of RIPA buffer (1% Triton X100, 150 mM NaCl, 25 mM Tris-Cl pH7.4, 0.005% sodium deoxycholate, protease inhibitor cocktail (Roche #11873580001) at 2 mg/mL and 0.3 mM Pefablock SC (Roche #11429868001)) for 15 min at 0° C. After centrifugation for 20 min at 20,000 g, the supernatant is transferred to an Eppendorf tube containing 30 microL of pre-washed 50% v/v NeutrAvidin agarose resin beads (Thermo Scientific #29200) in RIPA buffer. The supernatant is incubated with the avidin beads for 16 hrs at 4° C. with gentle rocking. Beads are harvested by centrifugation at 4° C., 20,000 g for 20 sec and washed twice with RIPA buffer, twice with (25 mM Tris-Cl pH 7.4, 150 mM NaCl, 1% Triton X100) at 0° C. and twice with (25 mM Tris-Cl pH 7.4, 150 mM NaCl) at 0° C. Beads are harvested by centrifugation at 4° C., 20,000 g for 20 sec and resuspended in 15 microl of (24 mM Tris-Cl pH 6.8, 4% glycerol, 50 mM dithiotreitol, 0.04% bromophenol-blue) and incubated for 20 min at 37° C. The supernatant is analyzed on Western blots (BioRad Criterion XT gels, 3-8% polyacrylamide #3450131). Western blots are probed with a rat antibody raised against CFTR (monoclonal 3G11), an antibody against a protein not expressed on the cell surface as a negative control (anti laminA, Sigma #L1293) and an antibody against a protein constitutively expressed on the cell surface as a positive control (E-cadherin, Abcam #ab1416). Secondary antibodies are: ECLTM anti-rabbit IgG, HRP-Linked whole Ab (from donkey) (GE Healthcare #NA934-1), ImmunoPure Goat Anti-Rat IgG, HRP conjugated (Thermo Scientific #31470), ImmunoPure Goat Anti-Mouse IgG, HRP conjugated (Thermo Scientific #31430). Development of the blots is performed with enhanced chemiluminescence on a Biorad ChemiDoc XRS. Quantification of the cell surface expression of ΔF508 CFTR was performed with Biorad Quantity One software.

[0231] Positive and negative controls for the biotinylation include incubation of cell culture at 27° C. for 48 hrs to correct misfolding and trafficking of ΔF508 CFTR, and omission of Ad-siRNAs respectively. No signal is detected when the biotinylation reagent was omitted. The cell surface expression of ΔF508 CFTR is quantitated relative to the signal obtained without Ad-siRNAs (relative to the E-cadherin signal, and set at 0) and the signal obtained at 27° C. for 48 hrs (relative to the E-cadherin signal, and set at 1). Quantification is performed both for band B ΔF508 CFTR (core glycosylated) and band C ΔF508 CFTR (fully glycosylated). The analysis of 142 hits yields 19 TARGETS that show expression of band C ΔF508 CFTR and band B ΔF508 CFTR on the cell surface of CFBE41o-cells upon Ad-siRNAs-mediated knock-down of that TARGET. These TARGETS are listed in Table 1.

TABLE-US-00005 TABLE 5 Cell surface exprerssion of CFTR ΔF508 in CFBE41o- cell culture upon TARGET Ad-siRNA application CFTRΔF508 C-band/ TARGET Gene SEQ ID NO: cell surface B-band Symbol DNA expression ratio UGT3A2 2 0.906 0.278 PHGDH 3 0.573 0.173 B3GNT3 4 0.113 0.121 PPIH 5 0.408 0.176 CELSR3 6 2.179 0.213 MC2R 7 1.082 0.412 MAS1L 8 0.179 0.289 LRRK2 9 1.293 0.280 NLRP1 10, 11, 12, 13, 14 0.761 0.718 PMS1 15, 16, 17 0.461 0.284 MAK 18 0.201 0.309 CPD 19 1.294 0.220 CST7 20 0.740 0.238 DUSP5 21 1.219 0.241 PTPRG 22 0.380 0.139 IL6R 23, 24 1.135 0.294 GHR 25 0.576 0.241 CSF3 26, 27, 28 1.663 0.223 SPNS1 29 0.276 0.305 low temperature positive control 1.000 0.754 rescue

Example 8

Analysis of the Trans-Epithelial Chloride Flux in CFTR ΔF508 Homozygous Primary Bronchial Epithelial Cells

[0232] A further validation of the correction of ΔF508 CFTR is the correction of trans-epithelial chloride transport in primary bronchial epithelial cell cultures from a CF patient, grown in a filter support. These well-differentiated primary human bronchial epithelial cell cultures derived from CF patients homozygous for the ΔF508 CFTR mutation show a residual forskolin and genistein-stimulated chloride flux that is less than 2% of non-CF control cell cultures. A standard drug addition protocol (Devor et al., 2000) can be used to detect transepithelial currents due to CFTR. Short-circuit current (I_sc) across HBE primary cultures can be measured as described (Myerburg et al., 2006; Myerburg et al., 2008). Cells cultured on filter supports are mounted in modified Ussing chambers, and the cultures are continuously short-circuited with an automatic voltage clamp (Physiological Instruments, San Diego, Calif.). The basolateral bathing solution composition is: 120 mM NaCl, 25 mM NaHCO₃, 3.3 mM KH₂PO₄, 0.8 mM K₂HPO₄, 1.2 mN MgCl₂, 1.2 mM CaCl₂, and 10 mM glucose. A basal-to-apical Cl gradient can be imposed by reducing the NaCl concentration of the apical bathing solution by replacing NaCl with equimolar Na-gluconate. The chambers are maintained at 37° C. and gassed continuously with a mixture of 95% O₂-5% CO₂ which fixed the pH at 7.4. Following a 5 min equilibration period, the baseline I_sc is recorded. Sodium currents are blocked by addition of the epithelial sodium channel (ENaC) blocker, amiloride (10 μM), to the apical bath. Subsequently, the cAMP agonist--forskolin (10 μM, Sigma), the CFTR potentiator--genistein (50 μM, Sigma), and the CFTR channel blocker--CFTRinh-172 (10 μM; Calbiochem, San Diego, Calif.) are added sequentially, at the current steady-state, to determine cAMP-stimulated CFTR currents. Addition of the CFTR inhibitor CFTRinh-172 is done to show specificity of ion flux through CFTR (Ma et al., 2002). Using this analysis, the transepithelial currents associated with knockdown of the targets are shown in Table 6. Each of these targets shows a significant increase in chloride transport across the epithelial monolayer. Interestingly, the level of CFTR response can reach up to 20% of wild-type CFTR-mediated currents, suggesting a clinically meaningful level of CFTR channel activity (Sheppard et al., 1993).

TABLE-US-00006 TABLE 6 Efficacy of the restoration of chloride transport in primary CF bronchial epithelial cell culture relevant to the present expression-inhibitory agent invention Forskolin-Genistein induced chloride flux in CF primary TARGET Gene epithelial cells compared to Symbol SEQ ID NO: DNA control cells (non-CF) UGT3A2 2 22.9% PHGDH 3 6.6% B3GNT3 4 4.7% PPIH 5 9.1% CELSR3 6 11.8% MC2R 7 6.8% MAS1L 8 6.6% LRRK2 9 15.9% NLRP1 10, 11, 12, 13, 14 9.0% PMS1 15, 16, 17 9.3% MAK 18 9.5% CPD 19 14.8% CST7 20 10.7% DUSP5 21 15.5% PTPRG 22 10.7% IL6R 23, 24 19.9% GHR 25 11.6% CSF3 26, 27, 28 9.4% SPNS1 29 13.4%

[0233] In the table above the knock-down sequence corresponding to SEQ 57 was used, which demonstrates a specific effect with UGT3A2. However due to the close homology and the high level of sequence identity between UGT3A2 and UGT3A1 it would be expected that a knock down of UGT3A1 would have a similar effect on the restoration of chloride transport in primary CF bronchial epithelial cells.

REFERENCES

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[0235] Bilan, F., V. Thoreau, M. Nacfer, R. Derand, C. Norez, A. Cantereau, M. Garcia, F. Becq, and A. Kitzis. 2004. Syntaxin 8 impairs trafficking of cystic fibrosis transmembrane conductance regulator (CFTR) and inhibits its channel activity. J Cell Sci. 117:1923-35.

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[0239] Devor, D. C., Bridges, R. J., and Pilewski, J. M. (2000). Pharmacological modulation of ion transport across wild-type and DeltaF508 CFTR-expressing human bronchial epithelia. Am J Physiol Cell Physiol 279, C461-479.

[0240] Fischer, D. F., A. K. Scaffidi, S. Griffioen, M. Roseboom, and R. A. Janssen. 2006. Identification of novel drug targets to treat cystic fibrosis using adenoviral knock-down technology. Ped Pulmonol. 41:Suppl. 29, p. 209.

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[0246] Lambert, G., B. Becker, R. Schreiber, A. Boucherot, M. Reth, and K. Kunzelmann. 2001. Control of Cystic Fibrosis Transmembrane Conductance Regulator Expression by BAP31. J Biol. Chem. 276:20340-20345.

[0247] Li, H., D. N. Sheppard, and M. J. Hug. 2004. Transepithelial electrical measurements with the Ussing chamber. J Cyst Fibros. 3 Suppl 2:123-6.

[0248] Ma, L., H. A. Bluyssen, M. De Raeymaeker, V. Laurysens, N. van der Beek, H. Pavliska, A. J. van Zonneveld, P. Tomme, and H. H. van Es. 2001. Rapid determination of adenoviral vector titers by quantitative real-time PCR. J Virol Methods. 93:181-8.

[0249] Ma, T., Thiagarajah, J. R., Yang, H., Sonawane, N. D., Folli, C., Galietta, L. J., and Verkman, A. S. (2002). Thiazolidinone CFTR inhibitor identified by high-throughput screening blocks cholera toxin-induced intestinal fluid secretion. J Clin Invest 110, 1651-1658.

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[0259] All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.

[0260] From the foregoing description, various modifications and changes in the compositions and methods of this invention will occur to those skilled in the art. All such modifications coming within the scope of the appended claims are intended to be included therein.

Sequence CWU 1

1

10312824DNAHomo sapiens 1daacgaacag aagggcgaga gaattggcag gatccgtctc ctacctcttc ctaggcccac 60agccagtgcc tttggagtac tgaggcgcgc acagagtcct tagcccggcg cagggcgcgc 120agcccaggct gagatccgct gcttctgtgg aagtgagcat ggttgggcag cgggtgctgc 180ttctagtggc cttccttctt tctggggtcc tgctctcaga ggctgccaaa atcctgacaa 240tatctacact gggtggaagc cattacctac tgttggaccg ggtgtctcag attcttcaag 300agcatggtca taatgtgact atgcttcatc agagtggaaa gtttttgatc ccagatatta 360aagaggagga aaaatcatac caagttatca ggtggttttc acctgaagat catcaaaaaa 420gaattaagaa gcattttgat agctacatag aaacagcatt ggatggcaga aaagaatctg 480aagcccttgt aaagctaatg gaaatatttg ggactcaatg tagttatttg ctaagcagaa 540aggatataat ggattcctta aagaatgaga actgtgatct ggtatttgtt gaagcatttg 600atttctgttc tttcctgatt gctgagaagc ttgtgaaacc atttgtggcc attcttccca 660ccacattcgg ctctttggat tttgggctac caagcccctt gtcttatgtt ccagtattcc 720cttccttgct gactgatcac atggacttct ggggccgagt gaagaatttt ctgatgttct 780ttagtttctc caggagccaa tgggacatgc agtctacatt tgacaacacc atcaaggagc 840atttcccaga aggctctagg ccagttttgt ctcatcttct actgaaagca gagttgtggt 900ttgttaactc tgattttgcc tttgattttg cccggcccct gcttcccaac actgtttata 960ttggaggctt gatggaaaaa cctattaaac cagtaccaca agacttggac aacttcattg 1020ccaactttgg ggatgcaggg tttgtccttg tggcctttgg ctccatgttg aacacccatc 1080agtcccagga agtcctcaag aagatgcaca atgcctttgc ccacctccct caaggagtga 1140tatggacatg tcagagttct cattggccca gagatgttca tttggccaca aatgtgaaaa 1200ttgtggactg gcttcctcag agtgacctcc tggctcaccc cagcatccgt ctttttgtca 1260ctcatggtgg gcagaacagc gtaatggaga ccatccgtca tggtgtgccc atggtgggat 1320taccagtcaa tggagaccag catggaaaca tggtccgagt agtagccaaa aattatggtg 1380tctctatccg gttgaatcag gtcacagccg acacactgac acttacaatg aaacaagtca 1440tagaagacaa gaggtacaag tcggcagtgg tggcagccag tgtcatcctg cactctcagc 1500ccctgagccc cgcacagcgg ctggtgggct ggatcgacca catcctccag actgggggag 1560cgacgcacct caagccctat gtcttccagc agccttggca tgagcagtac ctcattgatg 1620tctttgtgtt tctgctgggg ctcactctgg gcactatgtg gctttgtggg aagctgctgg 1680gtgtggtggc caggtggctg cgtggggcca ggaaggtgaa gaagacatga ggctaggtgt 1740agccttgggt gaggggaggg catccctggt cctttgaagg ttctccccac cccagcacac 1800gccacccctc tgttctctct tcagctccac ccgccactga tcctgcaact tgcttctttc 1860tattctctgc ctctgtttag aaatcttcac acaccactga ggcttcttga cttgcccctt 1920gtgacttgaa accccagctc agatacaaat tttcacctgc cagccctgcc tcctcctttc 1980tcccttttcc tagacacagg actctgacaa cttcatcctc cttgtttaga tgacttccca 2040gtttccagtc cccatttctc cttctatcac ttttcataaa aaaactcagg aaatatttga 2100catatcttcc atttcaaatt cttccatttt atgcagatat cttgcccttc ctataagctc 2160tcctcaaagc tcaggaaacc tggtctgctc tcctgcattt agggaaggag aacccctgcc 2220aagacctttg ctcactgcct gagacccctt ccttagagag cacctccttt gctggtcaga 2280catggagcct gcagttggtc acagatgata ctgctttatt tcagttttta cagttgcctt 2340cttaagattc ccgtcttata aatggagtac agggaacctc aagtagtgaa gtggaaatcc 2400atgtgtaagg ctttgtggct tcaggtacca gtggctaagg tagttttaaa gactttgttg 2460attttagaaa aagtccatct tccatcccct acatggcagt taataccctt ctatatggta 2520aaaccttaga gattacctta atctgctagg aacagaagca agaaaaacca tggcgtaaac 2580acccccagag tttttgttca tttgtttcat ctttcttgat aaagcccgaa ggtagcccat 2640tcagggctgt tgtggttggt tgctccatca tgtcatcaat agcccatatc ttttcttttt 2700tatcttcctt agtataacac caaactacct ctctgatagc tggtgttcat gaaatatttt 2760accttcaaat gattgtacct ttttatttgc tttagagttc tgaaataaaa tgaaattcca 2820ctgt 282422341DNAHomo sapiens 2agtgcctttg gcgcactgag gtgcacaggg tcccttagcc gggcgcaggg cgcgcagccc 60aggctgagat ccgcggcttc cgtagaagtg agcatggctg ggcagcgagt gcttcttcta 120gtgggcttcc ttctccctgg ggtcctgctc tcagaggctg ccaaaatcct gacaatatct 180acagtaggtg gaagccatta tctactgatg gaccgggttt ctcagattct tcaagatcac 240ggtcataatg tcaccatgct taaccacaaa agaggtcctt ttatgccaga ttttaaaaag 300gaagaaaaat catatcaagt tatcagttgg cttgcacctg aagatcatca aagagaattt 360aaaaagagtt ttgatttctt tctggaagaa actttaggtg gcagaggaaa atttgaaaac 420ttattaaatg ttctagaata cttggcgttg cagtgcagtc attttttaaa tagaaaggat 480atcatggatt ccttaaagaa tgagaacttc gacatggtga tagttgaaac ttttgactac 540tgtcctttcc tgattgctga gaagcttggg aagccatttg tggccattct ttccacttca 600ttcggctctt tggaatttgg gctaccaatc cccttgtctt atgttccagt attccgttcc 660ttgctgactg atcacatgga cttctggggc cgagtgaaga attttctgat gttctttagt 720ttctgcagga ggcaacagca catgcagtct acatttgaca acaccatcaa ggaacatttc 780acagaaggct ctaggccagt tttgtctcat cttctactga aagcagagtt gtggttcatt 840aactctgact ttgcctttga ttttgctcga cctctgcttc ccaacactgt ttatgttgga 900ggcttgatgg aaaaacctat taaaccagta ccacaagact tggagaactt cattgccaag 960tttgaggact ctggttttgt ccttgtgacc ttgggctcca tggtgaacac ctgtcagaat 1020ccggaaatct tcaaggagat gaacaatgcc tttgctcacc taccccaagg ggtgatatgg 1080aagtgtcagt gttctcattg gcccaaagat gtccacctgg ctgcaaatgt gaaaattgtg 1140gactggcttc ctcagagtga cctcctggct cacccaagca tccgtctgtt tgtcacccac 1200ggcgggcaga atagcataat ggaggccatc cagcatggtg tgcccatggt ggggatccct 1260ctctttggag accagcctga aaacatggtc cgagtagaag ccaaaaagtt tggtgtttct 1320attcagttaa agaagctcaa ggcagagaca ttggctctta agatgaaaca aatcatggaa 1380gacaagagat acaagtccgc ggcagtggct gccagtgtca tcctgcgctc ccacccgctc 1440agccccacac agcggctggt gggctggatt gaccacgtcc tccagacagg gggcgcgacg 1500cacctcaagc cctatgtctt tcagcagccc tggcatgagc agtacctgct cgacgttttt 1560gtgtttctgc tggggctcac tctggggact ctatggcttt gtgggaagct gctgggcatg 1620gctgtctggt ggctgcgtgg ggccagaaag gtgaaggaga cataaggcca ggtgcagcct 1680tggcggggtc tgtttggtgg gcgatgtcac catttctagg gagcttccca ctagttctgg 1740cagccccatt ctctagtcct tctagttatc tcctgttttc ttgaagaaca ggaaaaatgg 1800ccaaaaatca tcctttccac ttgctaattt tgctacaaat tcatccttac tagctcctgc 1860ctgctagcag aattctttcc agtcctcttg tcctcctttg tttgccatca gcaagggcta 1920tgctgtgatt ctgtctctga gtgacttgga ccactgaccc tcagatttcc agccttaaaa 1980tccaccttcc ttctcatgcg cctctccgaa tcacaccctg actcttccag cctccatgtc 2040cagacctagt cagcctctct cactcctgcc cctactatct atcatggaat aacatccaag 2100aaagacacct tgcatattct ttcagtttct gttttgttct cccacatatt ctcttcaatg 2160ctcaggaagc ctgccctgtg cttgagagtt cagggccgga cacaggctca caggtctcca 2220cattgggtcc ctgtctctgg tgcccacagt gagctccttc ttggctgagc aggcatggag 2280actgtaggtt tccagatttc ctgaaaaata aaagtttaca gcgttatctc tccccaacct 2340c 234131968DNAHomo sapiens 3gaggaggagg aggagatgac tggggagcgg gagctcgaga atactgccca gttactctag 60cgcgccaggc cgaaccgcag cttcttggct taggtacttc tactcacagc ggccgattcc 120gaggccaact ccagcaatgg cttttgcaaa tctgcggaaa gtgctcatca gtgacagcct 180ggacccttgc tgccggaaga tcttgcaaga tggagggctg caggtggtgg aaaagcagaa 240ccttagcaaa gaggagctga tagcggagct gcaggactgt gaaggcctta ttgttcgctc 300tgccaccaag gtgaccgctg atgtcatcaa cgcagctgag aaactccagg tggtgggcag 360ggctggcaca ggtgtggaca atgtggatct ggaggccgca acaaggaagg gcatcttggt 420tatgaacacc cccaatggga acagcctcag tgccgcagaa ctcacttgtg gaatgatcat 480gtgcctggcc aggcagattc cccaggcgac ggcttcgatg aaggacggca aatgggagcg 540gaagaagttc atgggaacag agctgaatgg aaagaccctg ggaattcttg gcctgggcag 600gattgggaga gaggtagcta cccggatgca gtcctttggg atgaagacta tagggtatga 660ccccatcatt tccccagagg tctcggcctc ctttggtgtt cagcagctgc ccctggagga 720gatctggcct ctctgtgatt tcatcactgt gcacactcct ctcctgccct ccacgacagg 780cttgctgaat gacaacacct ttgcccagtg caagaagggg gtgcgtgtgg tgaactgtgc 840ccgtggaggg atcgtggacg aaggcgccct gctccgggcc ctgcagtctg gccagtgtgc 900cggggctgca ctggacgtgt ttacggaaga gccgccacgg gaccgggcct tggtggacca 960tgagaatgtc atcagctgtc cccacctggg tgccagcacc aaggaggctc agagccgctg 1020tggggaggaa attgctgttc agttcgtgga catggtgaag gggaaatctc tcacgggggt 1080tgtgaatgcc caggccctta ccagtgcctt ctctccacac accaagcctt ggattggtct 1140ggcagaagct ctggggacac tgatgcgagc ctgggctggg tcccccaaag ggaccatcca 1200ggtgataaca cagggaacat ccctgaagaa tgctgggaac tgcctaagcc ccgcagtcat 1260tgtcggcctc ctgaaagagg cttccaagca ggcggatgtg aacttggtga acgctaagct 1320gctggtgaaa gaggctggcc tcaatgtcac cacctcccac agccctgctg caccagggga 1380gcaaggcttc ggggaatgcc tcctggccgt ggccctggca ggcgcccctt accaggctgt 1440gggcttggtc caaggcacta cacctgtact gcaggggctc aatggagctg tcttcaggcc 1500agaagtgcct ctccgcaggg acctgcccct gctcctattc cggactcaga cctctgaccc 1560tgcaatgctg cctaccatga ttggcctcct ggcagaggca ggcgtgcggc tgctgtccta 1620ccagacttca ctggtgtcag atggggagac ctggcacgtc atgggcatct cctccttgct 1680gcccagcctg gaagcgtgga agcagcatgt gactgaagcc ttccagttcc acttctaacc 1740ttggagctca ctggtccctg cctctggggc ttttctgaag aaacccaccc actgtgatca 1800atagggagag aaaatccaca ttcttgggct gaacgcgggc ctctgacact gcttacactg 1860cactctgacc ctgtagtaca gcaataaccg tctaataaag agcctacccc caaaaaaaaa 1920aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 196842720DNAHomo sapiens 4agaggggcgg gagctctggc tcaggtaaaa actctttctt cggctcgcga gctgagagga 60gcaggtagag gggcagaggc gggactgtcg tctgggggag ccgcccagga ggctcctcag 120gccgacccca gaccctggct ggccaggatg aagtatctcc ggcaccggcg gcccaatgcc 180accctcattc tggccatcgg cgctttcacc ctcctcctct tcagtctgct agtgtcacca 240cccacctgca aggtccagga gcagccaccg gcgatccccg aggccctggc ctggcccact 300ccacccaccc gcccagcccc ggccccgtgc catgccaaca cctctatggt cacccacccg 360gacttcgcca cgcagccgca gcacgttcag aacttcctcc tgtacagaca ctgccgccac 420tttcccctgc tgcaggacgt gcccccctct aagtgcgcgc agccggtctt cctgctgctg 480gtgatcaagt cctcccctag caactatgtg cgccgcgagc tgctgcggcg cacgtggggc 540cgcgagcgca aggtacgggg tttgcagctg cgcctcctct tcctggtggg cacagcctcc 600aacccgcacg aggcccgcaa ggtcaaccgg ctgctggagc tggaggcaca gactcacgga 660gacatcctgc agtgggactt ccacgactcc ttcttcaacc tcacgctcaa gcaggtcctg 720ttcttacagt ggcaggagac aaggtgcgcc aacgccagct tcgtgctcaa cggggatgat 780gacgtctttg cacacacaga caacatggtc ttctacctgc aggaccatga ccctggccgc 840cacctcttcg tggggcaact gatccaaaac gtgggcccca tccgggcttt ttggagcaag 900tactatgtgc cagaggtggt gactcagaat gagcggtacc caccctattg tgggggtggt 960ggcttcttgc tgtcccgctt cacggccgct gccctgcgcc gtgctgccca tgtcttggac 1020atcttcccca ttgatgatgt cttcctgggt atgtgtctgg agcttgaggg actgaagcct 1080gcctcccaca gcggcatccg cacgtctggc gtgcgggctc catcgcaacg cctgtcctcc 1140tttgacccct gcttctaccg agacctgctg ctggtgcacc gcttcctacc ttatgagatg 1200ctgctcatgt gggatgcgct gaaccagccc aacctcacct gcggcaatca gacacagatc 1260tactgagtca gcatcagggt ccccagcctc tgggctcctg tttccatagg aaggggcgac 1320accttcctcc caggaagctg agacctttgt ggtctgagca taagggagtg ccagggaagg 1380tttgaggttt gatgagtgaa tattctggct ggcgaactcc tacacatcct tcaaaaccca 1440cctggtactg ttccagcatc ttccctggat ggctggagga actccagaaa atatccatct 1500tctttttgtg gctgctaatg gcagaagtgc ctgtgctaga gttccaactg tggatgcatc 1560cgtcccgttt gagtcaaagt cttacttccc tgctctcacc tactcacaga cgggatgcta 1620agcagtgcac ctgcagtggt ttaatggcag ataagctccg tctgcagttc caggccagcc 1680agaaactcct gtgtccacat agagctgacg tgagaaatat ctttcagccc aggagagagg 1740ggtcctgatc ttaacccttt cctgggtctc agacaactca gaaggttggg gggataccag 1800agaggtggtg gaataggacc gccccctcct tacttgtggg atcaaatgct gtaatggtgg 1860aggtgtgggc agaggaggga ggcaagtgtc ctttgaaagt tgtgagagct cagagtttct 1920ggggtcctca ttaggagccc ccatccctgt gttccccaag aattcagaga acagcactgg 1980ggctggaatg atctttaatg ggcccaaggc caacaggcat atgcctcact actgcctgga 2040gaagggagag attcaggtcc tccagcagcc tccctcaccc agtatgtttt acagattacg 2100gggggaccgg gtgagccagt gaccccctgt agcccccagc ttcaggcctc agtgtctgcc 2160agtcaagctt cacaggcatt gtgatggggc agccttgggg aatataaaat tttgtgaaga 2220cttggagatc tttttttttt tttaagcaaa tttacaagtt tcaacagaca agtccacatt 2280catccctaaa agtctcattt tccagtagaa aatatacact ggtaaaaacg gggcatgggg 2340ccgtggctca gggctgtaat tctagcacat tgggagacca aagtgggagg atcacttgag 2400cccaggagtt ctggatcctg tctctgcaca aaataaaaaa ttactcaggc gtggtggtgc 2460tcacatgcct gtagtcccag ctatacttgg gaggctgagg cgagaggatc gcttgagccc 2520aggagttgga ggctgcagtg aaccatgatt gcgccactgt actccactgg gcggcaataa 2580gaagacaaaa acataaaaca ggacatgtgt gaggcaaaag ctgcaggaat ttctatcagg 2640cagatctgac ctcatcccac ccaccccctg ctcagatacc cttcatagct ccttattgct 2700ttcagctcat aaccccacat 27205813DNAHomo sapiens 5gaaatccgcg gaccgggctt taggttcgcc ggaatcccac gctcccgact tctgcttccg 60ggtcggagcc atggcggtgg caaattcaag tcctgttaac cccgtggtgt tctttgatgt 120cagtattggc ggtcaggaag ttggccgcat gaagatcgag ctctttgcag acgttgtgcc 180taagacggcc gagaacttta ggcagttctg caccggagaa ttcaggaaag atggggttcc 240aataggatac aaaggaagca ccttccacag ggtcataaag gatttcatga ttcagggtgg 300agattttgtt aatggagatg gtactggagt cgccagtatt taccgggggc catttgcaga 360tgaaaatttt aaacttagac actcagctcc aggcctgctt tccatggcga acagtggtcc 420aagtacaaat ggctgtcagt tctttatcac ctgctctaag tgcgattggc tggatgggaa 480gcatgtggtg tttggaaaaa tcatcgatgg acttctagtg atgagaaaga ttgagaatgt 540tcccacaggc cccaacaata agcccaagct acctgtggtg atctcgcagt gtggggagat 600gtagtccaga caaagactga atcaggcctt cccttcttct tggtggtgtt cttgagtaag 660ataatctgga ctggcccccg tctttgcttc cctgcctgct gctgccccat ttgatcaaga 720gaccatggaa gtgtcagaga ttcagaatcc aagattgtct ttaagttttc aactgtaaat 780aaagtttttt tgtatgcgta aaaaaaaaaa aaa 813611974DNAhomo sapiens 6agcgaaccat cggggcggcc gggagccatg ttggagcggc gggaggcggc agcagcgtcg 60gggatgctgt ggtgggggcg gaaaaagcca gggccgcacg ccggaggggc tccggccgcg 120gagtagatgg tgcccagagg gcggcggggg tgcggagaga caggcggagg ggcgggggcc 180cggggcggcg gcaggggccc gggagggggc ccgagcggcg gggccagccc aaggcccgga 240ccggggcggg gggcggtgga ggccgtgcag ggaggcgggg gatgatggcg aggcggccgc 300cgtggcgggg cctcggggga cggtcgaccc ccatactcct gctccttctc ctctctttgt 360tccccctcag ccaggaggag ctggggggcg gtgggcacca gggctgggac ccaggcttag 420ctgccactac ggggccaagg gcgcatatcg gtggcggagc cttagctctt tgtccggagt 480cttccggggt ccgggaggat ggggggcctg gcctgggggt cagggagcct atcttcgtgg 540ggctccgagg gagaaggcaa agcgcccgga atagtcgagg gccccctgag cagccgaatg 600aggagctggg gattgaacac ggcgtccagc cattgggcag ccgcgaacga gagacaggac 660agggaccagg gtctgtgtta tactggcgcc cagaggtctc ctcttgcggg cggacaggac 720ctttgcaaag aggtagtctg tcaccagggg ctctgtcctc aggggtcccg ggctcgggga 780acagctcgcc cctcccttca gactttttga ttcggcacca cggtcccaag ccggtgtcct 840cccagcggaa cgctgggaca ggctcccgca aaagagtggg caccgcgcgc tgctgtgggg 900aattatgggc aacagggagc aagggtcagg gcgagagagc cacgacatcc ggagcagaaa 960ggacagcccc ccggcggaac tgtcttccag gggcctcggg atctggcccc gagctggatt 1020cagcaccacg cacggcgagg acagctcctg catcaggttc agcaccccgc gagtctcgga 1080cagctcccga gccggcgccc aagcgcatgc gctcccgggg tctcttccgc tgccgcttcc 1140tcccgcagcg ccccgggccg cgtcccccgg gactcccggc ccgtcctgaa gccaggaaag 1200taacctcggc gaaccgggca cgctttcgtc gcgccgcaaa ccgccacccg cagtttccgc 1260agtacaacta ccagacgctg gtgccggaga atgaggcagc aggcaccgcg gtgctacgcg 1320tggttgctca ggacccggac gccggcgagg ccgggcgcct agtctactcg ctggcggcac 1380tcatgaacag ccgctcgctg gagctgttca gcatcgaccc gcagagcggc cttatccgta 1440cggcggcagc tctggaccgc gagagcatgg agcgtcacta cctgcgtgtg accgcgcagg 1500accacgggtc gccgcgcctc tcggccacca cgatggtggc cgtgacagta gccgaccgca 1560acgaccactc gccggttttt gagcaagcgc agtaccggga gacccttcgc gagaatgtgg 1620aggagggcta ccctatcctg cagctgcgtg ccactgacgg cgacgcgccc cccaacgcca 1680acctgcgcta ccgcttcgtg gggccgccag ctgcgcgcgc tgcagctgcc gccgccttcg 1740agattgatcc acgctccggc ctcatcagca ccagcggccg agtggaccgc gagcacatgg 1800aaagctatga gctggtggtg gaagccagcg accagggcca ggaacccggg ccgcgctcgg 1860ccactgtgcg cgtacacata actgtgctag acgagaacga caatgctcct cagttcagcg 1920agaagcgcta cgtggcgcag gtgcgcgagg atgtgcgccc ccacacagtc gtgctgcgcg 1980tcacggccac tgaccgggac aaggacgcca acggattggt gcactacaac atcatcagtg 2040gcaatagccg tggacacttt gccatcgaca gcctcactgg cgagatccag gtggtggcac 2100ctctggactt cgaggcagag agagagtatg ccttgcgcat cagggcgcag gatgctggcc 2160ggccaccgct gtccaacaac acgggcctgg ccagcatcca ggtggtggac atcaatgacc 2220acattcctat ttttgtcagc acgcccttcc aagtttctgt cttggaaaat gctcccttgg 2280gtcactcagt catccacatt caggcagtcg atgcagacca tggggagaat gccagattgg 2340agtactccct aactggtgtg gcacctgata ctccttttgt gataaacagc gccactggct 2400gggtctctgt gagtggtccc ctggaccgtg agtctgtgga gcattacttc tttggtgtgg 2460aggctcgaga ccatggctca cccccactct ctgcctcagc cagtgtcacc gtgactgtgc 2520tggacgttaa tgacaatcgg cctgagttca caatgaagga gtaccaccta cgactgaatg 2580aggatgcagc tgtgggcacc agtgtggtca gcgtgaccgc agtagaccgt gatgccaaca 2640gtgccatcag ctaccagatc acaggcggca acacccggaa tcgctttgcc atcagcaccc 2700aggggggtgt gggtctggtg actctggctc tgccactgga ctacaagcag gaacgctact 2760tcaagctggt actaactgca tctgaccgtg cccttcatga tcactgctat gtgcacatca 2820acatcacaga tgccaacact catcggccgg tctttcaaag tgcccactac tcagtgagtg 2880tgaatgaaga tcggccaatg ggtagcacca tagtggtcat cagtgcctct gatgatgacg 2940tgggtgagaa tgctcgtatc acctatctcc tggaggacaa cctgccccag ttccgcattg 3000atgcagactc aggagccatt acattacagg ccccattaga ctatgaggac caggtgacct 3060acaccctggc tatcacagct cgggacaatg gcatcccaca gaaggcagac actacttatg 3120tggaggtgat ggtcaatgac gtgaatgaca atgctccaca atttgtggcc tcccactata 3180cagggctggt ctctgaggat gccccacctt tcaccagtgt cctgcagatc tcagccactg 3240accgggatgc tcatgccaat ggccgggtcc agtacacttt ccagaatggt gaagatgggg 3300atggagattt taccattgag cccacctctg gaattgtccg tacagtaagg cggctagacc 3360gggaggcagt atcagtgtat gagttgactg cctacgcagt ggacagaggt gtgcccccac 3420tccggactcc agtcagtatc caggtgatgg tgcaggatgt gaacgacaat gcacctgtct 3480tcccagctga ggagtttgag gtgcgggtga aagagaatag cattgtgggc tcagtggtgg 3540cccagatcac tgcagtggac cctgacgaag gccccaatgc ccatataatg taccagatcg 3600tggaggggaa catccctgag ctgttccaaa tggacatctt ctctggagaa ctgacggcac 3660tcattgacct agactatgag gctcgccaag aatatgtgat tgtggtgcag gccacatctg 3720ctcctttggt cagccgggcc actgtgcacg tccgcctggt tgaccagaat gacaacagcc 3780ctgtgctcaa caacttccag atcctcttca acaactatgt atccaaccgt tcagacacct 3840tcccgtcggg cattattggg cgcatcccag cttatgaccc cgatgtctcc gaccacctct 3900tctactcctt tgagcgtggc aatgagctgc agctgctggt agtcaaccag accagtgggg 3960agctgcgact cagccgaaag ctagacaata accgcccact ggtggcctcc atgttggtga 4020ctgtcacaga tggcctgcac agcgtgacgg cgcagtgtgt gctgcgcgtg gtcatcatca

4080cggaggagtt gctggccaac agcctgaccg tgcgccttga gaacatgtgg caggagcgct 4140tcctgtcacc gctgctgggc cgcttcctcg agggcgtggc tgcggtgctc gctacgcccg 4200ctgaggacgt cttcatcttc aacatccaga acgacacaga cgtagggggc accgtgctca 4260atgtgagttt ctcggcgcta gctccacgtg gggccggggc gggcgctgca gggccctggt 4320tcagctccga ggagctgcag gagcagttgt acgtgcgccg ggcggcgctg gcggctcgct 4380ccctgctcga cgtactgccc ttcgacgaca acgtgtgcct gcgagagccc tgtgagaact 4440acatgaaatg cgtgtccgtg ctccgctttg actcgtccgc gcccttcctg gcctcggcct 4500ccacgctgtt ccgacccatc cagcccatcg ctggcctgcg ctgccgctgc ccgcccggat 4560tcacgggaga cttttgcgag accgagctcg acctctgcta ctccaaccca tgtcgcaacg 4620gcggagcctg cgcgcggcgc gagggaggct acacgtgcgt ctgccgcccg cgcttcaccg 4680gagaggactg cgagctggac accgaggccg gccgctgcgt gccgggcgtc tgccgcaacg 4740ggggcacctg caccgacgcg cccaacggcg gctttcgctg ccagtgcccg gcaggcggcg 4800ccttcgaggg cccgcgctgc gaggtggctg cgcgctcctt cccgcccagt tcgttcgtca 4860tgtttcgcgg cctgcggcag cgattccacc ttacgctgtc cctctcgttc gcgacagtgc 4920agcagagcgg gctgctcttc tacaacgggc gcctgaacga gaagcacgac ttcctggccc 4980tggaactcgt ggctggccaa gtgcggctca catattccac gggtgaatcc aacaccgtgg 5040tcagccccac agttccaggg ggcttgagtg acgggcaatg gcatacagtg catctgagat 5100actacaacaa gccccggaca gatgccctag ggggtgcaca gggcccctcc aaggacaagg 5160tggctgtgct aagcgtggat gattgtgatg tggccgtggc tctgcagttt ggtgctgaga 5220ttggcaacta ctcatgcgcg gctgctggtg tgcaaacaag ctccaagaag tccctggacc 5280tgacgggccc tcttcttctg ggaggtgtcc ccaacctccc cgagaacttc cccgtatccc 5340ataaggactt catcggctgt atgcgggacc tgcacattga tggccgccga gtggacatgg 5400cggcttttgt cgcaaataat ggcaccatgg caggctgcca agccaagcta cacttttgtg 5460actcaggccc ctgcaagaac agtggcttct gctcggagcg ctggggcagc ttcagctgcg 5520actgccctgt gggcttcggc ggcaaagact gtcagcttac tatggcccat ccccaccatt 5580tccgtggcaa cggcacactg agctggaact ttggaagtga catggctgtg tctgtgccat 5640ggtacctggg gctggcattt cggacacggg caacgcaggg ggtcctgatg caagtgcagg 5700ctgggccaca cagcacgctc ctttgccagc tagatcgggg gttactgtct gtgacagtga 5760ccaggggctc gggccgtgct tcccatctcc ttctggacca ggtgactgtc agtgatggcc 5820ggtggcacga tctgcggctg gagttgcagg aggaaccagg tggccggcgg ggccaccatg 5880tccttatggt ctcactggac tttagcctct tccaggacac catggcggtg gggagtgagc 5940tgcagggcct gaaggtaaag cagctccacg tgggaggcct gccccccggc agtgcagagg 6000aggctcctca gggtctggtt ggctgcatcc agggggtgtg gctcggctcc acaccctctg 6060gctccccggc cctgctaccc cccagccacc gagtgaatgc ggagcctggc tgtgttgtga 6120ccaacgcctg tgcctctggg ccctgcccac ctcacgcaga ctgccgggac ctctggcaga 6180ccttttcttg cacctgccag ccaggttact acggcccagg ctgtgtggat gcctgcctcc 6240tgaacccctg tcagaaccag ggatcatgcc ggcacctgcc aggagccccc catggctata 6300cctgtgactg tgtgggtggc tatttcgggc accactgtga gcacaggatg gaccagcagt 6360gcccacgggg ctggtggggg agcccaacct gtggcccctg caactgtgat gttcacaaag 6420gttttgatcc caactgcaac aagacaaatg ggcagtgtca ctgcaaggag ttccactacc 6480gaccgcgggg cagtgactct tgcctcccat gtgactgcta ccctgtgggc tccacctcgc 6540gctcatgtgc accccacagc gggcagtgcc cctgtcgccc aggagccctt ggccgccagt 6600gcaacagctg tgacagtccc ttcgcagagg tgacagccag cggctgccgg gtgctctatg 6660atgcctgccc taagtccctg agatctggtg tgtggtggcc ccagacaaag tttggcgtcc 6720tggccacagt gccctgtccc cggggggccc tgggtgctgc tgtgcggctg tgtgatgagg 6780cccagggttg gctggagccc gacctcttca actgtacctc ccctgccttt cgagagctca 6840gtctgctgct ggatggccta gagctgaaca agacggcact ggataccatg gaggccaaga 6900agctggctca gcggctacgg gaggtgactg gccacactga ccactatttt agccaagatg 6960ttcgagtcac tgcccgcctg ctggcccacc tgctggcctt cgagagccat cagcagggct 7020tcgggctgac agccacacag gatgcccact tcaatgagaa tctgctgtgg gccggctctg 7080cactgcttgc cccagagaca ggggacttgt gggcggcgct ggggcagcgg gcccctgggg 7140gctccccagg cagcgcggga ctggtgaggc acctggagga gtatgcagcc acactcgcaa 7200ggaatatgga actcacatac ctgaatccca tggggctggt gacgcctaat atcatgctca 7260gcattgaccg catggagcac cccagttctc cccggggggc ccgtcgctac cctcgctacc 7320atagcaacct ctttcgaggc caggatgcct gggatcctca cacccatgtg ctgctgcctt 7380cccagtcccc acggccatcc ccatctgaag ttctgcccac aagcagcagc atagaaaact 7440ccaccacctc aagtgtggtc cccccaccag ccccgccaga gccagagcct gggatctcca 7500ttatcattct cctcgtttac cgcaccttag ggggactgct ccctgcccag ttccaggcag 7560aacgccgagg tgccaggctt cctcagaacc ccgtcatgaa ctccccggtg gtcagcgtgg 7620ctgtgttcca cggacgcaac ttcctaaggg gaatcctgga gtcccccatc agcctagagt 7680ttcgcctgct acagacagcg aatcggagca aggcgatctg tgtgcagtgg gacccacctg 7740gcctggcgga gcagcatggt gtgtggacag cacgggactg cgagctggtg cacaggaatg 7800ggtcccacgc acggtgtcgc tgcagccgga cagggacctt tggggtcctc atggatgcct 7860ctccccgtga gaggctggag ggcgacctgg agctgctggc tgtgttcacc cacgtggtcg 7920tggctgtgtc tgtggctgcg ctggtgctga ctgcagccat cctgctgagc ctgcgcagcc 7980tcaagtccaa tgtgcgtggg atccatgcca atgtggcagc cgccctgggg gtggcagagc 8040tcctcttcct gctggggatt cacaggaccc acaatcagct ggtgtgcact gcagtcgcca 8100tcctcctgca ctacttcttc ctcagcacct tcgcgtggct cttcgtgcag gggctgcacc 8160tctaccgcat gcaggttgag ccacgcaacg tggaccgcgg cgccatgcgc ttctaccatg 8220ccctgggctg gggcgtccct gctgtgctgc tgggccttgc tgtgggcctg gaccctgagg 8280gctatgggaa ccctgacttc tgctggatct cagtccacga gcccctcatc tggagctttg 8340ctggccctgt tgtcctggtc atagtgatga acgggaccat gtttctcctc gctgcccgca 8400catcctgctc cacagggcag agggaggcca agaagacctc tgcactgacc cttcgcagct 8460ccttcctgct gcttctgctg gtcagtgcct cctggctctt tgggctcctg gcagtcaacc 8520acagcatcct agccttccac tacctccatg ctggactctg cggcctccag ggcctggcgg 8580tgctgctgct cttctgtgtc ctaaatgcag atgctcgggc tgcctggatg ccagcctgtc 8640tgggcaggaa ggcagcgcct gaggaggcaa ggccagcacc tgggctggga cctggggcct 8700acaacaacac ggctctcttt gaggagagtg gcctcatccg catcactctg ggcgcctcca 8760ccgtctcctc tgtgagcagt gcccgctccg gccggaccca ggaccaggac agccagcggg 8820gccgcagcta cctcagggac aatgtcctgg ttcgacatgg ctcagccgct gaccacactg 8880accacagcct ccaggctcat gctggcccca ctgacctgga cgtggccatg ttccatcgag 8940atgctggcgc agactccgac tctgacagtg acctgtcctt ggaggaggag aggagtctct 9000ccattccatc ttcagaaagc gaggacaatg gccggacgcg ggggcgcttc caacggccac 9060tctgccgagc agcccagagt gagaggctcc tcacccaccc caaagatgtg gatggcaatg 9120acctcctgtc ctactggcca gccctggggg agtgcgaggc agccccctgt gctctgcaga 9180cttggggctc tgaaaggcgc ctggggctgg acaccagcaa ggatgcagct aacaacaacc 9240agccagaccc ggccctgacc agtggggatg agacttctct gggccgggcc cagcgccaga 9300ggaaaggcat cctgaagaac cggttgcaat acccactggt gccacagacc cgaggtgccc 9360ctgagctgtc ctggtgccgt gcagccacct tgggccaccg tgctgtgcca gctgcctctt 9420acggtcgcat ctatgctggc gggggcacgg gcagcctttc acagccagcc agccgctact 9480cttctagaga acagctggac ctgctcctcc ggcggcaact gagccgtgag cgactagagg 9540aagcccctgc ccctgttcta cgtcccctga gccggccagg gtcccaggaa tgcatggatg 9600ctgcaccagg ccgactggag cccaaagatc ggggcagcac cctgccacgg aggcagccac 9660ctcgggacta ccctggcgcc atggctggcc gcttcgggtc acgggatgcg ctcgacttag 9720gggcacctcg agagtggttg agcacgctgc ctccgccccg ccgcacccgg gaccttgacc 9780cacagccccc acctctgccc ctgtctcccc agcggcaact ctcaagggac cccctcttgc 9840catcccggcc gctggactct ctgtctagga gctcgaactc tcgggagcag ctggaccagg 9900tgcctagccg gcacccctca cgagaagccc ttgggccact cccgcagctg ctcagagcta 9960gggaggactc ggtcagtggc cccagccatg gcccctccac agaacagttg gacattcttt 10020cctccatcct tgcctctttc aactcctcgg ccctctcctc tgtgcaatct tcaagcacac 10080ccttgggccc tcacaccact gccacacctt ctgccacagc ctctgtgctt gggccctcca 10140cgccacgttc tgccacgtct cacagcatct cggagctgtc gccagactca gaagttccca 10200gaagtgaggg tcactcctga ggggatgacg gcgtggacga ggaacagctg agggcgacag 10260aggatctagg ctaacaggag agactccagg agtgggggca gatcccaagg cagcctcctg 10320ctccccagtg gtgggtgccc cagctctacc tggtgtggca gggctgaggc tccatgtgca 10380tctgtgagca tgcgtgtgac aggtgcagag acgggggact ggagggagac ttttatacgt 10440tttgtacctt tgtaaccaga gagatgctta tgttattttt cagcttttct gtctcctggg 10500gggtttgagg ctgggctggg agggggaggg agatagaggg agagatgcag tttgacccca 10560tttgggtcct gagcaaaccc tatgctcatc tctctctcct tcctggggtg gactcagatg 10620ggtgggacac atgccttcct ccccctattc cacccccaag ttgatctgag tatcgtcagg 10680ggcccaaagt acagaattgt tctttgcttt ttattgaatg ctccaaaggc caaacttctg 10740gggctggggg ttggtcttgg aaacaggggt cctctgactt cctcatgggg gcttgctcat 10800accgcccctc ctggtggatg tgtgtgttta ttatgtggag tccctgccac ttactgcctt 10860atgacctagg actgatgctg tggggtgctg gtggagcagc tgatgtcgtg tttacagagc 10920aaggcttccc tgtctcccac ggggaggggc tcgggcctct agtcagacat tcctgcagag 10980ggtcggtgga ggggtcattc acctgcccct gcagcaagca aaagttgtct gtggtgccat 11040ttgattccct gacactgccc cctgcttgaa ttgattccga agggtagggt gggaaggtga 11100gcaaagggag cagaaacaag ggaattcaag acccagaatg taggtgccac tgcctcctat 11160gtttacagga tcctccgtgg ccctaggcac ctgggctgca ggaagtgact ccgttccact 11220cctcctttat tcccttaaaa agggaaaaat gactgttacg accctgttca caaaactctt 11280acttttgcta ttttgtctgc tgtccagaac tgaagacttt aaaattttgt tactgtttac 11340aagtccagat tcaaaaaatg tttttacttt gtttacaact caaaactttg agttttacac 11400tttgtttaca gtagataatt ttttttcctt tgtttccaag tgaaaggtag ggaaagtggg 11460agagggactt ggaggaccca cctgtgagga ccctgacctg gccatcttga ggggttttct 11520aacccccagg tctcccaggc cgaaggtcag ccttgagtcc cgtttaacag cagatccaga 11580agaccttgag agtaggcgtc ctctaaccac gggggagagt ggctgtgcag ggctgggggg 11640tggtctgtgc agacacctcc tcacccacca ccccatgcat actcttggga agcagcttcc 11700tgggagatta gaaattctac ttccctgact ggagctaaat cccaccagcc aggacccaaa 11760ctctccttac cgagaaggac cccagctctt gaagggctga gtggcctgct gggggtggga 11820gggtgtcttt actatgtcct aggtttcgta gatgcccctc tctggggttc ccctcctcca 11880gcccagcggc cctctttcct gtctgtgtaa attgttccgt gaagccgcgc tctgttttgg 11940gaataaactt ctatagaaaa caaaaaaaaa aaaa 1197473652DNAhomo sapiens 7attccttctc attcattttg cccagaaagt tcctgcttca gagctgaagg tgattgggag 60attttaactt agatctccag caagtgctac aaggaagaaa agatcctgaa gaatcaatca 120agttttccgt gaagtcaagt ccaagtaaca tccccgcctt aaccacaagc aggagaaatg 180aagcacatta tcaactcgta tgaaaacatc aacaacacag caagaaataa ttccgactgt 240cctcgtgtgg ttttgccgga ggagatattt ttcacaattt ccattgttgg agttttggag 300aatctgatcg tcctgctggc tgtgttcaag aataagaatc tccaggcacc catgtacttt 360ttcatctgta gcttggccat atctgatatg ctgggcagcc tatataagat cttggaaaat 420atcctgatca tattgagaaa catgggctat ctcaagccac gtggcagttt tgaaaccaca 480gccgatgaca tcatcgactc cctgtttgtc ctctccctgc ttggctccat cttcagcctg 540tctgtgattg ctgcggaccg ctacatcacc atcttccacg cactgcggta ccacagcatc 600gtgaccatgc gccgcactgt ggtggtgctt acggtcatct ggacgttctg cacggggact 660ggcatcacca tggtgatctt ctcccatcat gtgcccacag tgatcacctt cacgtcgctg 720ttcccgctga tgctggtctt catcctgtgc ctctatgtgc acatgttcct gctggctcga 780tcccacacca ggaagatctc caccctcccc agagccaaca tgaaaggggc catcacactg 840accatcctgc tcggggtctt catcttctgc tgggccccct ttgtgcttca tgtcctcttg 900atgacattct gcccaagtaa cccctactgc gcctgctaca tgtctctctt ccaggtgaac 960ggcatgttga tcatgtgcaa tgccgtcatt gaccccttca tatatgcctt ccggagccca 1020gagctcaggg acgcattcaa aaagatgatc ttctgcagca ggtactggta gaatggctga 1080tccctggttt tagaatccat gggaataacg ttgccaagtg ccagaatagt gtaacattcc 1140aacaaatgcc agtgctcctc actggccttc cttccctaat ggatgcaagg atgatcccac 1200cagctagtgt ttctaatagc taggttctat gtgaacagtc ttattgtagg ggcaacctct 1260taactttgtg actggacaga taaaacgatg tagtaaaaga aggatagaat acaaagtatt 1320aggtaggtac aaaagtaatt aaggtttttg ccattacttt caatgaccaa aaattgcaat 1380tacttttgca ccaatctagt aaaacagcaa taaaaattca agggctttgg gctaaggcaa 1440agacttgctt tcctgtggac atctaacaag ccagttctga ggtggccttt ccaggtggag 1500gccattgcag ccaatttcca gaagttaagt acctggacat gcgactccag gcagaagatg 1560tagggtctct gtaagccaat aataaattgg aaggaatgca ttgctgcagc tgaatttgtc 1620tgtctcccac agccatgtgg aatctccacc ctcctctttc tccctgttag tctgatgtat 1680tgatgccacc tcagtttcag aaagtaggct gagtataaac tataaatgtc aaataacgag 1740cttcgagttt ccaatgataa atggaccttc tctgttagtc ttctttgctc actcagtatc 1800ccactggcct taaaaccctt tcctgttaca tttcctcatg ctttatgagc atacatttca 1860aaggaagaaa tgaaaattta atccatttag ttcccatgtg ggaatacata aaggccagat 1920gaaaattgtc actatttgaa gaagctgtaa ccaaactatg tgtgttacaa tgtagaagta 1980caagaaaaga gccccaacat gtattttaag aaataaagag agagagacag agacagacag 2040agagagagag agagagagag agagagagtg tgtgtgtgtg tgtgtgtgtg tgtgtgtgtg 2100tgtgtgtgtg tgtgtgtgta ttttccccat gcttttggac tatggggaaa accaaaacca 2160aagcaagaca tcaagcaatg gtgctgttat tatagcccca agtcaaagac ctgagggagg 2220caaacaccac ctcattctgc agatgaatgt gaaagcagac ccagtcactg ggaaatgtca 2280tcctcccatc agccaagatg ccagcaatgg aagagtggca accccagtag gaataaaaga 2340aacataattt gcaagttcat tcatttttaa tagctaaaaa tcagcttaaa ggagaagcac 2400atcctgattg taagtcccca ctaagttgga gggtgacttg aatggggtga aaggtgaaag 2460ggacagagga gagcagtggg gcttcagagg ccaccaggct caggatctgc aggatggatg 2520gtatcttcca gaacaggcaa tgctttgccc tcaggagaat ttcccagagc tgctgagggg 2580agaagacagc cacacacagg acagaccatt tggtgatggg tttgatatta gaagtggcag 2640ggacaggaac ttcagaagca aaggaggcaa ggcagctgga gtcaagtgag gacagtggca 2700ggcgtgcttt cacatggcct gtcccacaga tggaggtgaa aggtgcacct tcttgtcctc 2760tgttctgtag aaatccttcc ctgtttgatc cttcccctgc caaatgaact atgttactct 2820aatactaacc tgtattaatt aatatatgag atatatataa gttaattttt catgaaatct 2880aaagcacaac cctagaacta atttttaaaa gtgttatttc taccattgaa aaagtaatgt 2940ataacatatt ttatgtgatt aaagtgcgta ttctcaataa gaggtaacct ttttttgatg 3000ctgcaatgct ctgtgatacc acagaggtaa gcaatgccac ttaacctgta tcataaatag 3060tcccaaactg ctcttcctat aaaattctgc ctttgtcaac agctttgctg tctcctaatc 3120actctcaagc tctctgctgt gcatgtgact gttgtcagaa ggaaaatcac caagaaactt 3180cacctctcac tgcctttgat ttgttgcagt taatctaaga aacaaaatga agatggctag 3240tctaatggtg gatgaaacaa aaatgaagtc tgagtgctaa ttcagagaac ttgcaattcc 3300agacattttc aattctaggt cttctgctat attccaatca gaacagaagc ttcagggctc 3360atagttactg agaaaactca cgtttttcta cctctaactt catatagaat tccaaatgaa 3420agcaccacca aactgcacat atttgtgtga ggaagatcaa caagcttcag acttttccca 3480tgaggactta attcttttat caaattaccc aatttttaaa ctgctgtgtg gatactgtga 3540gtgttcagct ttatcgatga cctagccttg gaccagatag ctgaaaatgt tcaggatgtg 3600tactcaagct gatagtaatt ctgagccctg tctaataaaa aaggaaggat gt 365281137DNAhomo sapiens 8atggtctggg ggaaaatttg ctggttcagc cagagggctg gatggacagt gtttgctgag 60tcacagatat ctctctcatg tagcctttgt ctccacagtg gtgaccagga ggcacagaac 120ccaaacctgg tatctcagct ctgtggcgtc tttcttcaaa atgagacgaa tgaaaccata 180catatgcaga tgagcatggc agtgggacag caggccctgc ccttgaatat cattgccccc 240aaggctgtgc tggtctccct ctgtggggtc ttattgaatg gcactgtctt ctggctgctt 300tgctgtgggg ccacgaatcc ctacatggta tacatcctcc acctggtcgc tgctgacgtg 360atctatcttt gctgctcggc agtggggttc ttacaggtga ctctgctaac ttatcatgga 420gtcgtgtttt ttatccctga tttcctggcc atattgtctc ccttctcctt tgaggtgtgt 480ctctgtctcc tggtggccat cagcacagag cggtgtgtgt gtgtcctctt ccccatctgg 540tacagatgcc accgcccaaa atacacatct aatgttgtct gcaccctcat ctggggcctg 600cctttttgca tcaacatagt aaaatcactt ttcctaactt actggaaaca tgtaaaggca 660tgtgtcatat ttctaaagct ttctgggctc ttccatgcta tcctttcact tgtgatgtgt 720gtgtcgagtc tgactctact cattagattc ctgtgctgct cccagcagca aaaggccacc 780agggtctatg cggtggtgca gatctcggcc cccatgttcc tactctgggc cctacccctg 840agcgtggcac ccctcataac agatttcaaa atgtttgtca ccacctccta tttaatttcc 900ttgttcctca ttataaacag cagcgccaac cctatcattt atttctttgt ggggagcctc 960agaaagaaaa ggctgaagga atctctcaga gtgattctcc aacgggcgtt agcagataag 1020ccagaggtgg ggaggaacaa aaaggcagct ggcatcgacc caatggagca accacactct 1080actcagcatg tggagaacct tcttcccagg gagcacaggg tcgatgtgga aacataa 113799239DNAhomo sapiens 9gcgctggctg cgggcggtga gctgagctcg cccccgggga gctgtggccg gcgcccctgc 60cggttccctg agcagcggac gttcatgctg ggagggcggc gggttggaag caggtgccac 120catggctagt ggcagctgtc aggggtgcga agaggacgag gaaactctga agaagttgat 180agtcaggctg aacaatgtcc aggaaggaaa acagatagaa acgctggtcc aaatcctgga 240ggatctgctg gtgttcacgt actccgagca cgcctccaag ttatttcaag gcaaaaatat 300ccatgtgcct ctgttgatcg tcttggactc ctatatgaga gtcgcgagtg tgcagcaggt 360gggttggtca cttctgtgca aattaataga agtctgtcca ggtacaatgc aaagcttaat 420gggaccccag gatgttggaa atgattggga agtccttggt gttcaccaat tgattcttaa 480aatgctaaca gttcataatg ccagtgtaaa cttgtcagtg attggactga agaccttaga 540tctcctccta acttcaggta aaatcacctt gctgatattg gatgaagaaa gtgatatttt 600catgttaatt tttgatgcca tgcactcatt tccagccaat gatgaagtcc agaaacttgg 660atgcaaagct ttacatgtgc tgtttgagag agtctcagag gagcaactga ctgaatttgt 720tgagaacaaa gattatatga tattgttaag tgcgttaaca aattttaaag atgaagagga 780aattgtgctt catgtgctgc attgtttaca ttccctagcg attccttgca ataatgtgga 840agtcctcatg agtggcaatg tcaggtgtta taatattgtg gtggaagcta tgaaagcatt 900ccctatgagt gaaagaattc aagaagtgag ttgctgtttg ctccataggc ttacattagg 960taattttttc aatatcctgg tattaaacga agtccatgag tttgtggtga aagctgtgca 1020gcagtaccca gagaatgcag cattgcagat ctcagcgctc agctgtttgg ccctcctcac 1080tgagactatt ttcttaaatc aagatttaga ggaaaagaat gagaatcaag agaatgatga 1140tgagggggaa gaagataaat tgttttggct ggaagcctgt tacaaagcat taacgtggca 1200tagaaagaac aagcacgtgc aggaggccgc atgctgggca ctaaataatc tccttatgta 1260ccaaaacagt ttacatgaga agattggaga tgaagatggc catttcccag ctcataggga 1320agtgatgctc tccatgctga tgcattcttc atcaaaggaa gttttccagg catctgcgaa 1380tgcattgtca actctcttag aacaaaatgt taatttcaga aaaatactgt tatcaaaagg 1440aatacacctg aatgttttgg agttaatgca gaagcatata cattctcctg aagtggctga 1500aagtggctgt aaaatgctaa atcatctttt tgaaggaagc aacacttccc tggatataat 1560ggcagcagtg gtccccaaaa tactaacagt tatgaaacgt catgagacat cattaccagt 1620gcagctggag gcgcttcgag ctattttaca ttttatagtg cctggcatgc cagaagaatc 1680cagggaggat acagaatttc atcataagct aaatatggtt aaaaaacagt gtttcaagaa 1740tgatattcac aaactggtcc tagcagcttt gaacaggttc attggaaatc ctgggattca 1800gaaatgtgga ttaaaagtaa tttcttctat tgtacatttt cctgatgcat tagagatgtt 1860atccctggaa ggtgctatgg attcagtgct tcacacactg cagatgtatc cagatgacca 1920agaaattcag tgtctgggtt taagtcttat aggatacttg attacaaaga agaatgtgtt 1980cataggaact ggacatctgc tggcaaaaat tctggtttcc agcttatacc gatttaagga 2040tgttgctgaa atacagacta aaggatttca gacaatctta gcaatcctca aattgtcagc 2100atctttttct aagctgctgg tgcatcattc atttgactta gtaatattcc atcaaatgtc 2160ttccaatatc atggaacaaa aggatcaaca gtttctaaac ctctgttgca agtgttttgc 2220aaaagtagct atggatgatt acttaaaaaa tgtgatgcta gagagagcgt gtgatcagaa

