Method and means for treatment of osteoarthritis

Abstract

The present invention relates to in vivo and in vitro methods, agents and compound screening assays for inducing anabolic stimulation of chondrocytes, including cartilage formation enhancing pharmaceutical compositions, and the use thereof in treating and/or preventing a disease involving a systemic or local decrease in mean cartilage thickness in a subject.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application No. 60/581,568, filed Jun. 21, 2004, the disclosure of which is incorporated herein by reference.

FIELD OF THE INVENTION

[0002] The invention relates to the field of medicinal research, cartilage physiology and diseases involving the degeneration of cartilage tissue. More specifically, the invention relates to methods and means for identifying compounds that stimulate anabolic processes in chondrocytes and that typically induce the synthesis of cartilage. The invention also relates to the compounds that are useful in the treatment of osteoarthritis.

[0003] Cartilage is an avascular tissue made up largely of cartilage-specific cells, the chondrocytes, proteoglycans and collagen proteins, which are structural proteins that provide structural strength to connective tissue, such as skin, bone and cartilage. Collagen II, together with the protein collagen IX, forms a "biological alloy", which is molded into a fibril-like structure and is arranged in a precise network, providing cartilage with great mechanical strength. The chondrocytes in normal articular cartilage occupy approximately 5% of the tissue volume, while the extra-cellular matrix makes up the remaining 95% of the tissue. The chondrocytes secrete the components of the matrix, which in turn supplies the chondrocytes with an environment suitable for their survival under mechanical stress.

[0004] Breakdown of articular cartilage, which is part of joints and which cushions the ends of the bones, causes the bones to rub against each other leading to pain and loss of movement. Cartilage degradation may also be the result of an imbalance in cartilage synthesizing (anabolic) and cartilage degrading (catabolic) processes. Unlike most tissues, cartilage does not self-repair following injury. The inability of cartilage to self-repair after injury, disease, or surgery is a major limiting factor in rehabilitation of degrading joint surfaces and injury to meniscal cartilage.

[0005] There are many diseases involving the degeneration of cartilage. Rheumatoid arthritis and osteoarthritis are among the most prominent. Osteoarthritis (also referred to as OA, or as wear-and-tear arthritis) is the most common form of arthritis and is characterized by loss of articular cartilage, often associated with hypertrophy of the bone. The disease mainly affects hands and weight-bearing joints such as knees, hips and spines. This process thins the cartilage through a phenomenon called apoptosis, or programmed cell death. When the surface area has disappeared due to the thinning, there is a grade I osteoarthritis; when the tangential surface area has disappeared, there is a grade two osteoarthritis. There are other levels of degeneration and destruction, which affect the deep and the calcified layers that border with the subchondral bone.

[0006] The clinical manifestations of the development of the osteoarthritis condition are: increased volume of the joint, pain, crepitation and functional disability that, gradually and steadily, first hinders the performance of lengthy walks and forced flexion and extension movements, depending on the affected joint, and then pain and limitation of minimum efforts emerge as well as pain at rest which interrupts sleeping. If the condition persists without correction and/or therapy, the joint is destroyed, leading the patient to major replacement surgery with total prosthesis, or to disability.

[0007] Therapeutic methods for the correction of the articular cartilage lesions that appear during the osteoarthritic disease have been developed, but so far none of them have been able to achieve the regeneration of articular cartilage in situ and in vivo.

REPORTED DEVELOPMENTS

[0008] Osteoarthritis is difficult to treat. At present, no cure is available and treatment focuses on relieving pain and preventing the affected joint from becoming deformed. Common treatments include the use of non-steroidal anti-inflammatory drugs (NSAID's), which are often used to relieve pain, while specific COX-2 inhibitors are used to relieve severe pain. Medicines such as chondroitin and glucosamine are thought to improve the cartilage itself. These treatments may be relatively successful, but not a substantive amount of research data is available.

[0009] In severe cases, joint replacement may be necessary. This is especially true for hips and knees. If a joint is extremely painful and cannot be replaced, it may be fused. This procedure stops the pain, but results in the permanent loss of joint function, making walking and bending difficult.

[0010] The treatment that has 74% to 90% effectiveness and produces excellent results is the transplantation of cultured autologous chondrocytes, by taking chondral cellular material from the patient, sending it to a laboratory where it is seeded in a proper medium for its proliferation, and, once enough volume is achieved after a variable period that may last from weeks to months, transporting it in a special container and implanting it in the damaged tissues to cover the tissue's defects.

[0011] Another treatment includes the intraarticular instillation of Hylan G-F 20 (Synvisc, Hyalgan, Artz etc.), a substance that improves temporarily the rheology of the synovial fluid, producing an almost immediate sensation of free movement and a marked reduction of pain. The residual effects of this substance act on the synovial receptors causing a pain reduction that lasts several weeks and even months. However, this isolated effect is counterproductive for the course of the disease and for the viability of the cartilage because, as it masks the symptoms, the joint is used with more intensity and its destruction is accelerated as the original problem is not corrected and the damaged articular cartilage is not restored.

[0012] Other reported methods include application of tendinous, periosteal, fascial, muscular or perichondral grafts; implantation of fibrin or cultured chondrocytes; implantation of synthetic matrices, such as collagen, carbon fiber; administration of electromagnetic fields. All of these have reported minimal and incomplete results with formation of repair, but not regenerative tissue, resulting in a poor quality tissue that can neither support the weighted load nor allow the restoration of an articular function with normal movement.

[0013] Stimulation of the anabolic processes, blocking catabolic processes, or a combination of these two, may result in stabilization of the cartilage, and perhaps even reversion of the damage, and therefore prevent further progression of the disease. Various triggers may stimulate anabolic stimulation of chondrocytes. Insulin-like growth factor-I (IGF-I) is the predominant anabolic growth factor in synovial fluid and stimulates the synthesis of both proteoglycans and collagen. It has also been shown that members of the bone morphogenetic protein (BMP) family, notably BMP2, BMP4, BMP6, and BMP7, and members of the human transforming growth factor-b (TGF-b) family can induce chondrocyte anabolic stimulation (Chubinskaya and Kuettner, 2003). A compound has recently been identified that induces anabolic stimulation of chondrocytes (U.S. Pat. No. 6,500,854; EP 1.391211). However, most of these compounds show severe side effects and, consequently, there is a strong need for compounds that stimulate chondrocyte differentiation without severe side effects.

[0014] The present invention relates to the relationship between the function of selected proteins identified by the present inventors (hereinafter referred to as "TARGETS") and anabolic stimulation of chondrocytes.

SUMMARY OF THE INVENTION

[0015] The present invention relates to a method for identifying compounds that induce cartilage-synthesizing processes, which lead to anabolic stimulation of chondrocytes, comprising contacting the compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594, or a functional fragment or derivative thereof, under conditions that allow said polypeptide to bind to the compound, and measuring a compound-polypeptide property related to the anabolic stimulation of chondrocytes.

[0016] The present invention also relates to expression inhibitory agents, pharmaceutical compositions comprising the same, methods for the in vitro production of cartilage tissue, and host cells expressing said agents.

[0017] Aspects of the present method include the in vitro assay of compounds using polypeptide of a TARGET, and cellular assays wherein TARGET inhibition is followed by observing indicators of efficacy, including collagen type II, alpha-1 (col2.alpha.1) and aggrecan levels.

[0018] Another aspect of the invention is a method of treatment or prevention of a condition involving de-differentiation of chondrocytes and/or loss of cartilage thickness, in a subject suffering or susceptible thereto, by administering a pharmaceutical composition comprising an effective cartilage formation-enhancing amount of a TARGET inhibitor.

[0019] A further aspect of the present invention is a pharmaceutical composition for use in said method wherein said inhibitor comprises a polynucleotide selected from the group of an antisense polynucleotide, a ribozyme, and a small interfering RNA (siRNA), wherein said inhibitor comprises a nucleic acid sequence complementary to, or engineered from, a naturally occurring polynucleotide sequence encoding a polypeptide, comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594, or a fragment thereof.

[0020] Another further aspect of the present invention is a pharmaceutical composition comprising a therapeutically effective cartilage formation-enhancing amount of a TARGET inhibitor or its pharmaceutically acceptable salt, hydrate, solvate, or prodrug thereof in admixture with a pharmaceutically acceptable carrier. The present polynucleotides and TARGET inhibitor compounds are also useful for the manufacturing of a medicament for the treatment of conditions involving de-differentiation of chondrocytes and/or cartilage thickness loss.

[0021] Furthermore, the invention relates also to diagnostic methods.

BRIEF DESCRIPTION OF THE DRAWINGS

[0022] FIG. 1. Quantification of Col2.alpha.1 expression in primary human chondrocytes 12 days post infection with the indicated viruses.

[0023] FIG. 2. Example of duplicate screening results for Col2.alpha.1 expression of part of the SilenceSelect library.

[0024] FIG. 3 (A-N): Quantification of Col2.alpha.1 expression in primary human chondrocytes 12 days post infection with the indicated viruses.

[0025] FIG. 4. Quantification of alcian blue staining on human primary chondrocytes, 12 days after infection with the indicated viruses, compared to uninfected cells.

[0026] FIG. 5 (A-N): Quantification of aggrecan expression in primary human chondrocytes 12 days post infection with the indicated viruses.

[0027] FIG. 6 (A-K): On target analysis with different constructs targeting the indicated genes. The on target analysis is assessed through detection of the Col2.alpha.1 expression in primary human chondrocytes 12 days post infection with the indicated viruses. Data are represented as luminescence units. The different thresholds corresponding to the different infection volumes are indicated as a line. Increasing the infection volumes leads to an increased threshold.

[0028] FIG. 7 (A-L): GAG analysis on chondrocytes in alginate cell culture 10 days post infection. The data are represented as relative GAG levels to the average of KD control 1 and KD control 2, being Ad-siRNA targeting PTGER4 and GRM7 respectively. Two individual data points are shown for every condition.

[0029] FIG. 8 (A-L): Hydroxyproline analysis on chondrocytes in alginate cell culture 10 days post infection. The data are represented as relative hydroxyproline levels to the average of KD control 1 and KD control 2, being Ad-siRNA targeting PTGER4 and GRM7 respectively. Two individual data points are shown for every condition.

[0030] FIG. 9 (A-L): mRNA marker analysis on chondrocytes in alginate cell culture 10 days post infection. The cells are infected with either Ad5/ALPL and Ad5/BMP2 overexpressing viruses, and with an Ad-siRNA targeting the indicated gene. The data are represented as relative mRNA levels to the ALPL control.

DETAILED DESCRIPTION

[0031] The following terms are used herein in accordance with the following definitions:

[0032] The term "agent" means any molecule, including polypeptides, polynucleotides and small molecules.

[0033] The term "anabolic stimulation of chondrocytes" should be understood as inducing chondrogenesis or as inducing or enhancing the anabolic activity of chondrocytes. Anabolic stimulation takes place for instance by stimulating the synthesis of cartilage components, or inducing synthesis of components that are required for cartilage synthesis. "Anabolic stimulation of chondrocytes" may also be understood as a process in which the expression of the matrix Gla protein (MGP) is induced. Anabolic stimulation of chondrocytes may furthermore be understood as inducing the expression of cartilage derived retinoic acid sensitive protein (CD-RAP), as inducing the expression of cartilage oligomeric matrix protein (COMP), as inducing the expression of aggrecan 1 (agc1, also termed chondroitin sulfate proteoglycan core protein 1, or CSPG1), or as inducing synthesis of collagen II, also known as collagen, type II, alpha-1 (col2.alpha.1), collagen of cartilage, chondrocalcin, and collagen, type xi, alpha-3 (col11.alpha.3).

[0034] The term `antisense nucleic acid` refers to an oligonucleotide that has a nucleotide sequence that interacts through base pairing with a specific complementary nucleic acid sequence involved in the expression of the target such that the expression of the gene is reduced. Preferably, the specific nucleic acid sequence involved in the expression of the gene is a genomic DNA molecule or mRNA molecule that encodes (a part of) the gene. This genomic DNA molecule can comprise regulatory regions of the gene, or the coding sequence for the mature gene.

[0035] 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.

[0036] 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.sub.D).

[0037] 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.TM., polyethylene glycol (PEG), and PLURONICS.TM..

[0038] The term "complex" means the entity created when two or more compounds-bind to each other.

[0039] 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 or from natural sources. The compounds include inorganic or organic compounds such as polynucleotides, lipids or hormone analogs that are characterized by relatively low molecular weights. 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, such as antibodies or antibody conjugates.

[0040] The term `complementary to a nucleotide sequence` in the context of antisense oligonucleotides and methods should be understood as sufficiently complementary to such a sequence as to allow hybridization to that sequence in a cell, i.e., under physiological conditions.

[0041] The term "condition" or "disease" means the overt presentation of symptoms (i.e., illness) or the manifestation of abnormal clinical indicators (e.g., biochemical indicators). Alternatively, the term "disease" refers to a genetic or environmental risk of or propensity for developing such symptoms or abnormal clinical indicators.

[0042] The term "contact" or "contacting" means bringing at least two moieties together, whether in an in vitro system or an in vivo system.

[0043] The term "de-differentiation" refers to a general process wherein chondrocytes differentiate away from a cell phenotype that synthesizes cartilage components. Such components include, but are not limited to, collagen II, aggrecan 1, versican, link protein, perlecan, SZP/lubricin, biglycan (DS-PGI), decorin (DS-PGII), epiphycan (DS-PGIII), fibromodulin, lumican, CILP, C-type lectin, fibronectin, PRELP, COMP (thrombospondin-5), thrombospondin-1 and -3, CMP (matrilin-1), matrilin-3, C-type lectin, fibronectin, condroadherin, tenascin-C, fibrillin, elastin, gp-39/YKL-40, matrix Gla protein/MGP, pleiotrophin, chondromodulin-I/SCGP, chondromodulin-II, CD-RAP, chondrocalcin, PARP, lysozyme, and phospholipase A2.

[0044] The term "effective amount" or "therapeutically effective amount" means that amount of a compound or 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 inducing anabolic stimulation of chondrocytes, the term "effective amount" is intended to mean an effective differentiation-promoting amount of an compound or agent that will bring about a biologically meaningful increase in the levels of chondrocyte markers, representative for the process of an increase in chondrocyte anabolism.

[0045] The term "expressible nucleic acid" means a nucleic acid coding for a proteinaceous molecule, an RNA molecule, or a DNA molecule.

[0046] The term "endogenous" shall mean a material that a mammal 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 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 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 not a 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.

[0047] The term "expression" comprises both endogenous expression and overexpression by transduction.

[0048] 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 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.

[0049] The term "expressible nucleic acid" means a nucleic acid coding for a proteinaceous molecule, an RNA molecule, or a DNA molecule.

[0050] The term `genetic antisense` as used herein refers to the incorporation of antisense constructs complementary to sequences of genes into the genome of a cell. Such incorporation allows for the continued synthesis of the antisense molecule.

[0051] 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 (e.g., C.sub.0t or R.sub.0t analysis) or formed between one nucleic acid sequence present in solution and another nucleic acid sequence immobilized on a solid support (e.g., 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, e.g., 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.

[0052] 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.

[0053] The term "inhibition" refers to the reduction, down regulation of a process or the elimination of a stimulus for a process that results in the absence or minimization of the expression of a protein or polypeptide.

[0054] The term "induction" refers to the inducing, up-regulation, or stimulation of a process that results in the expression of a protein or polypeptide, and that may also result in a phenotypical cellular change.

[0055] The term "ligand" means an endogenous, naturally occurring molecule specific for an endogenous, naturally occurring receptor.

[0056] The term "pharmaceutically acceptable salts" refers to the non-toxic, inorganic and organic acid addition salts, and base addition salts, of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of compounds useful in the present invention.

[0057] 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 preferably 70 percent of its base pairs are in common, most preferably 90 percent, and in a special embodiment 100 percent of its base pairs. The polynucleotides include polyribonucleic acids, polydeoxyribonucleic acids, and synthetic analogues thereof. The polynucleotides are described by sequences that vary in length, that range from about 10 to about 5000 bases, preferably about 100 to about 4000 bases, more preferably about 250 to about 2500 bases. A preferred polynucleotide embodiment comprises from about 10 to about 30 bases in length. A special embodiment of polynucleotide is the polyribonucleotide of from about 10 to about 22 nucleotides, more commonly described as small interfering RNAs (siRNAs). Another special embodiment are nucleic acids with modified backcartilages 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.

[0058] The term "polypeptide" relates to proteins (such as TARGETS), proteinaceous molecules, fractions of proteins peptides and oligopeptides.

[0059] The term `ribozymes` as used herein relates to catalytic RNA molecules capable of cleaving other RNA molecules at phosphodiester bonds in a manner specific to the sequence.

[0060] 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.

[0061] The term "subject" includes humans and other mammals.

[0062] The term "treating" means an intervention performed with the intention of preventing the development or altering the pathology of, and thereby alleviating a disorder, disease or condition, including one or more symptoms of such disorder or condition. Accordingly, "treating" refers to both therapeutic treatment and prophylactic or preventative measures. Those in need of treating include those already with the disorder as well as those in which the disorder is to be prevented. The related term "treatment," as used herein, refers to the act of treating a disorder, symptom, disease or condition, as the term "treating" is defined above.

[0063] 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.

[0064] The term "vertebrate cells" means cells derived from animals having vertera 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 murine, such as mice and rats, and rabbits.

Applicants' Invention Based on TARGET Relationship to Anabolic Stimulation of Chondrocytes

[0065] As noted above, the present invention is based on the present inventors' discovery that TARGETS are factors in the up-regulation and/or induction of anabolic processes of chondrocytes. The term "TARGET" or "TARGETS" means the proteins identified in accordance with the assay described below to be involved in the induction of the anabolic stimulation of chondrocytes. The preferred TARGETS are identified as SEQ ID NOS. 101-128 and 401-594 in Table 1A. Table 1A lists the polypeptides, polynucleotides and knock-down target sequences of the present invention. Table 1B lists exemplary fragments of the transmembrane protein TARGETS. Table 1C lists exemplary KD target sequences useful in the practice of the present expression-inhibitory agent invention. TABLE-US-00001 TABLE 1A Target KD Hit Gene GenBank SEQ ID KD Target Sequence Symbol Accession Name Class DNA Protein NO. H33- CCRTGAATGTGACTGTGGAC DGKB- NM_020238 diacylglycerol kinase, beta Kinase 1 101 202- 025 (SEQ ID NO: 209) INCENP NM_004080 90 kDa/inner centromere pro- 2 102 209 NM_145695 tein antigens 135/155 kDa 3 103 H33- GACTGACTGGCCTGAAGGC ICK NM_016513 intestinal cell (MAK-like) Kinase 4 104 210- 032 (SEQ ID NO: 210) NM_014920 kinase 5 105 217 H33- GATCTACACCACCTTCATC GPR103 AF411117 G protein-coupled receptor GPCR 6 106 218- 034 (SEQ ID NO: 219) NM_198179 103 7 107 225 H33- GGTGTATGGGCTCATGTAC FZD1 NM_003505 frizzled homolog 1 GPCR 8 108 226- 041 (SEQ ID NO: 226) (Drosophila) 232 H33- AGAACTGGGTGATGACAGC ELA1 NM_001971 elastase 1, pancreatic Protease 9 109 233- 056 (SEQ ID NO: 234) 240 H33- ATGAACTCTGTGATCCAGC USP9Y NM_004654 ubiquitin specific protease Protease 10 110 241- 061 (SEQ ID NO: 241) 9, Y-linked (fat facets-like, 248 Drosophila) H33- TTGGAATTCCAGTGTACCC DUSP11 NM_003584 dual specificity phosphatase Phosphatase 11 111 249- 082 (SEQ ID NO: 250) 11 (RNA/RNP complex 1-inter- 256 acting) H33- GCTAGTTATCGCCTACCTC DUSP3 NM_004090 dual specificity phosphatase Phosphatase 12 112 257- 083 (SEQ ID NO: 257) 3 (vaccinia virus phosphatase 263 VH1-related) H33- AGATTCCAGATGCAACCCC JAK1 SK185- Janus kinase 1 (a protein ty- Kinase 13 113 264- 096 (SEQ ID NO: 266) NM_002227 rosine kinase) 14 114 272 H33- CTGAACTACTGGTACAGCC ABCG1 NM_016818 ATP-binding cassette, sub- Transporter 15 115 273- 107 (SEQ ID NO: 275) NM_004915 family G (WHITE), member 1 16 116 280 NM_207174 17 117 NM_207627 18 118 NM_207628 19 119 NM_207629 20 120 NM_207630 21 121 H33- GCGAATTCCACCAGCATTC SLC26A8 NM_052961 solute carrier family 26, Transporter 22 122 281- 130 (SEQ ID NO: 283) member 8 293 H33- ACATTGACCAGGAAGTGAC GGTLA4 NM_178312 gamma-glutamyltransferase- Enzyme 23 123 294- 192 (SEQ ID NO: 296) NM_178311 like activity 4 24 124 300 NM_080920 25 125 H33- GAAGCTGAATTAGGGCTTC PDE1A NM_005019 phosphodiesterase 1A, PDE 26 126 301- 217 (SEQ ID NO: 302) NM_00100- calmodulin-dependent 27 127 308 3683 H33- GAAGCCATCTCCGACAATC SLC15A2 NM_021082 solute carrier family 15 (H+/ Transporter 28 128 309- 279 (SEQ ID NO: 310) peptide transporter), member 315 2

[0066] TABLE-US-00002 TABLE 1B Seq ID protein Accession Name Protein Segment segment AF411117 GPR103 Extracellular domain 401 AF411117 GPR103 Transmembrane domain 402 AF411117 GPR103 Intracellular domain 403 AF411117 GPR103 Transmembrane domain 404 AF411117 GPR103 Extracellular domain 405 AF411117 GPR103 Transmembrane domain 406 AF411117 GPR103 Intracellular domain 407 AF411117 GPR103 Transmembrane domain 408 AF411117 GPR103 Extracellular domain 409 AF411117 GPR103 Transmembrane domain 410 AF411117 GPR103 Intracellular domain 411 AF411117 GPR103 Transmembrane domain 412 AF411117 GPR103 Extracellular domain 413 NM_198179 GPR103 Extracellular domain 414 NM_198179 GPR103 Transmembrane domain 415 NM_198179 GPR103 Intracellular domain 416 NM_198179 GPR103 Transmembrane domain 417 NM_198179 GPR103 Extracellular domain 418 NM_198179 GPR103 Transmembrane domain 419 NM_198179 GPR103 Intracellular domain 420 NM_198179 GPR103 Transmembrane domain 421 NM_198179 GPR103 Extracellular domain 422 NM_198179 GPR103 Transmembrane domain 423 NM_198179 GPR103 Intracellular domain 424 NM_198179 GPR103 Transmembrane domain 425 NM_198179 GPR103 Extracellular domain 426 NM_198179 GPR103 Transmembrane domain 427 NM_198179 GPR103 Intracellular domain 428 NM_003505 FZD1 Extracellular domain 429 NM_003505 FZD1 Transmembrane domain 430 NM_003505 FZD1 Intracellular domain 431 NM_003505 FZD1 Transmembrane domain 432 NM_003505 FZD1 Extracellular domain 433 NM_003505 FZD1 Transmembrane domain 434 NM_003505 FZD1 Intracellular domain 435 NM_003505 FZD1 Transmembrane domain 436 NM_003505 FZD1 Extracellular domain 437 NM_003505 FZD1 Transmembrane domain 438 NM_003505 FZD1 Intracellular domain 439 NM_003505 FZD1 Transmembrane domain 440 NM_003505 FZD1 Extracellular domain 441 NM_003505 FZD1 Transmembrane domain 442 NM_003505 FZD1 Intracellular domain 443 NM_016818 ABCG1 Extracellular domain 444 NM_016818 ABCG1 Transmembrane domain 445 NM_016818 ABCG1 Intracellular domain 446 NM_016818 ABCG1 Transmembrane domain 447 NM_016818 ABCG1 Extracellular domain 448 NM_016818 ABCG1 Transmembrane domain 449 NM_016818 ABCG1 Intracellular domain 450 NM_016818 ABCG1 Transmembrane domain 451 NM_016818 ABCG1 Extracellular domain 452 NM_016818 ABCG1 Transmembrane domain 453 NM_016818 ABCG1 Intracellular domain 454 NM_016818 ABCG1 Transmembrane domain 455 NM_016818 ABCG1 Extracellular domain 456 NM_016818 ABCG1 Transmembrane domain 457 NM_016818 ABCG1 Intracellular domain 458 NM_004915 ABCG1 Extracellular domain 459 NM_004915 ABCG1 Transmembrane domain 460 NM_004915 ABCG1 Intracellular domain 461 NM_004915 ABCG1 Transmembrane domain 462 NM_004915 ABCG1 Extracellular domain 463 NM_004915 ABCG1 Transmembrane domain 464 NM_004915 ABCG1 Intracellular domain 465 NM_004915 ABCG1 Transmembrane domain 466 NM_004915 ABCG1 Extracellular domain 467 NM_004915 ABCG1 Transmembrane domain 468 NM_004915 ABCG1 Intracellular domain 469 NM_004915 ABCG1 Transmembrane domain 470 NM_004915 ABCG1 Extracellular domain 471 NM_004915 ABCG1 Transmembrane domain 472 NM_004915 ABCG1 Intracellular domain 473 NM_207174 ABCG1 Extracellular domain 474 NM_207174 ABCG1 Transmembrane domain 475 NM_207174 ABCG1 Intracellular domain 476 NM_207174 ABCG1 Transmembrane domain 477 NM_207174 ABCG1 Extracellular domain 478 NM_207174 ABCG1 Transmembrane domain 479 NM_207174 ABCG1 Intracellular domain 480 NM_207174 ABCG1 Transmembrane domain 481 NM_207174 ABCG1 Extracellular domain 482 NM_207174 ABCG1 Transmembrane domain 483 NM_207174 ABCG1 Intracellular domain 484 NM_207174 ABCG1 Transmembrane domain 485 NM_207174 ABCG1 Extracellular domain 486 NM_207174 ABCG1 Transmembrane domain 487 NM_207174 ABCG1 Intracellular domain 488 NM_207627 ABCG1 Extracellular domain 489 NM_207627 ABCG1 Transmembrane domain 490 NM_207627 ABCG1 Intracellular domain 491 NM_207627 ABCG1 Transmembrane domain 492 NM_207627 ABCG1 Extracellular domain 493 NM_207627 ABCG1 Transmembrane domain 494 NM_207627 ABCG1 Intracellular domain 495 NM_207627 ABCG1 Transmembrane domain 496 NM_207627 ABCG1 Extracellular domain 497 NM_207627 ABCG1 Transmembrane domain 498 NM_207627 ABCG1 Intracellular domain 499 NM_207627 ABCG1 Transmembrane domain 500 NM_207627 ABCG1 Extracellular domain 501 NM_207627 ABCG1 Transmembrane domain 502 NM_207627 ABCG1 Intracellular domain 503 NM_207628 ABCG1 Extracellular domain 504 NM_207628 ABCG1 Transmembrane domain 505 NM_207628 ABCG1 Intracellular domain 506 NM_207628 ABCG1 Transmembrane domain 507 NM_207628 ABCG1 Extracellular domain 508 NM_207628 ABCG1 Transmembrane domain 509 NM_207628 ABCG1 Intracellular domain 510 NM_207628 ABCG1 Transmembrane domain 511 NM_207628 ABCG1 Extracellular domain 512 NM_207628 ABCG1 Transmembrane domain 513 NM_207628 ABCG1 Intracellular domain 514 NM_207628 ABCG1 Transmembrane domain 515 NM_207628 ABCG1 Extracellular domain 516 NM_207628 ABCG1 Transmembrane domain 517 NM_207628 ABCG1 Intracellular domain 518 NM_207629 ABCG1 Extracellular domain 519 NM_207629 ABCG1 Transmembrane domain 520 NM_207629 ABCG1 Intracellular domain 521 NM_207629 ABCG1 Transmembrane domain 522 NM_207629 ABCG1 Extracellular domain 523 NM_207629 ABCG1 Transmembrane domain 524 NM_207629 ABCG1 Intracellular domain 525 NM_207629 ABCG1 Transmembrane domain 526 NM_207629 ABCG1 Extracellular domain 527 NM_207629 ABCG1 Transmembrane domain 528 NM_207629 ABCG1 Intracellular domain 529 NM_207629 ABCG1 Transmembrane domain 530 NM_207629 ABCG1 Extracellular domain 531 NM_207629 ABCG1 Transmembrane domain 532 NM_207629 ABCG1 Intracellular domain 533 NM_207630 ABCG1 Extracellular domain 534 NM_207630 ABCG1 Transmembrane domain 535 NM_207630 ABCG1 Intracellular domain 536 NM_207630 ABCG1 Transmembrane domain 537 NM_207630 ABCG1 Extracellular domain 538 NM_207630 ABCG1 Transmembrane domain 539 NM_207630 ABCG1 Intracellular domain 540 NM_207630 ABCG1 Transmembrane domain 541 NM_207630 ABCG1 Extracellular domain 542 NM_207630 ABCG1 Transmembrane domain 543 NM_207630 ABCG1 Intracellular domain 544 NM_207630 ABCG1 Transmembrane domain 545 NM_207630 ABCG1 Extracellular domain 546 NM_207630 ABCG1 Transmembrane domain 547 NM_207630 ABCG1 Intracellular domain 548 NM_052961 SLC26A8 Intracellular domain 549 NM_052961 SLC26A8 Transmembrane domain 550 NM_052961 SLC26A8 Extracellular domain 551 NM_052961 SLC26A8 Transmembrane domain 552 NM_052961 SLC26A8 Intracellular domain 553 NM_052961 SLC26A8 Transmembrane domain 554 NM_052961 SLC26A8 Extracellular domain 555 NM_052961 SLC26A8 Transmembrane domain 556 NM_052961 SLC26A8 Intracellular domain 557 NM_052961 SLC26A8 Transmembrane domain 558 NM_052961 SLC26A8 Extracellular domain 559 NM_052961 SLC26A8 Transmembrane domain 560 NM_052961 SLC26A8 Intracellular domain 561 NM_052961 SLC26A8 Transmembrane domain 562 NM_052961 SLC26A8 Extracellular domain 563 NM_052961 SLC26A8 Transmembrane domain 564 NM_052961 SLC26A8 Intracellular domain 565 NM_052961 SLC26A8 Transmembrane domain 566 NM_052961 SLC26A8 Extracellular domain 567 NM_052961 SLC26A8 Transmembrane domain 568 NM_052961 SLC26A8 Intracellular domain 569 NM_052961 SLC26A8 Transmembrane domain 570 NM_052961 SLC26A8 Extracellular domain 571 NM_021082 SLC15A2 Intracellular domain 572 NM_021082 SLC15A2 Transmembrane domain 573 NM_021082 SLC15A2 Extracellular domain 574 NM_021082 SLC15A2 Transmembrane domain 575 NM_021082 SLC15A2 Intracellular domain 576 NM_021082 SLC15A2 Transmembrane domain 577 NM_021082 SLC15A2 Extracellular domain 578 NM_021082 SLC15A2 Transmembrane domain 579 NM_021082 SLC15A2 Intracellular domain 580 NM_021082 SLC15A2 Transmembrane domain 581 NM_021082 SLC15A2 Extracellular domain 582 NM_021082 SLC15A2 Transmembrane domain 583 NM_021082 SLC15A2 Intracellular domain 584 NM_021082 SLC15A2 Transmembrane domain 585 NM_021082 SLC15A2 Extracellular domain 586 NM_021082 SLC15A2 Transmembrane domain 587 NM_021082 SLC15A2 Intracellular domain 588 NM_021082 SLC15A2 Transmembrane domain 589 NM_021082 SLC15A2 Extracellular domain 590 NM_021082 SLC15A2 Transmembrane domain 591 NM_021082 SLC15A2 Intracellular domain 592 NM_021082 SLC15A2 Transmembrane domain 593 NM_021082 SLC15A2 Extracellular domain 594