2280taacagcatc atggttgaat gcttgcttct attgggagca gatgccaatc aagcaaagga 2340gggatcttct ttaatttgtc aggtatgtga gaaagagagc agtcccaaat tggtggaact 2400cttactgaat agtggatctc gtgaacaaga tgtacgaaaa gcgttgacga taagcattgg 2460gaaaggtgac agccagatca tcagcttgct cttaaggagg ctggccctgg atgtggccaa 2520caatagcatt tgccttggag gattttgtat aggaaaagtt gaaccttctt ggcttggtcc 2580tttatttcca gataagactt ctaatttaag gaaacaaaca aatatagcat ctacactagc 2640aagaatggtg atcagatatc agatgaaaag tgctgtggaa gaaggaacag cctcaggcag 2700cgatggaaat ttttctgaag atgtgctgtc taaatttgat gaatggacct ttattcctga 2760ctcttctatg gacagtgtgt ttgctcaaag tgatgacctg gatagtgaag gaagtgaagg 2820ctcatttctt gtgaaaaaga aatctaattc aattagtgta ggagaatttt accgagatgc 2880cgtattacag cgttgctcac caaatttgca aagacattcc aattccttgg ggcccatttt 2940tgatcatgaa gatttactga agcgaaaaag aaaaatatta tcttcagatg attcactcag 3000gtcatcaaaa cttcaatccc atatgaggca ttcagacagc atttcttctc tggcttctga 3060gagagaatat attacatcac tagacctttc agcaaatgaa ctaagagata ttgatgccct 3120aagccagaaa tgctgtataa gtgttcattt ggagcatctt gaaaagctgg agcttcacca 3180gaatgcactc acgagctttc cacaacagct atgtgaaact ctgaagagtt tgacacattt 3240ggacttgcac agtaataaat ttacatcatt tccttcttat ttgttgaaaa tgagttgtat 3300tgctaatctt gatgtctctc gaaatgacat tggaccctca gtggttttag atcctacagt 3360gaaatgtcca actctgaaac agtttaacct gtcatataac cagctgtctt ttgtacctga 3420gaacctcact gatgtggtag agaaactgga gcagctcatt ttagaaggaa ataaaatatc 3480agggatatgc tcccccttga gactgaagga actgaagatt ttaaacctta gtaagaacca 3540catttcatcc ctatcagaga actttcttga ggcttgtcct aaagtggaga gtttcagtgc 3600cagaatgaat tttcttgctg ctatgccttt cttgcctcct tctatgacaa tcctaaaatt 3660atctcagaac aaattttcct gtattccaga agcaatttta aatcttccac acttgcggtc 3720tttagatatg agcagcaatg atattcagta cctaccaggt cccgcacact ggaaatcttt 3780gaacttaagg gaactcttat ttagccataa tcagatcagc atcttggact tgagtgaaaa 3840agcatattta tggtctagag tagagaaact gcatctttct cacaataaac tgaaagagat 3900tcctcctgag attggctgtc ttgaaaatct gacatctctg gatgtcagtt acaacttgga 3960actaagatcc tttcccaatg aaatggggaa attaagcaaa atatgggatc ttcctttgga 4020tgaactgcat cttaactttg attttaaaca tataggatgt aaagccaaag acatcataag 4080gtttcttcaa cagcgattaa aaaaggctgt gccttataac cgaatgaaac ttatgattgt 4140gggaaatact gggagtggta aaaccacctt attgcagcaa ttaatgaaaa ccaagaaatc 4200agatcttgga atgcaaagtg ccacagttgg catagatgtg aaagactggc ctatccaaat 4260aagagacaaa agaaagagag atctcgtcct aaatgtgtgg gattttgcag gtcgtgagga 4320attctatagt actcatcccc attttatgac gcagcgagca ttgtaccttg ctgtctatga 4380cctcagcaag ggacaggctg aagttgatgc catgaagcct tggctcttca atataaaggc 4440tcgcgcttct tcttcccctg tgattctcgt tggcacacat ttggatgttt ctgatgagaa 4500gcaacgcaaa gcctgcatga gtaaaatcac caaggaactc ctgaataagc gagggttccc 4560tgccatacga gattaccact ttgtgaatgc caccgaggaa tctgatgctt tggcaaaact 4620tcggaaaacc atcataaacg agagccttaa tttcaagatc cgagatcagc ttgttgttgg 4680acagctgatt ccagactgct atgtagaact tgaaaaaatc attttatcgg agcgtaaaaa 4740tgtgccaatt gaatttcccg taattgaccg gaaacgatta ttacaactag tgagagaaaa 4800tcagctgcag ttagatgaaa atgagcttcc tcacgcagtt cactttctaa atgaatcagg 4860agtccttctt cattttcaag acccagcact gcagttaagt gacttgtact ttgtggaacc 4920caagtggctt tgtaaaatca tggcacagat tttgacagtg aaagtggaag gttgtccaaa 4980acaccctaag ggcattattt cgcgtagaga tgtggaaaaa tttctttcaa aaaaaaggaa 5040atttccaaag aactacatgt cacagtattt taagctccta gaaaaattcc agattgcttt 5100gccaatagga gaagaatatt tgctggttcc aagcagtttg tctgaccaca ggcctgtgat 5160agagcttccc cattgtgaga actctgaaat tatcatccga ctatatgaaa tgccttattt 5220tccaatggga ttttggtcaa gattaatcaa tcgattactt gagatttcac cttacatgct 5280ttcagggaga gaacgagcac ttcgcccaaa cagaatgtat tggcgacaag gcatttactt 5340aaattggtct cctgaagctt attgtctggt aggatctgaa gtcttagaca atcatccaga 5400gagtttctta aaaattacag ttccttcttg tagaaaaggc tgtattcttt tgggccaagt 5460tgtggaccac attgattctc tcatggaaga atggtttcct gggttgctgg agattgatat 5520ttgtggtgaa ggagaaactc tgttgaagaa atgggcatta tatagtttta atgatggtga 5580agaacatcaa aaaatcttac ttgatgactt gatgaagaaa gcagaggaag gagatctctt 5640agtaaatcca gatcaaccaa ggctcaccat tccaatatct cagattgccc ctgacttgat 5700tttggctgac ctgcctagaa atattatgtt gaataatgat gagttggaat ttgaacaagc 5760tccagagttt ctcctaggtg atggcagttt tggatcagtt taccgagcag cctatgaagg 5820agaagaagtg gctgtgaaga tttttaataa acatacatca ctcaggctgt taagacaaga 5880gcttgtggtg ctttgccacc tccaccaccc cagtttgata tctttgctgg cagctgggat 5940tcgtccccgg atgttggtga tggagttagc ctccaagggt tccttggatc gcctgcttca 6000gcaggacaaa gccagcctca ctagaaccct acagcacagg attgcactcc acgtagctga 6060tggtttgaga tacctccact cagccatgat tatataccga gacctgaaac cccacaatgt 6120gctgcttttc acactgtatc ccaatgctgc catcattgca aagattgctg actacggcat 6180tgctcagtac tgctgtagaa tggggataaa aacatcagag ggcacaccag ggtttcgtgc 6240acctgaagtt gccagaggaa atgtcattta taaccaacag gctgatgttt attcatttgg 6300tttactactc tatgacattt tgacaactgg aggtagaata gtagagggtt tgaagtttcc 6360aaatgagttt gatgaattag aaatacaagg aaaattacct gatccagtta aagaatatgg 6420ttgtgcccca tggcctatgg ttgagaaatt aattaaacag tgtttgaaag aaaatcctca 6480agaaaggcct acttctgccc aggtctttga cattttgaat tcagctgaat tagtctgtct 6540gacgagacgc attttattac ctaaaaacgt aattgttgaa tgcatggttg ctacacatca 6600caacagcagg aatgcaagca tttggctggg ctgtgggcac accgacagag gacagctctc 6660atttcttgac ttaaatactg aaggatacac ttctgaggaa gttgctgata gtagaatatt 6720gtgcttagcc ttggtgcatc ttcctgttga aaaggaaagc tggattgtgt ctgggacaca 6780gtctggtact ctcctggtca tcaataccga agatgggaaa aagagacata ccctagaaaa 6840gatgactgat tctgtcactt gtttgtattg caattccttt tccaagcaaa gcaaacaaaa 6900aaattttctt ttggttggaa ccgctgatgg caagttagca atttttgaag ataagactgt 6960taagcttaaa ggagctgctc ctttgaagat actaaatata ggaaatgtca gtactccatt 7020gatgtgtttg agtgaatcca caaattcaac ggaaagaaat gtaatgtggg gaggatgtgg 7080cacaaagatt ttctcctttt ctaatgattt caccattcag aaactcattg agacaagaac 7140aagccaactg ttttcttatg cagctttcag tgattccaac atcataacag tggtggtaga 7200cactgctctc tatattgcta agcaaaatag ccctgttgtg gaagtgtggg ataagaaaac 7260tgaaaaactc tgtggactaa tagactgcgt gcacttttta agggaggtaa tggtaaaaga 7320aaacaaggaa tcaaaacaca aaatgtctta ttctgggaga gtgaaaaccc tctgccttca 7380gaagaacact gctctttgga taggaactgg aggaggccat attttactcc tggatctttc 7440aactcgtcga cttatacgtg taatttacaa cttttgtaat tcggtcagag tcatgatgac 7500agcacagcta ggaagcctta aaaatgtcat gctggtattg ggctacaacc ggaaaaatac 7560tgaaggtaca caaaagcaga aagagataca atcttgcttg accgtttggg acatcaatct 7620tccacatgaa gtgcaaaatt tagaaaaaca cattgaagtg agaaaagaat tagctgaaaa 7680aatgagacga acatctgttg agtaagagag aaataggaat tgtctttgga taggaaaatt 7740attctctcct cttgtaaata tttattttaa aaatgttcac atggaaaggg tactcacatt 7800ttttgaaata gctcgtgtgt atgaaggaat gttattattt ttaatttaaa tatatgtaaa 7860aatacttacc agtaaatgtg tattttaaag aactatttaa aacacaatgt tatatttctt 7920ataaatacca gttactttcg ttcattaatt aatgaaaata aatctgtgaa gtacctaatt 7980taagtactca tactaaaatt tataaggccg ataatttttt gttttcttgt ctgtaatgga 8040ggtaaacttt attttaaatt ctgtgcttaa gacaggacta ttgcttgtcg atttttctag 8100aaatctgcac ggtataatga aaatattaag acagtttccc atgtaatgta ttccttctta 8160gattgcatcg aaatgcacta tcatatatgc ttgtaaatat tcaaatgaat ttgcactaat 8220aaagtccttt gttggtatgt gaattctctt tgttgctgtt gcaaacagtg catcttacac 8280aacttcactc aattcaaaag aaaactccat taaaagtact aatgaaaaaa catgacatac 8340tgtcaaagtc ctcatatcta ggaaagacac agaaactctc tttgtcacag aaactctctg 8400tgtctttcct agacataata gagttgtttt tcaactctat gtttgaatgt ggataccctg 8460aattttgtat aattagtgta aatacagtgt tcagtccttc aagtgatatt tttatttttt 8520tattcatacc actagctact tgttttctaa tctgcttcat tctaatgctt atattcatct 8580tttccctaaa tttgtgatgc tgcagatcct acatcattca gatagaaacc tttttttttt 8640tcagaattat agaattccac agctcctacc aagaccatga ggataaatat ctaacacttt 8700tcagttgctg aaggagaaag gagctttagt tatgatggat aaaaatatct gccaccctag 8760gcttccaaat tatacttaaa ttgtttacat agcttaccac aataggagta tcagggccaa 8820atacctatgt aataatttga ggtcatttct gctttaggaa aagtactttc ggtaaattct 8880ttggccctga ccagtattca ttatttcaga taattccctg tgataggaca actagtacat 8940ttaatattct cagaacttat ggcattttac tatgtgaaaa ctttaaattt atttatatta 9000agggtaatca aattcttaaa gatgaaagat tttctgtatt ttaaaggaag ctatgcttta 9060acttgttatg taattaacaa aaaaatcata tataatagag ctctttgttc cagtgttatc 9120tctttcattg ttactttgta tttgcaattt tttttaccaa agacaaatta aaaaaatgaa 9180taccatattt aaatggaata ataaaggttt tttaaaaact ttaaaaaaaa aaaaaaaaa 9239105100DNAhomo sapiens 10cttgttgact aggcgctgtt cttgctggct ggtgccccag ggcctggaga ggtctgaaga 60aacctgggag ccagcagccc ggggctccac tctgggttct gaaagcccat tccctgctct 120gcggctcctc ccaccccacc tcttctcagc cttgcagctc aagggttgat ctcaggagtc 180caggacccag gagagggaag aatctgagga acacagaaca gtgagcgttg cccacacccc 240atctcccgtc accacatctc ccctcaccct caccctccct gcctggccct ggaccccatc 300ccaggacctc cctatcagct gacttcttcc agtgtcttgc aggcccctct gggctcctcc 360ctcccctggc ttttcctacc actccccctc tatcggcgtc tatctgtagg tgccctggga 420tttataaaac tgggttccga atgctgaata agagacggta agagccaagg caaaggacag 480cactgttctc tgcctgcctg ataccctcac cacctgggaa catcccccag acaccctctt 540aactccggga cagagatggc tggcggagcc tggggccgcc tggcctgtta cttggagttc 600ctgaagaagg aggagctgaa ggagttccag cttctgctcg ccaataaagc gcactccagg 660agctcttcgg gtgagacacc cgctcagcca gagaagacga gtggcatgga ggtggcctcg 720tacctggtgg ctcagtatgg ggagcagcgg gcctgggacc tagccctcca tacctgggag 780cagatggggc tgaggtcact gtgcgcccaa gcccaggaag gggcaggcca ctctccctca 840ttcccctaca gcccaagtga accccacctg gggtctccca gccaacccac ctccaccgca 900gtgctaatgc cctggatcca tgaattgccg gcggggtgca cccagggctc agagagaagg 960gttttgagac agctgcctga cacatctgga cgccgctgga gagaaatctc tgcctcactc 1020ctctaccaag ctcttccaag ctccccagac catgagtctc caagccagga gtcacccaac 1080gcccccacat ccacagcagt gctggggagc tggggatccc cacctcagcc cagcctagca 1140cccagagagc aggaggctcc tgggacccaa tggcctctgg atgaaacgtc aggaatttac 1200tacacagaaa tcagagaaag agagagagag aaatcagaga aaggcaggcc cccatgggca 1260gcggtggtag gaacgccccc acaggcgcac accagcctac agccccacca ccacccatgg 1320gagccttctg tgagagagag cctctgttcc acatggccct ggaaaaatga ggattttaac 1380caaaaattca cacagctgct acttctacaa agacctcacc ccagaagcca agatcccctg 1440gtcaagagaa gctggcctga ttatgtggag gagaatcgag gacatttaat tgagatcaga 1500gacttatttg gcccaggcct ggatacccaa gaacctcgca tagtcatact gcagggggct 1560gctggaattg ggaagtcaac actggccagg caggtgaagg aagcctgggg gagaggccag 1620ctgtatgggg accgcttcca gcatgtcttc tacttcagct gcagagagct ggcccagtcc 1680aaggtggtga gtctcgctga gctcatcgga aaagatggga cagccactcc ggctcccatt 1740agacagatcc tgtctaggcc agagcggctg ctcttcatcc tcgatggtgt agatgagcca 1800ggatgggtct tgcaggagcc gagttctgag ctctgtctgc actggagcca gccacagccg 1860gcggatgcac tgctgggcag tttgctgggg aaaactatac ttcccgaggc atccttcctg 1920atcacggctc ggaccacagc tctgcagaac ctcattcctt ctttggagca ggcacgttgg 1980gtagaggtcc tggggttctc tgagtccagc aggaaggaat atttctacag atatttcaca 2040gatgaaaggc aagcaattag agcctttagg ttggtcaaat caaacaaaga gctctgggcc 2100ctgtgtcttg tgccctgggt gtcctggctg gcctgcactt gcctgatgca gcagatgaag 2160cggaaggaaa aactcacact gacttccaag accaccacaa ccctctgtct acattacctt 2220gcccaggctc tccaagctca gccattggga ccccagctca gagacctctg ctctctggct 2280gctgagggca tctggcaaaa aaagaccctt ttcagtccag atgacctcag gaagcatggg 2340ttagatgggg ccatcatctc caccttcttg aagatgggta ttcttcaaga gcaccccatc 2400cctctgagct acagcttcat tcacctctgt ttccaagagt tctttgcagc aatgtcctat 2460gtcttggagg atgagaaggg gagaggtaaa cattctaatt gcatcataga tttggaaaag 2520acgctagaag catatggaat acatggcctg tttggggcat caaccacacg tttcctattg 2580ggcctgttaa gtgatgaggg ggagagagag atggagaaca tctttcactg ccggctgtct 2640caggggagga acctgatgca gtgggtcccg tccctgcagc tgctgctgca gccacactct 2700ctggagtccc tccactgctt gtacgagact cggaacaaaa cgttcctgac acaagtgatg 2760gcccatttcg aagaaatggg catgtgtgta gaaacagaca tggagctctt agtgtgcact 2820ttctgcatta aattcagccg ccacgtgaag aagcttcagc tgattgaggg caggcagcac 2880agatcaacat ggagccccac catggtagtc ctgttcaggt gggtcccagt cacagatgcc 2940tattggcaga ttctcttctc cgtcctcaag gtcaccagaa acctgaagga gctggaccta 3000agtggaaact cgctgagcca ctctgcagtg aagagtcttt gtaagaccct gagacgccct 3060cgctgcctcc tggagaccct gcggttggct ggctgtggcc tcacagctga ggactgcaag 3120gaccttgcct ttgggctgag agccaaccag accctgaccg agctggacct gagcttcaat 3180gtgctcacgg atgctggagc caaacacctt tgccagagac tgagacagcc gagctgcaag 3240ctacagcgac tgcagctggt cagctgtggc ctcacgtctg actgctgcca ggacctggcc 3300tctgtgctta gtgccagccc cagcctgaag gagctagacc tgcagcagaa caacctggat 3360gacgttggcg tgcgactgct ctgtgagggg ctcaggcatc ctgcctgcaa actcatacgc 3420ctggggctgg accagacaac tctgagtgat gagatgaggc aggaactgag ggccctggag 3480caggagaaac ctcagctgct catcttcagc agacggaaac caagtgtgat gacccctact 3540gagggcctgg atacgggaga gatgagtaat agcacatcct cactcaagcg gcagagactc 3600ggatcagaga gggcggcttc ccatgttgct caggctaatc tcaaactcct ggacgtgagc 3660aagatcttcc caattgctga gattgcaggc aagagccacg aggaaagctc cccagaggta 3720gtaccggtgg aactcttgtg cgtgccttct cctgcctctc aaggggacct gcatacgaag 3780cctttgggga ctgacgatga cttctggggc cccacggggc ctgtggctac tgaggtagtt 3840gacaaagaaa agaacttgta ccgagttcac ttccctgtag ctggctccta ccgctggccc 3900aacacgggtc tctgctttgt gatgagagaa gcggtgaccg ttgagattga attctgtgtg 3960tgggaccagt tcctgggtga gatcaaccca cagcacagct ggatggtggc agggcctctg 4020ctggacatca aggctgagcc tggagctgtg gaagctgtgc acctccctca ctttgtggct 4080ctccaagggg gccatgtgga cacatccctg ttccaaatgg cccactttaa agaggagggg 4140atgctcctgg agaagccagc cagggtggag ctgcatcaca tagttctgga aaaccccagc 4200ttctccccct tgggagtcct cctgaaaatg atccataatg ccctgcgctt cattcccgtc 4260acctctgtgg tgttgcttta ccaccgcgtc catcctgagg aagtcacctt ccacctctac 4320ctgatcccaa gtgactgctc cattcggaag gccatagatg atctagaaat gaaattccag 4380tttgtgcgaa tccacaagcc acccccgctg accccacttt atatgggctg tcgttacact 4440gtgtctgggt ctggttcagg gatgctggaa atactcccca aggaactgga gctctgctat 4500cgaagccctg gagaagacca gctgttctcg gagttctacg ttggccactt gggatcaggg 4560atcaggctgc aagtgaaaga caagaaagat gagactctgg tgtgggaggc cttggtgaaa 4620ccaggaagga acaccagcca gccgtggaac ctcaggtgca acagagacgc caggagatac 4680tagtgcccag cagcctgcgg cagtaccaat gaagccagag agggcttggt ggatgacaag 4740gaggcctgag tagaccgcag gtgggtctga gaaatgggct taggtgaggc aggtctttga 4800aggatttgtt cttaatcata tgcgagatgc tcaaaaggct ggatgcctgc ttttgtgggt 4860gaagagcaag aagagaaaac aggttgtaca catacagatg cagatggaga gacagagaaa 4920aaaaaggaag aaggcagaga aatgcaccaa ttcttgagct gtattatctc tggaccttgg 4980gattgtggga ggctttattt tactactgat tttgcctaca ctgttttctc aatttctagt 5040tttctacaaa gatgatgtgt tagctttttc acgcattaag attaaaattt aaaacagaaa 5100115491DNAhomo sapiens 11cttgttgact aggcgctgtt cttgctggct ggtgccccag ggcctggaga ggtctgaaga 60aacctgggag ccagcagccc ggggctccac tctgggttct gaaagcccat tccctgctct 120gcggctcctc ccaccccacc tcttctcagc cttgcagctc aagggttgat ctcaggagtc 180caggacccag gagagggaag aatctgagga acacagaaca gtgagcgttg cccacacccc 240atctcccgtc accacatctc ccctcaccct caccctccct gcctggccct ggaccccatc 300ccaggacctc cctatcagct gacttcttcc agtgtcttgc aggcccctct gggctcctcc 360ctcccctggc ttttcctacc actccccctc tatcggcgtc tatctgtagg tgccctggga 420tttataaaac tgggttccga atgctgaata agagacggta agagccaagg caaaggacag 480cactgttctc tgcctgcctg ataccctcac cacctgggaa catcccccag acaccctctt 540aactccggga cagagatggc tggcggagcc tggggccgcc tggcctgtta cttggagttc 600ctgaagaagg aggagctgaa ggagttccag cttctgctcg ccaataaagc gcactccagg 660agctcttcgg gtgagacacc cgctcagcca gagaagacga gtggcatgga ggtggcctcg 720tacctggtgg ctcagtatgg ggagcagcgg gcctgggacc tagccctcca tacctgggag 780cagatggggc tgaggtcact gtgcgcccaa gcccaggaag gggcaggcca ctctccctca 840ttcccctaca gcccaagtga accccacctg gggtctccca gccaacccac ctccaccgca 900gtgctaatgc cctggatcca tgaattgccg gcggggtgca cccagggctc agagagaagg 960gttttgagac agctgcctga cacatctgga cgccgctgga gagaaatctc tgcctcactc 1020ctctaccaag ctcttccaag ctccccagac catgagtctc caagccagga gtcacccaac 1080gcccccacat ccacagcagt gctggggagc tggggatccc cacctcagcc cagcctagca 1140cccagagagc aggaggctcc tgggacccaa tggcctctgg atgaaacgtc aggaatttac 1200tacacagaaa tcagagaaag agagagagag aaatcagaga aaggcaggcc cccatgggca 1260gcggtggtag gaacgccccc acaggcgcac accagcctac agccccacca ccacccatgg 1320gagccttctg tgagagagag cctctgttcc acatggccct ggaaaaatga ggattttaac 1380caaaaattca cacagctgct acttctacaa agacctcacc ccagaagcca agatcccctg 1440gtcaagagaa gctggcctga ttatgtggag gagaatcgag gacatttaat tgagatcaga 1500gacttatttg gcccaggcct ggatacccaa gaacctcgca tagtcatact gcagggggct 1560gctggaattg ggaagtcaac actggccagg caggtgaagg aagcctgggg gagaggccag 1620ctgtatgggg accgcttcca gcatgtcttc tacttcagct gcagagagct ggcccagtcc 1680aaggtggtga gtctcgctga gctcatcgga aaagatggga cagccactcc ggctcccatt 1740agacagatcc tgtctaggcc agagcggctg ctcttcatcc tcgatggtgt agatgagcca 1800ggatgggtct tgcaggagcc gagttctgag ctctgtctgc actggagcca gccacagccg 1860gcggatgcac tgctgggcag tttgctgggg aaaactatac ttcccgaggc atccttcctg 1920atcacggctc ggaccacagc tctgcagaac ctcattcctt ctttggagca ggcacgttgg 1980gtagaggtcc tggggttctc tgagtccagc aggaaggaat atttctacag atatttcaca 2040gatgaaaggc aagcaattag agcctttagg ttggtcaaat caaacaaaga gctctgggcc 2100ctgtgtcttg tgccctgggt gtcctggctg gcctgcactt gcctgatgca gcagatgaag 2160cggaaggaaa aactcacact gacttccaag accaccacaa ccctctgtct acattacctt 2220gcccaggctc tccaagctca gccattggga ccccagctca gagacctctg ctctctggct 2280gctgagggca tctggcaaaa aaagaccctt ttcagtccag atgacctcag gaagcatggg 2340ttagatgggg ccatcatctc caccttcttg aagatgggta ttcttcaaga gcaccccatc 2400cctctgagct acagcttcat tcacctctgt ttccaagagt tctttgcagc aatgtcctat 2460gtcttggagg atgagaaggg gagaggtaaa cattctaatt gcatcataga tttggaaaag 2520acgctagaag catatggaat acatggcctg tttggggcat caaccacacg tttcctattg 2580ggcctgttaa gtgatgaggg ggagagagag atggagaaca tctttcactg ccggctgtct 2640caggggagga acctgatgca gtgggtcccg tccctgcagc tgctgctgca gccacactct 2700ctggagtccc tccactgctt gtacgagact cggaacaaaa cgttcctgac acaagtgatg 2760gcccatttcg aagaaatggg catgtgtgta gaaacagaca tggagctctt agtgtgcact 2820ttctgcatta aattcagccg ccacgtgaag aagcttcagc tgattgaggg caggcagcac 2880agatcaacat ggagccccac catggtagtc ctgttcaggt gggtcccagt cacagatgcc 2940tattggcaga ttctcttctc

cgtcctcaag gtcaccagaa acctgaagga gctggaccta 3000agtggaaact cgctgagcca ctctgcagtg aagagtcttt gtaagaccct gagacgccct 3060cgctgcctcc tggagaccct gcggttggct ggctgtggcc tcacagctga ggactgcaag 3120gaccttgcct ttgggctgag agccaaccag accctgaccg agctggacct gagcttcaat 3180gtgctcacgg atgctggagc caaacacctt tgccagagac tgagacagcc gagctgcaag 3240ctacagcgac tgcagctggt cagctgtggc ctcacgtctg actgctgcca ggacctggcc 3300tctgtgctta gtgccagccc cagcctgaag gagctagacc tgcagcagaa caacctggat 3360gacgttggcg tgcgactgct ctgtgagggg ctcaggcatc ctgcctgcaa actcatacgc 3420ctggggctgg accagacaac tctgagtgat gagatgaggc aggaactgag ggccctggag 3480caggagaaac ctcagctgct catcttcagc agacggaaac caagtgtgat gacccctact 3540gagggcctgg atacgggaga gatgagtaat agcacatcct cactcaagcg gcagagactc 3600ggatcagaga gggcggcttc ccatgttgct caggctaatc tcaaactcct ggacgtgagc 3660aagatcttcc caattgctga gattgcagag gaaagctccc cagaggtagt accggtggaa 3720ctcttgtgcg tgccttctcc tgcctctcaa ggggacctgc atacgaagcc tttggggact 3780gacgatgact tctggggccc cacggggcct gtggctactg aggtagttga caaagaaaag 3840aacttgtacc gagttcactt ccctgtagct ggctcctacc gctggcccaa cacgggtctc 3900tgctttgtga tgagagaagc ggtgaccgtt gagattgaat tctgtgtgtg ggaccagttc 3960ctgggtgaga tcaacccaca gcacagctgg atggtggcag ggcctctgct ggacatcaag 4020gctgagcctg gagctgtgga agctgtgcac ctccctcact ttgtggctct ccaagggggc 4080catgtggaca catccctgtt ccaaatggcc cactttaaag aggaggggat gctcctggag 4140aagccagcca gggtggagct gcatcacata gttctggaaa accccagctt ctcccccttg 4200ggagtcctcc tgaaaatgat ccataatgcc ctgcgcttca ttcccgtcac ctctgtggtg 4260ttgctttacc accgcgtcca tcctgaggaa gtcaccttcc acctctacct gatcccaagt 4320gactgctcca ttcggaagga actggagctc tgctatcgaa gccctggaga agaccagctg 4380ttctcggagt tctacgttgg ccacttggga tcagggatca ggctgcaagt gaaagacaag 4440aaagatgaga ctctggtgtg ggaggccttg gtgaaaccag gagatctcat gcctgcaact 4500actctgatcc ctccagcccg catagccgta ccttcacctc tggatgcccc gcagttgctg 4560cactttgtgg accagtatcg agagcagctg atagcccgag tgacatcggt ggaggttgtc 4620ttggacaaac tgcatggaca ggtgctgagc caggagcagt acgagagggt gctggctgag 4680aacacgaggc ccagccagat gcggaagctg ttcagcttga gccagtcctg ggaccggaag 4740tgcaaagatg gactctacca agccctgaag gagacccatc ctcacctcat tatggaactc 4800tgggagaagg gcagcaaaaa gggactcctg ccactcagca gctgaagtat caacaccagc 4860ccttgaccct tgagtcctgg ctttggctga cccttctttg ggtctcagtt tctttctctg 4920caaacaagtt gccatctggt ttgccttcca gcactaaagt aatggaactt tgatgatgcc 4980tttgctgggc attatgtgtc catgccaggg atgccacagg gggccccagt ccaggtggcc 5040taacagcatc tcagggaatg tccatctgga gctggcaaga cccctgcaga cctcatagag 5100cctcatctgg tggccacagc agccaagcct agagccctcc ggatcccatc caggcgcaaa 5160gaggaatagg agggacatgg aaccatttgc ctctggctgt gtcacagggt gagccccaaa 5220attggggttc agcgtgggag gccacgtgga ttcttggctt tgtacaggaa gatctacaag 5280agcaagccaa cagagtaaag tggaaggaag tttattcaga aaataaagga gtatcacagc 5340tcttttagaa tttgtctagc aggctttcca gtttttacca gaaaacccct ataaattaaa 5400aattttttac ttaaatttaa gaattaaaaa aatacaaaaa agaaaaaatg aaaataaagg 5460aataagaagt tacctactcc aaaaaaaaaa a 5491125623DNAhomo sapiens 12cttgttgact aggcgctgtt cttgctggct ggtgccccag ggcctggaga ggtctgaaga 60aacctgggag ccagcagccc ggggctccac tctgggttct gaaagcccat tccctgctct 120gcggctcctc ccaccccacc tcttctcagc cttgcagctc aagggttgat ctcaggagtc 180caggacccag gagagggaag aatctgagga acacagaaca gtgagcgttg cccacacccc 240atctcccgtc accacatctc ccctcaccct caccctccct gcctggccct ggaccccatc 300ccaggacctc cctatcagct gacttcttcc agtgtcttgc aggcccctct gggctcctcc 360ctcccctggc ttttcctacc actccccctc tatcggcgtc tatctgtagg tgccctggga 420tttataaaac tgggttccga atgctgaata agagacggta agagccaagg caaaggacag 480cactgttctc tgcctgcctg ataccctcac cacctgggaa catcccccag acaccctctt 540aactccggga cagagatggc tggcggagcc tggggccgcc tggcctgtta cttggagttc 600ctgaagaagg aggagctgaa ggagttccag cttctgctcg ccaataaagc gcactccagg 660agctcttcgg gtgagacacc cgctcagcca gagaagacga gtggcatgga ggtggcctcg 720tacctggtgg ctcagtatgg ggagcagcgg gcctgggacc tagccctcca tacctgggag 780cagatggggc tgaggtcact gtgcgcccaa gcccaggaag gggcaggcca ctctccctca 840ttcccctaca gcccaagtga accccacctg gggtctccca gccaacccac ctccaccgca 900gtgctaatgc cctggatcca tgaattgccg gcggggtgca cccagggctc agagagaagg 960gttttgagac agctgcctga cacatctgga cgccgctgga gagaaatctc tgcctcactc 1020ctctaccaag ctcttccaag ctccccagac catgagtctc caagccagga gtcacccaac 1080gcccccacat ccacagcagt gctggggagc tggggatccc cacctcagcc cagcctagca 1140cccagagagc aggaggctcc tgggacccaa tggcctctgg atgaaacgtc aggaatttac 1200tacacagaaa tcagagaaag agagagagag aaatcagaga aaggcaggcc cccatgggca 1260gcggtggtag gaacgccccc acaggcgcac accagcctac agccccacca ccacccatgg 1320gagccttctg tgagagagag cctctgttcc acatggccct ggaaaaatga ggattttaac 1380caaaaattca cacagctgct acttctacaa agacctcacc ccagaagcca agatcccctg 1440gtcaagagaa gctggcctga ttatgtggag gagaatcgag gacatttaat tgagatcaga 1500gacttatttg gcccaggcct ggatacccaa gaacctcgca tagtcatact gcagggggct 1560gctggaattg ggaagtcaac actggccagg caggtgaagg aagcctgggg gagaggccag 1620ctgtatgggg accgcttcca gcatgtcttc tacttcagct gcagagagct ggcccagtcc 1680aaggtggtga gtctcgctga gctcatcgga aaagatggga cagccactcc ggctcccatt 1740agacagatcc tgtctaggcc agagcggctg ctcttcatcc tcgatggtgt agatgagcca 1800ggatgggtct tgcaggagcc gagttctgag ctctgtctgc actggagcca gccacagccg 1860gcggatgcac tgctgggcag tttgctgggg aaaactatac ttcccgaggc atccttcctg 1920atcacggctc ggaccacagc tctgcagaac ctcattcctt ctttggagca ggcacgttgg 1980gtagaggtcc tggggttctc tgagtccagc aggaaggaat atttctacag atatttcaca 2040gatgaaaggc aagcaattag agcctttagg ttggtcaaat caaacaaaga gctctgggcc 2100ctgtgtcttg tgccctgggt gtcctggctg gcctgcactt gcctgatgca gcagatgaag 2160cggaaggaaa aactcacact gacttccaag accaccacaa ccctctgtct acattacctt 2220gcccaggctc tccaagctca gccattggga ccccagctca gagacctctg ctctctggct 2280gctgagggca tctggcaaaa aaagaccctt ttcagtccag atgacctcag gaagcatggg 2340ttagatgggg ccatcatctc caccttcttg aagatgggta ttcttcaaga gcaccccatc 2400cctctgagct acagcttcat tcacctctgt ttccaagagt tctttgcagc aatgtcctat 2460gtcttggagg atgagaaggg gagaggtaaa cattctaatt gcatcataga tttggaaaag 2520acgctagaag catatggaat acatggcctg tttggggcat caaccacacg tttcctattg 2580ggcctgttaa gtgatgaggg ggagagagag atggagaaca tctttcactg ccggctgtct 2640caggggagga acctgatgca gtgggtcccg tccctgcagc tgctgctgca gccacactct 2700ctggagtccc tccactgctt gtacgagact cggaacaaaa cgttcctgac acaagtgatg 2760gcccatttcg aagaaatggg catgtgtgta gaaacagaca tggagctctt agtgtgcact 2820ttctgcatta aattcagccg ccacgtgaag aagcttcagc tgattgaggg caggcagcac 2880agatcaacat ggagccccac catggtagtc ctgttcaggt gggtcccagt cacagatgcc 2940tattggcaga ttctcttctc cgtcctcaag gtcaccagaa acctgaagga gctggaccta 3000agtggaaact cgctgagcca ctctgcagtg aagagtcttt gtaagaccct gagacgccct 3060cgctgcctcc tggagaccct gcggttggct ggctgtggcc tcacagctga ggactgcaag 3120gaccttgcct ttgggctgag agccaaccag accctgaccg agctggacct gagcttcaat 3180gtgctcacgg atgctggagc caaacacctt tgccagagac tgagacagcc gagctgcaag 3240ctacagcgac tgcagctggt cagctgtggc ctcacgtctg actgctgcca ggacctggcc 3300tctgtgctta gtgccagccc cagcctgaag gagctagacc tgcagcagaa caacctggat 3360gacgttggcg tgcgactgct ctgtgagggg ctcaggcatc ctgcctgcaa actcatacgc 3420ctggggctgg accagacaac tctgagtgat gagatgaggc aggaactgag ggccctggag 3480caggagaaac ctcagctgct catcttcagc agacggaaac caagtgtgat gacccctact 3540gagggcctgg atacgggaga gatgagtaat agcacatcct cactcaagcg gcagagactc 3600ggatcagaga gggcggcttc ccatgttgct caggctaatc tcaaactcct ggacgtgagc 3660aagatcttcc caattgctga gattgcagag gaaagctccc cagaggtagt accggtggaa 3720ctcttgtgcg tgccttctcc tgcctctcaa ggggacctgc atacgaagcc tttggggact 3780gacgatgact tctggggccc cacggggcct gtggctactg aggtagttga caaagaaaag 3840aacttgtacc gagttcactt ccctgtagct ggctcctacc gctggcccaa cacgggtctc 3900tgctttgtga tgagagaagc ggtgaccgtt gagattgaat tctgtgtgtg ggaccagttc 3960ctgggtgaga tcaacccaca gcacagctgg atggtggcag ggcctctgct ggacatcaag 4020gctgagcctg gagctgtgga agctgtgcac ctccctcact ttgtggctct ccaagggggc 4080catgtggaca catccctgtt ccaaatggcc cactttaaag aggaggggat gctcctggag 4140aagccagcca gggtggagct gcatcacata gttctggaaa accccagctt ctcccccttg 4200ggagtcctcc tgaaaatgat ccataatgcc ctgcgcttca ttcccgtcac ctctgtggtg 4260ttgctttacc accgcgtcca tcctgaggaa gtcaccttcc acctctacct gatcccaagt 4320gactgctcca ttcggaaggc catagatgat ctagaaatga aattccagtt tgtgcgaatc 4380cacaagccac ccccgctgac cccactttat atgggctgtc gttacactgt gtctgggtct 4440ggttcaggga tgctggaaat actccccaag gaactggagc tctgctatcg aagccctgga 4500gaagaccagc tgttctcgga gttctacgtt ggccacttgg gatcagggat caggctgcaa 4560gtgaaagaca agaaagatga gactctggtg tgggaggcct tggtgaaacc aggagatctc 4620atgcctgcaa ctactctgat ccctccagcc cgcatagccg taccttcacc tctggatgcc 4680ccgcagttgc tgcactttgt ggaccagtat cgagagcagc tgatagcccg agtgacatcg 4740gtggaggttg tcttggacaa actgcatgga caggtgctga gccaggagca gtacgagagg 4800gtgctggctg agaacacgag gcccagccag atgcggaagc tgttcagctt gagccagtcc 4860tgggaccgga agtgcaaaga tggactctac caagccctga aggagaccca tcctcacctc 4920attatggaac tctgggagaa gggcagcaaa aagggactcc tgccactcag cagctgaagt 4980atcaacacca gcccttgacc cttgagtcct ggctttggct gacccttctt tgggtctcag 5040tttctttctc tgcaaacaag ttgccatctg gtttgccttc cagcactaaa gtaatggaac 5100tttgatgatg cctttgctgg gcattatgtg tccatgccag ggatgccaca gggggcccca 5160gtccaggtgg cctaacagca tctcagggaa tgtccatctg gagctggcaa gacccctgca 5220gacctcatag agcctcatct ggtggccaca gcagccaagc ctagagccct ccggatccca 5280tccaggcgca aagaggaata ggagggacat ggaaccattt gcctctggct gtgtcacagg 5340gtgagcccca aaattggggt tcagcgtggg aggccacgtg gattcttggc tttgtacagg 5400aagatctaca agagcaagcc aacagagtaa agtggaagga agtttattca gaaaataaag 5460gagtatcaca gctcttttag aatttgtcta gcaggctttc cagtttttac cagaaaaccc 5520ctataaatta aaaatttttt acttaaattt aagaattaaa aaaatacaaa aaagaaaaaa 5580tgaaaataaa ggaataagaa gttacctact ccaaaaaaaa aaa 5623135533DNAhomo sapiens 13cttgttgact aggcgctgtt cttgctggct ggtgccccag ggcctggaga ggtctgaaga 60aacctgggag ccagcagccc ggggctccac tctgggttct gaaagcccat tccctgctct 120gcggctcctc ccaccccacc tcttctcagc cttgcagctc aagggttgat ctcaggagtc 180caggacccag gagagggaag aatctgagga acacagaaca gtgagcgttg cccacacccc 240atctcccgtc accacatctc ccctcaccct caccctccct gcctggccct ggaccccatc 300ccaggacctc cctatcagct gacttcttcc agtgtcttgc aggcccctct gggctcctcc 360ctcccctggc ttttcctacc actccccctc tatcggcgtc tatctgtagg tgccctggga 420tttataaaac tgggttccga atgctgaata agagacggta agagccaagg caaaggacag 480cactgttctc tgcctgcctg ataccctcac cacctgggaa catcccccag acaccctctt 540aactccggga cagagatggc tggcggagcc tggggccgcc tggcctgtta cttggagttc 600ctgaagaagg aggagctgaa ggagttccag cttctgctcg ccaataaagc gcactccagg 660agctcttcgg gtgagacacc cgctcagcca gagaagacga gtggcatgga ggtggcctcg 720tacctggtgg ctcagtatgg ggagcagcgg gcctgggacc tagccctcca tacctgggag 780cagatggggc tgaggtcact gtgcgcccaa gcccaggaag gggcaggcca ctctccctca 840ttcccctaca gcccaagtga accccacctg gggtctccca gccaacccac ctccaccgca 900gtgctaatgc cctggatcca tgaattgccg gcggggtgca cccagggctc agagagaagg 960gttttgagac agctgcctga cacatctgga cgccgctgga gagaaatctc tgcctcactc 1020ctctaccaag ctcttccaag ctccccagac catgagtctc caagccagga gtcacccaac 1080gcccccacat ccacagcagt gctggggagc tggggatccc cacctcagcc cagcctagca 1140cccagagagc aggaggctcc tgggacccaa tggcctctgg atgaaacgtc aggaatttac 1200tacacagaaa tcagagaaag agagagagag aaatcagaga aaggcaggcc cccatgggca 1260gcggtggtag gaacgccccc acaggcgcac accagcctac agccccacca ccacccatgg 1320gagccttctg tgagagagag cctctgttcc acatggccct ggaaaaatga ggattttaac 1380caaaaattca cacagctgct acttctacaa agacctcacc ccagaagcca agatcccctg 1440gtcaagagaa gctggcctga ttatgtggag gagaatcgag gacatttaat tgagatcaga 1500gacttatttg gcccaggcct ggatacccaa gaacctcgca tagtcatact gcagggggct 1560gctggaattg ggaagtcaac actggccagg caggtgaagg aagcctgggg gagaggccag 1620ctgtatgggg accgcttcca gcatgtcttc tacttcagct gcagagagct ggcccagtcc 1680aaggtggtga gtctcgctga gctcatcgga aaagatggga cagccactcc ggctcccatt 1740agacagatcc tgtctaggcc agagcggctg ctcttcatcc tcgatggtgt agatgagcca 1800ggatgggtct tgcaggagcc gagttctgag ctctgtctgc actggagcca gccacagccg 1860gcggatgcac tgctgggcag tttgctgggg aaaactatac ttcccgaggc atccttcctg 1920atcacggctc ggaccacagc tctgcagaac ctcattcctt ctttggagca ggcacgttgg 1980gtagaggtcc tggggttctc tgagtccagc aggaaggaat atttctacag atatttcaca 2040gatgaaaggc aagcaattag agcctttagg ttggtcaaat caaacaaaga gctctgggcc 2100ctgtgtcttg tgccctgggt gtcctggctg gcctgcactt gcctgatgca gcagatgaag 2160cggaaggaaa aactcacact gacttccaag accaccacaa ccctctgtct acattacctt 2220gcccaggctc tccaagctca gccattggga ccccagctca gagacctctg ctctctggct 2280gctgagggca tctggcaaaa aaagaccctt ttcagtccag atgacctcag gaagcatggg 2340ttagatgggg ccatcatctc caccttcttg aagatgggta ttcttcaaga gcaccccatc 2400cctctgagct acagcttcat tcacctctgt ttccaagagt tctttgcagc aatgtcctat 2460gtcttggagg atgagaaggg gagaggtaaa cattctaatt gcatcataga tttggaaaag 2520acgctagaag catatggaat acatggcctg tttggggcat caaccacacg tttcctattg 2580ggcctgttaa gtgatgaggg ggagagagag atggagaaca tctttcactg ccggctgtct 2640caggggagga acctgatgca gtgggtcccg tccctgcagc tgctgctgca gccacactct 2700ctggagtccc tccactgctt gtacgagact cggaacaaaa cgttcctgac acaagtgatg 2760gcccatttcg aagaaatggg catgtgtgta gaaacagaca tggagctctt agtgtgcact 2820ttctgcatta aattcagccg ccacgtgaag aagcttcagc tgattgaggg caggcagcac 2880agatcaacat ggagccccac catggtagtc ctgttcaggt gggtcccagt cacagatgcc 2940tattggcaga ttctcttctc cgtcctcaag gtcaccagaa acctgaagga gctggaccta 3000agtggaaact cgctgagcca ctctgcagtg aagagtcttt gtaagaccct gagacgccct 3060cgctgcctcc tggagaccct gcggttggct ggctgtggcc tcacagctga ggactgcaag 3120gaccttgcct ttgggctgag agccaaccag accctgaccg agctggacct gagcttcaat 3180gtgctcacgg atgctggagc caaacacctt tgccagagac tgagacagcc gagctgcaag 3240ctacagcgac tgcagctggt cagctgtggc ctcacgtctg actgctgcca ggacctggcc 3300tctgtgctta gtgccagccc cagcctgaag gagctagacc tgcagcagaa caacctggat 3360gacgttggcg tgcgactgct ctgtgagggg ctcaggcatc ctgcctgcaa actcatacgc 3420ctggggaaac caagtgtgat gacccctact gagggcctgg atacgggaga gatgagtaat 3480agcacatcct cactcaagcg gcagagactc ggatcagaga gggcggcttc ccatgttgct 3540caggctaatc tcaaactcct ggacgtgagc aagatcttcc caattgctga gattgcagag 3600gaaagctccc cagaggtagt accggtggaa ctcttgtgcg tgccttctcc tgcctctcaa 3660ggggacctgc atacgaagcc tttggggact gacgatgact tctggggccc cacggggcct 3720gtggctactg aggtagttga caaagaaaag aacttgtacc gagttcactt ccctgtagct 3780ggctcctacc gctggcccaa cacgggtctc tgctttgtga tgagagaagc ggtgaccgtt 3840gagattgaat tctgtgtgtg ggaccagttc ctgggtgaga tcaacccaca gcacagctgg 3900atggtggcag ggcctctgct ggacatcaag gctgagcctg gagctgtgga agctgtgcac 3960ctccctcact ttgtggctct ccaagggggc catgtggaca catccctgtt ccaaatggcc 4020cactttaaag aggaggggat gctcctggag aagccagcca gggtggagct gcatcacata 4080gttctggaaa accccagctt ctcccccttg ggagtcctcc tgaaaatgat ccataatgcc 4140ctgcgcttca ttcccgtcac ctctgtggtg ttgctttacc accgcgtcca tcctgaggaa 4200gtcaccttcc acctctacct gatcccaagt gactgctcca ttcggaaggc catagatgat 4260ctagaaatga aattccagtt tgtgcgaatc cacaagccac ccccgctgac cccactttat 4320atgggctgtc gttacactgt gtctgggtct ggttcaggga tgctggaaat actccccaag 4380gaactggagc tctgctatcg aagccctgga gaagaccagc tgttctcgga gttctacgtt 4440ggccacttgg gatcagggat caggctgcaa gtgaaagaca agaaagatga gactctggtg 4500tgggaggcct tggtgaaacc aggagatctc atgcctgcaa ctactctgat ccctccagcc 4560cgcatagccg taccttcacc tctggatgcc ccgcagttgc tgcactttgt ggaccagtat 4620cgagagcagc tgatagcccg agtgacatcg gtggaggttg tcttggacaa actgcatgga 4680caggtgctga gccaggagca gtacgagagg gtgctggctg agaacacgag gcccagccag 4740atgcggaagc tgttcagctt gagccagtcc tgggaccgga agtgcaaaga tggactctac 4800caagccctga aggagaccca tcctcacctc attatggaac tctgggagaa gggcagcaaa 4860aagggactcc tgccactcag cagctgaagt atcaacacca gcccttgacc cttgagtcct 4920ggctttggct gacccttctt tgggtctcag tttctttctc tgcaaacaag ttgccatctg 4980gtttgccttc cagcactaaa gtaatggaac tttgatgatg cctttgctgg gcattatgtg 5040tccatgccag ggatgccaca gggggcccca gtccaggtgg cctaacagca tctcagggaa 5100tgtccatctg gagctggcaa gacccctgca gacctcatag agcctcatct ggtggccaca 5160gcagccaagc ctagagccct ccggatccca tccaggcgca aagaggaata ggagggacat 5220ggaaccattt gcctctggct gtgtcacagg gtgagcccca aaattggggt tcagcgtggg 5280aggccacgtg gattcttggc tttgtacagg aagatctaca agagcaagcc aacagagtaa 5340agtggaagga agtttattca gaaaataaag gagtatcaca gctcttttag aatttgtcta 5400gcaggctttc cagtttttac cagaaaaccc ctataaatta aaaatttttt acttaaattt 5460aagaattaaa aaaatacaaa aaagaaaaaa tgaaaataaa ggaataagaa gttacctact 5520ccaaaaaaaa aaa 5533145401DNAhomo sapiens 14cttgttgact aggcgctgtt cttgctggct ggtgccccag ggcctggaga ggtctgaaga 60aacctgggag ccagcagccc ggggctccac tctgggttct gaaagcccat tccctgctct 120gcggctcctc ccaccccacc tcttctcagc cttgcagctc aagggttgat ctcaggagtc 180caggacccag gagagggaag aatctgagga acacagaaca gtgagcgttg cccacacccc 240atctcccgtc accacatctc ccctcaccct caccctccct gcctggccct ggaccccatc 300ccaggacctc cctatcagct gacttcttcc agtgtcttgc aggcccctct gggctcctcc 360ctcccctggc ttttcctacc actccccctc tatcggcgtc tatctgtagg tgccctggga 420tttataaaac tgggttccga atgctgaata agagacggta agagccaagg caaaggacag 480cactgttctc tgcctgcctg ataccctcac cacctgggaa catcccccag acaccctctt 540aactccggga cagagatggc tggcggagcc tggggccgcc tggcctgtta cttggagttc 600ctgaagaagg aggagctgaa ggagttccag cttctgctcg ccaataaagc gcactccagg 660agctcttcgg gtgagacacc cgctcagcca gagaagacga gtggcatgga ggtggcctcg 720tacctggtgg ctcagtatgg ggagcagcgg gcctgggacc tagccctcca tacctgggag 780cagatggggc tgaggtcact gtgcgcccaa gcccaggaag gggcaggcca ctctccctca 840ttcccctaca gcccaagtga accccacctg gggtctccca gccaacccac ctccaccgca 900gtgctaatgc cctggatcca tgaattgccg gcggggtgca cccagggctc agagagaagg 960gttttgagac agctgcctga cacatctgga cgccgctgga gagaaatctc tgcctcactc 1020ctctaccaag ctcttccaag ctccccagac catgagtctc caagccagga gtcacccaac 1080gcccccacat ccacagcagt gctggggagc tggggatccc cacctcagcc cagcctagca 1140cccagagagc aggaggctcc tgggacccaa tggcctctgg atgaaacgtc aggaatttac 1200tacacagaaa tcagagaaag

agagagagag aaatcagaga aaggcaggcc cccatgggca 1260gcggtggtag gaacgccccc acaggcgcac accagcctac agccccacca ccacccatgg 1320gagccttctg tgagagagag cctctgttcc acatggccct ggaaaaatga ggattttaac 1380caaaaattca cacagctgct acttctacaa agacctcacc ccagaagcca agatcccctg 1440gtcaagagaa gctggcctga ttatgtggag gagaatcgag gacatttaat tgagatcaga 1500gacttatttg gcccaggcct ggatacccaa gaacctcgca tagtcatact gcagggggct 1560gctggaattg ggaagtcaac actggccagg caggtgaagg aagcctgggg gagaggccag 1620ctgtatgggg accgcttcca gcatgtcttc tacttcagct gcagagagct ggcccagtcc 1680aaggtggtga gtctcgctga gctcatcgga aaagatggga cagccactcc ggctcccatt 1740agacagatcc tgtctaggcc agagcggctg ctcttcatcc tcgatggtgt agatgagcca 1800ggatgggtct tgcaggagcc gagttctgag ctctgtctgc actggagcca gccacagccg 1860gcggatgcac tgctgggcag tttgctgggg aaaactatac ttcccgaggc atccttcctg 1920atcacggctc ggaccacagc tctgcagaac ctcattcctt ctttggagca ggcacgttgg 1980gtagaggtcc tggggttctc tgagtccagc aggaaggaat atttctacag atatttcaca 2040gatgaaaggc aagcaattag agcctttagg ttggtcaaat caaacaaaga gctctgggcc 2100ctgtgtcttg tgccctgggt gtcctggctg gcctgcactt gcctgatgca gcagatgaag 2160cggaaggaaa aactcacact gacttccaag accaccacaa ccctctgtct acattacctt 2220gcccaggctc tccaagctca gccattggga ccccagctca gagacctctg ctctctggct 2280gctgagggca tctggcaaaa aaagaccctt ttcagtccag atgacctcag gaagcatggg 2340ttagatgggg ccatcatctc caccttcttg aagatgggta ttcttcaaga gcaccccatc 2400cctctgagct acagcttcat tcacctctgt ttccaagagt tctttgcagc aatgtcctat 2460gtcttggagg atgagaaggg gagaggtaaa cattctaatt gcatcataga tttggaaaag 2520acgctagaag catatggaat acatggcctg tttggggcat caaccacacg tttcctattg 2580ggcctgttaa gtgatgaggg ggagagagag atggagaaca tctttcactg ccggctgtct 2640caggggagga acctgatgca gtgggtcccg tccctgcagc tgctgctgca gccacactct 2700ctggagtccc tccactgctt gtacgagact cggaacaaaa cgttcctgac acaagtgatg 2760gcccatttcg aagaaatggg catgtgtgta gaaacagaca tggagctctt agtgtgcact 2820ttctgcatta aattcagccg ccacgtgaag aagcttcagc tgattgaggg caggcagcac 2880agatcaacat ggagccccac catggtagtc ctgttcaggt gggtcccagt cacagatgcc 2940tattggcaga ttctcttctc cgtcctcaag gtcaccagaa acctgaagga gctggaccta 3000agtggaaact cgctgagcca ctctgcagtg aagagtcttt gtaagaccct gagacgccct 3060cgctgcctcc tggagaccct gcggttggct ggctgtggcc tcacagctga ggactgcaag 3120gaccttgcct ttgggctgag agccaaccag accctgaccg agctggacct gagcttcaat 3180gtgctcacgg atgctggagc caaacacctt tgccagagac tgagacagcc gagctgcaag 3240ctacagcgac tgcagctggt cagctgtggc ctcacgtctg actgctgcca ggacctggcc 3300tctgtgctta gtgccagccc cagcctgaag gagctagacc tgcagcagaa caacctggat 3360gacgttggcg tgcgactgct ctgtgagggg ctcaggcatc ctgcctgcaa actcatacgc 3420ctggggaaac caagtgtgat gacccctact gagggcctgg atacgggaga gatgagtaat 3480agcacatcct cactcaagcg gcagagactc ggatcagaga gggcggcttc ccatgttgct 3540caggctaatc tcaaactcct ggacgtgagc aagatcttcc caattgctga gattgcagag 3600gaaagctccc cagaggtagt accggtggaa ctcttgtgcg tgccttctcc tgcctctcaa 3660ggggacctgc atacgaagcc tttggggact gacgatgact tctggggccc cacggggcct 3720gtggctactg aggtagttga caaagaaaag aacttgtacc gagttcactt ccctgtagct 3780ggctcctacc gctggcccaa cacgggtctc tgctttgtga tgagagaagc ggtgaccgtt 3840gagattgaat tctgtgtgtg ggaccagttc ctgggtgaga tcaacccaca gcacagctgg 3900atggtggcag ggcctctgct ggacatcaag gctgagcctg gagctgtgga agctgtgcac 3960ctccctcact ttgtggctct ccaagggggc catgtggaca catccctgtt ccaaatggcc 4020cactttaaag aggaggggat gctcctggag aagccagcca gggtggagct gcatcacata 4080gttctggaaa accccagctt ctcccccttg ggagtcctcc tgaaaatgat ccataatgcc 4140ctgcgcttca ttcccgtcac ctctgtggtg ttgctttacc accgcgtcca tcctgaggaa 4200gtcaccttcc acctctacct gatcccaagt gactgctcca ttcggaagga actggagctc 4260tgctatcgaa gccctggaga agaccagctg ttctcggagt tctacgttgg ccacttggga 4320tcagggatca ggctgcaagt gaaagacaag aaagatgaga ctctggtgtg ggaggccttg 4380gtgaaaccag gagatctcat gcctgcaact actctgatcc ctccagcccg catagccgta 4440ccttcacctc tggatgcccc gcagttgctg cactttgtgg accagtatcg agagcagctg 4500atagcccgag tgacatcggt ggaggttgtc ttggacaaac tgcatggaca ggtgctgagc 4560caggagcagt acgagagggt gctggctgag aacacgaggc ccagccagat gcggaagctg 4620ttcagcttga gccagtcctg ggaccggaag tgcaaagatg gactctacca agccctgaag 4680gagacccatc ctcacctcat tatggaactc tgggagaagg gcagcaaaaa gggactcctg 4740ccactcagca gctgaagtat caacaccagc ccttgaccct tgagtcctgg ctttggctga 4800cccttctttg ggtctcagtt tctttctctg caaacaagtt gccatctggt ttgccttcca 4860gcactaaagt aatggaactt tgatgatgcc tttgctgggc attatgtgtc catgccaggg 4920atgccacagg gggccccagt ccaggtggcc taacagcatc tcagggaatg tccatctgga 4980gctggcaaga cccctgcaga cctcatagag cctcatctgg tggccacagc agccaagcct 5040agagccctcc ggatcccatc caggcgcaaa gaggaatagg agggacatgg aaccatttgc 5100ctctggctgt gtcacagggt gagccccaaa attggggttc agcgtgggag gccacgtgga 5160ttcttggctt tgtacaggaa gatctacaag agcaagccaa cagagtaaag tggaaggaag 5220tttattcaga aaataaagga gtatcacagc tcttttagaa tttgtctagc aggctttcca 5280gtttttacca gaaaacccct ataaattaaa aattttttac ttaaatttaa gaattaaaaa 5340aatacaaaaa agaaaaaatg aaaataaagg aataagaagt tacctactcc aaaaaaaaaa 5400a 5401153538DNAhomo sapiens 15ggcaagacaa cgaggatttg cgtagggggc gagcctctga ggccacttgg ctcttacggc 60cacgcagggc gccgcagatg cagccggagc ccgcttttcc ctctcaggac gacccctagg 120ccgccagcag ttccctaccg acgaaggcga ctgtacagcg tccaccgcgt tcgtgcccac 180ttacccgccg ccccactccg ggccgccggc tcgcagcagg accagcccgg ctgctacggc 240cgcggataca cgccctcagg cccggcgctg cgcagcttgc ggaagctttc ccggacagac 300tcgctgccag cggattggct gcgagcagcg ccaatctcac gttgcccccg ggcgaggcgg 360gactcagtgc cgcgctctct gcacccgctc tgccgcgcgc gtgcgtgctg ggtgcgggtg 420cgggtgcggg gttgggcctg cgcatcgggt gagacgctgg ctgcttgcgg ctagtggatg 480gtaattgcct gcctcgcgct agcaggaagc tgctctgtta aaagcgaaaa tgaaacaatt 540gcctgcggca acagttcgac tcctttcaag ttctcagatc atcacttcgg tggtcagtgt 600tgtaaaagag cttattgaaa actccttgga tgctggtgcc acaagcgtag atgttaaact 660ggagaactat ggatttgata aaattgaggt gcgagataac ggggagggta tcaaggctgt 720tgatgcacct gtaatggcaa tgaagtacta cacctcaaaa ataaatagtc atgaagatct 780tgaaaatttg acaacttacg gttttcgtgg agaagccttg gggtcaattt gttgtatagc 840tgaggtttta attacaacaa gaacggctgc tgataatttt agcacccagt atgttttaga 900tggcagtggc cacatacttt ctcagaaacc ttcacatctt ggtcaaggta caactgtaac 960tgctttaaga ttatttaaga atctacctgt aagaaagcag ttttactcaa ctgcaaaaaa 1020atgtaaagat gaaataaaaa agatccaaga tctcctcatg agctttggta tccttaaacc 1080tgacttaagg attgtctttg tacataacaa ggcagttatt tggcagaaaa gcagagtatc 1140agatcacaag atggctctca tgtcagttct ggggactgct gttatgaaca atatggaatc 1200ctttcagtac cactctgaag aatctcagat ttatctcagt ggatttcttc caaagtgtga 1260tgcagaccac tctttcacta gtctttcaac accagaaaga agtttcatct tcataaacag 1320tcgaccagta catcaaaaag atatcttaaa gttaatccga catcattaca atctgaaatg 1380cctaaaggaa tctactcgtt tgtatcctgt tttctttctg aaaatcgatg ttcctacagc 1440tgatgttgat gtaaatttaa caccagataa aagccaagta ttattacaaa ataaggaatc 1500tgttttaatt gctcttgaaa atctgatgac gacttgttat ggaccattac ctagtacaaa 1560ttcttatgaa aataataaaa cagatgtttc cgcagctgac atcgttctta gtaaaacagc 1620agaaacagat gtgcttttta ataaagtgga atcatctgga aagaattatt caaatgttga 1680tacttcagtc attccattcc aaaatgatat gcataatgat gaatctggaa aaaacactga 1740tgattgttta aatcaccaga taagtattgg tgactttggt tatggtcatt gtagtagtga 1800aatttctaac attgataaaa acactaagaa tgcatttcag gacatttcaa tgagtaatgt 1860atcatgggag aactctcaga cggaatatag taaaacttgt tttataagtt ccgttaagca 1920cacccagtca gaaaatggca ataaagacca tatagatgag agtggggaaa atgaggaaga 1980agcaggtctt gaaaactctt cggaaatttc tgcagatgag tggagcaggg gaaatatact 2040taaaaattca gtgggagaga atattgaacc tgtgaaaatt ttagtgcctg aaaaaagttt 2100accatgtaaa gtaagtaata ataattatcc aatccctgaa caaatgaatc ttaatgaaga 2160ttcatgtaac aaaaaatcaa atgtaataga taataaatct ggaaaagtta cagcttatga 2220tttacttagc aatcgagtaa tcaagaaacc catgtcagca agtgctcttt ttgttcaaga 2280tcatcgtcct cagtttctca tagaaaatcc taagactagt ttagaggatg caacactaca 2340aattgaagaa ctgtggaaga cattgagtga agaggaaaaa ctgaaatatg aagagaaggc 2400tactaaagac ttggaacgat acaatagtca aatgaagaga gccattgaac aggagtcaca 2460aatgtcacta aaagatggca gaaaaaagat aaaacccacc agcgcatgga atttggccca 2520gaagcacaag ttaaaaacct cattatctaa tcaaccaaaa cttgatgaac tccttcagtc 2580ccaaattgaa aaaagaagga gtcaaaatat taaaatggta cagatcccct tttctatgaa 2640aaacttaaaa ataaatttta agaaacaaaa caaagttgac ttagaagaga aggatgaacc 2700ttgcttgatc cacaatctca ggtttcctga tgcatggcta atgacatcca aaacagaggt 2760aatgttatta aatccatata gagtagaaga agccctgcta tttaaaagac ttcttgagaa 2820tcataaactt cctgcagagc cactggaaaa gccaattatg ttaacagaga gtctttttaa 2880tggatctcat tatttagacg ttttatataa aatgacagca gatgaccaaa gatacagtgg 2940atcaacttac ctgtctgatc ctcgtcttac agcgaatggt ttcaagataa aattgatacc 3000aggagtttca attactgaaa attacttgga aatagaagga atggctaatt gtctcccatt 3060ctatggagta gcagatttaa aagaaattct taatgctata ttaaacagaa atgcaaagga 3120agtttatgaa tgtagacctc gcaaagtgat aagttattta gagggagaag cagtgcgtct 3180atccagacaa ttacccatgt acttatcaaa agaggacatc caagacatta tctacagaat 3240gaagcaccag tttggaaatg aaattaaaga gtgtgttcat ggtcgcccat tttttcatca 3300tttaacctat cttccagaaa ctacatgatt aaatatgttt aagaagatta gttaccattg 3360aaattggttc tgtcataaaa cagcatgagt ctggttttaa attatctttg tattatgtgt 3420cacatggtta ttttttaaat gaggattcac tgacttgttt ttatattgaa aaaagttcca 3480cgtattgtag aaaacgtaaa taaactaata tagactattc aaaaaaaaaa aaaaaaaa 3538163421DNAhomo sapiens 16ggcaagacaa cgaggatttg cgtagggggc gagcctctga ggccacttgg ctcttacggc 60cacgcagggc gccgcagatg cagccggagc ccgcttttcc ctctcaggac gacccctagg 120ccgccagcag ttccctaccg acgaaggcga ctgtacagcg tccaccgcgt tcgtgcccac 180ttacccgccg ccccactccg ggccgccggc tcgcagcagg accagcccgg ctgctacggc 240cgcggataca cgccctcagg cccggcgctg cgcagcttgc ggaagctttc ccggacagac 300tcgctgccag cggattggct gcgagcagcg ccaatctcac gttgcccccg ggcgaggcgg 360gactcagtgc cgcgctctct gcacccgctc tgccgcgcgc gtgcgtgctg ggtgcgggtg 420cgggtgcggg gttgggcctg cgcatcgggt gagacgctgg ctgcttgcgg ctagtggatg 480gtaattgcct gcctcgcgct agcaggaagc tgctctgtta aaagcgaaaa tgaaacaatt 540gcctgcggca acagttcgac tcctttcaag ttctcagatc atcacttcgg tggtcagtgt 600tgtaaaagag cttattgaaa actccttgga tgctggtgcc acaagcgtag atgttaaact 660ggagaactat ggatttgata aaattgaggt gcgagataac ggggagggta tcaaggctgt 720tgatgcacct gtaatggcaa tgaagtacta cacctcaaaa ataaatagtc atgaagatct 780tgaaaatttg acaacttacg gttttcgtgg agaagccttg gggtcaattt gttgtatagc 840tgaggtttta attacaacaa gaacggctgc tgataatttt agcacccagt atgttttaga 900tggcagtggc cacatacttt ctcagaaacc ttcacatctt ggtcaaggta caactgtaac 960tgctttaaga ttatttaaga atctacctgt aagaaagcag ttttactcaa ctgcaaaaaa 1020atgtaaagat gaaataaaaa agatccaaga tctcctcatg agctttggta tccttaaacc 1080tgacttaagg attgtctttg tacataacaa gatttatctc agtggatttc ttccaaagtg 1140tgatgcagac cactctttca ctagtctttc aacaccagaa agaagtttca tcttcataaa 1200cagtcgacca gtacatcaaa aagatatctt aaagttaatc cgacatcatt acaatctgaa 1260atgcctaaag gaatctactc gtttgtatcc tgttttcttt ctgaaaatcg atgttcctac 1320agctgatgtt gatgtaaatt taacaccaga taaaagccaa gtattattac aaaataagga 1380atctgtttta attgctcttg aaaatctgat gacgacttgt tatggaccat tacctagtac 1440aaattcttat gaaaataata aaacagatgt ttccgcagct gacatcgttc ttagtaaaac 1500agcagaaaca gatgtgcttt ttaataaagt ggaatcatct ggaaagaatt attcaaatgt 1560tgatacttca gtcattccat tccaaaatga tatgcataat gatgaatctg gaaaaaacac 1620tgatgattgt ttaaatcacc agataagtat tggtgacttt ggttatggtc attgtagtag 1680tgaaatttct aacattgata aaaacactaa gaatgcattt caggacattt caatgagtaa 1740tgtatcatgg gagaactctc agacggaata tagtaaaact tgttttataa gttccgttaa 1800gcacacccag tcagaaaatg gcaataaaga ccatatagat gagagtgggg aaaatgagga 1860agaagcaggt cttgaaaact cttcggaaat ttctgcagat gagtggagca ggggaaatat 1920acttaaaaat tcagtgggag agaatattga acctgtgaaa attttagtgc ctgaaaaaag 1980tttaccatgt aaagtaagta ataataatta tccaatccct gaacaaatga atcttaatga 2040agattcatgt aacaaaaaat caaatgtaat agataataaa tctggaaaag ttacagctta 2100tgatttactt agcaatcgag taatcaagaa acccatgtca gcaagtgctc tttttgttca 2160agatcatcgt cctcagtttc tcatagaaaa tcctaagact agtttagagg atgcaacact 2220acaaattgaa gaactgtgga agacattgag tgaagaggaa aaactgaaat atgaagagaa 2280ggctactaaa gacttggaac gatacaatag tcaaatgaag agagccattg aacaggagtc 2340acaaatgtca ctaaaagatg gcagaaaaaa gataaaaccc accagcgcat ggaatttggc 2400ccagaagcac aagttaaaaa cctcattatc taatcaacca aaacttgatg aactccttca 2460gtcccaaatt gaaaaaagaa ggagtcaaaa tattaaaatg gtacagatcc ccttttctat 2520gaaaaactta aaaataaatt ttaagaaaca aaacaaagtt gacttagaag agaaggatga 2580accttgcttg atccacaatc tcaggtttcc tgatgcatgg ctaatgacat ccaaaacaga 2640ggtaatgtta ttaaatccat atagagtaga agaagccctg ctatttaaaa gacttcttga 2700gaatcataaa cttcctgcag agccactgga aaagccaatt atgttaacag agagtctttt 2760taatggatct cattatttag acgttttata taaaatgaca gcagatgacc aaagatacag 2820tggatcaact tacctgtctg atcctcgtct tacagcgaat ggtttcaaga taaaattgat 2880accaggagtt tcaattactg aaaattactt ggaaatagaa ggaatggcta attgtctccc 2940attctatgga gtagcagatt taaaagaaat tcttaatgct atattaaaca gaaatgcaaa 3000ggaagtttat gaatgtagac ctcgcaaagt gataagttat ttagagggag aagcagtgcg 3060tctatccaga caattaccca tgtacttatc aaaagaggac atccaagaca ttatctacag 3120aatgaagcac cagtttggaa atgaaattaa agagtgtgtt catggtcgcc cattttttca 3180tcatttaacc tatcttccag aaactacatg attaaatatg tttaagaaga ttagttacca 3240ttgaaattgg ttctgtcata aaacagcatg agtctggttt taaattatct ttgtattatg 3300tgtcacatgg ttatttttta aatgaggatt cactgacttg tttttatatt gaaaaaagtt 3360ccacgtattg tagaaaacgt aaataaacta atatagacta ttcaaaaaaa aaaaaaaaaa 3420a 3421173052DNAhomo sapiens 17ggcaagacaa cgaggatttg cgtagggggc gagcctctga ggccacttgg ctcttacggc 60cacgcagggc gccgcagatg cagccggagc ccgcttttcc ctctcaggac gacccctagg 120ccgccagcag ttccctaccg acgaaggcga ctgtacagcg tccaccgcgt tcgtgcccac 180ttacccgccg ccccactccg ggccgccggc tcgcagcagg accagcccgg ctgctacggc 240cgcggataca cgccctcagg cccggcgctg cgcagcttgc ggaagctttc ccggacagac 300tcgctgccag cggattggct gcgagcagcg ccaatctcac gttgcccccg ggcgaggcgg 360gactcagtgc cgcgctctct gcacccgctc tgccgcgcgc gtgcgtgctg ggtgcgggtg 420cgggtgcggg gttgggcctg cgcatcgggt gagacgctgg ctgcttgcgg ctagtggatg 480gtaattgcct gcctcgcgct agcaggaagc tgctctgtta aaagcgaaaa tgaaacaatt 540gcctgcggca acagttcgac tcctttcaag ttctcagatc atcacttcgg tggtcagtgt 600tgtaaaagag cttattgaaa actccttgga tgctggtgcc acaagcgtag atgttaaact 660ggagaactat ggatttgata aaattgaggt gcgagataac ggggagggta tcaaggctgt 720tgatgcacct gtaatggcaa tgaagtacta cacctcaaaa ataaatagtc atgaagatct 780tgaaaatttg acaacttacg gttttcgtgg agaagccttg gggtcaattt gttgtatagc 840tgaggtttta attacaacaa gaacggctgc tgataatttt agcacccagt atgttttaga 900tggcagtggc cacatacttt ctcagaaacc ttcacatctt ggtcaaggta caactgtaac 960tgctttaaga ttatttaaga atctacctgt aagaaagcag ttttactcaa ctgcaaaaaa 1020atgtaaagat gaaataaaaa agatccaaga tctcctcatg agctttggta tccttaaacc 1080tgacttaagg attgtctttg tacataacaa ggcagttatt tggcagaaaa gcagagtatc 1140agatcacaag atggctctca tgtcagttct ggggactgct gttatgaaca atatggaatc 1200ctttcagtac cactctgaag aatctcagat ttatctcagt ggatttcttc caaagtgtga 1260tgcagaccac tctttcacta gtctttcaac accagaaaga agtttcatct tcataaacag 1320tcgaccagta catcaaaaag atatcttaaa gttaatccga catcattaca atctgaaatg 1380cctaaaggaa tctactcgtt tgtatcctgt tttctttctg aaaatcgatg ttcctacagc 1440tgatgttgat gtaaatttaa caccagataa aagccaagta ttattacaaa ataaggaatc 1500tgttttaatt gctcttgaaa atctgatgac gacttgttat ggaccattac ctagtacaaa 1560ttcttatgaa aataataaaa cagatgtttc cgcagctgac atcgttctta gtaaaacagc 1620agaaacagat gtgcttttta ataaagtgga atcatctgga aagaattatt caaatgttga 1680tacttcagtc attccattcc aaaatgatat gcataatgat gaatctggaa aaaacactga 1740tgattgttta aatcaccaga taagtattgg tgactttggt tatggtcatt gtagtagtga 1800aatttctaac attgataaaa acactaagaa tgcatttcag gacatttcaa tgagtaatgt 1860atcatgggag aactctcaga cggaatatag taaaacttgt tttataagtt ccgttaagca 1920cacccagtca gaaaatggca ataaagacca tatagatgag agtggggaaa atgaggaaga 1980agcaggtctt gaaaactctt cggaaatttc tgcagatgag tggagcaggg gaaatatact 2040taaaaattca gtgggagaga atattgaacc tgtgaaaatt ttagtgcctg aaaaaagttt 2100accatgtaaa gtaagtaata ataattatcc aatccctgaa caaatgaatc ttaatgaaga 2160ttcatgtaac aaaaaatcaa atgtaataga taataaatct ggaaaagtta cagcttatga 2220tttacttagc aatcgagtaa tcaagaaacc catgtcagca agtgctcttt ttgttcaaga 2280tcatcgtcct cagtttctca tagaaaatcc taagactagt ttagaggatg caacactaca 2340aattgaagaa ctgtggaaga cattgagtga agaggaaaaa ctgaatcttt ttaatggatc 2400tcattattta gacgttttat ataaaatgac agcagatgac caaagataca gtggatcaac 2460ttacctgtct gatcctcgtc ttacagcgaa tggtttcaag ataaaattga taccaggagt 2520ttcaattact gaaaattact tggaaataga aggaatggct aattgtctcc cattctatgg 2580agtagcagat ttaaaagaaa ttcttaatgc tatattaaac agaaatgcaa aggaagttta 2640tgaatgtaga cctcgcaaag tgataagtta tttagaggga gaagcagtgc gtctatccag 2700acaattaccc atgtacttat caaaagagga catccaagac attatctaca gaatgaagca 2760ccagtttgga aatgaaatta aagagtgtgt tcatggtcgc ccattttttc atcatttaac 2820ctatcttcca gaaactacat gattaaatat gtttaagaag attagttacc attgaaattg 2880gttctgtcat aaaacagcat gagtctggtt ttaaattatc tttgtattat gtgtcacatg 2940gttatttttt aaatgaggat tcactgactt gtttttatat tgaaaaaagt tccacgtatt 3000gtagaaaacg taaataaact aatatagact attcaaaaaa aaaaaaaaaa aa 3052183830DNAhomo sapiens 18ggtgtttata agaatggaag tgttgtttcc ttgcccgatt ccttcatgct atatctcatg 60aacctctgta atcttggggg agagactata tttaatgatg acaaacctgt caccagtgta 120gcaacaacag tgtgaggaca aaagcaaata aaaattaaga agcgttcaaa tttatattca 180acaaggaagt catttcaatc aacaacttct gctgcattat ttttccaaga tgaaccgata 240cacaaccatg agacagttgg gggacggcac gtatgggagt gtgcttatgg gcaagagtaa 300tgaatccggg gagctggtgg ccatcaaaag gatgaagaga aagttctatt cttgggatga 360atgcatgaac ttgagagaag ttaagtctct gaagaaactt aatcatgcca atgttattaa 420attgaaagaa gttatcagag aaaatgacca tctttatttt atatttgaat atatgaaaga 480aaacctctat caattaatga aagacagaaa caagttgttc cctgaatcag tcatcagaaa 540tattatgtat caaatattgc aagggctggc ttttatccat aaacatggct tttttcatag 600ggacatgaaa ccagaaaact tgctttgtat gggtccagag cttgtgaaaa ttgctgattt