[0067] TABLE-US-00003 TABLE 1C SEQ ID TARGET Name siRNA_Name KD Target Sequence NO. ABCG1 A150100-ABCG1_v5 NM_004915_idx1797 AGTGGATGTCCTACATCTC 274 A150100-ABCG1_v6 NM_004915_idx500 ATCATGCAGGATGACATGC 274 A150100-ABCG1_v7 NM_004915_idx1481 CTGAACTACTGGTACAGCC 275 A150100-ABCG1_v10 NM_004915_idx872 CAGCTTTACGTCCTGAGTC 276 A150100-ABCG1_v11 NM_004915_idx1067 TCAGACCACAAGAGAGACC 277 A150100-ABCG1_v12 NM_004915_idx1789 GTACCTACAGTGGATGTCC 278 A150100-ABCG1_v8 NM_016818_idx603 TGGTCAAGGAGATACTGAC 279 A150100-ABCG1_v9 NM_016818_idx718 CCCTCCAGTCATGTTCTTC 280 DGKB A150100-DGKB_v1 NM_004080_idx104 TTCCATGGTAATGGTGTGC 202 A150100-DGKB_v2 NM_004080_idx1064 CCTGAATGTGACTGTGGAC 209 A150100-DGKB_v3 NM_004080_idx2398 CCGAAGCAAGGAATAATCC 203 A150100-DGKB_v10 NM_004080_idx466 TATGTTTCGCCTTTATGAC 204 A150100-DGKB_v11 NM_004080_idx654 GGATTCAAGGAGGAATGAC 205 A150100-DGKB_v12 NM_004080_idx870 CTCCCTCTTGCATCAAGAC 206 A150100-DGKB_v13 NM_004080_idx1387 AAATCCTCGTCAGGTTTAC 207 A150100-DGKB_v14 NM_004080_idx1729 AGTGCCTTACAGTATCATC 208 DUSP11 A150100-DUSP11_v1 NM_003584_idx427 CAGAGGATTTGCCAGAAAC 249 A150100-DUSP11_v2 NM_003584_idx743 TTGGAATTCCAGTGTACCC 250 A150100-DUSP11_v3 NM_003584_idx945 CAGAGACACCATCTCCCTC 251 A150100-DUSP11_v4 NM_003584_idx885 ACCCAGACCCAAAGTTTGC 252 A150100-DUSP11_v5 NM_003584_idx221 AAGGTGGAAAGACTATCTC 253 A150100-DUSP11_v6 NM_003584_idx420 TATAAACCAGAGGATTTGC 254 A150100-DUSP11_v7 NM_003584_idx836 GTATAATCTACATCAGATC 255 A150100-DUSP11_v8 NM_003584_idx933 CCACATGTTTACCAGAGAC 256 DUSP3 A150100-DUSP3_v1 NM_004090_idx425 GCTAGTTATCGCCTACCTC 257 A150100-DUSP3_v2 NM_004090_idx300 GACACACAGGAGTTCAACC 258 A150100-DUSP3_v3 NM_004090_idx176 GCTGCAGAAACTAGGCATC 259 A150100-DUSP3_v4 NM_004090_idx248 TGCCAACTTCTACAAGGAC 260 A150100-DUSP3_v5 NM_004090_idx299 CGACACACAGGAGTTCAAC 261 A150100-DUSP3_v6 NM_004090_idx458 GATGGACGTCAAGTCTGCC 262 A150100-DUSP3_v7 NM_004090_idx4305 ACAGGAGTTCAACCTCAGC 263 ELA1 A150100-ELA1_v1 NM_001971_idx754 TAATGTCATCGCCTCCAAC 233 A150100-ELA1_v2 NM_001971_idx162 AGAACTGGGTGATGACAGC 234 A150100-ELA1_v3 NM_001971_idx421 CAACAGTCCCTGCTACATC 235 A150100-ELA1_v4 NM_001971_idx280 GATCGTGGTGCATCCATAC 236 A150100-ELA1_v5 NM_001971_idx230 GCGTGGATTACCAGAAGAC 237 A150100-ELA1_v6 NM_001971_idx459 TAACAACAGTCCCTGCTAC 238 A150100-ELA1_v7 NM_001971_idx669 CCATTGCTTGGTGAATGGC 239 A150100-ELA1_v8 NM_001971_idx692 ATTCTCTCCATGGAGTGAC 240 FZD1 A150100-FZD1_v10 NM_003505_idx1323 GGTGTATGGGCTCATGTAC 226 A150100-FZD1_v11 NM_003505_idx2058 CATCGTCATCGCCTGCTAC 227 A150100-FZD1_v9 NM_003505_idx2007 GCTCATGGTGCGCATTGGC 228 A150100-FZD1_v12 NM_003505_idx2229 GTACCTTATGACGCTGATC 229 A150100-FZD1_v13 NM_003505_idx3317 ACCTGGTATGGGTTTGGCC 230 A150100-FZD1_v14 NM_003505_idx3883 ARTGTGTGCAGGTCTACTGC 231 A150100-FZD1_v15 NM_003505_idx2704 TTATTTAGGGCGGTTTAAC 232 GGTLA4 A150100-GGT1_v8 NM_080839_idx451 ACTGGCCATCATCTACAAC 294 A150100-GGTLA4_v5 NM_080920_idx292 TGCTCACCTGTCTGTGGTC 295 A150100-GGTLA4_v6 NM_080920_idx702 ACATTGACCAGGAAGTGAC 296 A150100-GGTLA4_v7 NM_080920_idx411 TGGATGACTTCAGCTCTAC 297 A150100-GGT1_v10 NM_278311_idx629 CTACAACCTCTGGTTCGGC 298 A150100-GGT1_v11 NM_178311_idx707 CACGACAGTGGAGAGAAAC 299 A150100-GGTLA4_v8 NM_178311_idx287 GTTCTACATGCCGGATGAC 300 GPR103 A150100-GPR103_v5 NM_AF411117_idx611 AGGCACCAGGGACTTGTGC 218 A150100-GPR103_v6 NM_AF411117_idx820 GATCTACACCACCTTCATC 219 A150100-GPR103_v7 NM_AF411117_idx288 TGGTGTTCTACGTGGTGAC 220 A150100-GPR103_v8 NM_AF411117_idx136 TGTTAGGCGCCTGCATTGC 221 A150100-GPR103_v10 NM_AF411117_idx424 CAACATCTTTATCTGCTCC 222 A150100-GPR103_v11 NM_AF411117_idx662 CGAAGGGCTTTCACAATGC 223 A150100-GPR103_v12 NM_AF411117_idx106 GTACTACGTTGTAGCCCAC 224 A150100-GPR103_v9 NM_AF411117_idx186 TGCAGGCGCTTAACATTAC 225 ICK A150100-ICK_v1 NM_016513_idx870 GACTGACTGGCCTGAAGGC 210 A150100-ICK_v2 NM_016513_idx1665 GCAGCACTATTTGAAGCAC 211 A150100-ICK_v3 NM_016513_idx588 GCCTGAGAACCTCCTCTGC 212 A150100-ICK_v10 NM_016513_idx1027 ACAGCTAGTCAGGCACTTC 213 A150100-ICK_v11 NM_016513_idx1707 TATAAGAAATGGCATACTC 214 A150100-ICK_v12 NM_016513_idx1754 CTAATCCATGGTCTAGTTC 215 A150100-ICK_v8 NM_016513_idx504 GTCTGCTATAAGGAATATC 216 A150100-ICK_v9 NM_016513_idx713 AAGTACTCCTGAGGTCTAC 217 JAK1 A150100-JAK1_v1 oKD271 TTGGCATGGAACCAACGAC 264 A150100-JAK1_v2 oKD270 CCTCTTTGCCCTGTATGAC 265 A150100-JAK1_v7 oKD272 AGATTCCAGATGCAACCCC 266 A150100-JAK1_v7 SK185_idx1743 CATGAGCCAGCTGAGTTTC 267 A150100-JAK1_v9 SK185_idx142 GTGGAAGTGATCTTCTATC 268 A150100-JAK1_v12 NM_002227_idx1351 TGGCTGTCATGGTCCAATC 269 A150100-JAK1_v13 NM_002227_idx2512 CCGCTGCATGAACTATGAC 270 A150100-JAK1_v14 NM_002227_idx3093 TTGGAGACTTCGGTTTAAC 271 A150100-JAK1_v15 NM_002227_idx3269 RTGTGATTCAGATTCTAGTC 272 PDE1A A150100-PDE1A_v5 NM_005019_idx913 GAAGCTGAATTAGGGCTTC 302 A150100-PDE1A_v7 NM_005019_idx1709 CTGGTGGACATCATTCAGC 303 A150100-PDE1A_v10 NM_005019_idx1413 TTTGTGATCGGAAGTCAAC 304 A150100-PDE1A_v11 NM_005019_idx1601 ATTGCTGATGCACTAAGAC 305 A150100-PDE1A_v12 NM_005019_idx754 CAGATATGATCTTATCAAC 306 A150100-PDE1A_v13 NM_005019_idx887 ACTGTGCATTACATAATGC 307 A150100-PDE1A_v9 NM_005019_idx1073 CACGTGAGTGCAGCTTATC 308 SLC15A2 A150100-SLC15A2_v1 NM_021082_idx457 AGTCCTATCATTGATCGGC 309 A150100-SLC15A2_v2 NM_021082_idx121 GAAGCCATCTCCGACAATC 310 A150100-SLC15A2_v3 NM_021082_idx1166 ATGGCTGTTGGTATGATCC 311 A150100-SLC15A2_v4 NM_021082_idx1575 CCGTGAGGTTTGTTAACAC 312 A150100-SLC15A2_v5 NM_021082_idx423 TTGGGTGCCTTACCAATAC 313 A150100-SLC15A2_v6 NM_021082_idx1136 CTCCAAGTGTGGAATTAAC 314 A150100-SLC15A2_v7 NM_021082_idx1534 GCATGATGGTAAAGGATAC 315 SLC26A8 A150100-SLC26A8_v10 NM_052961_idx1925 TTCTGCAACTGTGATGATC 281 A150100-SLC26A8_v11 NM_052961_idx2288 GTACACTACGTGGATTCAC 282 A150100-SLC26A8_v2 NM_052961_idx923 GCGAATTCCACCAGCATTC 283 A150100-SLC26A8_v3 NM_052961_idx1761 TCTTCCAGTGCTGCAGCTC 284 A150100-SLC26A8_v4 NM_052961_idx2693 TCAGAACAAGAGGCTGGGC 285 A150100-SLC26A8_v5 NM_052961_idx1228 GAAGATTGCCAGTCTTCAC 286 A150100-SLC26A8_v6 NM_052961_idx457 GATTCCTCCTCTCAACATC 287 A150100-SLC26A8_v7 NM_052961_idx936 GCATTCTAGTATTTCTAAC 288 A150100-SLC26A8_v8 NM_052961_idx1249 TTACAGTGTCAATTCCAAC 289 A150100-SLC26A8_v9 NM_052961_idx1723 TGATTATCGGGAGATCATC 290 A150100-SLC26A8_v12 NM_052961_idx338 GAATGGATGTGTATGTATC 291 A150100-SLC26A8_v13 NM_052961_idx1105 TGACATGATTCCTTATAGC 292 A150100-SLC26A8_v14 NM_052961_idx1446 TCTACACACTGCCAAATGC 293 USP9Y A1500100-USP9Y_v1 NM_004654_idx5651 ATGAACTCTGTGATCCAGC 241 A1500100-USP9Y_v2 NM_004654_idx1600 AGGTTGGCTAGTGGATCTC 242 A1500100-USP9Y_v3 NM_004654_idx2636 AAGTGGGTAATTCCTGCTC 243 A1500100-USP9Y_v4 NM_004654_idx1189 CGAATGGCAGAATGGATAC 244 A1500100-USP9Y_v5 NM_004654_idx7911 TCTGGCAGGTTGCATATTC 245 A1500100-USP9Y_v4 NM_004654_idx1489 CTGCAAGTTTCATATCTAC 246 A1500100-USP9Y_v5 NM_004654_idx2820 ATAGCATCAGATTGTATGC 247 A1500100-USP9Y_v6 NM_004654_idx5731 TTTACACGATGATATGTTC 248

[0068] The present invention relates to a method for assaying for compounds that induce anabolic stimulation of chondrocytes, comprising contacting the compound with a polypeptide comprising an amino acid sequence of the polypeptides of SEQ ID NO: 101-128 ("TARGETS") or a functional 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. One preferred 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 that induces anabolic stimulation of chondrocytes, the method comprising further: [0070] (a) contacting a population of chondrocyte cells with one or more of said compound that exhibits binding affinity for said TARGETS, and [0071] (b) measuring a compound-polypeptide property related to the anabolic stimulation of chondrocytes.

[0072] The compound-polypeptide property referred to above is related to the anabolic stimulation of chondrocytes, and is a measurable phenomenon chosen by the person of ordinary skill in the art. The measurable property may e.g. be the binding affinity for a peptide domain of the polypeptide TARGET or the level of any one of a number of biochemical marker levels of increased chondrocyte anabolism. Anabolic stimulation of chondrocytes can e.g. be measured by measuring the level of proteins and other molecules that are induced during the differentiation process, such as key components of normal cartilage. In particular, the induction of the major protein component of cartilage, collagen II, is measured.

[0073] In addition, compound-polypeptide properties related to the anabolic stimulation of chondrocytes are measured in C20/A4; T/C-28a2; T/C-28a4; C-28/12; Ch-4,8,N; Ch-8-OA; TC6; MCT;MC615; IRC; RCS2; Hig82; and D1 ORL UVA (D1) cells. However, such porterties are also measured in non-chondrocyte cell systems. For example, in situ binding assays that determine the affinity of compounds to bind to polypeptides of the invention are performed using any cell type that expresses the polypeptide. Expression of the polypeptide is exogenous or endogenous. Furthermore, when the compound-polypeptide property is activation of a biological pathway, any cell that contains the pathway cellular components is used to measure the compound-polypeptide property. For example, induction of col2.alpha.1 or aggrecan in chondrocytes is indicative of anabolic stimulation of chondrocytes. Specifically, non-chondrocyte cells can be engineered to contain a reporter molecule activated by the col2.alpha.1 or aggrecan promoters. In this way a non-chondrocyte can be used to measure a property indicative of anabolic stimulation of chondrocytes.

[0074] The invention relates to a method for identifying a compound that induces and/or increases anabolic stimulation of chondrocytes, said method comprising the steps of: culturing a population of cells expressing a polypeptide of any one of those listed in Table 1A, or a functional fragment or derivative thereof; determining a first level of chondrogenic differentiation in said population of cells; exposing said population of cells to a compound, or a mixture of compounds; determining the level of chondrogenic differentiation in said population of cells during or after exposure of said population of cells to the compound, or the mixture of compounds; and identifying the compound that induces and/or increases chondrogenic differentiation.

[0075] The invention also relates to a method for identifying a compound that decreases the expression and/or activity of any one of the polypeptides listed in Table 1A, said method comprising the steps of: culturing a population of cells expressing said polypeptide, or a fragment, or a derivative thereof; determining a first level of expression and/or activity of said polypeptide; exposing said population of cells to a compound, or a mixture of compounds; determining the level of expression and/or activity of said polypeptide during or after exposure of said population of cells to the compound, or the mixture of compounds; and identifying the compound that decreases the expression and/or activity of said polypeptide. If the polypeptide activity is not readily measurable, the identification of the compound may benefit from an extra step comprising exposing said population of cells to an agonist of said polypeptide. Furthermore, the methods of the present invention may comprise the step of introducing a gene encoding any one of the polypeptides listed in Table 1A, in said population of cells. For high-throughput purposes it may be beneficial to have the gene stably integrated in the genome of said cells.

[0076] In a preferred embodiment, the level of chondrocyte (re-)differentiation is determined by measuring the expression level of a marker gene, wherein a preferred marker gene encodes collagen type II, alpha-1 (col2.alpha.1) or aggrecan. For proper anabolic stimulation it is preferred that the expression and/or activity of col2.alpha.1 or aggrecan is increased.

[0077] The present invention provides in one particular embodiment methods for identifying novel compounds, wherein the polypeptide is a GPCR. If so, the expression and/or activity of said GPCR is preferably determined by measuring the level of a second messenger. Preferred second messengers are cyclic AMP, Ca.sup.2+ or both. Typically, the level of the second messenger is determined with a reporter gene under the control of a promoter that is responsive to the second messenger, wherein it is preferred that the promoter is a cyclic AMP-responsive promoter, an NF-KB responsive promoter, or a NF-AT responsive promoter, and wherein the reporter gene is selected from the group consisting of: alkaline phosphatase, GFP, eGFP, dGFP, luciferase and .beta.-galactosidase.

[0078] In another particular embodiment, the invention provides methods for identifying novel compounds, wherein the polypeptide is a kinase or a phosphatase. Preferably, the activity of said kinase or phosphatase is determined by measuring the level of phosphorylation of a substrate of said kinase or phosphatase.

[0079] In yet another particular embodiment, the invention provides methods for identifying novel compounds, wherein the polypeptide is a protease. Preferably, the activity of said protease is measured by determining the level of cleavage of a substrate of said protease.

[0080] Methods for determining second messenger levels, use of the reporter genes and second-messenger responsive promoters as well as phosphatase assays and protease assays are well known in the art and not further elaborated upon herein.

[0081] In a preferred embodiment, the compound that inhibits the polypeptide exhibits a binding affinity to the polypeptide of at most 10 micromolar.

[0082] In a preferred embodiment of the invention, the polypeptide TARGET comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594 (Tables 1A and 1B). In an especially preferred embodiment of the invention, the polypeptide TARGET comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 (Table 1A).

[0083] 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 polypeptide to thereby induce the anabolic stimulation of chondrocytes. For example, an assay designed to determine the binding affinity of a compound to the polypeptide, or fragment thereof, may be necessary, but not sufficient, to ascertain whether the test compound would be useful for increasing mean cartilage thickness 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 up the biochemical pathway, such as cartilage component synthesis, assayed by measuring the amount of collagen II. Such second assay may be designed to confirm that the test compound, having binding affinity for the polypeptide, actually induces the anabolic stimulation of chondrocytes. Suitable controls should always be in place to insure against false positive readings.

[0084] 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 polypeptide. Alternatively, one may screen a set of compounds identified as having binding affinity for a polypeptide domain, or a class of compounds identified as being an inhibitor of the polypeptide. However, for the present assay to be meaningful to the ultimate use of the drug candidate compounds, a measurement of collagen II levels or aggrecan is necessary. 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.

[0085] The binding affinity of the compound with the polypeptide TARGET 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.RTM.) 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 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.

[0086] The present assay method may also be practiced in a cellular assay, A host cell expressing 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 using host cells that over-express 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 such cellular assay, the biological activity of TARGET may be measured by following the production of cartilage component synthesis.

[0087] The present invention further relates to a method for identifying a compound that induces anabolic stimulation of chondrocytes, comprising: [0088] (a) contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594; [0089] (b) determining the binding affinity of the compound to the polypeptide; [0090] (c) contacting a population of mammalian cells expressing said polypeptide with the compound that exhibits a binding affinity of at least 10 micromolar; and [0091] (d) identifying the compound that induces the synthesis of proteins that are a constituent of normal cartilage and/or that are required for the formation of cartilage.

[0092] For high-throughput purposes, libraries of compounds may be used such as antibody fragment libraries, peptide phage display libraries, peptide libraries (e.g. LOPAP.TM., Sigma Aldrich), lipid libraries (BioMol), synthetic compound libraries (e.g. LOPAC.TM., Sigma Aldrich) or natural compound libraries (Specs, TimTec).

[0093] 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.

[0094] Another preferred class of drug candidate compounds is an antibody. The present invention also provides antibodies directed against a TARGET. These antibodies may be endogenously produced to bind to the TARGET within the cell, or added to the tissue to bind to 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.

[0095] 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.

[0096] 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.

[0097] 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.

[0098] 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).

[0099] Techniques known in the art for the production of single chain antibodies can be adapted to produce single chain antibodies to the TARGET polypeptides and proteins of the present invention. 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.

[0100] 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 same or different TARGET.

[0101] 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.

[0102] According to another preferred embodiment, the assay method uses a drug candidate compound identified as having a binding affinity for a TARGET, and/or has already been identified as having down-regulating activity such as antagonist activity vis-a-vis one or more TARGET.

[0103] The present invention further relates to a method for inducing anabolic stimulation of chondrocytes comprising contacting said cells with an expression inhibitory agent comprising a polynucleotide sequence that complements at least about 17 nucleotides of the polyribonucleotide comprising a nucleotide sequence selected from the group consisting of SEQ ID NO: 1-28. In a preferred embodiment the expression-inhibitory agent comprises a polynucleotide sequence that complements a nucleotide sequence selected from the group consisting of SEQ ID NO: 202-315.

[0104] Another aspect of the present invention relates to a method for inducing the anabolic stimulation of chondrocytes, comprising by contacting said cell with an expression-inhibiting agent that inhibits the translation in the cell of a polyribonucleotide encoding a TARGET polypeptide. 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 TARGET mRNA, and thereby down-regulate or block the expression of TARGET polypeptide. 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 an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128. In a preferred embodiment the expression-inhibiting agent is complementary to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 1-28. In an especially preferred embodiment the expression-inhibiting agent is complementary to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 202-315.

[0105] 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: 101-128, a small interfering RNA (siRNA, preferably shRNA,) that is sufficiently complementary to a portion of the polyribonucleotide coding for SEQ ID NO: 101-128, 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: 1-28. In an especially preferred embodiment the expression-inhibiting agent is complementary to a polynucleotide sequence selected from the group consisting of SEQ ID NO: 202-315.

[0106] A special embodiment of the present invention relates to a method wherein the expression-inhibiting agent is a nucleic acid expressing the antisense RNA, antisense oligodeoxynucleotide (ODN), a ribozyme that cleaves the polyribonucleotide coding for SEQ ID NO: 101-128, a small interfering RNA (siRNA, preferably shRNA,) that is sufficiently complementary to a portion of the polyribonucleotide coding for SEQ ID NO: 101-128, such that the siRNA, preferably shRNA, interferes with the translation of the TARGET polyribonucleotide to the TARGET polypeptide. Preferably the nucleotide sequence is complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 1-28. In an especially preferred embodiment nucleotide sequence is complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 202-315.

[0107] 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 a TARGET polypeptide or the corresponding messenger RNA. In addition, antisense nucleic acids may be designed which decrease expression of the nucleic acid sequence capable of encoding a TARGET polypeptide 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 a TARGET. 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.

[0108] One embodiment of expression-inhibitory agent is a nucleic acid that is antisense to a nucleic acid comprising SEQ ID NO: 1-28. 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 nucleic acids comprising SEQ ID NO: 1-28. Antisense oligonucleotides preferably comprise a sequence containing from about 17 to about 100 nucleotides and more preferably the antisense oligonucleotides comprise from about 18 to about 30 nucleotides. 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: 1-28.

[0109] 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 RN202-315NA duplex activates the endogenous enzyme ribonuclease (RNase) H, which cleaves the mRNA component of the hybrid molecule.

[0110] 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.

[0111] Another type of expression-inhibitory agent that reduces the levels of 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.

[0112] 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).

[0113] 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.

[0114] 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).

[0115] 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 17-25 nucleotides complementary or homologous to a contiguous 17-25 nucleotide sequence selected from the group of sequences described in SEQ ID NO: 1-28, preferably from the group of sequences described in SEQ ID No: 202-315, and an antisense strand of 17-23 nucleotides complementary to the sense strand. Exemplary sequences are described as sequences complementary to SEQ ID NO: 202-315. 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.

[0116] 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 8 nucleotides long. In a most preferred embodiment the linker sequence is UUGCUAUA (SEQ ID NO: 201). Self-complementary single stranded siRNAs form hairpin loops and are more stable than ordinary dsRNA. In addition, they are more easily produced from vectors.

[0117] 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, WO2004094636, published Nov. 4, 2004, and UA20030198627, are hereby incorporated by reference).

[0118] The present invention also relates to compositions, and methods using said compositions, comprising a DNA expression vector capable of expressing a polynucleotide capable of inducing anabolic stimulation of chondrocytes and described hereinabove as an expression inhibition agent.

[0119] A special aspect of these compositions and methods relates to the down-regulation or blocking of the expression of a TARGET polypeptide by the induced expression of a polynucleotide encoding an intracellular binding protein that is capable of selectively interacting with the TARGET polypeptide. 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 the TARGET polypeptide of SEQ ID NO: 101-128 and 401-594. More preferably, the intracellular binding protein is a single chain antibody.

[0120] A special 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 SEQ ID NO: 101-128, and a small interfering RNA (siRNA) that is sufficiently homologous to a portion of the polyribonucleotide coding for SEQ ID NO: 101-128, such that the siRNA interferes with the translation of the TARGET polyribonucleotide to the TARGET polypeptide, The polynucleotide expressing the expression-inhibiting agent is preferably 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 sendaviral vector systems, and all may be used to introduce and express polynucleotide sequence for the expression-inhibiting agents in TARGET cells.

[0121] Preferably, 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.

[0122] 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 Published Patent Applications 20030180258 and 20040071660, hereby incorporated by reference.

[0123] 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.

[0124] 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.

[0125] 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.

[0126] 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.

[0127] 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.sub.r, P.sub.l, 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).

[0128] 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.

[0129] 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 (Felgner, 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 (Felgner 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).

[0130] 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 (Curiel, et al. (1992) Hum. Gene Ther. 3:147-54; Wu and Wu, (1987) J. Biol. Chem. 262:4429-32).

[0131] The present invention also provides biologically compatible, cartilage formation-enhancing compositions comprising an effective amount of one or more compounds identified as TARGET inhibitors, and/or the expression-inhibiting agents as described hereinabove.

[0132] 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 a TARGET; a vector would be able to transfect a TARGET cell and expression the antisense, antibody, ribozyme or siRNA as described hereinabove; an antibody would bind a TARGET polypeptide domain.

[0133] A preferred 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, intraarterial 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.

[0134] A particularly preferred embodiment of the present composition invention is a cartilage formation-enhancing 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 condition a systemic or local decrease in mean cartilage thickness, or a susceptibility to the condition, comprising an effective cartilage formation-enhancing amount of a TARGET antagonist or inverse agonist, its pharmaceutically acceptable salts, hydrates, solvates, or prodrugs thereof in admixture with a pharmaceutically acceptable carrier.

[0135] 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.

[0136] 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.

[0137] 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.

[0138] 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.

[0139] 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.

[0140] 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.

[0141] 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.TM.. (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.degree. 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.

[0142] 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 is 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.

[0143] 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.

[0144] 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.

[0145] 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.

[0146] 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 10.sup.4 and about 10.sup.14 pfu. In the case of AAVs and adenoviruses, doses of from about 10.sup.6 to about 10.sup.11 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.

[0147] The present invention also provides methods of enhancing cartilage formation, which comprise the administration to said subject a therapeutically effective amount of an expression-inhibiting agent of the invention. A further aspect of the invention relates to a method of treating or preventing a disease involving chondrocyte anabolic stimulation, comprising administering to said subject a cartilage formation-enhancing pharmaceutical composition as described herein.

[0148] Examples of diseases involving anabolic stimulation of chondrocytes that are treatable using the means and methods of the present invention include, but are not limited to osteoarthritis, rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, endemic forms of arthritis like osteoarthritis deformans endemica, Mseleni disease, and Handigodu disease; degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, and ankylosing spondylitis. Furthermore, people suffering from congenital cartilage malformations, including hereditary chondrolysis, chondrodysplasias and pseudoachondrodysplasias, are likely to benefit from programs that result in anabolic stimulation of chondrocytes, and these diseases therefore may also be treated by using the methods and means of the present invention. Non-limiting examples of congenital cartilage malformation related diseases are microtia, anotia, and metaphyseal chondrodysplasia.

[0149] The polypeptides or the polynucleotides employed in the methods of the present invention 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.35S-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.

[0150] 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.

[0151] Another embodiment of the present invention relates to a method for in vitro production of cartilage tissue, comprising the steps of contacting chondrocyte cells with a polynucleotide sequence comprising a sequence selected from the group consisting of sequences complementary to SEQ ID No: 1-28, preferably selected from the group consisting of sequences complementary to SEQ ID NO: 202-315 for a time sufficient to re-differentiate the chondrocytes thereby producing a cartilaginous matrix.

[0152] In a preferred embodiment, the method comprises the steps of: [0153] (a) applying chondrocyte cells on a substrate to form a cellular substrate, [0154] (b) introducing a polynucleotide comprising a nucleotide sequence selected from the group consisting of sequences complementary to SEQ ID No: 1-28, preferably selected from the group consisting of sequences complementary to SEQ ID NO: 202-315, for a time sufficient to re-differentiate the chondrocyte cells, thereby producing a cartilaginous matrix.

[0155] The invention thus provides a method for producing a substrate with a matrix grown thereon, which matrix may be used for the provision of load-bearing implants, including joint prostheses, such as artificial knee joints and finger joints, and maxillofacial implants. It can also be used for special surgery devices, such as spacers, or cartilage fillers, and for use in augmentation, obliteration or reconstitution of cartilage defects and damaged or lost cartilage.

[0156] The present invention also relates to a combination of a load-bearing implant (preferably coated with a matrix as described above) with a cartilage filler comprising a matrix as described.

[0157] The method of the invention is also very suitable in relation to revision surgery, i.e., when previous surgical devices require replacement.

[0158] Suitable cells are stem cells cells, including mesenchymal stem cells cells and in particular chondrosyte precursor cells. The mesenchymal stem cells, and especially the chondrosyte precursor cells are found to be very effective in the cartilage producing process when taken from their original environment. In addition, cells derived from cartilage biopsies of a subject may be cultured and utilized with the present invention.

[0159] The mesenchymal stem cells can be directly applied on the substrate or they can advantageously be multiplied in the absence of the substrate before being applied on the substrate. In the latter mode, the cells are still largely multipotent after multiplication and, for the purpose of the invention, they are still referred to as undifferentiated. Subsequently, the cells are allowed to differentiate. Differentiation can be induced or enhanced by the presence of suitable inductors, such as bone morphogenic proteins (BMP2; BM4; BMP7), transforming growth factor beta (TGFbeta), CDMP1 and CDMP2. Especially suitable inductors of differentiation are the expression inhibitory agents of the present invention.

[0160] The use of mesenchymal stem cells provides several advantages. Firstly, their lower differentiation implies a higher proliferation rate and allows the eventual functionality to be better directed and controlled. Moreover, culturing these cells not only produces the required cartilage matrix containing organic and inorganic components, but also results in the presence, in the culture medium and in the matrix, of several factors which are essential for growth of the tissue and for adaptation to existing living tissue. Also, the culture medium can be a source of active factors such as growth factors, to be used in connection with the implanting process. Furthermore, such undifferentiated cells are often available in large quantities and more conveniently than e.g., mature cartilage cells, and exhibit a lower morbidity during recovery. Moreover, the undifferentiated cells can be obtained from the patient for whom the implant is intended. The cartilage resulting from these cells is autologous to the patient and thus no immune response will be induced. Matrices as thick as 100 .mu.m can be produced as a result of the use of undifferentiated cells.

[0161] The substrate on which the undifferentiated cells can be applied and cultured can be a metal, such as titanium, cobalt/chromium alloy or stainless steel, a bioactive surface such as a calcium phosphate, polymer surfaces such as polyethylene, and the like. Although less preferred, siliceous material such as glass ceramics, can also be used as a substrate. Most preferred are metals, such as titanium, and calcium phosphates, even though calcium phosphate is not an indispensable component of the substrate. The substrate may be porous or non-porous. The cells can be applied at a rate of e.g., 10.sup.3-10.sup.6 per cm.sup.2, in particular 10.sup.4-2.times.10.sup.5 cells per cm.sup.2.

[0162] The culture medium to be used in the method according to the invention can be a commonly known culture medium such as MEM (minimum essential medium). Advantageously, the medium can be a conditioned medium. In this context, a conditioned medium is understood to be a medium wherein similar cells have previously been incubated, causing the medium to contain factors such as polypeptides, secreted by the cells which are important for cell growth and cell differentiation.

[0163] The cells are cultured for a time sufficient to produce a matrix layer, e.g., a matrix layer having a thickness of at least 0.5 .mu.m, in particular from 1 up to 100 .mu.m, more in particular of 10-50 .mu.m. The cells may be contacted with the culture medium for e.g. 2-15 weeks, in particular 4-10 weeks.

[0164] The production of the matrix, when applied on a substrate, results in a continuous or quasi-continuous coating covering the substrate for at least 50%, in particular at least 80% of its surface area.

[0165] In yet another aspect of the invention, the invention provides a method for diagnosing a pathological condition involving chondrocyte de-differentiation, said method comprising the steps of: determining the nucleic acid sequence of any one of the genes encoding the polypeptides listed in Table 1A in a genomic DNA sample; comparing the sequence from step (a) with the nucleic acid sequence of a healthy subject; and identifying any difference(s) related to the pathological condition. Such differences may be further checked in in vitro assays applying similar marker genes as disclosed herein. Such assays will reveal the role of the gene or its encoded polypeptide in anabolic stimulation processes of chondrocytes. If such mutations are identified this knowledge can be further exploited in test-kits for diagnosis of similar diseases.

[0166] Still another aspect or the invention relates to a method for diagnosing a pathological condition involving chondrocyte anabolic stimulation or a susceptibility to the condition in a subject, comprising determining the amount of polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 101-128 and 401-594 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. Clearly, the activity and/or expression levels of the target genes as disclosed herein may have an effect on anabolic stimulation of chondrocytes. It remains to be determined to what level the activity should be elevated to diagnose for the disease. However, by comparing levels found in patients, individuals without symptoms and clearly healthy individuals the skilled person may easily determine these relevant levels. Since the skilled person is now aware which polypeptides should be monitored, the present invention provides novel tools for test assays for such diagnostics. A prominent disease that may be controlled, checked and diagnosed by using the knowledge provided by the present invention is osteoarthritis.

[0167] The rate of chondrocyte anabolic stimulation can typically be measured by determining the deposition of cartilage, or cartilage components, or cartilage-containing extra-cellular matrix produced by the chondrocytes, in the medium. A cell-based ELISA, enzymatic assays, or other general techniques known in the art can be used to measure cartilage components, like the ones described in Walsh G., Proteins: Biotechnology and Biochemistry. John Wiley and Sons, 2001.

[0168] The invention is further illustrated in the following figures and examples.

EXAMPLES

Example 1

Development of a High-Throughput Screening Method for the Detection of Endogenous Collagen Type II, Alpha-1 (col2.alpha.1)

Principle of the Assay:

[0169] Normal human articular chondrocytes (NHAC's) that are grown in two-dimensional cultures become dedifferentiated and gradually cease to synthesize cartilage. They can be re-differentiated into anabolic, active chondrocytes in the presence of appropriate factors (e.g. BMP2). An assay to screen for such factors was developed by monitoring the levels of collagen type II, alpha-1 (col2.alpha.1), a major constituent of normal cartilage. NHAC's are seeded in 384 well plates and 1 day after plating infected with individual siRNA adenoviruses (Ad-siRNA) from the SilenceSelect collection (see WO03/020931). Col2.alpha.1 deposition is determined at 14 days after the start of the infection (14 dpi).

Control Viruses

Ad-BMP2; described in WO 03/018799

BMP4; Ad5 dE1/E2A adenoviruses that mediate the expression of full length bone morphogenetic protein 4 pre-protein (see NP.sub.--570912).

Ad-LacZ; referred to as pIPspAdApt6-lacZ in WO 02/070744

Ad-eGFP; referred to as pIPspAdApt6-eGFP in WO 02/070744

Ad-Empty; described in WO 02/070744

Development of the Assay

[0170] NHAC's were isolated from donors who died from unrelated causes, and were obtained after informed consent (Cambrex, Verviers, Belgium).

[0171] In a series of experiments, carried out in 384-well plates, several parameters are optimized: cell seeding density, multiplicities of infection (MOI) of control viruses (Ad-BMP2 or Ad-eGFP), duration of infection, toxicity, infection efficiency (using Ad-eGFP) and the day of readout.

[0172] Using Ad-BMP2 (BMP2 over-expression) as a positive control for assay development, the following protocol resulted in the highest dynamic range for the assay with the lowest standard deviation on the background signal:

[0173] NHAC's are seeded on day 0 at 1500 cells/well of a 384-well plate in 60 .mu.l of DMEM/F12 (InVitrogen), containing 10% heat-inactivated fetal calf serum (FBS-HI) and Pen/Strep) and infected the next day with 2.5 .mu.l of Ad-control-virus (Ad-BMP2 or Ad-eGFP; this corresponds to an assumed MOI of 2000). After 7 days, 10 .mu.l of a 50 .mu.g/ml 2-Phospho-L-ascorbic acid in assay culture medium is added to each well. Up-regulation of Col2a1 is read at 10 dpi: The medium is removed with a VacuSafe; 50 .mu.l ice-cold MeOH is added with a multidrop and removed immediately with a VacuSafe; 80 .mu.l of ice-cold MeOH is added with a multidrop to fixate the cells, and plates are incubated for 20 min at -20.degree. C.; MeOH is removed with a VacuSafe; plates are air-dried for 20 min, followed by 2.times.washing with 80 .mu.l of phosphate buffered saline (PBS); 75 .mu.l of blocking buffer (0.1% casein in PBS) is added and plates are incubated for at least 2 h at room temperature (RT); blocking buffer is removed; cells are washed with 25 .mu.l of EC buffer (20 mM sodium phosphate, 2 mM EDTA, 400 mM NaCl, 0.2% BSA, 0.05% CHAPS, 0.4% casein, 0.05% NaN3, pH 7) and 35 .mu.l of the primary antibody (Collagen II Ab-2 Neomarkers. Catalogus number MS-235-P) diluted 1/450, 1/225 in buffer C (20 mM sodium phosphate, 2 mM EDTA, 400 mM NaCl, 1% BSA, pH 7)) is added with a multichannel pipette; plates are incubated overnight at 4.degree. C.; primary antibody is removed; cells are washed twice with 80 .mu.l of PBST (0.5% Tween 20 in PBS) and once with 80 .mu.l PBS; 35 .mu.l of the secondary antibody (Goat-anti-mouse Immunoglobulins/HRP. DAKO. Catalogus number P0477; diluted 1/2000 in buffer C) is added with multichannel pipette; plates are incubated at RT for 1 h; secondary antibody is removed and cells are washed twice with 80 .mu.l PBST and once with 80 .mu.l PBS; 50 .mu.l of luminol substrate is added and after 5 minutes read-out is determined on a luminometer.

[0174] After optimization of the assay (see FIG. 1), a 384 well control plate is prepared that contains positive control viruses (BMP2 and BMP4) and neutral viruses (eGFP; lacZ and empty, see FIG. 1). Aliquots of the control plate are prepared and frozen at -20.degree. C. A control plate is thawed and taken along in every screening batch.

Example 2

Screening of 9216 Adenoviral siRNA Vectors in the Chondrogenesis Assay

[0175] The optimized protocol for screening the SilenceSelect library runs as follows: on day 0, propagated human primary chondrocytes are seeded in Greiner white, flat bottom, TC-treated 384 well plates with clear bottom (Catalogue number 781080) in 60 .mu.l medium at a density of 1500 cells per well. One day later, 2.5 .mu.l Ad-siRNA virus from each well of the SilenceSelect.TM. collection (WO 03/020931), stored in 384 well plates (estimated titer of 1.times.10.sup.9 viral particles per ml) is transferred with the aid of a 96/384 channel dispenser (Tecan Freedom 200 equipped with TeMO96, TeMO384 and RoMa, Tecan AG, Switzerland) to individual wells of the 384 well plates containing chondrocytes. The control plate is run under the same conditions as the aliquot plates from the SilenceSelect collection. All Ad-siRNA viruses are screened in duplicate on independent assay plates. After infection, plates are incubated at 37.degree. C. Seven days post infection the medium containing the adenoviruses is replaced by fresh medium. Thirteen days post infection, the amounts of col2.alpha.1 depositions per well is determined with the cELISA method. A typical result of a 384 well screening plate is depicted in FIG. 2.

[0176] The duplicate screen is repeated once. Ad-siRNA viruses are nominated as hits if at least 2 data points of the four tested (two times screened in duplicate) score above threshold. Threshold is set at average plus 2.5 times standard deviation of all data points per plate.

[0177] A total of 282 hits are isolated that scored above the threshold, representing 274 independent genes. A representative example is provided in FIG. 2, in which the "times standard deviation" of duplicate data points are indicated on the X-axis and Y-axis. The threshold (2.5 times standard deviation) is indicated by dotted lines. Negative values indicate data points that scored below average.

[0178] The results for some of the genes are shown in FIG. 3. A clear induction of the collagen II levels is observed upon infection of the Ad-siRNA targeting the indicated gene. The data are represented as relative light units (rlu) correlating to collagen II levels.

Example 3

Propagation of Hits

[0179] The 282 Ad-siRNA hits are subjected to further analysis to establish their therapeutic potential to induce chondrocyte anabolic stimulation. A first step entails a quality control on the Ad-siRNA selected for further analysis (this example). Next steps are the screening of the targets in other assays to validate their role in chondrocyte anabolic stimulation such as the induction of aggrecan, another main constituent of cartilage besides collagen II (Example 4), the ability to induce chondrocyte anabolic stimulation in chondrocytes from other donors (Example 5), the induction of a correct marker profile in three-dimensional chondrocyte cultures (example 11), the presence of posttranslational modifications on aggrecan (example 9) and collagen II (example 10) in three-dimensional chondrocyte cultures, the development of additional Ad-siRNAs targeting the identified transcripts (example 7), and confirmation that the corresponding genes are indeed expressed in residing chondrocytes (example 12).

[0180] To propagate the 282 hits of the chondrogenesis assay, 2.25.times.10.sup.4 PerC6.E2A cells are seeded in 200 .mu.l of DMEM containing 10% non-heat inactivated FCS into each well of a 96 well plate and incubated overnight at 39.degree. C. in a humidified incubator at 10% CO.sub.2. Subsequently, 1 .mu.l of crude lysate from the siRNA adenovirus stocks in matrix tubes is added and incubation proceeds at 34.degree. C. in a humidified incubator at 10% CO.sub.2 for 7 days. All hits are propagated in duplicate on two independent plates. The two lysates are pooled and aliquots are frozen at -20.degree. C.

[0181] The propagated Ad-siRNAs are re-screened at three MOI's in the chondrogenesis assay in duplicate (see Example 1). The Ad-siRNAs have to score at least once above threshold (average+2.5 times standard deviation) to pass this quality control step.

Example 4

Aggrecan Induction

[0182] A second assay to screen for chondrocyte anabolic factors is developed by monitoring the levels of aggrecan, another major constituent of cartilage. In this assay, glycosaminoglycans on aggrecan are stained by Alcian blue. NHACs are seeded in 384 well plates and 1 day after plating infected with individual Ad-siRNA from the SilenceSelect.TM. collection. Aggrecan deposition is determined at 14 days post infection. Using Ad-BMP2 as a positive control, we confirm in a series of experiments that several parameters optimized for the ColII cELISA assay are also applicable for the Alcian blue stain assay for aggrecan. These parameters include cell seeding density, MOIs of control viruses, duration of infection, and the day of readout.

[0183] NHAC's are seeded on day 0 at 1500 cells/well of a 384 well black-plate with clear bottom in 60 .mu.l of DMEM/F12, containing 10% FBS-HI and Pen/Strep and infected the next day with 2.5 .mu.l of Ad-BMP2 or Ad-eGFP; at an MOI of 2000. After 7 days, 10 .mu.l of a 50 .mu.g/ml 2-Phospho-L-ascorbic acid in assay culture medium is added to each well. Up-regulation of aggrecan is read at 10 dpi with Alcian blue staining: The medium is removed with a VacuSafe; 50 .mu.l ice-cold MeOH is added with a multidrop and removed immediately with a VacuSafe; 80 .mu.l of ice-cold MeOH is added with a multidrop to fixate the cells, and plates are incubated for 20 min at -20.degree. C.; MeOH is removed with a VacuSafe; plates are air dried for 20 min. After washing once with 80 .mu.l of PBS; 80 .mu.l of 0.05% Alcian blue stain buffer (0.05% Alcian blue, Sigma, catalog number S-2889; 0.4 M MgCl.sub.2/25 mM sodium acetate, pH5.5) is added and plates are incubated overnight at RT. The next day cells are washed subsequently in 80 .mu.l of 3% acetic acid, 25% ethanol/3% acetic acid, and 50% ethanol/3% acetic acid. Solutions are added with a multidrop and removed with a Vacusafe. After replacing 50% ethanol/3% acetic acid with 70% ethanol/3% acetic acid, each individual well is photographed with a SONY CCD camera, images are analyzed using a Galapagos Alcian blue quantification algorithm based on the separation of the blue signal through a color threshold procedure after a noise reduction filter. The amount of blue staining, which is proportional to aggrecan content, is expressed in pixel unit (see FIG. 4).

[0184] The propagated hits from Example 3 are used to transduce NHAc cells at three MOI's in duplicate in the chondrogenesis assay (see Example 1). The Ad-siRNAs have to score in duplicate in at least one MOI above threshold (average+2.5.times.standard deviation) to pass this secondary assay. In total, 101 out of 282 hits passed the Alcian blue assay for aggrecan (see Table 1). The results for some of the genes are shown in FIG. 5. Values represent the numerical output of the described algorithm and are correlated to Alcian blue staining levels. A clear induction of the aggrecan levels is observed upon infection of the Ad-siRNA targeting the indicated gene. The Ad-siRNA targeting FZD1 does not seem to induce Alcian blue staining. TABLE-US-00004 TABLE 1 Overview of the 101 target sequences and their respective SEQ ID NOS (316-416) corresponding to the genes encoding the different polypeptides involved in chondrogenic differentiation. The GenBank numbers and target gene symbols (general names) are also given. KD Target Hit Gene GenBank Sequence ID KD Target Sequence Symbol Accession Name Class SEQ ID NO H33- ATAAGCGGTTATCACTGCC PCTK2 NM_002592 PCTAIRE proteine kinase 2 Kinase 316 006 K33- GCTGGGATTCCAAGTGGAC RYK SK340- RYK receptor-like tyrosine kinase Kinase 317 007 NM_002958 H33- AACTGTGCAGGGCCTCTCC NRRK1 NM_002529 neurotrophic tyrosine kinase, recep- Kinase 318 008 tor, type 1 H33- GCTGCTGGATGTCATTCAC CDK2 NM_052827- cyclin-dependent kinase 2 Kinase 319 009 NM_001798 H33- AGAGACACAGTGCCCATCC PCK1 NM_002591 phosphoenolpyruvate carboxylase 1 Kinase 320 010 (soluble) H33- ACTGAACCTCCGAAATGCC NEK4 SK256- NIMA (never in mitosis gene a)-rela- Kinase 321 011 NM_003157 ted kinase 4 H33- GTGCTGGAGTGCTTCCATC MAPK NM_004635 mitogen-activated protein kinase- Kinase 322 013 APK3 activated protein kinase 3 H33- TTCAGACCTACCTTCAGTC UMP- NM_016308 UMP-CMP kinase Kinase 323 020 CMPK H33- CCTGAATGTGACTGTGGAC DGKB- NM_020238- diacylglycerol kinase, beta 90 kDa/ Kinase 324 025 INCENP NM_004080- inner centromere protein antigens NM_145695 135/155 kDa H33- GAGTCACACAGAGATGAGC ROCK1 NM_005406 Rho-associated, coiled-coil contain- Kinase 325 027 ing protein kinase 1 H33- CGATGTGCCTTCAAGATTC PRKCN SK489- protein kinase C, nu Kinase 326 028 NM_005813 H33- CAGTGGTTTGGGAATCTGC PLK4- SK341- serine/threonine kinase 18 (STK18)/ Kinase 327 031 STK18 NM_014264 polo-like kinase-4 (Drosophila) H33- GACTGACTGGCCTGAAGGC ICK NM_016513- intenstinal cell (MAK-like) kinase Kinase 328 032 NM_014920 H33- GATCTACACCACCTTCATC GPR103 AF11117- G protein-coupled receptor 103 GPCR 329 034 NM_198179 H33- GTGACTACACAAGGACTCC CCR2 NM_000647 chemokine (C-C motif) receptor 2 PGCR 330 036 H33- GACTGATTCGCTCTTTGCC FPRL2 NM_002030 formyl peptide receptor-like 2 GPCR 331 040 H33- GGTGTATGGGCTCATGTAC FZD1 NM_003505 frizzled homolog 1 (Drosophila) GPCR 332 041 H33- AGTGCAGCCTTGTGGGTTC P2RY10 NM_198333- purinergic receptor P2Y, G-protein GPCR 333 042 NM_014499 coupled 10 H33- TAACACTCACTGCACCTGC EMR3 NM_152939- egf-like module containing, mucin- GPCR 334 044 NM_032571 like, hormone receptor-like 3 H33- TAACTGAAACTCAGCTAGC PROZ NM_003891 protein Z, vitamin K-dependent plasma Protease 335 049 glycoprotein H33- ACTGAAGTAGCCCTCCTTC THRB NM_000461 thyroid hormone receptor, beta (ery- NHR 336 054 throblastic leukemia viral (verb-a) oncogene homolog 2, avian) H33- AGAACTGGGTGATGACAGC ELA1 NM_001971 elastase 1, pancreatic Protease 337 056 H33- AGTGCAGTACAGCGATGAC COL7A1 NM_000094 collagen, type VII, alpha 1 Not 338 058 (epidermolysis bullosa, dystrophic, classified dominant and recessive) H33- TTCACATCGCTGAGCACCC CPA NM_003652 carboxypeptidase Z Protease 339 059 H33- ATGAACTCTGTGATCCAGC USP9Y NM_004654 ubiquitin specific protease 9, Y- Protease 340 061 linked (fat facets-like, Drosophila) H33- AGCCAGCAACGACATGTAC CST3 NM_000099 cystatin C (amyloid angiopathy and Not 341 063 cerebral hemorrhage) classified H33- GCTGCTGGGCATGTCCTTC LNPEP NM_005575 leucyl/cystinyl aminopeptidase Protease 342 065 H33- TGTGATCGTCATCACAGTC NLGN1 NM_014932 neuroligin 1 Enzyme 343 066 H33- AACATGATATGTGCTGGAC KLK10 NM_145888- kallikrein 10 Protease 344 068 NM_002776 H33- CTGAGAAGGCTTCCACTGC LOC11 XM_061692 similar to glutamyl aminopeptidase Protease 345 069 9795 (aminopeptidase A); gp160 H33- TGATACGTGGATCCAGGCC LOC12 NM_178453 similar to distal intestinal serine Protease 346 070 4221- protease MGC52 282 H33- CTACAGTGACAAGGCTAAC OVTN- XM_089945- (similar to) oviductin protease Protease 347 072 LOC15 NM_198185 9938 H33- GAACTGGATAGCCCTCATC LOC20 XM_116274- similar to KIAA1214 protein/ring Protease 348 073 6008- XM_371709 finger protein 150 RNF150 H33- CCCTGGTAAAGCTGCATTC LOC22 XM_166659 similar to evidence:NAS.about.hypothetical Protease 349 074 0213 protein.about.putative H33- GATGAAGGCTTCGGGCTTC XYLB NM_005108 xylulokinase homolog (H. influenzae) Kinase 350 076 H33- TGTAAAGCTGGAAAGGGACA PTEN NM_000314- putative protein tyrosine phosphatase Phosphatase 351 080 BC038293- homologue AF017999 H33- CTGAAGAAGCTGGAGTTGC PTPN23 NM_015466 protein tyrosine phosphatase, non- Phosphatase 352 081 receptor type 23/protein tyrosine phosphatase TD14 H33- TTGGAATTCCAGTGTACCC DUSP11 NM_003584 dual specificity phosphatase 11 (RNA/ Phosphatase 353 082 RNP complex 1-interacting) H33- GCTAGTTATCGCCTACCTC DUSP3 NM_004090 dual specificity phosphatase 3 (vacc- Phosphatase 354 083 inia virus phosphatase VH1-related) H33- TCCTTGCAGCAGGCACATC SLC24A1 NM_004727 solute carrier family 24 (sodium/po- Ion 355 084 tassium calcium exchanger), member 1 H33- TCTGTGCGTGGACTGGAAC GABRP NM_014211 gamma-aminobutyric acid (GABA) A re- Ion 356 092 cepetor, pi Channel H33- CTTTGCTCGGAAGACGTTC RAF1 NM_002880 v-raf-1 murine leukemia viral onco- Kinase 357 095 gene homolog 1 H33- AGATTCCAGATGCAACCCC JAK1 SK185- Janus kinase 1 (a protein tyrosine Kinase 358 096 NM_002227 kinase) H33- GAAGGCTTTGGAAAGTGTC LOC16 XM_094437- hypothetical protein MGC42105 Kinase 359 098 7359- NM_153361 MGC42 105 H33- GTGAACTCTHGCTGCGACTC PKD1L XM_091397- similar to KIAA1979 protein/polycys- GPCR 360 102 3- NM_181536 tic kidney disease 1-like 3 LOC16 2163 H33- GACAAGGCTATGATGCTGC RPS6KA3 NM_004586 ribosomal protein S6 kinase, 90 kDa, Kinase 361 104 polypeptide 3 H33- GGATGTGTGGTGCTGTCAC RBKS NM_022128 ribokinase Kinase 362 105 H33- CTGAACTACTGGTACAGCC ABCG1 NM_016818- ATP-binding cassette, sub-family G Transporter 363 107 NM_004915 (WHITE), member 1 H33- CTCTGTGTTCCACTTCGGC DPYD NM_000110 dihydropyrimidine dehydrogenase Enzyme 364 108 H33- CAGCAATGCAGAGTGTGAC TNFRSF9 NM_001561 tumor necrosis factor receptor super- Other 365 110 family, member 9 drugable or secreted H33- CAAAGCTGGCTACTACTAC TNFSF14 NM_172014- tumor necrosis factor (ligand) super- Other 366 114 NM_003807 family, member 14 drugable or secreted H33- CAGTGCAAAGAGCCCAAAC GAPDS NM_014364 glyceraldehyde-3-phosphatedehydrogen Enzyme 367 117 ase, testis-specific H33- GTATTCTGTACACCCTGGC RDH11 NM_016026 retinol dehydrogenase 11 (all-trans Enzyme 368 118 and 9-cis) H33- GTGATCGACAGGATTGCTC PRKAG3 NM_017431 protein kinase, AMP-activated, gamma Kinase 369 120 3 non-catalytic subunit

H33- GCGAATTCCACCAGCATTC SLC26A8 NM_052961 solute carrier family 26, member 8 Transporter 370 130 H33- CACAGTGAAACCTTCCTGC B4GALT5 NM_004776 UDP-Gal:betaGlcNAc beta 1,4-galacto Enzyme 371 138 syltransferase, polypeptide 5 H33- ATCTGTGACACTGGATCGC LOC12 XM_064820 similar to Aldose Reductase Enzyme 372 145 5836 (E.C.1.1.1.21) H33- AGAGACTGGAGTTGTCAGC GNPN NM_198066 glucosamine-phosphate N-acetyltrans Enzyme 373 147 AT1 ferase 1 H33- CCTGAGTTGAATGTCATAC CYP17A1 NM_000102 cytochrome P450, family 17, subfamily Cytochrome 374 152 A, polypeptide 1 P450 H33- CTGAACTAGTGACTATCCC MAGI3 NM_152900- membrane-associated guanylate kinase- Kinase 375 158 NM_020965 related H33- ATAAGCACCGTGAGCGACC LOC13 XM_017222 similar to cytochrome P450 1A1 Cytochrome 376 161 8967 P450 H33- CATTGGGCCACAGACCTAC ADORA1 NM_000674 adenosine A1 recpeotr GPCR 377 167 H33- GATGAAGACAGCAACCAAC OPRK1 NM_000912 opioid receptor, kappa 1 GPCR 378 168 H33- AGCATATGATGACCTTGGC CTSC NM_148170- cathepsin C Protease 379 175 NM_001814 H33- ATTCCACTACTACAGCTGC H105E3 NM_015922 NAD(P) dependent steroid dehydrogen- Enzyme 380 180 ase-like H33- GAAACTGTGGCAGGCTAAC LOC25 XM_171056 similar to Putative serine/threonine- Kinase 381 182 6519 protein kinase D1044.3 in chromosome III H33- CTGATGAAGGCCTTCGACC LOC12 XM_063593 similar to NADH-ubiquinone oxidore Enzyme 382 186 3326 ductase PDSW subunit (Complex I-PDSW) (CI-PDSW) H33- TTGAAACAAGAGGAAGTCC ACYP1 XM_370768- (similar to) acylphosphatase 1, ery- Phosphatase 383 188 NM_203488- throcyte (common) type NM_001107 H33- TGAACTTGCTCTGAGCTGC KCNJ14 NM_170720- potassium inwardly-rectifying Ion 384 190 NM_013348 channel, subfamily J, member 14 Channel H33- ATCTGTAACCTCAGCACAC PPP3CC S46622- protein phosphatase 3 (formerly 2B), Phosphatase 385 191 NM_005605 catalytic subunit, gamma isoform (calcineurin A gamma) H33- ACATTGACCAGGAAGTGAC GGTLA4 NM_178312- gamma-glutamyltransferase-like Enzyme 386 192 NM_178311- activity 4 NM_080920 H33- GAAGCTAAGCCTCGGTTAC P1K4CA NM_058004 phosphatidylinositol 4-kinase, cata- Kinase 387 202 lytic, alpha polypeptide H33- TAACCGTGGCATCTACCTC TPP2 NM_003291 tripeptidyl peptidase II Protease 388 204 H33- TGACCACCTGGAGTATCAC CST11 NM_130794 cystatin 11 Not 389 205 classified H33- GTGGACATCTTTGAGCTTC GRIK4 NM_014619 glutamate receptor, ionotropic, Ion 390 208 kainate 4 H33- GCTGAGAAGTACTTCCACC ARHG NM_014448 Rho guanine exchange factor (GEF) 16 Other 391 209 EF16 drugable or secreted H33- AGACTACTGCAAGGGCGGC STK23 NM_014370 serine/threonine kinase 23 Kinase 392 210 H33- GAGTATTTGCTGGCATTCC SLCO1 XM_372282- solute carrier organic anion trans- Protease 393 213 A2- NM_134431- porter family, member 1A2/cytokine CRLF2 NM_022148- receptor-like factor 2 NM_021094 H33- GAAGCTGAATTAGGGCTTC PDE1A NM_005019 phosphodiesterase 1A, calmodulin- PDE 394 217 dependent H33- GGAGACACGGAATAAACTC PPP1R12B NM_032105- protein phosphatase 1, regulatory Phosphatase 395 219 NM_002481 (inhibitor) subunit 12B H33- CCGAGACCACCTCAATGTC ACAD8 NM_014384 acyl-Coenzyme A dehydrogenase family, Enzyme 396 222 member 8 H33- ATGGACATCTCCACGGGAC PTPRN NM_002846 protein tyrosine phosphatase, recep- Phosphatase 397 223 tor type, N H33- TATCCTGACCTTCCTGCGC KCNG1 NM_172318- potassium voltage-gated channel, sub- Ion 398 230 NM_002237 family G, member 1 H33- CACATGATCAAGCTAGGTC LOC22 XM_055551 similar to Heat shock protein HSP 90- Kinase 399 236 0763 beta (HSP 84) (HSP 90) H33- GAAGCCAGGCATCTTCATC SPOCK2 NM_014767 sparc/osteonectin, cwcv and kazal- Enzyme 400 237 like domains proteoglycan (testican) 2 H33- GCTGAAGTTATCCAGTCTC PTPN13 NM_080685- protein tyrosine phosphatase, non- Phosphatase 401 238 NM_080684- receptor type 13 (APO-1/CD95 (Fas)- NM_080683- associated phosphatase) NM_006264 H33- AGCATTGGACCAGTTGATC GABRG1 NM_173536 gamma-aminobutyric acid (GABA) A re- Ion 402 239 ceptor, gamma 1 Channel H33- GTGATCTACGTGAACTGGC DPP3 NM_005700 dipeptidylpeptidase 3 Protease 403 243 H33- GCCGACAGTGGTGCACTAC LYPLA3 NM_012320 lysophospholipase 3 (lysosomal phos Enzyme 404 245 pholipase A2) H33- AACATGATGGCTCAGAACC CTSE NM_148964- cathespin E Protease 405 251 NM_001910 H33- TACAGTGATGGATCATAGC SULT1B1 NM_014465 sulfotransferase family, cytosolic, Enzyme 406 253 1B, member 1 H33- ACCAATATGCCTACCTTCC KLKB1 NM_000892 kallikrein B, plasma (Fletcher Protease 407 255 factor) 1 H33- ACTGTATCCCAGCAGTCCC SENP7 NM_020654 sentrin/SUMO-specific protease Protease 408 258 H33- AAGCTGAACATAACCTTGC PTPRR NM_002849 protein tyrosine phosphatase, Phosphatase 409 259 receptor type, R H33- TTGAATAGCTCGGTGTCCC LOC16 XM_095455 similar to Mitogen-activated protein Kinase 410 261 9014 kinase 6 (Extracellular signal- regulated kinase 3) (ERK-3) (MAP kinase isoform p97) (p97-MAPK) H33- GTGGAAGGCAAGATCTTCC ABCD1- XM_372940- ATP-binding cassette, sub-family D Transporter 411 263 LOC38 XM_370972- (ALD), member 1/similar to Adreno- 8253- NM_000033 leukodystrophy protein (ALDP) LOC39 1403 H33- TGTATGGCTGGTCGATCAC ABCA7 NM_033308- ATP-binding cassette, sub-family A Transporter 412 264 NM_019112 (ABC1), member 7 H33- GCTGCGACAACTTCTGTTC GPR110 NM_153840 G protein-coupled receptor 110 GPCR 413 269 H33- GCCCACGGTCTTCCACTAC ACPT NM_080791- acid phosphatase, testicular Phosphatase 414 276 NM_080789- NM_033068 H33- GAAGCCATCTCCGACAATC SLC15A2 NM_021082 solute carrier family 15 (H+/pep- Transporter 415 279 tide transporter), member 2 H33- GACTGAATCAGGCCTTCCC PPIH NM_006347 peptidyl prolyl isomerase H (cyclo- Enzyme 416 295 philin H)

Example 5

Donor Dependency

[0185] The 282 hits identified by the ColII cELISA assay are further subject to a donor dependency test to demonstrate that the induction of ColII production by a given hit is not restricted to a single donor. In addition to the 11-year-old donor (donor I) previously used, NHAC's from multiple donors with ages of 24 (donor II), 41 (donor III), and 50 (donor IV), are obtained after informed consent (Cambrex, Verviers, Belgium). Cells are seeded as described in Examples 1 and 3. The propagated Ad-siRNAs are used to transduce NHAc cells from these different donors at three MOI's in duplicate in the chondrogenesis assay (see Examples 1 and 3). The Ad-siRNAs have to score at least once above threshold (average+2.5 times standard deviation) to pass this donor dependency test.

[0186] Out of 101 hits that passed the Alcian blue assay for aggrecan, 97 score positive in Donor IV. Of the remaining 4, 1 score positive in Donor II. The other 3 did not score in the other donors tested. In addition, 40 of the 101 hits score positive in all three additional donors. These results demonstrate that 98 out of these 101 hits function in a non-donor-dependent manner. Exceptions are H33-145; H33-182; and H33-263 (see Table 1). Indicated in this Table 1 are the Target Gene Symbol, Gene Bank Accession Number, and drugability class of the genes that correspond to the target sequences. The results for some of the genes are shown in Table 2. These data show that knocking down the RNA levels of the indicated genes induces collagen II levels in at least 2 donors. The values represent times standard deviation of the background. TABLE-US-00005 TABLE 2 overview donor dependency data. N = 2 for every condition. All data points are represented as fold standard deviation of the background. All values above 2.5 are considered to be positive and are shaded grey. ##STR1## ##STR2## ##STR3## ##STR4## ##STR5## ##STR6##

Example 6

Quality Control of Target Ad-siRNAs

[0187] Target Ad-siRNAs are propagated using derivatives of PER.C6.RTM. cells (Crucell, Leiden, The Netherlands) at a 96-well plate level, followed by re-screening these viruses at several MOI's in the primary assay (see Example 1) and by sequencing the siRNAs encoded by the target Ad-siRNA viruses. PER.E2A cells are seeded in 96 well plates at a density of 40,000 cells per well in 180 .mu.l PER.E2A medium. Cells are then incubated overnight at 39.degree. C. in a 10% C0.sub.2 humidified incubator. One day later, cells are infected with 1 .mu.l of crude cell lysate from SilenceSelect stocks containing target Ad-siRNAs. Cells are incubated further at 34.degree. C., 10% CO.sub.2 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: 12 .mu.l crude lysate is added to 4 .mu.l Lysis buffer (1.times. Expand High Fidelity buffer with MgCl.sub.2 (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) in sterile PCR tubes. These are incubated at 55.degree. C. for 2 h followed by a 15 min inactivation step at 95.degree. C. For the PCR reaction, 1 .mu.l lysate is added to a PCR master mix composed of 5 .mu.l 10.times. Expand High Fidelity buffer with MgCl.sub.2, 0.5 .mu.l of dNTP mix (10 mM for each dNTP), 1 .mu.l of `Forward primer` (10 mM stock, sequence: 5' CCG TTT ACG TGG AGA CTC GCC, SEQ ID NO: 29), 1 .mu.l of `Reverse Primer` (10 mM stock, sequence: 5' CCC CCA CCT TAT ATA TAT TCT TTC C, SEQ ID NO: 30), 0.2 .mu.l of Expand High Fidelity DNA polymerase (3.5 U/.mu.l, Roche Molecular Biochemicals) and 41.3 .mu.l of H.sub.2O. PCR is performed in a PE Biosystems GeneAmp PCR system 9700 as follows: the PCR mixture (50 .mu.l in total) is incubated at 95.degree. C. for 5 min; each cycle runs at 95.degree. C. for 15 sec, 55.degree. C. for 30 sec, 68.degree. C. for 4 min, and is repeated for 35 cycles. A final incubation at 68.degree. C. is performed for 7 min. 5 .mu.l of the PCR mixture is mixed with 2 .mu.l of 6.times. gel loading buffer, loaded on a 0.8% agarose gel containing 0.5 .mu.g/.mu.l ethidium bromide to resolve the amplification products. The size of the amplified fragments is estimated from a standard DNA ladder loaded on the same gel. The expected size is .about.500 bp. 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 7

Evaluation of the On Target Effect of the Identified siRNA Sequences

[0188] To evaluate whether the identified siRNA sequences really increase collagen II and aggrecan levels through the knock down of the target mRNA, a second siRNA sequence is identified that exerts the same effect.

[0189] A number of additional siRNA sequences targeting the HIT sequences are designed and incorporated in adenoviruses according to WO 03/020931. After production of these adenoviruses, the Ad-siRNAs are infected at different volumes (1.5 .mu.l, 5 .mu.l and 15 .mu.l) in the chondrocytes and their effect on collagen II is assessed as described in example 1. The threshold (average+2.5 standard deviation) is calculated for every volume. If a virus scores above the threshold for one or more of the different infection volumes, it is considered to be positive. The on target results are shown in FIG. 6. These results indicate that at least one additional siRNA, which targets the HIT sequence, can be identified. This underscores the on target effect of the siRNA sequences identified during the screening of the Silence Select library.

Example 8

Development of a Three-Dimensional-Alginate Culture System for a Quantitative Marker Analysis for Stable Cartilage and the Assessment of Glycosaminoglycans (GAG) and Hydroxyprolines (Hyp) Synthesis

Principle of the Assay:

[0190] Normal human articular chondrocytes (NHAC's) grown in three-dimensional cultures are able to maintain a "differentiated state" as measured by the expression of Collagen type II and aggrecan. De-differentiated chondrocytes cultured in a two-dimensional system for a limited amount of passages can revert to a differentiated state when transferred into a three-dimensional culture system. This system was established to test the capability of siRNA adenoviruses (Ad-siRNA) 1) to induce a mRNA expression pattern that correlates with anabolic active chondrocytes and 2) to induce protein modification of collagen type II (hydroxyprolines) and aggrecan (glycosaminoglycans) involved in the stability of cartilage. Normal cartilage NHAC's are cultured in a two-dimensional culture system for two or three passages for cell expansion purposes. Cells are transduced with individual siRNA adenoviruses (Ad-siRNA) in the two-dimensional culture system and three days later are transferred into the three-dimensional alginate culture system. After 10 days in the alginate culture, various parameters can be assessed (e.g. mRNA marker analysis and protein modifications).

Assay Procedure

[0191] Using Ad-BMP2 (BMP2: "strong" collagen II inducer) and Ad-BMP7 (BMP7: "weak" collagen II inducer) as positive controls and Ad-ALPL as negative control the following protocol is set up (for both mRNA marker analysis and protein modification assessment): After two or three passages in monolayer culture conditions NHAC's are seeded at 2.10E+06 cells/T175 flask in 30 ml of chondrocyte growing medium (Cambrex) and transduced the following day with control-viruses (Ad-BMP2, Ad-BMP4, Ad-BMP7, Ad-ALPL) using an MOI of 2000. After three days, cells are trypsinised using the chondrocyte reagent pack (Cambrex) and washed once with 155 mM sodium chloride/20 mM Hepes ph 7.4 (Cambrex). Cells are re-suspended at a density of 2.times.10.sup.6 cells/ml in 1.2% sodium alginate (Cambrex). The cell suspension is transferred into a syringe attached to a 21-22 gauge needle and expelled in a drop-wise fashion into 102 mM calcium chloride/5 mM Hepes pH 7.4 (1 ml and 5 ml respectively in 24-well and 6-well plate) Five and 50 beads per well are produced respectively in the 24-well and 6-well plates. Plates containing the alginate beads are incubated for 10 minutes with gentle shaking every 2 minutes. The calcium chloride solution is aspirated with a Vacusafe system and beads are washed three times with the sodium chloride solution using the Vacusafe and once with DMEMF/12 supplemented with 10% heat inactivated fetal bovine serum (FBS-HI) and 1% penicillin/streptomycin. Alginate beads are finally re-suspended into 0.5 ml and 3 ml (respectively in 24-well and 6-well plate) of DMEMF/12 supplemented with 10% heat inactivated fetal calf serum (FBS-HI), 1% penicillin/streptomycin and 25 .mu.g/ml of ascorbic acid (Fluka, Sigm101-128 and 401-5941drich). The alginate cultures are incubated in a humidified incubator at 37.degree. C. and 5% CO.sub.2 during 10 days with a medium refreshment every 48/72 h.

[0192] For each adenoviral transduction, 60 alginate beads are generated: 2.times.5 beads were cultured in 24-well plates for the GAGs/Hyps assessments and 50 beads are cultured in a single well of a 6-well plate for the mRNA expression pattern determination.

Control Viruses

Ad-BMP2; described in WO 03/018799

Ad-BMP7; Ad5 dE1/E2A adenoviruses that mediate the expression of full length bone morphogenetic protein 7 pre-protein (NP.sub.--001710).

Ad-BMP4; Ad5 dE1/E2A adenoviruses that mediate the expression of full length bone morphogenetic protein 4 pre-protein (see NP.sub.--570912).

Ad-ALPL; Ad5 dE1/E2A adenoviruses that mediate the expression of full length liver/bone/kidney alkaline phosphatase (NP.sub.--000469).

Example 9

Effect of Knock Down of Target Genes in Chondrocytes Embedded in Alginate Beads, on the Glycosaminoglycans (GAGs) Levels

[0193] Chondrocytes are infected and embedded in alginate beads according to example 8. After 10 days in culture the alginate beads are treated with papain in order to solubilise the glycosaminoglycans prior to quantification: Beads cultured in the 24-well plates are washed once with a 50 mM Phosphate buffer pH 6.5 and incubated for 3 to 4 h at 65.degree. C. with 250 .mu.l/well of the same buffer containing 2 mM EDTA, 2 mM L-cystein and 126 .mu.g/ml papain (Sigma). Complete digestion of the beads is assessed by microscopic observation. Papain digests are frozen at -20.degree. C. until glycosaminoglycans quantification is performed. The GAGs produced by the primary chondrocytes in the alginate culture system are measured using the Blyscan.TM. assay (Biocolor Ltd, Newtownabbey, Northern Ireland).

Principle of the Blyscan Assay

[0194] The Blyscan Assay is a quantitative dye-binding method for the analysis of sulfated GAGs. The dye label used in the assay is 1,9-dimethylmethylene blue employed under conditions that produce a specific label for the sulfated polysaccharides component of proteoglycans and/or the protein-free sulfated glycosaminoglycan chains. Aggrecan is the predomninant proteoglycan in articular cartilage, representing .+-.90% of the cartilage proteoglycans. It is composed of a central core protein attached to .+-.50 keratan sulfate and .+-.100 chondroitin sulfate chains known as GAGs required for the biological function and the stability of aggrecan.

Assay Description

[0195] The papain digests generated after culturing the chondrocytes for 10 days in alginate beads (Example 7) are diluted in water 1:100, 1:200 if cells were originally transduced with the positives controls and 1:50, 1:100 if transduced with the negative controls. This dilution step allows readout values within the standard range of the assay. The GAG standard provided by the manufacturer contains 100 .mu.g/ml of chondroitin 4-sulfate purified from bovine trachea. This standard is run in duplicate at four concentrations corresponding to 1, 2, 3 and 5 .mu.g of GAGs. Standard and controls are individually diluted in 100 .mu.l final volume in eppendorf tubes. One milliliter of the Blyscan Dye Reagent is added to each tube and incubated for 30 minutes at room temperature with continuous shaking. When formed, the GAG-dye complex becomes insoluble and is then separated from the remaining excess soluble unbound dye by centrifugation (10000.times.g for 10 minutes). Supernatant are discarded by inverting and careful draining of the tube contents. One milliliter of Blyscan Dissociation Reagent is added to each tube and incubated for one hour to one and a half hour with continuous shaking. This reagent brings the GAG-bound dye back into solution. The GAG content of the assayed samples is spectrophotometrically determined by the amount of dye recovered from the GAGs in the test sample. Two hundred microliters of the dissociation dye solutions are added to the wells of a 96-well plate and reading is performed on an automatic plate reader set at a dual wavelength (656 and 450 nm).

[0196] The GAGs concentrations measured in the Blyscan assay are normalized to DNA content by performing a fluorimetric Hoechst assay on the same papain digests. Hoechst 33342 dye reagent (Molecular Probes), a bisbenzimidasole dye that binds to adenine/thymine rich regions on DNA. Papain digests were diluted 1:1.7 and 1:3.3 in TE buffer, this dilution step allows readout values within the standard range of the assay. Purified calf thymus DNA (Sigm101-128 and 401-5941drich) is used as standard DNA: the initial stock solution (2 .mu.g/ml) is sequentially diluted in TE buffer in order to obtain the following concentration range: 1.5, 1.0, 0.75, 0.50, 0.2 .mu.g/ml. Standard and test samples are diluted in TE to a final volume of 100 .mu.l and added to a 96-well plate. One hundred microliters of Hoechst 33342 dye reagent are added to the wells, reading is performed on a multifunctional microplate reader (Fluostar Galaxy, BMG Labtechnologies GmbH) with an excitation wavelength set at 360 nm and an emission wavelength set at 440 nm.

[0197] When GAG concentrations are normalized to DNA content the resulting values expressed as the ratio GAG concentration (.mu.g/ml)/DNA concentration (.mu.g/ml) are used to calculate the assay window. This window is calculated as the ratio normalized GAG Ad-BMP2 (or Ad-BMP4)/normalized GAG Ad-ALPL.

[0198] The effect of the knock down of the 14 target genes on the GAG levels is assessed as described. The results are shown in FIG. 7. The results are expressed as fold induction of the GAG levels compared to the average of the normalized GAG values obtained for two negative control knock-down adenoviruses (Ad-PTGER4 and Ad-GRM7). Knock down of the mRNA of the respective genes results in an increase of the GAG levels.

Control Viruses

Ad-BMP2: described in WO 03/018799

Ad-BMP4: Ad5 dE1/E2A adenoviruses that mediate the expression of full length bone morphogenetic protein 4 pre-protein (see NP.sub.--570912).

Ad-ALPL: Ad5 dE1/E2A adenoviruses that mediate the expression of full length liver/bone/kidney alkaline phosphatase (NP.sub.--000469).

[0199] Ad-PTGER4: Ad5 dE1/E2A adenoviruses that comprise the siRNA sequence CCATGCCTATTTCTACAGC (SEQ ID NO: 31) to knock down the prostaglandin E receptor 4 mRNA. [0200] Ad-GRM7: Ad5 dE1/E2A adenoviruses that comprise the siRNA sequence TCAGTAACAGCTCCCAGAC (SEQ ID NO: 32) to knock down the metabotropic glutamate receptor 7 mRNA.