660tggacttgca agagaattaa ggtcacagcc accatacact gattatgtat ctaccagatg 720gtatcgtgcc cctgaagttt tactgagatc ttcagtttat agttctccca ttgatgtgtg 780ggctgttgga agtatcatgg ctgaactcta tatgttaagg ccacttttcc cagggacaag 840tgaggtcgat gaaatcttta aaatttgcca agttttaggg actcccaaaa aaagtgactg 900gccagaagga taccagctgg catcctctat gaacttccgt tttccccagt gtgttcctat 960aaacttaaaa actcttattc ccaatgccag taatgaagct attcagctca tgaccgaaat 1020gttgaattgg gatccaaaga aacgaccgac agcaagccag gcattgaaac acccatattt 1080tcaagttggt caggtattag gcccttcgtc aaatcatctg gaatcaaaac agtctttaaa 1140taagcagctg caaccattag aatcaaagcc atctttagtt gaggtagagc ctaagcctct 1200gccggatata atcgatcagg ttgttggaca accccagcca aaaactagcc agcagccact 1260gcagcccatt cagccgccac agaacctgag cgtccagcaa cctccaaagc aacagagtca 1320ggagaaaccg ccacaaacgc tattcccgag catcgtcaaa aacatgccaa ctaagccaaa 1380tggcacactg agtcataaaa gtggtaggag gcgttggggt cagactatct tcaagtctgg 1440agatagctgg gaagagttgg aggactatga tttcggagcc tcccattcca agaagccaag 1500catgggtgtt tttaaagaaa aaaggaaaaa agattctcca tttcggcttc cagagccagt 1560accctcaggc tccaaccact cgacagggga aaacaagagc ttacctgctg ttacttccct 1620aaaatctgat tccgaattgt caactgctcc aacctctaaa cagtactact tgaaacaatc 1680aagatatctt ccaggtgtga atcccaagaa ggtgtccttg atagccagtg gaaaggaaat 1740aaacccccac acttggagca accagttatt ccccaagtca ctgggacccg ttggggcaga 1800acttgctttc aaaaggagca atgcaggaaa tcttggaagt tatgctactt acaatcagtc 1860aggatatatt ccttcctttc tcaaaaaaga agtgcagtca gctggccaga ggatccactt 1920agcacctctc aatgcaacgg cttcagaata tacctggaac acaaaaactg gtcgggggca 1980gttttcagga cgtacttata atcctacagc aaaaaaccta aatattgtga accgtgcaca 2040gcccattccc tcagtgcatg ggaggacaga ctgggtggcc aagtatggag gccaccggta 2100ggagtctatg gtgtgaaacc ctacagcatt gctccgtaga gtacgtgcaa gttccttgac 2160cctgggaaat gtctacaaat gtctatttct actgagttct ggaagaaata tgcaaaagtg 2220ggtacttgga agggcaaaaa tcatccccta ttttacttat ttccaagaaa tgcattttct 2280tagcatcatt gcccacagtg ttgatatatg ggtaggatgt tacaaagtat tgaataaact 2340atttgccaaa gtatgaagta tttgatctac aatttaataa atagtaaatc caataagaac 2400ccttaaaaaa aaacaacttc cagaaaatgt ttagagtgtt ttagttttca tttgttgtat 2460gtgcccaaat ggtttagtag ttcttcactt tgctgtggtt ggcttaagag gtttgtcttt 2520tgtttttgta cagcagttgg gccaaccttt gctggctgtc agctgtggtt cttatttgac 2580taaggctctg cgctgccatt ttgtcaatga cagaaagatt gcaattattt gtttttctac 2640tttgaagcta tgggagcgat ggtaatttca atcttgagca ggatatcttt tttttttttt 2700ttgaggcgat gtttcactct tgtgtccagg ctggagtgca gtggcactat cttggcttac 2760tgcaacctcc acctcctggg ttcaagtgat tctcctgcct cagcctcccg agtagctggg 2820attagaggcg tgtgccacca tgcctggcta atttttgtag tattagtaga gacagggttt 2880caccatgttg gtcaggctca ggctggtctc aaactcctga cctcaggtga tccacctgcc 2940tcggcctccc aaagtgcagg gcttacaggt gtgagccaca gtgcccagct tttttttttt 3000ttttttagaa ataaatttat ctttaacata gagaatatca aagttatgcc acttgatttt 3060agtggacggc ttgtgttttg atcttgacca gtacagttcc catgaattca aggtgacaat 3120caagcccaat ggcttgatga cttcaatagt aaccaagtca aggttctctt ggctggacat 3180cattaagaaa gttctggaaa ctgtgtttgt ttgatgctgg ttcattggac ttttcaaatt 3240gttttgtttc tgtgtcccta ccagacacaa agatgaagtg tgccagctgg ttcccccaag 3300ccagctcatg ctgctgacca ctgactcagc tctgaccttc acatttgctc tgaagcaagt 3360gcgttcagct gctggggcag tgatatcaca tagtacatat attatttcct tagtttattt 3420ccaaactggt attttaaata gacacttcga actttgggct actctgttta aatctgccac 3480tttctggact ggaccttagt actgtaaatt ctttttaaag aataataatg ttaccaactg 3540ctgagatttt tatgtatttt gtgactttgt aacaactgct attgtaataa gtgtcatctt 3600gtgggcatta tacaaaggca tattataaaa taataatgat atttttgtat agaagagtca 3660actgttcaga tgtaagatgt tgaaaaatgt taaaatctaa agagtaattt atcctagtgg 3720taatggttat atgtatttgt acagtttaaa ttaatgtctc aaagctgtgc agtcttttgt 3780tactgggaca cttttaaact ctgaataggc attaaaaaaa atatggctaa 3830198025DNAhomo sapiens 19cggcgctgct ggaagatggc gagcggccgg gacgagcggc cgccttggcg gctagggcgg 60ctcctgttgc tcatgtgcct gctgctgctg gggagctcgg cccgggcggc tcacatcaag 120aaggcggagg cgactaccac aactacgagc gcgggcgccg aggcggccga gggccagttc 180gaccgctact accacgaaga ggagttggag tcggcgctga gggaggcggc ggccgcgggc 240ctccccggcc tggcccgcct ctttagcatc ggccgctcgg tggaaggccg gccgctgtgg 300gtgcttcgcc tcaccgccgg cctggggtcg ctaatccctg agggcgacgc ggggcctgac 360gctgccgggc ccgacgctgc ggggccgctg ctgcccggcc ggccccaggt gaagctggtg 420ggcaacatgc atggcgacga gaccgtgtcg cgccaggtgt tgatctactt ggcccgcgag 480ctggcggccg gctaccgccg cggggacccg cgcctggtcc gcctgctcaa caccaccgac 540gtgtacctgc tgcccagcct caaccccgat ggcttcgagc gtgcccgcga gggcgactgt 600ggcttcggcg acggcggccc gtccggggcc agcggccgcg acaatagtcg cggccgcgac 660ctcaaccgaa gctttcccga ccagtttagc accggcgaac cccccgccct ggacgaggtg 720cccgaggtgc gcgccctcat cgagtggatc cgcaggaaca agtttgtgct ttctggaaat 780ctgcatggtg gctcagtggt agcaagctat ccttttgatg attctccaga acataaggcc 840actggaatct atagcaaaac ctcagatgat gaagtattta aatacttggc aaaagcttat 900gcttcaaacc accccataat gaaaactggt gagcctcatt gtccaggaga tgaagacgag 960actttcaaag atggaatcac aaacggcgca cattggtatg atgtggaagg tggtatgcaa 1020gattacaatt atgtgtgggc caactgtttt gagatcacat tagaactgtc ttgttgcaag 1080tacccacctg cttcacagct tcgacaggaa tgggagaaca atcgtgagtc tttgatcaca 1140ttgattgaaa aggttcacat tggagtgaaa ggatttgtta aagattccat aacaggatct 1200gggttagaga atgcaaccat ctcagtggct ggtattaatc ataatatcac aacaggcaga 1260tttggtgatt tctaccgatt acttgttcct ggaacttaca accttacagt agttttaact 1320gggtatatgc cattgactgt tactaatgta gtggtgaaag aaggaccagc cacagaggtg 1380gatttttctc ttaggccaac tgtaacttca gtaatccctg acacgacaga ggctgtatca 1440actgctagca cagttgctat acctaatatt ctttctggaa catcatcctc ctaccagcca 1500attcagccaa aggactttca ccaccaccat ttccctgata tggaaatctt cttgagaagg 1560tttgccaatg aatatcctaa cattacccgg ctttattcct tgggaaaatc agtagagtca 1620agagaacttt atgtgatgga gatatctgat aatccgggtg tccatgaacc aggtgaacca 1680gaatttaagt acattggaaa tatgcatgga aatgaagtgg ttggaagaga actgctgttg 1740aacctcatag aatacctttg taagaacttt ggaacagacc ctgaagtcac agatttggtt 1800cataacacta gaattcacct tatgccatcc atgaatcctg atgggtatga aaagtcccag 1860gaaggagatt caataagtgt aattggcaga aacaacagca acaactttga cctgaaccga 1920aatttcccag accagtttgt tcagatcaca gatcctacgc aaccagaaac tattgctgta 1980atgagctgga tgaagtccta tccatttgta ctttcagcaa acctgcatgg aggttctttg 2040gtggttaact acccttttga tgatgatgaa caaggacttg ccacatatag taaatcacca 2100gatgatgctg tgttccaaca aatagcactt tcttattcca aggaaaattc ccagatgttt 2160caaggtagac cttgcaagaa tatgtatcct aatgaatatt ttcctcatgg aataacaaat 2220ggagctagtt ggtataatgt gccaggagga atgcaggact ggaactattt acaaacaaat 2280tgctttgaag tgactattga actaggttgt gtgaaatatc cacttgagaa agagctgcca 2340aacttttggg aacagaatcg aagatcacta atccagttta tgaaacaggt tcatcagggc 2400gtcagaggat ttgttctaga tgccacagat ggcaggggta tattaaatgc caccattagt 2460gttgctgaga ttaatcaccc agtgactact tacaaaactg gagattactg gcgtctcttg 2520gttccaggaa cttataaaat cacagcatct gctcgagggt ataatccagt taccaagaat 2580gtgactgtca agagtgaagg cgctattcag gtcaacttca cacttgttcg atcctcaaca 2640gattcaaaca atgaatcaaa gaaaggaaaa ggggctagca gcagcaccaa tgatgccagt 2700gatccaacta ctaaagagtt tgaaacttta attaaagacc tttcagcgga gaatggtttg 2760gaaagcctca tgttacgctc ctcctcaaat ctggctctgg ctctttatcg ataccattcc 2820tacaaagact tatcagagtt tctgagagga cttgtaatga actatccaca tattacaaat 2880cttaccaatt tgggacagag cactgaatat cgtcacattt ggtcccttga aatctccaat 2940aagcccaatg tatctgagcc tgaagaacca aagattcgtt ttgttgctgg tatccatgga 3000aatgcgccag ttggaactga actgcttttg gctctggcag aatttctctg cctgaactac 3060aaaaagaacc cagctgttac ccaattggtt gacaggacta ggattgtgat tgtcccttct 3120ctaaatccag atgggcgaga gagagctcaa gagaaagact gtacttcaaa aataggacaa 3180acaaatgctc gtggcaaaga tttggataca gacttcacaa ataatgcctc ccaacctgag 3240accaaagcca tcattgaaaa tttgattcaa aaacaggact ttagtctttc tgttgcctta 3300gatggtggtt ccatgctggt cacatatcct tatgacaagc cagtacagac agtggaaaat 3360aaagagactc tgaagcattt ggcatctctt tatgcaaata atcatccatc catgcacatg 3420ggtcagccca gttgcccaaa taaatcagat gagaatattc caggaggagt aatgcgtgga 3480gcagaatggc atagtcacct gggcagcatg aaggattata gtgtcaccta tggccattgt 3540ccggaaatca cagtatacac aagctgctgt tactttccta gtgctgcacg actcccttcc 3600ttgtgggcag acaataagag atctcttctt agtatgttag tggaggttca caagggagtt 3660catggatttg ttaaagataa gactggaaag ccaatctcta aagcagtcat tgtacttaat 3720gaaggaataa aggtacaaac aaaagaggga ggttatttcc atgtactctt agcgccaggt 3780gtccataaca ttattgccat cgctgatggg taccagcaac aacattcaca ggtctttgtg 3840catcatgatg cagctagttc tgtggtgata gtctttgaca cagataaccg gatatttggt 3900ttgccaaggg agcttgtggt aactgtatca ggtgctacta tgtcggcatt gatcctaaca 3960gcttgcatta tttggtgcat ctgctcaatc aagtctaata gacacaagga tggctttcat 4020cggctcaggc agcatcatga tgagtatgaa gatgaaattc gcatgatgtc taccggctcc 4080aagaagtccc tcctaagcca tgagttccag gatgaaacag acactgaaga ggaaacatta 4140tattctagca aacattgaaa aacacatttt gcatatctcc cagcataagt accaagcaaa 4200attacagttc ctcttgggag aacactgcat taagaagaga gactctcttg cttcttcaaa 4260gagctttggg aaattaaatt gctaaatttg tattctctgt gaatttcact ggcagttttg 4320aacttccctt ccttaaagta ctctaaacct ttaaaaaaaa atctgattta tgcagcagag 4380atgggacagc cactttttct ttttaattta agatgagcta tttggagctt atgtaataat 4440ggcataaagc caactagagg atgttgtatt ttgcacatca gatgtttact agtggcttta 4500gtatttttct ttgttttaaa tggccaaaag aatccagaaa cattaaggca gggacagcag 4560tcagaatcga cataaagctt taaaaactca aggttttttc aacctactga ggagtacttt 4620tctctagttg ttaaatagct ggagtttttc ttattcaggt ttaatggagg ttgaattgat 4680ttttaaacac atataacagt aggaaatgaa taaatgggct tctgcatttg gctttctacc 4740tgttccaagg ctagatcgga actggtagac tacgctgtaa gcaggatttc actacctctc 4800ttaaggttta gcaaacttct aaatagccca ttttaaggga gaacttacta actttattgt 4860gaaaggtcta aatgcccact tgaatgaagc tgagagagag atctagcaaa agctaaaact 4920catgttgtct atctttgaac ttggtaaaaa cccacaggtg ctgctgctta tatctgtgaa 4980gcactagctt attctaggaa tgcctgattc tttaatattg cctaaatcgg aacctttttc 5040tatgttgcac acatggtttt cagatgaccc agccatctac aagatctgaa ttctactgaa 5100aatatctaga aatgtggaag agacctactt gcacattctt aacctgtatt tgaacacaaa 5160atatctatac ttcatgctcc agcccaagcc tataccctgt aatagcatac tattattgaa 5220atcgcttgac cggtcttgtt cacataggcc tctgggagtg atttggttct ttgccctaat 5280gtttcatttg acggtctctt tttgatcaac caatttttct aaaagttcag tcgaaagctt 5340ttaagtatag cttcctccct tgaaaaaaaa tgtaaactat gactgctgag tgataaaaca 5400ctgtggtgtg aaagtgtcat cttcactgcc aatcaggcaa agaccggaaa gatttgcatt 5460ttattatgtc tgtcttatca tgcaatggaa atgatgcttt ttgtaagtat gcatcttacc 5520aatgatgtaa cggtttaata cctttgaatg ttttaataac caagttgctg ctgaacttat 5580actaaatcag gggaccaaaa aacttgctct tatcttctca aattgtattc tatatccatt 5640aatgtatcag ttatcccaaa gccttcaggt ggaggggttt accaccttcc taggtcgttc 5700aaccaggttt tgtgaggaat gcattcaaag tggctttata aaagaagatt ttctttagca 5760agaataatga ggtcatgtca tttgttaata agtatctgtg ataaatccgt ggttcaaggt 5820taagccattc tggtattctg gtattagcaa ctgtaaattc tgccacctca tacatggaac 5880agagcttgtg ggatgctaat agttagtgaa gtatacatga tttaatttct aataatcttt 5940atgttttctt taaggatggt ggtgtattgc tctttttcag ctttattttt aagagtacag 6000tcaggaaacc aacaaggggc ctaagagtgg ctgcccctgc ttgggacatt acagcaagtg 6060aaacaaagtt aatgtgacaa gctttgcttt gttatcattg gtcttcacta gaggatacct 6120tttacatgta cttctctctt ggatcaaata tgtctttaac tgtacatctc agtggctgga 6180ggccatgcct tttaagcatg tgtaaaattt ttaaagaaat gaacatacac atagttattt 6240tagtaatatt tcctgaaaga aaaaccaaat tctgctataa gtcttgatct tcaatgaact 6300tttaaataat gcatttagct ggaaaacaag actttcccag cttgtattac ctagaagcgt 6360gaatgtatag gatacctgac tactaagact atattctcag ccctgccctg tcttttattt 6420gcgggtctaa tctaatatta gaatatatta accgcttaag gcattgaagc catatgggat 6480ggggaatgca tttcttcagt gtttctccga gagactttcc atttccttgg agttatggcg 6540gcaagtaagt atcatagtat taagaaattt gcctaaatct gagttgtgcc tttctttact 6600cacaaggcat gggctttgtc ctggtgatca gtttgtaagc cttcttcctt cccagctcct 6660taataaaagc aaagtgattg agtaggtaat gttcaaagtg tctgcctgtg tacatgtact 6720tgtattgatt atgtagttca gtaagatgtg cccaagtcat ttcagaaaga aagacccttc 6780agttttgatg cattttgctg aacacttggg tagtgagtgg gatcctatcc agttgaggaa 6840tgcttgcaat gctcattgaa gggatttgct ttgggacttt gtcatcttcc agaaaggaaa 6900catattgtat atttggccca gtgtgattga ttgctttatc tttggtaact tttacttgaa 6960tgggatttgc tgaattaatg actattgaat ttaaaactaa ttatgagttg acaaataaat 7020aaaaggtagt gtttatgtct gagcttattg tgtttgagct aacaccaggt tactcagtaa 7080ccatgacctg ctcctccatt tccatttatt ctcaacatta aatagtttta tcttgttgtt 7140gccagaaatg cacttgtgcc aggtattgtc cctgctgtat gaaaagcttc ttggcaatga 7200attctgtaat agtgccctac attatggttt tctggtggaa ttgttttaac agtgacaacc 7260caggatttcc aatatatttt tgttttattg ttattaccaa aaattccact atgattgatg 7320ttcagtgatt ttctatagca acttttttgg taactctttg ggtttctgat ttgttttagc 7380taaaattttg gggatatgat ttgggtcttt gattaatgtc agctgaactt ggatttctag 7440ttcatgaaga aatctctccc aatacccatt tatcctattt ttagcaataa ttcgttaatg 7500attccacttg attttcagaa tattgtcctg gttgattttg atttgacagc atacattatg 7560aaatttgaaa gtaggttacc attttgaggc agttggatat aaattatgta aatatgtatg 7620attatgattt ttataaatgg cataacatga gtgtactaac taccttctat gctggccatg 7680ctacagattt tctggaggta tgacaatagt atttttttat gctcagatta aaaatcagct 7740tttcacctct ccagtttttc caagtgatac tcccagttct agagcaatct acagctgttt 7800atgtgaggtg cccaacaccc attcatctca agtgcttcag tctttggttt atttcatgca 7860ctgtgccttc aaaatgaaat ttttaaaagg gactttaaat gaagttgaat agtagttttt 7920aaaagtcaat ttgtaattta tgtgaaatct aactgtaatg aggtcctttc tgttttttat 7980atgtaaacag atctactaat cctgtataaa agttatttta cgatg 802520928DNAhomo sapiens 20gctgtggccc tggcacctgc ccctgggctg ggacagccca ctgttccatg ctgcccaaga 60aggctcagca caggcacaaa ccattgcccg gcactggccc gtgctgcctg agaaggattg 120gcacgggcac agaccactgc ccccacctgc cctgcgccat ctacccaaga aggctcggca 180cgggcaccaa ccactgcctc caactgcccc atgctgcctg agaaggcact gcacggccac 240ccccaactgc cccgcactgt ccctacccgg gcagccatgc gagcggctgg aactctgctg 300gccttctgct gcctggtctt gagcaccact gggggccctt ccccagatac ttgttcccag 360gaccttaact cacgtgtgaa gccaggattt cctaaaacaa taaagaccaa tgacccagga 420gtcctccaag cagccagata cagtgttgaa aagttcaaca actgcacgaa cgacatgttc 480ttgttcaagg agtcccgcat cacaagggcc ctagttcaga tagtgaaagg cctgaaatat 540atgctggagg tggaaattgg cagaactacc tgcaagaaaa accagcacct gcgtctggat 600gactgtgact tccaaaccaa ccacaccttg aagcagactc tgagctgcta ctctgaagtc 660tgggtcgtgc cctggctcca gcacttcgag gtgcctgttc tccgttgtca ctgacccccg 720cctcttcagc aagaccacag ccatgacaaa caccaggatg catgctcctt gtcccctccc 780acccgcctca tgacccagcc tcacagaccc tctcaggcct ctgacgagtg agcgggtgaa 840gtgccactgg gtcaccgcag ggcagctgga atggcagcat ggtagcacct cctaacagat 900taaatagatc acatttgctt ctaaaatt 928212545DNAhomo sapiens 21actcattcac ataaaacgct gcgcggccgg cggaatcccc ggcttctagg gcggcgagcg 60gccgggctgg ctatcgagcg agcggggcgg gaacgcggag ttgcgccgcc gctcgggcgc 120cgggctccgt cgcggccgca gccccgcggg tcgccctccc gtgcctcgcc cgcggacacc 180ctggccgtgg acaccctggc cgtgggcacc cgcggggcgc gcggcgcggg gccgctggcc 240ggcggcggcg gcggcatgaa ggtcacgtcg ctcgacgggc gccagctgcg caagatgctc 300cgcaaggagg cggcggcgcg ctgcgtggtg ctcgactgcc ggccctatct ggccttcgct 360gcctcgaacg tgcgcggctc gctcaacgtc aacctcaact cggtggtgct gcggcgggcc 420cggggcggcg cggtgtcggc gcgctacgtg ctgcccgacg aggcggcgcg cgcgcggctc 480ctgcaggagg gcggcggcgg cgtcgcggcc gtggtggtgc tggaccaggg cagccgccac 540tggcagaagc tgcgagagga gagcgccgcg cgtgtcgtcc tcacctcgct actcgcttgc 600ctacccgccg gcccgcgggt ctacttcctc aaagggggat atgagacttt ctactcggaa 660tatcctgagt gttgcgtgga tgtaaaaccc atttcacaag agaagattga gagtgagaga 720gccctcatca gccagtgtgg aaaaccagtg gtaaatgtca gctacaggcc agcttatgac 780cagggtggcc cagttgaaat ccttcccttc ctctaccttg gaagtgccta ccatgcatcc 840aagtgcgagt tcctcgccaa cctgcacatc acagccctgc tgaatgtctc ccgacggacc 900tccgaggcct gcgcgaccca cctacactac aaatggatcc ctgtggaaga cagccacacg 960gctgacatta gctcccactt tcaagaagca atagacttca ttgactgtgt cagggaaaag 1020ggaggcaagg tcctggtcca ctgtgaggct gggatctccc gttcacccac catctgcatg 1080gcttacctta tgaagaccaa gcagttccgc ctgaaggagg ccttcgatta catcaagcag 1140aggaggagca tggtctcgcc caactttggc ttcatgggcc agctcctgca gtacgaatct 1200gagatcctgc cctccacgcc caacccccag cctccctcct gccaagggga ggcagcaggc 1260tcttcactga taggccattt gcagacactg agccctgaca tgcagggtgc ctactgcaca 1320ttccctgcct cggtgctggc accggtgcct acccactcaa cagtctcaga gctcagcaga 1380agccctgtgg caacggccac atcctgctaa aactgggatg gaggaatcgg cccagcccca 1440agagcaactg tgatttttgt ttttaagact catggacatt tcatacctgt gcaatactga 1500agacctcatt ctgtcatgct gccccagtga gatagtgagt ggtcaccagg cttgcaaatg 1560aacttcagac ggacctcagg gtaggttctc gggactgaag gaaggccaag ccattacggg 1620agcacagcat gtgctgacta ctgtacttcc agacccctgc cctcttggga ctgcccagtc 1680cttgcacctc agagttcgcc ttttcatttc aagcataagg caataaatac ctgcagcaac 1740gtgggagaaa gaagttgctg gaccaggaga aaaggcagtt atgaagccaa ttcattttga 1800aggaagcaca atttccacct tattttttga actttggcag tttcaatgtc tgtctctgtt 1860gcttcggggc ataagctgat caccgtctag ttgggaaagt aaccctacag ggtttgtagg 1920gacatgatca gcatcctgat ttgaaccctg aaatgttgtg tagacaccct cttgggtcca 1980atgaggtagt tggttgaagt agcaagatgt tggcttttct ggattttttt tgccatgggt 2040tcttcactga ccttggactt tggcatgatt cttagtcata cttgaacttg tctcattcca 2100cctcttctca gagcaactct tcctttggga aaagagttct tcagatcata gaccaaaaaa 2160gtcatacctt cgaggtggta gcagtagatt ccaggaggag aagggtactt gctaggtatc 2220ctgggtcagt ggcggtgcaa actggtttcc tcagctgcct gtccttctgt gtgcttatgt 2280ctcttgtgac aattgttttc ctccctgccc ctggaggttg tcttcaagct gtggacttct 2340gggatttgca gattttgcaa cgtggtacta cttttttttt ctttttgtct gttagttatt 2400tctccagggg aaaaggcaat aattttctaa gacccgtgtg aatgtgaaga aaagcagtat 2460gttactggtt gttgttgttg ttcttgtttt ttatagtgta aaataaaaat agtaaaagga 2520gaaaagcaaa aaaaaaaaaa aaaaa 2545226648DNAhomo sapiens 22acatgttact tcctgtatgg aggcatggcc agtttccagc cccgcgctct tcgttccttc 60ccagcctgcg ccggagccac aactttcagg agcatggact gaaggcgccc tcgccccagc 120gcccctctga gatcctttgt gttttcctcc gtttcctccg gccgtttcta ttttgggggg 180ctctccgctc cccctgcctc tcccctcccc ttcccctctc

gcaaacatgc ctccttcctt 240cccggggccc tggaaggagc tgcctgcctg aagcccggag acgccgcgcc gcgctcagcc 300ccgccgccgc ccgccggctc tcgggctgtg ctgcgctgcc gactcaagtt ggggatcctc 360ggctgctcgc cgccgccgcc cgcggtccct gcctgcccca ggcccggggc atcgccgccg 420gccgccgact ccgcgccctg cccgatcggc tctctccttt ttaaacggaa agcagccttt 480ctccgccgag aggatcgtcc ccagcgtggc tctgcgttcc cggtcacttt ttgagatttt 540ccggggggcg ctcggcggct tcccggattc caaggggact cgggccgccg agcgcggggg 600gcccgtggag cgggcgagcc ggggaagcgc cccggcttag cggaggctcg cacggaggca 660agaacttatt caacaagttt acctccctgc tttcctcttt tcgatgtgcg ttttcggaca 720tgcggaggtt actggaaccg tgttggtgga ttttgttcct gaaaatcacc agttccgtgc 780tccattatgt cgtgtgcttc cccgcgttga cagaaggcta cgttggggcc ctgcacgaga 840atagacacgg cagcgcagtg cagatccgca ggcgcaaggc ttcaggcgac ccgtactggg 900cctactctgg tgcctatggt cctgagcact gggtcacgtc tagtgtcagc tgtgggggcc 960gtcaccagtc tcctattgac attttagacc agtatgcgcg tgttggggaa gaataccagg 1020aactgcaact cgatggcttc gacaatgagt cttctaacaa aacctggatg aaaaacacag 1080ggaaaacagt cgccatcctt ctgaaagacg actattttgt cagtggagct ggtctacctg 1140gcagattcaa agctgagaag gtggaatttc actggggcca cagcaatggc tcagcgggct 1200ctgaacacag catcaatggc aggaggtttc ctgttgagat gcagattttc ttttacaatc 1260cagatgactt tgacagcttt caaaccgcaa tttctgagaa cagaataatc ggagccatgg 1320ccatattttt tcaagtcagt ccgagggaca attctgcact ggatcctatt atccacgggt 1380tgaagggtgt cgtacatcat gagaaggaga cctttctgga tcctttcgtc ctccgggacc 1440tcctgcctgc atccctgggc agctattatc ggtacacagg ttccttgacc acaccaccgt 1500gtagcgaaat agtggagtgg atagtcttcc ggagacccgt ccccatctct taccatcagc 1560ttgaggcttt ttattccatc ttcaccacgg agcagcaaga ccatgtcaag tcggtggagt 1620atctgagaaa taactttcga ccacagcagc gtctgcatga cagggtggtg tccaagtccg 1680ccgtccgtga ctcctggaac cacgacatga cagacttctt agaaaaccca ctggggacag 1740aagcctctaa agtttgcagc tctccaccca tccacatgaa ggtgcagcct ctgaaccaga 1800cggcactgca ggtgtcctgg agccagccgg agactatcta ccacccaccc atcatgaact 1860acatgatctc ctacagctgg accaagaatg aggacgagaa ggagaagacg tttacaaagg 1920acagcgacaa agacttgaaa gccaccatta gccatgtctc acccgatagc ctttacctgt 1980tccgagtcca ggccgtgtgt cggaacgaca tgcgcagcga ctttagccag acgatgctgt 2040ttcaagctaa taccactcga atattccaag ggaccagaat agtgaaaaca ggagtgccca 2100cagcgtctcc tgcctcttca gccgacatgg cccccatcag ctcggggtct tctacctgga 2160cgtcctctgg catcccattc tcatttgttt ccatggcaac tgggatgggc ccctcctcca 2220gtggcagcca ggccacagtg gcctcggtgg tcaccagcac gctgctcgcc ggcctggggt 2280tcggcggtgg tggcatctcc tctttcccca gcactgtgtg gcccacgcgc ctcccgacgg 2340ccgcctcagc cagcaagcag gcggctaggc cagtcctagc caccacagag gccttggctt 2400ctccagggcc cgatggtgat tcgtcaccaa ccaaggacgg cgagggcacc gaggaaggag 2460agaaggatga gaaaagcgag agtgaggatg gggagcggga gcacgaggag gatggagaga 2520aggactccga aaagaaggag aagagtgggg tgacccacgc tgccgaggag cggaatcaga 2580cggagcccag ccccacaccc tcgtctccta acaggactgc cgagggaggg catcagacta 2640tacctgggca tgagcaggat cacactgccg tccccacaga ccagacgggc ggaaggaggg 2700atgccggccc aggcctggac cccgacatgg tcacctccac ccaagtgccc cccaccgcca 2760cagaggagca gtatgcaggg agtgatccca agaggcccga aatgccatct aaaaagccta 2820tgtcccgcgg ggaccgattt tctgaagaca gcagatttat cactgttaat ccagcggaaa 2880aaaacacctc tggaatgata agccgccctg ctccagggag gatggagtgg atcatccctc 2940tgattgtggt atcagccttg accttcgtgt gcctcatcct tctcattgct gtgctcgttt 3000actggagagg gtgtaacaaa ataaagtcca agggctttcc cagacgtttc cgtgaagtgc 3060cttcttctgg ggagagagga gagaagggga gcagaaaatg ttttcagact gctcatttct 3120atgtggaaga cagcagttca cctcgagtgg tccctaatga aagtatccct attattccta 3180ttccggatga catggaagcc attcctgtca aacagtttgt caaacacatc ggtgagctct 3240attctaataa ccagcatggg ttctctgagg attttgagga agtccagcgc tgtactgctg 3300atatgaacat cactgcagag cattccaatc atccagaaaa caagcacaaa aacagataca 3360tcaacatttt agcatatgat cacagtaggg tgaagttaag acctttacca ggaaaagact 3420ctaagcacag cgactacatt aatgcaaact atgttgatgg ttacaacaaa gcaaaagcct 3480acattgccac ccaaggacct ttgaagtcta catttgaaga tttctggagg atgatttggg 3540aacaaaacac tggaatcatt gtgatgatta cgaaccttgt ggaaaaagga agacgaaaat 3600gtgatcagta ttggccaaca gagaacagtg aggaatatgg aaacattatt gtcacgctga 3660agagcacaaa aatacatgcc tgctacactg ttcgtcgttt ttcaatcaga aatacaaaag 3720tgaaaaaggg tcagaaggga aatcccaagg gtcgtcagaa tgaaagggta gtgatccagt 3780atcactatac acagtggcct gacatgggag ttcccgagta tgcccttcca gtactgactt 3840tcgtgaggag atcctcagca gctcggatgc cagaaacggg ccctgtgttg gtgcactgca 3900gtgctggtgt gggcagaaca ggcacctata ttgtaataga cagcatgctg caacagataa 3960aagacaaaag cacagttaac gtcctgggat tcctgaagca tatcaggaca cagcgtaact 4020acctcgtcca gactgaggag cagtacattt tcatccatga tgccttgttg gaagccattc 4080ttggaaagga gactgaagta tcttcaaatc agctgcacag ctatgttaac agcatcctta 4140taccaggagt aggaggaaag acacgactgg aaaagcaatt caagctggtc acacagtgta 4200atgcaaaata tgtggaatgt ttcagtgctc agaaagagtg taacaaagaa aagaacagaa 4260actcttcagt tgtgccatct gagcgtgctc gagtgggtct tgcaccattg cctggaatga 4320aaggaacaga ttacattaat gcttcttata tcatgggcta ttataggagc aatgaattta 4380ttataactca gcatcctctg ccacatacta cgaaagattt ctggcgaatg atttgggatc 4440ataacgcaca gatcattgtc atgctgccag acaaccagag cttggcagaa gatgagtttg 4500tgtactggcc aagtcgagaa gaatccatga actgtgaggc ctttaccgtc acccttatca 4560gcaaagacag actgtgcctc tctaatgaag aacaaattat catccatgac tttatccttg 4620aagctacaca ggatgactat gtcttagaag ttcggcactt tcagtgtccc aaatggccta 4680acccagatgc ccccataagt agtacctttg aacttatcaa cgtcatcaag gaagaggcct 4740taacaaggga tggtcccacc attgttcatg atgagtatgg agcagtttca gcaggaatgt 4800tatgtgccct taccaccctg tcccagcaac tggagaatga aaatgctgtg gatgttttcc 4860aggttgcaaa aatgatcaat cttatgaggc ctggagtatt cacagacatt gaacaatacc 4920agttcatcta taaagcaatg cttagcttgg tcagcactaa agaaaatgga aatggtccca 4980tgacagtaga caaaaatggt gctgttctta ttgcagatga atcagaccct gctgagagca 5040tggagtccct agtgtgactg gaatcctgaa agggcactta atttgtaaac ttctgaagac 5100tgagaacttt tttgaggcct tttttgccag actctaggtt atacaataac ccagttactt 5160ttttacactg ataaaagttt tgatatttat tttttgccat tttatgtctt aatggtatcc 5220tactgagcat ttgcacctct gttcatttca cacagtgaaa cgcaatttta cctagtttgc 5280actatatgat cagtgttact gcctataatc ttatacaaca gcaaaccctg atgtgacatt 5340ccatgacgac atacatgcta ctttttttta gttcaataca gtgaaggtct ttgttatgac 5400agtgaatatt gcttttatta ttattattgc tgaagtggtt gcattctact agcaggcaat 5460gctgtacttt tcttcagtcc tcctctcctt tttattttag gcactgttca atactgtatg 5520ccttctgtat tttaatggag tggatagcat tgttttcttt tacagactag caggctactg 5580ggacctaaaa aggtctgtta atgtcatggc cttgaaacag ttccatttat gctggttaag 5640agatccctta agaagttaga aggcttaaga actgcttcat gtgaacatcc cttattagtt 5700acaaagttat attcacagtt ttttaaaaat gtgtcaaaat aaaggataac tctgtattac 5760agctttcaca gtagctatgt ggacaatgtg ttatttccat tttgactctc taaaatagct 5820acatcctaaa atcagggcta tctttaacaa tagcaagata gcaatattat atacaactca 5880gttatgagac cctttagtta ttctccatta atgcttctta gtttgtaata ccatacctca 5940cagtaggtag aagaatgaaa acttctgcag gtgtgtaatt ttgaaactag tcctctaaaa 6000attccctatt actcctatag caatctaata aaaactacct acatagttac tgttttcttt 6060ccttctttgc caaatgtttt ataataaatc tcttaattac atacattttt ctacttaaga 6120ttaaattgga aatactgtct tagcaaaagt cttgggacta tctaaactcc cacacataga 6180taaatctgat ttggagagag aaatttaaaa tatttaatta aaggtgatac ccacattttc 6240aagtttttaa aagagggaga tggctttgta tgcttttgtg tagtttagaa cagatacaca 6300ttagtaaaag ataccaataa tcattagagc tcaaggaagt tattaggtgc agcctctgga 6360gccatactca cgctgcagtg cataatggga aaattaggag cattaataag aaatttcagt 6420agtgtttgta aggaaaataa gctacttact gagatctgtt tcttctattg catgtttgct 6480tttgagggac agcttctgtc aaaagtgaaa tcatcaccag aactgggcct gttaggaaga 6540atagggtttt atttactttt tatgtcaatt aacttcaaca aaaaggccac gctggctgct 6600gtcatgccat ctgggtatgc attaaacatt aatgatgatc agcactga 6648234176DNAhomo sapiens 23ggcggtcccc tgttctcccc gctcaggtgc ggcgctgtgg caggaagcca ccccctcggt 60cggccggtgc gcggggctgt tgcgccatcc gctccggctt tcgtaaccgc accctgggac 120ggcccagaga cgctccagcg cgagttcctc aaatgttttc ctgcgttgcc aggaccgtcc 180gccgctctga gtcatgtgcg agtgggaagt cgcactgaca ctgagccggg ccagagggag 240aggagccgag cgcggcgcgg ggccgaggga ctcgcagtgt gtgtagagag ccgggctcct 300gcggatgggg gctgcccccg gggcctgagc ccgcctgccc gcccaccgcc ccgccccgcc 360cctgccaccc ctgccgcccg gttcccatta gcctgtccgc ctctgcggga ccatggagtg 420gtagccgagg aggaagcatg ctggccgtcg gctgcgcgct gctggctgcc ctgctggccg 480cgccgggagc ggcgctggcc ccaaggcgct gccctgcgca ggaggtggcg agaggcgtgc 540tgaccagtct gccaggagac agcgtgactc tgacctgccc gggggtagag ccggaagaca 600atgccactgt tcactgggtg ctcaggaagc cggctgcagg ctcccacccc agcagatggg 660ctggcatggg aaggaggctg ctgctgaggt cggtgcagct ccacgactct ggaaactatt 720catgctaccg ggccggccgc ccagctggga ctgtgcactt gctggtggat gttccccccg 780aggagcccca gctctcctgc ttccggaaga gccccctcag caatgttgtt tgtgagtggg 840gtcctcggag caccccatcc ctgacgacaa aggctgtgct cttggtgagg aagtttcaga 900acagtccggc cgaagacttc caggagccgt gccagtattc ccaggagtcc cagaagttct 960cctgccagtt agcagtcccg gagggagaca gctctttcta catagtgtcc atgtgcgtcg 1020ccagtagtgt cgggagcaag ttcagcaaaa ctcaaacctt tcagggttgt ggaatcttgc 1080agcctgatcc gcctgccaac atcacagtca ctgccgtggc cagaaacccc cgctggctca 1140gtgtcacctg gcaagacccc cactcctgga actcatcttt ctacagacta cggtttgagc 1200tcagatatcg ggctgaacgg tcaaagacat tcacaacatg gatggtcaag gacctccagc 1260atcactgtgt catccacgac gcctggagcg gcctgaggca cgtggtgcag cttcgtgccc 1320aggaggagtt cgggcaaggc gagtggagcg agtggagccc ggaggccatg ggcacgcctt 1380ggacagaatc caggagtcct ccagctgaga acgaggtgtc cacccccatg caggcactta 1440ctactaataa agacgatgat aatattctct tcagagattc tgcaaatgcg acaagcctcc 1500cagtgcaaga ttcttcttca gtaccactgc ccacattcct ggttgctgga gggagcctgg 1560ccttcggaac gctcctctgc attgccattg ttctgaggtt caagaagacg tggaagctgc 1620gggctctgaa ggaaggcaag acaagcatgc atccgccgta ctctttgggg cagctggtcc 1680cggagaggcc tcgacccacc ccagtgcttg ttcctctcat ctccccaccg gtgtccccca 1740gcagcctggg gtctgacaat acctcgagcc acaaccgacc agatgccagg gacccacgga 1800gcccttatga catcagcaat acagactact tcttccccag atagctggct gggtggcacc 1860agcagcctgg accctgtgga tgataaaaca caaacgggct cagcaaaaga tgcttctcac 1920tgccatgcca gcttatctca ggggtgtgcg gcctttggct tcacggaaga gccttgcgga 1980aggttctacg ccaggggaaa atcagcctgc tccagctgtt cagctggttg aggtttcaaa 2040cctccctttc caaatgccca gcttaaaggg gctagagtga acttgggcca ctgtgaagag 2100aaccatatca agactctttg gacactcaca cggacactca aaagctgggc aggttggtgg 2160gggcctcggt gtggagaagc ggctggcagc ccacccctca acacctctgc acaagctgca 2220ccctcaggca ggtgggatgg atttccagcc aaagcctcct ccagccgcca tgctcctggc 2280ccactgcatc gtttcatctt ccaactcaaa ctcttaaaac ccaagtgcct tagcaaattc 2340tgtttttcta ggcctgggga cggcttttac ttaaaccgcc aaggctgggg gaagaagctc 2400tctcctccct ttcttcccta cagttgaaaa acagctgagg gtgagtgggt gaataataca 2460gtatctcagg gcctggtcgt tttcaacaga attataatta gttcctcatt agcattttgc 2520taaatgtgaa tgatgatcct aggcatttgc tgaatacaga ggcaactgca ttggctttgg 2580gttgcaggac ctcaggtgag aagcagagga aggagaggag aggggcacag ggtctctacc 2640atcccctgta gagtgggagc tgagtggggg atcacagcct ctgaaaacca atgttctctc 2700ttctccacct cccacaaagg agagctagca gcagggaggg cttctgccat ttctgagatc 2760aaaacggttt tactgcagct ttgtttgttg tcagctgaac ctgggtaact agggaagata 2820atattaagga agacaatgtg aaaagaaaaa tgagcctggc aagaatgtgt ttaaacttgg 2880tttttaaaaa actgctgact gttttctctt gagagggtgg aatatccaat attcgctgtg 2940tcagcataga agtaacttac ttaggtgtgg gggaagcacc ataactttgt ttagcccaaa 3000accaagtcaa gtgaaaaagg aggaagagaa aaaatatttt cctgccaggc atggtggccc 3060acgcacttcg ggaggtcgag gcaggaggat cacttgagtc cagaagtttg agatcagcct 3120gggcaatgtg ataaaacccc atctctacaa aaagcataaa aattagccaa gtgtggtaga 3180gtgtgcctga agtcccagat acttgggggg ctgaggtggg aggatctctt gagcctggga 3240ggtcaaggct gcagtgagcc gagattgcac cactgcactc cagcctgggt gacagagcaa 3300gtgagaccct gtctcaaaaa aagaaaaaga aaaagaaaaa atattttccc tattagagaa 3360gagattgtgg tttcattctg tattttgttt ttgtcttaaa aagtggaaaa atagcctgcc 3420tcttctctac tctagggaaa aaccagcgtg tgactactcc cccaggtggt tatggagagg 3480gtgtccggtc cctgtcccag tgccgagaag gaagcctccc acgactgccc ggcagggtcc 3540tagaaattcc ccaccctgaa agccctgagc tttctgctat caaagaggtt ttaaaaaaat 3600cccatttaaa aaaaatccct tacctcggtg ccttcctctt tttatttagt tccttgagtt 3660gattcagctc tgcaagaatt gaagcaggac taaatgtcta gttgtaacac catgattaac 3720cacttcagct gacttttctg tccgagcttt gaaaattcag tggtgttagt ggttacccag 3780ttagctctca agttatcagg gtattccaga gtggggatat gatttaaatc agccgtgtaa 3840ccatggaccc aatatttacc agaccacaaa acttttctaa tactctaccc tcttagaaaa 3900accaccacca tcaccagaca ggtgcgaaag gatgaaagtg accatgtttt gtttacggtt 3960ttccaggttt aagctgttac tgtcttcagt aagccgtgat tttcattgct gggcttgtct 4020gtagatttta gaccctattg ctgcttgagg caactcatct taggttggca aaaaggcagg 4080atggccgggc gcggtggctc acgcctgtaa tcctagcact ttgggaggcc aaggtgggag 4140gattgcttga gctcaggagt ttgagaccaa cctggg 4176244082DNAhomo sapiens 24ggcggtcccc tgttctcccc gctcaggtgc ggcgctgtgg caggaagcca ccccctcggt 60cggccggtgc gcggggctgt tgcgccatcc gctccggctt tcgtaaccgc accctgggac 120ggcccagaga cgctccagcg cgagttcctc aaatgttttc ctgcgttgcc aggaccgtcc 180gccgctctga gtcatgtgcg agtgggaagt cgcactgaca ctgagccggg ccagagggag 240aggagccgag cgcggcgcgg ggccgaggga ctcgcagtgt gtgtagagag ccgggctcct 300gcggatgggg gctgcccccg gggcctgagc ccgcctgccc gcccaccgcc ccgccccgcc 360cctgccaccc ctgccgcccg gttcccatta gcctgtccgc ctctgcggga ccatggagtg 420gtagccgagg aggaagcatg ctggccgtcg gctgcgcgct gctggctgcc ctgctggccg 480cgccgggagc ggcgctggcc ccaaggcgct gccctgcgca ggaggtggcg agaggcgtgc 540tgaccagtct gccaggagac agcgtgactc tgacctgccc gggggtagag ccggaagaca 600atgccactgt tcactgggtg ctcaggaagc cggctgcagg ctcccacccc agcagatggg 660ctggcatggg aaggaggctg ctgctgaggt cggtgcagct ccacgactct ggaaactatt 720catgctaccg ggccggccgc ccagctggga ctgtgcactt gctggtggat gttccccccg 780aggagcccca gctctcctgc ttccggaaga gccccctcag caatgttgtt tgtgagtggg 840gtcctcggag caccccatcc ctgacgacaa aggctgtgct cttggtgagg aagtttcaga 900acagtccggc cgaagacttc caggagccgt gccagtattc ccaggagtcc cagaagttct 960cctgccagtt agcagtcccg gagggagaca gctctttcta catagtgtcc atgtgcgtcg 1020ccagtagtgt cgggagcaag ttcagcaaaa ctcaaacctt tcagggttgt ggaatcttgc 1080agcctgatcc gcctgccaac atcacagtca ctgccgtggc cagaaacccc cgctggctca 1140gtgtcacctg gcaagacccc cactcctgga actcatcttt ctacagacta cggtttgagc 1200tcagatatcg ggctgaacgg tcaaagacat tcacaacatg gatggtcaag gacctccagc 1260atcactgtgt catccacgac gcctggagcg gcctgaggca cgtggtgcag cttcgtgccc 1320aggaggagtt cgggcaaggc gagtggagcg agtggagccc ggaggccatg ggcacgcctt 1380ggacagaatc caggagtcct ccagctgaga acgaggtgtc cacccccatg caggcactta 1440ctactaataa agacgatgat aatattctct tcagagattc tgcaaatgcg acaagcctcc 1500caggttcaag aagacgtgga agctgcgggc tctgaaggaa ggcaagacaa gcatgcatcc 1560gccgtactct ttggggcagc tggtcccgga gaggcctcga cccaccccag tgcttgttcc 1620tctcatctcc ccaccggtgt cccccagcag cctggggtct gacaatacct cgagccacaa 1680ccgaccagat gccagggacc cacggagccc ttatgacatc agcaatacag actacttctt 1740ccccagatag ctggctgggt ggcaccagca gcctggaccc tgtggatgat aaaacacaaa 1800cgggctcagc aaaagatgct tctcactgcc atgccagctt atctcagggg tgtgcggcct 1860ttggcttcac ggaagagcct tgcggaaggt tctacgccag gggaaaatca gcctgctcca 1920gctgttcagc tggttgaggt ttcaaacctc cctttccaaa tgcccagctt aaaggggcta 1980gagtgaactt gggccactgt gaagagaacc atatcaagac tctttggaca ctcacacgga 2040cactcaaaag ctgggcaggt tggtgggggc ctcggtgtgg agaagcggct ggcagcccac 2100ccctcaacac ctctgcacaa gctgcaccct caggcaggtg ggatggattt ccagccaaag 2160cctcctccag ccgccatgct cctggcccac tgcatcgttt catcttccaa ctcaaactct 2220taaaacccaa gtgccttagc aaattctgtt tttctaggcc tggggacggc ttttacttaa 2280accgccaagg ctgggggaag aagctctctc ctccctttct tccctacagt tgaaaaacag 2340ctgagggtga gtgggtgaat aatacagtat ctcagggcct ggtcgttttc aacagaatta 2400taattagttc ctcattagca ttttgctaaa tgtgaatgat gatcctaggc atttgctgaa 2460tacagaggca actgcattgg ctttgggttg caggacctca ggtgagaagc agaggaagga 2520gaggagaggg gcacagggtc tctaccatcc cctgtagagt gggagctgag tgggggatca 2580cagcctctga aaaccaatgt tctctcttct ccacctccca caaaggagag ctagcagcag 2640ggagggcttc tgccatttct gagatcaaaa cggttttact gcagctttgt ttgttgtcag 2700ctgaacctgg gtaactaggg aagataatat taaggaagac aatgtgaaaa gaaaaatgag 2760cctggcaaga atgtgtttaa acttggtttt taaaaaactg ctgactgttt tctcttgaga 2820gggtggaata tccaatattc gctgtgtcag catagaagta acttacttag gtgtggggga 2880agcaccataa ctttgtttag cccaaaacca agtcaagtga aaaaggagga agagaaaaaa 2940tattttcctg ccaggcatgg tggcccacgc acttcgggag gtcgaggcag gaggatcact 3000tgagtccaga agtttgagat cagcctgggc aatgtgataa aaccccatct ctacaaaaag 3060cataaaaatt agccaagtgt ggtagagtgt gcctgaagtc ccagatactt ggggggctga 3120ggtgggagga tctcttgagc ctgggaggtc aaggctgcag tgagccgaga ttgcaccact 3180gcactccagc ctgggtgaca gagcaagtga gaccctgtct caaaaaaaga aaaagaaaaa 3240gaaaaaatat tttccctatt agagaagaga ttgtggtttc attctgtatt ttgtttttgt 3300cttaaaaagt ggaaaaatag cctgcctctt ctctactcta gggaaaaacc agcgtgtgac 3360tactccccca ggtggttatg gagagggtgt ccggtccctg tcccagtgcc gagaaggaag 3420cctcccacga ctgcccggca gggtcctaga aattccccac cctgaaagcc ctgagctttc 3480tgctatcaaa gaggttttaa aaaaatccca tttaaaaaaa atcccttacc tcggtgcctt 3540cctcttttta tttagttcct tgagttgatt cagctctgca agaattgaag caggactaaa 3600tgtctagttg taacaccatg attaaccact tcagctgact tttctgtccg agctttgaaa 3660attcagtggt gttagtggtt acccagttag ctctcaagtt atcagggtat tccagagtgg 3720ggatatgatt taaatcagcc gtgtaaccat ggacccaata tttaccagac cacaaaactt 3780ttctaatact ctaccctctt agaaaaacca ccaccatcac cagacaggtg cgaaaggatg 3840aaagtgacca tgttttgttt acggttttcc aggtttaagc tgttactgtc ttcagtaagc 3900cgtgattttc attgctgggc ttgtctgtag attttagacc ctattgctgc ttgaggcaac 3960tcatcttagg ttggcaaaaa ggcaggatgg ccgggcgcgg tggctcacgc ctgtaatcct 4020agcactttgg gaggccaagg tgggaggatt gcttgagctc aggagtttga gaccaacctg 4080gg 4082254370DNAhomo sapiens 25ccgcgctctc tgatcagagg cgaagctcgg aggtcctaca ggtatggatc tctggcagct 60gctgttgacc ttggcactgg caggatcaag tgatgctttt tctggaagtg aggccacagc 120agctatcctt agcagagcac cctggagtct gcaaagtgtt aatccaggcc taaagacaaa 180ttcttctaag gagcctaaat tcaccaagtg ccgttcacct