Example 10

Quantitative Analysis of Hydroxyprolines (Hyps)

[0201] In articular cartilage, approximately 95% of the collagen is type II collagen. Its polymers are the fibrils that form the basic cohesive framework of the tissue. The collagen biosynthesis involves several unique posttranslational modifications including hydroxylation of proline and lysine residues. These modifications are crucial for collagen stability and resistance to proteolytic enzymes.

[0202] Chondrocytes are infected and embedded in alginate beads according to example 8. After 10 days in culture the alginate beads are treated with papain: Beads cultured in the 24-well plates are washed once with a 50 mM Phosphate buffer pH 6.5 and incubated for 3 to 4 h at 65.degree. C. with 250 .mu.l/well of the same buffer containing 2 mM EDTA, 2 mM L-cystein and 126 .mu.g/ml papain (Sigma). Complete digestion of the beads is assessed by microscopic observation. Papain digests are frozen at -20.degree. C. until hydroxyproline quantification is performed.

[0203] Hydroxyproline asessment in the papain digests is performed by HPLC after acid hydrolysis and FMOC (9-fluorenylmethyl chloroformate) derivatisation of the samples. This method is described in "Bank R A, Jansen E J, Beekman B and Te Koppele J M. (1996) Amino acid analysis by reverse-phase high performance liquid chromatography: Improved derivatisation and detection conditions with 9-fluorenylmethyl chloroformate. Anal Biochem. 240(2): 167-176.

[0204] The effect of the knock down of the 14 target genes on the hydroxyproline levels is assessed as described. The results are shown in FIG. 8. The results are expressed as fold induction compared to the average of Hyp concentrations measured for the two KD controls (Ad-PTGER4 and AD-GRM7). Knock down of the mRNA of the respective genes results in an increase of the hydroxyproline levels.

Control Viruses

Ad-BMP2; described in WO 03/018799

Ad-BMP4; Ad5 dE1/E2A adenoviruses that mediate the expression of full length bone morphogenetic protein 4 pre-protein (see NP.sub.--570912).

Ad-ALPL: Ad5 dE1/E2A adenoviruses that mediate the expression of full length liver/bone/kidney alkaline phosphatase (NP.sub.--000469).

Ad-PTGER4: Ad5 dE1/E2A adenoviruses that comprise the siRNA sequence CCATGCCTATTTCTACAGC (SEQ ID NO: 33) to knock down the prostaglandin E receptor 4 mRNA.

Ad-GRM7: Ad5 dE1/E2A adenoviruses that comprise the siRNA sequence TCAGTAACAGCTCCCAGAC (SEQ ID NO: 34) to knock down the metabotropic glutamate receptor 7 mRNA.

Example 11

Quantitative Analysis of Markers for Stable Cartilage

Assay General Principle:

[0205] Chondrocyte phenotypes can be categorized by characteristic patterns of gene expression. Quantitative RT-PCR techniques are used to monitor the expression pattern of a set of key marker molecules to define which phenotype is induced on the chondrocytes. Positive markers included collagen type II and FGFR3, typically expressed by cartilage chondrocytes. Negative makers included (1) collagens types I and III for dedifferentiated or fibroblast-like chondrocytes, a phenotype that can also be induced by retinoic acid or interleukin-1; (2) collagen X, PTHLH and ALK-1 for hypertrophic chondrocytes that are found in the calcified zone of adult cartilage and the lower hypertrophic zone of the fetal growth-plate cartilage; and (3) MMP13 as proteolytic enzyme involved in cartilage degradation. Functional cartilage chondrocytes should express high levels of positive markers but low or not detectable levels of negative markers.

Assay Description

[0206] Chondrocytes are infected and embedded in alginate beads according to example 8. After 10 days in culture the alginate beads are treated with 55 mM sodium citrate (Cambrex) in order to recover the chondrocytes from the alginate beads and harvest RNA: Incubation medium was removed from the 6-well plates with the Vacusafe and 5 ml of 55 mM sodium citrate are added to each well and incubated for 15 minutes at room temperature. The partially solubilised beads are gently mixed and transferred to a FALCON tube, wells are rinsed once with 2 ml of sodium citrate solution to collect the remaining beads and released cells. Tubes are laid on their side and gently mixed every 2-3 minutes until beads have completely solubilised (+/-15 minutes). Tubes are centrifuged at 1000 rpm for 10 minutes. Supernatant is discarded and the cell pellet is re-suspended in 2 ml of sodium citrate solution and left for 5 minutes. Six milliliters of 155 mM sodium chloride/20 mM Hepes ph 7.4 (Cambrex) are added to each tube prior to a 5 minutes centrifugation at 210 g. Cell pellet is lysed in 180 .mu.l SV40 lysing buffer (Promega SV40 total RNA extraction kit) and frozen at -20.degree. C. until RNA isolation is performed with the Promega SV40 total RNA extraction kit according to the manufacturer's instructions. Purified RNA is quantified using ribogreen reagent (Molecular Probes) and yeast RNA (Ambion) as standard RNA.

[0207] Purified RNA from chondrocytes transduced with control adenoviruses and cultured for 10 days in the alginate 3-dimensional culture system is used in a reverse transcription (RT) reaction. RNA is first diluted in water (Life Technologies-Invitrogen, Breda, The Netherlands) depending on the initial concentration of the sample: For RNA concentration below 25 ng/ml, samples are used undiluted, for RNA concentration between 25 and 50 ng/ml samples are diluted 1:2.5, For RNA concentration between 50 and 100 ng/ml samples are diluted 1:5 and for RNA concentration between 100 and 160 ng/ml samples are diluted 1:10. Two microliters of diluted/undiluted RNA are added to 5 .mu.l of a reaction mix consisting of: 1.times. Taqman RT buffer, 5 mM MgCl2, 500 .mu.M dNTPs (2.5 mM each), 2.5 .mu.M Random hexamers, 0.4 U/.mu.l of RNAse inhibitor and 1.25 U/.mu.l of MultiScribe Reverse Transcriptase (all reagents purchased from Applied Biosystems). The PCR reaction is performed in a Peltier Thermal Cycler-200 (BIOzym, Landgraaf, The Netherlands) as followed: the PCR total mixture (60 .mu.l) is incubated 10 minutes at 25.degree. C. followed by 30 minutes at 48.degree. C., followed by 5 minutes at 95.degree. C. Each reaction is run in parallel with a control that does not contain any RNAse inhibitor or Reverse Transcriptase.

[0208] Reverse transcription is followed by a quantitative PCR for specific amplification of the selected positive and negative marker genes, GAPDH is included as the endogenous control. Five microliters of cDNA (from RT reaction) are added to 20 .mu.l of a PCR reaction mix consisting of: 1.times. Brilliant.RTM. SYBR.RTM. Green QPCR Master Mix (Sratagene Europe, Amsterdam, The Netherlands), 300 .mu.M of each forward and reverse primers (table 3) (except for GAPDH and ALK-1, used at 100 .mu.M) (Life Technologies-Invitrogen, Breda, The Netherlands) and 300 nM of reference dye (Stratagene) (diluted 1:100 in H.sub.2O). The PCR mixture (25 .mu.l) is incubated for 10 minutes at 95.degree. C. followed by 40 cycles: 15 seconds at 95.degree. C. followed by 1 minute at 60.degree. C. in the ABI PRISM.RTM. 7000 Sequence Detection System (Applied Biosystems, Nieuwerkerk A/D Ijssel, The Netherlands). TABLE-US-00006 TABLE 3 primer sequences for the positive and negative markers: Primer Gene Primer sequence SEQ ID NO Forward Collagen 2a1 L10347 GGCAATAGCAGGTTCACGTACA 35 Reverse Collagen 2a1 L10347 CGATAACAGTCTTGCCCCACTT 36 Forward FGFR3 NM_000142 ACGGCACACCCTACGTTACC 37 Reverse FGFR3 NM_000142 TGTGCAAGGAGAGAACCTCTAGCT 38 Forward BMP-2 NM_001200 CCAACACTGTGCGCAGCTT 39 Reverse BMP-2 NM_001200 AAGAATCTCCGGGTTGTTTTCC 40 Forward ALK-1 NM_000020 CAGTCTCATCCTGAAAGCATCTGA 41 Reverse ALK-1 NM_000020 TTTCCCACACACTCCACCAA 42 Forward collagen 10a1 TGGAGTGTTTTACGCTGAACGAT 43 NM_000493 Reverse collagen 10a1 CCTCTTACTGCTATACCTTTACTCTT 44 NM_000493 Forward Collagen 1A1 TGCCATCAAAGTCTTCTGCAA 45 NM_000088 Reverse Collagen 1A1 CGCCATACTCGAACTGGAATC 46 NM_000088 Forward Collagen 3a1 CACTATTATTTTGGCACAACAGGAA 47 NM_000090 Reverse Collagen 3a1 AGACACATATTTGGCATGGTTCTG 48 NM_000090 Forward MMP13 NM_002427 CAAGGGATCCAGTCTCTCTATGGT 49 Reverse MMP13 NM_002427 GGATAAGGAAGGGTCACATTTGTC 50 Forward PTHLH NM_002820 GCTCGGTGGAGGGTCTCA 51 Reverse PTHLH NM_002820 CTGTGTGGATTTCTGCGATCA 52 Forward GAPDH NM_002046 CATCCATGACAACTTTGGTATCG 53 Reverse GAPDH NM_002046 AGTCTTCTGGGTGGCAGTGAT 54

[0209] Results are expressed for each tested marker gene as the relative expression in the sample (transduction with tested adenovirus) versus control (knock-down control adenoviruses) (Relative expression=2.sup.ddCt, where ddct=dCt.sub.KD sample-dCt.sub.KD control and dCt=Ct.sub.sample-Ct.sub.GAPDH). The results for the 14 genes are shown in FIG. 9. The knock down of the mRNA of the respective genes results in expression of the positive markers, while the levels of the negative markers are either low or not detectable.

Control Viruses

Ad-BMP2; described in WO 03/018799

Ad-ALPL: Ad5 dE1/E2A adenoviruses that mediate the expression of full length liver/bone/kidney alkaline phosphatase (NP.sub.--000469).

Example 12

Expression of cDNA's in Human Cartilage

[0210] Upon identification of a modulator of cartilage synthesis, it is of the highest importance to evaluate whether the modulator is expressed in the tissue and the cells of interest. This can be achieved by measuring the RNA and/or protein levels. In recent years, RNA levels are being quantified through real time PCR technologies, whereby the RNA is first transcribed to cDNA and then the amplification of the cDNA of interest is monitored during a quantitative PCR reaction. The amplification plot and the resulting Ct value are indicators for the amount of a specific RNA transcript present in the sample. Ct values are determined in the presence or absence of the reverse transcriptase step (+RT versus -RT). An amplification signal in the -RT condition indicates the occurrence of non-specific PCR products originating from the genomic DNA. If the +RT Ct value is 3 Ct values higher than the -RT Ct value, then the investigated RNA is present in the sample.

[0211] To assess whether the polypeptides of the genes identified in the above assays are expressed in human cartilage, real time PCR with specific primers for the polynucleotides ("Assay on Demand" Applied Biosystems) is performed on human cartilage total RNA (Clinomics Biosciences). 2 samples of non-osteoarthritis and 2 of osteoarthritis patients are analyzed.

[0212] In short, 40 ng of RNA is transcribed to DNA using the MultiScribe Reverse Transcriptase (50 U/.mu.l) enzyme (Applied BioSystems). The resulting cDNA is amplified with AmpliTaq Gold DNA polymerase (Applied BioSystems) during 40 cycles using an ABI PRISM.RTM. 7000 Sequence Detection System. Amplification of the transcript is detected via SybrGreen which results in a fluorescent signal upon intercalation in double stranded DNA.

[0213] Total RNA isolated from human cartilage is analyzed for the presence of transcripts listed in Table 4 via quantitative real time PCR.

[0214] For the genes listed in Table 5 the obtained Ct values indicate that they are detected in all RNA samples. ELA1 RNA is not detected in the real time PCR analysis, underscoring the need for additional patient analysis. TABLE-US-00007 TABLE 4 Ct values Normal Cartilage OA Cartilage TARGET Ct Sample 1 Ct Sample 2 Ct Sample 1 Ct Sample 2 PDE1A 30.8 28.5 30.7 30.2 GPR103 33.1 33.3 38.4 37.4 JAK1 26.2 24.1 27 26 ICK 36.3 33.8 36.1 35.5 DGKB 28.5 26.7 29.7 28.7 DUSP3 27.1 24.2 27 27.1 DUSP11 28.8 27.5 29.9 29.2 SLC26A8 36.13 34.04 37.12 37.22 SLC15A2 32.5 28.1 34.7 32.9 ABCG1 29.7 28 31.1 29.5 FZD1 28.1 25.4 34.1 27.1 ELA1 40 40 40 39.1

Example 13

Identification of Small Molecules that Inhibit TARGET Kinase Activity

[0215] Compounds are screened for inhibition of the activity of the TARGETS that are kinase polypeptides. The affinity of the compounds to the polypeptides is determined in an experiment detecting changed reaction conditions after phosphorylation. The TARGET kinase polypeptides are incubated with its substrate and ATP in an appropriate buffer. The combination of these components results in the in vitro phosphorylation of the substrate. Sources of compounds include commercially available screening library, peptides in a phage display library or an antibody fragment library, and compounds that have been demonstrated to have binding affinity for a TARGET kinase.

[0216] The TARGET kinase polypeptides can be prepared in a number of ways depending on whether the assay will be run using cells, cell fractions or biochemically, on purified proteins. The polypeptides can be applied as complete polypeptides or as polypeptide fragments, which still comprise TARGET kinase catalytic activity.

[0217] Identification of small molecules inhibiting the activity of the TARGET kinase polypeptides is performed by measuring changes in levels of phosphorylated substrate or ATP. Since ATP is consumed during the phosphorylation of the substrate, its levels correlate with the kinase activity. Measuring ATP levels via chemiluminescent reactions therefore represents a method to measure kinase activity in vitro (Perkin Elmer). In a second type of assay, changes in the levels of phosphorylated substrate are detected with phosphospecific agents and are correlated to kinase activity. These levels are detected in solution or after immobilization of the substrate on a microtiter plate or other carrier. In solution, the phosphorylated substrate is detected via fluorescence resonance energy transfer (FRET) between the Eu labeled substrate and an APC labeled phosphospecific antibody (Perkin Elmer), via fluorescence polarization (FP) after binding of a phosphospecific antibody to the fluorescently labeled phosphorylated substrate (Panvera), via an Amplified Luminescent Proximity Homogeneous Assay (ALPHA) using the phosphorylated substrate and phosphospecific antibody, both coupled to ALPHA beads (Perkin Elmer) or using the IMAP binding reagent that specifically detects phosphate groups and thus alleviates the use of the phosphospecific antibody (Molecular Devices). Alternatively, the substrate is immobilized directly or by using biotin-streptavidin on a microtiter plate. After immobilization, the level of phosphorylated substrate is detected using a classical ELISA where binding of the phosphospecific antibody is either monitored via an enzyme such as horseradish peroxidase (HRP) or alkaline phospahtase (AP) which are either directly coupled to the phosphospecific antibody or are coupled to a secondary antibody. Enzymatic activity correlates to phosphorylated substrate levels. Alternatively, binding of the Eu-labeled phosphospecific antibody to the immobilized phosphorylated substrate is determined via time resolved fluorescence energy (TRF) (Perkin Elmer). In addition, the substrate can be coated on FLASH plates (Perkin Elmer) and phosphorylation of the substrate is detected using .sup.33P labeled ATP or .sup.125I labeled phosphospecific antibody.

[0218] Small molecules are randomly screened or are preselected based upon drug class, (i.e. known kinase inhibitors), or upon virtual ligand screening (VLS) results. VLS uses virtual docking technology to test large numbers of small molecules in silico for their binding to the polypeptide of the invention. Small molecules are added to the kinase reaction and their effect on levels of phosphorylated substrate is measured with one or more of the above-described technologies.

[0219] Small molecules that inhibit the kinase activity are identified and are subsequently tested at different concentrations. IC.sub.50 values are calculated from these dose response curves. Strong binders have an IC.sub.50 in the nanomolar and even picomolar range. Compounds that have an IC.sub.50 of at least 10 micromol or better (nmol to pmol) are applied in collagen II assay to check for their effect on the induction of chondrocyte anabolic stimulation.

Example 14

Ligand Screens for TARGET GPCRs

Example 14 A

Reporter Gene Screen

[0220] Mammalian cells such as Hek293 or CHO-K1 cells are either stably transfected with a plasmid harboring the luciferase gene under the control of a cAMP dependent promoter (CRE elements) or transduced with an adenovirus harboring a luciferase gene under the control of a cAMP dependent promoter. In addition reporter constructs can be used with the luciferase gene under the control of a Ca.sup.2+ dependent promoter (NF-AT elements) or a promoter that is controlled by activated NF-.kappa.B. These cells, expressing the reporter construct, are then transduced with an adenovirus harboring the cDNA of a TARGET GPCR. Forty (40) hours after transduction the cells are treated with the following:

[0221] a) an agonist for the receptor and screened against a large collection of reference compounds comprising peptides (LOPAP, Sigma Aldrich), lipids (Biomol, TimTech), carbohydrates (Specs), natural compounds (Specs, TimTech), small chemical compounds (Tocris), commercially available screening libraries, and compounds that have been demonstrated to have binding affinity for a polypeptide comprising an amino acid sequence selected from the group consisting of the SEQ ID NOs of the TARGET GPCRs; or

[0222] b) a large collection of reference compounds comprising peptides (LOPAP, Sigma Aldrich), lipids (Biomol, TimTech), carbohydrates (Specs), natural compounds (Specs, TimTech), small chemical compounds (Tocris), commercially available screening libraries, and compounds that have been demonstrated to have binding affinity for a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs of the TARGET GPCRs.

[0223] Compounds, which decrease the agonist induced increase in luciferase activity or the constitutive activity, are considered to be antagonists or inverse agonists for a TARGET GPCR. These compounds are screened again for verification and screened against their effect on anabolic stimulation of chondrocytes. The compounds are also screened to verify binding to the GPCR. The binding and reporter activity assays can be performed in essentially any order to screen compounds.

[0224] In addition, cells expressing the NF-AT reporter gene can be transduced with an adenovirus harboring the cDNA encoding the .alpha.-subunit of G.sub.15 or chimerical G.alpha. subunits. G.sub.15 is a promiscuous G protein of the G.sub.q class that couples to many different GPCRs and as such re-directs their signaling towards the release of intracellular Ca.sup.2+ stores. The chimerical G alpha subunits are members of the G.sub.s and G.sub.i/o family by which the last 5 C-terminal residues are replaced by those of G.sub..alpha.q, these chimerical G-proteins also redirect cAMP signaling to Ca.sup.2+ signaling.

Example 14 B

FLIPR Screen

[0225] Mammalian cells such as Hek293 or CHO-K1 cells are stably transfected with an expression plasmid construct harboring the cDNA of a TARGET GPCR. Cells are seeded, grown, and selected until sufficient stable cells can be obtained. Cells are loaded with a Ca.sup.2+ dependent fluorophore such as Fura3 or Fura4. After washing away the excess of fluorophore the cells are screened against a large collection of reference compounds comprising peptides (LOPAP, Sigma Aldrich), lipids (Biomol, TimTech), carbohydrates (Specs), natural compounds (Specs, TimTech), small chemical compounds (Tocris), commercially available screening libraries, and compounds that have been demonstrated to have binding affinity for a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs of the TARGET GPCRs, by simultaneously adding an agonist (alternatively no agonist need be added if the constitutive activity of the receptor is used) and a compound to the cells. Activation of the receptor is measured as an almost instantaneously increase in fluorescence due to the interaction of the fluorophore and the Ca.sup.2+ that is released. Compounds that reduce or inhibit the agonist induced increase in fluorescence (or constitutive fluorescence) are considered to be antagonists or inverse agonists for the receptor they are screened against. These compounds are screened again to measure the amount of anabolic stimulation of chondrocytes as well as binding to a TARGET GPCR.

Example 14 C

AequoScreen

[0226] CHO cells, stably expressing Apoaequorin are stably transfected with a plasmid construct harboring the cDNA of a TARGET GPCR. Cells are seeded, grown, and selected until sufficient stable cells can be obtained. The cells are loaded with coelenterazine, a cofactor for apoaequorin. Upon receptor activation intracellular Ca.sup.2+ stores are emptied and the aequorin will react with the coelenterazine in a light emitting process. The emitted light is a measure for receptor activation. The CHO, stable expressing both the apoaequorin and the receptor are screened against a large collection of reference compounds comprising peptides (LOPAP, Sigma Aldrich), lipids (Biomol, TimTech), carbohydrates (Specs), natural compounds (Specs, TimTech), small chemical compounds (Tocris), commercially available screening libraries, and compounds that have been demonstrated to have binding affinity for a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NOs of the TARGET GPCRs, by simultaneously adding an agonist (alternatively no agonist need be added if the constitutive activity of the receptor is used) and a compound to the cells. Activation of the receptor is measured as an almost instantaneously light flash due to the interaction of the apoaequorin, coelenterazine, and the Ca.sup.2+ that is released. Compounds that reduce or inhibit the agonist induced increase in light or the constitutive activity are considered to be antagonists or inverse agonists for the receptor they are screened against. These compounds are screened again to measure the amount of anabolic stimulation of chondrocytes as well as binding to a TARGET GPCR.

[0227] In addition, CHO cells stable expressing the apoaequorin gene are stably transfected with a plasmid construct harboring the cDNA encoding the .alpha.-subunit of G.sub.15 or chimerical G.sub..alpha. subunits. G.sub.15 is a promiscuous G protein of the G.sub.q class that couples to many different GPCRs and as such redirects their signaling towards the release of intracellular Ca.sup.2+ stores. The chimerical G alpha subunits are members of the G.sub.s and G.sub.i/o family by which the last 5 C-terminal residues are replaced by those of G.sub..alpha.q, these chimerical G-proteins also redirect cAMP signaling to Ca.sup.2+ signaling.

Example 14 D

Screening for Compounds that Bind to the GPCR Polypeptides (Displacement Experiment)

[0228] Compounds are screened for binding to the TARGET GPCR polypeptides. The affinity of the compounds to the polypeptides is determined in a displacement experiment. In brief, the GPCR polypeptides are incubated with a labeled (radiolabeled, fluorescent labeled) ligand that is known to bind to the polypeptide and with an unlabeled compound. The displacement of the labeled ligand from the polypeptide is determined by measuring the amount of labeled ligand that is still associated with the polypeptide. The amount associated with the polypeptide is plotted against the concentration of the compound to calculate IC.sub.50 values. This value reflects the binding affinity of the compound to its TARGET, i.e. the TARGET GPCR polypeptides. Strong binders have an IC.sub.50 in the nanomolar and even picomolar range. Compounds that have an IC.sub.50 of at least 10 micromol or better (nmol to pmol) are applied an anabolic stimulation of chondrocytes assay to check for their effect on osteogenesis. The TARGET GPCR polypeptides can be prepared in a number of ways depending on whether the assay are run on cells, cell fractions or biochemically, on purified proteins.

Example 14 E

Screening for Compounds that Bind to a TARGET GPCR (Generic GPCR Screening Assay)

[0229] When a G protein receptor becomes constitutively active, it binds to a G protein (G.sub.q, G.sub.s, G.sub.i, G.sub.o) and stimulates the binding of GTP to the G protein. The G protein then acts as a GTPase and slowly hydrolyses the GTP to GDP, whereby the receptor, under normal conditions, becomes deactivated. However, constitutively activated receptors continue to exchange GDP to GTP. A non-hydrolyzable analog of GTP, [.sup.35S]GTP.gamma.S, can be used to monitor enhanced binding to membranes which express constitutively activated receptors. It is reported that [.sup.35S]GTP.gamma.S can be used to monitor G protein coupling to membranes in the absence and presence of ligand. Moreover, a preferred approach is the use of a GPCR-G protein fusion protein. The strategy to generate a TARGET GPCR-G protein fusion protein is well known for those known in the art. Membranes expressing TARGET GPCR-G protein fusion protein are prepared for use in the direct identification of candidate compounds such as inverse agonist. Homogenized membranes with TARGET GPCR-G protein fusion protein are transferred in a 96-well plate. A pin-tool is used to transfer a candidate compound in each well plus [.sup.35 S]GTP.gamma.S, followed by incubation on a shaker for 60 minutes at room temperature. The assay is stopped by spinning of the plates at 4000 RPM for 15 minutes at 22.degree. C. The plates are then aspirated and radioactivity is then read.

Example 14 F

Receptor Ligand Binding Study on Cell Surface

[0230] The receptor is expressed in mammalian cells (Hek293, CHO, COS7) by adenoviral transducing the cells (see U.S. Pat. No. 6,340,595). The cells are incubated with both labeled ligand (iodinated, tritiated, or fluorescent) and the unlabeled compound at various concentrations, ranging from 10 .mu.M to 10 .mu.M (3 hours at 4.degree. C.: 25 mM HEPES, 140 mM NaCl, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2 and 0.2% BSA, adjusted to pH 7.4). Reactions mixtures are aspirated onto PEI-treated GF/B glass filters using a cell harvester (Packard). The filters are washed twice with ice cold wash buffer (25 mM HEPES, 500 mM NaCl, 1 mM CaCl.sub.2, 5 mM MgCl.sub.2, adjusted to pH 7.4). Scintillant (MicroScint-10; 35 .mu.l) is added to dried filters and the filters counted in a (Packard Topcount) scintillation counter. Data are analyzed and plotted using Prism software (GraphPad Software, San Diego, Calif.). Competition curves are analyzed and IC.sub.50 values calculated. If one or more data points do not fall within the sigmoidal range of the competition curve or close to the sigmoidal range the assay is repeated and concentrations of labeled ligand and unlabeled compound adapted to have more data points close to or in the sigmoidal range of the curve.

Example 14 G

Receptor Ligand Binding Studies on Membrane Preparations

[0231] Membranes preparations are isolated from mammalian cells (Hek293, CHO, COS7) cells over expressing the receptor is done as follows: Medium is aspirated from the transduced cells and cells are harvested in 1.times.PBS by gentle scraping. Cells are pelleted (2500 rpm 5 min) and resuspended in 50 mM Tris pH 7.4 (10.times.10.sup.6 cells/ml). The cell pellet is homogenized by sonicating 3.times.5 sec (UP50H; sonotrode MSI; max amplitude: 140 .mu.m; max Sonic Power Thickness: 125 W/cm.sup.2). Membrane fractions are prepared by centrifuging 20 min at maximal speed (13,000 rpm .about.15,000 to 20,000 g or rcf). The resulting pellet is resuspended in 500 .mu.l 50 mM Tris pH 7.4 and sonicated again for 3.times.5 sec. The membrane fraction is isolated by centrifugation and finally resuspended in PBS. Binding competition and derivation of IC.sub.50 values are determined as described above.

Example 14 H

Internalization Screen (1)

[0232] Activation of a GPCR-associated signal transduction pathway commonly leads to translocation of specific signal transduction molecules from the cytoplasm to the plasma membrane or from the cytoplasm to the nucleus. Norak has developed their transfluor assay based on agonist-induced translocation of receptor-.beta.-arrestin-GFP complex from the cytosol to the plasma membrane and subsequent internalization of this complex, which occurs during receptor desensitization. A similar assay uses GFP tagged receptor instead of O-arrestin. Hek293 cells are transduced with a TARGET GPCR vector that translates for a TARGET GPCR-eGFP fusion protein. 48 hours after transduction, the cells are set to fresh serum-free medium for 60 minutes and treated with a ligand for 15, 30, 60 or 120 minutes at 37.degree. C. and 5% CO.sub.2. After indicated exposure times, cells are washed with PBS and fixed with 5% paraformaldehyde for 20 minutes at RT. GFP fluorescence is visualized with a Zeiss microscope with a digital camera. This method aims for the identification of compounds that inhibit a ligand-mediated (constitutive activity-mediated) translocation of the fusion protein to intracellular compartments.

Example 14 I

Internalization Screen (2)

[0233] Various variations on translocation assays exists using .beta.-arrestin and .beta.-galactosidase enzyme complementation and BRET based assays with receptor as energy donor and .beta.-arrestin as energy acceptor. Also the use of specific receptor antibodies labeled with pH sensitive dyes are used to detect agonist induced receptor translocation to acidic lysosomes. All of the translocation assays are used for screening for both agonistic and antagonistic acting ligands.

Example 14 J

Melanophore Assay (Arena Pharmaceutical)

[0234] The melanophore assay is based on the ability of GPCRs to alter the distribution of melanin containing melanosomes in Xenopus melanophores. The distribution of the melanosomes depends on the exogenous receptor that is either G.sub.i/o or G.sub.s/q coupled. The distribution of the melanosomes (dispersed or aggregated) is easily detected by measuring light absorption. This type of assay is used for both agonist as well as antagonist compound screens.

Example 15

Identification of Small Molecules that Inhibit Protease Activity

[0235] Compounds are screened for inhibition of the activity of the polypeptides of the present invention. The affinity of the compounds to the polypeptides is determined in an experiment detecting changes in levels of cleaved substrate. In brief, the polypeptides of the present invention are incubated with its substrate in an appropriate buffer. The combination of these components results in the cleavage of the substrate.

[0236] The polypeptides can be applied as complete polypeptides or as polypeptide fragments, which still comprise the catalytic activity of the polypeptide of the invention.

[0237] Cleavage of the substrate can be followed in several ways. In a first method, the substrate protein is heavily labeled with a fluorescent dye, like fluorescein, resulting in a complete quenching of the fluorescent signal. Cleavage of the substrate however, releases individual fragments, which contain less fluorescent labels. This results in the loss of quenching and the generation of a fluorescent signal, which correlates to the levels of cleaved substrate. Cleavage of the protein, which results in smaller peptide fragments, can also be measured using fluorescent polarization (FP). Alternatively, cleavage of the substrate can also be detected using fluorescence resonance energy transfer (FRET): a peptide substrate is labeled on both sides with either a quencher and fluorescent molecule, like DABCYL and EDANS. Upon cleavage of the substrate both molecules are separated resulting in fluorescent signal correlating to the levels of cleaved substrate. In addition, cleavage of a peptide substrate can also generate a new substrate for another enzymatic reaction, which is then detected via a fluorescent, chemiluminescent or colorimetric method.

[0238] Small molecules are randomly screened or are preselected based upon drug class, i.e. protease, or upon virtual ligand screening (VLS) results. VLS uses virtual docking technology to test large numbers of small molecules in silico for their binding to the polypeptide of the invention. Small molecules are added to the proteolytic reaction and their effect on levels of cleaved substrate is measured with the described technologies.

[0239] Small molecules that inhibit the protease activity are identified and are subsequently tested at different concentrations. IC50 values are calculated from these dose response curves. Strong binders have an IC50 in the nanomolar and even picomolar range. Compounds that have an IC50 of at least 10 micromol or better (nmol to pmol) are applied in amyloid beta secretion assay to check for their effect on the beta amyloid secretion and processing.

Example 16

Identification of Small Molecules that Inhibit Phosphodiesterase Activity

[0240] Compounds are screened for inhibition of the activity of the polypeptides of the present invention. The affinity of the compounds to the polypeptides is determined in an experiment detecting changes in levels of substrate or product. In brief, the polypeptides of the present invention are incubated with its substrate in an appropriate buffer. The combination of these components results in the conversion of the substrate into its product.

[0241] The polypeptides can be applied as complete polypeptides or as polypeptide fragments, which still comprise the catalytic activity of the polypeptide of the invention.

[0242] Conversion of cAMP or cGMP in AMP or GMP can be followed 1) by determining the cAMP or cGMP levels using e.g. ELISA. Alpha screen technology, Time resolved fluorescent technology, IMAP 2) by determining the levels of the products AMP and GMP using a colorimetric assay. The basis for the latter assay is the cleavage of cAMP or

[0243] cGMP by a cyclic nucleotide phosphodiesterase. The 5'-nucleotide released is further cleaved into the nucleoside and phosphate by the enzyme 5'-nucleotidase. The phosphate released due to enzymatic cleavage is quantified using BIOMOL GREEN reagent in a modified Malachite Green assay.

[0244] Small molecules are randomly screened or are preselected based upon drug class, i.e. PDE, or upon virtual ligand screening (VLS) results. VLS uses virtual docking technology to test large numbers of small molecules in silico for their binding to the polypeptide of the invention. Small molecules are added to the PDE reaction and their effect on cyclic nucleotide levels is measured with the described technologies.

[0245] Small molecules that inhibit the PDE activity are identified and are subsequently tested at different concentrations. IC50 values are calculated from these dose response curves. Strong binders have an IC50 in the nanomolar and even picomolar range. Compounds that have an IC50 of at least 10 micromol or better (nmol to pmol) are applied in assays evaluating the anabolic activity of chondrocytes. This can be achieved by determining col2.alpha.1 and aggrecan levels produced by the chondrocytes.

REFERENCES

[0246] Arts et al. (2003) Genome Res 10:2325-32 [0247] Chubinskaya and Kuettner (2003). Int J Biochem Cell Biol 35; 1323-40 [0248] Cortez-Retamozo et al. (2004). Cancer Res 64: 2853-7 [0249] Dorsett Y, Tuschl T. (2004). Nature Reviews Drug Discovery 3: 318-329 [0250] Harborth J, et al. (2003) Antisense Nucleic Acid Drug Dev 13(2): 83-105 [0251] Khvorova A, et al. (2003) Cell. 115(2): 209-16 [0252] Lipinsky, C A, et al. (2001). Adv Drug Deliv Rev 46: 3-26 [0253] Reynolds A, et al. (2004) Nat Biotechnol 22: 326-30 [0254] Tuschl, (2002). Nature Biotechnol. 20:446-8 [0255] Ui-Tei K, et al. (2004) Nucleic Acids Res. 32(3): 936-48 [0256] Wang L and Mu F Y. (2004) Bioinformatics (In press)

Sequence CWU 1

1

478 1 3536 DNA Homo sapiens 1 atggggacga cggccccagg gcccattcac ctgctggagc tatgtgacca gaagctcatg 60 gagtttctct gcaacatgga taataaggac ttggtgtggc ttgaggagat ccaagaggag 120 gccgagcgca tgttcaccag agaattcagc aaagagccag agctgatgcc caaaacacct 180 tctcagaaga accgacggaa gaagagacgg atttcttatg ttcaggatga aaacagagat 240 cccatcagga gaaggttatc ccgcagaaag tctcggagca gccagctgag ctcccgacgc 300 ctccgcagca aggacagtgt agagaagctg gctacagtgg tcggggagaa cggctccgtt 360 ctgcggcgtg tgacccgtgc tgcggctgca gctgccgcgg ctaccatggc attggctgca 420 ccttcttcac ccacccctga gtctcccacg atgctgacta agaagcccga ggataaccac 480 acccagtgcc agctggtgcc tgtggtggag atcggcatca gtgagcgcca gaatgctgag 540 cagcatgtca cccagctcat gtccaccgag cctctgcccc gcactctgtc cccgactcca 600 gcttcagcca cagctccaac ctcccagggc atcccgacat cagatgagga atcaacacct 660 aagaagtcga aggccaggat actggagtcc atcacagtga gctccctgat ggctacaccc 720 caggacccca agggtcaagg ggtcgggacg gggcggtctg cgtctaagct caggattgcg 780 caggtctccc ctggcccacg ggactcgcca gcctttccag attctccatg gcgggagcgg 840 gtgctggctc ccatcctgcc ggataacttc tccacgccca cgggctctcg cacggactct 900 caatcggtgc ggcacagccc gatcgccccg tcttccccga gtccccaagt cttagcccag 960 aagtactctc tggtggccaa acaggaaagt gttgtccgca gggcgagcag aaggcttgcc 1020 aagaagactg ccgaagagcc agctgcctct ggccgcatca tctgtcacag ttacctggag 1080 aggctcctga atgttgaggt gccccagaaa gttggttctg agcagaagga accccccgag 1140 gaggctgagc ctgtggcggc agctgagcca gaggtccctg agaacaacgg aaataactcg 1200 tggccccaca atgacacgga gattgccaac agcacaccca acccgaagcc tgcagccagc 1260 agcccggaaa caccctctgc agggcagcaa gaggccaaga cggaccaagc agatggaccc 1320 agagagccac cgcagagtgc caggaggaag cgcagctaca agcaggccgt gagtgagctg 1380 gacgaggagc agcacctgga ggatgaggag ctgcagcccc ccaggagcaa gaccccttcc 1440 tcaccctgcc cagccagcaa ggtggtacgg cccctccgga cctttctgca cacagtgcag 1500 aggaaccaga tgctcatgac ccctacctca gccccacgca gcgtcatgaa gtcctttatt 1560 aagcgcaaca ctcccctgcg catggacccc aaggagaagg agcggcagcg cctggagaat 1620 ctgcggcgga aggaggaggc cgagcagctg cgcaggcaga aggtggagga ggacaagcgg 1680 cggcggctgg aggaggtgaa gctgaagcgt gaggaacgcc tccgcaaggt gctgcaggcc 1740 cgcgagcggg tggagcagat gaaggaggag aagaagaagc agattgagca gaagtttgct 1800 cagatcgacg agaagactga gaaggccaag gaggagcggc tggcagagga gaaggccaag 1860 aaaaaggcgg cggccaagaa gatggaggag gtggaagcac gcaggaagca ggaagaggat 1920 gcacgtaggc tcaggtggct gcagcaggag gaggaagagc ggcggcacca agagctgctg 1980 cagaagaaga aggaagagga gcaggagcgg ctgcggaagg cggccgaggc taagcggctg 2040 gcagagcagc gggagcagga gcggcgggag caggagcggc gggagcagga gcggcgcgag 2100 caggagcggc gcgagcagga gcggcgggag caggagcggc gcgagcagga gcgacagctg 2160 gcagagcagg agcgtcggcg ggagcaggag cggctccaag ccgagaggga gctgcaggag 2220 cgggagaagg ccctgcggct gcagaaggag cagctgcaga gggaactgga ggagaagaag 2280 aagaaggaag agcagcagcg tctggctgag cggcagctgc aggaggagca agagaagaaa 2340 gccaaggagg cagcaggggc cagcaaggcc ctgaatgtga ctgtggacgt gcagtctcca 2400 gcttgtacct catctcccat cactccgcaa gggcacaagg cccctcccca gatcaacccc 2460 cacaactacg ggatggatct gaatagcgac gactccaccg atgatgaggc ccatccccgg 2520 aagcccatcc ccacctgggc ccgaggcacc ccgctcagcc aggctatcat tcaccagtac 2580 taccagccac cgaaccttct ggagctcttt ggaaccattc tcccactgga cttggaggat 2640 atcttcaaga agagcaagcc ccgctatcac aagcgcacca gctctgctgt ctggaactca 2700 ccgcccctgc agggcgccag ggtccccagc agcctggcct acagcctgaa gaagcactga 2760 ggctggcctg cggccttctt ggcagcctcg cctcctgtcc atgtctatct gtctgtctgt 2820 cggtctgtgt cttggtctgt tgccctcctt cttggcatgc cattgtggag ggcttggcca 2880 ggtgtatata aacgtcctct gtgctgggtg tttctgctgc aggtggcagg tggccccagg 2940 cctgtttgga ggatgggctg ggtgggtggg tggggaagaa atgggcccag ccccacatgg 3000 cctgcagaca gtgctctgta aatagttgtt ttaatttagc tgaatgttag cattttagtc 3060 tttggcattt tagcgtttgg gaggtagatt aataaagtat attccttcaa gcctgctgtt 3120 gataccatga agactgggcg cctcagtccc agccctgtag ctgtgtgtct tgggccacca 3180 gtggcctgca ggacgaaggt actgttccat cacctgcggt gtgcctcagg atcaccaggt 3240 gcaggccccc accctcggag atgctgctgc agtgagtggt tccactgcct ggataaccct 3300 tgaggaacac gtcagttact gtcacgatgg ggcaggtgga gctccttcct attttttggg 3360 gtgctccctg tttgtaaagg ggagtttgtt cattgggaaa gacctgggtc ttgacacggc 3420 cctgccactt agtcccctac cctctccatt ccccaggctc cacccgtgct gctcaagtgc 3480 aaatggactt gagagtattt atgtgctggt gaagtatgag gtctgagtag aaaagg 3536 2 3926 DNA Homo sapiens 2 atgacaaacc aggaaaaatg ggcccacctc agcccttcgg aattttccca acttcagaaa 60 tatgctgagt attctacaaa gaaattaaag gatgttcttg aagaattcca tggtaatggt 120 gtgcttgcaa agtataatcc tgaagggaaa caagacattc ttaaccaaac aatagatttt 180 gaaggtttca aactattcat gaagacattc ctggaagccg agcttcctga tgatttcact 240 gcacaccttt tcatgtcatt tagcaacaag tttcctcatt ctagtccaat ggtaaaaagt 300 aagcctgctc tcctatcagg cggtctgaga atgaataaag gtgccatcac ccctccccga 360 actacttctc ctgcaaatac gtgttcccca gaagtaatcc atctgaagga cattgtctgt 420 tacctgtctc tgcttgaaag aggaagacct gaggataagc ttgagtttat gtttcgcctt 480 tatgacacgg atgggaatgg cttcctggac agctcggagc tagaaaatat catcagtcag 540 atgatgcatg ttgcagaata ccttgagtgg gatgtcactg aacttaatcc aatcctccat 600 gaaatgatgg aagaaattga ctatgatcat gatggaaccg tgtctctgga ggaatggatt 660 caaggaggaa tgacaacgat tccacttctt gtgctcctgg gcttagaaaa taacgtgaag 720 gatgatggac agcacgtgtg gcgactgaag cactttaaca aacctgccta ttgcaacctt 780 tgcctgaaca tgctgattgg cgtggggaag cagggcctct gctgttcctt ctgcaagtac 840 acagtccatg agcgctgtgt ggctcgagca cctccctctt gcatcaagac ctatgtgaag 900 tccaaaagga acactgatgt catgcaccat tactgggttg aaggtaactg cccaaccaag 960 tgtgataagt gccacaaaac tgttaaatgt taccagggcc tgacaggact gcattgtgtt 1020 tggtgtcaga tcacactgca taataaatgt gcttctcatc taaaacctga atgtgactgt 1080 ggacctttga aggaccatat tttaccaccc acaacaatct gtccagtggt actgcagact 1140 ctgcccactt caggagtttc agttcctgag gaaagacaat caacagtgaa aaaggaaaag 1200 agtggttccc agcagccaaa caaagtgatt gacaagaata aaatgcaaag agccaactct 1260 gttactgtag atggacaagg cctgcaggtc actcctgtgc ctggtactca cccactttta 1320 gtttttgtga accccaaaag tggtggaaaa caaggagaac gaatttacag aaaattccag 1380 tatctattaa atcctcgtca ggtttacagt ctttctggaa atggaccaat gccagggtta 1440 aactttttcc gtgatgttcc tgacttcaga gtgttagcct gtggtggaga tggaaccgtg 1500 ggctgggttt tggattgcat agaaaaggcc aatgtaggca agcatcctcc agttgcgatt 1560 ctgcctcttg ggactggcaa tgatctagca agatgcctgc gatggggagg aggttacgaa 1620 ggtgagaatc tgatgaaaat tctaaaagac attgaaaaca gcacagaaat catgttggac 1680 aggtggaagt ttgaagtcat acctaatgac aaagatgaga aaggagaccc agtgccttac 1740 agtatcatca ataattactt ttccattggc gtggatgcct ccattgcaca cagattccac 1800 atcatgagag aaaaacaccc agagaaattc aacagtagaa tgaagaacaa attttggtat 1860 tttgagtttg gcacatctga aactttctca gccacctgca agaagctaca tgaatctgta 1920 gaaatagaat gtgatggagt acagatagat ttaataaaca tctctctgga aggaattgct 1980 attttgaata taccaagcat gcatggagga tccaatcttt ggggagagtc taagaaaaga 2040 cgaagccatc gacgaataga gaaaaaaggg tctgacaaaa ggaccaccgt cacagatgcc 2100 aaagagttga agtttgcaag tcaagatctc agtgaccagc tgctggaggt ggtcggcttg 2160 gaaggagcca tggagatggg gcaaatatac acaggcctga aaagtgctgg ccggcggctg 2220 gctcagtgct cctgcgtggt catcaggacg agcaagtctc tgccaatgca aattgatggg 2280 gagccatgga tgcagacccc atgcacaata aaaattacac acaagaacca agccccaatg 2340 ctgatgggcc cgcctccaaa aaccggttta ttctgctccc tcgtcaaaag gacaagaaac 2400 cgaagcaagg aataatcctg tgttgtttca ctcttagaaa ttgaattagc ataattgggc 2460 catggaacac atatgctgga aatctttgaa ccatttcaag tctcctgctc atgcaaaatc 2520 atggaagtgg tttaacagtt tttgttacta agctaatgta aaattcagct attagaaaat 2580 ttattgtctc agtttttata ggcatctttg catgaagaaa gcagaagttt acctgaagtg 2640 atactgcata tttttggtgc atgcattccc atagattttt acatctccca cccaactctt 2700 ccccaatttc cttttactaa cctgtgagaa aaacccgtga aacatgaaaa aggaaatacc 2760 atgggaaacg tgattctcag tgtgattcca attattacga agcactaatc agtaacgcta 2820 caatgatcat aattgcagat tgctatacgt ttccctttta gaatcagtgt atcagtgacc 2880 tatgacttga ggagaaactt ttaattcgaa gattttatta aatagttgac tacaatacct 2940 tgctatatat acatagtttt tcttcaacat cttaactctt ctgagtggaa ataaaaatat 3000 caggcataag gttttctcat gctgaaaaat agaacgcggt ttttattttg cttagttttc 3060 tttttaattc cagaaataag tgaaaacatg ttacttgaca gtcaagtgtg gtaatatggc 3120 aagccttgtt cctttctgca tgagaatcta ggagagaatt cataaccaca ccaataacga 3180 aatagaagtt ttaaactatg tgcctaatca atgtgtttcc caccaaagat tcagaaaaca 3240 atgcttgaga gaaatgggtt aatgcataat taattaagca ttgtggagca aatttagggt 3300 tcctgtgatt aattttgtga tgactaaaat gctggaaagc aagtgagttg cccattaatt 3360 atgattaaaa ttctcacctt tcacagacag acaataagcc agacaacaca atcaaagctc 3420 aatagatgat ttcttgcttt tttcagtcat ttataaatat aggtgtaatt tttcatggat 3480 cagttaagta cacttgaagg aagtaaatga ttgtatcagt ttatttctag tataaatggg 3540 tacctgtaat aatactgagc tcttggaagc gaatcatgca tgcaattagc tccctcctcc 3600 tcacctactc cactcccatc tttatgacat ttcaaatgtt tatttggaaa caacagccta 3660 gatcactgtt gaaggtgttc atggcatagt tggagtctct gactgtttaa agaaatcaca 3720 gaacagtact tttcttttag tgtttcatta agcctatgat gtaaaatgaa atgcttctga 3780 gcagtcttgt aatattgttc attcatattg acctgcatct catcattgca tgttttatgt 3840 tttcaaacat gccataagga aaacgagtgc ctgaactgca tgatttatta gtttctctcc 3900 actctgcatt aaagtgctaa tgattt 3926 3 3172 DNA Homo sapiens 3 atgacaaacc aggaaaaatg ggcccacctc agcccttcgg aattttccca acttcagaaa 60 tatgctgagt attctacaaa gaaattaaag gatgttcttg aagaattcca tggtaatggt 120 gtgcttgcaa agtataatcc tgaagggaaa caagacattc ttaaccaaac aatagatttt 180 gaaggtttca aactattcat gaagacattc ctggaagccg agcttcctga tgatttcact 240 gcacaccttt tcatgtcatt tagcaacaag tttcctcatt ctagtccaat ggtaaaaagt 300 aagcctgctc tcctatcagg cggtctgaga atgaataaag gtgccatcac ccctccccga 360 actacttctc ctgcaaatac gtgttcccca gaagtaatcc atctgaagga cattgtctgt 420 tacctgtctc tgcttgaaag aggaagacct gaggataagc ttgagtttat gtttcgcctt 480 tatgacacgg atgggaatgg cttcctggac agctcggagc tagaaaatat catcagtcag 540 atgatgcatg ttgcagaata ccttgagtgg gatgtcactg aacttaatcc aatcctccat 600 gaaatgatgg aagaaattga ctatgatcat gatggaaccg tgtctctgga ggaatggatt 660 caaggaggaa tgacaacgat tccacttctt gtgctcctgg gcttagaaaa taacgtgaag 720 gatgatggac agcacgtgtg gcgactgaag cactttaaca aacctgccta ttgcaacctt 780 tgcctgaaca tgctgattgg cgtggggaag cagggcctct gctgttcctt ctgcaagtac 840 acagtccatg agcgctgtgt ggctcgagca cctccctctt gcatcaagac ctatgtgaag 900 tccaaaagga acactgatgt catgcaccat tactgggttg aaggtaactg cccaaccaag 960 tgtgataagt gccacaaaac tgttaaatgt taccagggcc tgacaggact gcattgtgtt 1020 tggtgtcaga tcacactgca taataaatgt gcttctcatc taaaacctga atgtgactgt 1080 ggacctttga aggaccatat tttaccaccc acaacaatct gtccagtggt actgcagact 1140 ctgcccactt caggagtttc agttcctgag gaaagacaat caacagtgaa aaaggaaaag 1200 agtggttccc agcagccaaa caaagtgatt gacaagaata aaatgcaaag agccaactct 1260 gttactgtag atggacaagg cctgcaggtc actcctgtgc ctggtactca cccactttta 1320 gtttttgtga accccaaaag tggtggaaaa caaggagaac gaatttacag aaaattccag 1380 tatctattaa atcctcgtca ggtttacagt ctttctggaa atggaccaat gccagggtta 1440 aactttttcc gtgatgttcc tgacttcaga gtgttagcct gtggtggaga tggaaccgtg 1500 ggctgggttt tggattgcat agaaaaggcc aatgtaggca agcatcctcc agttgcgatt 1560 ctgcctcttg ggactggcaa tgatctagca agatgcctgc gatggggagg aggttacgaa 1620 ggtgagaatc tgatgaaaat tctaaaagac attgaaaaca gcacagaaat catgttggac 1680 aggtggaagt ttgaagtcat acctaatgac aaagatgaga aaggagaccc agtgccttac 1740 agtatcatca ataattactt ttccattggc gtggatgcct ccattgcaca cagattccac 1800 atcatgagag aaaaacaccc agagaaattc aacagtagaa tgaagaacaa attttggtat 1860 tttgagtttg gcacatctga aactttctca gccacctgca agaagctaca tgaatctgta 1920 gaaatagaat gtgatggagt acagatagat ttaataaaca tctctctgga aggaattgct 1980 attttgaata taccaagcat gcatggagga tccaatcttt ggggagagtc taagaaaaga 2040 cgaagccatc gacgaataga gaaaaaaggg tctgacaaaa ggaccaccgt cacagatgcc 2100 aaagagttga agtttgcaag tcaagatctc agtgaccagc tgctggaggt ggtcggcttg 2160 gaaggagcca tggagatggg gcaaatatac acaggcctga aaagtgctgg ccggcggctg 2220 gctcagtgct cctgcgtggt catcaggacg agcaagtctc tgccaatgca aattgatggg 2280 gagccatgga tgcagacccc atgcacagtg agtacagagt agttgatatg ctatgtcaat 2340 ctcagttttg ctttcctctt tgactaaata accacaataa ctgatttttt tctttatttc 2400 ttttcaacct atcagcaaat agtctttttg ttgttgttgt tatgtgtgtg tcagagccac 2460 tacatttagg ctgtagacat tatataccct tggcaatgat ttagctcttg aatgtttgtg 2520 ctagcctaag tataaataga tcttttaaat agatcaatta taaaccatag atcaattata 2580 aactatggag ctaaacaaaa tattaataaa agtttatctg aaactttttt gtttatttca 2640 gagcacatta ttagaatatt atttgcgaga aatgcagacc taagcttata tgtgaactta 2700 tttctcagct tttctatgcc tccatttggg gatttgaggg ctttcttctc cataagaaaa 2760 aaatttctct ccagtttcta ccataattaa ttgtgttttc cagaatgagg tattatttaa 2820 ggcagacact gcccctctca aaaaaaatca gttttcattt gcatagtgaa tattttattg 2880 catttcaaaa acatgctagg aactgctttt ggcactggga gtagacacat gaacaagacc 2940 aacagtgtaa tttccttcaa gttacttaca ttcctataat agaggaccga ataaataaac 3000 aactacatga taaatataac ttcagactgt gagagttatt aaaaaataag gtgaaatgat 3060 gataagaagc tggattaggt gtggagaata aatactactt gagataaggg agacctcttt 3120 gaaaggacat agccaaaagc ttagtataaa attaaaaaaa ataaaaaaaa aa 3172 4 6228 DNA Homo sapiens 4 cgggttcctg ctgcactacc atgcgccgtg cggcccgtgc gactcgccgg acctcgcggg 60 cgtccctgta cggagccctc ggccggtcct agcagggatt gtccccattt ccagctccgg 120 agcgggcggc tgcgccccgc tcgtcgagga gctgcgctca cctcaggggc gggcccccgc 180 ctgcgttcgc ggcgccaaga agagtattcc tttccactta caactaaata agacctgctt 240 ttgctggagc tgtgctaggc tgagggaatt ccacactgaa ttttacaagc gggatggatt 300 tctctaaggc agaagactga tttttggaaa tatgtatttg ggagacagtc acgtcctatt 360 gaataccttg tgctggtgct gccatcgaaa aatctggtta cactctgggg aggactgcta 420 ccactgcaga actgaaccac ttcggccgtg agatgagtgt ccggcctgag caggcacacc 480 atgaatagat acacaacaat caggcagctc ggggatggaa cctacggttc cgtcctgctg 540 ggaagaagca ttgagtctgg ggagctgatc gctattaaaa aaatgaaaag aaaattttat 600 tcctgggagg aatgcatgaa ccttcgggag gttaagtctt taaagaagct caaccatgcc 660 aatgtagtca aattaaaaga agttatcagg gaaaatgatc atctttattt tatcttcgag 720 tacatgaagg aaaatcttta ccagctcatt aaagagagaa ataagttgtt tcctgagtct 780 gctataagga atatcatgta tcagatatta caaggactcg catttattca caaacacggc 840 ttctttcatc gagacttaaa gcctgagaac ctcctctgca tgggaccaga acttgtgaaa 900 attgcagact ttggtttggc ccgagaaata cgatcaaaac ctccatatac agattatgta 960 tctaccagat ggtacagggc tccagaagta ctcctgaggt ctaccaacta cagctccccc 1020 attgacgtct gggcggtggg ctgcatcatg gcagaagttt acaccctcag gccactcttc 1080 cctggagcca gtgaaattga cacaatattc aaaatttgcc aagtgctggg gacaccaaaa 1140 aagactgact ggcctgaagg ctatcaactt tcaagtgcaa tgaacttccg ttggccacag 1200 tgtgtaccca ataacttaaa gaccttgatt cccaatgcta gcagtgaagc agtccagctc 1260 ctgagagaca tgcttcagtg ggatcccaag aaacgaccaa cagctagtca ggcacttcga 1320 tatccttact tccaagttgg acacccacta ggcagcacca cacaaaacct tcaggattca 1380 gaaaaaccac agaaaggcat cctggaaaag gcaggcccac ctccttatat taagccagtc 1440 ccacctgccc agccaccagc caagccacac acacgaattt cttcacgaca gcatcaagcc 1500 agccagcccc ctctgcatct cacgtacccc tacaaagcag aggtctccag gacagatcac 1560 ccaagccatc tccaggagga caagccaagc ccgttgcttt tcccatccct ccacaacaag 1620 catccacagt cgaaaatcac agctggcctg gagcacaaaa atggtgagat aaagccaaag 1680 agtaggagaa ggtggggtct tatttccagg tcaacaaagg attcagatga ttgggctgac 1740 ttggatgact tggatttcag tccatccctc agcaggattg acctgaaaaa caagaaaaga 1800 cagagtgatg acactctctg caggtttgag agtgttttgg acctgaagcc ctctgagcct 1860 gtgggcacag gaaacagtgc ccccacccag acgtcatatc agcggcgaga cacgcccacc 1920 ctgagatctg cagccaagca gcactatttg aagcactctc gatacttgcc tgggatcagt 1980 ataagaaatg gcatactctc gaatccaggc aaggaattta ttccacctaa tccatggtct 2040 agttctggct tgtctggaaa atcttcaggg acaatgtcag taatcagcaa agtaaattca 2100 gttggttcca gctctacaag ttctagtgga ctgactggaa actatgtccc ttcctttctg 2160 aaaaaagaaa tcggttctgc tatgcagagg gtacacctag cacctattcc agacccttcc 2220 cctggttatt cctccctgaa ggccatgaga cctcatcctg ggcgaccatt cttccacacc 2280 cagcctagaa gcactcctgg gttgatacca cggcctccag ccgcccagcc agtgcatggc 2340 cggacagact gggcttccaa gtacgcatct cggcgatgac tgtctgcctt ggtgatgaat 2400 ctcttcctag ggagaagcag gatactttcc ctcagctgac tggtgttcta cctgcaagat 2460 gtgcagaggg cataaaagca aatcaacact ttatagttat tcttctgaac taagacatgt 2520 caatattctt ttttaaagtt tttttttaaa atattgattt gaatgcagta ggcttttttg 2580 tataaaatta ttttattcta aaactgggtc ccattatttt cttaaacaac agcattttgt 2640 atatatggat tatgttttag cattttatac agtcaacttt gtaatgaact ttttaaaaat 2700 taattgattt tcctttgggg ttccagataa tattttctac agattttgaa aaatgtaata 2760 atattaatgc agtattgcaa caggggtgca atttaaggct atgtgataga gggttattta 2820 ctcagtgtgt gcagatattt atgaagtggt gaaatttcaa gtgtggctca ctaggtactt 2880 caggccttct tggactgttg ttagaaaagt gatcctctgc ttttcttagt aggtcattgg 2940 tttgattttt ggataccact ctgctgttct aaaaggacta ttatattata taattcactt 3000 tgttttactt ttgttcccca gatgaaagaa ctctaagtaa atacatttta aaaaattttt 3060 ctgacaccct ttaatgtggt tgcagatctc agatgaaacc aagcttaatt atactatgcc 3120 attatattct aatttattcc atttttgaaa tcaagttgta tgtgtaccaa taaaagagat 3180 ttctgcttca aaaggctctc aacatgaagg ttaacacagt caatcaaact tacattcctg 3240 ccaagatgca tggccaaaaa actaagtatc aaagcagcag aaggtttttg attatagtaa 3300 ctgagatgga attttgtgcc tagctcagtt ctccagatct ggctaggagc agtcaatgac 3360 taatgttctg tcctagccaa attctcagga caatttgggg agcagaaaga gttatggcag 3420 aggttccact catctacaaa gtcacagtca catgccacat ttgatctcct aaccctggtg 3480 tagtttcttt caagagtgag aactttattt gttgggcaga ggctgttcca ttgagaggaa 3540 tgtttacagc agtttcaaaa atgacaaagt cagtttggag acagaaaaag acaaaaggtc 3600 cagtctcatc catctctata tggtacattt gcctcactta tggttgcctt aaaggcaaga 3660 gggaaggtca ccatcagtga acgcaatgca atctcaacag tgtattgatt catattctcc 3720 tagggctcaa actactctct attggttcca ggataatgac aaattgaacc atatgtaagt 3780 aatcttttat tttttatttt ttttttgaga cagagtctca ctctgtcacc caggctggag 3840 tgcagtggcg cgatcttagc tctctgcaac ctctgcctcc caggttcaag cctcctgagt 3900 aactgggact acaggcgccc gccaccacgc ccagctaatt ttttgtattt ttagtagaga 3960 cggggtttca ctgtgttagc caggacggcc tcgatctcct gacctcgtga tccaccctcc 4020 tccacctccc aaagtactgg gattacaggc atgagccact gcacccagcc aagtgatcat 4080 ttttataggt taaaatgata ggtgaaatga atatagacac tttcatatgg ttcaacctaa 4140 tgacttggta aattattgcc ttggtgtatt aataatatgt tgcattctga acaaataacc 4200 atggcttcca aagggcccta acctaaaatc ggagagtaat ttatgctttg gagaatttga 4260 ctcaaatata tacttgacca