gagcgagaga ctttttcatg 240ccactggaca gatgaggttc atcatggtac aaagaaccta ggacccatac agctgttcta 300taccagaagg aacactcaag aatggactca agaatggaaa gaatgccctg attatgtttc 360tgctggggaa aacagctgtt actttaattc atcgtttacc tccatctgga taccttattg 420tatcaagcta actagcaatg gtggtacagt ggatgaaaag tgtttctctg ttgatgaaat 480agtgcaacca gatccaccca ttgccctcaa ctggacttta ctgaacgtca gtttaactgg 540gattcatgca gatatccaag tgagatggga agcaccacgc aatgcagata ttcagaaagg 600atggatggtt ctggagtatg aacttcaata caaagaagta aatgaaacta aatggaaaat 660gatggaccct atattgacaa catcagttcc agtgtactca ttgaaagtgg ataaggaata 720tgaagtgcgt gtgagatcca aacaacgaaa ctctggaaat tatggcgagt tcagtgaggt 780gctctatgta acacttcctc agatgagcca atttacatgt gaagaagatt tctactttcc 840atggctctta attattatct ttggaatatt tgggctaaca gtgatgctat ttgtattctt 900attttctaaa cagcaaagga ttaaaatgct gattctgccc ccagttccag ttccaaagat 960taaaggaatc gatccagatc tcctcaagga aggaaaatta gaggaggtga acacaatctt 1020agccattcat gatagctata aacccgaatt ccacagtgat gactcttggg ttgaatttat 1080tgagctagat attgatgagc cagatgaaaa gactgaggaa tcagacacag acagacttct 1140aagcagtgac catgagaaat cacatagtaa cctaggggtg aaggatggcg actctggacg 1200taccagctgt tgtgaacctg acattctgga gactgatttc aatgccaatg acatacatga 1260gggtacctca gaggttgctc agccacagag gttaaaaggg gaagcagatc tcttatgcct 1320tgaccagaag aatcaaaata actcacctta tcatgatgct tgccctgcta ctcagcagcc 1380cagtgttatc caagcagaga aaaacaaacc acaaccactt cctactgaag gagctgagtc 1440aactcaccaa gctgcccata ttcagctaag caatccaagt tcactgtcaa acatcgactt 1500ttatgcccag gtgagcgaca ttacaccagc aggtagtgtg gtcctttccc cgggccaaaa 1560gaataaggca gggatgtccc aatgtgacat gcacccggaa atggtctcac tctgccaaga 1620aaacttcctt atggacaatg cctacttctg tgaggcagat gccaaaaagt gcatccctgt 1680ggctcctcac atcaaggttg aatcacacat acagccaagc ttaaaccaag aggacattta 1740catcaccaca gaaagcctta ccactgctgc tgggaggcct gggacaggag aacatgttcc 1800aggttctgag atgcctgtcc cagactatac ctccattcat atagtacagt ccccacaggg 1860cctcatactc aatgcgactg ccttgccctt gcctgacaaa gagtttctct catcatgtgg 1920ctatgtgagc acagaccaac tgaacaaaat catgccttag cctttctttg gtttcccaag 1980agctacgtat ttaatagcaa agaattgact ggggcaataa cgtttaagcc aaaacaatgt 2040ttaaaccttt tttgggggag tgacaggatg gggtatggat tctaaaatgc cttttcccaa 2100aatgttgaaa tatgatgtta aaaaaataag aagaatgctt aatcagatag atattcctat 2160tgtgcaatgt aaatatttta aagaattgtg tcagactgtt tagtagcagt gattgtctta 2220atattgtggg tgttaatttt tgatactaag cattgaatgg ctatgttttt aatgtatagt 2280aaatcacgct ttttgaaaaa gcgaaaaaat caggtggctt ttgcggttca ggaaaattga 2340atgcaaacca tagcacaggc taattttttg ttgtttctta aataagaaac ttttttattt 2400aaaaaactaa aaactagagg tgagaaattt aaactataag caagaaggca aaaatagttt 2460ggatatgtaa aacatttatt ttgacataaa gttgataaag attttttaat aatttagact 2520tcaagcatgg ctattttata ttacactaca cactgtgtac tgcagttggt atgacccctc 2580taaggagtgt agcaactaca gtctaaagct ggtttaatgt tttggccaat gcacctaaag 2640aaaaacaaac tcgtttttta caaagccctt ttatacctcc ccagactcct tcaacaattc 2700taaaatgatt gtagtaatct gcattattgg aatataattg ttttatctga atttttaaac 2760aagtatttgt taatttagaa aactttaaag cgtttgcaca gatcaactta ccaggcacca 2820aaagaagtaa aagcaaaaaa gaaaaccttt cttcaccaaa tcttggttga tgccaaaaaa 2880aaatacatgc taagagaagt agaaatcata gctggttcac actgaccaag atacttaagt 2940gctgcaattg cacgcggagt gagtttttta gtgcgtgcag atggtgagag ataagatcta 3000tagcctctgc agcggaatct gttcacaccc aacttggttt tgctacataa ttatccagga 3060agggaataag gtacaagaag cattttgtaa gttgaagcaa atcgaatgaa attaactggg 3120taatgaaaca aagagttcaa gaaataagtt tttgtttcac agcctataac cagacacata 3180ctcatttttc atgataatga acagaacata gacagaagaa acaaggtttt cagtccccac 3240agataactga aaattattta aaccgctaaa agaaactttc tttctcacta aatcttttat 3300aggatttatt taaaatagca aaagaagaag tttcatcatt ttttacttcc tctctgagtg 3360gactggcctc aaagcaagca ttcagaagaa aaagaagcaa cctcagtaat ttagaaatca 3420ttttgcaatc ccttaatatc ctaaacatca ttcatttttg ttgttgttgt tgttgttgag 3480acagagtctc gctctgtcgc caggctagag tgcggtggcg cgatcttgac tcactgcaat 3540ctccacctcc cacaggttca ggcgattccc gtgcctcagc ctcctgagta gctgggacta 3600caggcacgca ccaccatgcc aggctaattt ttttgtattt tagcagagac ggggtttcac 3660catgttggcc aggatggtct cgatctcctg acctcgtgat ccacccgact cggcctccca 3720aagtgctggg attacaggtg taagccaccg tgcccagccc taaacatcat tcttgagagc 3780attgggatat ctcctgaaaa ggtttatgaa aaagaagaat ctcatctcag tgaagaatac 3840ttctcatttt ttaaaaaagc ttaaaacttt gaagttagct ttaacttaaa tagtatttcc 3900catttatcgc agaccttttt taggaagcaa gcttaatggc tgataatttt aaattctctc 3960tcttgcagga aggactatga aaagctagaa ttgagtgttt aaagttcaac atgttatttg 4020taatagatgt ttgatagatt ttctgctact ttgctgctat ggttttctcc aagagctaca 4080taatttagtt tcatataaag tatcatcagt gtagaaccta attcaattca aagctgtgtg 4140tttggaagac tatcttacta tttcacaaca gcctgacaac atttctatag ccaaaaatag 4200ctaaatacct caatcagtct cagaatgtca ttttggtact ttggtggcca cataagccat 4260tattcactag tatgactagt tgtgtctggc agtttatatt taactctctt tatgtctgtg 4320gattttttcc ttcaaagttt aataaattta ttttcttgga aaaaaaaaaa 4370261518DNAhomo sapiens 26aaaacagccc ggagcctgca gcccagcccc acccagaccc atggctggac ctgccaccca 60gagccccatg aagctgatgg ccctgcagct gctgctgtgg cacagtgcac tctggacagt 120gcaggaagcc acccccctgg gccctgccag ctccctgccc cagagcttcc tgctcaagtg 180cttagagcaa gtgaggaaga tccagggcga tggcgcagcg ctccaggaga agctggtgag 240tgagtgtgcc acctacaagc tgtgccaccc cgaggagctg gtgctgctcg gacactctct 300gggcatcccc tgggctcccc tgagcagctg ccccagccag gccctgcagc tggcaggctg 360cttgagccaa ctccatagcg gccttttcct ctaccagggg ctcctgcagg ccctggaagg 420gatctccccc gagttgggtc ccaccttgga cacactgcag ctggacgtcg ccgactttgc 480caccaccatc tggcagcaga tggaagaact gggaatggcc cctgccctgc agcccaccca 540gggtgccatg ccggccttcg cctctgcttt ccagcgccgg gcaggagggg tcctggttgc 600ctcccatctg cagagcttcc tggaggtgtc gtaccgcgtt ctacgccacc ttgcccagcc 660ctgagccaag ccctccccat cccatgtatt tatctctatt taatatttat gtctatttaa 720gcctcatatt taaagacagg gaagagcaga acggagcccc aggcctctgt gtccttccct 780gcatttctga gtttcattct cctgcctgta gcagtgagaa aaagctcctg tcctcccatc 840ccctggactg ggaggtagat aggtaaatac caagtattta ttactatgac tgctccccag 900ccctggctct gcaatgggca ctgggatgag ccgctgtgag cccctggtcc tgagggtccc 960cacctgggac ccttgagagt atcaggtctc ccacgtggga gacaagaaat ccctgtttaa 1020tatttaaaca gcagtgttcc ccatctgggt ccttgcaccc ctcactctgg cctcagccga 1080ctgcacagcg gcccctgcat ccccttggct gtgaggcccc tggacaagca gaggtggcca 1140gagctgggag gcatggccct ggggtcccac gaatttgctg gggaatctcg tttttcttct 1200taagactttt gggacatggt ttgactcccg aacatcaccg acgtgtctcc tgtttttctg 1260ggtggcctcg ggacacctgc cctgccccca cgagggtcag gactgtgact ctttttaggg 1320ccaggcaggt gcctggacat ttgccttgct ggacggggac tggggatgtg ggagggagca 1380gacaggagga atcatgtcag gcctgtgtgt gaaaggaagc tccactgtca ccctccacct 1440cttcaccccc cactcaccag tgtcccctcc actgtcacat tgtaactgaa cttcaggata 1500ataaagtgtt tgcctcca 1518271509DNAhomo sapiens 27aaaacagccc ggagcctgca gcccagcccc acccagaccc atggctggac ctgccaccca 60gagccccatg aagctgatgg ccctgcagct gctgctgtgg cacagtgcac tctggacagt 120gcaggaagcc acccccctgg gccctgccag ctccctgccc cagagcttcc tgctcaagtg 180cttagagcaa gtgaggaaga tccagggcga tggcgcagcg ctccaggaga agctgtgtgc 240cacctacaag ctgtgccacc ccgaggagct ggtgctgctc ggacactctc tgggcatccc 300ctgggctccc ctgagcagct gccccagcca ggccctgcag ctggcaggct gcttgagcca 360actccatagc ggccttttcc tctaccaggg gctcctgcag gccctggaag ggatctcccc 420cgagttgggt cccaccttgg acacactgca gctggacgtc gccgactttg ccaccaccat 480ctggcagcag atggaagaac tgggaatggc ccctgccctg cagcccaccc agggtgccat 540gccggccttc gcctctgctt tccagcgccg ggcaggaggg gtcctggttg cctcccatct 600gcagagcttc ctggaggtgt cgtaccgcgt tctacgccac cttgcccagc cctgagccaa 660gccctcccca tcccatgtat ttatctctat ttaatattta tgtctattta agcctcatat 720ttaaagacag ggaagagcag aacggagccc caggcctctg tgtccttccc tgcatttctg 780agtttcattc tcctgcctgt agcagtgaga aaaagctcct gtcctcccat cccctggact 840gggaggtaga taggtaaata ccaagtattt attactatga ctgctcccca gccctggctc 900tgcaatgggc actgggatga gccgctgtga gcccctggtc ctgagggtcc ccacctggga 960cccttgagag tatcaggtct cccacgtggg agacaagaaa tccctgttta atatttaaac 1020agcagtgttc cccatctggg tccttgcacc cctcactctg gcctcagccg actgcacagc 1080ggcccctgca tccccttggc tgtgaggccc ctggacaagc agaggtggcc agagctggga 1140ggcatggccc tggggtccca cgaatttgct ggggaatctc gtttttcttc ttaagacttt 1200tgggacatgg tttgactccc gaacatcacc gacgtgtctc ctgtttttct gggtggcctc 1260gggacacctg ccctgccccc acgagggtca ggactgtgac tctttttagg gccaggcagg 1320tgcctggaca tttgccttgc tggacgggga ctggggatgt gggagggagc agacaggagg 1380aatcatgtca ggcctgtgtg tgaaaggaag ctccactgtc accctccacc tcttcacccc 1440ccactcacca gtgtcccctc cactgtcaca ttgtaactga acttcaggat aataaagtgt 1500ttgcctcca 1509281703DNAhomo sapiens 28aaaacagccc ggagcctgca gcccagcccc acccagaccc atggctggac ctgccaccca 60gagccccatg aagctgatgg gtgagtgtct tggcccagga tgggagagcc gcctgccctg 120gcatgggagg gaggctggtg tgacagaggg gctggggatc cccgttctgg gaatggggat 180taaaggcacc cagtgtcccc gagagggcct caggtggtag ggaacagcat gtctcctgag 240cccgctctgt ccccagccct gcagctgctg ctgtggcaca gtgcactctg gacagtgcag 300gaagccaccc ccctgggccc tgccagctcc ctgccccaga gcttcctgct caagtgctta 360gagcaagtga ggaagatcca gggcgatggc gcagcgctcc aggagaagct gtgtgccacc 420tacaagctgt gccaccccga ggagctggtg ctgctcggac actctctggg catcccctgg 480gctcccctga gcagctgccc cagccaggcc ctgcagctgg caggctgctt gagccaactc 540catagcggcc ttttcctcta ccaggggctc ctgcaggccc tggaagggat ctcccccgag 600ttgggtccca ccttggacac actgcagctg gacgtcgccg actttgccac caccatctgg 660cagcagatgg aagaactggg aatggcccct gccctgcagc ccacccaggg tgccatgccg 720gccttcgcct ctgctttcca gcgccgggca ggaggggtcc tggttgcctc ccatctgcag 780agcttcctgg aggtgtcgta ccgcgttcta cgccaccttg cccagccctg agccaagccc 840tccccatccc atgtatttat ctctatttaa tatttatgtc tatttaagcc tcatatttaa 900agacagggaa gagcagaacg gagccccagg cctctgtgtc cttccctgca tttctgagtt 960tcattctcct gcctgtagca gtgagaaaaa gctcctgtcc tcccatcccc tggactggga 1020ggtagatagg taaataccaa gtatttatta ctatgactgc tccccagccc tggctctgca 1080atgggcactg ggatgagccg ctgtgagccc ctggtcctga gggtccccac ctgggaccct 1140tgagagtatc aggtctccca cgtgggagac aagaaatccc tgtttaatat ttaaacagca 1200gtgttcccca tctgggtcct tgcacccctc actctggcct cagccgactg cacagcggcc 1260cctgcatccc cttggctgtg aggcccctgg acaagcagag gtggccagag ctgggaggca 1320tggccctggg gtcccacgaa tttgctgggg aatctcgttt ttcttcttaa gacttttggg 1380acatggtttg actcccgaac atcaccgacg tgtctcctgt ttttctgggt ggcctcggga 1440cacctgccct gcccccacga gggtcaggac tgtgactctt tttagggcca ggcaggtgcc 1500tggacatttg ccttgctgga cggggactgg ggatgtggga gggagcagac aggaggaatc 1560atgtcaggcc tgtgtgtgaa aggaagctcc actgtcaccc tccacctctt caccccccac 1620tcaccagtgt cccctccact gtcacattgt aactgaactt caggataata aagtgtttgc 1680ctccaaaaaa aaaaaaaaaa aaa 1703292165DNAhomo sapiens 29ctgagcgaca gcaagtgcag cgggctccta ccccgggtga ggggtggcct ccgcgtggga 60tcgtgccctc ttcagcccgc tcctgtcccc gacatcacgt gtattccgca cgtcccctcc 120gcgctgtgtg tctactgaga cggggaggcg tgacagggcc cgggtccctt ctcagtggtg 180ctctgtgctt cagggcaagc tccccgtctc cgggcgcact tccctcgcct gtgttcggtc 240catcctcctt tctccagcct cctcccctcg caggtgggat cgtcggtggg accggagcgc 300gggcgggcgc ggccccccgg gaccatggcc gggtccgaca ccgcgccctt cctcagccag 360gcggatgacc cggacgacgg gccagtgcct ggcaccccgg ggttgccagg gtccacgggg 420aacccgaagt ccgaggagcc cgaggtcccg gaccaggagg ggctgcagcg catcaccggc 480ctgtctcccg gccgttcggc tctcatagtg gcggtgctgt gctacatcaa tctcctgaac 540tacatggacc gcttcaccgt ggctggcgtc cttcccgaca tcgagcagtt cttcaacatc 600ggggacagta gctctgggct catccagacc gtgttcatct ccagttacat ggtgttggca 660cctgtgtttg gctacctggg tgacaggtac aatcggaagt atctcatgtg cgggggcatt 720gccttctggt ccctggtgac actggggtca tccttcatcc ccggagagca tttctggctg 780ctcctcctga cccggggcct ggtgggggtc ggggaggcca gttattccac catcgcgccc 840actctcattg ccgacctctt tgtggccgac cagcggagcc ggatgctcag catcttctac 900tttgccattc cggtgggcag tggtctgggc tacattgcag gctccaaagt gaaggatatg 960gctggagact ggcactgggc tctgagggtg acaccgggtc taggagtggt ggccgttctg 1020ctgctgttcc tggtagtgcg ggagccgcca aggggagccg tggagcgcca ctcagatttg 1080ccacccctga accccacctc gtggtgggca gatctgaggg ctctggcaag aaatcctagt 1140ttcgtcctgt cttccctggg cttcactgct gtggcctttg tcacgggctc cctggctctg 1200tgggctccgg cattcctgct gcgttcccgc gtggtccttg gggagacccc accctgcctt 1260cccggagact cctgctcttc ctctgacagt ctcatctttg gactcatcac ctgcctgacc 1320ggagtcctgg gtgtgggcct gggtgtggag atcagccgcc ggctccgcca ctccaacccc 1380cgggctgatc ccctggtctg tgccactggc ctcctgggct ctgcaccctt cctcttcctg 1440tcccttgcct gcgcccgtgg tagcatcgtg gccacttata ttttcatctt cattggagag 1500accctcctgt ccatgaactg ggccatcgtg gccgacattc tgctgtacgt ggtgatccct 1560acccgacgct ccaccgccga ggccttccag atcgtgctgt cccacctgct gggtgatgct 1620gggagcccct acctcattgg cctgatctct gaccgcctgc gccggaactg gcccccctcc 1680ttcttgtccg agttccgggc tctgcagttc tcgctcatgc tctgcgcgtt tgttggggca 1740ctgggcggcg cagccttcct gggcaccgcc atcttcattg aggccgaccg ccggcgggca 1800cagctgcacg tgcagggcct gctgcacgaa gcagggtcca cagacgaccg gattgtggtg 1860ccccagcggg gccgctccac ccgcgtgccc gtggccagtg tgctcatctg agaggctgcc 1920gctcacctac ctgcacatct gccacagctg gccctgggcc caccccacga agggcctggg 1980cctaacccct tggcctggcc cagcttccag agggaccctg ggccgtgtgc cagctcccag 2040acactacatg ggtagctcag gggaggaggt gggggtccag gagggggatc cctctccaca 2100ggggcagccc caagggctcg gtgctatttg taacggaata aaatttgtgc cagaaaaaaa 2160aaaaa 216530240PRThomo sapiens 30Met Val Gly Gln Arg Val Leu Leu Leu Val Ala Phe Leu Leu Ser Gly 1 5 10 15 Val Leu Leu Ser Glu Ala Ala Lys Ile Leu Thr Ile Ser Thr Leu Gly 20 25 30 Gly Ser His Tyr Leu Leu Leu Asp Arg Val Ser Gln Ile Leu Gln Glu 35 40 45 His Gly His Asn Val Thr Met Leu His Gln Ser Gly Lys Phe Leu Ile 50 55 60 Pro Asp Ile Lys Glu Glu Glu Lys Ser Tyr Gln Val Ile Arg Trp Phe 65 70 75 80 Ser Pro Glu Asp His Gln Lys Arg Ile Lys Lys His Phe Asp Ser Tyr 85 90 95 Ile Glu Thr Ala Leu Asp Gly Arg Lys Glu Ser Glu Ala Leu Val Lys 100 105 110 Leu Met Glu Ile Phe Gly Thr Gln Cys Ser Tyr Leu Leu Ser Arg Lys 115 120 125 Asp Ile Met Asp Ser Leu Lys Asn Glu Asn Cys Asp Leu Val Phe Val 130 135 140 Glu Ala Phe Asp Phe Cys Ser Phe Leu Ile Ala Glu Lys Leu Val Lys 145 150 155 160 Pro Phe Val Ala Ile Leu Pro Thr Thr Phe Gly Ser Leu Asp Phe Gly 165 170 175 Leu Pro Ser Pro Leu Ser Tyr Val Pro Val Phe Pro Ser Leu Leu Thr 180 185 190 Asp His Met Asp Phe Trp Gly Arg Val Lys Asn Phe Leu Met Phe Phe 195 200 205 Ser Phe Ser Arg Ser Gln Trp Asp Met Gln Ser Thr Phe Asp Asn Thr 210 215 220 Ile Lys Glu His Phe Pro Glu Gly Ser Arg Pro Val Leu Ser His Leu 225 230 235 240 31523PRThomo sapiens 31Met Ala Gly Gln Arg Val Leu Leu Leu Val Gly Phe Leu Leu Pro Gly 1 5 10 15 Val Leu Leu Ser Glu Ala Ala Lys Ile Leu Thr Ile Ser Thr Val Gly 20 25 30 Gly Ser His Tyr Leu Leu Met Asp Arg Val Ser Gln Ile Leu Gln Asp 35 40 45 His Gly His Asn Val Thr Met Leu Asn His Lys Arg Gly Pro Phe Met 50 55 60 Pro Asp Phe Lys Lys Glu Glu Lys Ser Tyr Gln Val Ile Ser Trp Leu 65 70 75 80 Ala Pro Glu Asp His Gln Arg Glu Phe Lys Lys Ser Phe Asp Phe Phe 85 90 95 Leu Glu Glu Thr Leu Gly Gly Arg Gly Lys Phe Glu Asn Leu Leu Asn 100 105 110 Val Leu Glu Tyr Leu Ala Leu Gln Cys Ser His Phe Leu Asn Arg Lys 115 120 125 Asp Ile Met Asp Ser Leu Lys Asn Glu Asn Phe Asp Met Val Ile Val 130 135 140 Glu Thr Phe Asp Tyr Cys Pro Phe Leu Ile Ala Glu Lys Leu Gly Lys 145 150 155 160 Pro Phe Val Ala Ile Leu Ser Thr Ser Phe Gly Ser Leu Glu Phe Gly 165 170 175 Leu Pro Ile Pro Leu Ser Tyr Val Pro Val Phe Arg Ser Leu Leu Thr 180 185 190 Asp His Met Asp Phe Trp Gly Arg Val Lys Asn Phe Leu Met Phe Phe 195 200 205 Ser Phe Cys Arg Arg Gln Gln His Met Gln Ser Thr Phe Asp Asn Thr 210 215 220 Ile Lys Glu His Phe Thr Glu Gly Ser Arg Pro Val Leu Ser His Leu 225 230 235 240 Leu Leu Lys Ala Glu Leu Trp Phe Ile Asn Ser Asp Phe Ala Phe Asp 245 250 255 Phe Ala Arg Pro Leu Leu Pro Asn Thr Val Tyr Val Gly Gly Leu Met 260 265 270 Glu Lys Pro Ile Lys Pro Val Pro Gln Asp Leu Glu Asn Phe Ile Ala 275 280 285 Lys Phe Glu Asp Ser Gly Phe Val Leu Val Thr Leu Gly Ser Met Val 290 295 300 Asn Thr Cys Gln Asn Pro Glu Ile Phe Lys Glu Met Asn Asn Ala Phe 305 310 315 320 Ala His Leu Pro Gln Gly Val Ile Trp Lys Cys Gln Cys Ser His Trp

325 330 335 Pro Lys Asp Val His Leu Ala Ala Asn Val Lys Ile Val Asp Trp Leu 340 345 350 Pro Gln Ser Asp Leu Leu Ala His Pro Ser Ile Arg Leu Phe Val Thr 355 360 365 His Gly Gly Gln Asn Ser Ile Met Glu Ala Ile Gln His Gly Val Pro 370 375 380 Met Val Gly Ile Pro Leu Phe Gly Asp Gln Pro Glu Asn Met Val Arg 385 390 395 400 Val Glu Ala Lys Lys Phe Gly Val Ser Ile Gln Leu Lys Lys Leu Lys 405 410 415 Ala Glu Thr Leu Ala Leu Lys Met Lys Gln Ile Met Glu Asp Lys Arg 420 425 430 Tyr Lys Ser Ala Ala Val Ala Ala Ser Val Ile Leu Arg Ser His Pro 435 440 445 Leu Ser Pro Thr Gln Arg Leu Val Gly Trp Ile Asp His Val Leu Gln 450 455 460 Thr Gly Gly Ala Thr His Leu Lys Pro Tyr Val Phe Gln Gln Pro Trp 465 470 475 480 His Glu Gln Tyr Leu Leu Asp Val Phe Val Phe Leu Leu Gly Leu Thr 485 490 495 Leu Gly Thr Leu Trp Leu Cys Gly Lys Leu Leu Gly Met Ala Val Trp 500 505 510 Trp Leu Arg Gly Ala Arg Lys Val Lys Glu Thr 515 520 32533PRThomo sapiens 32Met Ala Phe Ala Asn Leu Arg Lys Val Leu Ile Ser Asp Ser Leu Asp 1 5 10 15 Pro Cys Cys Arg Lys Ile Leu Gln Asp Gly Gly Leu Gln Val Val Glu 20 25 30 Lys Gln Asn Leu Ser Lys Glu Glu Leu Ile Ala Glu Leu Gln Asp Cys 35 40 45 Glu Gly Leu Ile Val Arg Ser Ala Thr Lys Val Thr Ala Asp Val Ile 50 55 60 Asn Ala Ala Glu Lys Leu Gln Val Val Gly Arg Ala Gly Thr Gly Val 65 70 75 80 Asp Asn Val Asp Leu Glu Ala Ala Thr Arg Lys Gly Ile Leu Val Met 85 90 95 Asn Thr Pro Asn Gly Asn Ser Leu Ser Ala Ala Glu Leu Thr Cys Gly 100 105 110 Met Ile Met Cys Leu Ala Arg Gln Ile Pro Gln Ala Thr Ala Ser Met 115 120 125 Lys Asp Gly Lys Trp Glu Arg Lys Lys Phe Met Gly Thr Glu Leu Asn 130 135 140 Gly Lys Thr Leu Gly Ile Leu Gly Leu Gly Arg Ile Gly Arg Glu Val 145 150 155 160 Ala Thr Arg Met Gln Ser Phe Gly Met Lys Thr Ile Gly Tyr Asp Pro 165 170 175 Ile Ile Ser Pro Glu Val Ser Ala Ser Phe Gly Val Gln Gln Leu Pro 180 185 190 Leu Glu Glu Ile Trp Pro Leu Cys Asp Phe Ile Thr Val His Thr Pro 195 200 205 Leu Leu Pro Ser Thr Thr Gly Leu Leu Asn Asp Asn Thr Phe Ala Gln 210 215 220 Cys Lys Lys Gly Val Arg Val Val Asn Cys Ala Arg Gly Gly Ile Val 225 230 235 240 Asp Glu Gly Ala Leu Leu Arg Ala Leu Gln Ser Gly Gln Cys Ala Gly 245 250 255 Ala Ala Leu Asp Val Phe Thr Glu Glu Pro Pro Arg Asp Arg Ala Leu 260 265 270 Val Asp His Glu Asn Val Ile Ser Cys Pro His Leu Gly Ala Ser Thr 275 280 285 Lys Glu Ala Gln Ser Arg Cys Gly Glu Glu Ile Ala Val Gln Phe Val 290 295 300 Asp Met Val Lys Gly Lys Ser Leu Thr Gly Val Val Asn Ala Gln Ala 305 310 315 320 Leu Thr Ser Ala Phe Ser Pro His Thr Lys Pro Trp Ile Gly Leu Ala 325 330 335 Glu Ala Leu Gly Thr Leu Met Arg Ala Trp Ala Gly Ser Pro Lys Gly 340 345 350 Thr Ile Gln Val Ile Thr Gln Gly Thr Ser Leu Lys Asn Ala Gly Asn 355 360 365 Cys Leu Ser Pro Ala Val Ile Val Gly Leu Leu Lys Glu Ala Ser Lys 370 375 380 Gln Ala Asp Val Asn Leu Val Asn Ala Lys Leu Leu Val Lys Glu Ala 385 390 395 400 Gly Leu Asn Val Thr Thr Ser His Ser Pro Ala Ala Pro Gly Glu Gln 405 410 415 Gly Phe Gly Glu Cys Leu Leu Ala Val Ala Leu Ala Gly Ala Pro Tyr 420 425 430 Gln Ala Val Gly Leu Val Gln Gly Thr Thr Pro Val Leu Gln Gly Leu 435 440 445 Asn Gly Ala Val Phe Arg Pro Glu Val Pro Leu Arg Arg Asp Leu Pro 450 455 460 Leu Leu Leu Phe Arg Thr Gln Thr Ser Asp Pro Ala Met Leu Pro Thr 465 470 475 480 Met Ile Gly Leu Leu Ala Glu Ala Gly Val Arg Leu Leu Ser Tyr Gln 485 490 495 Thr Ser Leu Val Ser Asp Gly Glu Thr Trp His Val Met Gly Ile Ser 500 505 510 Ser Leu Leu Pro Ser Leu Glu Ala Trp Lys Gln His Val Thr Glu Ala 515 520 525 Phe Gln Phe His Phe 530 33372PRThomo sapiens 33Met Lys Tyr Leu Arg His Arg Arg Pro Asn Ala Thr Leu Ile Leu Ala 1 5 10 15 Ile Gly Ala Phe Thr Leu Leu Leu Phe Ser Leu Leu Val Ser Pro Pro 20 25 30 Thr Cys Lys Val Gln Glu Gln Pro Pro Ala Ile Pro Glu Ala Leu Ala 35 40 45 Trp Pro Thr Pro Pro Thr Arg Pro Ala Pro Ala Pro Cys His Ala Asn 50 55 60 Thr Ser Met Val Thr His Pro Asp Phe Ala Thr Gln Pro Gln His Val 65 70 75 80 Gln Asn Phe Leu Leu Tyr Arg His Cys Arg His Phe Pro Leu Leu Gln 85 90 95 Asp Val Pro Pro Ser Lys Cys Ala Gln Pro Val Phe Leu Leu Leu Val 100 105 110 Ile Lys Ser Ser Pro Ser Asn Tyr Val Arg Arg Glu Leu Leu Arg Arg 115 120 125 Thr Trp Gly Arg Glu Arg Lys Val Arg Gly Leu Gln Leu Arg Leu Leu 130 135 140 Phe Leu Val Gly Thr Ala Ser Asn Pro His Glu Ala Arg Lys Val Asn 145 150 155 160 Arg Leu Leu Glu Leu Glu Ala Gln Thr His Gly Asp Ile Leu Gln Trp 165 170 175 Asp Phe His Asp Ser Phe Phe Asn Leu Thr Leu Lys Gln Val Leu Phe 180 185 190 Leu Gln Trp Gln Glu Thr Arg Cys Ala Asn Ala Ser Phe Val Leu Asn 195 200 205 Gly Asp Asp Asp Val Phe Ala His Thr Asp Asn Met Val Phe Tyr Leu 210 215 220 Gln Asp His Asp Pro Gly Arg His Leu Phe Val Gly Gln Leu Ile Gln 225 230 235 240 Asn Val Gly Pro Ile Arg Ala Phe Trp Ser Lys Tyr Tyr Val Pro Glu 245 250 255 Val Val Thr Gln Asn Glu Arg Tyr Pro Pro Tyr Cys Gly Gly Gly Gly 260 265 270 Phe Leu Leu Ser Arg Phe Thr Ala Ala Ala Leu Arg Arg Ala Ala His 275 280 285 Val Leu Asp Ile Phe Pro Ile Asp Asp Val Phe Leu Gly Met Cys Leu 290 295 300 Glu Leu Glu Gly Leu Lys Pro Ala Ser His Ser Gly Ile Arg Thr Ser 305 310 315 320 Gly Val Arg Ala Pro Ser Gln Arg Leu Ser Ser Phe Asp Pro Cys Phe 325 330 335 Tyr Arg Asp Leu Leu Leu Val His Arg Phe Leu Pro Tyr Glu Met Leu 340 345 350 Leu Met Trp Asp Ala Leu Asn Gln Pro Asn Leu Thr Cys Gly Asn Gln 355 360 365 Thr Gln Ile Tyr 370 34177PRThomo sapiens 34Met Ala Val Ala Asn Ser Ser Pro Val Asn Pro Val Val Phe Phe Asp 1 5 10 15 Val Ser Ile Gly Gly Gln Glu Val Gly Arg Met Lys Ile Glu Leu Phe 20 25 30 Ala Asp Val Val Pro Lys Thr Ala Glu Asn Phe Arg Gln Phe Cys Thr 35 40 45 Gly Glu Phe Arg Lys Asp Gly Val Pro Ile Gly Tyr Lys Gly Ser Thr 50 55 60 Phe His Arg Val Ile Lys Asp Phe Met Ile Gln Gly Gly Asp Phe Val 65 70 75 80 Asn Gly Asp Gly Thr Gly Val Ala Ser Ile Tyr Arg Gly Pro Phe Ala 85 90 95 Asp Glu Asn Phe Lys Leu Arg His Ser Ala Pro Gly Leu Leu Ser Met 100 105 110 Ala Asn Ser Gly Pro Ser Thr Asn Gly Cys Gln Phe Phe Ile Thr Cys 115 120 125 Ser Lys Cys Asp Trp Leu Asp Gly Lys His Val Val Phe Gly Lys Ile 130 135 140 Ile Asp Gly Leu Leu Val Met Arg Lys Ile Glu Asn Val Pro Thr Gly 145 150 155 160 Pro Asn Asn Lys Pro Lys Leu Pro Val Val Ile Ser Gln Cys Gly Glu 165 170 175 Met 353312PRThomo sapiens 35Met Met Ala Arg Arg Pro Pro Trp Arg Gly Leu Gly Gly Arg Ser Thr 1 5 10 15 Pro Ile Leu Leu Leu Leu Leu Leu Ser Leu Phe Pro Leu Ser Gln Glu 20 25 30 Glu Leu Gly Gly Gly Gly His Gln Gly Trp Asp Pro Gly Leu Ala Ala 35 40 45 Thr Thr Gly Pro Arg Ala His Ile Gly Gly Gly Ala Leu Ala Leu Cys 50 55 60 Pro Glu Ser Ser Gly Val Arg Glu Asp Gly Gly Pro Gly Leu Gly Val 65 70 75 80 Arg Glu Pro Ile Phe Val Gly Leu Arg Gly Arg Arg Gln Ser Ala Arg 85 90 95 Asn Ser Arg Gly Pro Pro Glu Gln Pro Asn Glu Glu Leu Gly Ile Glu 100 105 110 His Gly Val Gln Pro Leu Gly Ser Arg Glu Arg Glu Thr Gly Gln Gly 115 120 125 Pro Gly Ser Val Leu Tyr Trp Arg Pro Glu Val Ser Ser Cys Gly Arg 130 135 140 Thr Gly Pro Leu Gln Arg Gly Ser Leu Ser Pro Gly Ala Leu Ser Ser 145 150 155 160 Gly Val Pro Gly Ser Gly Asn Ser Ser Pro Leu Pro Ser Asp Phe Leu 165 170 175 Ile Arg His His Gly Pro Lys Pro Val Ser Ser Gln Arg Asn Ala Gly 180 185 190 Thr Gly Ser Arg Lys Arg Val Gly Thr Ala Arg Cys Cys Gly Glu Leu 195 200 205 Trp Ala Thr Gly Ser Lys Gly Gln Gly Glu Arg Ala Thr Thr Ser Gly 210 215 220 Ala Glu Arg Thr Ala Pro Arg Arg Asn Cys Leu Pro Gly Ala Ser Gly 225 230 235 240 Ser Gly Pro Glu Leu Asp Ser Ala Pro Arg Thr Ala Arg Thr Ala Pro 245 250 255 Ala Ser Gly Ser Ala Pro Arg Glu Ser Arg Thr Ala Pro Glu Pro Ala 260 265 270 Pro Lys Arg Met Arg Ser Arg Gly Leu Phe Arg Cys Arg Phe Leu Pro 275 280 285 Gln Arg Pro Gly Pro Arg Pro Pro Gly Leu Pro Ala Arg Pro Glu Ala 290 295 300 Arg Lys Val Thr Ser Ala Asn Arg Ala Arg Phe Arg Arg Ala Ala Asn 305 310 315 320 Arg His Pro Gln Phe Pro Gln Tyr Asn Tyr Gln Thr Leu Val Pro Glu 325 330 335 Asn Glu Ala Ala Gly Thr Ala Val Leu Arg Val Val Ala Gln Asp Pro 340 345 350 Asp Ala Gly Glu Ala Gly Arg Leu Val Tyr Ser Leu Ala Ala Leu Met 355 360 365 Asn Ser Arg Ser Leu Glu Leu Phe Ser Ile Asp Pro Gln Ser Gly Leu 370 375 380 Ile Arg Thr Ala Ala Ala Leu Asp Arg Glu Ser Met Glu Arg His Tyr 385 390 395 400 Leu Arg Val Thr Ala Gln Asp His Gly Ser Pro Arg Leu Ser Ala Thr 405 410 415 Thr Met Val Ala Val Thr Val Ala Asp Arg Asn Asp His Ser Pro Val 420 425 430 Phe Glu Gln Ala Gln Tyr Arg Glu Thr Leu Arg Glu Asn Val Glu Glu 435 440 445 Gly Tyr Pro Ile Leu Gln Leu Arg Ala Thr Asp Gly Asp Ala Pro Pro 450 455 460 Asn Ala Asn Leu Arg Tyr Arg Phe Val Gly Pro Pro Ala Ala Arg Ala 465 470 475 480 Ala Ala Ala Ala Ala Phe Glu Ile Asp Pro Arg Ser Gly Leu Ile Ser 485 490 495 Thr Ser Gly Arg Val Asp Arg Glu His Met Glu Ser Tyr Glu Leu Val 500 505 510 Val Glu Ala Ser Asp Gln Gly Gln Glu Pro Gly Pro Arg Ser Ala Thr 515 520 525 Val Arg Val His Ile Thr Val Leu Asp Glu Asn Asp Asn Ala Pro Gln 530 535 540 Phe Ser Glu Lys Arg Tyr Val Ala Gln Val Arg Glu Asp Val Arg Pro 545 550 555 560 His Thr Val Val Leu Arg Val Thr Ala Thr Asp Arg Asp Lys Asp Ala 565 570 575 Asn Gly Leu Val His Tyr Asn Ile Ile Ser Gly Asn Ser Arg Gly His 580 585 590 Phe Ala Ile Asp Ser Leu Thr Gly Glu Ile Gln Val Val Ala Pro Leu 595 600 605 Asp Phe Glu Ala Glu Arg Glu Tyr Ala Leu Arg Ile Arg Ala Gln Asp 610 615 620 Ala Gly Arg Pro Pro Leu Ser Asn Asn Thr Gly Leu Ala Ser Ile Gln 625 630 635 640 Val Val Asp Ile Asn Asp His Ile Pro Ile Phe Val Ser Thr Pro Phe 645 650 655 Gln Val Ser Val Leu Glu Asn Ala Pro Leu Gly His Ser Val Ile His 660 665 670 Ile Gln Ala Val Asp Ala Asp His Gly Glu Asn Ala Arg Leu Glu Tyr 675 680 685 Ser Leu Thr Gly Val Ala Pro Asp Thr Pro Phe Val Ile Asn Ser Ala 690 695 700 Thr Gly Trp Val Ser Val Ser Gly Pro Leu Asp Arg Glu Ser Val Glu 705 710 715 720 His Tyr Phe Phe Gly Val Glu Ala Arg Asp His Gly Ser Pro Pro Leu 725 730 735 Ser Ala Ser Ala Ser Val Thr Val Thr Val Leu Asp Val Asn Asp Asn 740 745 750 Arg Pro Glu Phe Thr Met Lys Glu Tyr His Leu Arg Leu Asn Glu Asp 755 760 765 Ala Ala Val Gly Thr Ser Val Val Ser Val Thr Ala Val Asp Arg Asp 770 775 780 Ala Asn Ser Ala Ile Ser Tyr Gln Ile Thr Gly Gly Asn Thr Arg Asn 785 790 795 800 Arg Phe Ala Ile Ser Thr Gln Gly Gly Val Gly Leu Val Thr Leu Ala 805 810 815 Leu Pro Leu Asp Tyr Lys Gln Glu Arg Tyr Phe Lys Leu Val Leu Thr 820 825 830 Ala Ser Asp Arg Ala Leu His Asp His Cys Tyr Val His Ile Asn Ile 835 840 845 Thr Asp Ala Asn Thr His Arg Pro Val Phe Gln Ser Ala His Tyr Ser 850 855 860 Val Ser Val Asn Glu Asp Arg Pro Met Gly Ser Thr Ile Val Val Ile 865 870 875 880 Ser Ala Ser Asp Asp Asp Val Gly Glu Asn Ala Arg Ile Thr Tyr Leu 885 890 895 Leu Glu Asp Asn Leu Pro Gln Phe Arg Ile Asp Ala Asp Ser Gly Ala 900 905 910 Ile Thr Leu Gln Ala Pro Leu Asp Tyr Glu Asp Gln Val Thr Tyr Thr 915 920 925 Leu Ala Ile Thr Ala Arg Asp Asn Gly Ile Pro Gln Lys Ala Asp Thr 930 935 940 Thr Tyr Val Glu Val Met Val Asn Asp Val Asn Asp Asn Ala Pro Gln 945 950 955 960 Phe Val Ala Ser His Tyr Thr Gly Leu Val Ser Glu Asp Ala Pro Pro 965 970 975 Phe Thr Ser Val Leu Gln Ile Ser Ala Thr Asp Arg Asp Ala His Ala 980 985 990 Asn Gly Arg Val Gln Tyr Thr Phe Gln Asn Gly Glu Asp Gly Asp Gly 995 1000 1005 Asp Phe Thr Ile Glu Pro Thr Ser Gly Ile Val Arg Thr Val Arg 1010

1015 1020 Arg Leu Asp Arg Glu Ala Val Ser Val Tyr Glu Leu Thr Ala Tyr 1025 1030 1035 Ala Val Asp Arg Gly Val Pro Pro Leu Arg Thr Pro Val Ser Ile 1040 1045 1050 Gln Val Met Val Gln Asp Val Asn Asp Asn Ala Pro Val Phe Pro 1055 1060 1065 Ala Glu Glu Phe Glu Val Arg Val Lys Glu Asn Ser Ile Val Gly 1070 1075 1080 Ser Val Val Ala Gln Ile Thr Ala Val Asp Pro Asp Glu Gly Pro 1085 1090 1095 Asn Ala His Ile Met Tyr Gln Ile Val Glu Gly Asn Ile Pro Glu 1100 1105 1110 Leu Phe Gln Met Asp Ile Phe Ser Gly Glu Leu Thr Ala Leu Ile 1115 1120 1125 Asp Leu Asp Tyr Glu Ala Arg Gln Glu Tyr Val Ile Val Val Gln 1130 1135 1140 Ala Thr Ser Ala Pro Leu Val Ser Arg Ala Thr Val His Val Arg 1145 1150 1155 Leu Val Asp Gln Asn Asp Asn Ser Pro Val Leu Asn Asn Phe Gln 1160 1165 1170 Ile Leu Phe Asn Asn Tyr Val Ser Asn Arg Ser Asp Thr Phe Pro 1175 1180 1185 Ser Gly Ile Ile Gly Arg Ile Pro Ala Tyr Asp Pro Asp Val Ser 1190 1195 1200 Asp His Leu Phe Tyr Ser Phe Glu Arg Gly Asn Glu Leu Gln Leu 1205 1210 1215 Leu Val Val Asn Gln Thr Ser Gly Glu Leu Arg Leu Ser Arg Lys 1220 1225 1230 Leu Asp Asn Asn Arg Pro Leu Val Ala Ser Met Leu Val Thr Val 1235 1240 1245 Thr Asp Gly Leu His Ser Val Thr Ala Gln Cys Val Leu Arg Val 1250 1255 1260 Val Ile Ile Thr Glu Glu Leu Leu Ala Asn Ser Leu Thr Val Arg 1265 1270 1275 Leu Glu Asn Met Trp Gln Glu Arg Phe Leu Ser Pro Leu Leu Gly 1280 1285 1290 Arg Phe Leu Glu Gly Val Ala Ala Val Leu Ala Thr Pro Ala Glu 1295 1300 1305 Asp Val Phe Ile Phe Asn Ile Gln Asn Asp Thr Asp Val Gly Gly 1310 1315 1320 Thr Val Leu Asn Val Ser Phe Ser Ala Leu Ala Pro Arg Gly Ala 1325 1330 1335 Gly Ala Gly Ala Ala Gly Pro Trp Phe Ser Ser Glu Glu Leu Gln 1340 1345 1350 Glu Gln Leu Tyr Val Arg Arg Ala Ala Leu Ala Ala Arg Ser Leu 1355 1360 1365 Leu Asp Val Leu Pro Phe Asp Asp Asn Val Cys Leu Arg Glu Pro 1370 1375 1380 Cys Glu Asn Tyr Met Lys Cys Val Ser Val Leu Arg Phe Asp Ser 1385 1390 1395 Ser Ala Pro Phe Leu Ala Ser Ala Ser Thr Leu Phe Arg Pro Ile 1400 1405 1410 Gln Pro Ile Ala Gly Leu Arg Cys Arg Cys Pro Pro Gly Phe Thr 1415 1420 1425 Gly Asp Phe Cys Glu Thr Glu Leu Asp Leu Cys Tyr Ser Asn Pro 1430 1435 1440 Cys Arg Asn Gly Gly Ala Cys Ala Arg Arg Glu Gly Gly Tyr Thr 1445 1450 1455 Cys Val Cys Arg Pro Arg Phe Thr Gly Glu Asp Cys Glu Leu Asp 1460 1465 1470 Thr Glu Ala Gly Arg Cys Val Pro Gly Val Cys Arg Asn Gly Gly 1475 1480 1485 Thr Cys Thr Asp Ala Pro Asn Gly Gly Phe Arg Cys Gln Cys Pro 1490 1495 1500 Ala Gly Gly Ala Phe Glu Gly Pro Arg Cys Glu Val Ala Ala Arg 1505 1510 1515 Ser Phe Pro Pro Ser Ser Phe Val Met Phe Arg Gly Leu Arg Gln 1520 1525 1530 Arg Phe His Leu Thr Leu Ser Leu Ser Phe Ala Thr Val Gln Gln 1535 1540 1545 Ser Gly Leu Leu Phe Tyr Asn Gly Arg Leu Asn Glu Lys His Asp 1550 1555 1560 Phe Leu Ala Leu Glu Leu Val Ala Gly Gln Val Arg Leu Thr Tyr 1565 1570 1575 Ser Thr Gly Glu Ser Asn Thr Val Val Ser Pro Thr Val Pro Gly 1580 1585 1590 Gly Leu Ser Asp Gly Gln Trp His Thr Val His Leu Arg Tyr Tyr 1595 1600 1605 Asn Lys Pro Arg Thr Asp Ala Leu Gly Gly Ala Gln Gly Pro Ser 1610 1615 1620 Lys Asp Lys Val Ala Val Leu Ser Val Asp Asp Cys Asp Val Ala 1625 1630 1635 Val Ala Leu Gln Phe Gly Ala Glu Ile Gly Asn Tyr Ser Cys Ala 1640 1645 1650 Ala Ala Gly Val Gln Thr Ser Ser Lys Lys Ser Leu Asp Leu Thr 1655 1660 1665 Gly Pro Leu Leu Leu Gly Gly Val Pro Asn Leu Pro Glu Asn Phe 1670 1675 1680 Pro Val Ser His Lys Asp Phe Ile Gly Cys Met Arg Asp Leu His 1685 1690 1695 Ile Asp Gly Arg Arg Val Asp Met Ala Ala Phe Val Ala Asn Asn 1700 1705 1710 Gly Thr Met Ala Gly Cys Gln Ala Lys Leu His Phe Cys Asp Ser 1715 1720 1725 Gly Pro Cys Lys Asn Ser Gly Phe Cys Ser Glu Arg Trp Gly Ser 1730 1735 1740 Phe Ser Cys Asp Cys Pro Val Gly Phe Gly Gly Lys Asp Cys Gln 1745 1750 1755 Leu Thr Met Ala His Pro His His Phe Arg Gly Asn Gly Thr Leu 1760 1765 1770 Ser Trp Asn Phe Gly Ser Asp Met Ala Val Ser Val Pro Trp Tyr 1775 1780 1785 Leu Gly Leu Ala Phe Arg Thr Arg Ala Thr Gln Gly Val Leu Met 1790 1795 1800 Gln Val Gln Ala Gly Pro His Ser Thr Leu Leu Cys Gln Leu Asp 1805 1810 1815 Arg Gly Leu Leu Ser Val Thr Val Thr Arg Gly Ser Gly Arg Ala 1820 1825 1830 Ser His Leu Leu Leu Asp Gln Val Thr Val Ser Asp Gly Arg Trp 1835 1840 1845 His Asp Leu Arg Leu Glu Leu Gln Glu Glu Pro Gly Gly Arg Arg 1850 1855 1860 Gly His His Val Leu Met Val Ser Leu Asp Phe Ser Leu Phe Gln 1865 1870 1875 Asp Thr Met Ala Val Gly Ser Glu Leu Gln Gly Leu Lys Val Lys 1880 1885 1890 Gln Leu His Val Gly Gly Leu Pro Pro Gly Ser Ala Glu Glu Ala 1895 1900 1905 Pro Gln Gly Leu Val Gly Cys Ile Gln Gly Val Trp Leu Gly Ser 1910 1915 1920 Thr Pro Ser Gly Ser Pro Ala Leu Leu Pro Pro Ser His Arg Val 1925 1930 1935 Asn Ala Glu Pro Gly Cys Val Val Thr Asn Ala Cys Ala Ser Gly 1940 1945 1950 Pro Cys Pro Pro His Ala Asp Cys Arg Asp Leu Trp Gln Thr Phe 1955 1960 1965 Ser Cys Thr Cys Gln Pro Gly Tyr Tyr Gly Pro Gly Cys Val Asp 1970 1975 1980 Ala Cys Leu Leu Asn Pro Cys Gln Asn Gln Gly Ser Cys Arg His 1985 1990 1995 Leu Pro Gly Ala Pro His Gly Tyr Thr Cys Asp Cys Val Gly Gly 2000 2005 2010 Tyr Phe Gly His His Cys Glu His Arg Met Asp Gln Gln Cys Pro 2015 2020 2025 Arg Gly Trp Trp Gly Ser Pro Thr Cys Gly Pro Cys Asn Cys Asp 2030 2035 2040 Val His Lys Gly Phe Asp Pro Asn Cys Asn Lys Thr Asn Gly Gln 2045 2050 2055 Cys His Cys Lys Glu Phe His Tyr Arg Pro Arg Gly Ser Asp Ser 2060 2065 2070 Cys Leu Pro Cys Asp Cys Tyr Pro Val Gly Ser Thr Ser Arg Ser 2075 2080 2085 Cys Ala Pro His Ser Gly Gln Cys Pro Cys Arg Pro Gly Ala Leu 2090 2095 2100 Gly Arg Gln Cys Asn Ser Cys Asp Ser Pro Phe Ala Glu Val Thr 2105 2110 2115 Ala Ser Gly Cys Arg Val Leu Tyr Asp Ala Cys Pro Lys Ser Leu 2120 2125 2130 Arg Ser Gly Val Trp Trp Pro Gln Thr Lys Phe Gly Val Leu Ala 2135 2140 2145 Thr Val Pro Cys Pro Arg Gly Ala Leu Gly Ala Ala Val Arg Leu 2150 2155 2160 Cys Asp Glu Ala Gln Gly Trp Leu Glu Pro Asp Leu Phe Asn Cys 2165 2170 2175 Thr Ser Pro Ala Phe Arg Glu Leu Ser Leu Leu Leu Asp Gly Leu 2180 2185 2190 Glu Leu Asn Lys Thr Ala Leu Asp Thr Met Glu Ala Lys Lys Leu 2195 2200 2205 Ala Gln Arg Leu Arg Glu Val Thr Gly His Thr Asp His Tyr Phe 2210 2215 2220 Ser Gln Asp Val Arg Val Thr Ala Arg Leu Leu Ala His Leu Leu 2225 2230 2235 Ala Phe Glu Ser His Gln Gln Gly Phe Gly Leu Thr Ala Thr Gln 2240 2245 2250 Asp Ala His Phe Asn Glu Asn Leu Leu Trp Ala Gly Ser Ala Leu 2255 2260 2265 Leu Ala Pro Glu Thr Gly Asp Leu Trp Ala Ala Leu Gly Gln Arg 2270 2275 2280 Ala Pro Gly Gly Ser Pro Gly Ser Ala Gly Leu Val Arg His Leu 2285 2290 2295 Glu Glu Tyr Ala Ala Thr Leu Ala Arg Asn Met Glu Leu Thr Tyr 2300 2305 2310 Leu Asn Pro Met Gly Leu Val Thr Pro Asn Ile Met Leu Ser Ile 2315 2320 2325 Asp Arg Met Glu His Pro Ser Ser Pro Arg Gly Ala Arg Arg Tyr 2330 2335 2340 Pro Arg Tyr His Ser Asn Leu Phe Arg Gly Gln Asp Ala Trp Asp 2345 2350 2355 Pro His Thr His Val Leu Leu Pro Ser Gln Ser Pro Arg Pro Ser 2360 2365 2370 Pro Ser Glu Val Leu Pro Thr Ser Ser Ser Ile Glu Asn Ser Thr 2375 2380 2385 Thr Ser Ser Val Val Pro Pro Pro Ala Pro Pro Glu Pro Glu Pro 2390 2395 2400 Gly Ile Ser Ile Ile Ile Leu Leu Val Tyr Arg Thr Leu Gly Gly 2405 2410 2415 Leu Leu Pro Ala Gln Phe Gln Ala Glu Arg Arg Gly Ala Arg Leu 2420 2425 2430 Pro Gln Asn Pro Val Met Asn Ser Pro Val Val Ser Val Ala Val 2435 2440 2445 Phe His Gly Arg Asn Phe Leu Arg Gly Ile Leu Glu Ser Pro Ile 2450 2455 2460 Ser Leu Glu Phe Arg Leu Leu Gln Thr Ala Asn Arg Ser Lys Ala 2465 2470 2475 Ile Cys Val Gln Trp Asp Pro Pro Gly Leu Ala Glu Gln His Gly 2480 2485 2490 Val Trp Thr Ala Arg Asp Cys Glu Leu Val His Arg Asn Gly Ser 2495 2500 2505 His Ala Arg Cys Arg Cys Ser Arg Thr Gly Thr Phe Gly Val Leu 2510 2515 2520 Met Asp Ala Ser Pro Arg Glu Arg Leu Glu Gly Asp Leu Glu Leu 2525 2530 2535 Leu Ala Val Phe Thr His Val Val Val Ala Val Ser Val Ala Ala 2540 2545 2550 Leu Val Leu Thr Ala Ala Ile Leu Leu Ser Leu Arg Ser Leu Lys 2555 2560 2565 Ser Asn Val Arg Gly Ile His Ala Asn Val Ala Ala Ala Leu Gly 2570 2575 2580 Val Ala Glu Leu Leu Phe Leu Leu Gly Ile His Arg Thr His Asn 2585 2590 2595 Gln Leu Val Cys Thr Ala Val Ala Ile Leu Leu His Tyr Phe Phe 2600 2605 2610 Leu Ser Thr Phe Ala Trp Leu Phe Val Gln Gly Leu His Leu Tyr 2615 2620 2625 Arg Met Gln Val Glu Pro Arg Asn Val Asp Arg Gly Ala Met Arg 2630 2635 2640 Phe Tyr His Ala Leu Gly Trp Gly Val Pro Ala Val Leu Leu Gly 2645 2650 2655 Leu Ala Val Gly Leu Asp Pro Glu Gly Tyr Gly Asn Pro Asp Phe 2660 2665 2670 Cys Trp Ile Ser Val His Glu Pro Leu Ile Trp Ser Phe Ala Gly 2675 2680 2685 Pro Val Val Leu Val Ile Val Met Asn Gly Thr Met Phe Leu Leu 2690 2695 2700 Ala Ala Arg Thr Ser Cys Ser Thr Gly Gln Arg Glu Ala Lys Lys 2705 2710 2715 Thr Ser Ala Leu Thr Leu Arg Ser Ser Phe Leu Leu Leu Leu Leu 2720 2725 2730 Val Ser Ala Ser Trp Leu Phe Gly Leu Leu Ala Val Asn His Ser 2735 2740 2745 Ile Leu Ala Phe His Tyr Leu His Ala Gly Leu Cys Gly Leu Gln 2750 2755 2760 Gly Leu Ala Val Leu Leu Leu Phe Cys Val Leu Asn Ala Asp Ala 2765 2770 2775 Arg Ala Ala Trp Met Pro Ala Cys Leu Gly Arg Lys Ala Ala Pro 2780 2785 2790 Glu Glu Ala Arg Pro Ala Pro Gly Leu Gly Pro Gly Ala Tyr Asn 2795 2800 2805 Asn Thr Ala Leu Phe Glu Glu Ser Gly Leu Ile Arg Ile Thr Leu 2810 2815 2820 Gly Ala Ser Thr Val Ser Ser Val Ser Ser Ala Arg Ser Gly Arg 2825 2830 2835 Thr Gln Asp Gln Asp Ser Gln Arg Gly Arg Ser Tyr Leu Arg Asp 2840 2845 2850 Asn Val Leu Val Arg His Gly Ser Ala Ala Asp His Thr Asp His 2855 2860 2865 Ser Leu Gln Ala His Ala Gly Pro Thr Asp Leu Asp Val Ala Met 2870 2875 2880 Phe His Arg Asp Ala Gly Ala Asp Ser Asp Ser Asp Ser Asp Leu 2885 2890 2895 Ser Leu Glu Glu Glu Arg Ser Leu Ser Ile Pro Ser Ser Glu Ser 2900 2905 2910 Glu Asp Asn Gly Arg Thr Arg Gly Arg Phe Gln Arg Pro Leu Cys 2915 2920 2925 Arg Ala Ala Gln Ser Glu Arg Leu Leu Thr His Pro Lys Asp Val 2930 2935 2940 Asp Gly Asn Asp Leu Leu Ser Tyr Trp Pro Ala Leu Gly Glu Cys 2945 2950 2955 Glu Ala Ala Pro Cys Ala Leu Gln Thr Trp Gly Ser Glu Arg Arg 2960 2965 2970 Leu Gly Leu Asp Thr Ser Lys Asp Ala Ala Asn Asn Asn Gln Pro 2975 2980 2985 Asp Pro Ala Leu Thr Ser Gly Asp Glu Thr Ser Leu Gly Arg Ala 2990 2995 3000 Gln Arg Gln Arg Lys Gly Ile Leu Lys Asn Arg Leu Gln Tyr Pro 3005 3010 3015 Leu Val Pro Gln Thr Arg Gly Ala Pro Glu Leu Ser Trp Cys Arg 3020 3025 3030 Ala Ala Thr Leu Gly His Arg Ala Val Pro Ala Ala Ser Tyr Gly 3035 3040 3045 Arg Ile Tyr Ala Gly Gly Gly Thr Gly Ser Leu Ser Gln Pro Ala 3050 3055 3060 Ser Arg Tyr Ser Ser Arg Glu Gln Leu Asp Leu Leu Leu Arg Arg 3065 3070 3075 Gln Leu Ser Arg Glu Arg Leu Glu Glu Ala Pro Ala Pro Val Leu 3080 3085 3090 Arg Pro Leu Ser Arg Pro Gly Ser Gln Glu Cys Met Asp Ala Ala 3095 3100 3105 Pro Gly Arg Leu Glu Pro Lys Asp Arg Gly Ser Thr Leu Pro Arg 3110 3115 3120 Arg Gln Pro Pro Arg Asp Tyr Pro Gly Ala Met Ala Gly Arg Phe 3125 3130 3135 Gly Ser Arg Asp Ala Leu Asp Leu Gly Ala Pro Arg Glu Trp Leu 3140 3145 3150 Ser Thr Leu Pro Pro Pro Arg Arg Thr Arg Asp Leu Asp Pro Gln 3155 3160 3165 Pro Pro Pro Leu Pro Leu Ser Pro Gln Arg Gln Leu Ser Arg Asp 3170 3175 3180 Pro Leu Leu Pro Ser Arg Pro Leu Asp Ser Leu Ser Arg Ser Ser 3185 3190 3195 Asn Ser Arg Glu Gln Leu Asp Gln Val Pro Ser Arg His Pro Ser 3200 3205 3210

Arg Glu Ala Leu Gly Pro Leu Pro Gln Leu Leu Arg Ala Arg Glu 3215 3220 3225 Asp Ser Val Ser Gly Pro Ser His Gly Pro Ser Thr Glu Gln Leu 3230 3235 3240 Asp Ile Leu Ser Ser Ile Leu Ala Ser Phe Asn Ser Ser Ala Leu 3245 3250 3255 Ser Ser Val Gln Ser Ser Ser Thr Pro Leu Gly Pro His Thr Thr 3260 3265 3270 Ala Thr Pro Ser Ala Thr Ala Ser Val Leu Gly Pro Ser Thr Pro 3275 3280 3285 Arg Ser Ala Thr Ser His Ser Ile Ser Glu Leu Ser Pro Asp Ser 3290 3295 3300 Glu Val Pro Arg Ser Glu Gly His Ser 3305 3310 36297PRThomo sapiens 36Met Lys His Ile Ile Asn Ser Tyr Glu Asn Ile Asn Asn Thr Ala Arg 1 5 10 15 Asn Asn Ser Asp Cys Pro Arg Val Val Leu Pro Glu Glu Ile Phe Phe 20 25 30 Thr Ile Ser Ile Val Gly Val Leu Glu Asn Leu Ile Val Leu Leu Ala 35 40 45 Val Phe Lys Asn Lys Asn Leu Gln Ala Pro Met Tyr Phe Phe Ile Cys 50 55 60 Ser Leu Ala Ile Ser Asp Met Leu Gly Ser Leu Tyr Lys Ile Leu Glu 65 70 75 80 Asn Ile Leu Ile Ile Leu Arg Asn Met Gly Tyr Leu Lys Pro Arg Gly 85 90 95 Ser Phe Glu Thr Thr Ala Asp Asp Ile Ile Asp Ser Leu Phe Val Leu 100 105 110 Ser Leu Leu Gly Ser Ile Phe Ser Leu Ser Val Ile Ala Ala Asp Arg 115 120 125 Tyr Ile Thr Ile Phe His Ala Leu Arg Tyr His Ser Ile Val Thr Met 130 135 140 Arg Arg Thr Val Val Val Leu Thr Val Ile Trp Thr Phe Cys Thr Gly 145 150 155 160 Thr Gly Ile Thr Met Val Ile Phe Ser His His Val Pro Thr Val Ile 165 170 175 Thr Phe Thr Ser Leu Phe Pro Leu Met Leu Val Phe Ile Leu Cys Leu 180 185 190 Tyr Val His Met Phe Leu Leu Ala Arg Ser His Thr Arg Lys Ile Ser 195 200 205 Thr Leu Pro Arg Ala Asn Met Lys Gly Ala Ile Thr Leu Thr Ile Leu 210 215 220 Leu Gly Val Phe Ile Phe Cys Trp Ala Pro Phe Val Leu His Val Leu 225 230 235 240 Leu Met Thr Phe Cys Pro Ser Asn Pro Tyr Cys Ala Cys Tyr Met Ser 245 250 255 Leu Phe Gln Val Asn Gly Met Leu Ile Met Cys Asn Ala Val Ile Asp 260 265 270 Pro Phe Ile Tyr Ala Phe Arg Ser Pro Glu Leu Arg Asp Ala Phe Lys 275 280 285 Lys Met Ile Phe Cys Ser Arg Tyr Trp 290 295 37378PRThomo sapiens 37Met Val Trp Gly Lys Ile Cys Trp Phe Ser Gln Arg Ala Gly Trp Thr 1 5 10 15 Val Phe Ala Glu Ser Gln Ile Ser Leu Ser Cys Ser Leu Cys Leu His 20 25 30 Ser Gly Asp Gln Glu Ala Gln Asn Pro Asn Leu Val Ser Gln Leu Cys 35 40 45 Gly Val Phe Leu Gln Asn Glu Thr Asn Glu Thr Ile His Met Gln Met 50 55 60 Ser Met Ala Val Gly Gln Gln Ala Leu Pro Leu Asn Ile Ile Ala Pro 65 70 75 80 Lys Ala Val Leu Val Ser Leu Cys Gly Val Leu Leu Asn Gly Thr Val 85 90 95 Phe Trp Leu Leu Cys Cys Gly Ala Thr Asn Pro Tyr Met Val Tyr Ile 100 105 110 Leu His Leu Val Ala Ala Asp Val Ile Tyr Leu Cys Cys Ser Ala Val 115 120 125 Gly Phe Leu Gln Val Thr Leu Leu Thr Tyr His Gly Val Val Phe Phe 130 135 140 Ile Pro Asp Phe Leu Ala Ile Leu Ser Pro Phe Ser Phe Glu Val Cys 145 150 155 160 Leu Cys Leu Leu Val Ala Ile Ser Thr Glu Arg Cys Val Cys Val Leu 165 170 175 Phe Pro Ile Trp Tyr Arg Cys His Arg Pro Lys Tyr Thr Ser Asn Val 180 185 190 Val Cys Thr Leu Ile Trp Gly Leu Pro Phe Cys Ile Asn Ile Val Lys 195 200 205 Ser Leu Phe Leu Thr Tyr Trp Lys His Val Lys Ala Cys Val Ile Phe 210 215 220 Leu Lys Leu Ser Gly Leu Phe His Ala Ile Leu Ser Leu Val Met Cys 225 230 235 240 Val Ser Ser Leu Thr Leu Leu Ile Arg Phe Leu Cys Cys Ser Gln Gln 245 250 255 Gln Lys Ala Thr Arg Val Tyr Ala Val Val Gln Ile Ser Ala Pro Met 260 265 270 Phe Leu Leu Trp Ala Leu Pro Leu Ser Val Ala Pro Leu Ile Thr Asp 275 280 285 Phe Lys Met Phe Val Thr Thr Ser Tyr Leu Ile Ser Leu Phe Leu Ile 290 295 300 Ile Asn Ser Ser Ala Asn Pro Ile Ile Tyr Phe Phe Val Gly Ser Leu 305 310 315 320 Arg Lys Lys Arg Leu Lys Glu Ser Leu Arg Val Ile Leu Gln Arg Ala 325 330 335 Leu Ala Asp Lys Pro Glu Val Gly Arg Asn Lys Lys Ala Ala Gly Ile 340 345 350 Asp Pro Met Glu Gln Pro His Ser Thr Gln His Val Glu Asn Leu Leu 355 360 365 Pro Arg Glu His Arg Val Asp Val Glu Thr 370 375 382527PRThomo sapiens 38Met Ala Ser Gly Ser Cys Gln Gly Cys Glu Glu Asp Glu Glu Thr Leu 1 5 10 15 Lys Lys Leu Ile Val Arg Leu Asn Asn Val Gln Glu Gly Lys Gln Ile 20 25 30 Glu Thr Leu Val Gln Ile Leu Glu Asp Leu Leu Val Phe Thr Tyr Ser 35 40 45 Glu His Ala Ser Lys Leu Phe Gln Gly Lys Asn Ile His Val Pro Leu 50 55 60 Leu Ile Val Leu Asp Ser Tyr Met Arg Val Ala Ser Val Gln Gln Val 65 70 75 80 Gly Trp Ser Leu Leu Cys Lys Leu Ile Glu Val Cys Pro Gly Thr Met 85 90 95 Gln Ser Leu Met Gly Pro Gln Asp Val Gly Asn Asp Trp Glu Val Leu 100 105 110 Gly Val His Gln Leu Ile Leu Lys Met Leu Thr Val His Asn Ala Ser 115 120 125 Val Asn Leu Ser Val Ile Gly Leu Lys Thr Leu Asp Leu Leu Leu Thr 130 135 140 Ser Gly Lys Ile Thr Leu Leu Ile Leu Asp Glu Glu Ser Asp Ile Phe 145 150 155 160 Met Leu Ile Phe Asp Ala Met His Ser Phe Pro Ala Asn Asp Glu Val 165 170 175 Gln Lys Leu Gly Cys Lys Ala Leu His Val Leu Phe Glu Arg Val Ser 180 185 190 Glu Glu Gln Leu Thr Glu Phe Val Glu Asn Lys Asp Tyr Met Ile Leu 195 200 205 Leu Ser Ala Leu Thr Asn Phe Lys Asp Glu Glu Glu Ile Val Leu His 210 215 220 Val Leu His Cys Leu His Ser Leu Ala Ile Pro Cys Asn Asn Val Glu 225 230 235 240 Val Leu Met Ser Gly Asn Val Arg Cys Tyr Asn Ile Val Val Glu Ala 245 250 255 Met Lys Ala Phe Pro Met Ser Glu Arg Ile Gln Glu Val Ser Cys Cys 260 265 270 Leu Leu His Arg Leu Thr Leu Gly Asn Phe Phe Asn Ile Leu Val Leu 275 280 285 Asn Glu Val His Glu Phe Val Val Lys Ala Val Gln Gln Tyr Pro Glu 290 295 300 Asn Ala Ala Leu Gln Ile Ser Ala Leu Ser Cys Leu Ala Leu Leu Thr 305 310 315 320 Glu Thr Ile Phe Leu Asn Gln Asp Leu Glu Glu Lys Asn Glu Asn Gln 325 330 335 Glu Asn Asp Asp Glu Gly Glu Glu Asp Lys Leu Phe Trp Leu Glu Ala 340 345 350 Cys Tyr Lys Ala Leu Thr Trp His Arg Lys Asn Lys His Val Gln Glu 355 360 365 Ala Ala Cys Trp Ala Leu Asn Asn Leu Leu Met Tyr Gln Asn Ser Leu 370 375 380 His Glu Lys Ile Gly Asp Glu Asp Gly His Phe Pro Ala His Arg Glu 385 390 395 400 Val Met Leu Ser Met Leu Met His Ser Ser Ser Lys Glu Val Phe Gln 405 410 415 Ala Ser Ala Asn Ala Leu Ser Thr Leu Leu Glu Gln Asn Val Asn Phe 420 425 430 Arg Lys Ile Leu Leu Ser Lys Gly Ile His Leu Asn Val Leu Glu Leu 435 440 445 Met Gln Lys His Ile His Ser Pro Glu Val Ala Glu Ser Gly Cys Lys 450 455 460 Met Leu Asn His Leu Phe Glu Gly Ser Asn Thr Ser Leu Asp Ile Met 465 470 475 480 Ala Ala Val Val Pro Lys Ile Leu Thr Val Met Lys Arg His Glu Thr 485 490 495 Ser Leu Pro Val Gln Leu Glu Ala Leu Arg Ala Ile Leu His Phe Ile 500 505 510 Val Pro Gly Met Pro Glu Glu Ser Arg Glu Asp Thr Glu Phe His His 515 520 525 Lys Leu Asn Met Val Lys Lys Gln Cys Phe Lys Asn Asp Ile His Lys 530 535 540 Leu Val Leu Ala Ala Leu Asn Arg Phe Ile Gly Asn Pro Gly Ile Gln 545 550 555 560 Lys Cys Gly Leu Lys Val Ile Ser Ser Ile Val His Phe Pro Asp Ala 565 570 575 Leu Glu Met Leu Ser Leu Glu Gly Ala Met Asp Ser Val Leu His Thr 580 585 590 Leu Gln Met Tyr Pro Asp Asp Gln Glu Ile Gln Cys Leu Gly Leu Ser 595 600 605 Leu Ile Gly Tyr Leu Ile Thr Lys Lys Asn Val Phe Ile Gly Thr Gly 610 615 620 His Leu Leu Ala Lys Ile Leu Val Ser Ser Leu Tyr Arg Phe Lys Asp 625 630 635 640 Val Ala Glu Ile Gln Thr Lys Gly Phe Gln Thr Ile Leu Ala Ile Leu 645 650 655 Lys Leu Ser Ala Ser Phe Ser Lys Leu Leu Val His His Ser Phe Asp 660 665 670 Leu Val Ile Phe His Gln Met Ser Ser Asn Ile Met Glu Gln Lys Asp 675 680 685 Gln Gln Phe Leu Asn Leu Cys Cys Lys Cys Phe Ala Lys Val Ala Met 690 695 700 Asp Asp Tyr Leu Lys Asn Val Met Leu Glu Arg Ala Cys Asp Gln Asn 705 710 715 720 Asn Ser Ile Met Val Glu Cys Leu Leu Leu Leu Gly Ala Asp Ala Asn 725 730 735 Gln Ala Lys Glu Gly Ser Ser Leu Ile Cys Gln Val Cys Glu Lys Glu 740 745 750 Ser Ser Pro Lys Leu Val Glu Leu Leu Leu Asn Ser Gly Ser Arg Glu 755 760 765 Gln Asp Val Arg Lys Ala Leu Thr Ile Ser Ile Gly Lys Gly Asp Ser 770 775 780 Gln Ile Ile Ser Leu Leu Leu Arg Arg Leu Ala Leu Asp Val Ala Asn 785 790 795 800 Asn Ser Ile Cys Leu Gly Gly Phe Cys Ile Gly Lys Val Glu Pro Ser 805 810 815 Trp Leu Gly Pro Leu Phe Pro Asp Lys Thr Ser Asn Leu Arg Lys Gln 820 825 830 Thr Asn Ile Ala Ser Thr Leu Ala Arg Met Val Ile Arg Tyr Gln Met 835 840 845 Lys Ser Ala Val Glu Glu Gly Thr Ala Ser Gly Ser Asp Gly Asn Phe 850 855 860 Ser Glu Asp Val Leu Ser Lys Phe Asp Glu Trp Thr Phe Ile Pro Asp 865 870 875 880 Ser Ser Met Asp Ser Val Phe Ala Gln Ser Asp Asp Leu Asp Ser Glu 885 890 895 Gly Ser Glu Gly Ser Phe Leu Val Lys Lys Lys Ser Asn Ser Ile Ser 900 905 910 Val Gly Glu Phe Tyr Arg Asp Ala Val Leu Gln Arg Cys Ser Pro Asn 915 920 925 Leu Gln Arg His Ser Asn Ser Leu Gly Pro Ile Phe Asp His Glu Asp 930 935 940 Leu Leu Lys Arg Lys Arg Lys Ile Leu Ser Ser Asp Asp Ser Leu Arg 945 950 955 960 Ser Ser Lys Leu Gln Ser His Met Arg His Ser Asp Ser Ile Ser Ser 965 970 975 Leu Ala Ser Glu Arg Glu Tyr Ile Thr Ser Leu Asp Leu Ser Ala Asn 980 985 990 Glu Leu Arg Asp Ile Asp Ala Leu Ser Gln Lys Cys Cys Ile Ser Val 995 1000 1005 His Leu Glu His Leu Glu Lys Leu Glu Leu His Gln Asn Ala Leu 1010 1015 1020 Thr Ser Phe Pro Gln Gln Leu Cys Glu Thr Leu Lys Ser Leu Thr 1025 1030 1035 His Leu Asp Leu His Ser Asn Lys Phe Thr Ser Phe Pro Ser Tyr 1040 1045 1050 Leu Leu Lys Met Ser Cys Ile Ala Asn Leu Asp Val Ser Arg Asn 1055 1060 1065 Asp Ile Gly Pro Ser Val Val Leu Asp Pro Thr Val Lys Cys Pro 1070 1075 1080 Thr Leu Lys Gln Phe Asn Leu Ser Tyr Asn Gln Leu Ser Phe Val 1085 1090 1095 Pro Glu Asn Leu Thr Asp Val Val Glu Lys Leu Glu Gln Leu Ile 1100 1105 1110 Leu Glu Gly Asn Lys Ile Ser Gly Ile Cys Ser Pro Leu Arg Leu 1115 1120 1125 Lys Glu Leu Lys Ile Leu Asn Leu Ser Lys Asn His Ile Ser Ser 1130 1135 1140 Leu Ser Glu Asn Phe Leu Glu Ala Cys Pro Lys Val Glu Ser Phe 1145 1150 1155 Ser Ala Arg Met Asn Phe Leu Ala Ala Met Pro Phe Leu Pro Pro 1160 1165 1170 Ser Met Thr Ile Leu Lys Leu Ser Gln Asn Lys Phe Ser Cys Ile 1175 1180 1185 Pro Glu Ala Ile Leu Asn Leu Pro His Leu Arg Ser Leu Asp Met 1190 1195 1200 Ser Ser Asn Asp Ile Gln Tyr Leu Pro Gly Pro Ala His Trp Lys 1205 1210 1215 Ser Leu Asn Leu Arg Glu Leu Leu Phe Ser His Asn Gln Ile Ser 1220 1225 1230 Ile Leu Asp Leu Ser Glu Lys Ala Tyr Leu Trp Ser Arg Val Glu 1235 1240 1245 Lys Leu His Leu Ser His Asn Lys Leu Lys Glu Ile Pro Pro Glu 1250 1255 1260 Ile Gly Cys Leu Glu Asn Leu Thr Ser Leu Asp Val Ser Tyr Asn 1265 1270 1275 Leu Glu Leu Arg Ser Phe Pro Asn Glu Met Gly Lys Leu Ser Lys 1280 1285 1290 Ile Trp Asp Leu Pro Leu Asp Glu Leu His Leu Asn Phe Asp Phe 1295 1300 1305 Lys His Ile Gly Cys Lys Ala Lys Asp Ile Ile Arg Phe Leu Gln 1310 1315 1320 Gln Arg Leu Lys Lys Ala Val Pro Tyr Asn Arg Met Lys Leu Met 1325 1330 1335 Ile Val Gly Asn Thr Gly Ser Gly Lys Thr Thr Leu Leu Gln Gln 1340 1345 1350 Leu Met Lys Thr Lys Lys Ser Asp Leu Gly Met Gln Ser Ala Thr 1355 1360 1365 Val Gly Ile Asp Val Lys Asp Trp Pro Ile Gln Ile Arg Asp Lys 1370 1375 1380 Arg Lys Arg Asp Leu Val Leu Asn Val Trp Asp Phe Ala Gly Arg 1385 1390 1395 Glu Glu Phe Tyr Ser Thr His Pro His Phe Met Thr Gln Arg Ala 1400 1405 1410 Leu Tyr Leu Ala Val Tyr Asp Leu Ser Lys Gly Gln Ala Glu Val 1415 1420 1425 Asp Ala Met Lys Pro Trp Leu Phe Asn Ile Lys Ala Arg Ala Ser 1430 1435 1440 Ser Ser Pro Val Ile Leu Val Gly Thr His Leu Asp Val Ser Asp 1445 1450 1455 Glu Lys Gln Arg Lys Ala Cys Met Ser Lys Ile Thr Lys Glu Leu 1460 1465 1470 Leu Asn Lys Arg Gly Phe Pro Ala Ile Arg Asp Tyr His Phe Val 1475 1480 1485 Asn Ala Thr Glu Glu Ser Asp Ala Leu Ala Lys Leu

Arg Lys Thr 1490 1495 1500 Ile Ile Asn Glu Ser Leu Asn Phe Lys Ile Arg Asp Gln Leu Val 1505 1510 1515 Val Gly Gln Leu Ile Pro Asp Cys Tyr Val Glu Leu Glu Lys Ile 1520 1525 1530 Ile Leu Ser Glu Arg Lys Asn Val Pro Ile Glu Phe Pro Val Ile 1535 1540 1545 Asp Arg Lys Arg Leu Leu Gln Leu Val Arg Glu Asn Gln Leu Gln 1550 1555 1560 Leu Asp Glu Asn Glu Leu Pro His Ala Val His Phe Leu Asn Glu 1565 1570 1575 Ser Gly Val Leu Leu His Phe Gln Asp Pro Ala Leu Gln Leu Ser 1580 1585 1590 Asp Leu Tyr Phe Val Glu Pro Lys Trp Leu Cys Lys Ile Met Ala 1595 1600 1605 Gln Ile Leu Thr Val Lys Val Glu Gly Cys Pro Lys His Pro Lys 1610 1615 1620 Gly Ile Ile Ser Arg Arg Asp Val Glu Lys Phe Leu Ser Lys Lys 1625 1630 1635 Arg Lys Phe Pro Lys Asn Tyr Met Ser Gln Tyr Phe Lys Leu Leu 1640 1645 1650 Glu Lys Phe Gln Ile Ala Leu Pro Ile Gly Glu Glu Tyr Leu Leu 1655 1660 1665 Val Pro Ser Ser Leu Ser Asp His Arg Pro Val Ile Glu Leu Pro 1670 1675 1680 His Cys Glu Asn Ser Glu Ile Ile Ile Arg Leu Tyr Glu Met Pro 1685 1690 1695 Tyr Phe Pro Met Gly Phe Trp Ser Arg Leu Ile Asn Arg Leu Leu 1700 1705 1710 Glu Ile Ser Pro Tyr Met Leu Ser Gly Arg Glu Arg Ala Leu Arg 1715 1720 1725 Pro Asn Arg Met Tyr Trp Arg Gln Gly Ile Tyr Leu Asn Trp Ser 1730 1735 1740 Pro Glu Ala Tyr Cys Leu Val Gly Ser Glu Val Leu Asp Asn His 1745 1750 1755 Pro Glu Ser Phe Leu Lys Ile Thr Val Pro Ser Cys Arg Lys Gly 1760 1765 1770 Cys Ile Leu Leu Gly Gln Val Val Asp His Ile Asp Ser Leu Met 1775 1780 1785 Glu Glu Trp Phe Pro Gly Leu Leu Glu Ile Asp Ile Cys Gly Glu 1790 1795 1800 Gly Glu Thr Leu Leu Lys Lys Trp Ala Leu Tyr Ser Phe Asn Asp 1805 1810 1815 Gly Glu Glu His Gln Lys Ile Leu Leu Asp Asp Leu Met Lys Lys 1820 1825 1830 Ala Glu Glu Gly Asp Leu Leu Val Asn Pro Asp Gln Pro Arg Leu 1835 1840 1845 Thr Ile Pro Ile Ser Gln Ile Ala Pro Asp Leu Ile Leu Ala Asp 1850 1855 1860 Leu Pro Arg Asn Ile Met Leu Asn Asn Asp Glu Leu Glu Phe Glu 1865 1870 1875 Gln Ala Pro Glu Phe Leu Leu Gly Asp Gly Ser Phe Gly Ser Val 1880 1885 1890 Tyr Arg Ala Ala Tyr Glu Gly Glu Glu Val Ala Val Lys Ile Phe 1895 1900 1905 Asn Lys His Thr Ser Leu Arg Leu Leu Arg Gln Glu Leu Val Val 1910 1915 1920 Leu Cys His Leu His His Pro Ser Leu Ile Ser Leu Leu Ala Ala 1925 1930 1935 Gly Ile Arg Pro Arg Met Leu Val Met Glu Leu Ala Ser Lys Gly 1940 1945 1950 Ser Leu Asp Arg Leu Leu Gln Gln Asp Lys Ala Ser Leu Thr Arg 1955 1960 1965 Thr Leu Gln His Arg Ile Ala Leu His Val Ala Asp Gly Leu Arg 1970 1975 1980 Tyr Leu His Ser Ala Met Ile Ile Tyr Arg Asp Leu Lys Pro His 1985 1990 1995 Asn Val Leu Leu Phe Thr Leu Tyr Pro Asn Ala Ala Ile Ile Ala 2000 2005 2010 Lys Ile Ala Asp Tyr Gly Ile Ala Gln Tyr Cys Cys Arg Met Gly 2015 2020 2025 Ile Lys Thr Ser Glu Gly Thr Pro Gly Phe Arg Ala Pro Glu Val 2030 2035 2040 Ala Arg Gly Asn Val Ile Tyr Asn Gln Gln Ala Asp Val Tyr Ser 2045 2050 2055 Phe Gly Leu Leu Leu Tyr Asp Ile Leu Thr Thr Gly Gly Arg Ile 2060 2065 2070 Val Glu Gly Leu Lys Phe Pro Asn Glu Phe Asp Glu Leu Glu Ile 2075 2080 2085 Gln Gly Lys Leu Pro Asp Pro Val Lys Glu Tyr Gly Cys Ala Pro 2090 2095 2100 Trp Pro Met Val Glu Lys Leu Ile Lys Gln Cys Leu Lys Glu Asn 2105 2110 2115 Pro Gln Glu Arg Pro Thr Ser Ala Gln Val Phe Asp Ile Leu Asn 2120 2125 2130 Ser Ala Glu Leu Val Cys Leu Thr Arg Arg Ile Leu Leu Pro Lys 2135 2140 2145 Asn Val Ile Val Glu Cys Met Val Ala Thr His His Asn Ser Arg 2150 2155 2160 Asn Ala Ser Ile Trp Leu Gly Cys Gly His Thr Asp Arg Gly Gln 2165 2170 2175 Leu Ser Phe Leu Asp Leu Asn Thr Glu Gly Tyr Thr Ser Glu Glu 2180 2185 2190 Val Ala Asp Ser Arg Ile Leu Cys Leu Ala Leu Val His Leu Pro 2195 2200 2205 Val Glu Lys Glu Ser Trp Ile Val Ser Gly Thr Gln Ser Gly Thr 2210 2215 2220 Leu Leu Val Ile Asn Thr Glu Asp Gly Lys Lys Arg His Thr Leu 2225 2230 2235 Glu Lys Met Thr Asp Ser Val Thr Cys Leu Tyr Cys Asn Ser Phe 2240 2245 2250 Ser Lys Gln Ser Lys Gln Lys Asn Phe Leu Leu Val Gly Thr Ala 2255 2260 2265 Asp Gly Lys Leu Ala Ile Phe Glu Asp Lys Thr Val Lys Leu Lys 2270 2275 2280 Gly Ala Ala Pro Leu Lys Ile Leu Asn Ile Gly Asn Val Ser Thr 2285 2290 2295 Pro Leu Met Cys Leu Ser Glu Ser Thr Asn Ser Thr Glu Arg Asn 2300 2305 2310 Val Met Trp Gly Gly Cys Gly Thr Lys Ile Phe Ser Phe Ser Asn 2315 2320 2325 Asp Phe Thr Ile Gln Lys Leu Ile Glu Thr Arg Thr Ser Gln Leu 2330 2335 2340 Phe Ser Tyr Ala Ala Phe Ser Asp Ser Asn Ile Ile Thr Val Val 2345 2350 2355 Val Asp Thr Ala Leu Tyr Ile Ala Lys Gln Asn Ser Pro Val Val 2360 2365 2370 Glu Val Trp Asp Lys Lys Thr Glu Lys Leu Cys Gly Leu Ile Asp 2375 2380 2385 Cys Val His Phe Leu Arg Glu Val Met Val Lys Glu Asn Lys Glu 2390 2395 2400 Ser Lys His Lys Met Ser Tyr Ser Gly Arg Val Lys Thr Leu Cys 2405 2410 2415 Leu Gln Lys Asn Thr Ala Leu Trp Ile Gly Thr Gly Gly Gly His 2420 2425 2430 Ile Leu Leu Leu Asp Leu Ser Thr Arg Arg Leu Ile Arg Val Ile 2435 2440 2445 Tyr Asn Phe Cys Asn Ser Val Arg Val Met Met Thr Ala Gln Leu 2450 2455 2460 Gly Ser Leu Lys Asn Val Met Leu Val Leu Gly Tyr Asn Arg Lys 2465 2470 2475 Asn Thr Glu Gly Thr Gln Lys Gln Lys Glu Ile Gln Ser Cys Leu 2480 2485 2490 Thr Val Trp Asp Ile Asn Leu Pro His Glu Val Gln Asn Leu Glu 2495 2500 2505 Lys His Ile Glu Val Arg Lys Glu Leu Ala Glu Lys Met Arg Arg 2510 2515 2520 Thr Ser Val Glu 2525 391375PRThomo sapiens 39Met Ala Gly Gly Ala Trp Gly Arg Leu Ala Cys Tyr Leu Glu Phe Leu 1 5 10 15 Lys Lys Glu Glu Leu Lys Glu Phe Gln Leu Leu Leu Ala Asn Lys Ala 20 25 30 His Ser Arg Ser Ser Ser Gly Glu Thr Pro Ala Gln Pro Glu Lys Thr 35 40 45 Ser Gly Met Glu Val Ala Ser Tyr Leu Val Ala Gln Tyr Gly Glu Gln 50 55 60 Arg Ala Trp Asp Leu Ala Leu His Thr Trp Glu Gln Met Gly Leu Arg 65 70 75 80 Ser Leu Cys Ala Gln Ala Gln Glu Gly Ala Gly His Ser Pro Ser Phe 85 90 95 Pro Tyr Ser Pro Ser Glu Pro His Leu Gly Ser Pro Ser Gln Pro Thr 100 105 110 Ser Thr Ala Val Leu Met Pro Trp Ile His Glu Leu Pro Ala Gly Cys 115 120 125 Thr Gln Gly Ser Glu Arg Arg Val Leu Arg Gln Leu Pro Asp Thr Ser 130 135 140 Gly Arg Arg Trp Arg Glu Ile Ser Ala Ser Leu Leu Tyr Gln Ala Leu 145 150 155 160 Pro Ser Ser Pro Asp His Glu Ser Pro Ser Gln Glu Ser Pro Asn Ala 165 170 175 Pro Thr Ser Thr Ala Val Leu Gly Ser Trp Gly Ser Pro Pro Gln Pro 180 185 190 Ser Leu Ala Pro Arg Glu Gln Glu Ala Pro Gly Thr Gln Trp Pro Leu 195 200 205 Asp Glu Thr Ser Gly Ile Tyr Tyr Thr Glu Ile Arg Glu Arg Glu Arg 210 215 220 Glu Lys Ser Glu Lys Gly Arg Pro Pro Trp Ala Ala Val Val Gly Thr 225 230 235 240 Pro Pro Gln Ala His Thr Ser Leu Gln Pro His His His Pro Trp Glu 245 250 255 Pro Ser Val Arg Glu Ser Leu Cys Ser Thr Trp Pro Trp Lys Asn Glu 260 265 270 Asp Phe Asn Gln Lys Phe Thr Gln Leu Leu Leu Leu Gln Arg Pro His 275 280 285 Pro Arg Ser Gln Asp Pro Leu Val Lys Arg Ser Trp Pro Asp Tyr Val 290 295 300 Glu Glu Asn Arg Gly His Leu Ile Glu Ile Arg Asp Leu Phe Gly Pro 305 310 315 320 Gly Leu Asp Thr Gln Glu Pro Arg Ile Val Ile Leu Gln Gly Ala Ala 325 330 335 Gly Ile Gly Lys Ser Thr Leu Ala Arg Gln Val Lys Glu Ala Trp Gly 340 345 350 Arg Gly Gln Leu Tyr Gly Asp Arg Phe Gln His Val Phe Tyr Phe Ser 355 360 365 Cys Arg Glu Leu Ala Gln Ser Lys Val Val Ser Leu Ala Glu Leu Ile 370 375 380 Gly Lys Asp Gly Thr Ala Thr Pro Ala Pro Ile Arg Gln Ile Leu Ser 385 390 395 400 Arg Pro Glu Arg Leu Leu Phe Ile Leu Asp Gly Val Asp Glu Pro Gly 405 410 415 Trp Val Leu Gln Glu Pro Ser Ser Glu Leu Cys Leu His Trp Ser Gln 420 425 430 Pro Gln Pro Ala Asp Ala Leu Leu Gly Ser Leu Leu Gly Lys Thr Ile 435 440 445 Leu Pro Glu Ala Ser Phe Leu Ile Thr Ala Arg Thr Thr Ala Leu Gln 450 455 460 Asn Leu Ile Pro Ser Leu Glu Gln Ala Arg Trp Val Glu Val Leu Gly 465 470 475 480 Phe Ser Glu Ser Ser Arg Lys Glu Tyr Phe Tyr Arg Tyr Phe Thr Asp 485 490 495 Glu Arg Gln Ala Ile Arg Ala Phe Arg Leu Val Lys Ser Asn Lys Glu 500 505 510 Leu Trp Ala Leu Cys Leu Val Pro Trp Val Ser Trp Leu Ala Cys Thr 515 520 525 Cys Leu Met Gln Gln Met Lys Arg Lys Glu Lys Leu Thr Leu Thr Ser 530 535 540 Lys Thr Thr Thr Thr Leu Cys Leu His Tyr Leu Ala Gln Ala Leu Gln 545 550 555 560 Ala Gln Pro Leu Gly Pro Gln Leu Arg Asp Leu Cys Ser Leu Ala Ala 565 570 575 Glu Gly Ile Trp Gln Lys Lys Thr Leu Phe Ser Pro Asp Asp Leu Arg 580 585 590 Lys His Gly Leu Asp Gly Ala Ile Ile Ser Thr Phe Leu Lys Met Gly 595 600 605 Ile Leu Gln Glu His Pro Ile Pro Leu Ser Tyr Ser Phe Ile His Leu 610 615 620 Cys Phe Gln Glu Phe Phe Ala Ala Met Ser Tyr Val Leu Glu Asp Glu 625 630 635 640 Lys Gly Arg Gly Lys His Ser Asn Cys Ile Ile Asp Leu Glu Lys Thr 645 650 655 Leu Glu Ala Tyr Gly Ile His Gly Leu Phe Gly Ala Ser Thr Thr Arg 660 665 670 Phe Leu Leu Gly Leu Leu Ser Asp Glu Gly Glu Arg Glu Met Glu Asn 675 680 685 Ile Phe His Cys Arg Leu Ser Gln Gly Arg Asn Leu Met Gln Trp Val 690 695 700 Pro Ser Leu Gln Leu Leu Leu Gln Pro His Ser Leu Glu Ser Leu His 705 710 715 720 Cys Leu Tyr Glu Thr Arg Asn Lys Thr Phe Leu Thr Gln Val Met Ala 725 730 735 His Phe Glu Glu Met Gly Met Cys Val Glu Thr Asp Met Glu Leu Leu 740 745 750 Val Cys Thr Phe Cys Ile Lys Phe Ser Arg His Val Lys Lys Leu Gln 755 760 765 Leu Ile Glu Gly Arg Gln His Arg Ser Thr Trp Ser Pro Thr Met Val 770 775 780 Val Leu Phe Arg Trp Val Pro Val Thr Asp Ala Tyr Trp Gln Ile Leu 785 790 795 800 Phe Ser Val Leu Lys Val Thr Arg Asn Leu Lys Glu Leu Asp Leu Ser 805 810 815 Gly Asn Ser Leu Ser His Ser Ala Val Lys Ser Leu Cys Lys Thr Leu 820 825 830 Arg Arg Pro Arg Cys Leu Leu Glu Thr Leu Arg Leu Ala Gly Cys Gly 835 840 845 Leu Thr Ala Glu Asp Cys Lys Asp Leu Ala Phe Gly Leu Arg Ala Asn 850 855 860 Gln Thr Leu Thr Glu Leu Asp Leu Ser Phe Asn Val Leu Thr Asp Ala 865 870 875 880 Gly Ala Lys His Leu Cys Gln Arg Leu Arg Gln Pro Ser Cys Lys Leu 885 890 895 Gln Arg Leu Gln Leu Val Ser Cys Gly Leu Thr Ser Asp Cys Cys Gln 900 905 910 Asp Leu Ala Ser Val Leu Ser Ala Ser Pro Ser Leu Lys Glu Leu Asp 915 920 925 Leu Gln Gln Asn Asn Leu Asp Asp Val Gly Val Arg Leu Leu Cys Glu 930 935 940 Gly Leu Arg His Pro Ala Cys Lys Leu Ile Arg Leu Gly Leu Asp Gln 945 950 955 960 Thr Thr Leu Ser Asp Glu Met Arg Gln Glu Leu Arg Ala Leu Glu Gln 965 970 975 Glu Lys Pro Gln Leu Leu Ile Phe Ser Arg Arg Lys Pro Ser Val Met 980 985 990 Thr Pro Thr Glu Gly Leu Asp Thr Gly Glu Met Ser Asn Ser Thr Ser 995 1000 1005 Ser Leu Lys Arg Gln Arg Leu Gly Ser Glu Arg Ala Ala Ser His 1010 1015 1020 Val Ala Gln Ala Asn Leu Lys Leu Leu Asp Val Ser Lys Ile Phe 1025 1030 1035 Pro Ile Ala Glu Ile Ala Gly Lys Ser His Glu Glu Ser Ser Pro 1040 1045 1050 Glu Val Val Pro Val Glu Leu Leu Cys Val Pro Ser Pro Ala Ser 1055 1060 1065 Gln Gly Asp Leu His Thr Lys Pro Leu Gly Thr Asp Asp Asp Phe 1070 1075 1080 Trp Gly Pro Thr Gly Pro Val Ala Thr Glu Val Val Asp Lys Glu 1085 1090 1095 Lys Asn Leu Tyr Arg Val His Phe Pro Val Ala Gly Ser Tyr Arg 1100 1105 1110 Trp Pro Asn Thr Gly Leu Cys Phe Val Met Arg Glu Ala Val Thr 1115 1120 1125 Val Glu Ile Glu Phe Cys Val Trp Asp Gln Phe Leu Gly Glu Ile 1130 1135 1140 Asn Pro Gln His Ser Trp Met Val Ala Gly Pro Leu Leu Asp Ile 1145 1150 1155 Lys Ala Glu Pro Gly Ala Val Glu Ala Val His Leu Pro His Phe 1160 1165 1170 Val Ala Leu Gln Gly Gly His Val Asp Thr Ser Leu Phe Gln Met 1175 1180 1185 Ala His Phe Lys Glu Glu Gly Met Leu Leu Glu Lys Pro Ala Arg 1190 1195 1200 Val Glu Leu His His Ile Val Leu Glu Asn

Pro Ser Phe Ser Pro 1205 1210 1215 Leu Gly Val Leu Leu Lys Met Ile His Asn Ala Leu Arg Phe Ile 1220 1225 1230 Pro Val Thr Ser Val Val Leu Leu Tyr His Arg Val His Pro Glu 1235 1240 1245 Glu Val Thr Phe His Leu Tyr Leu Ile Pro Ser Asp Cys Ser Ile 1250 1255 1260 Arg Lys Ala Ile Asp Asp Leu Glu Met Lys Phe Gln Phe Val Arg 1265 1270 1275 Ile His Lys Pro Pro Pro Leu Thr Pro Leu Tyr Met Gly Cys Arg 1280 1285 1290 Tyr Thr Val Ser Gly Ser Gly Ser Gly Met Leu Glu Ile Leu Pro 1295 1300 1305 Lys Glu Leu Glu Leu Cys Tyr Arg Ser Pro Gly Glu Asp Gln Leu 1310 1315 1320 Phe Ser Glu Phe Tyr Val Gly His Leu Gly Ser Gly Ile Arg Leu 1325 1330 1335 Gln Val Lys Asp Lys Lys Asp Glu Thr Leu Val Trp Glu Ala Leu 1340 1345 1350 Val Lys Pro Gly Arg Asn Thr Ser Gln Pro Trp Asn Leu Arg Cys 1355 1360 1365 Asn Arg Asp Ala Arg Arg Tyr 1370 1375 401429PRThomo sapiens 40Met Ala Gly Gly Ala Trp Gly Arg Leu Ala Cys Tyr Leu Glu Phe Leu 1 5 10 15 Lys Lys Glu Glu Leu Lys Glu Phe Gln Leu Leu Leu Ala Asn Lys Ala 20 25 30 His Ser Arg Ser Ser Ser Gly Glu Thr Pro Ala Gln Pro Glu Lys Thr 35 40 45 Ser Gly Met Glu Val Ala Ser Tyr Leu Val Ala Gln Tyr Gly Glu Gln 50 55 60 Arg Ala Trp Asp Leu Ala Leu His Thr Trp Glu Gln Met Gly Leu Arg 65 70 75 80 Ser Leu Cys Ala Gln Ala Gln Glu Gly Ala Gly His Ser Pro Ser Phe 85 90 95 Pro Tyr Ser Pro Ser Glu Pro His Leu Gly Ser Pro Ser Gln Pro Thr 100 105 110 Ser Thr Ala Val Leu Met Pro Trp Ile His Glu Leu Pro Ala Gly Cys 115 120 125 Thr Gln Gly Ser Glu Arg Arg Val Leu Arg Gln Leu Pro Asp Thr Ser 130 135 140 Gly Arg Arg Trp Arg Glu Ile Ser Ala Ser Leu Leu Tyr Gln Ala Leu 145 150 155 160 Pro Ser Ser Pro Asp His Glu Ser Pro Ser Gln Glu Ser Pro Asn Ala 165 170 175 Pro Thr Ser Thr Ala Val Leu Gly Ser Trp Gly Ser Pro Pro Gln Pro 180 185 190 Ser Leu Ala Pro Arg Glu Gln Glu Ala Pro Gly Thr Gln Trp Pro Leu 195 200 205 Asp Glu Thr Ser Gly Ile Tyr Tyr Thr Glu Ile Arg Glu Arg Glu Arg 210 215 220 Glu Lys Ser Glu Lys Gly Arg Pro Pro Trp Ala Ala Val Val Gly Thr 225 230 235 240 Pro Pro Gln Ala His Thr Ser Leu Gln Pro His His His Pro Trp Glu 245 250 255 Pro Ser Val Arg Glu Ser Leu Cys Ser Thr Trp Pro Trp Lys Asn Glu 260 265 270 Asp Phe Asn Gln Lys Phe Thr Gln Leu Leu Leu Leu Gln Arg Pro His 275 280 285 Pro Arg Ser Gln Asp Pro Leu Val Lys Arg Ser Trp Pro Asp Tyr Val 290 295 300 Glu Glu Asn Arg Gly His Leu Ile Glu Ile Arg Asp Leu Phe Gly Pro 305 310 315 320 Gly Leu Asp Thr Gln Glu Pro Arg Ile Val Ile Leu Gln Gly Ala Ala 325 330 335 Gly Ile Gly Lys Ser Thr Leu Ala Arg Gln Val Lys Glu Ala Trp Gly 340 345 350 Arg Gly Gln Leu Tyr Gly Asp Arg Phe Gln His Val Phe Tyr Phe Ser 355 360 365 Cys Arg Glu Leu Ala Gln Ser Lys Val Val Ser Leu Ala Glu Leu Ile 370 375 380 Gly Lys Asp Gly Thr Ala Thr Pro Ala Pro Ile Arg Gln Ile Leu Ser 385 390 395 400 Arg Pro Glu Arg Leu Leu Phe Ile Leu Asp Gly Val Asp Glu Pro Gly 405 410 415 Trp Val Leu Gln Glu Pro Ser Ser Glu Leu Cys Leu His Trp Ser Gln 420 425 430 Pro Gln Pro Ala Asp Ala Leu Leu Gly Ser Leu Leu Gly Lys Thr Ile 435 440 445 Leu Pro Glu Ala Ser Phe Leu Ile Thr Ala Arg Thr Thr Ala Leu Gln 450 455 460 Asn Leu Ile Pro Ser Leu Glu Gln Ala Arg Trp Val Glu Val Leu Gly 465 470 475 480 Phe Ser Glu Ser Ser Arg Lys Glu Tyr Phe Tyr Arg Tyr Phe Thr Asp 485 490 495 Glu Arg Gln Ala Ile Arg Ala Phe Arg Leu Val Lys Ser Asn Lys Glu 500 505 510 Leu Trp Ala Leu Cys Leu Val Pro Trp Val Ser Trp Leu Ala Cys Thr 515 520 525 Cys Leu Met Gln Gln Met Lys Arg Lys Glu Lys Leu Thr Leu Thr Ser 530 535 540 Lys Thr Thr Thr Thr Leu Cys Leu His Tyr Leu Ala Gln Ala Leu Gln 545 550 555 560 Ala Gln Pro Leu Gly Pro Gln Leu Arg Asp Leu Cys Ser Leu Ala Ala 565 570 575 Glu Gly Ile Trp Gln Lys Lys Thr Leu Phe Ser Pro Asp Asp Leu Arg 580 585 590 Lys His Gly Leu Asp Gly Ala Ile Ile Ser Thr Phe Leu Lys Met Gly 595 600 605 Ile Leu Gln Glu His Pro Ile Pro Leu Ser Tyr Ser Phe Ile His Leu 610 615 620 Cys Phe Gln Glu Phe Phe Ala Ala Met Ser Tyr Val Leu Glu Asp Glu 625 630 635 640 Lys Gly Arg Gly Lys His Ser Asn Cys Ile Ile Asp Leu Glu Lys Thr 645 650 655 Leu Glu Ala Tyr Gly Ile His Gly Leu Phe Gly Ala Ser Thr Thr Arg 660 665 670 Phe Leu Leu Gly Leu Leu Ser Asp Glu Gly Glu Arg Glu Met Glu Asn 675 680 685 Ile Phe His Cys Arg Leu Ser Gln Gly Arg Asn Leu Met Gln Trp Val 690 695 700 Pro Ser Leu Gln Leu Leu Leu Gln Pro His Ser Leu Glu Ser Leu His 705 710 715 720 Cys Leu Tyr Glu Thr Arg Asn Lys Thr Phe Leu Thr Gln Val Met Ala 725 730 735 His Phe Glu Glu Met Gly Met Cys Val Glu Thr Asp Met Glu Leu Leu 740 745 750 Val Cys Thr Phe Cys Ile Lys Phe Ser Arg His Val Lys Lys Leu Gln 755 760 765 Leu Ile Glu Gly Arg Gln His Arg Ser Thr Trp Ser Pro Thr Met Val 770 775 780 Val Leu Phe Arg Trp Val Pro Val Thr Asp Ala Tyr Trp Gln Ile Leu 785 790 795 800 Phe Ser Val Leu Lys Val Thr Arg Asn Leu Lys Glu Leu Asp Leu Ser 805 810 815 Gly Asn Ser Leu Ser His Ser Ala Val Lys Ser Leu Cys Lys Thr Leu 820 825 830 Arg Arg Pro Arg Cys Leu Leu Glu Thr Leu Arg Leu Ala Gly Cys Gly 835 840 845 Leu Thr Ala Glu Asp Cys Lys Asp Leu Ala Phe Gly Leu Arg Ala Asn 850 855 860 Gln Thr Leu Thr Glu Leu Asp Leu Ser Phe Asn Val Leu Thr Asp Ala 865 870 875 880 Gly Ala Lys His Leu Cys Gln Arg Leu Arg Gln Pro Ser Cys Lys Leu 885 890 895 Gln Arg Leu Gln Leu Val Ser Cys Gly Leu Thr Ser Asp Cys Cys Gln 900 905 910 Asp Leu Ala Ser Val Leu Ser Ala Ser Pro Ser Leu Lys Glu Leu Asp 915 920 925 Leu Gln Gln Asn Asn Leu Asp Asp Val Gly Val Arg Leu Leu Cys Glu 930 935 940 Gly Leu Arg His Pro Ala Cys Lys Leu Ile Arg Leu Gly Leu Asp Gln 945 950 955 960 Thr Thr Leu Ser Asp Glu Met Arg Gln Glu Leu Arg Ala Leu Glu Gln 965 970 975 Glu Lys Pro Gln Leu Leu Ile Phe Ser Arg Arg Lys Pro Ser Val Met 980 985 990 Thr Pro Thr Glu Gly Leu Asp Thr Gly Glu Met Ser Asn Ser Thr Ser 995 1000 1005 Ser Leu Lys Arg Gln Arg Leu Gly Ser Glu Arg Ala Ala Ser His 1010 1015 1020 Val Ala Gln Ala Asn Leu Lys Leu Leu Asp Val Ser Lys Ile Phe 1025 1030 1035 Pro Ile Ala Glu Ile Ala Glu Glu Ser Ser Pro Glu Val Val Pro 1040 1045 1050 Val Glu Leu Leu Cys Val Pro Ser Pro Ala Ser Gln Gly Asp Leu 1055 1060 1065 His Thr Lys Pro Leu Gly Thr Asp Asp Asp Phe Trp Gly Pro Thr 1070 1075 1080 Gly Pro Val Ala Thr Glu Val Val Asp Lys Glu Lys Asn Leu Tyr 1085 1090 1095 Arg Val His Phe Pro Val Ala Gly Ser Tyr Arg Trp Pro Asn Thr 1100 1105 1110 Gly Leu Cys Phe Val Met Arg Glu Ala Val Thr Val Glu Ile Glu 1115 1120 1125 Phe Cys Val Trp Asp Gln Phe Leu Gly Glu Ile Asn Pro Gln His 1130 1135 1140 Ser Trp Met Val Ala Gly Pro Leu Leu Asp Ile Lys Ala Glu Pro 1145 1150 1155 Gly Ala Val Glu Ala Val His Leu Pro His Phe Val Ala Leu Gln 1160 1165 1170 Gly Gly His Val Asp Thr Ser Leu Phe Gln Met Ala His Phe Lys 1175 1180 1185 Glu Glu Gly Met Leu Leu Glu Lys Pro Ala Arg Val Glu Leu His 1190 1195 1200 His Ile Val Leu Glu Asn Pro Ser Phe Ser Pro Leu Gly Val Leu 1205 1210 1215 Leu Lys Met Ile His Asn Ala Leu Arg Phe Ile Pro Val Thr Ser 1220 1225 1230 Val Val Leu Leu Tyr His Arg Val His Pro Glu Glu Val Thr Phe 1235 1240 1245 His Leu Tyr Leu Ile Pro Ser Asp Cys Ser Ile Arg Lys Glu Leu 1250 1255 1260 Glu Leu Cys Tyr Arg Ser Pro Gly Glu Asp Gln Leu Phe Ser Glu 1265 1270 1275 Phe Tyr Val Gly His Leu Gly Ser Gly Ile Arg Leu Gln Val Lys 1280 1285 1290 Asp Lys Lys Asp Glu Thr Leu Val Trp Glu Ala Leu Val Lys Pro 1295 1300 1305 Gly Asp Leu Met Pro Ala Thr Thr Leu Ile Pro Pro Ala Arg Ile 1310 1315 1320 Ala Val Pro Ser Pro Leu Asp Ala Pro Gln Leu Leu His Phe Val 1325 1330 1335 Asp Gln Tyr Arg Glu Gln Leu Ile Ala Arg Val Thr Ser Val Glu 1340 1345 1350 Val Val Leu Asp Lys Leu His Gly Gln Val Leu Ser Gln Glu Gln 1355 1360 1365 Tyr Glu Arg Val Leu Ala Glu Asn Thr Arg Pro Ser Gln Met Arg 1370 1375 1380 Lys Leu Phe Ser Leu Ser Gln Ser Trp Asp Arg Lys Cys Lys Asp 1385 1390 1395 Gly Leu Tyr Gln Ala Leu Lys Glu Thr His Pro His Leu Ile Met 1400 1405 1410 Glu Leu Trp Glu Lys Gly Ser Lys Lys Gly Leu Leu Pro Leu Ser 1415 1420 1425 Ser 411473PRThomo sapiens 41Met Ala Gly Gly Ala Trp Gly Arg Leu Ala Cys Tyr Leu Glu Phe Leu 1 5 10 15 Lys Lys Glu Glu Leu Lys Glu Phe Gln Leu Leu Leu Ala Asn Lys Ala 20 25 30 His Ser Arg Ser Ser Ser Gly Glu Thr Pro Ala Gln Pro Glu Lys Thr 35 40 45 Ser Gly Met Glu Val Ala Ser Tyr Leu Val Ala Gln Tyr Gly Glu Gln 50 55 60 Arg Ala Trp Asp Leu Ala Leu His Thr Trp Glu Gln Met Gly Leu Arg 65 70 75 80 Ser Leu Cys Ala Gln Ala Gln Glu Gly Ala Gly His Ser Pro Ser Phe 85 90 95 Pro Tyr Ser Pro Ser Glu Pro His Leu Gly Ser Pro Ser Gln Pro Thr 100 105 110 Ser Thr Ala Val Leu Met Pro Trp Ile His Glu Leu Pro Ala Gly Cys 115 120 125 Thr Gln Gly Ser Glu Arg Arg Val Leu Arg Gln Leu Pro Asp Thr Ser 130 135 140 Gly Arg Arg Trp Arg Glu Ile Ser Ala Ser Leu Leu Tyr Gln Ala Leu 145 150 155 160 Pro Ser Ser Pro Asp His Glu Ser Pro Ser Gln Glu Ser Pro Asn Ala 165 170 175 Pro Thr Ser Thr Ala Val Leu Gly Ser Trp Gly Ser Pro Pro Gln Pro 180 185 190 Ser Leu Ala Pro Arg Glu Gln Glu Ala Pro Gly Thr Gln Trp Pro Leu 195 200 205 Asp Glu Thr Ser Gly Ile Tyr Tyr Thr Glu Ile Arg Glu Arg Glu Arg 210 215 220 Glu Lys Ser Glu Lys Gly Arg Pro Pro Trp Ala Ala Val Val Gly Thr 225 230 235 240 Pro Pro Gln Ala His Thr Ser Leu Gln Pro His His His Pro Trp Glu 245 250 255 Pro Ser Val Arg Glu Ser Leu Cys Ser Thr Trp Pro Trp Lys Asn Glu 260 265 270 Asp Phe Asn Gln Lys Phe Thr Gln Leu Leu Leu Leu Gln Arg Pro His 275 280 285 Pro Arg Ser Gln Asp Pro Leu Val Lys Arg Ser Trp Pro Asp Tyr Val 290 295 300 Glu Glu Asn Arg Gly His Leu Ile Glu Ile Arg Asp Leu Phe Gly Pro 305 310 315 320 Gly Leu Asp Thr Gln Glu Pro Arg Ile Val Ile Leu Gln Gly Ala Ala 325 330 335 Gly Ile Gly Lys Ser Thr Leu Ala Arg Gln Val Lys Glu Ala Trp Gly 340 345 350 Arg Gly Gln Leu Tyr Gly Asp Arg Phe Gln His Val Phe Tyr Phe Ser 355 360 365 Cys Arg Glu Leu Ala Gln Ser Lys Val Val Ser Leu Ala Glu Leu Ile 370 375 380 Gly Lys Asp Gly Thr Ala Thr Pro Ala Pro Ile Arg Gln Ile Leu Ser 385 390 395 400 Arg Pro Glu Arg Leu Leu Phe Ile Leu Asp Gly Val Asp Glu Pro Gly 405 410 415 Trp Val Leu Gln Glu Pro Ser Ser Glu Leu Cys Leu His Trp Ser Gln 420 425 430 Pro Gln Pro Ala Asp Ala Leu Leu Gly Ser Leu Leu Gly Lys Thr Ile 435 440 445 Leu Pro Glu Ala Ser Phe Leu Ile Thr Ala Arg Thr Thr Ala Leu Gln 450 455 460 Asn Leu Ile Pro Ser Leu Glu Gln Ala Arg Trp Val Glu Val Leu Gly 465 470 475 480 Phe Ser Glu Ser Ser Arg Lys Glu Tyr Phe Tyr Arg Tyr Phe Thr Asp 485 490 495 Glu Arg Gln Ala Ile Arg Ala Phe Arg Leu Val Lys Ser Asn Lys Glu 500 505 510 Leu Trp Ala Leu Cys Leu Val Pro Trp Val Ser Trp Leu Ala Cys Thr 515 520 525 Cys Leu Met Gln Gln Met Lys Arg Lys Glu Lys Leu Thr Leu Thr Ser 530 535 540 Lys Thr Thr Thr Thr Leu Cys Leu His Tyr Leu Ala Gln Ala Leu Gln 545 550 555 560 Ala Gln Pro Leu Gly Pro Gln Leu Arg Asp Leu Cys Ser Leu Ala Ala 565 570 575 Glu Gly Ile Trp Gln Lys Lys Thr Leu Phe Ser Pro Asp Asp Leu Arg 580 585 590 Lys His Gly Leu Asp Gly Ala Ile Ile Ser Thr Phe Leu Lys Met Gly 595 600 605 Ile Leu Gln Glu His Pro Ile Pro Leu Ser Tyr Ser Phe Ile His Leu 610 615 620 Cys Phe Gln Glu Phe Phe Ala Ala Met Ser Tyr Val Leu Glu Asp Glu 625 630 635 640 Lys Gly Arg Gly Lys His Ser Asn Cys Ile Ile Asp Leu Glu Lys Thr 645 650 655 Leu Glu Ala Tyr Gly Ile His Gly Leu Phe Gly Ala Ser Thr Thr Arg 660 665 670 Phe Leu Leu Gly Leu Leu Ser