agcaccatga tccctagggg catgagaaaa gcacataatg 4320 gatgtggatg tgataggtgg tcttttcctg ttaacaagct ggcagcaaag cttcagaaaa 4380 tatatatgca agcacaactt gaagctgaat tcatttctgt attatattct caactcgtta 4440 tctaaagcat cagaacatgt gttttcagag atgagtcctt tactataagg ttaatattta 4500 ttttcatttt ctgtattata tatgaaaagt aaattaatgt gaaacctggc ccagcttgct 4560 ggaaagcagg ttttaaattg taaatattcc ttagaggagc aaatggattg tttaatacca 4620 tagtctcagt aatctagctt atataaggtc attacatttt ttaactgaaa aacctagtta 4680 cctgattatt gcacattata aaattgtttt tctaatactt tatagggccc aacttcagaa 4740 aatacttcgc ttttttcttt ttatgctttc gtttgtttac cagcaagcaa cttccctggg 4800 gaagccaaac acatattcat aaaaaaaatc aagtagctga tgtgcagttg agaaaactag 4860 aggactgaaa aaacaaattt taactagcaa atgctgtgaa ttactcttcc tccccttctc 4920 tgaaatgggt aaaggacaaa ttgtgtaaaa aaacctatgc actatagaag ggaatagtaa 4980 ccatttcttt tgtctctctg tttctgttct gactgagaac ctgcagccat ttcttgttac 5040 atgaaaacaa aatgctactt gttacctcta ttttttgtta ctatacaatt atgaaatgta 5100 atgtaagaca ccaacagaaa tgatatacct gtaactgtac ctatcaggac tatacctcat 5160 ttacagtcag aaagcttact gggatgtcag gaaatgatac agggttggtt ctcatttcgt 5220 gccgaaatga gacagaaatt cagtgacgaa ggtgcgttgt aggggtattg atgtgcccca 5280 ggtagtgcca gcagagtagg gaaaactgca tttgcataaa aactactctt gacatgattg 5340 ttcattttac aaaaaaattc cattaattac caagccctca cccagcccat gtgtgatagg 5400 atttatgtag gaagaaactt gattttcaaa taatttttta aatgtatctc ttgcctaaag 5460 gactatatac atctaataaa gtaacactgt gtcatcttct ggagttatca aaaattgtat 5520 acaatcaaga caacacaaga attattttat ttttgagtgc aaatacaggt actgttggag 5580 ttgatgggca ccatgctttc tcatgaagta gcatttccct accatcaagc cattgttttg 5640 tgccattcag gagaggaaaa aaaggaattt atgctgtaca tttcagttca gtgtatgacc 5700 aaaagcaata tgtttataag aagatgtttg acatactaat tattttatat catttaaacc 5760 atactgtagc aacataatat atggagctaa tttgtagaat tatttttacg atttccaaac 5820 aaatgtactg tactgttata taatttattg tgaggacctt ctcatggaag ccattaggaa 5880 aacaaactag aggtaaatat cacattaatc tgtattatca atttctcata gacactgtgc 5940 taatgtgaat tttaaatgac ctgcatcaag tcttctgatc tcagataact cagtacagat 6000 agcaattagt cagctgattt gattacaatg gagtaaccga caatatattt atttataaag 6060 cacatattca taataacgag aagaattcag aaaaccactt aagcaagacc cttctgaaat 6120 aaaaaatgtt gctttttaaa tagtttgtcc taaggtgttt aaaacatgtc aaccttatgt 6180 aaggaaaaat ttcctggtcc aaataaagtt gaagtttaag aaaaattg 6228 5 6095 DNA Homo sapiens 5 gcgccgtgcg gcccgtgcga ctcgccggac ctcgcgggcg tccctgtacg gagccctcgg 60 ccggtcctag cagggattgt ccccatttcc agctccggag cgggcggctg cgccccgctc 120 gtcgaggagc tgcgctcacc tcaggggcgg gcccccgcct gcgttcgcgg cgccagcaga 180 agactgattt ttggaaatat gtatttggga gacagtcacg tcctattgaa taccttgtgc 240 tggtgctgcc atcgaaaaat ctggttacac tctggggagg actgctacca ctgcagaact 300 gaaccacttc ggccgtgaga tgagtgtccg gcctgagcag gcacaccatg aatagataca 360 caacaatcag gcagctcggg gatggaacct acggttccgt cctgctggga agaagcattg 420 agtctgggga gctgatcgct attaaaaaaa tgaaaagaaa attttattcc tgggaggaat 480 gcatgaacct tcgggaggtt aagtctttaa agaagctcaa ccatgccaat gtagtcaaat 540 taaaagaagt tatcagggaa aatgatcatc tttattttat cttcgagtac atgaaggaaa 600 atctttacca gctcattaaa gagagaaata agttgtttcc tgagtctgct ataaggaata 660 tcatgtatca gatattacaa ggactcgcat ttattcacaa acacggcttc tttcatcgag 720 acttaaagcc tgagaacctc ctctgcatgg gaccagaact tgtgaaaatt gcagactttg 780 gtttggcccg agaaatacga tcaaaacctc catatacaga ttatgtatct accagatggt 840 acagggctcc agaagtactc ctgaggtcta ccaactacag ctcccccatt gacgtctggg 900 cggtgggctg catcatggca gaagtttaca ccctcaggcc actcttccct ggagccagtg 960 aaattgacac aatattcaaa atttgccaag tgctggggac accaaaaaag actgactggc 1020 ctgaaggcta tcaactttca agtgcaatga acttccgttg gccacagtgt gtacccaata 1080 acttaaagac cttgattccc aatgctagca gtgaagcagt ccagctcctg agagacatgc 1140 ttcagtggga tcccaagaaa cgaccaacag ctagtcaggc acttcgatat ccttacttcc 1200 aagttggaca cccactaggc agcaccacac aaaaccttca ggattcagaa aaaccacaga 1260 aaggcatcct ggaaaaggca ggcccacctc cttatattaa gccagtccca cctgcccagc 1320 caccagccaa gccacacaca cgaatttctt cacgacagca tcaagccagc cagccccctc 1380 tgcatctcac gtacccctac aaagcagagg tctccaggac agatcaccca agccatctcc 1440 aggaggacaa gccaagcccg ttgcttttcc catccctcca caacaagcat ccacagtcga 1500 aaatcacagc tggcctggag cacaaaaatg gtgagataaa gccaaagagt aggagaaggt 1560 ggggtcttat ttccaggtca acaaaggatt cagatgattg ggctgacttg gatgacttgg 1620 atttcagtcc atccctcagc aggattgacc tgaaaaacaa gaaaagacag agtgatgaca 1680 ctctctgcag gtttgagagt gttttggacc tgaagccctc tgagcctgtg ggcacaggaa 1740 acagtgcccc cacccagacg tcatatcagc ggcgagacac gcccaccctg agatctgcag 1800 ccaagcagca ctatttgaag cactctcgat acttgcctgg gatcagtata agaaatggca 1860 tactctcgaa tccaggcaag gaatttattc cacctaatcc atggtctagt tctggcttgt 1920 ctggaaaatc ttcagggaca atgtcagtaa tcagcaaagt aaattcagtt ggttccagct 1980 ctacaagttc tagtggactg actggaaact atgtcccttc ctttctgaaa aaagaaatcg 2040 gttctgctat gcagagggta cacctagcac ctattccaga cccttcccct ggttattcct 2100 ccctgaaggc catgagacct catcctgggc gaccattctt ccacacccag cctagaagca 2160 ctcctgggtt gataccacgg cctccagccg cccagccagt gcatggccgg acagactggg 2220 cttccaagta cgcatctcgg cgatgactgt ctgccttggt gatgaatctc ttcctaggga 2280 gaagcaggat actttccctc agctgactgg tgttctacct gcaagatgtg cagagggcat 2340 aaaagcaaat caacacttta tagttattct tctgaactaa gacatgtcaa tattcttttt 2400 taaagttttt ttttaaaata ttgatttgaa tgcagtaggc ttttttgtat aaaattattt 2460 tattctaaaa ctgggtccca ttattttctt aaacaacagc attttgtata tatggattat 2520 gttttagcat tttatacagt caactttgta atgaactttt taaaaattaa ttgattttcc 2580 tttggggttc cagataatat tttctacaga ttttgaaaaa tgtaataata ttaatgcagt 2640 attgcaacag gggtgcaatt taaggctatg tgatagaggg ttatttactc agtgtgtgca 2700 gatatttatg aagtggtgaa atttcaagtg tggctcacta ggtacttcag gccttcttgg 2760 actgttgtta gaaaagtgat cctctgcttt tcttagtagg tcattggttt gatttttgga 2820 taccactctg ctgttctaaa aggactatta tattatataa ttcactttgt tttacttttg 2880 ttccccagat gaaagaactc taagtaaata cattttaaaa aatttttctg acacccttta 2940 atgtggttgc agatctcaga tgaaaccaag cttaattata ctatgccatt atattctaat 3000 ttattccatt tttgaaatca agttgtatgt gtaccaataa aagagatttc tgcttcaaaa 3060 ggctctcaac atgaaggtta acacagtcaa tcaaacttac attcctgcca agatgcatgg 3120 ccaaaaaact aagtatcaaa gcagcagaag gtttttgatt atagtaactg agatggaatt 3180 ttgtgcctag ctcagttctc cagatctggc taggagcagt caatgactaa tgttctgtcc 3240 tagccaaatt ctcaggacaa tttggggagc agaaagagtt atggcagagg ttccactcat 3300 ctacaaagtc acagtcacat gccacatttg atctcctaac cctggtgtag tttctttcaa 3360 gagtgagaac tttatttgtt gggcagaggc tgttccattg agaggaatgt ttacagcagt 3420 ttcaaaaatg acaaagtcag tttggagaca gaaaaagaca aaaggtccag tctcatccat 3480 ctctatatgg tacatttgcc tcacttatgg ttgccttaaa ggcaagaggg aaggtcacca 3540 tcagtgaacg caatgcaatc tcaacagtgt attgattcat attctcctag ggctcaaact 3600 actctctatt ggttccagga taatgacaaa ttgaaccata tgtaagtaat cttttatttt 3660 ttattttttt tttgagacag agtctcactc tgtcacccag gctggagtgc agtggcgcga 3720 tcttagctct ctgcaacctc tgcctcccag gttcaagcct cctgagtaac tgggactaca 3780 ggcgcccgcc accacgccca gctaattttt tgtattttta gtagagacgg ggtttcactg 3840 tgttagccag gacggcctcg atctcctgac ctcgtgatcc accctcctcc acctcccaaa 3900 gtactgggat tacaggcatg agccactgca cccagccaag tgatcatttt tataggttaa 3960 aatgataggt gaaatgaata tagacacttt catatggttc aacctaatga cttggtaaat 4020 tattgccttg gtgtattaat aatatgttgc attctgaaca aataaccatg gcttccaaag 4080 ggccctaacc taaaatcgga gagtaattta tgctttggag aatttgactc aaatatatac 4140 ttgaccaagc accatgatcc ctaggggcat gagaaaagca cataatggat gtggatgtga 4200 taggtggtct tttcctgtta acaagctggc agcaaagctt cagaaaatat atatgcaagc 4260 acaacttgaa gctgaattca tttctgtatt atattctcaa ctcgttatct aaagcatcag 4320 aacatgtgtt ttcagagatg agtcctttac tataaggtta atatttattt tcattttctg 4380 tattatatat gaaaagtaaa ttaatgtgaa acctggccca gcttgctgga aagcaggttt 4440 taaattgtaa atattcctta gaggagcaaa tggattgttt aataccatag tctcagtaat 4500 ctagcttata taaggtcatt acatttttta actgaaaaac ctagttacct gattattgca 4560 cattataaaa ttgtttttct aatactttat agggcccaac ttcagaaaat acttcgcttt 4620 tttcttttta tgctttcgtt tgtttaccag caagcaactt ccctggggaa gccaaacaca 4680 tattcataaa aaaaatcaag tagctgatgt gcagttgaga aaactagagg actgaaaaaa 4740 caaattttaa ctagcaaatg ctgtgaatta ctcttcctcc ccttctctga aatgggtaaa 4800 ggacaaattg tgtaaaaaaa cctatgcact atagaaggga atagtaacca tttcttttgt 4860 ctctctgttt ctgttctgac tgagaacctg cagccatttc ttgttacatg aaaacaaaat 4920 gctacttgtt acctctattt tttgttacta tacaattatg aaatgtaatg taagacacca 4980 acagaaatga tatacctgta actgtaccta tcaggactat acctcattta cagtcagaaa 5040 gcttactggg atgtcaggaa atgatacagg gttggttctc atttcgtgcc gaaatgagac 5100 agaaattcag tgacgaaggt gcgttgtagg ggtattgatg tgccccaggt agtgccagca 5160 gagtagggaa aactgcattt gcataaaaac tactcttgac atgattgttc attttacaaa 5220 aaaattccat taattaccaa gccctcaccc agcccatgtg tgataggatt tatgtaggaa 5280 gaaacttgat tttcaaataa ttttttaaat gtatctcttg cctaaaggac tatatacatc 5340 taataaagta acactgtgtc atcttctgga gttatcaaaa attgtataca atcaagacaa 5400 cacaagaatt attttatttt tgagtgcaaa tacaggtact gttggagttg atgggcacca 5460 tgctttctca tgaagtagca tttccctacc atcaagccat tgttttgtgc cattcaggag 5520 aggaaaaaaa ggaatttatg ctgtacattt cagttcagtg tatgaccaaa agcaatatgt 5580 ttataagaag atgtttgaca tactaattat tttatatcat ttaaaccata ctgtagcaac 5640 ataatatatg gagctaattt gtagaattat ttttacgatt tccaaacaaa tgtactgtac 5700 tgttatataa tttattgtga ggaccttctc atggaagcca ttaggaaaac aaactagagg 5760 taaatatcac attaatctgt attatcaatt tctcatagac actgtgctaa tgtgaatttt 5820 aaatgacctg catcaagtct tctgatctca gataactcag tacagatagc aattagtcag 5880 ctgatttgat tacaatggag taaccgacaa tatatttatt tataaagcac atattcataa 5940 taacgagaag aattcagaaa accacttaag caagaccctt ctgaaataaa aaatgttgct 6000 ttttaaatag tttgtcctaa ggtgtttaaa acatgtcaac cttatgtaag gaaaaatttc 6060 ctggtccaaa taaagttgaa gtttaagaaa aattg 6095 6 1368 DNA Homo sapiens 6 atgatctgct gcagtgctct gagccctagg attcatcttt cttttcaccg tagcctgact 60 ggcattgtat tagcaaactc atcactagac atcgtactac acgacacgta ctacgttgta 120 gcccactgcg ggggaaatgt taggcgcctg cattgcggtg gccccgcgtc ccgggagcgc 180 acagcaatgc aggcgcttaa cattaccccg gagcagttct ctcggctgct gcgggaccac 240 aacctgacgc gggagcagtt catcgctctg taccggctgc gaccgctcgt ctacacccca 300 gagctgccgg gacgcgccaa gctggccctc gtgctcaccg gcgtgctcat cttcgccctg 360 gcactctttg gcaatgctct ggtgttctac gtggtgaccc gcagcaaggc catgcgcacc 420 gtcaccaaca tctttatctg ctccttggcg ctcagtgacc tgctcatcac cttcttctgc 480 attcccgtca ccatgctcca gaacatttcc gacaactggc tggggggtgc tttcatttgc 540 aagatggtgc catttgtcca gtctaccgct gttgtgacag aaatcctcac tatgacctgc 600 attgctgtgg aaaggcacca gggacttgtg catcctttta aaatgaagtg gcaatacacc 660 aaccgaaggg ctttcacaat gctaggtgtg gtctggctgg tggcagtcat cgtaggatca 720 cccatgtggc acgtgcaaca acttgagatc aaatatgact tcctatatga aaaggaacac 780 atctgctgct tagaagagtg gaccagccct gtgcaccaga agatctacac caccttcatc 840 ctgtcatcct cttcctcctg cctcttatgg aagaagaaac gagctgtcat tatgatggtg 900 acagtggtgg ctctctttgc tgtgtgctgg gcaccattcc atgttgtcca tatgatgatt 960 gaatacagta attttgaaaa ggaatatgat gatgtcacaa tcaagatgat ttttgctatc 1020 gtgcaaatta ttggattttc caactccatc tgtaatccca ttgtctatgc atttatgaat 1080 gaaaacttca aaaaaaatgt tttgtctgca gtttgttatt gcatagtaaa taaaaccttc 1140 tctccagcac aaaggcatgg aaattcagga attacaatga tgcggaagaa agcaaagttt 1200 tccctcagag agaatccagt ggaggaaacc aaaggagaag cattcagtga tggcaacatt 1260 gaagtcaaat tgtgtgaaca gacagaggag aagaaaaagc tcaaacgaca tcttgctctc 1320 tttaggtctg aactggctga gaattctcct ttagacagtg ggcattaa 1368 7 1296 DNA Homo sapiens 7 atgcaggcgc ttaacattac cccggagcag ttctctcggc tgctgcggga ccacaacctg 60 acgcgggagc agttcatcgc agttcatcgc ctgcgaccgc tcgtctacac cccagagctg 120 ccgggacgcg ccaagctggc cctcgtgctc accggcgtgc tcatcttcgc cctggcgctc 180 tttggcaatg ctctggtgtt ctacgtggtg acccgcagca aggccatgcg caccgtcacc 240 aacatcttta tctgctcctt ggcgctcagt gacctgctca tcaccttctt ctgcattccc 300 gtcaccatgc tccagaacat ttccgacaac tggctggggg gtgctttcat ttgcaagatg 360 gtgccatttg tccagtctac cgctgttgtg acagaaatcc tcactatgac ctgcattgct 420 gtggaaaggc accagggact tgtgcatcct tttaaaatga agtggcaata caccaaccga 480 agggctttca caatgctagg tgtggtctgg ctggtggcag tcatcgtagg atcacccatg 540 tggcacgtgc aacaacttga gatcaaatat gacttcctat atgaaaagga acacatctgc 600 tgcttagaag agtggaccag ccctgtgcac cagaagatct acaccacctt catccttgtc 660 atcctcttcc tcctgcctct tatggtgatg cttattctgt acagtaaaat tggttatgaa 720 ctttggataa agaaaagagt tggggatggt tcagtgcttc gaactattca tggaaaagaa 780 atgtccaaaa tagccaggaa gaagaaacga gctgtcatta tgatggtgac agtggtggct 840 ctctttgctg tgtgctgggc accattccat gttgtccata tgatgattga atacagtaat 900 tttgaaaagg aatatgatga tgtcacaatc aagatgattt ttgctatcgt gcaaattatt 960 ggattttcca actccatctg taatcccatt gtctatgcat ttatgaatga aaacttcaaa 1020 aaaaatgttt tgtctgcagt ttgttattgc atagtaaata aaaccttctc tccagcacaa 1080 aggcatggaa attcaggaat tacaatgatg cggaagaaag caaagttttc cctcagagag 1140 aatccagtgg aggaaaccaa aggagaagca ttcagtgatg gcaacattga agtcaaattg 1200 tgtgaacaga cagaggagaa gaaaaagctc aaacgacatc ttgctctctt taggtctgaa 1260 ctggctgaga attctccttt agacagtggg cattaa 1296 8 4350 DNA Homo sapiens 8 agttgaggga ttgacacaaa tggtcaggcg gcggcggcgg agaaggaggc ggaggcgcag 60 gggggagccg agcccgctgg gctgcggaga gttgcgctct ctacggggcc gcggccacta 120 gcgcggcgcc gccagccggg agccagcgag ccgagggcca ggaaggcggg acacgacccc 180 ggcgcgccct agccacccgg gttctccccg ccgcccgcgc ttcatgaatc gcaagtttcc 240 gcggcggcgg cggctgcggt acgcagaaca ggagccgggg gagcgggccg aaagcggctt 300 gggctcgacg gagggcaccc gcgcagaggt ctccctggcc gcagggggag ccgccgccgg 360 ccgtgcccct ggcagcccca gcggagcggc gccaagagag gagccgagaa agtatggctg 420 aggaggaggc gcctaagaag tcccgggccg ccggcggtgg cgcgagctgg gaactttgtg 480 ccggggcgct ctcggcccgg ctggcggagg agggcagcgg ggacgccggt ggccgccgcc 540 gcccgccagt tgacccccgg cgattggcgc gccagctgct gctgctgctt tggctgctgg 600 aggctccgct gctgctgggg gtccgggccc aggcggcggg ccaggggcca ggccaggggc 660 ccgggccggg gcagcaaccg ccgccgccgc ctcagcagca acagagcggg cagcagtaca 720 acggcgagcg gggcatctcc gtcccggacc acggctattg ccagcccatc tccatcccgc 780 tgtgcacgga catcgcgtac aaccagacca tcatgcccaa cctgctgggc cacacgaacc 840 aggaggacgc gggcctggag gtgcaccagt tctaccctct agtgaaagtg cagtgttccg 900 ctgagctcaa gttcttcctg tgctccatgt acgcgcccgt gtgcaccgtg ctagagcagg 960 cgctgccgcc ctgccgctcc ctgtgcgagc gcgcgcgcca gggctgcgag gcgctcatga 1020 acaagttcgg cttccagtgg ccagacacgc tcaagtgtga gaagttcccg gtgcacggcg 1080 ccggcgagct gtgcgtgggc cagaacacgt ccgacaaggg caccccgacg ccctcgctgc 1140 ttccagagtt ctggaccagc aaccctcagc acggcggcgg agggcaccgt ggcggcttcc 1200 cggggggcgc cggcgcgtcg gagcgaggca agttctcctg cccgcgcgcc ctcaaggtgc 1260 cctcctacct caactaccac ttcctggggg agaaggactg cggcgcacct tgtgagccga 1320 ccaaggtgta tgggctcatg tacttcgggc ccgaggagct gcgcttctcg cgcacctgga 1380 ttggcatttg gtcagtgctg tgctgcgcct ccacgctctt cacggtgctt acgtacctgg 1440 tggacatgcg gcgcttcagc tacccggagc ggcccatcat cttcttgtcc ggctgttaca 1500 cggccgtggc cgtggcctac atcgccggct tcctcctgga agaccgagtg gtgtgtaatg 1560 acaagttcgc cgaggacggg gcacgcactg tggcgcaggg caccaagaag gagggctgca 1620 ccatcctctt catgatgctc tacttcttca gcatggccag ctccatctgg tgggtgatcc 1680 tgtcgctcac ctggttcctg gcggctggca tgaagtgggg ccacgaggcc atcgaagcca 1740 actcacagta ttttcacctg gccgcctggg ctgtgccggc catcaagacc atcaccatcc 1800 tggcgctggg ccaggtggac ggcgatgtgc tgagcggagt gtgcttcgtg gggcttaaca 1860 acgtggacgc gctgcgtggc ttcgtgctgg cgcccctctt cgtgtacctg tttatcggca 1920 cgtcctttct gctggccggc tttgtgtcgc tcttccgcat ccgcaccatc atgaagcacg 1980 atggcaccaa gaccgagaag ctggagaagc tcatggtgcg cattggcgtc ttcagcgtgc 2040 tgtacactgt gccagccacc atcgtcatcg cctgctactt ctacgagcag gccttccggg 2100 accagtggga acgcagctgg gtggcccaga gctgcaagag ctacgctatc ccctgccctc 2160 acctccaggc gggcggaggc gccccgccgc acccgcccat gagcccggac ttcacggtct 2220 tcatgattaa gtaccttatg acgctgatcg tgggcatcac gtcgggcttc tggatctggt 2280 ccggcaagac cctcaactcc tggaggaagt tctacacgag gctcaccaac agcaaacaag 2340 gggagactac agtctgagac ccggggctca gcccatgccc aggcctcggc cggggcgcag 2400 cgatccccca aagccagcgc cgtggagttc gtgccaatcc tgacatctcg aggtttcctc 2460 actagacaac tctctttcgc aggctccttt gaacaactca gctcctgcaa aagcttccgt 2520 ccctgaggca aaaggacacg agggcccgac tgccagaggg aggatggaca gacctcttgc 2580 cctcacactc tggtaccagg actgttcgct tttatgattg taaatagcct gtgtaagatt 2640 tttgtaagta tatttgtatt taaatgacga ccgatcacgc gtttttcttt ttcaaaagtt 2700 tttaattatt tagggcggtt taaccatttg aggcttttcc ttcttgccct tttcggagta 2760 ttgcaaagga gctaaaactg gtgtgcaacc gcacagcgct cctggtcgtc ctcgcgcgcc 2820 tctccctacc acgggtgctc gggacggctg ggcgccagct ccggggcgag ttcagcactg 2880 cggggtgcga ctagggctgc gctgccaggg tcacttcccg cctcctcctt ttgccccctc 2940 cccctccttc tgtcccctcc ctttctttcc tggcttgagg taggggctct taaggtacag 3000 aactccacaa accttccaaa tctggaggag ggcccccata cattacaatt cctcccttgc 3060 tcggcggtgg attgcgaagg cccgtccctt cgacttcctg aagctggatt tttaactgtc 3120 cagaactttc ctccaacttc atgggggccc acgggtgtgg gcgctggcag tctcagcctc 3180 cctccacggt caccttcaac gcccagacac tcccttctcc caccttagtt ggttacaggg 3240 tgagtgagat aaccaatgcc aaactttttg aagtctaatt tttgaggggt gagctcattt 3300 cattctctag tgtctaaaac ctggtatggg tttggccagc gtcatggaaa gatgtggtta 3360 ctgagatttg ggaagaagca tgaagctttg tgtgggttgg aagagactga agatatgggt 3420 tataaaatgt taattctaat tgcatacgga tgcctggcaa ccttgccttt gagaatgaga 3480 cagcctgcgc ttagatttta ccggtctgta aaatggaaat gttgaggtca cctggaaagc 3540 tttgttaagg agttgatgtt tgctttcctt aacaagacag caaaacgtaa acagaaattg 3600 aaaacttgaa ggatatttca gtgtcatgga cttcctcaaa atgaagtgct attttcttat 3660 ttttaatcaa ataactagac atatatcaga aactttaaaa tgtaaaagtt gtacactttc 3720 aacattttat tacgattatt attcagcagc acattctgag gggggaacaa ttcacaccac 3780 caataataac ctggtaagat ttcaggaggt aaagaaggtg gaataattga cggggagata 3840 gcgcctgaaa taaacaaaat atgggcatgc atgctaaagg gaaaatgtgt gcaggtctac 3900 tgcattaaat cctgtgtgct cctcttttgg atttacagaa atgtgtcaaa tgtaaatctt 3960 tcaaagccat ttaaaaatat tcactttagt tctctgtgaa gaagaggaga aaagcaatcc 4020 tcctgattgt attgttttaa actttaagaa tttatcaaaa tgccggtact taggacctaa 4080 atttatctat gtctgtcata cgctaaaatg atattggtct ttgaatttgg tatacattta 4140 ttctgttcac tatcacaaaa

tcatctatat ttatagagga atagaagttt atatatatat 4200 aataccatat ttttaatttc acaaataaaa aattcaaagt tttgtacaaa attatatgga 4260 ttttgtgcct gaaaataata gagcttgagc tgtctgaact attttacatt ttatggtgtc 4320 tcatagccaa tcccacagtg taaaaattca 4350 9 952 DNA Homo sapiens 9 ttggtccaag caagaaggca gtggtctact ccatcggcaa catgctggtc ctttatggac 60 acagcaccca ggaccttccg gaaaccaatg cccgcgtagt cggagggact gaggccggga 120 ggaattcctg gccctctcag atttccctcc agtaccggtc tggaggttcc cggtatcaca 180 cctgtggagg gacccttatc agacagaact gggtgatgac agctgctcac tgcgtggatt 240 accagaagac tttccgcgtg gtggctggag accataacct gagccagaat gatggcactg 300 agcagtacgt gagtgtgcag aagatcgtgg tgcatccata ctggaacagc gataacgtgg 360 ctgccggcta tgacatcgcc ctgctgcgcc tggcccagag cgttaccctc aatagctatg 420 tccagctggg tgttctgccc caggagggag ccatcctggc taacaacagt ccctgctaca 480 tcacaggctg gggcaagacc aagaccaatg ggcagctggc ccagaccctg cagcaggctt 540 acctgccctc tgtggactac gccatctgct ccagctcctc ctactggggc tccactgtga 600 agaacaccat ggtgtgtgct ggtggagatg gagttcgctc tggatgccag ggtgactctg 660 ggggccccct ccattgcttg gtgaatggca agtattctgt ccatggagtg accagctttg 720 tgtccagccg gggctgtaat gtctccagga agcctacagt cttcacccag gtctctgctt 780 acatctcctg gataaataat gtcatcgcct ccaactgaac attttcctga gtccaacgac 840 cttcccaaaa tggttcttag atctgcaata ggacttgcga tcaaaaagta aaacacattc 900 tgaaagacta ttgagccatt gatagaaaag caaataaaac tagatataca tt 952 10 9372 DNA Homo sapiens 10 tgaataattg aactttgttt atttctccat atttttgcag tggtaattcc attataaaac 60 ctaatgaaac aatgttttta tagatggtgt ggaaagactt ttctgggctc agaggtgaaa 120 ctgacccttg tgtatcagca gcatttctga ctgactgaga gagtgtagtg attaacagag 180 ttgtgatgtt agttaagaaa cttagatttg ccattgtagc ttttctacca attagcagat 240 tgtttaactc actgaaattg taaagtggta gacgtggact tagtcattac tgggcagctt 300 atgaattgta ttcatttact catgatgtaa aaatggttag tctccacttt taaggctcta 360 gttctagtgg ctaaataggt acttatttat acagtatgat aactgctgta ttaaaataca 420 tgtctcaaat gtggaatagt agaagaggtg aagaaaatca tagtttgagg tagaatactg 480 tttgctggtc ttaaaaactg tggtattttg gtgattccat aaattaggtc agatacttcc 540 actggaggga aacagtttaa aggatatatg tgatactatt aatagaatga ggaagacaca 600 ccagatattt aggagggaat tagcgagctt gaaactaaga gctggtttga atgagactgg 660 gtcataagtg atttcaagta ccagattaag gcactgagat tttattttta agcactgaag 720 tcagattttt tccttttaaa agaaaggatt catgatgaaa tctgcttttt gttttgcaga 780 gagcttggag ataattctgg tggctgtgtg gagtatgtgt tggaggtatt aaattttcac 840 agtatatata aggcagcaat tgataggcct ttcacagatt cttctgataa ctacataaag 900 agacaaaaaa aagaaaaaag agcaaagatc tgtgctgtgt caagtatgac agccatcact 960 catggctctc cagtaggagg gaacgacagc cagggccagg ttcttgatgg ccagtctcag 1020 catctcttcc aacagaacca gacttcatca cctgattctt ccaatgagaa ttccgtagca 1080 actcctcctc cagaggaaca agggcaaggt gatgccccac cacagcatga agatgaagag 1140 cctgcatttc cacatactga gctggcaaac ctggatgaca tgatcaacag gcctcgatgg 1200 gtggttcctg ttttgccaaa aggggaatta gaagtgcttt tagaagctgc tattgatctt 1260 agtgtaaaag gccttgatgt taaaagtgaa gcatgccaac gtttttttcg agatggacta 1320 acaatatctt tcactaaaat tcttatggat gaggctgtga gtggctggaa gtttgaaatt 1380 catagatgta ttattaacaa tactcatcgc ctagtggagc tttgtgtggc caagttgtcc 1440 caagattggt ttccacttct agaacttctc gccatggcct taaatcctca ctgcaagttt 1500 catatctaca atggtacacg tccgtgtgaa ttaatttcct caaatgctca gttgcctgaa 1560 gaagaattat ttgctcgttc ttcagatcct cgatcaccaa aaggttggct agtggatctc 1620 atcaataaat ttggcacatt aaatgggttc cagattttgc atgatcgttt ttttaatgga 1680 tcagcattaa atattcaaat aattgcagct cttattaaac catttggaca atgctatgag 1740 tttctcagtc aacatacact gaaaaagtac ttcattccag ttatagaaat agttccacat 1800 ttattggaaa acttaactga tgaagaactg aaaaaggagg caaagaatga agccaaaaat 1860 gatgcccttt caatgattat taaatctttg aagaacttag cttcaagaat ttcaggacaa 1920 gatgagacta taaaaaattt ggaaattttt aggttaaaga tgatactcag attgttgcaa 1980 atttcctctt ttaatggaaa gatgaatgca ctgaatgaaa taaataaggt tatatctagt 2040 gtatcatatt atactcatcg gcatagtaat cctgaggagg aagaatggct gacagctgag 2100 cgaatggcag aatggataca gcaaaataat atcttatcca tagtcttgca agacagtctt 2160 catcaaccac aatatgtaga aaagctagag aaaattcttc gttttgtgat taaagaaaag 2220 gctcttacat tacaggacct tgataatatc tgggcagcac aggcaggaaa acatgaagcc 2280 attgtgaaga atgtacatga tctgctagca aagttggctt gggatttttc tcctggacaa 2340 cttgatcatc tttttgattg ctttaaggca agttggacaa atgcaagtaa aaagcaacgt 2400 gaaaagctcc ttgagttgat acgccgtctt gcagaagatg ataaagatgg tgtgatggca 2460 cacaaagtgt tgaaccttct ttggaacctg gctcagagtg atgatgtgcc tgtagacatc 2520 atggaccttg ctcttagtgc ccacataaaa atactagatt atagttgttc ccaggatcga 2580 gatgcacaga agatccagtg gatagatcac tttatagaag aacttcgcac aaatgacaag 2640 tgggtaattc ctgctctgaa acaaataaga gaaatttgta gtttgtttgg tgaagcatct 2700 caaaatttga gtcaaactca gcgaagtccc cacatatttt atcgccatga tttaatcaac 2760 cagcttcaac aaaatcatgc tttagttact ttggtagcag aaaaccttgc aacctacatg 2820 aatagcatca gattgtatgc tggagatcat gaagactatg atccacaaac agtgaggctt 2880 ggaagtcgat acagtcatgt tcaagaagtt caagaacgac taaacttcct tagattttta 2940 ctgaaggatg gccaactgtg gctctgtgct cctcaggcaa aacaaatatg gaagtgctta 3000 gcagaaaatg cagtttatct ttgtgatcgt gaagcctgtt ttaagtggta ttccaagtta 3060 atgggggatg aaccagactt ggatcctgat attaataagg acttctttga aagtaatgta 3120 cttcagcttg atccttccct tttaactgaa aatggaatga aatgctttga aagatttttc 3180 aaagctgtca attgtcgaga aaggaaacta atagcaaaaa gaagatccta tatgatggat 3240 gatttggaat taattggact agactacctt tggagggttg tgattcagag tagtgacgag 3300 attgctaaca gagctataga tcttcttaaa gagatataca caaaccttgg cccaagatta 3360 aaagccaatc aggtggttat ccatgaagac ttcattcagt cttgctttga tcgtttaaaa 3420 gcatcatatg atacactgtg tgtttttgat ggtgacaaaa acagcattaa ttgtgcaaga 3480 caagaagcca ttcgaatggt tagagtatta actgttataa aagagtacat taatgaatgt 3540 gacagtgatt atcacaagga aagaatgatt ttacctatgt cgagagcatt ttgtggcaaa 3600 cacctctctc ttatagttcg gtttccaaac cagggcagac aggttgatga gttggatata 3660 tggtttcata cgaatgacac aattggttca gtacggcgat gtattgttaa tcgtattaaa 3720 gccaatgtag cccacaaaaa aattgaactt tttgtgggtg gtgagctgat agattctgaa 3780 aatgacagaa agctaattgg acaattaaac ttaaaagata aatctctaat tacagccaaa 3840 cttacacaaa taaatttcaa tatgccatca agtcctgata gctcttccga ttcctcaact 3900 gcatctcctg gaaaccaccg taatcattac aatgatggtc ccaatctaaa ggtggaaagt 3960 tgtttgcctg gggtgataat gtcagtgcat cccaaataca tctctttcct ttggcaattt 4020 gcaaacttag gtagcaacct gaatatgcca cctcttaaaa atggagcaag agtacttatg 4080 aaacttatgc caccagatag aacagctgta gaaaaattac gaactgtttg tttggaccat 4140 gcaaaccttg gagaaggcaa acttagtcca ccccttgact cccttttctt tggtccttct 4200 gcctcccaag ttctatacct aacagaggta gtttatgcct tgttaatgcc tgctggtgtg 4260 cctctaactg atgggtcctc tgactttcaa gttcacttct tgaaaagtgg tggcttacct 4320 cttgtactga gtatgctaat aagaaataac ttcttgccaa atacagatat ggaaactcga 4380 aggggtgctt atttaaatgc tcttaaaata gccaaactgt tgttaactgc gattggctat 4440 ggccatgttc gagctgtagc agaagcttgt cagccagttg tagatggtac agaccccata 4500 acacagatta accaagttac tcatgatcaa gcagtggtgc tacaaagtgc ccttcagagc 4560 attcctaatc cctcatccga gtgcgtactt agaaatgagt ccatacttct tgctcaggaa 4620 atatctaatg aggcttcaag atatatgcct gatatttgtg taattagggc tatacagaaa 4680 attatctggg catcagcatg tggggcatta ggactatttt ttagcccaaa tgaagaaata 4740 actaaaattt atcagatgac caccaatgga agcaataagc tggaggtgga agatgaacaa 4800 gtttgttgtg aagcactgga agtgatgacc ttatgttttg ctttacttcc aacagcgttg 4860 gatgcactta gtaaagaaaa agcctggcag accttcatca ttgacttatt attgcactgt 4920 ccaagcaaaa ctgttcgtca gttggcacag gagcagttct ttttaatgtg caccagatgt 4980 tgcatgggac acaggcctct gcttttcttc attactttac tctttaccat actggggagc 5040 acagcaagag agaagggtaa atattcaggt gattatttca cacttttacg gcaccttctc 5100 aattatgctt acaatggcaa tattaacata cccaatgctg aagttcttct tgtcagtgaa 5160 attgattggc tcaaaaggat tagggataat gttaaaaaca caggtgaaac aggtgtcgaa 5220 gagccaatac tggaaggcca ccttggggta acaaaagagt tattggcctt tcaaacttct 5280 gagaaaaagt atcactttgg ttgtgaaaaa ggaggtgcta atctcattaa agaattaatt 5340 gatgatttca tctttcccgc atccaaagtt tacctgcagt atttaagaag tggagaacta 5400 ccagctgagc aggctattcc agtctgtagt tcacccgtta ccatcaatgc cggttttgag 5460 ctacttgtag cattagctat tggctgtgtg aggaatctca aacagatagt agactgtttg 5520 actgaaatgt attacatggg cacagcaatt actacttgtg aagcacttac tgagtgggaa 5580 tatctgcccc ctgttggacc ccgcccacca aaaggatttg tgggactcaa aaatgctggt 5640 gctacgtgtt acatgaactc tgtgatccag cagctataca tgattccttc tatcaggaac 5700 agtattcttg caattgaagg cacaggtagt gatttacacg atgatatgtt cggggatgag 5760 aagcaggaca gtgagagtaa tgttgatccc cgagatgatg tatttggata tcctcatcaa 5820 tttgaagaca agccagcatt aagtaagaca gaagatagga aagagtataa tattggtgtc 5880 ctaagacacc ttcaggtcat ctttggtcat ttagctgctt cccaactaca atactatgta 5940 cccagaggat tttggaaaca gttcaggctt tggggtgaac ctgttaatct ccgtgaacaa 6000 catgatgcct tagagttttt taattctttg gtggatagtt tagatgaagc tttaaaagct 6060 ttaggacacc cggctatact aagtaaagtc ctaggaggct cctttgctga tcagaagatc 6120 tgccagggct gcccacatag gtttgaatgt gaagaatctt ttacaacttt gaatgtggat 6180 attagaaatc atcaaaatct tcttgactct ttggaacagt atatcaaagg agatttattg 6240 gaaggtgcaa atgcatatca ttgtgaaaaa tgtgataaaa aggttgacac agtaaagcgc 6300 ctgctaatta aaaaattgcc tcgggttctt gctatccaac tcaaacgatt tgactatgac 6360 tgggaaagag aatgtgcaat taaattcaat gattattttg aatttcctcg agagctggat 6420 atgggacctt acacagtagc aggtgttgca aacctggaaa gggataatgt aaactcagaa 6480 aatgagttga ttgaacagaa agagcagtct gacaatgaaa ctgcaggagg cacaaagtac 6540 agacttgtag gagtgcttgt acacagtggt caagcaagcg gtgggcatta ttattcttac 6600 atcattcaaa ggaatggtaa agatgatcag acagatcact ggtataaatt tgatgatgga 6660 gatgtaacag aatgcaaaat ggatgatgat gaagaaatga aaaatcagtg ttttggtgga 6720 gagtacatgg gagaagtatt tgatcacatg atgaagcgca tgtcatatag gcgacagaag 6780 aggtggtgga atgcttacat acctttttat gaacaaatgg atatgataga tgaagatgat 6840 gagatgataa gatacatatc agagctaact attgcaagac cccatcagat cattatgtca 6900 ccagccattg agagaagtgt acggaaacaa aatgtgaaat ttatgcataa ccgattgcaa 6960 tatagtttag agtattttca gtttgtgaaa aaactgctta catgtaatgg tgtttattta 7020 aaccctgctc cagggcagga ttatttgttg cctgaagcag aagaaattac tatgattagt 7080 attcagcttg ctgctagatt cctctttacc actggatttc acaccaagaa aatagttcgt 7140 ggtcctgcca gtgactggta tgatgcactg tgcgttcttc tccgtcacag caaaaatgta 7200 cgtttttggt ttactcataa tgtccttttt aatgtatcaa atcgcttctc tgaatacctc 7260 ctggagtgcc ctagtgcaga agtgaggggt gcatttgcaa aacttatagt gtttattgca 7320 cacttttcct tgcaagatgg gtcttgtcct tctccttttg catctccagg accttctagt 7380 caggcatgtg ataacttgag cttgagtgac cacttactaa gagccacact aaatctcttg 7440 agaagggaag tttcagagca tggacatcat ttacagcaat attttaattt gtttgtaatg 7500 tatgccaatt taggtgtggc agaaaaaaca cagcttctga aattgaatgt acctgctacc 7560 tttatgcttg tgtctttaga cgagggacca ggtcctccaa tcaaatatca gtatgctgaa 7620 ttaggcaagt tatattcagt agtgtctcag ctgattcgtt gttgcaatgt gtcatcaaca 7680 atgcagtctt caatcaatgg taatccccct ctccccaatc ctttcggtga ccttaattta 7740 tcacagccta taatgccaat tcagcagaat gtgttagaca ttttatttgt gagaacaagt 7800 tatgtgaaga aaattattga agactgcagt aactcagagg ataccatcaa attacttcgc 7860 ttttgctctt gggagaatcc tcagttctca tctactgtcc tcagcgaact tctctggcag 7920 gttgcatatt catataccta tgaacttcgg ccatatttag atctactttt ccaaatttta 7980 ctgattgagg actcctggca gactcacaga attcataatg cacttaaagg aattccagat 8040 gacagagatg ggctgttcga tacaatacag cgctcgaaga atcactatca aaaacgagca 8100 tatcagtgca taaaatgtat ggtagctcta tttagcagtt gtcctgttgc ttaccagatc 8160 ttacagggta acggagatct taaaagaaaa tggacctggg cagtggaatg gctaggagat 8220 gaacttgaaa gaagaccata tactggcaat cctcagtata gttacaacaa ttggtctcct 8280 ccagtacaaa gcaatgaaac agcaaatggt tatttcttag aaagatcaca tagtgctagg 8340 atgacacttg caaaagcttg tgaactctgt ccagaagagg agccagatga ccaggatgcc 8400 ccagatgagc atgagccctc tccatcagaa gatgccccat tatatcctca ttcacctgcc 8460 tctcagtatc aacagaataa tcatgtacat ggacagccat atacaggacc agcagcacat 8520 cacttgaaca accctcagaa aacaggccaa cgaacacaag aaaattatga aggcaatgaa 8580 gaagtatcct cacctcagat gaaggatcag tgaaaagcaa taattaactg cttcctttat 8640 gactatgcac taaggtctta tagtccaaac tttctctgtg tctggctagt attgaaaact 8700 agataaactg ctccaaacca acatggagta aagagcatat tcactggttt atttgcagta 8760 atttgcaatt tgtcagtgta taagacacat gcagggtgaa gtgtacagag ttttgtaaca 8820 aatgactggt cctaatctgt aaatgagaaa ggtatatata ctatgttaat gtctgactgt 8880 taattcttaa gcaagaaact ttttttgatg aaaacaagtc agatctacac agtcacacaa 8940 ttattttttg ttgtgttcac tacattgtgc aattgatatt gcctgctttg agcagtttgg 9000 tcaacttacc aacttccccc caaaaaaggg aacataaaag agcccatctt tgtcagttta 9060 caccaatagt ttcttgttaa tccttctttc ctggatatat aaggctggtg gtaacttttg 9120 aattatatgg ttgatgtgga aaattggcag tgtaacattt ctagatactt ttcattacct 9180 ttttattctg gtatataggc taaccacttt aaagctattc ttatgctgta acagttagca 9240 tggcttcaca ctgtttgtgt agccaagagg acagaattac atgaatgaca gtgcccagag 9300 tgacagctgt atattgctca gagcttttat ttcttatacc tagaataaat ataaaatggg 9360 ggaaaaaaaa aa 9372 11 1593 DNA Homo sapiens 11 ctgggagcgc ggcgtaggtg gctgccgagt cttttcctgt ttagggtctt atcctggcat 60 tgagggcgcc ggactggcgc ttttggccgg cttggcattg ggtgggcggc ttcttgggac 120 ccacatgagc cagtggcatc atccccgcag tggctggggc cggagacgcg acttttcagg 180 acgctcctca gccaagaaga agggcggaaa ccacatcccc gaaaggtgga aagactatct 240 cccagttgga cagcggatgc ctgggactcg tttcattgct ttcaaagttc ctttgcaaaa 300 gagttttgaa aagaaacttg ctccagaaga atgcttttcc cctttggatc tttttaacaa 360 aatccgagaa caaaatgaag aacttggact gattattgat ttaacatata ctcaacgcta 420 ttataaacca gaggatttgc cagaaactgt tccttactta aaaattttta cagttggaca 480 tcaagtgcct gatgatgaga ctatttttaa attcaaacac gctgttaatg ggtttttgaa 540 agaaaataaa gataatgata aacttattgg tgtccactgt acccatggtt taaacaggac 600 tggctacctc atttgcagat atttgattga tgtagaaggc gtgaggccag atgatgcaat 660 tgaattattc aataggtgcc ggggacattg cttagaaaga caaaactaca ttgaagacct 720 tcagaatggt cctatcagaa agaattggaa ttccagtgta cccaggtcaa gtgattttga 780 agactcagca catctcatgc aaccagtcca caataagcct gttaaacaag gacctaggta 840 taatctacat cagatccagg gtcactcagc tcctcgacat ttccacaccc agacccaaag 900 tttgcaacaa tcagtcagaa aattttcaga gaatccacat gtttaccaga gacaccatct 960 ccctcctcct ggtccccctg gagaggacta ttcacacagg aggtattctt ggaatgtgaa 1020 gcccaatgcc agtcgggcag cccaggatag aagaaggtgg tatccttata attactccag 1080 actctcctat ccagcctgtt gggaatggac ccagtgatac aaacctgtcc tggaattcta 1140 cctggagacc agagctggcc tgaaaattac tggtgtgact tttaattagt tcaggtctaa 1200 tcaggtttct ttattgttcc cttatgtatt caagcttaag gaaaaattgc attgctgttt 1260 acctctttgc tgataaattt gcagtaatta cagcattgca ggaaaaacaa tctgttattc 1320 cagtcttaaa tttttctaaa agaagacaat attttagaac tgaagcattg agaacttccc 1380 ttgcaaatta tttttaaaat tctatcttgt ttttctatgt atttctttct gactagactt 1440 gtgatatgcg tgtgtttatg tacagaaatt tttagtgttt ttgttatgtt ctgttattga 1500 cccaaaggcc atctttattt tctataactg ttcaaaattt atattaaaat ctacttagga 1560 gataatttct ttagaaaaaa aaaaaaaaaa aaa 1593 12 4116 DNA Homo sapiens 12 cgccgctctc cgcctcgctt gctcctgccg ggcgtgcagg gccccgccgc cgccatgtcg 60 ggctcgttcg agctctcggt gcaggatctc aacgacctgc tctcggacgg cagcggctgc 120 tacagcctcc cgagccagcc ctgcaacgag gtcaccccgc ggatctacgt gggcaacgcg 180 tctgtggctc aggacatccc caagctgcag aaactaggca tcacccatgt gctgaacgcg 240 gctgagggca ggtccttcat gcacgtcaac accaatgcca acttctacaa ggactccggc 300 atcacatacc tgggcatcaa ggccaacgac acacaggagt tcaacctcag cgcttacttt 360 gaaagggctg ccgacttcat tgaccaggct ttggctcaaa agaatggccg ggtgctcgtc 420 cactgccggg aaggttatag ccgctcccca acgctagtta tcgcctacct catgatgcgg 480 cagaagatgg acgtcaagtc tgccctgagc atcgtgaggc agaaccgtga gatcggcccc 540 aacgatggct tcctggccca gctctgccag ctcaatgaca gactagccaa ggaggggaag 600 ttgaaaccct agggcacccc caccgcctct gctcgagagg tccgtggggg aggccgtggg 660 caaaggtgtc ccgagctgcc atgtttagga aacacactgt accctgctcc cagcatcaca 720 aggcacttgt ctacaagtgt gtcccaacac agtcctgggc cactttcccc accctgggga 780 gcacataaag aagcttgcca aggggggcgt ccttgctccc cagttgtcct gtttctgtaa 840 cttatgatgt cttttccctg agatgggggc tcagaggggg aaggcctgtg gcctgcatgc 900 ttcccgatgg cccacggcag gaggtgtgtg gaagtgtaag gcctaagatg ctcacagagg 960 tccctcatga cctcccttcc ccaactcccg aatcctctct tgagtgtgga cctcaacacc 1020 ttgagcccta gtaaaggaac tatgcaaatg caggccactc tccccaccac gtctgtgccc 1080 cgcactgtcc ccacagcctt ccacaccctg tgcataggca gccctctcac gtcttgaggt 1140 ccgaagctgg ggtgggggtg tccgtcagtt attagtggat ggagattccc acagcaaggc 1200 tgcatttgaa tgatttcctt aggatgaatg gtccctacac aaagaggcct tgtgggcaaa 1260 cctggagaac cctcctaaat ccatagagtt ttcaaaatgt gaatctttgg aagccttgag 1320 ttcagaatct gctgctctgg aatatttccc ttcgatctta tctcagtcac ttcgtttttg 1380 agaagagtga tgccttgggc atgctttttt ttttttcttt tttagaaaac agggagttga 1440 agtccaacct atttaaaaac cccaccattt ggagaattac aagggttttg tcctgaattg 1500 tagtgttggc aagcccaagc cactcgtgct aactgctttt tgtctcggtt gctattccaa 1560 gaacagaagg aggaagttgg ccaattacag cgtgtgtgca tggatgtgtg tggggggcgt 1620 gcctctcaga aacgcggcca gaagacaagc agggaagtga aaggtcccag gcacacaccc 1680 tgcccattgc aggtggctct tacagctctc tggtgccagc acgggatccc tgaagtgact 1740 cagccaggca gacatgagac atggcggagt gtccaaatgg atcctttatt ggtggtagag 1800 caaaaaaacc caaacacgat aaacctttca aaagactttc taaggatgat attggaatgc 1860 accagccctc acatgtgtat gcacatttgc cagaatataa gagttttgtt ttaaatacag 1920 tcttgttagg attttacgtt attgttatta tggaaagtga ttgtgatgct atttatcttc 1980 agggtcactc tgggcaaaga gaaggtcctc agccatgccc ccagcacctt gcacataggt 2040 gtctgataaa agtttaagaa attaaacact ttttgagcac caaatatata tagggcattg 2100 ttctggtggg tgtgtcacgc tcccagaaga ctgaatttat ggtaggatca ctcgcaaggc 2160 cttgtgaagg agtcttacct aaaacaaaag aaatatcagg gacttttgtt gactatttac 2220 aactcagttt tacatttaaa ttcaggcagt gttaatatgc caaggtaggg aatgtgcctt 2280 tttcagagtt ggccaggagc tcctggctgg gacacggaga ggcaggtgtg gcgtaaggcc 2340 tcactcccgg ctgtgaaggt ctctgatcac acagaagcag ccctgcccag cctggtcatt 2400 tgctgtccgc ttttctctgt gaccacagca gccctgaaca accagtatgt gtcttcttct 2460 ccagatagtg aaaaaggtgt ccagataaac ccacctaagt gaaatggcca tcctctaaac 2520 tgggtacctc actgcacagc ttctaggtag ccttccaact taatctaact tgagcctcac 2580 agtaaccctg taaagttagt agagcttgtt cttgtattgt gacctttttt aaaaaaaagg 2640 aactgaggtt cagaatgatt aagggcctgg cccccagggt tgtccagctc cataaggtgg 2700 agctgggcaa gattttgggt ttgctgctcc ctgaagctgg

attctttcat acgatactct 2760 ttctcaagaa gggggctccc tgggatctcc aggtgtactg cacttaccct caatccagcc 2820 ccggagaagc aagtgaaaag ggtgggtccc tcataggcta gaatgtgcag ctctttctcc 2880 aggtgggatg tagcacccca aagtagagct ttctgctctg ctcctggaaa aggctaggga 2940 gctggggctg gggctcccct cccatgacca ggcagtggtc accccatggg acaggcacag 3000 ctacttacgc gaacacagca ggttggtgtg gctggctaac taggacctct cgaaagtctc 3060 tgtgggggca tgagggagaa aaggccattg ggagaattac tgcctttact ttgggactac 3120 ttttatgctg ataacttggg atttcttgat agtccttcac ccctgaaacc ccgtatttac 3180 ttaacaagat ttagctctta gttcttcaag taaaattaaa gtctcttgtg taagagccaa 3240 cacatgccca gctgcggatg ggagctgttc ctggacagcc ttctactgcc tgggaagtga 3300 tggaacagga actcagggtg cccttacccc ctccccagac ctgttccctt tctttgactg 3360 acagagcacc atccaggcaa aattagagcg ccaaatggtt ttcttctcaa tcttaaagca 3420 gtataccttt ccacaggctc gtctgtgtcc ctgccactct gagttatcca gaaaccacca 3480 cctacaaatg aggggactca tctagaagac ctctaaggtc cccttttggc tctgaggggt 3540 ctctaataat ccccacttgg aattcagcac cgcaaggaaa ttatgggtat gtgagccata 3600 atatgatggc cagcaggtgg cgctgccttc cacccatggt gatggatggt ttggaaaggg 3660 aatgttggtg ccttttgtgc cacaagttaa gatgctactg ttttaaagga aaaaaaaaaa 3720 aaaaagtact gatcttcaat atgaagacat gagcttttct cgcaggaaat tttctttttc 3780 acagaactgg tgtcaggaat cactgaaggg ctaaccgtga tagtccttgc aagtaagtca 3840 aggttttatc ctgattggaa atagaagaca tttccggttg agagaacaga ttcgttggaa 3900 gcttaacttt tgttgcctct taacgccacc aaattttagg gtaatttgat tatgaaagag 3960 tgaatttttc tggacagaaa agggagagct accaaattgt ttttttcttt ttaaaaggaa 4020 gtttaatgtc cgttgtatca caaatcagtg ttaaaacacc agaactttag ccaaaataaa 4080 tgtcttacat tacaaaggta aaaaaaaaaa aaaaaa 4116 13 3540 DNA Homo sapiens 13 ccagtttgct tcttggagaa cactggacag ctgaataaat gcagtatcta aatataaaag 60 aggactgcaa tgccatggct ttctgtgcta aaatgaggag ctccaagaag actgaggtga 120 acctggaggc ccctgagcca ggggtggaag tgatcttcta tctgtcggac agggagcccc 180 tccggctggg cagtggagag tacacagcag aggaactgtg catcagggct gcacaggcat 240 gccgtatctc tcctctttgt cacaacctct ttgccctgta tgacgagaac accaagctct 300 ggtatgctcc aaatcgcacc atcaccgttg atgacaagat gtccctccgg ctccactacc 360 ggatgaggtt ctatttcacc aattggcatg gaaccaacga caatgagcag tcagtgtggc 420 gtcattctcc aaagaagcag aaaaatggct acgagaaaaa aaagattcca gatgcaaccc 480 ctctccttga tgccagctca ctggagtatc tgtttgctca gggacagtat gatttggtga 540 aatgcctggc tcctattcga gaccccaaga ccgagcagga tggacatgat attgagaacg 600 agtgtctagg gatggctgtc ctggccatct cacactatgc catgatgaag aagatgcagt 660 tgccagaact gcccaaggac atcagctaca agcgatatat tccagaaaca ttgaataagt 720 ccatcagaca gaggaacctt ctcaccagga tgcggataaa taatgttttc aaggatttcc 780 taaaggaatt taacaacaag accatttgtg acagcagcgt gtccacgcat gacctgaagg 840 tgaaatactt ggctaccttg gaaactttga caaaacatta cggtgctgaa atatttgaga 900 cttccatgtt actgatttca tcagaaaatg agatgaattg gtttcattcg aatgacggtg 960 gaaacgttct ctactacgaa gtgatggtga ctgggaatct tggaatccag tggaggcata 1020 aaccaaatgt tgtttctgtt gaaaaggaaa aaaataaact gaagcggaaa aaactggaaa 1080 ataaagacaa gaaggatgag gagaaaaaca agatccggga agagtggaac aatttttcat 1140 tcttccctga aatcactcac attgtaataa aggagtctgt ggtcagcatt aacaagcagg 1200 acaacaagaa aatggaactg aagctctctt cccacgagga ggccttgtcc tttgtgtccc 1260 tggtagatgg ctacttccgg ctcacagcag atgcccatca ttacctctgc accgacgtgg 1320 cccccccgtt gatcgtccac aacatacaga atggctgtca tggtccaatc tgtacagaat 1380 acgccatcaa taaattgcgg caagaaggaa gcgaggaggg gatgtacgtg ctgaggtgga 1440 gctgcaccga ctttgacaac atcctcatga ccgtcacctg ctttgagaag tctgagcagg 1500 tgcagggtgc ccagaagcag ttcaagaact ttcagatcga ggtgcagaag ggccgctaca 1560 gtctgcacgg ttcggaccgc agcttcccca gcttgggaga cctcatgagc cacctcaaga 1620 agcagatcct gcgcacggat aacatcagct tcatgctaaa acgctgctgc cagcccaagc 1680 cccgagaaat ctccaacctg ctggtggcta ctaagaaagc ccaggagtgg cagcccgtct 1740 accccatgag ccagctgagt ttcgatcgga tcctcaagaa ggatctggtg cagggcgagc 1800 accttgggag aggcacgaga acacacatct attctgggac cctgatggat tacaaggatg 1860 acgaaggaac ttctgaagag aagaagataa aagtgatcct caaagtctta gaccccagcc 1920 acagggatat ttccctggcc ttcttcgagg cagccagcat gatgagacag gtctcccaca 1980 aacacatcgt gtacctctat ggcgtctgtg tccgcgacgt ggagaatatc atggtggaag 2040 agtttgtgga agggggtcct ctggatctct tcatgcaccg gaaaagtgat gtccttacca 2100 caccatggaa attcaaagtt gccaaacagc tggccagtgc cctgagctac ttggaggata 2160 aagacctggt ccatggaaat gtgtgtacta aaaacctcct cctggcccgt gagggaatcg 2220 acagtgagtg tggcccattc atcaagctca gtgaccccgg catccccatt acggtgctgt 2280 ctaggcaaga atgcattgaa cgaatcccat ggattgctcc tgagtgtgtt gaggactcca 2340 agaacctgag tgtggctgct gacaagtgga gctttggaac cacgctctgg gaaatctgct 2400 acaatggcga gatccccttg aaagacaaga cgctgattga gaaagagaga ttctatgaaa 2460 gccggtgcag gccagtgaca ccatcatgta aggagctggc tgacctcatg acccgctgca 2520 tgaactatga ccccaatcag aggcctttct tccgagccat catgagagac attaataagc 2580 ttgaagagca gaatccagat attgtttcca gaaaaaaaaa ccagccaact gaagtggacc 2640 ccacacattt tgagaagcgc ttcctaaaga ggatccgtga cttgggagag ggccactttg 2700 ggaaggttga gctctgcagg tatgaccccg aagacaatac aggggagcag gtggctgtta 2760 aatctctgaa gcctgagagt ggaggtaacc acatagctga tctgaaaaag gaaatcgaga 2820 tcttaaggaa cctctatcat gagaacattg tgaagtacaa aggaatctgc acagaagacg 2880 gaggaaatgg tattaagctc atcatggaat ttctgccttc gggaagcctt aaggaatatc 2940 ttccaaagaa taagaacaaa ataaacctca aacagcagct aaaatatgcc gttcagattt 3000 gtaaggggat ggactatttg ggttctcggc aatacgttca ccgggacttg gcagcaagaa 3060 atgtccttgt tgagagtgaa caccaagtga aaattggaga cttcggttta accaaagcaa 3120 ttgaaaccga taaggagtat tacaccgtca aggatgaccg ggacagccct gtgttttggt 3180 atgctccaga atgtttaatg caatctaaat tttatattgc ctctgacgtc tggtcttttg 3240 gagtcactct gcatgagctg ctgacttact gtgattcaga ttctagtccc atggctttgt 3300 tcctgaaaat gataggccca acccatggcc agatgacagt cacaagactt gtgaatacgt 3360 taaaagaagg aaaacgcctg ccgtgcccac ctaactgtcc agatgaggtt tatcagctta 3420 tgagaaaatg ctgggaattc caaccatcca atcggacaag ctttcagaac cttattgaag 3480 gatttgaagc acttttaaaa taagaagcat gaataacatt taaattccac agattatcaa 3540 14 3541 DNA Homo sapiens 14 tccagtttgc ttcttggaga acactggaca gctgaataaa tgcagtatct aaatataaaa 60 gaggactgca atgccatggc tttctgtgct aaaatgagga gctccaagaa gactgaggtg 120 aacctggagg cccctgagcc aggggtggaa gtgatcttct atctgtcgga cagggagccc 180 ctccggctgg gcagtggaga gtacacagca gaggaactgt gcatcagggc tgcacaggca 240 tgccgtatct ctcctctttg tcacaacctc tttgccctgt atgacgagaa caccaagctc 300 tggtatgctc caaatcgcac catcaccgtt gatgacaaga tgtccctccg gctccactac 360 cggatgaggt tctatttcac caattggcat ggaaccaacg acaatgagca gtcagtgtgg 420 cgtcattctc caaagaagca gaaaaatggc tacgagaaaa aaaagattcc agatgcaacc 480 cctctccttg atgccagctc actggagtat ctgtttgctc agggacagta tgatttggtg 540 aaatgcctgg ctcctattcg agaccccaag accgagcagg atggacatga tattgagaac 600 gagtgtctag ggatggctgt cctggccatc tcacactatg ccatgatgaa gaagatgcag 660 ttgccagaac tgcccaagga catcagctac aagcgatata ttccagaaac attgaataag 720 tccatcagac agaggaacct tctcaccagg atgcggataa ataatgtttt caaggatttc 780 ctaaaggaat ttaacaacaa gaccatttgt gacagcagcg tgtccacgca tgacctgaag 840 gtgaaatact tggctacctt ggaaactttg acaaaacatt acggtgctga aatatttgag 900 acttccatgt tactgatttc atcagaaaat gagatgaatt ggtttcattc gaatgacggt 960 ggaaacgttc tctactacga agtgatggtg actgggaatc ttggaatcca gtggaggcat 1020 aaaccaaatg ttgtttctgt tgaaaaggaa aaaaataaac tgaagcggaa aaaactggaa 1080 aataaagaca agaaggatga ggagaaaaac aagatccggg aagagtggaa caatttttca 1140 ttcttccctg aaatcactca cattgtaata aaggagtctg tggtcagcat taacaagcag 1200 gacaacaaga aaatggaact gaagctctct tcccacgagg aggccttgtc ctttgtgtcc 1260 ctggtagatg gctacttccg gctcacagca gatgcccatc attacctctg caccgacgtg 1320 gcccccccgt tgatcgtcca caacatacag aatggctgtc atggtccaat ctgtacagaa 1380 tacgccatca ataaattgcg gcaagaagga agcgaggagg ggatgtacgt gctgaggtgg 1440 agctgcaccg actttgacaa catcctcatg accgtcacct gctttgagaa gtctgagcag 1500 gtgcagggtg cccagaagca gttcaagaac tttcagatcg aggtgcagaa gggccgctac 1560 agtctgcacg gttcggaccg cagcttcccc agcttgggag acctcatgag ccacctcaag 1620 aagcagatcc tgcgcacgga taacatcagc ttcatgctaa aacgctgctg ccagcccaag 1680 ccccgagaaa tctccaacct gctggtggct actaagaaag cccaggagtg gcagcccgtc 1740 taccccatga gccagctgag tttcgatcgg atcctcaaga aggatctggt gcagggcgag 1800 caccttggga gaggcacgag aacacacatc tattctggga ccctgatgga ttacaaggat 1860 gacgaaggaa cttctgaaga gaagaagata aaagtgatcc tcaaagtctt agaccccagc 1920 cacagggata tttccctggc cttcttcgag gcagccagca tgatgagaca ggtctcccac 1980 aaacacatcg tgtacctcta tggcgtctgt gtccgcgacg tggagaatat catggtggaa 2040 gagtttgtgg aagggggtcc tctggatctc ttcatgcacc ggaaaagtga tgtccttacc 2100 acaccatgga aattcaaagt tgccaaacag ctggccagtg ccctgagcta cttggaggat 2160 aaagacctgg tccatggaaa tgtgtgtact aaaaacctcc tcctggcccg tgagggaatc 2220 gacagtgagt gtggcccatt catcaagctc agtgaccccg gcatccccat tacggtgctg 2280 tctaggcaag aatgcattga acgaatccca tggattgctc ctgagtgtgt tgaggactcc 2340 aagaacctga gtgtggctgc tgacaagtgg agctttggaa ccacgctctg ggaaatctgc 2400 tacaatggcg agatcccctt gaaagacaag acgctgattg agaaagagag attctatgaa 2460 agccggtgca ggccagtgac accatcatgt aaggagctgg ctgacctcat gacccgctgc 2520 atgaactatg accccaatca gaggcctttc ttccgagcca tcatgagaga cattaataag 2580 cttgaagagc agaatccaga tattgtttcc agaaaaaaaa accagccaac tgaagtggac 2640 cccacacatt ttgagaagcg cttcctaaag aggatccgtg acttgggaga gggccacttt 2700 gggaaggttg agctctgcag gtatgacccc gaagacaata caggggagca ggtggctgtt 2760 aaatctctga agcctgagag tggaggtaac cacatagctg atctgaaaaa ggaaatcgag 2820 atcttaagga acctctatca tgagaacatt gtgaagtaca aaggaatctg cacagaagac 2880 ggaggaaatg gtattaagct catcatggaa tttctgcctt cgggaagcct taaggaatat 2940 cttccaaaga ataagaacaa aataaacctc aaacagcagc taaaatatgc cgttcagatt 3000 tgtaagggga tggactattt gggttctcgg caatacgttc accgggactt ggcagcaaga 3060 aatgtccttg ttgagagtga acaccaagtg aaaattggag acttcggttt aaccaaagca 3120 attgaaaccg ataaggagta ttacaccgtc aaggatgacc gggacagccc tgtgttttgg 3180 tatgctccag aatgtttaat gcaatctaaa ttttatattg cctctgacgt ctggtctttt 3240 ggagtcactc tgcatgagct gctgacttac tgtgattcag attctagtcc catggctttg 3300 ttcctgaaaa tgataggccc aacccatggc cagatgacag tcacaagact tgtgaatacg 3360 ttaaaagaag gaaaacgcct gccgtgccca cctaactgtc cagatgaggt ttatcagctt 3420 atgagaaaat gctgggaatt ccaaccatcc aatcggacaa gctttcagaa ccttattgaa 3480 ggatttgaag cacttttaaa ataagaagca tgaataacat ttaaattcca cagattatca 3540 a 3541 15 2982 DNA Homo sapiens 15 cgcaccccgc gcagcggctg agccgggagc cagcgcagcc tcggccccgc agctcaagcc 60 tcgtccccgc cgccgccgcc gccgccgccg ccgccgcccc cggggcatgg cctgtctgat 120 ggccgctttc tcggtcggca ccgccatgaa tgccagcagt tactctgcag agatgacgga 180 gcccaagtcg gtgtgtgtct cggtggatga ggtggtgtcc agcaacatgg aggccactga 240 gacggacctg ctgaatggac atctgaaaaa agtagataat aacctcacgg aagcccagcg 300 cttctcctcc ttgcctcgga gggcagctgt gaacattgaa ttcagggacc tttcctattc 360 ggttcctgaa ggaccctggt ggaggaagaa aggatacaag accctcctga aaggaatttc 420 cgggaagttc aatagtggtg agttggtggc cattatgggt ccttccgggg ccgggaagtc 480 cacgctgatg aacatcctgg ctggatacag ggagacgggc atgaaggggg ccgtcctcat 540 caacggcctg ccccgggacc tgcgctgctt ccggaaggtg tcctgctaca tcatgcagga 600 tgacatgctg ctgccgcatc tcactgtgca ggaggccatg atggtgtcgg cacatctgaa 660 gcttcaggag aaggatgaag gcagaaggga aatggtcaag gagatactga cagcgctggg 720 cttgctgtct tgcgccaaca cgcggaccgg gagcctgtca ggtggtcagc gcaagcgcct 780 ggccatcgcg ctggagctgg tgaacaaccc tccagtcatg ttcttcgatg agcccaccag 840 cggcctggac agcgcctcct gcttccaggt ggtctcgctg atgaaagggc tcgctcaagg 900 gggtcgctcc atcatttgca ccatccacca gcccagcgcc aaactcttcg agctgttcga 960 ccagctttac gtcctgagtc aaggacaatg tgtgtaccgg ggaaaagtct gcaatcttgt 1020 gccatatttg agggatttgg gtctgaactg cccaacctac cacaacccag cagattttgt 1080 catggaggtt gcatccggcg agtacggtga tcagaacagt cggctggtga gagcggttcg 1140 ggagggcatg tgtgactcag accacaagag agacctcggg ggtgatgccg aggtgaaccc 1200 ttttctttgg caccggccct ctgaagagga ctcctcgtcc atggaaggct gccacagctt 1260 ctctgccagc tgcctcacgc agttctgcat cctcttcaag aggaccttcc tcagcatcat 1320 gagggactcg gtcctgacac acctgcgcat cacctcgcac attgggatcg gcctcctcat 1380 tggcctgctg tacttgggga tcgggaacga agccaagaag gtcttgagca actccggctt 1440 cctcttcttc tccatgctgt tcctcatgtt cgcggccctc atgcctactg ttctgacatt 1500 tcccctggag atgggagtct ttcttcggga acacctgaac tactggtaca gcctgaaggc 1560 ctactacctg gccaagacca tggcagacgt gccctttcag atcatgttcc cagtggccta 1620 ctgcagcatc gtgtactgga tgacgtcgca gccgtccgac gccgtgcgct ttgtgctgtt 1680 tgccgcgctg ggcaccatga cctccctggt ggcacagtcc ctgggcctgc tgatcggagc 1740 cgcctccacg tccctgcagg tggccacttt cgtgggccca gtgacagcca tcccggtgct 1800 cctgttctcg gggttcttcg tcagcttcga caccatcccc acgtacctac agtggatgtc 1860 ctacatctcc tatgtcaggt atgggttcga aggggtcatc ctctccatct atggcttaga 1920 ccgggaagat ctgcactgtg acatcgacga gacgtgccac ttccagaagt cggaggccat 1980 cctgcgggag ctggacgtgg aaaatgccaa gctgtacctg gacttcatcg tactcgggat 2040 tttcttcatc tccctccgcc tcattgccta ttttgtcctc aggtacaaaa tccgggcaga 2100 gaggtaaaac acctgaatgc caggaaacag gaagattaga cactgtggcc gagggcacgt 2160 ctagaatcga ggaggcaagc ctgtgcccga ccgacgacac agagactctt ctgatccaac 2220 ccctagaacc gcgttgggtt tgtgggtgtc tcgtgctcag ccactctgcc cagctgggtt 2280 ggatcttctc tccattcccc tttctagctt taactaggaa gatgtaggca gattggtggt 2340 tttttttttt ttaacataca gaattttaaa taccacaact ggggcagaat ttaaagctgc 2400 aacacagctg gtgatgagag gcttcctcag tccagtcgct ccttagcacc aggcaccgtg 2460 ggtcctggat ggggaactgc aagcagcctc tcagctgatg gctgcacagt cagatgtctg 2520 gtggcagaga gtccgagcat ggagcgattc cattttatga ctgttgtttt tcacattttc 2580 atctttctaa ggtgtgtctc ttttccaatg agaagtcatt tttgcaagcc aaaagtcgat 2640 caatcgcatt cattttaaga aattatacct ttttagtact tgctgaagaa tgattcaggg 2700 taaatcacat actttgttta gagaggcgag gggtttaacc gagtcaccca gctggtctca 2760 tacatagaca gcacttgtga aggattgaat gcaggttcca ggtggaggga agacgtggac 2820 accatctcca ctgagccatg cagacatttt taaaagctat acaaaaaatt gtgagaagac 2880 attggccaac tctttcaaag tctttctttt tccacgtgct tcttatttta agcgaaatat 2940 attgtttgtt tcttcctaaa aaaaaaaaaa aaaaaaaaaa aa 2982 16 3018 DNA Homo sapiens 16 cgcaccccgc gcagcggctg agccgggagc cagcgcagcc tcggccccgc agctcaagcc 60 tcgtccccgc cgccgccgcc gccgccgccg ccgccgcccc cggggcatgg cctgtctgat 120 ggccgctttc tcggtcggca ccgccatgaa tgccagcagt tactctgcag agatgacgga 180 gcccaagtcg gtgtgtgtct cggtggatga ggtggtgtcc agcaacatgg aggccactga 240 gacggacctg ctgaatggac atctgaaaaa agtagataat aacctcacgg aagcccagcg 300 cttctcctcc ttgcctcgga gggcagctgt gaacattgaa ttcagggacc tttcctattc 360 ggttcctgaa ggaccctggt ggaggaagaa aggatacaag accctcctga aaggaatttc 420 cgggaagttc aatagtggtg agttggtggc cattatgggt ccttccgggg ccgggaagtc 480 cacgctgatg aacatcctgg ctggatacag ggagacgggc atgaaggggg ccgtcctcat 540 caacggcctg ccccgggacc tgcgctgctt ccggaaggtg tcctgctaca tcatgcagga 600 tgacatgctg ctgccgcatc tcactgtgca ggaggccatg atggtgtcgg cacatctgaa 660 gcttcaggag aaggatgaag gcagaaggga aatggtcaag gagatactga cagcgctggg 720 cttgctgtct tgcgccaaca cgcggaccgg gagcctgtca ggtggtcagc gcaagcgcct 780 ggccatcgcg ctggagctgg tgaacaaccc tccagtcatg ttcttcgatg agcccaccag 840 cggcctggac agcgcctcct gcttccaggt ggtctcgctg atgaaagggc tcgctcaagg 900 gggtcgctcc atcatttgca ccatccacca gcccagcgcc aaactcttcg agctgttcga 960 ccagctttac gtcctgagtc aaggacaatg tgtgtaccgg ggaaaagtct gcaatcttgt 1020 gccatatttg agggatttgg gtctgaactg cccaacctac cacaacccag cagattttgt 1080 catggaggtt gcatccggcg agtacggtga tcagaacagt cggctggtga gagcggttcg 1140 ggagggcatg tgtgactcag accacaagag agacctcggg ggtgatgccg aggtgaaccc 1200 ttttctttgg caccggccct ctgaagaggt aaagcagaca aaacgattaa aggggttgag 1260 aaaggactcc tcgtccatgg aaggctgcca cagcttctct gccagctgcc tcacgcagtt 1320 ctgcatcctc ttcaagagga ccttcctcag catcatgagg gactcggtcc tgacacacct 1380 gcgcatcacc tcgcacattg ggatcggcct cctcattggc ctgctgtact tggggatcgg 1440 gaacgaagcc aagaaggtct tgagcaactc cggcttcctc ttcttctcca tgctgttcct 1500 catgttcgcg gccctcatgc ctactgttct gacatttccc ctggagatgg gagtctttct 1560 tcgggaacac ctgaactact ggtacagcct gaaggcctac tacctggcca agaccatggc 1620 agacgtgccc tttcagatca tgttcccagt ggcctactgc agcatcgtgt actggatgac 1680 gtcgcagccg tccgacgccg tgcgctttgt gctgtttgcc gcgctgggca ccatgacctc 1740 cctggtggca cagtccctgg gcctgctgat cggagccgcc tccacgtccc tgcaggtggc 1800 cactttcgtg ggcccagtga cagccatccc ggtgctcctg ttctcggggt tcttcgtcag 1860 cttcgacacc atccccacgt acctacagtg gatgtcctac atctcctatg tcaggtatgg 1920 gttcgaaggg gtcatcctct ccatctatgg cttagaccgg gaagatctgc actgtgacat 1980 cgacgagacg tgccacttcc agaagtcgga ggccatcctg cgggagctgg acgtggaaaa 2040 tgccaagctg tacctggact tcatcgtact cgggattttc ttcatctccc tccgcctcat 2100 tgcctatttt gtcctcaggt acaaaatccg ggcagagagg taaaacacct gaatgccagg 2160 aaacaggaag attagacact gtggccgagg gcacgtctag aatcgaggag gcaagcctgt 2220 gcccgaccga cgacacagag actcttctga tccaacccct agaaccgcgt tgggtttgtg 2280 ggtgtctcgt gctcagccac tctgcccagc tgggttggat cttctctcca ttcccctttc 2340 tagctttaac taggaagatg taggcagatt ggtggttttt ttttttttaa catacagaat 2400 tttaaatacc acaactgggg cagaatttaa agctgcaaca cagctggtga tgagaggctt 2460 cctcagtcca gtcgctcctt agcaccaggc accgtgggtc ctggatgggg aactgcaagc 2520 agcctctcag ctgatggctg cacagtcaga tgtctggtgg cagagagtcc gagcatggag 2580 cgattccatt ttatgactgt tgtttttcac attttcatct ttctaaggtg tgtctctttt 2640 ccaatgagaa gtcatttttg caagccaaaa gtcgatcaat cgcattcatt ttaagaaatt 2700 ataccttttt agtacttgct gaagaatgat tcagggtaaa tcacatactt tgtttagaga 2760 ggcgaggggt ttaaccgagt cacccagctg gtctcataca tagacagcac ttgtgaagga 2820 ttgaatgcag gttccaggtg gagggaagac gtggacacca tctccactga gccatgcaga 2880 catttttaaa agctatacaa aaaattgtga gaagacattg gccaactctt tcaaagtctt 2940 tctttttcca cgtgcttctt attttaagcg aaatatattg tttgtttctt cctaaaaaaa 3000 aaaaaaaaaa aaaaaaaa 3018 17 2983 DNA Homo sapiens 17 gcgaggggca agcccggatt cctgccggcc gcctttctgc gcgcgccgga gagagagacg 60 cggtggggac agggatgcgc atttcacttc cccgagctcc ggagagggat ggcggggtgt 120 cggcgagttc actgctggac acagttacta atgccagcag ttactctgca gagatgacgg 180 agcccaagtc ggtgtgtgtc tcggtggatg aggtggtgtc cagcaacatg gaggccactg 240 agacggacct gctgaatgga catctgaaaa aagtagataa taacctcacg gaagcccagc 300 gcttctcctc cttgcctcgg