Asp Glu Gly Glu Arg Glu Met Glu Asn 675 680 685 Ile Phe His Cys Arg Leu Ser Gln Gly Arg Asn Leu Met Gln Trp Val 690 695 700 Pro Ser Leu Gln Leu Leu Leu Gln Pro His Ser Leu Glu Ser Leu His 705 710 715 720 Cys Leu Tyr Glu Thr Arg Asn Lys Thr Phe Leu Thr Gln Val Met Ala 725 730 735 His Phe Glu Glu Met Gly Met Cys Val Glu Thr Asp Met Glu Leu Leu 740 745 750 Val Cys Thr Phe Cys Ile Lys Phe Ser Arg His Val Lys Lys Leu Gln 755 760 765 Leu Ile Glu Gly Arg Gln His Arg Ser Thr Trp Ser Pro Thr Met Val 770 775 780 Val Leu Phe Arg Trp Val Pro Val Thr Asp Ala Tyr Trp Gln Ile Leu 785 790 795 800 Phe Ser Val Leu Lys Val Thr Arg Asn Leu Lys Glu Leu Asp Leu Ser 805 810 815 Gly Asn Ser Leu Ser His Ser Ala Val Lys Ser Leu Cys Lys Thr Leu 820 825 830 Arg Arg Pro Arg Cys Leu Leu Glu Thr Leu Arg Leu Ala Gly Cys Gly 835 840 845 Leu Thr Ala Glu Asp Cys Lys Asp Leu Ala Phe Gly Leu Arg Ala Asn 850 855 860 Gln Thr Leu Thr Glu Leu Asp Leu Ser Phe Asn Val Leu Thr Asp Ala 865 870 875 880 Gly Ala Lys His Leu Cys Gln Arg Leu Arg Gln Pro Ser Cys Lys Leu 885 890 895 Gln Arg Leu Gln Leu Val Ser Cys Gly Leu Thr Ser Asp Cys Cys Gln 900 905 910 Asp Leu Ala Ser Val Leu Ser Ala Ser Pro Ser Leu Lys Glu Leu Asp 915 920 925 Leu Gln Gln Asn Asn Leu Asp Asp Val Gly Val Arg Leu Leu Cys Glu 930 935 940 Gly Leu Arg His Pro Ala Cys Lys Leu Ile Arg Leu Gly Leu Asp Gln 945 950 955 960 Thr Thr Leu Ser Asp Glu Met Arg Gln Glu Leu Arg Ala Leu Glu Gln 965 970 975 Glu Lys Pro Gln Leu Leu Ile Phe Ser Arg Arg Lys Pro Ser Val Met 980 985 990 Thr Pro Thr Glu Gly Leu Asp Thr Gly Glu Met Ser Asn Ser Thr Ser 995 1000 1005 Ser Leu Lys Arg Gln Arg Leu Gly Ser Glu Arg Ala Ala Ser His 1010 1015 1020 Val Ala Gln Ala Asn Leu Lys Leu Leu Asp Val Ser Lys Ile Phe 1025 1030 1035 Pro Ile Ala Glu Ile Ala Glu Glu Ser Ser Pro Glu Val Val Pro 1040 1045 1050 Val Glu Leu Leu Cys Val Pro Ser Pro Ala Ser Gln Gly Asp Leu 1055 1060 1065 His Thr Lys Pro Leu Gly Thr Asp Asp Asp Phe Trp Gly Pro Thr 1070 1075 1080 Gly Pro Val Ala Thr Glu Val Val Asp Lys Glu Lys Asn Leu Tyr 1085 1090 1095 Arg Val His Phe Pro Val Ala Gly Ser Tyr Arg Trp Pro Asn Thr 1100 1105 1110 Gly Leu Cys Phe Val Met Arg Glu Ala Val Thr Val Glu Ile Glu 1115 1120 1125 Phe Cys Val Trp Asp Gln Phe Leu Gly Glu Ile Asn Pro Gln His 1130 1135 1140 Ser Trp Met Val Ala Gly Pro Leu Leu Asp Ile Lys Ala Glu Pro 1145 1150 1155 Gly Ala Val Glu Ala Val His Leu Pro His Phe Val Ala Leu Gln 1160 1165 1170 Gly Gly His Val Asp Thr Ser Leu Phe Gln Met Ala His Phe Lys 1175 1180 1185 Glu Glu Gly Met Leu Leu Glu Lys Pro Ala Arg Val Glu Leu His 1190 1195 1200 His Ile Val Leu Glu Asn Pro Ser Phe Ser Pro Leu Gly Val Leu 1205 1210 1215 Leu Lys Met Ile His Asn Ala Leu Arg Phe Ile Pro Val Thr Ser 1220 1225 1230 Val Val Leu Leu Tyr His Arg Val His Pro Glu Glu Val Thr Phe 1235 1240 1245 His Leu Tyr Leu Ile Pro Ser Asp Cys Ser Ile Arg Lys Ala Ile 1250 1255 1260 Asp Asp Leu Glu Met Lys Phe Gln Phe Val Arg Ile His Lys Pro 1265 1270 1275 Pro Pro Leu Thr Pro Leu Tyr Met Gly Cys Arg Tyr Thr Val Ser 1280 1285 1290 Gly Ser Gly Ser Gly Met Leu Glu Ile Leu Pro Lys Glu Leu Glu 1295 1300 1305 Leu Cys Tyr Arg Ser Pro Gly Glu Asp Gln Leu Phe Ser Glu Phe 1310 1315 1320 Tyr Val Gly His Leu Gly Ser Gly Ile Arg Leu Gln Val Lys Asp 1325 1330 1335 Lys Lys Asp Glu Thr Leu Val Trp Glu Ala Leu Val Lys Pro Gly 1340 1345 1350 Asp Leu Met Pro Ala Thr Thr Leu Ile Pro Pro Ala Arg Ile Ala 1355 1360 1365 Val Pro Ser Pro Leu Asp Ala Pro Gln Leu Leu His Phe Val Asp 1370 1375 1380 Gln Tyr Arg Glu Gln Leu Ile Ala Arg Val Thr Ser Val Glu Val 1385 1390 1395 Val Leu Asp Lys Leu His Gly Gln Val Leu Ser Gln Glu Gln Tyr 1400 1405 1410 Glu Arg Val Leu Ala Glu Asn Thr Arg Pro Ser Gln Met Arg Lys 1415 1420 1425 Leu Phe Ser Leu Ser Gln Ser Trp Asp Arg Lys Cys Lys Asp Gly 1430 1435 1440 Leu Tyr Gln Ala Leu Lys Glu Thr His Pro His Leu Ile Met Glu 1445 1450 1455 Leu Trp Glu Lys Gly Ser Lys Lys Gly Leu Leu Pro Leu Ser Ser 1460 1465 1470 421443PRThomo sapiens 42Met Ala Gly Gly Ala Trp Gly Arg Leu Ala Cys Tyr Leu Glu Phe Leu 1 5 10 15 Lys Lys Glu Glu Leu Lys Glu Phe Gln Leu Leu Leu Ala Asn Lys Ala 20 25 30 His Ser Arg Ser Ser Ser Gly Glu Thr Pro Ala Gln Pro Glu Lys Thr 35 40 45 Ser Gly Met Glu Val Ala Ser Tyr Leu Val Ala Gln Tyr Gly Glu Gln 50 55 60 Arg Ala Trp Asp Leu Ala Leu His Thr Trp Glu Gln Met Gly Leu Arg 65 70 75 80 Ser Leu Cys Ala Gln Ala Gln Glu Gly Ala Gly His Ser Pro Ser Phe 85 90 95 Pro Tyr Ser Pro Ser Glu Pro His Leu Gly Ser Pro Ser Gln Pro Thr 100 105 110 Ser Thr Ala Val Leu Met Pro Trp Ile His Glu Leu Pro Ala Gly Cys 115 120 125 Thr Gln Gly Ser Glu Arg Arg Val Leu Arg Gln Leu Pro Asp Thr Ser 130 135 140 Gly Arg Arg Trp Arg Glu Ile Ser Ala Ser Leu Leu Tyr Gln Ala Leu 145 150 155 160 Pro Ser Ser Pro Asp His Glu Ser Pro Ser Gln Glu Ser Pro Asn Ala 165 170 175 Pro Thr Ser Thr Ala Val Leu Gly Ser Trp Gly Ser Pro Pro Gln Pro 180 185 190 Ser Leu Ala Pro Arg Glu Gln Glu Ala Pro Gly Thr Gln Trp Pro Leu 195 200 205 Asp Glu Thr Ser Gly Ile Tyr Tyr Thr Glu Ile Arg Glu Arg Glu Arg 210 215 220 Glu Lys Ser Glu Lys Gly Arg Pro Pro Trp Ala Ala Val Val Gly Thr 225 230 235 240 Pro Pro Gln Ala His Thr Ser Leu Gln Pro His His His Pro Trp Glu 245 250 255 Pro Ser Val Arg Glu Ser Leu Cys Ser Thr Trp Pro Trp Lys Asn Glu 260 265 270 Asp Phe Asn Gln Lys Phe Thr Gln Leu Leu Leu Leu Gln Arg Pro His 275 280 285 Pro Arg Ser Gln Asp Pro Leu Val Lys Arg Ser Trp Pro Asp Tyr Val 290 295 300 Glu Glu Asn Arg Gly His Leu Ile Glu Ile Arg Asp Leu Phe Gly Pro 305 310 315 320 Gly Leu Asp Thr Gln Glu Pro Arg Ile Val Ile Leu Gln Gly Ala Ala 325 330 335 Gly Ile Gly Lys Ser Thr Leu Ala Arg Gln Val Lys Glu Ala Trp Gly 340 345 350 Arg Gly Gln Leu Tyr Gly Asp Arg Phe Gln His Val Phe Tyr Phe Ser 355 360 365 Cys Arg Glu Leu Ala Gln Ser Lys Val Val Ser Leu Ala Glu Leu Ile 370 375 380 Gly Lys Asp Gly Thr Ala Thr Pro Ala Pro Ile Arg Gln Ile Leu Ser 385 390 395 400 Arg Pro Glu Arg Leu Leu Phe Ile Leu Asp Gly Val Asp Glu Pro Gly 405 410 415 Trp Val Leu Gln Glu Pro Ser Ser Glu Leu Cys Leu His Trp Ser Gln 420 425 430 Pro Gln Pro Ala Asp Ala Leu Leu Gly Ser Leu Leu Gly Lys Thr Ile 435 440 445 Leu Pro Glu Ala Ser Phe Leu Ile Thr Ala Arg Thr Thr Ala Leu Gln 450 455 460 Asn Leu Ile Pro Ser Leu Glu Gln Ala Arg Trp Val Glu Val Leu Gly 465 470 475 480 Phe Ser Glu Ser Ser Arg Lys Glu Tyr Phe Tyr Arg Tyr Phe Thr Asp 485 490 495 Glu Arg Gln Ala Ile Arg Ala Phe Arg Leu Val Lys Ser Asn Lys Glu 500 505 510 Leu Trp Ala Leu Cys Leu Val Pro Trp Val Ser Trp Leu Ala Cys Thr 515 520 525 Cys Leu Met Gln Gln Met Lys Arg Lys Glu Lys Leu Thr Leu Thr Ser 530 535 540 Lys Thr Thr Thr Thr Leu Cys Leu His Tyr Leu Ala Gln Ala Leu Gln 545 550 555 560 Ala Gln Pro Leu Gly Pro Gln Leu Arg Asp Leu Cys Ser Leu Ala Ala 565 570 575 Glu Gly Ile Trp Gln Lys Lys Thr Leu Phe Ser Pro Asp Asp Leu Arg 580 585 590 Lys His Gly Leu Asp Gly Ala Ile Ile Ser Thr Phe Leu Lys Met Gly 595 600 605 Ile Leu Gln Glu His Pro Ile Pro Leu Ser Tyr Ser Phe Ile His Leu 610 615 620 Cys Phe Gln Glu Phe Phe Ala Ala Met Ser Tyr Val Leu Glu Asp Glu 625 630 635 640 Lys Gly Arg Gly Lys His Ser Asn Cys Ile Ile Asp Leu Glu Lys Thr 645 650 655 Leu Glu Ala Tyr Gly Ile His Gly Leu Phe Gly Ala Ser Thr Thr Arg 660 665 670 Phe Leu Leu Gly Leu Leu Ser Asp Glu Gly Glu Arg Glu Met Glu Asn 675 680 685 Ile Phe His Cys Arg Leu Ser Gln Gly Arg Asn Leu Met Gln Trp Val 690 695 700 Pro Ser Leu Gln Leu Leu Leu Gln Pro His Ser Leu Glu Ser Leu His 705 710 715 720 Cys Leu Tyr Glu Thr Arg Asn Lys Thr Phe Leu Thr Gln Val Met Ala 725 730 735 His Phe Glu Glu Met Gly Met Cys Val Glu Thr Asp Met Glu Leu Leu 740 745 750 Val Cys Thr Phe Cys Ile Lys Phe Ser Arg His Val Lys Lys Leu Gln 755 760 765 Leu Ile Glu Gly Arg Gln His Arg Ser Thr Trp Ser Pro Thr Met Val 770 775 780 Val Leu Phe Arg Trp Val Pro Val Thr Asp Ala Tyr Trp Gln Ile Leu 785 790 795 800 Phe Ser Val Leu Lys Val Thr Arg Asn Leu Lys Glu Leu Asp Leu Ser 805 810 815 Gly Asn Ser Leu Ser His Ser Ala Val Lys Ser Leu Cys Lys Thr Leu 820 825 830 Arg Arg Pro Arg Cys Leu Leu Glu Thr Leu Arg Leu Ala Gly Cys Gly 835 840 845 Leu Thr Ala Glu Asp Cys Lys Asp Leu Ala Phe Gly Leu Arg Ala Asn 850 855 860 Gln Thr Leu Thr Glu Leu Asp Leu Ser Phe Asn Val Leu Thr Asp Ala 865 870 875 880 Gly Ala Lys His Leu Cys Gln Arg Leu Arg Gln Pro Ser Cys Lys Leu 885 890 895 Gln Arg Leu Gln Leu Val Ser Cys Gly Leu Thr Ser Asp Cys Cys Gln 900 905 910 Asp Leu Ala Ser Val Leu Ser Ala Ser Pro Ser Leu Lys Glu Leu Asp 915 920 925 Leu Gln Gln Asn Asn Leu Asp Asp Val Gly Val Arg Leu Leu Cys Glu 930 935 940 Gly Leu Arg His Pro Ala Cys Lys Leu Ile Arg Leu Gly Lys Pro Ser 945 950 955 960 Val Met Thr Pro Thr Glu Gly Leu Asp Thr Gly Glu Met Ser Asn Ser 965 970 975 Thr Ser Ser Leu Lys Arg Gln Arg Leu Gly Ser Glu Arg Ala Ala Ser 980 985 990 His Val Ala Gln Ala Asn Leu Lys Leu Leu Asp Val Ser Lys Ile Phe 995 1000 1005 Pro Ile Ala Glu Ile Ala Glu Glu Ser Ser Pro Glu Val Val Pro 1010 1015 1020 Val Glu Leu Leu Cys Val Pro Ser Pro Ala Ser Gln Gly Asp Leu 1025 1030 1035 His Thr Lys Pro Leu Gly Thr Asp Asp Asp Phe Trp Gly Pro Thr 1040 1045 1050 Gly Pro Val Ala Thr Glu Val Val Asp Lys Glu Lys Asn Leu Tyr 1055 1060 1065 Arg Val His Phe Pro Val Ala Gly Ser Tyr Arg Trp Pro Asn Thr 1070 1075 1080 Gly Leu Cys Phe Val Met Arg Glu Ala Val Thr Val Glu Ile Glu 1085 1090 1095 Phe Cys Val Trp Asp Gln Phe Leu Gly Glu Ile Asn Pro Gln His 1100 1105 1110 Ser Trp Met Val Ala Gly Pro Leu Leu Asp Ile Lys Ala Glu Pro 1115 1120 1125 Gly Ala Val Glu Ala Val His Leu Pro His Phe Val Ala Leu Gln 1130 1135 1140 Gly Gly His Val Asp Thr Ser Leu Phe Gln Met Ala His Phe Lys 1145 1150 1155 Glu Glu Gly Met Leu Leu Glu Lys Pro Ala Arg Val Glu Leu His 1160 1165 1170 His Ile Val Leu Glu Asn Pro Ser Phe Ser Pro Leu Gly Val Leu 1175 1180 1185 Leu Lys Met Ile His Asn Ala Leu Arg Phe Ile Pro Val Thr Ser 1190 1195 1200 Val Val Leu Leu Tyr His Arg Val His Pro Glu Glu Val Thr Phe 1205 1210 1215 His Leu Tyr Leu Ile Pro Ser Asp Cys Ser Ile Arg Lys Ala Ile 1220 1225 1230 Asp Asp Leu Glu Met Lys Phe Gln Phe Val Arg Ile His Lys Pro 1235 1240 1245 Pro Pro Leu Thr Pro Leu Tyr Met Gly Cys Arg Tyr Thr Val Ser 1250 1255 1260 Gly Ser Gly Ser Gly Met Leu Glu Ile Leu Pro Lys Glu Leu Glu 1265 1270 1275 Leu Cys Tyr Arg Ser Pro Gly Glu Asp Gln Leu Phe Ser Glu Phe 1280 1285 1290 Tyr Val Gly His Leu Gly Ser Gly Ile Arg Leu Gln Val Lys Asp 1295 1300 1305 Lys Lys Asp Glu Thr Leu Val Trp Glu Ala Leu Val Lys Pro Gly 1310 1315 1320 Asp Leu Met Pro Ala Thr Thr Leu Ile Pro Pro Ala Arg Ile Ala 1325 1330 1335 Val Pro Ser Pro Leu Asp Ala Pro Gln Leu Leu His Phe Val Asp 1340 1345 1350 Gln Tyr Arg Glu Gln Leu Ile Ala Arg Val Thr Ser Val Glu Val 1355 1360 1365 Val Leu Asp Lys Leu His Gly Gln Val Leu Ser Gln Glu Gln Tyr 1370 1375 1380 Glu Arg Val Leu Ala Glu Asn Thr Arg Pro Ser Gln Met Arg Lys 1385 1390 1395 Leu Phe Ser Leu Ser Gln Ser Trp Asp Arg Lys Cys Lys Asp Gly 1400 1405 1410 Leu Tyr Gln Ala Leu Lys Glu Thr His Pro His Leu Ile Met Glu 1415 1420 1425 Leu Trp Glu Lys Gly Ser Lys Lys Gly Leu Leu Pro Leu Ser Ser 1430 1435 1440 43932PRThomo sapiens 43Met Lys Gln Leu Pro Ala Ala Thr Val Arg Leu Leu Ser Ser Ser Gln 1 5

10 15 Ile Ile Thr Ser Val Val Ser Val Val Lys Glu Leu Ile Glu Asn Ser 20 25 30 Leu Asp Ala Gly Ala Thr Ser Val Asp Val Lys Leu Glu Asn Tyr Gly 35 40 45 Phe Asp Lys Ile Glu Val Arg Asp Asn Gly Glu Gly Ile Lys Ala Val 50 55 60 Asp Ala Pro Val Met Ala Met Lys Tyr Tyr Thr Ser Lys Ile Asn Ser 65 70 75 80 His Glu Asp Leu Glu Asn Leu Thr Thr Tyr Gly Phe Arg Gly Glu Ala 85 90 95 Leu Gly Ser Ile Cys Cys Ile Ala Glu Val Leu Ile Thr Thr Arg Thr 100 105 110 Ala Ala Asp Asn Phe Ser Thr Gln Tyr Val Leu Asp Gly Ser Gly His 115 120 125 Ile Leu Ser Gln Lys Pro Ser His Leu Gly Gln Gly Thr Thr Val Thr 130 135 140 Ala Leu Arg Leu Phe Lys Asn Leu Pro Val Arg Lys Gln Phe Tyr Ser 145 150 155 160 Thr Ala Lys Lys Cys Lys Asp Glu Ile Lys Lys Ile Gln Asp Leu Leu 165 170 175 Met Ser Phe Gly Ile Leu Lys Pro Asp Leu Arg Ile Val Phe Val His 180 185 190 Asn Lys Ala Val Ile Trp Gln Lys Ser Arg Val Ser Asp His Lys Met 195 200 205 Ala Leu Met Ser Val Leu Gly Thr Ala Val Met Asn Asn Met Glu Ser 210 215 220 Phe Gln Tyr His Ser Glu Glu Ser Gln Ile Tyr Leu Ser Gly Phe Leu 225 230 235 240 Pro Lys Cys Asp Ala Asp His Ser Phe Thr Ser Leu Ser Thr Pro Glu 245 250 255 Arg Ser Phe Ile Phe Ile Asn Ser Arg Pro Val His Gln Lys Asp Ile 260 265 270 Leu Lys Leu Ile Arg His His Tyr Asn Leu Lys Cys Leu Lys Glu Ser 275 280 285 Thr Arg Leu Tyr Pro Val Phe Phe Leu Lys Ile Asp Val Pro Thr Ala 290 295 300 Asp Val Asp Val Asn Leu Thr Pro Asp Lys Ser Gln Val Leu Leu Gln 305 310 315 320 Asn Lys Glu Ser Val Leu Ile Ala Leu Glu Asn Leu Met Thr Thr Cys 325 330 335 Tyr Gly Pro Leu Pro Ser Thr Asn Ser Tyr Glu Asn Asn Lys Thr Asp 340 345 350 Val Ser Ala Ala Asp Ile Val Leu Ser Lys Thr Ala Glu Thr Asp Val 355 360 365 Leu Phe Asn Lys Val Glu Ser Ser Gly Lys Asn Tyr Ser Asn Val Asp 370 375 380 Thr Ser Val Ile Pro Phe Gln Asn Asp Met His Asn Asp Glu Ser Gly 385 390 395 400 Lys Asn Thr Asp Asp Cys Leu Asn His Gln Ile Ser Ile Gly Asp Phe 405 410 415 Gly Tyr Gly His Cys Ser Ser Glu Ile Ser Asn Ile Asp Lys Asn Thr 420 425 430 Lys Asn Ala Phe Gln Asp Ile Ser Met Ser Asn Val Ser Trp Glu Asn 435 440 445 Ser Gln Thr Glu Tyr Ser Lys Thr Cys Phe Ile Ser Ser Val Lys His 450 455 460 Thr Gln Ser Glu Asn Gly Asn Lys Asp His Ile Asp Glu Ser Gly Glu 465 470 475 480 Asn Glu Glu Glu Ala Gly Leu Glu Asn Ser Ser Glu Ile Ser Ala Asp 485 490 495 Glu Trp Ser Arg Gly Asn Ile Leu Lys Asn Ser Val Gly Glu Asn Ile 500 505 510 Glu Pro Val Lys Ile Leu Val Pro Glu Lys Ser Leu Pro Cys Lys Val 515 520 525 Ser Asn Asn Asn Tyr Pro Ile Pro Glu Gln Met Asn Leu Asn Glu Asp 530 535 540 Ser Cys Asn Lys Lys Ser Asn Val Ile Asp Asn Lys Ser Gly Lys Val 545 550 555 560 Thr Ala Tyr Asp Leu Leu Ser Asn Arg Val Ile Lys Lys Pro Met Ser 565 570 575 Ala Ser Ala Leu Phe Val Gln Asp His Arg Pro Gln Phe Leu Ile Glu 580 585 590 Asn Pro Lys Thr Ser Leu Glu Asp Ala Thr Leu Gln Ile Glu Glu Leu 595 600 605 Trp Lys Thr Leu Ser Glu Glu Glu Lys Leu Lys Tyr Glu Glu Lys Ala 610 615 620 Thr Lys Asp Leu Glu Arg Tyr Asn Ser Gln Met Lys Arg Ala Ile Glu 625 630 635 640 Gln Glu Ser Gln Met Ser Leu Lys Asp Gly Arg Lys Lys Ile Lys Pro 645 650 655 Thr Ser Ala Trp Asn Leu Ala Gln Lys His Lys Leu Lys Thr Ser Leu 660 665 670 Ser Asn Gln Pro Lys Leu Asp Glu Leu Leu Gln Ser Gln Ile Glu Lys 675 680 685 Arg Arg Ser Gln Asn Ile Lys Met Val Gln Ile Pro Phe Ser Met Lys 690 695 700 Asn Leu Lys Ile Asn Phe Lys Lys Gln Asn Lys Val Asp Leu Glu Glu 705 710 715 720 Lys Asp Glu Pro Cys Leu Ile His Asn Leu Arg Phe Pro Asp Ala Trp 725 730 735 Leu Met Thr Ser Lys Thr Glu Val Met Leu Leu Asn Pro Tyr Arg Val 740 745 750 Glu Glu Ala Leu Leu Phe Lys Arg Leu Leu Glu Asn His Lys Leu Pro 755 760 765 Ala Glu Pro Leu Glu Lys Pro Ile Met Leu Thr Glu Ser Leu Phe Asn 770 775 780 Gly Ser His Tyr Leu Asp Val Leu Tyr Lys Met Thr Ala Asp Asp Gln 785 790 795 800 Arg Tyr Ser Gly Ser Thr Tyr Leu Ser Asp Pro Arg Leu Thr Ala Asn 805 810 815 Gly Phe Lys Ile Lys Leu Ile Pro Gly Val Ser Ile Thr Glu Asn Tyr 820 825 830 Leu Glu Ile Glu Gly Met Ala Asn Cys Leu Pro Phe Tyr Gly Val Ala 835 840 845 Asp Leu Lys Glu Ile Leu Asn Ala Ile Leu Asn Arg Asn Ala Lys Glu 850 855 860 Val Tyr Glu Cys Arg Pro Arg Lys Val Ile Ser Tyr Leu Glu Gly Glu 865 870 875 880 Ala Val Arg Leu Ser Arg Gln Leu Pro Met Tyr Leu Ser Lys Glu Asp 885 890 895 Ile Gln Asp Ile Ile Tyr Arg Met Lys His Gln Phe Gly Asn Glu Ile 900 905 910 Lys Glu Cys Val His Gly Arg Pro Phe Phe His His Leu Thr Tyr Leu 915 920 925 Pro Glu Thr Thr 930 44623PRThomo sapiens 44Met Asn Arg Tyr Thr Thr Met Arg Gln Leu Gly Asp Gly Thr Tyr Gly 1 5 10 15 Ser Val Leu Met Gly Lys Ser Asn Glu Ser Gly Glu Leu Val Ala Ile 20 25 30 Lys Arg Met Lys Arg Lys Phe Tyr Ser Trp Asp Glu Cys Met Asn Leu 35 40 45 Arg Glu Val Lys Ser Leu Lys Lys Leu Asn His Ala Asn Val Ile Lys 50 55 60 Leu Lys Glu Val Ile Arg Glu Asn Asp His Leu Tyr Phe Ile Phe Glu 65 70 75 80 Tyr Met Lys Glu Asn Leu Tyr Gln Leu Met Lys Asp Arg Asn Lys Leu 85 90 95 Phe Pro Glu Ser Val Ile Arg Asn Ile Met Tyr Gln Ile Leu Gln Gly 100 105 110 Leu Ala Phe Ile His Lys His Gly Phe Phe His Arg Asp Met Lys Pro 115 120 125 Glu Asn Leu Leu Cys Met Gly Pro Glu Leu Val Lys Ile Ala Asp Phe 130 135 140 Gly Leu Ala Arg Glu Leu Arg Ser Gln Pro Pro Tyr Thr Asp Tyr Val 145 150 155 160 Ser Thr Arg Trp Tyr Arg Ala Pro Glu Val Leu Leu Arg Ser Ser Val 165 170 175 Tyr Ser Ser Pro Ile Asp Val Trp Ala Val Gly Ser Ile Met Ala Glu 180 185 190 Leu Tyr Met Leu Arg Pro Leu Phe Pro Gly Thr Ser Glu Val Asp Glu 195 200 205 Ile Phe Lys Ile Cys Gln Val Leu Gly Thr Pro Lys Lys Ser Asp Trp 210 215 220 Pro Glu Gly Tyr Gln Leu Ala Ser Ser Met Asn Phe Arg Phe Pro Gln 225 230 235 240 Cys Val Pro Ile Asn Leu Lys Thr Leu Ile Pro Asn Ala Ser Asn Glu 245 250 255 Ala Ile Gln Leu Met Thr Glu Met Leu Asn Trp Asp Pro Lys Lys Arg 260 265 270 Pro Thr Ala Ser Gln Ala Leu Lys His Pro Tyr Phe Gln Val Gly Gln 275 280 285 Val Leu Gly Pro Ser Ser Asn His Leu Glu Ser Lys Gln Ser Leu Asn 290 295 300 Lys Gln Leu Gln Pro Leu Glu Ser Lys Pro Ser Leu Val Glu Val Glu 305 310 315 320 Pro Lys Pro Leu Pro Asp Ile Ile Asp Gln Val Val Gly Gln Pro Gln 325 330 335 Pro Lys Thr Ser Gln Gln Pro Leu Gln Pro Ile Gln Pro Pro Gln Asn 340 345 350 Leu Ser Val Gln Gln Pro Pro Lys Gln Gln Ser Gln Glu Lys Pro Pro 355 360 365 Gln Thr Leu Phe Pro Ser Ile Val Lys Asn Met Pro Thr Lys Pro Asn 370 375 380 Gly Thr Leu Ser His Lys Ser Gly Arg Arg Arg Trp Gly Gln Thr Ile 385 390 395 400 Phe Lys Ser Gly Asp Ser Trp Glu Glu Leu Glu Asp Tyr Asp Phe Gly 405 410 415 Ala Ser His Ser Lys Lys Pro Ser Met Gly Val Phe Lys Glu Lys Arg 420 425 430 Lys Lys Asp Ser Pro Phe Arg Leu Pro Glu Pro Val Pro Ser Gly Ser 435 440 445 Asn His Ser Thr Gly Glu Asn Lys Ser Leu Pro Ala Val Thr Ser Leu 450 455 460 Lys Ser Asp Ser Glu Leu Ser Thr Ala Pro Thr Ser Lys Gln Tyr Tyr 465 470 475 480 Leu Lys Gln Ser Arg Tyr Leu Pro Gly Val Asn Pro Lys Lys Val Ser 485 490 495 Leu Ile Ala Ser Gly Lys Glu Ile Asn Pro His Thr Trp Ser Asn Gln 500 505 510 Leu Phe Pro Lys Ser Leu Gly Pro Val Gly Ala Glu Leu Ala Phe Lys 515 520 525 Arg Ser Asn Ala Gly Asn Leu Gly Ser Tyr Ala Thr Tyr Asn Gln Ser 530 535 540 Gly Tyr Ile Pro Ser Phe Leu Lys Lys Glu Val Gln Ser Ala Gly Gln 545 550 555 560 Arg Ile His Leu Ala Pro Leu Asn Ala Thr Ala Ser Glu Tyr Thr Trp 565 570 575 Asn Thr Lys Thr Gly Arg Gly Gln Phe Ser Gly Arg Thr Tyr Asn Pro 580 585 590 Thr Ala Lys Asn Leu Asn Ile Val Asn Arg Ala Gln Pro Ile Pro Ser 595 600 605 Val His Gly Arg Thr Asp Trp Val Ala Lys Tyr Gly Gly His Arg 610 615 620 451380PRThomo sapiens 45Met Ala Ser Gly Arg Asp Glu Arg Pro Pro Trp Arg Leu Gly Arg Leu 1 5 10 15 Leu Leu Leu Met Cys Leu Leu Leu Leu Gly Ser Ser Ala Arg Ala Ala 20 25 30 His Ile Lys Lys Ala Glu Ala Thr Thr Thr Thr Thr Ser Ala Gly Ala 35 40 45 Glu Ala Ala Glu Gly Gln Phe Asp Arg Tyr Tyr His Glu Glu Glu Leu 50 55 60 Glu Ser Ala Leu Arg Glu Ala Ala Ala Ala Gly Leu Pro Gly Leu Ala 65 70 75 80 Arg Leu Phe Ser Ile Gly Arg Ser Val Glu Gly Arg Pro Leu Trp Val 85 90 95 Leu Arg Leu Thr Ala Gly Leu Gly Ser Leu Ile Pro Glu Gly Asp Ala 100 105 110 Gly Pro Asp Ala Ala Gly Pro Asp Ala Ala Gly Pro Leu Leu Pro Gly 115 120 125 Arg Pro Gln Val Lys Leu Val Gly Asn Met His Gly Asp Glu Thr Val 130 135 140 Ser Arg Gln Val Leu Ile Tyr Leu Ala Arg Glu Leu Ala Ala Gly Tyr 145 150 155 160 Arg Arg Gly Asp Pro Arg Leu Val Arg Leu Leu Asn Thr Thr Asp Val 165 170 175 Tyr Leu Leu Pro Ser Leu Asn Pro Asp Gly Phe Glu Arg Ala Arg Glu 180 185 190 Gly Asp Cys Gly Phe Gly Asp Gly Gly Pro Ser Gly Ala Ser Gly Arg 195 200 205 Asp Asn Ser Arg Gly Arg Asp Leu Asn Arg Ser Phe Pro Asp Gln Phe 210 215 220 Ser Thr Gly Glu Pro Pro Ala Leu Asp Glu Val Pro Glu Val Arg Ala 225 230 235 240 Leu Ile Glu Trp Ile Arg Arg Asn Lys Phe Val Leu Ser Gly Asn Leu 245 250 255 His Gly Gly Ser Val Val Ala Ser Tyr Pro Phe Asp Asp Ser Pro Glu 260 265 270 His Lys Ala Thr Gly Ile Tyr Ser Lys Thr Ser Asp Asp Glu Val Phe 275 280 285 Lys Tyr Leu Ala Lys Ala Tyr Ala Ser Asn His Pro Ile Met Lys Thr 290 295 300 Gly Glu Pro His Cys Pro Gly Asp Glu Asp Glu Thr Phe Lys Asp Gly 305 310 315 320 Ile Thr Asn Gly Ala His Trp Tyr Asp Val Glu Gly Gly Met Gln Asp 325 330 335 Tyr Asn Tyr Val Trp Ala Asn Cys Phe Glu Ile Thr Leu Glu Leu Ser 340 345 350 Cys Cys Lys Tyr Pro Pro Ala Ser Gln Leu Arg Gln Glu Trp Glu Asn 355 360 365 Asn Arg Glu Ser Leu Ile Thr Leu Ile Glu Lys Val His Ile Gly Val 370 375 380 Lys Gly Phe Val Lys Asp Ser Ile Thr Gly Ser Gly Leu Glu Asn Ala 385 390 395 400 Thr Ile Ser Val Ala Gly Ile Asn His Asn Ile Thr Thr Gly Arg Phe 405 410 415 Gly Asp Phe Tyr Arg Leu Leu Val Pro Gly Thr Tyr Asn Leu Thr Val 420 425 430 Val Leu Thr Gly Tyr Met Pro Leu Thr Val Thr Asn Val Val Val Lys 435 440 445 Glu Gly Pro Ala Thr Glu Val Asp Phe Ser Leu Arg Pro Thr Val Thr 450 455 460 Ser Val Ile Pro Asp Thr Thr Glu Ala Val Ser Thr Ala Ser Thr Val 465 470 475 480 Ala Ile Pro Asn Ile Leu Ser Gly Thr Ser Ser Ser Tyr Gln Pro Ile 485 490 495 Gln Pro Lys Asp Phe His His His His Phe Pro Asp Met Glu Ile Phe 500 505 510 Leu Arg Arg Phe Ala Asn Glu Tyr Pro Asn Ile Thr Arg Leu Tyr Ser 515 520 525 Leu Gly Lys Ser Val Glu Ser Arg Glu Leu Tyr Val Met Glu Ile Ser 530 535 540 Asp Asn Pro Gly Val His Glu Pro Gly Glu Pro Glu Phe Lys Tyr Ile 545 550 555 560 Gly Asn Met His Gly Asn Glu Val Val Gly Arg Glu Leu Leu Leu Asn 565 570 575 Leu Ile Glu Tyr Leu Cys Lys Asn Phe Gly Thr Asp Pro Glu Val Thr 580 585 590 Asp Leu Val His Asn Thr Arg Ile His Leu Met Pro Ser Met Asn Pro 595 600 605 Asp Gly Tyr Glu Lys Ser Gln Glu Gly Asp Ser Ile Ser Val Ile Gly 610 615 620 Arg Asn Asn Ser Asn Asn Phe Asp Leu Asn Arg Asn Phe Pro Asp Gln 625 630 635 640 Phe Val Gln Ile Thr Asp Pro Thr Gln Pro Glu Thr Ile Ala Val Met 645 650 655 Ser Trp Met Lys Ser Tyr Pro Phe Val Leu Ser Ala Asn Leu His Gly 660 665 670 Gly Ser Leu Val Val Asn Tyr Pro Phe Asp Asp Asp Glu Gln Gly Leu 675 680 685 Ala Thr Tyr Ser Lys Ser Pro Asp Asp Ala Val Phe Gln Gln Ile Ala 690 695 700 Leu Ser Tyr Ser Lys Glu Asn Ser Gln Met Phe Gln Gly Arg Pro Cys 705 710 715 720 Lys Asn Met Tyr Pro Asn Glu Tyr Phe Pro His Gly Ile Thr Asn Gly 725 730 735 Ala Ser Trp Tyr Asn Val Pro Gly Gly Met Gln Asp Trp Asn Tyr Leu 740 745 750 Gln Thr Asn Cys Phe Glu Val Thr Ile Glu Leu Gly Cys

Val Lys Tyr 755 760 765 Pro Leu Glu Lys Glu Leu Pro Asn Phe Trp Glu Gln Asn Arg Arg Ser 770 775 780 Leu Ile Gln Phe Met Lys Gln Val His Gln Gly Val Arg Gly Phe Val 785 790 795 800 Leu Asp Ala Thr Asp Gly Arg Gly Ile Leu Asn Ala Thr Ile Ser Val 805 810 815 Ala Glu Ile Asn His Pro Val Thr Thr Tyr Lys Thr Gly Asp Tyr Trp 820 825 830 Arg Leu Leu Val Pro Gly Thr Tyr Lys Ile Thr Ala Ser Ala Arg Gly 835 840 845 Tyr Asn Pro Val Thr Lys Asn Val Thr Val Lys Ser Glu Gly Ala Ile 850 855 860 Gln Val Asn Phe Thr Leu Val Arg Ser Ser Thr Asp Ser Asn Asn Glu 865 870 875 880 Ser Lys Lys Gly Lys Gly Ala Ser Ser Ser Thr Asn Asp Ala Ser Asp 885 890 895 Pro Thr Thr Lys Glu Phe Glu Thr Leu Ile Lys Asp Leu Ser Ala Glu 900 905 910 Asn Gly Leu Glu Ser Leu Met Leu Arg Ser Ser Ser Asn Leu Ala Leu 915 920 925 Ala Leu Tyr Arg Tyr His Ser Tyr Lys Asp Leu Ser Glu Phe Leu Arg 930 935 940 Gly Leu Val Met Asn Tyr Pro His Ile Thr Asn Leu Thr Asn Leu Gly 945 950 955 960 Gln Ser Thr Glu Tyr Arg His Ile Trp Ser Leu Glu Ile Ser Asn Lys 965 970 975 Pro Asn Val Ser Glu Pro Glu Glu Pro Lys Ile Arg Phe Val Ala Gly 980 985 990 Ile His Gly Asn Ala Pro Val Gly Thr Glu Leu Leu Leu Ala Leu Ala 995 1000 1005 Glu Phe Leu Cys Leu Asn Tyr Lys Lys Asn Pro Ala Val Thr Gln 1010 1015 1020 Leu Val Asp Arg Thr Arg Ile Val Ile Val Pro Ser Leu Asn Pro 1025 1030 1035 Asp Gly Arg Glu Arg Ala Gln Glu Lys Asp Cys Thr Ser Lys Ile 1040 1045 1050 Gly Gln Thr Asn Ala Arg Gly Lys Asp Leu Asp Thr Asp Phe Thr 1055 1060 1065 Asn Asn Ala Ser Gln Pro Glu Thr Lys Ala Ile Ile Glu Asn Leu 1070 1075 1080 Ile Gln Lys Gln Asp Phe Ser Leu Ser Val Ala Leu Asp Gly Gly 1085 1090 1095 Ser Met Leu Val Thr Tyr Pro Tyr Asp Lys Pro Val Gln Thr Val 1100 1105 1110 Glu Asn Lys Glu Thr Leu Lys His Leu Ala Ser Leu Tyr Ala Asn 1115 1120 1125 Asn His Pro Ser Met His Met Gly Gln Pro Ser Cys Pro Asn Lys 1130 1135 1140 Ser Asp Glu Asn Ile Pro Gly Gly Val Met Arg Gly Ala Glu Trp 1145 1150 1155 His Ser His Leu Gly Ser Met Lys Asp Tyr Ser Val Thr Tyr Gly 1160 1165 1170 His Cys Pro Glu Ile Thr Val Tyr Thr Ser Cys Cys Tyr Phe Pro 1175 1180 1185 Ser Ala Ala Arg Leu Pro Ser Leu Trp Ala Asp Asn Lys Arg Ser 1190 1195 1200 Leu Leu Ser Met Leu Val Glu Val His Lys Gly Val His Gly Phe 1205 1210 1215 Val Lys Asp Lys Thr Gly Lys Pro Ile Ser Lys Ala Val Ile Val 1220 1225 1230 Leu Asn Glu Gly Ile Lys Val Gln Thr Lys Glu Gly Gly Tyr Phe 1235 1240 1245 His Val Leu Leu Ala Pro Gly Val His Asn Ile Ile Ala Ile Ala 1250 1255 1260 Asp Gly Tyr Gln Gln Gln His Ser Gln Val Phe Val His His Asp 1265 1270 1275 Ala Ala Ser Ser Val Val Ile Val Phe Asp Thr Asp Asn Arg Ile 1280 1285 1290 Phe Gly Leu Pro Arg Glu Leu Val Val Thr Val Ser Gly Ala Thr 1295 1300 1305 Met Ser Ala Leu Ile Leu Thr Ala Cys Ile Ile Trp Cys Ile Cys 1310 1315 1320 Ser Ile Lys Ser Asn Arg His Lys Asp Gly Phe His Arg Leu Arg 1325 1330 1335 Gln His His Asp Glu Tyr Glu Asp Glu Ile Arg Met Met Ser Thr 1340 1345 1350 Gly Ser Lys Lys Ser Leu Leu Ser His Glu Phe Gln Asp Glu Thr 1355 1360 1365 Asp Thr Glu Glu Glu Thr Leu Tyr Ser Ser Lys His 1370 1375 1380 46167PRThomo sapiens 46Met Leu Pro Glu Lys Ala Leu His Gly His Pro Gln Leu Pro Arg Thr 1 5 10 15 Val Pro Thr Arg Ala Ala Met Arg Ala Ala Gly Thr Leu Leu Ala Phe 20 25 30 Cys Cys Leu Val Leu Ser Thr Thr Gly Gly Pro Ser Pro Asp Thr Cys 35 40 45 Ser Gln Asp Leu Asn Ser Arg Val Lys Pro Gly Phe Pro Lys Thr Ile 50 55 60 Lys Thr Asn Asp Pro Gly Val Leu Gln Ala Ala Arg Tyr Ser Val Glu 65 70 75 80 Lys Phe Asn Asn Cys Thr Asn Asp Met Phe Leu Phe Lys Glu Ser Arg 85 90 95 Ile Thr Arg Ala Leu Val Gln Ile Val Lys Gly Leu Lys Tyr Met Leu 100 105 110 Glu Val Glu Ile Gly Arg Thr Thr Cys Lys Lys Asn Gln His Leu Arg 115 120 125 Leu Asp Asp Cys Asp Phe Gln Thr Asn His Thr Leu Lys Gln Thr Leu 130 135 140 Ser Cys Tyr Ser Glu Val Trp Val Val Pro Trp Leu Gln His Phe Glu 145 150 155 160 Val Pro Val Leu Arg Cys His 165 47384PRThomo sapiens 47Met Lys Val Thr Ser Leu Asp Gly Arg Gln Leu Arg Lys Met Leu Arg 1 5 10 15 Lys Glu Ala Ala Ala Arg Cys Val Val Leu Asp Cys Arg Pro Tyr Leu 20 25 30 Ala Phe Ala Ala Ser Asn Val Arg Gly Ser Leu Asn Val Asn Leu Asn 35 40 45 Ser Val Val Leu Arg Arg Ala Arg Gly Gly Ala Val Ser Ala Arg Tyr 50 55 60 Val Leu Pro Asp Glu Ala Ala Arg Ala Arg Leu Leu Gln Glu Gly Gly 65 70 75 80 Gly Gly Val Ala Ala Val Val Val Leu Asp Gln Gly Ser Arg His Trp 85 90 95 Gln Lys Leu Arg Glu Glu Ser Ala Ala Arg Val Val Leu Thr Ser Leu 100 105 110 Leu Ala Cys Leu Pro Ala Gly Pro Arg Val Tyr Phe Leu Lys Gly Gly 115 120 125 Tyr Glu Thr Phe Tyr Ser Glu Tyr Pro Glu Cys Cys Val Asp Val Lys 130 135 140 Pro Ile Ser Gln Glu Lys Ile Glu Ser Glu Arg Ala Leu Ile Ser Gln 145 150 155 160 Cys Gly Lys Pro Val Val Asn Val Ser Tyr Arg Pro Ala Tyr Asp Gln 165 170 175 Gly Gly Pro Val Glu Ile Leu Pro Phe Leu Tyr Leu Gly Ser Ala Tyr 180 185 190 His Ala Ser Lys Cys Glu Phe Leu Ala Asn Leu His Ile Thr Ala Leu 195 200 205 Leu Asn Val Ser Arg Arg Thr Ser Glu Ala Cys Ala Thr His Leu His 210 215 220 Tyr Lys Trp Ile Pro Val Glu Asp Ser His Thr Ala Asp Ile Ser Ser 225 230 235 240 His Phe Gln Glu Ala Ile Asp Phe Ile Asp Cys Val Arg Glu Lys Gly 245 250 255 Gly Lys Val Leu Val His Cys Glu Ala Gly Ile Ser Arg Ser Pro Thr 260 265 270 Ile Cys Met Ala Tyr Leu Met Lys Thr Lys Gln Phe Arg Leu Lys Glu 275 280 285 Ala Phe Asp Tyr Ile Lys Gln Arg Arg Ser Met Val Ser Pro Asn Phe 290 295 300 Gly Phe Met Gly Gln Leu Leu Gln Tyr Glu Ser Glu Ile Leu Pro Ser 305 310 315 320 Thr Pro Asn Pro Gln Pro Pro Ser Cys Gln Gly Glu Ala Ala Gly Ser 325 330 335 Ser Leu Ile Gly His Leu Gln Thr Leu Ser Pro Asp Met Gln Gly Ala 340 345 350 Tyr Cys Thr Phe Pro Ala Ser Val Leu Ala Pro Val Pro Thr His Ser 355 360 365 Thr Val Ser Glu Leu Ser Arg Ser Pro Val Ala Thr Ala Thr Ser Cys 370 375 380 481445PRThomo sapiens 48Met Arg Arg Leu Leu Glu Pro Cys Trp Trp Ile Leu Phe Leu Lys Ile 1 5 10 15 Thr Ser Ser Val Leu His Tyr Val Val Cys Phe Pro Ala Leu Thr Glu 20 25 30 Gly Tyr Val Gly Ala Leu His Glu Asn Arg His Gly Ser Ala Val Gln 35 40 45 Ile Arg Arg Arg Lys Ala Ser Gly Asp Pro Tyr Trp Ala Tyr Ser Gly 50 55 60 Ala Tyr Gly Pro Glu His Trp Val Thr Ser Ser Val Ser Cys Gly Gly 65 70 75 80 Arg His Gln Ser Pro Ile Asp Ile Leu Asp Gln Tyr Ala Arg Val Gly 85 90 95 Glu Glu Tyr Gln Glu Leu Gln Leu Asp Gly Phe Asp Asn Glu Ser Ser 100 105 110 Asn Lys Thr Trp Met Lys Asn Thr Gly Lys Thr Val Ala Ile Leu Leu 115 120 125 Lys Asp Asp Tyr Phe Val Ser Gly Ala Gly Leu Pro Gly Arg Phe Lys 130 135 140 Ala Glu Lys Val Glu Phe His Trp Gly His Ser Asn Gly Ser Ala Gly 145 150 155 160 Ser Glu His Ser Ile Asn Gly Arg Arg Phe Pro Val Glu Met Gln Ile 165 170 175 Phe Phe Tyr Asn Pro Asp Asp Phe Asp Ser Phe Gln Thr Ala Ile Ser 180 185 190 Glu Asn Arg Ile Ile Gly Ala Met Ala Ile Phe Phe Gln Val Ser Pro 195 200 205 Arg Asp Asn Ser Ala Leu Asp Pro Ile Ile His Gly Leu Lys Gly Val 210 215 220 Val His His Glu Lys Glu Thr Phe Leu Asp Pro Phe Val Leu Arg Asp 225 230 235 240 Leu Leu Pro Ala Ser Leu Gly Ser Tyr Tyr Arg Tyr Thr Gly Ser Leu 245 250 255 Thr Thr Pro Pro Cys Ser Glu Ile Val Glu Trp Ile Val Phe Arg Arg 260 265 270 Pro Val Pro Ile Ser Tyr His Gln Leu Glu Ala Phe Tyr Ser Ile Phe 275 280 285 Thr Thr Glu Gln Gln Asp His Val Lys Ser Val Glu Tyr Leu Arg Asn 290 295 300 Asn Phe Arg Pro Gln Gln Arg Leu His Asp Arg Val Val Ser Lys Ser 305 310 315 320 Ala Val Arg Asp Ser Trp Asn His Asp Met Thr Asp Phe Leu Glu Asn 325 330 335 Pro Leu Gly Thr Glu Ala Ser Lys Val Cys Ser Ser Pro Pro Ile His 340 345 350 Met Lys Val Gln Pro Leu Asn Gln Thr Ala Leu Gln Val Ser Trp Ser 355 360 365 Gln Pro Glu Thr Ile Tyr His Pro Pro Ile Met Asn Tyr Met Ile Ser 370 375 380 Tyr Ser Trp Thr Lys Asn Glu Asp Glu Lys Glu Lys Thr Phe Thr Lys 385 390 395 400 Asp Ser Asp Lys Asp Leu Lys Ala Thr Ile Ser His Val Ser Pro Asp 405 410 415 Ser Leu Tyr Leu Phe Arg Val Gln Ala Val Cys Arg Asn Asp Met Arg 420 425 430 Ser Asp Phe Ser Gln Thr Met Leu Phe Gln Ala Asn Thr Thr Arg Ile 435 440 445 Phe Gln Gly Thr Arg Ile Val Lys Thr Gly Val Pro Thr Ala Ser Pro 450 455 460 Ala Ser Ser Ala Asp Met Ala Pro Ile Ser Ser Gly Ser Ser Thr Trp 465 470 475 480 Thr Ser Ser Gly Ile Pro Phe Ser Phe Val Ser Met Ala Thr Gly Met 485 490 495 Gly Pro Ser Ser Ser Gly Ser Gln Ala Thr Val Ala Ser Val Val Thr 500 505 510 Ser Thr Leu Leu Ala Gly Leu Gly Phe Gly Gly Gly Gly Ile Ser Ser 515 520 525 Phe Pro Ser Thr Val Trp Pro Thr Arg Leu Pro Thr Ala Ala Ser Ala 530 535 540 Ser Lys Gln Ala Ala Arg Pro Val Leu Ala Thr Thr Glu Ala Leu Ala 545 550 555 560 Ser Pro Gly Pro Asp Gly Asp Ser Ser Pro Thr Lys Asp Gly Glu Gly 565 570 575 Thr Glu Glu Gly Glu Lys Asp Glu Lys Ser Glu Ser Glu Asp Gly Glu 580 585 590 Arg Glu His Glu Glu Asp Gly Glu Lys Asp Ser Glu Lys Lys Glu Lys 595 600 605 Ser Gly Val Thr His Ala Ala Glu Glu Arg Asn Gln Thr Glu Pro Ser 610 615 620 Pro Thr Pro Ser Ser Pro Asn Arg Thr Ala Glu Gly Gly His Gln Thr 625 630 635 640 Ile Pro Gly His Glu Gln Asp His Thr Ala Val Pro Thr Asp Gln Thr 645 650 655 Gly Gly Arg Arg Asp Ala Gly Pro Gly Leu Asp Pro Asp Met Val Thr 660 665 670 Ser Thr Gln Val Pro Pro Thr Ala Thr Glu Glu Gln Tyr Ala Gly Ser 675 680 685 Asp Pro Lys Arg Pro Glu Met Pro Ser Lys Lys Pro Met Ser Arg Gly 690 695 700 Asp Arg Phe Ser Glu Asp Ser Arg Phe Ile Thr Val Asn Pro Ala Glu 705 710 715 720 Lys Asn Thr Ser Gly Met Ile Ser Arg Pro Ala Pro Gly Arg Met Glu 725 730 735 Trp Ile Ile Pro Leu Ile Val Val Ser Ala Leu Thr Phe Val Cys Leu 740 745 750 Ile Leu Leu Ile Ala Val Leu Val Tyr Trp Arg Gly Cys Asn Lys Ile 755 760 765 Lys Ser Lys Gly Phe Pro Arg Arg Phe Arg Glu Val Pro Ser Ser Gly 770 775 780 Glu Arg Gly Glu Lys Gly Ser Arg Lys Cys Phe Gln Thr Ala His Phe 785 790 795 800 Tyr Val Glu Asp Ser Ser Ser Pro Arg Val Val Pro Asn Glu Ser Ile 805 810 815 Pro Ile Ile Pro Ile Pro Asp Asp Met Glu Ala Ile Pro Val Lys Gln 820 825 830 Phe Val Lys His Ile Gly Glu Leu Tyr Ser Asn Asn Gln His Gly Phe 835 840 845 Ser Glu Asp Phe Glu Glu Val Gln Arg Cys Thr Ala Asp Met Asn Ile 850 855 860 Thr Ala Glu His Ser Asn His Pro Glu Asn Lys His Lys Asn Arg Tyr 865 870 875 880 Ile Asn Ile Leu Ala Tyr Asp His Ser Arg Val Lys Leu Arg Pro Leu 885 890 895 Pro Gly Lys Asp Ser Lys His Ser Asp Tyr Ile Asn Ala Asn Tyr Val 900 905 910 Asp Gly Tyr Asn Lys Ala Lys Ala Tyr Ile Ala Thr Gln Gly Pro Leu 915 920 925 Lys Ser Thr Phe Glu Asp Phe Trp Arg Met Ile Trp Glu Gln Asn Thr 930 935 940 Gly Ile Ile Val Met Ile Thr Asn Leu Val Glu Lys Gly Arg Arg Lys 945 950 955 960 Cys Asp Gln Tyr Trp Pro Thr Glu Asn Ser Glu Glu Tyr Gly Asn Ile 965 970 975 Ile Val Thr Leu Lys Ser Thr Lys Ile His Ala Cys Tyr Thr Val Arg 980 985 990 Arg Phe Ser Ile Arg Asn Thr Lys Val Lys Lys Gly Gln Lys Gly Asn 995 1000 1005 Pro Lys Gly Arg Gln Asn Glu Arg Val Val Ile Gln Tyr His Tyr 1010 1015 1020 Thr Gln Trp Pro Asp Met Gly Val Pro Glu Tyr Ala Leu Pro Val 1025 1030 1035 Leu Thr Phe Val Arg Arg Ser Ser Ala Ala Arg Met Pro Glu Thr 1040 1045 1050 Gly Pro Val Leu Val His Cys Ser Ala Gly Val Gly Arg Thr Gly 1055 1060 1065 Thr Tyr Ile Val Ile Asp Ser Met Leu Gln Gln Ile Lys Asp Lys 1070 1075 1080 Ser Thr Val Asn Val Leu Gly Phe Leu Lys His Ile Arg Thr Gln 1085 1090 1095

Arg Asn Tyr Leu Val Gln Thr Glu Glu Gln Tyr Ile Phe Ile His 1100 1105 1110 Asp Ala Leu Leu Glu Ala Ile Leu Gly Lys Glu Thr Glu Val Ser 1115 1120 1125 Ser Asn Gln Leu His Ser Tyr Val Asn Ser Ile Leu Ile Pro Gly 1130 1135 1140 Val Gly Gly Lys Thr Arg Leu Glu Lys Gln Phe Lys Leu Val Thr 1145 1150 1155 Gln Cys Asn Ala Lys Tyr Val Glu Cys Phe Ser Ala Gln Lys Glu 1160 1165 1170 Cys Asn Lys Glu Lys Asn Arg Asn Ser Ser Val Val Pro Ser Glu 1175 1180 1185 Arg Ala Arg Val Gly Leu Ala Pro Leu Pro Gly Met Lys Gly Thr 1190 1195 1200 Asp Tyr Ile Asn Ala Ser Tyr Ile Met Gly Tyr Tyr Arg Ser Asn 1205 1210 1215 Glu Phe Ile Ile Thr Gln His Pro Leu Pro His Thr Thr Lys Asp 1220 1225 1230 Phe Trp Arg Met Ile Trp Asp His Asn Ala Gln Ile Ile Val Met 1235 1240 1245 Leu Pro Asp Asn Gln Ser Leu Ala Glu Asp Glu Phe Val Tyr Trp 1250 1255 1260 Pro Ser Arg Glu Glu Ser Met Asn Cys Glu Ala Phe Thr Val Thr 1265 1270 1275 Leu Ile Ser Lys Asp Arg Leu Cys Leu Ser Asn Glu Glu Gln Ile 1280 1285 1290 Ile Ile His Asp Phe Ile Leu Glu Ala Thr Gln Asp Asp Tyr Val 1295 1300 1305 Leu Glu Val Arg His Phe Gln Cys Pro Lys Trp Pro Asn Pro Asp 1310 1315 1320 Ala Pro Ile Ser Ser Thr Phe Glu Leu Ile Asn Val Ile Lys Glu 1325 1330 1335 Glu Ala Leu Thr Arg Asp Gly Pro Thr Ile Val His Asp Glu Tyr 1340 1345 1350 Gly Ala Val Ser Ala Gly Met Leu Cys Ala Leu Thr Thr Leu Ser 1355 1360 1365 Gln Gln Leu Glu Asn Glu Asn Ala Val Asp Val Phe Gln Val Ala 1370 1375 1380 Lys Met Ile Asn Leu Met Arg Pro Gly Val Phe Thr Asp Ile Glu 1385 1390 1395 Gln Tyr Gln Phe Ile Tyr Lys Ala Met Leu Ser Leu Val Ser Thr 1400 1405 1410 Lys Glu Asn Gly Asn Gly Pro Met Thr Val Asp Lys Asn Gly Ala 1415 1420 1425 Val Leu Ile Ala Asp Glu Ser Asp Pro Ala Glu Ser Met Glu Ser 1430 1435 1440 Leu Val 1445 49468PRThomo sapiens 49Met Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro 1 5 10 15 Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg 20 25 30 Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro 35 40 45 Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys 50 55 60 Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg 65 70 75 80 Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys 85 90 95 Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val 100 105 110 Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser 115 120 125 Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr 130 135 140 Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp 145 150 155 160 Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys 165 170 175 Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met 180 185 190 Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe 195 200 205 Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val 210 215 220 Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp 225 230 235 240 Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg 245 250 255 Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp 260 265 270 Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His 275 280 285 Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser 290 295 300 Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser 305 310 315 320 Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr 325 330 335 Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr 340 345 350 Ser Leu Pro Val Gln Asp Ser Ser Ser Val Pro Leu Pro Thr Phe Leu 355 360 365 Val Ala Gly Gly Ser Leu Ala Phe Gly Thr Leu Leu Cys Ile Ala Ile 370 375 380 Val Leu Arg Phe Lys Lys Thr Trp Lys Leu Arg Ala Leu Lys Glu Gly 385 390 395 400 Lys Thr Ser Met His Pro Pro Tyr Ser Leu Gly Gln Leu Val Pro Glu 405 410 415 Arg Pro Arg Pro Thr Pro Val Leu Val Pro Leu Ile Ser Pro Pro Val 420 425 430 Ser Pro Ser Ser Leu Gly Ser Asp Asn Thr Ser Ser His Asn Arg Pro 435 440 445 Asp Ala Arg Asp Pro Arg Ser Pro Tyr Asp Ile Ser Asn Thr Asp Tyr 450 455 460 Phe Phe Pro Arg 465 50365PRThomo sapiens 50Met Leu Ala Val Gly Cys Ala Leu Leu Ala Ala Leu Leu Ala Ala Pro 1 5 10 15 Gly Ala Ala Leu Ala Pro Arg Arg Cys Pro Ala Gln Glu Val Ala Arg 20 25 30 Gly Val Leu Thr Ser Leu Pro Gly Asp Ser Val Thr Leu Thr Cys Pro 35 40 45 Gly Val Glu Pro Glu Asp Asn Ala Thr Val His Trp Val Leu Arg Lys 50 55 60 Pro Ala Ala Gly Ser His Pro Ser Arg Trp Ala Gly Met Gly Arg Arg 65 70 75 80 Leu Leu Leu Arg Ser Val Gln Leu His Asp Ser Gly Asn Tyr Ser Cys 85 90 95 Tyr Arg Ala Gly Arg Pro Ala Gly Thr Val His Leu Leu Val Asp Val 100 105 110 Pro Pro Glu Glu Pro Gln Leu Ser Cys Phe Arg Lys Ser Pro Leu Ser 115 120 125 Asn Val Val Cys Glu Trp Gly Pro Arg Ser Thr Pro Ser Leu Thr Thr 130 135 140 Lys Ala Val Leu Leu Val Arg Lys Phe Gln Asn Ser Pro Ala Glu Asp 145 150 155 160 Phe Gln Glu Pro Cys Gln Tyr Ser Gln Glu Ser Gln Lys Phe Ser Cys 165 170 175 Gln Leu Ala Val Pro Glu Gly Asp Ser Ser Phe Tyr Ile Val Ser Met 180 185 190 Cys Val Ala Ser Ser Val Gly Ser Lys Phe Ser Lys Thr Gln Thr Phe 195 200 205 Gln Gly Cys Gly Ile Leu Gln Pro Asp Pro Pro Ala Asn Ile Thr Val 210 215 220 Thr Ala Val Ala Arg Asn Pro Arg Trp Leu Ser Val Thr Trp Gln Asp 225 230 235 240 Pro His Ser Trp Asn Ser Ser Phe Tyr Arg Leu Arg Phe Glu Leu Arg 245 250 255 Tyr Arg Ala Glu Arg Ser Lys Thr Phe Thr Thr Trp Met Val Lys Asp 260 265 270 Leu Gln His His Cys Val Ile His Asp Ala Trp Ser Gly Leu Arg His 275 280 285 Val Val Gln Leu Arg Ala Gln Glu Glu Phe Gly Gln Gly Glu Trp Ser 290 295 300 Glu Trp Ser Pro Glu Ala Met Gly Thr Pro Trp Thr Glu Ser Arg Ser 305 310 315 320 Pro Pro Ala Glu Asn Glu Val Ser Thr Pro Met Gln Ala Leu Thr Thr 325 330 335 Asn Lys Asp Asp Asp Asn Ile Leu Phe Arg Asp Ser Ala Asn Ala Thr 340 345 350 Ser Leu Pro Gly Ser Arg Arg Arg Gly Ser Cys Gly Leu 355 360 365 51638PRThomo sapiens 51Met Asp Leu Trp Gln Leu Leu Leu Thr Leu Ala Leu Ala Gly Ser Ser 1 5 10 15 Asp Ala Phe Ser Gly Ser Glu Ala Thr Ala Ala Ile Leu Ser Arg Ala 20 25 30 Pro Trp Ser Leu Gln Ser Val Asn Pro Gly Leu Lys Thr Asn Ser Ser 35 40 45 Lys Glu Pro Lys Phe Thr Lys Cys Arg Ser Pro Glu Arg Glu Thr Phe 50 55 60 Ser Cys His Trp Thr Asp Glu Val His His Gly Thr Lys Asn Leu Gly 65 70 75 80 Pro Ile Gln Leu Phe Tyr Thr Arg Arg Asn Thr Gln Glu Trp Thr Gln 85 90 95 Glu Trp Lys Glu Cys Pro Asp Tyr Val Ser Ala Gly Glu Asn Ser Cys 100 105 110 Tyr Phe Asn Ser Ser Phe Thr Ser Ile Trp Ile Pro Tyr Cys Ile Lys 115 120 125 Leu Thr Ser Asn Gly Gly Thr Val Asp Glu Lys Cys Phe Ser Val Asp 130 135 140 Glu Ile Val Gln Pro Asp Pro Pro Ile Ala Leu Asn Trp Thr Leu Leu 145 150 155 160 Asn Val Ser Leu Thr Gly Ile His Ala Asp Ile Gln Val Arg Trp Glu 165 170 175 Ala Pro Arg Asn Ala Asp Ile Gln Lys Gly Trp Met Val Leu Glu Tyr 180 185 190 Glu Leu Gln Tyr Lys Glu Val Asn Glu Thr Lys Trp Lys Met Met Asp 195 200 205 Pro Ile Leu Thr Thr Ser Val Pro Val Tyr Ser Leu Lys Val Asp Lys 210 215 220 Glu Tyr Glu Val Arg Val Arg Ser Lys Gln Arg Asn Ser Gly Asn Tyr 225 230 235 240 Gly Glu Phe Ser Glu Val Leu Tyr Val Thr Leu Pro Gln Met Ser Gln 245 250 255 Phe Thr Cys Glu Glu Asp Phe Tyr Phe Pro Trp Leu Leu Ile Ile Ile 260 265 270 Phe Gly Ile Phe Gly Leu Thr Val Met Leu Phe Val Phe Leu Phe Ser 275 280 285 Lys Gln Gln Arg Ile Lys Met Leu Ile Leu Pro Pro Val Pro Val Pro 290 295 300 Lys Ile Lys Gly Ile Asp Pro Asp Leu Leu Lys Glu Gly Lys Leu Glu 305 310 315 320 Glu Val Asn Thr Ile Leu Ala Ile His Asp Ser Tyr Lys Pro Glu Phe 325 330 335 His Ser Asp Asp Ser Trp Val Glu Phe Ile Glu Leu Asp Ile Asp Glu 340 345 350 Pro Asp Glu Lys Thr Glu Glu Ser Asp Thr Asp Arg Leu Leu Ser Ser 355 360 365 Asp His Glu Lys Ser His Ser Asn Leu Gly Val Lys Asp Gly Asp Ser 370 375 380 Gly Arg Thr Ser Cys Cys Glu Pro Asp Ile Leu Glu Thr Asp Phe Asn 385 390 395 400 Ala Asn Asp Ile His Glu Gly Thr Ser Glu Val Ala Gln Pro Gln Arg 405 410 415 Leu Lys Gly Glu Ala Asp Leu Leu Cys Leu Asp Gln Lys Asn Gln Asn 420 425 430 Asn Ser Pro Tyr His Asp Ala Cys Pro Ala Thr Gln Gln Pro Ser Val 435 440 445 Ile Gln Ala Glu Lys Asn Lys Pro Gln Pro Leu Pro Thr Glu Gly Ala 450 455 460 Glu Ser Thr His Gln Ala Ala His Ile Gln Leu Ser Asn Pro Ser Ser 465 470 475 480 Leu Ser Asn Ile Asp Phe Tyr Ala Gln Val Ser Asp Ile Thr Pro Ala 485 490 495 Gly Ser Val Val Leu Ser Pro Gly Gln Lys Asn Lys Ala Gly Met Ser 500 505 510 Gln Cys Asp Met His Pro Glu Met Val Ser Leu Cys Gln Glu Asn Phe 515 520 525 Leu Met Asp Asn Ala Tyr Phe Cys Glu Ala Asp Ala Lys Lys Cys Ile 530 535 540 Pro Val Ala Pro His Ile Lys Val Glu Ser His Ile Gln Pro Ser Leu 545 550 555 560 Asn Gln Glu Asp Ile Tyr Ile Thr Thr Glu Ser Leu Thr Thr Ala Ala 565 570 575 Gly Arg Pro Gly Thr Gly Glu His Val Pro Gly Ser Glu Met Pro Val 580 585 590 Pro Asp Tyr Thr Ser Ile His Ile Val Gln Ser Pro Gln Gly Leu Ile 595 600 605 Leu Asn Ala Thr Ala Leu Pro Leu Pro Asp Lys Glu Phe Leu Ser Ser 610 615 620 Cys Gly Tyr Val Ser Thr Asp Gln Leu Asn Lys Ile Met Pro 625 630 635 52207PRThomo sapiens 52Met Ala Gly Pro Ala Thr Gln Ser Pro Met Lys Leu Met Ala Leu Gln 1 5 10 15 Leu Leu Leu Trp His Ser Ala Leu Trp Thr Val Gln Glu Ala Thr Pro 20 25 30 Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu 35 40 45 Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys 50 55 60 Leu Val Ser Glu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu 65 70 75 80 Val Leu Leu Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser 85 90 95 Cys Pro Ser Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His 100 105 110 Ser Gly Leu Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile 115 120 125 Ser Pro Glu Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala 130 135 140 Asp Phe Ala Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala 145 150 155 160 Pro Ala Leu Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala 165 170 175 Phe Gln Arg Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser 180 185 190 Phe Leu Glu Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro 195 200 205 53204PRThomo sapiens 53Met Ala Gly Pro Ala Thr Gln Ser Pro Met Lys Leu Met Ala Leu Gln 1 5 10 15 Leu Leu Leu Trp His Ser Ala Leu Trp Thr Val Gln Glu Ala Thr Pro 20 25 30 Leu Gly Pro Ala Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu 35 40 45 Glu Gln Val Arg Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys 50 55 60 Leu Cys Ala Thr Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu 65 70 75 80 Gly His Ser Leu Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser 85 90 95 Gln Ala Leu Gln Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu 100 105 110 Phe Leu Tyr Gln Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu 115 120 125 Leu Gly Pro Thr Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala 130 135 140 Thr Thr Ile Trp Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu 145 150 155 160 Gln Pro Thr Gln Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg 165 170 175 Arg Ala Gly Gly Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu 180 185 190 Val Ser Tyr Arg Val Leu Arg His Leu Ala Gln Pro 195 200 54200PRThomo sapiens 54Met Ser Pro Glu Pro Ala Leu Ser Pro Ala Leu Gln Leu Leu Leu Trp 1 5 10 15 His Ser Ala Leu Trp Thr Val Gln Glu Ala Thr Pro Leu Gly Pro Ala 20 25 30 Ser Ser Leu Pro Gln Ser Phe Leu Leu Lys Cys Leu Glu Gln Val Arg 35

40 45 Lys Ile Gln Gly Asp Gly Ala Ala Leu Gln Glu Lys Leu Cys Ala Thr 50 55 60 Tyr Lys Leu Cys His Pro Glu Glu Leu Val Leu Leu Gly His Ser Leu 65 70 75 80 Gly Ile Pro Trp Ala Pro Leu Ser Ser Cys Pro Ser Gln Ala Leu Gln 85 90 95 Leu Ala Gly Cys Leu Ser Gln Leu His Ser Gly Leu Phe Leu Tyr Gln 100 105 110 Gly Leu Leu Gln Ala Leu Glu Gly Ile Ser Pro Glu Leu Gly Pro Thr 115 120 125 Leu Asp Thr Leu Gln Leu Asp Val Ala Asp Phe Ala Thr Thr Ile Trp 130 135 140 Gln Gln Met Glu Glu Leu Gly Met Ala Pro Ala Leu Gln Pro Thr Gln 145 150 155 160 Gly Ala Met Pro Ala Phe Ala Ser Ala Phe Gln Arg Arg Ala Gly Gly 165 170 175 Val Leu Val Ala Ser His Leu Gln Ser Phe Leu Glu Val Ser Tyr Arg 180 185 190 Val Leu Arg His Leu Ala Gln Pro 195 200 55528PRThomo sapiens 55Met Ala Gly Ser Asp Thr Ala Pro Phe Leu Ser Gln Ala Asp Asp Pro 1 5 10 15 Asp Asp Gly Pro Val Pro Gly Thr Pro Gly Leu Pro Gly Ser Thr Gly 20 25 30 Asn Pro Lys Ser Glu Glu Pro Glu Val Pro Asp Gln Glu Gly Leu Gln 35 40 45 Arg Ile Thr Gly Leu Ser Pro Gly Arg Ser Ala Leu Ile Val Ala Val 50 55 60 Leu Cys Tyr Ile Asn Leu Leu Asn Tyr Met Asp Arg Phe Thr Val Ala 65 70 75 80 Gly Val Leu Pro Asp Ile Glu Gln Phe Phe Asn Ile Gly Asp Ser Ser 85 90 95 Ser Gly Leu Ile Gln Thr Val Phe Ile Ser Ser Tyr Met Val Leu Ala 100 105 110 Pro Val Phe Gly Tyr Leu Gly Asp Arg Tyr Asn Arg Lys Tyr Leu Met 115 120 125 Cys Gly Gly Ile Ala Phe Trp Ser Leu Val Thr Leu Gly Ser Ser Phe 130 135 140 Ile Pro Gly Glu His Phe Trp Leu Leu Leu Leu Thr Arg Gly Leu Val 145 150 155 160 Gly Val Gly Glu Ala Ser Tyr Ser Thr Ile Ala Pro Thr Leu Ile Ala 165 170 175 Asp Leu Phe Val Ala Asp Gln Arg Ser Arg Met Leu Ser Ile Phe Tyr 180 185 190 Phe Ala Ile Pro Val Gly Ser Gly Leu Gly Tyr Ile Ala Gly Ser Lys 195 200 205 Val Lys Asp Met Ala Gly Asp Trp His Trp Ala Leu Arg Val Thr Pro 210 215 220 Gly Leu Gly Val Val Ala Val Leu Leu Leu Phe Leu Val Val Arg Glu 225 230 235 240 Pro Pro Arg Gly Ala Val Glu Arg His Ser Asp Leu Pro Pro Leu Asn 245 250 255 Pro Thr Ser Trp Trp Ala Asp Leu Arg Ala Leu Ala Arg Asn Pro Ser 260 265 270 Phe Val Leu Ser Ser Leu Gly Phe Thr Ala Val Ala Phe Val Thr Gly 275 280 285 Ser Leu Ala Leu Trp Ala Pro Ala Phe Leu Leu Arg Ser Arg Val Val 290 295 300 Leu Gly Glu Thr Pro Pro Cys Leu Pro Gly Asp Ser Cys Ser Ser Ser 305 310 315 320 Asp Ser Leu Ile Phe Gly Leu Ile Thr Cys Leu Thr Gly Val Leu Gly 325 330 335 Val Gly Leu Gly Val Glu Ile Ser Arg Arg Leu Arg His Ser Asn Pro 340 345 350 Arg Ala Asp Pro Leu Val Cys Ala Thr Gly Leu Leu Gly Ser Ala Pro 355 360 365 Phe Leu Phe Leu Ser Leu Ala Cys Ala Arg Gly Ser Ile Val Ala Thr 370 375 380 Tyr Ile Phe Ile Phe Ile Gly Glu Thr Leu Leu Ser Met Asn Trp Ala 385 390 395 400 Ile Val Ala Asp Ile Leu Leu Tyr Val Val Ile Pro Thr Arg Arg Ser 405 410 415 Thr Ala Glu Ala Phe Gln Ile Val Leu Ser His Leu Leu Gly Asp Ala 420 425 430 Gly Ser Pro Tyr Leu Ile Gly Leu Ile Ser Asp Arg Leu Arg Arg Asn 435 440 445 Trp Pro Pro Ser Phe Leu Ser Glu Phe Arg Ala Leu Gln Phe Ser Leu 450 455 460 Met Leu Cys Ala Phe Val Gly Ala Leu Gly Gly Ala Ala Phe Leu Gly 465 470 475 480 Thr Ala Ile Phe Ile Glu Ala Asp Arg Arg Arg Ala Gln Leu His Val 485 490 495 Gln Gly Leu Leu His Glu Ala Gly Ser Thr Asp Asp Arg Ile Val Val 500 505 510 Pro Gln Arg Gly Arg Ser Thr Arg Val Pro Val Ala Ser Val Leu Ile 515 520 525 5619DNAHomo sapiens 56cgcacctcaa gccctatgt 195719DNAHomo sapiens 57aacatggtcc gagtagaag 195819DNAHomo sapiens 58agaggagctg atagcggag 195919DNAHomo sapiens 59aatgggagcg gaagaagtt 196019DNAHomo sapiens 60catcctgcag tgggacttc 196119DNAHomo sapiens 61caacatggtc ttctacctg 196219DNAHomo sapiens 62gtacaaatgg ctgtcagtt 196319DNAHomo sapiens 63ttgagaatgt tcccacagg 196419DNAHomo sapiens 64atggagatgg tactggagt 196519DNAHomo sapiens 65aggatgcagc taacaacaa 196619DNAHomo sapiens 66actgtgcgcg tacacataa 196719DNAHomo sapiens 67atgctccaca atttgtggc 196819DNAHomo sapiens 68catgggctat ctcaagcca 196919DNAHomo sapiens 69aacatgggct atctcaagc 197019DNAHomo sapiens 70cagaacccaa acctggtat 197119DNAHomo sapiens 71gccatattgt ctcccttct 197219DNAHomo sapiens 72acagcagcgc caaccctat 197319DNAHomo sapiens 73aaggctcgcg cttcttctt 197419DNAHomo sapiens 74cattgagaca agaacaagc 197519DNAHomo sapiens 75agatggactc taccaagcc 197619DNAHomo sapiens 76attgggaagt caacactgg 197719DNAHomo sapiens 77cagatgtttc cgcagctga 197819DNAHomo sapiens 78ccagacaatt acccatgta 197919DNAHomo sapiens 79acctccaaag caacagagt 198019DNAHomo sapiens 80agttgttccc tgaatcagt 198119DNAHomo sapiens 81aagtcccagg aaggagatt 198219DNAHomo sapiens 82acattcacag gtctttgtg 198319DNAHomo sapiens 83cgaacgacat gttcttgtt 198419DNAHomo sapiens 84cttgttccca ggaccttaa 198519DNAHomo sapiens 85tgacattagc tcccacttt 198619DNAHomo sapiens 86actgggatgg aggaatcgg 198719DNAHomo sapiens 87ccaggagtag gaggaaaga 198819DNAHomo sapiens 88cggagcagca agaccatgt 198919DNAHomo sapiens 89acagtccggc cgaagactt 199019DNAHomo sapiens 90actattcatg ctaccgggc 199119DNAHomo sapiens 91caacatggat ggtcaagga 199219DNAHomo sapiens 92agtgagatgg gaagcacca 199319DNAHomo sapiens 93atgacataca tgagggtac 199419DNAHomo sapiens 94tggaagaact gggaatggc 199519DNAHomo sapiens 95ctttgccacc accatctgg 199619DNAHomo sapiens 96aagctcctgt cctcccatc 199719DNAHomo sapiens 97ccgccatctt cattgaggc 199819DNAHomo sapiens 98atcttctact ttgccattc 199919DNAhomo sapiens 99actacatgga ccgcttcac 1910012RNAArtificialLoop sequence 100guuugcuaua ac 121016132DNAHomo sapiens 101aattggaagc aaatgacatc acagcaggtc agagaaaaag ggttgagcgg caggcaccca 60gagtagtagg tctttggcat taggagcttg agcccagacg gccctagcag ggaccccagc 120gcccgagaga ccatgcagag gtcgcctctg gaaaaggcca gcgttgtctc caaacttttt 180ttcagctgga ccagaccaat tttgaggaaa ggatacagac agcgcctgga attgtcagac 240atataccaaa tcccttctgt tgattctgct gacaatctat ctgaaaaatt ggaaagagaa 300tgggatagag agctggcttc aaagaaaaat cctaaactca ttaatgccct tcggcgatgt 360tttttctgga gatttatgtt ctatggaatc tttttatatt taggggaagt caccaaagca 420gtacagcctc tcttactggg aagaatcata gcttcctatg acccggataa caaggaggaa 480cgctctatcg cgatttatct aggcataggc ttatgccttc tctttattgt gaggacactg 540ctcctacacc cagccatttt tggccttcat cacattggaa tgcagatgag aatagctatg 600tttagtttga tttataagaa gactttaaag ctgtcaagcc gtgttctaga taaaataagt 660attggacaac ttgttagtct cctttccaac aacctgaaca aatttgatga aggacttgca 720ttggcacatt tcgtgtggat cgctcctttg caagtggcac tcctcatggg gctaatctgg 780gagttgttac aggcgtctgc cttctgtgga cttggtttcc tgatagtcct tgcccttttt 840caggctgggc tagggagaat gatgatgaag tacagagatc agagagctgg gaagatcagt 900gaaagacttg tgattacctc agaaatgatt gaaaatatcc aatctgttaa ggcatactgc 960tgggaagaag caatggaaaa aatgattgaa aacttaagac aaacagaact gaaactgact 1020cggaaggcag cctatgtgag atacttcaat agctcagcct tcttcttctc agggttcttt 1080gtggtgtttt tatctgtgct tccctatgca ctaatcaaag gaatcatcct ccggaaaata 1140ttcaccacca tctcattctg cattgttctg cgcatggcgg tcactcggca atttccctgg 1200gctgtacaaa catggtatga ctctcttgga gcaataaaca aaatacagga tttcttacaa 1260aagcaagaat ataagacatt ggaatataac ttaacgacta cagaagtagt gatggagaat 1320gtaacagcct tctgggagga gggatttggg gaattatttg agaaagcaaa acaaaacaat 1380aacaatagaa aaacttctaa tggtgatgac agcctcttct tcagtaattt ctcacttctt 1440ggtactcctg tcctgaaaga tattaatttc aagatagaaa gaggacagtt gttggcggtt 1500gctggatcca ctggagcagg caagacttca cttctaatgg tgattatggg agaactggag 1560ccttcagagg gtaaaattaa gcacagtgga agaatttcat tctgttctca gttttcctgg 1620attatgcctg gcaccattaa agaaaatatc atctttggtg tttcctatga tgaatataga 1680tacagaagcg tcatcaaagc atgccaacta gaagaggaca tctccaagtt tgcagagaaa 1740gacaatatag ttcttggaga aggtggaatc acactgagtg gaggtcaacg agcaagaatt 1800tctttagcaa gagcagtata caaagatgct gatttgtatt tattagactc tccttttgga 1860tacctagatg ttttaacaga aaaagaaata tttgaaagct gtgtctgtaa actgatggct 1920aacaaaacta ggattttggt cacttctaaa atggaacatt taaagaaagc tgacaaaata 1980ttaattttgc atgaaggtag cagctatttt tatgggacat tttcagaact ccaaaatcta 2040cagccagact ttagctcaaa actcatggga tgtgattctt tcgaccaatt tagtgcagaa 2100agaagaaatt caatcctaac tgagacctta caccgtttct cattagaagg agatgctcct 2160gtctcctgga cagaaacaaa aaaacaatct tttaaacaga ctggagagtt tggggaaaaa 2220aggaagaatt ctattctcaa tccaatcaac tctatacgaa aattttccat tgtgcaaaag 2280actcccttac aaatgaatgg catcgaagag gattctgatg agcctttaga gagaaggctg 2340tccttagtac cagattctga gcagggagag gcgatactgc ctcgcatcag cgtgatcagc 2400actggcccca cgcttcaggc acgaaggagg cagtctgtcc tgaacctgat gacacactca 2460gttaaccaag gtcagaacat tcaccgaaag acaacagcat ccacacgaaa agtgtcactg 2520gcccctcagg caaacttgac tgaactggat atatattcaa gaaggttatc tcaagaaact 2580ggcttggaaa taagtgaaga aattaacgaa gaagacttaa aggagtgctt ttttgatgat 2640atggagagca taccagcagt gactacatgg aacacatacc ttcgatatat tactgtccac 2700aagagcttaa tttttgtgct aatttggtgc ttagtaattt ttctggcaga ggtggctgct 2760tctttggttg tgctgtggct ccttggaaac actcctcttc aagacaaagg gaatagtact 2820catagtagaa ataacagcta tgcagtgatt atcaccagca ccagttcgta ttatgtgttt 2880tacatttacg tgggagtagc cgacactttg cttgctatgg gattcttcag aggtctacca 2940ctggtgcata ctctaatcac agtgtcgaaa attttacacc acaaaatgtt acattctgtt 3000cttcaagcac ctatgtcaac cctcaacacg ttgaaagcag gtgggattct taatagattc 3060tccaaagata tagcaatttt ggatgacctt ctgcctctta ccatatttga cttcatccag 3120ttgttattaa ttgtgattgg agctatagca gttgtcgcag ttttacaacc ctacatcttt 3180gttgcaacag tgccagtgat agtggctttt attatgttga gagcatattt cctccaaacc 3240tcacagcaac tcaaacaact ggaatctgaa ggcaggagtc caattttcac tcatcttgtt 3300acaagcttaa aaggactatg gacacttcgt gccttcggac ggcagcctta ctttgaaact 3360ctgttccaca aagctctgaa tttacatact gccaactggt tcttgtacct gtcaacactg 3420cgctggttcc aaatgagaat agaaatgatt tttgtcatct tcttcattgc tgttaccttc 3480atttccattt taacaacagg agaaggagaa ggaagagttg gtattatcct gactttagcc 3540atgaatatca tgagtacatt gcagtgggct gtaaactcca gcatagatgt ggatagcttg 3600atgcgatctg tgagccgagt ctttaagttc attgacatgc caacagaagg taaacctacc 3660aagtcaacca aaccatacaa gaatggccaa ctctcgaaag ttatgattat tgagaattca 3720cacgtgaaga aagatgacat ctggccctca gggggccaaa tgactgtcaa agatctcaca 3780gcaaaataca cagaaggtgg aaatgccata ttagagaaca tttccttctc aataagtcct 3840ggccagaggg tgggcctctt gggaagaact ggatcaggga agagtacttt gttatcagct 3900tttttgagac tactgaacac tgaaggagaa atccagatcg atggtgtgtc ttgggattca 3960ataactttgc aacagtggag gaaagccttt ggagtgatac cacagaaagt atttattttt 4020tctggaacat ttagaaaaaa cttggatccc tatgaacagt ggagtgatca agaaatatgg 4080aaagttgcag atgaggttgg gctcagatct gtgatagaac agtttcctgg gaagcttgac 4140tttgtccttg tggatggggg ctgtgtccta agccatggcc acaagcagtt gatgtgcttg 4200gctagatctg ttctcagtaa ggcgaagatc ttgctgcttg atgaacccag tgctcatttg 4260gatccagtaa cataccaaat aattagaaga actctaaaac aagcatttgc tgattgcaca 4320gtaattctct gtgaacacag gatagaagca atgctggaat gccaacaatt tttggtcata 4380gaagagaaca aagtgcggca gtacgattcc atccagaaac tgctgaacga gaggagcctc 4440ttccggcaag ccatcagccc ctccgacagg gtgaagctct ttccccaccg gaactcaagc 4500aagtgcaagt ctaagcccca gattgctgct ctgaaagagg agacagaaga agaggtgcaa 4560gatacaaggc tttagagagc agcataaatg ttgacatggg acatttgctc atggaattgg 4620agctcgtggg acagtcacct catggaattg gagctcgtgg aacagttacc tctgcctcag 4680aaaacaagga tgaattaagt ttttttttaa aaaagaaaca tttggtaagg ggaattgagg 4740acactgatat gggtcttgat aaatggcttc ctggcaatag tcaaattgtg tgaaaggtac 4800ttcaaatcct tgaagattta ccacttgtgt tttgcaagcc agattttcct gaaaaccctt 4860gccatgtgct agtaattgga aaggcagctc taaatgtcaa tcagcctagt tgatcagctt 4920attgtctagt gaaactcgtt aatttgtagt gttggagaag aactgaaatc atacttctta 4980gggttatgat taagtaatga taactggaaa cttcagcggt ttatataagc ttgtattcct 5040ttttctctcc tctccccatg atgtttagaa acacaactat attgtttgct aagcattcca 5100actatctcat ttccaagcaa gtattagaat accacaggaa ccacaagact gcacatcaaa 5160atatgcccca ttcaacatct agtgagcagt caggaaagag aacttccaga tcctggaaat 5220cagggttagt attgtccagg tctaccaaaa atctcaatat ttcagataat cacaatacat 5280cccttacctg ggaaagggct gttataatct ttcacagggg acaggatggt tcccttgatg 5340aagaagttga tatgcctttt cccaactcca gaaagtgaca agctcacaga cctttgaact 5400agagtttagc tggaaaagta tgttagtgca aattgtcaca ggacagccct tctttccaca 5460gaagctccag gtagagggtg tgtaagtaga taggccatgg gcactgtggg tagacacaca 5520tgaagtccaa gcatttagat gtataggttg atggtggtat gttttcaggc tagatgtatg 5580tacttcatgc tgtctacact aagagagaat gagagacaca ctgaagaagc accaatcatg 5640aattagtttt atatgcttct gttttataat tttgtgaagc aaaatttttt ctctaggaaa 5700tatttatttt aataatgttt caaacatata taacaatgct gtattttaaa agaatgatta 5760tgaattacat ttgtataaaa taatttttat atttgaaata ttgacttttt atggcactag 5820tatttctatg aaatattatg ttaaaactgg gacaggggag aacctagggt gatattaacc 5880aggggccatg aatcaccttt tggtctggag ggaagccttg gggctgatgc agttgttgcc 5940cacagctgta tgattcccag ccagcacagc ctcttagatg cagttctgaa gaagatggta 6000ccaccagtct gactgtttcc atcaagggta cactgccttc tcaactccaa actgactctt 6060aagaagactg cattatattt attactgtaa gaaaatatca cttgtcaata aaatccatac 6120atttgtgtga aa 613210221DNAartificialPrimer 102ccgtttacgt ggagactcgc c 2110325DNAArtificialPrimer 103cccccacctt atatatattc tttcc 25

Claims

1. A method for identifying a compound that increases the functional activity of CF-associated mutant CFTR, comprising: (a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 45, 30, 32-44, and 46-55 and fragments thereof; and (b) measuring a compound-polypeptide property related to CF-associated mutant CFTR activity.

2. The method according to claim 1, wherein said polypeptide is in an in vitro cell-free preparation.

3. The method according to claim 1, wherein said polypeptide is present in a mammalian cell.

4. The method of claim 2, wherein said property is a binding affinity of said compound to said polypeptide.

5. The method of claim 1, wherein the method is used to identify compounds that promote migration of ΔF508-CFTR to the plasma membrane.

6. The method of claim 4, which additionally comprises the steps of: c) contacting a population of mammalian cells expressing said polypeptide with the compound that exhibits a binding affinity of at least 10 micromolar; and d) identifying a compound that increases the functional activity of CF-associated mutant CFTR.

7. The method of claim 1, wherein said property is increased activity of ΔF508-CFTR or CFTR.

8. The method according to claim 1, wherein said property is the activity of said polypeptide.

9. The method according to claim 1, wherein said property is the expression of said polypeptide.

10. The method according to claim 8, which additionally comprises the steps of: c) contacting a population of mammalian cells expressing said polypeptide with the compound that significantly inhibits the expression or activity of the polypeptide; and d) identifying the compound that increases the functional activity of CF-associated mutant CFTR.

11. The method according to claim 1, which additionally comprises the step of comparing the compound to be tested to a control.

12. The method according to claim 11, wherein said control is where the polypeptide has not been contacted with said compound.

13. The method according to claim 6, which additionally comprises the step of comparing the compound to a control, wherein said control is a population of mammalian cells that does not express said polypeptide.

14. The method according to claim 1, wherein said compound is selected from the group consisting of compounds of a commercially available screening library and compounds having binding affinity for a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 45, 30, 32-44, and 46-55.

15. The method according to claim 1, wherein said compound is a peptide in a phage display library or an antibody fragment library.

16. An agent effective in increasing the functional activity of CF-associated mutant CFTR, selected from the group consisting of an antisense polynucleotide, a ribozyme, and a small interfering RNA (siRNA), wherein said agent comprises a nucleic acid sequence complementary to, or engineered from, a naturally-occurring polynucleotide sequence of about 17 to about 30 contiguous nucleotides of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 19, 1, 3-18 and 20-29.

17. The agent according to claim 16, wherein a vector in a mammalian cell expresses said agent.

18. The agent according to claim 16, which increases the functional activity of CF-associated mutant CFTR.

19. The agent according to claim 17, wherein said vector is an adenoviral, retroviral, adeno-associated viral, lentiviral, a herpes simplex viral or a sendaiviral vector.

20. The agent according to claim 16, wherein said antisense polynucleotide and said siRNA comprise an antisense strand of 17-25 nucleotides complementary to a sense strand, wherein said sense strand is selected from 17-25 continuous nucleotides of a nucleic acid sequence selected from the group consisting of SEQ ID NO: 2, 19, 1, 3-18 and 20-29.

21. The agent according to claim 20, wherein said siRNA further comprises said sense strand.

22. The agent according to claim 21, wherein said sense strand is selected from the group consisting of SEQ ID NO: 56, 57, 81, 82, 58-80 and 83-99.

23. The agent according to claim 20, wherein said siRNA further comprises a loop region connecting said sense and said antisense strand.

24. The agent according to claim 23, wherein said loop region comprises a nucleic acid sequence selected from the group consisting of UUGCUAUA or GUUUGCUAUAAC (SEQ ID NO: 100).

25. The agent according to claim 16, wherein said agent is an antisense polynucleotide, ribozyme, or siRNA comprising a nucleic acid sequence complementary to a nucleic acid sequence selected from the group consisting of SEQ ID NO: 56, 57, 81, 82, 58-80 and 83-99.

26. A pharmaceutical composition comprising a therapeutically effective amount of an agent according to claim 16 in admixture with a pharmaceutically acceptable carrier.

27. A method for the treatment and/or prevention of a disease involving ER-associated protein misfolding in a subject suffering from or susceptible to the disease, comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 26.

28. The method according to claim 27 wherein the disease is selected from Cystic Fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pigmentosa, transthyretin-linked amyloidosis, Alzheimer's disease, prion disease, and inclusion body myositis.

29. The method according to claim 28, wherein the disease is Cystic Fibrosis.

30. A method for the treatment and/or prevention of a disease involving ER-associated protein misfolding, or the treatment or prevention of a condition characterized by ER-associated protein misfolding, comprising administering a therapeutically effective amount of an agent according to claim 16.

31. The method according to claim 30, wherein the disease is selected from the group consisting of Cystic Fibrosis, Parkinson's disease, Gaucher's disease, nephrogenic diabetes insipidus, emphysema and liver disease (alpha-1-antitrypsin deficiency), Maple syrup urine disease, Fabry's disease, hypogonadotropic hypogonadism, hyperinsulinemic hypoglycemia, beta-galactosidosis, Wilson's disease, long QT syndrome, retinitis pimentosa, transthyretin-linked amyloidosis, Alzheimer's disease, prion disease, and inclusion body myositis.

32. The method according to claim 30, wherein the disease is Cystic Fibrosis.

33. (canceled)

34. A method for diagnosing a pathological condition in a subject involving ER-associated protein misfolding, or a pathological condition involving inflammation, comprising determining a first amount or activity of polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 31, 45, 30, 32-44, and 46-55 present in a biological sample obtained from said subject, and comparing said first amount or activity with the ranges of amounts or activities of the polypeptide determined in a population of healthy subjects, wherein an increase of the amount or activity of polypeptide in said biological sample compared to the range of amounts or activities determined for healthy subjects is indicative of the presence of the pathological condition.

35. A method for the treatment and/or prevention of a disease involving inflammation in a subject suffering from or susceptible to the disease, comprising administering a therapeutically effective amount of a pharmaceutical composition according to claim 26.

36. The method according to claim 35 wherein the disease is selected from Cystic Fibrosis, COPD and asthma.

37. A method for the treatment and/or prevention of a disease involving or characterized by inflammation, comprising administering a therapeutically effective amount of an agent according to claim 16.

38. The method according to claim 37, wherein the disease is selected from the group consisting of Cystic Fibrosis, COPD and asthma.

39. (canceled)

40. (canceled)