agggcagctg tgaacattga attcagggac ctttcctatt 360 cggttcctga aggaccctgg tggaggaaga aaggatacaa gaccctcctg aaaggaattt 420 ccgggaagtt caatagtggt gagttggtgg ccattatggg tccttccggg gccgggaagt 480 ccacgctgat gaacatcctg gctggataca gggagacggg catgaagggg gccgtcctca 540 tcaacggcct gccccgggac ctgcgctgct tccggaaggt gtcctgctac atcatgcagg 600 atgacatgct gctgccgcat ctcactgtgc aggaggccat gatggtgtcg gcacatctga 660 agcttcagga gaaggatgaa ggcagaaggg aaatggtcaa ggagatactg acagcgctgg 720 gcttgctgtc ttgcgccaac acgcggaccg ggagcctgtc aggtggtcag cgcaagcgcc 780 tggccatcgc gctggagctg gtgaacaacc ctccagtcat gttcttcgat gagcccacca 840 gcggcctgga cagcgcctcc tgcttccagg tggtctcgct gatgaaaggg ctcgctcaag 900 ggggtcgctc catcatttgc accatccacc agcccagcgc caaactcttc gagctgttcg 960 accagcttta cgtcctgagt caaggacaat gtgtgtaccg gggaaaagtc tgcaatcttg 1020 tgccatattt gagggatttg ggtctgaact gcccaaccta ccacaaccca gcagattttg 1080 tcatggaggt tgcatccggc gagtacggtg atcagaacag tcggctggtg agagcggttc 1140 gggagggcat gtgtgactca gaccacaaga gagacctcgg gggtgatgcc gaggtgaacc 1200 cttttctttg gcaccggccc tctgaagagg actcctcgtc catggaaggc tgccacagct 1260 tctctgccag ctgcctcacg cagttctgca tcctcttcaa gaggaccttc ctcagcatca 1320 tgagggactc ggtcctgaca cacctgcgca tcacctcgca cattgggatc ggcctcctca 1380 ttggcctgct gtacttgggg atcgggaacg aagccaagaa ggtcttgagc aactccggct 1440 tcctcttctt ctccatgctg ttcctcatgt tcgcggccct catgcctact gttctgacat 1500 ttcccctgga gatgggagtc tttcttcggg aacacctgaa ctactggtac agcctgaagg 1560 cctactacct ggccaagacc atggcagacg tgccctttca gatcatgttc ccagtggcct 1620 actgcagcat cgtgtactgg atgacgtcgc agccgtccga cgccgtgcgc tttgtgctgt 1680 ttgccgcgct gggcaccatg acctccctgg tggcacagtc cctgggcctg ctgatcggag 1740 ccgcctccac gtccctgcag gtggccactt tcgtgggccc agtgacagcc atcccggtgc 1800 tcctgttctc ggggttcttc gtcagcttcg acaccatccc cacgtaccta cagtggatgt 1860 cctacatctc ctatgtcagg tatgggttcg aaggggtcat cctctccatc tatggcttag 1920 accgggaaga tctgcactgt gacatcgacg agacgtgcca cttccagaag tcggaggcca 1980 tcctgcggga gctggacgtg gaaaatgcca agctgtacct ggacttcatc gtactcggga 2040 ttttcttcat ctccctccgc ctcattgcct attttgtcct caggtacaaa atccgggcag 2100 agaggtaaaa cacctgaatg ccaggaaaca ggaagattag acactgtggc cgagggcacg 2160 tctagaatcg aggaggcaag cctgtgcccg accgacgaca cagagactct tctgatccaa 2220 cccctagaac cgcgttgggt ttgtgggtgt ctcgtgctca gccactctgc ccagctgggt 2280 tggatcttct ctccattccc ctttctagct ttaactagga agatgtaggc agattggtgg 2340 tttttttttt tttaacatac agaattttaa ataccacaac tggggcagaa tttaaagctg 2400 caacacagct ggtgatgaga ggcttcctca gtccagtcgc tccttagcac caggcaccgt 2460 gggtcctgga tggggaactg caagcagcct ctcagctgat ggctgcacag tcagatgtct 2520 ggtggcagag agtccgagca tggagcgatt ccattttatg actgttgttt ttcacatttt 2580 catctttcta aggtgtgtct cttttccaat gagaagtcat ttttgcaagc caaaagtcga 2640 tcaatcgcat tcattttaag aaattatacc tttttagtac ttgctgaaga atgattcagg 2700 gtaaatcaca tactttgttt agagaggcga ggggtttaac cgagtcaccc agctggtctc 2760 atacatagac agcacttgtg aaggattgaa tgcaggttcc aggtggaggg aagacgtgga 2820 caccatctcc actgagccat gcagacattt ttaaaagcta tacaaaaaat tgtgagaaga 2880 cattggccaa ctctttcaaa gtctttcttt ttccacgtgc ttcttatttt aagcgaaata 2940 tattgtttgt ttcttcctaa aaaaaaaaaa aaaaaaaaaa aaa 2983 18 3142 DNA Homo sapiens 18 agacactgaa tcatcatttg tagtttgggg ggctttacat gcctgcagtg gtgaaaactg 60 aaattttgtc ccacttaagg gagtttcttc ttccctttat taattgcaaa ataaatatat 120 gtcacttcag agggcagcag ctggactacc tatgtttgtg gcgctacacc aacctgaact 180 tcgcttcctg agacctaaga ttcagccccg tgctcagcag acatcaggga tcaccgactc 240 tgtgccagga gctgttcttg atgctgggaa cgcaggggtg gacaaaacag agaaagccct 300 gccctcagaa tgccagcagt tactctgcag agatgacgga gcccaagtcg gtgtgtgtct 360 cggtggatga ggtggtgtcc agcaacatgg aggccactga gacggacctg ctgaatggac 420 atctgaaaaa agtagataat aacctcacgg aagcccagcg cttctcctcc ttgcctcgga 480 gggcagctgt gaacattgaa ttcagggacc tttcctattc ggttcctgaa ggaccctggt 540 ggaggaagaa aggatacaag accctcctga aaggaatttc cgggaagttc aatagtggtg 600 agttggtggc cattatgggt ccttccgggg ccgggaagtc cacgctgatg aacatcctgg 660 ctggatacag ggagacgggc atgaaggggg ccgtcctcat caacggcctg ccccgggacc 720 tgcgctgctt ccggaaggtg tcctgctaca tcatgcagga tgacatgctg ctgccgcatc 780 tcactgtgca ggaggccatg atggtgtcgg cacatctgaa gcttcaggag aaggatgaag 840 gcagaaggga aatggtcaag gagatactga cagcgctggg cttgctgtct tgcgccaaca 900 cgcggaccgg gagcctgtca ggtggtcagc gcaagcgcct ggccatcgcg ctggagctgg 960 tgaacaaccc tccagtcatg ttcttcgatg agcccaccag cggcctggac agcgcctcct 1020 gcttccaggt ggtctcgctg atgaaagggc tcgctcaagg gggtcgctcc atcatttgca 1080 ccatccacca gcccagcgcc aaactcttcg agctgttcga ccagctttac gtcctgagtc 1140 aaggacaatg tgtgtaccgg ggaaaagtct gcaatcttgt gccatatttg agggatttgg 1200 gtctgaactg cccaacctac cacaacccag cagattttgt catggaggtt gcatccggcg 1260 agtacggtga tcagaacagt cggctggtga gagcggttcg ggagggcatg tgtgactcag 1320 accacaagag agacctcggg ggtgatgccg aggtgaaccc ttttctttgg caccggccct 1380 ctgaagagga ctcctcgtcc atggaaggct gccacagctt ctctgccagc tgcctcacgc 1440 agttctgcat cctcttcaag aggaccttcc tcagcatcat gagggactcg gtcctgacac 1500 acctgcgcat cacctcgcac attgggatcg gcctcctcat tggcctgctg tacttgggga 1560 tcgggaacga agccaagaag gtcttgagca actccggctt cctcttcttc tccatgctgt 1620 tcctcatgtt cgcggccctc atgcctactg ttctgacatt tcccctggag atgggagtct 1680 ttcttcggga acacctgaac tactggtaca gcctgaaggc ctactacctg gccaagacca 1740 tggcagacgt gccctttcag atcatgttcc cagtggccta ctgcagcatc gtgtactgga 1800 tgacgtcgca gccgtccgac gccgtgcgct ttgtgctgtt tgccgcgctg ggcaccatga 1860 cctccctggt ggcacagtcc ctgggcctgc tgatcggagc cgcctccacg tccctgcagg 1920 tggccacttt cgtgggccca gtgacagcca tcccggtgct cctgttctcg gggttcttcg 1980 tcagcttcga caccatcccc acgtacctac agtggatgtc ctacatctcc tatgtcaggt 2040 atgggttcga aggggtcatc ctctccatct atggcttaga ccgggaagat ctgcactgtg 2100 acatcgacga gacgtgccac ttccagaagt cggaggccat cctgcgggag ctggacgtgg 2160 aaaatgccaa gctgtacctg gacttcatcg tactcgggat tttcttcatc tccctccgcc 2220 tcattgccta ttttgtcctc aggtacaaaa tccgggcaga gaggtaaaac acctgaatgc 2280 caggaaacag gaagattaga cactgtggcc gagggcacgt ctagaatcga ggaggcaagc 2340 ctgtgcccga ccgacgacac agagactctt ctgatccaac ccctagaacc gcgttgggtt 2400 tgtgggtgtc tcgtgctcag ccactctgcc cagctgggtt ggatcttctc tccattcccc 2460 tttctagctt taactaggaa gatgtaggca gattggtggt tttttttttt ttaacataca 2520 gaattttaaa taccacaact ggggcagaat ttaaagctgc aacacagctg gtgatgagag 2580 gcttcctcag tccagtcgct ccttagcacc aggcaccgtg ggtcctggat ggggaactgc 2640 aagcagcctc tcagctgatg gctgcacagt cagatgtctg gtggcagaga gtccgagcat 2700 ggagcgattc cattttatga ctgttgtttt tcacattttc atctttctaa ggtgtgtctc 2760 ttttccaatg agaagtcatt tttgcaagcc aaaagtcgat caatcgcatt cattttaaga 2820 aattatacct ttttagtact tgctgaagaa tgattcaggg taaatcacat actttgttta 2880 gagaggcgag gggtttaacc gagtcaccca gctggtctca tacatagaca gcacttgtga 2940 aggattgaat gcaggttcca ggtggaggga agacgtggac accatctcca ctgagccatg 3000 cagacatttt taaaagctat acaaaaaatt gtgagaagac attggccaac tctttcaaag 3060 tctttctttt tccacgtgct tcttatttta agcgaaatat attgtttgtt tcttcctaaa 3120 aaaaaaaaaa aaaaaaaaaa aa 3142 19 3060 DNA Homo sapiens 19 acttcagagg gcagcagctg gactacctat gtttgtggcg ctacaccaac ctgaacttcg 60 cttcctgaga cctaagattc agccccgtgc tcagcagaca tcagggatca ccgactctgt 120 gccaggagct gttcttgatg ctgggaacgc aggggtggac aaaacagaga aagccctgcc 180 ctcagtgaga aatatgctgt catgtaaatt gctttttccc ctatagaatg ccagcagtta 240 ctctgcagag atgacggagc ccaagtcggt gtgtgtctcg gtggatgagg tggtgtccag 300 caacatggag gccactgaga cggacctgct gaatggacat ctgaaaaaag tagataataa 360 cctcacggaa gcccagcgct tctcctcctt gcctcggagg gcagctgtga acattgaatt 420 cagggacctt tcctattcgg ttcctgaagg accctggtgg aggaagaaag gatacaagac 480 cctcctgaaa ggaatttccg ggaagttcaa tagtggtgag ttggtggcca ttatgggtcc 540 ttccggggcc gggaagtcca cgctgatgaa catcctggct ggatacaggg agacgggcat 600 gaagggggcc gtcctcatca acggcctgcc ccgggacctg cgctgcttcc ggaaggtgtc 660 ctgctacatc atgcaggatg acatgctgct gccgcatctc actgtgcagg aggccatgat 720 ggtgtcggca catctgaagc ttcaggagaa ggatgaaggc agaagggaaa tggtcaagga 780 gatactgaca gcgctgggct tgctgtcttg cgccaacacg cggaccggga gcctgtcagg 840 tggtcagcgc aagcgcctgg ccatcgcgct ggagctggtg aacaaccctc cagtcatgtt 900 cttcgatgag cccaccagcg gcctggacag cgcctcctgc ttccaggtgg tctcgctgat 960 gaaagggctc gctcaagggg gtcgctccat catttgcacc atccaccagc ccagcgccaa 1020 actcttcgag ctgttcgacc agctttacgt cctgagtcaa ggacaatgtg tgtaccgggg 1080 aaaagtctgc aatcttgtgc catatttgag ggatttgggt ctgaactgcc caacctacca 1140 caacccagca gattttgtca tggaggttgc atccggcgag tacggtgatc agaacagtcg 1200 gctggtgaga gcggttcggg agggcatgtg tgactcagac cacaagagag acctcggggg 1260 tgatgccgag gtgaaccctt ttctttggca ccggccctct gaagaggact cctcgtccat 1320 ggaaggctgc cacagcttct ctgccagctg cctcacgcag ttctgcatcc tcttcaagag 1380 gaccttcctc agcatcatga gggactcggt cctgacacac ctgcgcatca cctcgcacat 1440 tgggatcggc ctcctcattg gcctgctgta cttggggatc gggaacgaag ccaagaaggt 1500 cttgagcaac tccggcttcc tcttcttctc catgctgttc ctcatgttcg cggccctcat 1560 gcctactgtt ctgacatttc ccctggagat gggagtcttt cttcgggaac acctgaacta 1620 ctggtacagc ctgaaggcct actacctggc caagaccatg gcagacgtgc cctttcagat 1680 catgttccca gtggcctact gcagcatcgt gtactggatg acgtcgcagc cgtccgacgc 1740 cgtgcgcttt gtgctgtttg ccgcgctggg caccatgacc tccctggtgg cacagtccct 1800 gggcctgctg atcggagccg cctccacgtc cctgcaggtg gccactttcg tgggcccagt 1860 gacagccatc ccggtgctcc tgttctcggg gttcttcgtc agcttcgaca ccatccccac 1920 gtacctacag tggatgtcct acatctccta tgtcaggtat gggttcgaag gggtcatcct 1980 ctccatctat ggcttagacc gggaagatct gcactgtgac atcgacgaga cgtgccactt 2040 ccagaagtcg gaggccatcc tgcgggagct ggacgtggaa aatgccaagc tgtacctgga 2100 cttcatcgta ctcgggattt tcttcatctc cctccgcctc attgcctatt ttgtcctcag 2160 gtacaaaatc cgggcagaga ggtaaaacac ctgaatgcca ggaaacagga agattagaca 2220 ctgtggccga gggcacgtct agaatcgagg aggcaagcct gtgcccgacc gacgacacag 2280 agactcttct gatccaaccc ctagaaccgc gttgggtttg tgggtgtctc gtgctcagcc 2340 actctgccca gctgggttgg atcttctctc cattcccctt tctagcttta actaggaaga 2400 tgtaggcaga ttggtggttt tttttttttt aacatacaga attttaaata ccacaactgg 2460 ggcagaattt aaagctgcaa cacagctggt gatgagaggc ttcctcagtc cagtcgctcc 2520 ttagcaccag gcaccgtggg tcctggatgg ggaactgcaa gcagcctctc agctgatggc 2580 tgcacagtca gatgtctggt ggcagagagt ccgagcatgg agcgattcca ttttatgact 2640 gttgtttttc acattttcat ctttctaagg tgtgtctctt ttccaatgag aagtcatttt 2700 tgcaagccaa aagtcgatca atcgcattca ttttaagaaa ttataccttt ttagtacttg 2760 ctgaagaatg attcagggta aatcacatac tttgtttaga gaggcgaggg gtttaaccga 2820 gtcacccagc tggtctcata catagacagc acttgtgaag gattgaatgc aggttccagg 2880 tggagggaag acgtggacac catctccact gagccatgca gacattttta aaagctatac 2940 aaaaaattgt gagaagacat tggccaactc tttcaaagtc tttctttttc cacgtgcttc 3000 ttattttaag cgaaatatat tgtttgtttc ttcctaaaaa aaaaaaaaaa aaaaaaaaaa 3060 20 2946 DNA Homo sapiens 20 gctttataaa ggggagtttc cctgcacaag ctctctctct tgtctgccgc catgtgagac 60 atgcctttca ccttccgcca tgatcatgag gcttccccag ccacatggaa ctaatgccag 120 cagttactct gcagagatga cggagcccaa gtcggtgtgt gtctcggtgg atgaggtggt 180 gtccagcaac atggaggcca ctgagacgga cctgctgaat ggacatctga aaaaagtaga 240 taataacctc acggaagccc agcgcttctc ctccttgcct cggagggcag ctgtgaacat 300 tgaattcagg gacctttcct attcggttcc tgaaggaccc tggtggagga agaaaggata 360 caagaccctc ctgaaaggaa tttccgggaa gttcaatagt ggtgagttgg tggccattat 420 gggtccttcc ggggccggga agtccacgct gatgaacatc ctggctggat acagggagac 480 gggcatgaag ggggccgtcc tcatcaacgg cctgccccgg gacctgcgct gcttccggaa 540 ggtgtcctgc tacatcatgc aggatgacat gctgctgccg catctcactg tgcaggaggc 600 catgatggtg tcggcacatc tgaagcttca ggagaaggat gaaggcagaa gggaaatggt 660 caaggagata ctgacagcgc tgggcttgct gtcttgcgcc aacacgcgga ccgggagcct 720 gtcaggtggt cagcgcaagc gcctggccat cgcgctggag ctggtgaaca accctccagt 780 catgttcttc gatgagccca ccagcggcct ggacagcgcc tcctgcttcc aggtggtctc 840 gctgatgaaa gggctcgctc aagggggtcg ctccatcatt tgcaccatcc accagcccag 900 cgccaaactc ttcgagctgt tcgaccagct ttacgtcctg agtcaaggac aatgtgtgta 960 ccggggaaaa gtctgcaatc ttgtgccata tttgagggat ttgggtctga actgcccaac 1020 ctaccacaac ccagcagatt ttgtcatgga ggttgcatcc ggcgagtacg gtgatcagaa 1080 cagtcggctg gtgagagcgg ttcgggaggg catgtgtgac tcagaccaca agagagacct 1140 cgggggtgat gccgaggtga acccttttct ttggcaccgg ccctctgaag aggactcctc 1200 gtccatggaa ggctgccaca gcttctctgc cagctgcctc acgcagttct gcatcctctt 1260 caagaggacc ttcctcagca tcatgaggga ctcggtcctg acacacctgc gcatcacctc 1320 gcacattggg atcggcctcc tcattggcct gctgtacttg gggatcggga acgaagccaa 1380 gaaggtcttg agcaactccg gcttcctctt cttctccatg ctgttcctca tgttcgcggc 1440 cctcatgcct actgttctga catttcccct ggagatggga gtctttcttc gggaacacct 1500 gaactactgg tacagcctga aggcctacta cctggccaag accatggcag acgtgccctt 1560 tcagatcatg ttcccagtgg cctactgcag catcgtgtac tggatgacgt cgcagccgtc 1620 cgacgccgtg cgctttgtgc tgtttgccgc gctgggcacc atgacctccc tggtggcaca 1680 gtccctgggc ctgctgatcg gagccgcctc cacgtccctg caggtggcca ctttcgtggg 1740 cccagtgaca gccatcccgg tgctcctgtt ctcggggttc ttcgtcagct tcgacaccat 1800 ccccacgtac ctacagtgga tgtcctacat ctcctatgtc aggtatgggt tcgaaggggt 1860 catcctctcc atctatggct tagaccggga agatctgcac tgtgacatcg acgagacgtg 1920 ccacttccag aagtcggagg ccatcctgcg ggagctggac gtggaaaatg ccaagctgta 1980 cctggacttc atcgtactcg ggattttctt catctccctc cgcctcattg cctattttgt 2040 cctcaggtac aaaatccggg cagagaggta aaacacctga atgccaggaa acaggaagat 2100 tagacactgt ggccgagggc acgtctagaa tcgaggaggc aagcctgtgc ccgaccgacg 2160 acacagagac tcttctgatc caacccctag aaccgcgttg ggtttgtggg tgtctcgtgc 2220 tcagccactc tgcccagctg ggttggatct tctctccatt cccctttcta gctttaacta 2280 ggaagatgta ggcagattgg tggttttttt ttttttaaca tacagaattt taaataccac 2340 aactggggca gaatttaaag ctgcaacaca gctggtgatg agaggcttcc tcagtccagt 2400 cgctccttag caccaggcac cgtgggtcct ggatggggaa ctgcaagcag cctctcagct 2460 gatggctgca cagtcagatg tctggtggca gagagtccga gcatggagcg attccatttt 2520 atgactgttg tttttcacat tttcatcttt ctaaggtgtg tctcttttcc aatgagaagt 2580 catttttgca agccaaaagt cgatcaatcg cattcatttt aagaaattat acctttttag 2640 tacttgctga agaatgattc agggtaaatc acatactttg tttagagagg cgaggggttt 2700 aaccgagtca cccagctggt ctcatacata gacagcactt gtgaaggatt gaatgcaggt 2760 tccaggtgga gggaagacgt ggacaccatc tccactgagc catgcagaca tttttaaaag 2820 ctatacaaaa aattgtgaga agacattggc caactctttc aaagtctttc tttttccacg 2880 tgcttcttat tttaagcgaa atatattgtt tgtttcttcc taaaaaaaaa aaaaaaaaaa 2940 aaaaaa 2946 21 3498 DNA Homo sapiens 21 ttctttccaa gggtctctgg gtgaggcccg tgaccttccc aagcctctcc ctgtcttgtg 60 aaacctgggc gtgatatacc tcccttttag ggctgctgcg atcatttagg cagattaaac 120 ctcataagtg gtttcccata caagaaagat gctagcagtg caacagacag aacacttacc 180 tgcctgccct cccgccagga ggtggtcttc caacttttgc ccggagtcta cagagggtgg 240 gccctctctg ctggggctcc gggacatggt caggagaggt tggtctgtct gtaccgccat 300 tctcttggcc agactgtggt gtctggtccc tactcacacc ttcctgtcag agtatccaga 360 ggccgcagag tatccacacc ctggctgggt gtactggcta cagatggctg tggctccagg 420 tcacctgcgt gcctgggtga tgagaaataa tgtcacaaca aatatcccat ctgcattctc 480 tgggacactg acccatgaag agaaagcagt tctcacagtt tttacaggca cagccacagc 540 cgtgcatgta caggtggcag ctttagcttc tgctaaactg gagagctcag tgtttgtgac 600 agactgcgtg tcctgcaaaa tcgaaaatgt ctgtgattca gctcttcagg gaaaaagggt 660 gccgatgtct ggcctacagg gctcaagcat tgtcatcatg cccccatcca accgtccact 720 cgccagtgcg gcatcctgca cgtggtcagt ccaagtccag ggagggcccc atcacctggg 780 ggtggtcgct atcagtggca aagtcttgtc agcagctcat ggggcaggaa gggcctatgg 840 ttgggggttt cctggcgatc ccatggagga aggatacaag accctcctga aaggaatttc 900 cgggaagttc aatagtggtg agttggtggc cattatgggt ccttccgggg ccgggaagtc 960 cacgctgatg aacatcctgg ctggatacag ggagacgggc atgaaggggg ccgtcctcat 1020 caacggcctg ccccgggacc tgcgctgctt ccggaaggtg tcctgctaca tcatgcagga 1080 tgacatgctg ctgccgcatc tcactgtgca ggaggccatg atggtgtcgg cacatctgaa 1140 gcttcaggag aaggatgaag gcagaaggga aatggtcaag gagatactga cagcgctggg 1200 cttgctgtct tgcgccaaca cgcggaccgg gagcctgtca ggtggtcagc gcaagcgcct 1260 ggccatcgcg ctggagctgg tgaacaaccc tccagtcatg ttcttcgatg agcccaccag 1320 cggcctggac agcgcctcct gcttccaggt ggtctcgctg atgaaagggc tcgctcaagg 1380 gggtcgctcc atcatttgca ccatccacca gcccagcgcc aaactcttcg agctgttcga 1440 ccagctttac gtcctgagtc aaggacaatg tgtgtaccgg ggaaaagtct gcaatcttgt 1500 gccatatttg agggatttgg gtctgaactg cccaacctac cacaacccag cagattttgt 1560 catggaggtt gcatccggcg agtacggtga tcagaacagt cggctggtga gagcggttcg 1620 ggagggcatg tgtgactcag accacaagag agacctcggg ggtgatgccg aggtgaaccc 1680 ttttctttgg caccggccct ctgaagaggt aaagcagaca aaacgattaa aggggttgag 1740 aaaggactcc tcgtccatgg aaggctgcca cagcttctct gccagctgcc tcacgcagtt 1800 ctgcatcctc ttcaagagga ccttcctcag catcatgagg gactcggtcc tgacacacct 1860 gcgcatcacc tcgcacattg ggatcggcct cctcattggc ctgctgtact tggggatcgg 1920 gaacgaagcc aagaaggtct tgagcaactc cggcttcctc ttcttctcca tgctgttcct 1980 catgttcgcg gccctcatgc ctactgttct gacatttccc ctggagatgg gagtctttct 2040 tcgggaacac ctgaactact ggtacagcct gaaggcctac tacctggcca agaccatggc 2100 agacgtgccc tttcagatca tgttcccagt ggcctactgc agcatcgtgt actggatgac 2160 gtcgcagccg tccgacgccg tgcgctttgt gctgtttgcc gcgctgggca ccatgacctc 2220 cctggtggca cagtccctgg gcctgctgat cggagccgcc tccacgtccc tgcaggtggc 2280 cactttcgtg ggcccagtga cagccatccc ggtgctcctg ttctcggggt tcttcgtcag 2340 cttcgacacc atccccacgt acctacagtg gatgtcctac atctcctatg tcaggtatgg 2400 gttcgaaggg gtcatcctct ccatctatgg cttagaccgg gaagatctgc actgtgacat 2460 cgacgagacg tgccacttcc agaagtcgga ggccatcctg cgggagctgg acgtggaaaa 2520 tgccaagctg tacctggact tcatcgtact cgggattttc ttcatctccc tccgcctcat 2580 tgcctatttt gtcctcaggt acaaaatccg ggcagagagg taaaacacct gaatgccagg 2640 aaacaggaag attagacact gtggccgagg gcacgtctag aatcgaggag gcaagcctgt 2700 gcccgaccga cgacacagag actcttctga tccaacccct agaaccgcgt tgggtttgtg 2760 ggtgtctcgt gctcagccac tctgcccagc tgggttggat cttctctcca ttcccctttc 2820 tagctttaac taggaagatg taggcagatt ggtggttttt ttttttttaa catacagaat 2880 tttaaatacc acaactgggg cagaatttaa agctgcaaca cagctggtga tgagaggctt 2940 cctcagtcca gtcgctcctt agcaccaggc accgtgggtc ctggatgggg aactgcaagc 3000 agcctctcag ctgatggctg

cacagtcaga tgtctggtgg cagagagtcc gagcatggag 3060 cgattccatt ttatgactgt tgtttttcac attttcatct ttctaaggtg tgtctctttt 3120 ccaatgagaa gtcatttttg caagccaaaa gtcgatcaat cgcattcatt ttaagaaatt 3180 ataccttttt agtacttgct gaagaatgat tcagggtaaa tcacatactt tgtttagaga 3240 ggcgaggggt ttaaccgagt cacccagctg gtctcataca tagacagcac ttgtgaagga 3300 ttgaatgcag gttccaggtg gagggaagac gtggacacca tctccactga gccatgcaga 3360 catttttaaa agctatacaa aaaattgtga gaagacattg gccaactctt tcaaagtctt 3420 tctttttcca cgtgcttctt attttaagcg aaatatattg tttgtttctt cctaaaaaaa 3480 aaaaaaaaaa aaaaaaaa 3498 22 3400 DNA Homo sapiens 22 ggaaccgccg ccggtatccg cgtccgcagc gccgccagcc aggcgagagc cgtgtgggat 60 cccagcgccc gcactcccgc ccccgccaag gagccaggaa tggcacaact agagaggagc 120 gccatctctg gcttcagctc taagtccagg cgaaactcat tcgcatatga tgttaagcgt 180 gaagtataca atgaggagac ctttcaacag gaacacaaaa ggaaggcctc ctcttctggg 240 aacatgaaca tcaacatcac caccttcaga caccacgtcc agtgccgctg ctcatggcac 300 aggttcctac gatgcgtgct tacaatcttt cccttcctag aatggatgtg tatgtatcga 360 ttaaaggatt ggcttctggg agacttactt gctggtataa gtgttggcct tgtgcaagtt 420 ccccaaggcc tgacacttag tttgctggca aggcaactga ttcctcctct caacatcgct 480 tatgcagctt tctgttcttc ggtaatctat gtaatttttg gatcgtgtca tcaaatgtcc 540 attggttcct tcttcctggt gagtgctctg ctgatcaacg ttctgaaagt gagcccattc 600 aacaacggtc aactggtcat gggatctttc gtcaagaatg agttttcggc cccctcctac 660 cttatgggct ataataaatc cttgagtgtg gtggcaacca caacttttct gactgggatt 720 attcagctaa taatgggcgt attgggtttg ggcttcattg ccacttacct tccggagtct 780 gcaatgagtg cttacctggc tgctgtggca cttcatatca tgctgtccca gctgactttc 840 atctttggga ttatgattag tttccatgcc ggtcccatct ccttcttcta tgacataatt 900 aattactgtg tagctctccc aaaagcgaat tccaccagca ttctagtatt tctaactgtt 960 gttgttgctc tgcgaatcaa caaatgtatc agaatttctt tcaatcagta tcccattgag 1020 tttcccatgg aattatttct gattattggc ttcactgtga ttgcaaacaa gataagcatg 1080 gccacagaaa ccagccagac gcttattgac atgattcctt atagctttct gcttcctgta 1140 acaccagatt tcagccttct tcccaagata attttacaag ccttctcctt atctttggtg 1200 agctcctttc tgctcatatt tctgggcaag aagattgcca gtcttcacaa ttacagtgtc 1260 aattccaacc aggatttaat agccatcggc ctttgcaatg tcgtcagttc atttttcaga 1320 tcttgtgtgt ttactggtgc tattgctagg actattatcc aggataaatc tggaggaaga 1380 caacagtttg catctctggt aggcgcaggt gtgatgctgc tcctgatggt gaagatggga 1440 cactttttct acacactgcc aaatgctgtg ctggctggta ttattctgag caacgtcatt 1500 ccctaccttg aaaccatttc taacctaccc agcctgtgga ggcaggacca atatgactgt 1560 gctctttgga tgatgacatt ctcatcttca attttcctgg gactggacat tggactaatt 1620 atctcagtag tttctgcttt cttcatcacc actgttcgtt cacacagagc taagattctt 1680 ctcctgggtc aaatccctaa caccaacatt tatagaagca tcaatgatta tcgggagatc 1740 atcaccattc ctggggtgaa aatcttccag tgctgcagct caattacatt tgtaaatgtt 1800 tactacctaa agcataagct gttaaaagag gttgatatgg taaaggtgcc tcttaaagaa 1860 gaagaaattt tcagcttgtt taattcaagt gacaccaatc tacaaggagg aaagatttgc 1920 aggtgtttct gcaactgtga tgatctggag ccgctgccca ggattcttta cacagagcga 1980 tttgaaaata aactggatcc cgaagcatcc tccattaacc tgattcactg ctcacatttt 2040 gagagcatga acacaagcca aactgcatcc gaagaccaag tgccatacac agtatcgtcc 2100 gtgtctcaga aaaatcaagg gcaacagtat gaggaggtgg aggaagtttg gcttcctaat 2160 aactcatcaa gaaacagctc accaggactg cctgatgtgg cggaaagcca ggggaggaga 2220 tcactcatcc cttactcaga tgcgtctcta ctgcccagtg tccacaccat catcctggat 2280 ttctccatgg tacactacgt ggattcacgg gggttagtcg tattaagaca gatatgcaat 2340 gcctttcaaa acgccaacat tttgatactc attgcagggt gtcactcttc catagtcagg 2400 gcatttgaga ggaatgattt ctttgacgct ggcatcacca agacccagct gttcctcagc 2460 gttcacgacg ccgtgctgtt tgccttgtca aggaaggtca taggctcctc tgagttaagc 2520 atcgatgaat ccgagacagt gatacgggaa acctactcag aaacagacaa gaatgacaat 2580 tcaagatata aaatgagcag cagttttcta ggaagccaaa aaaatgtaag tccaggcttc 2640 atcaagatcc aacagcctgt agaagaggag tcggagttgg atttggagct ggaatcagaa 2700 caagaggctg ggctgggtct ggacctagac ctggatcggg agctggagcc tgaaatggag 2760 cccaaggctg agaccgagac caagacccag accgagatgg agccccagcc tgagactgag 2820 cctgagatgg agcccaaccc caaatctagg ccaagagctc acacttttcc tcagcagcgt 2880 tactggccta tgtatcatcc gtctatggct tccacccagt ctcagactca gactcggaca 2940 tggtcagtgg agaggagacg ccatcctatg gattcatact caccagaggg caacagcaat 3000 gaagatgtct aggagatgaa ctagaaataa ggggtcagat aatgctggca aatcctccta 3060 cccaaaaagg ggtcaattgt ccagagacct agactggata cgaactagca gtacttcctt 3120 cctgactgtg actcctacta cctgccagcc ttcttccttg ctctgcgctg ggatcatact 3180 cccaaatcac attactaaat gccaacaatt atctctgaat tccctatcca ggctcccctc 3240 atttcacctt cagcatatat tctagtcatg aatttccttc ttcacacacc ccacatctct 3300 gggctttgtg ccagaccatc tctaacttaa tcctctcatc cctgttcccc tttctccaaa 3360 gagatgaagc tcaaataaaa tgtataactc tagtaaaaaa 3400 23 977 DNA Homo sapiens 23 attgaatgca gcaagggtct ggaggctgag gaccaggcag acaaacattc agagttgctg 60 gaatgcgaca gagacaggga gtcagactgg tcatgcaagg ccagctctgg ggtctcggca 120 ggtggtccgc gacatgacct ccgagttctt ctctgcccag ctccgggccc agatctctga 180 cgacaccact cacccgatct cctactacaa gcccgagttc tacatgccgg atgacggggg 240 cactgctcac ctgtctgtgg tcgcagagga cggcagtgct gtgtccgcca ccagcaccat 300 caacctctac tttggctcca aggtgcgctc cccagtcagc gggatcctgc tcaataatga 360 aatggatgac ttcagctcta ccagcatcac caacgagttt ggggtacccc cctcacctgc 420 caatttcatc cagccaggga agcagccgct ctcgtccatg tgcccgacga tcatggtggg 480 ccaggacggc caggtccgga tggtggtggg agctgccggg ggcacgcaga tcaccatggc 540 cactgcactg gccatcatct acaacctctg gttcggctat gacgtgaagt gggccgtgga 600 ggagccccgg ctgcacaacc agcttctgcc caacgtcacg acagtggaga gaaacattga 660 ccaggaagtg actgcagccc tggagacccg gcaccatcac acccagatca cgtccacctt 720 cattgctgtg gtgcaagcca tcgtccgcat ggctggtggc tgggcagctg cctcggactc 780 caggaaaggt ggggaacctg ctggctactg attgctccag gcggacaagg ctgacaagca 840 atccaggaac aaaatactca ccaggacgag gaagaggact ttgggggaca ggcttctcct 900 gtgagcagca gagcagcaca ataaatgagg ccactgtgcc aggctccagg tggcctccct 960 ggcctgtctc cccactc 977 24 1049 DNA Homo sapiens 24 ctcgagagct gggctctgcg tcctcgtcca gccgccaact cggccaaagg cgaagccagc 60 agtttcttct gctgccgggc aacgcgcctt ttaaacctga gggagtgggc gcgtgagcac 120 ttaatggcgc cggtgacaga gtgagcttaa cggattaata agcgcagcca ggccagctct 180 ggggtctcgg caggtggtcc gcgacatgac ctccgagttc ttctctgccc agctccgggc 240 ccagatctct gacgacacca ctcacccgat ctcctactac aagcccgagt tctacatgcc 300 ggatgacggg ggcactgctc acctgtctgt ggtcgcagag gacggcagtg ctgtgtccgc 360 caccagcacc atcaacctct actttggctc caaggtgcgc tccccagtca gcgggatcct 420 gctcaataat gaaatggatg acttcagctc taccagcatc accaacgagt ttggggtacc 480 cccctcacct gccaatttca tccagccagg gaagcagccg ctctcgtcca tgtgcccgac 540 gatcatggtg ggccaggacg gccaggtccg gatggtggtg ggagctgccg ggggcacgca 600 gatcaccatg gccactgcac tggccatcat ctacaacctc tggttcggct atgacgtgaa 660 gtgggccgtg gaggagcccc ggctgcacaa ccagcttctg cccaacgtca cgacagtgga 720 gagaaacatt gaccaggaag tgactgcagc cctggagacc cggcaccatc acacccagat 780 cacgtccacc ttcattgctg tggtgcaagc catcgtccgc atggctggtg gctgggcagc 840 tgcctcggac tccaggaaag gtggggaacc tgctggctac tgattgctcc aggcggacaa 900 ggctgacaag caatccagga acaaaatact caccaggacg aggaagagga ctttggggga 960 caggcttctc ctgtgagcag cagagcagca caataaatga ggccactgtg ccaggctcca 1020 ggtggcctcc ctggcctgtc tccccactc 1049 25 1108 DNA Homo sapiens 25 attgaatgca gcaagggtct ggaggctgag gaccaggcag acaaacattc agagttgctg 60 gaatgcgaca gagacaggga gtcagactgg tcatgcaagg tcctgggcct gcccttgggt 120 cctggggagc cacggaaggt tgtgggtgcc agagggttgt ggtcagagcc acagtcaggg 180 gccttctgag acctgtgccc cctccccacc ctccctcccc acctccctag gccagctctg 240 gggtctcggc aggtggtccg cgacatgacc tccgagttct tctctgccca gctccgggcc 300 cagatctctg acgacaccac tcacccgatc tcctactaca agcccgagtt ctacatgccg 360 gatgacgggg gcactgctca cctgtctgtg gtcgcagagg acggcagtgc tgtgtccgcc 420 accagcacca tcaacctcta ctttggctcc aaggtgcgct ccccagtcag cgggatcctg 480 ctcaataatg aaatggatga cttcagctct accagcatca ccaacgagtt tggggtaccc 540 ccctcacctg ccaatttcat ccagccaggg aagcagccgc tctcgtccat gtgcccgacg 600 atcatggtgg gccaggacgg ccaggtccgg atggtggtgg gagctgccgg gggcacgcag 660 atcaccatgg ccactgcact ggccatcatc tacaacctct ggttcggcta tgacgtgaag 720 tgggccgtgg aggagccccg gctgcacaac cagcttctgc ccaacgtcac gacagtggag 780 agaaacattg accaggaagt gactgcagcc ctggagaccc ggcaccatca cacccagatc 840 acgtccacct tcattgctgt ggtgcaagcc atcgtccgca tggctggtgg ctgggcagct 900 gcctcggact ccaggaaagg tggggaacct gctggctact gattgctcca ggcggacaag 960 gctgacaagc aatccaggaa caaaatactc accaggacga ggaagaggac tttgggggac 1020 aggcttctcc tgtgagcagc agagcagcac aataaatgag gccactgtgc caggctccag 1080 gtggcctccc tggcctgtct ccccactc 1108 26 2414 DNA Homo sapiens 26 gtcagagtct tccctcagct ttgtacatca gcactgtttt gatagataag agaggctact 60 gtataagtgt gtaagatttg taatggactg aggaatgctt gttctagctg ctgaaactga 120 ctgtaactgt attgtcttag gagcatcatc atggggtcta gtgccacaga gattgaagaa 180 ttggaaaaca ccacttttaa gtatcttaca ggagaacaga ctgaaaaaat gtggcagcgc 240 ctgaaaggaa tactaagatg cttggtgaag cagctggaaa gaggtgatgt taacgtcgtc 300 gacttaaaga agaatattga atatgcggca tctgtgctgg aagcagttta tatcgatgaa 360 acaagaagac ttctggatac tgaagatgag ctcagtgaca ttcagactga ctcagtccca 420 tctgaagtcc gggactggtt ggcttctacc tttacacgga aaatggggat gacaaaaaag 480 aaacctgagg aaaaaccaaa atttcggagc attgtgcatg ctgttcaagc tggaattttt 540 gtggaaagaa tgtaccgaaa aacatatcat atggttggtt tggcatatcc agcagctgtc 600 atcgtaacat taaaggatgt tgataaatgg tctttcgatg tatttgccct aaatgaagca 660 agtggagagc atagtctgaa gtttatgatt tatgaactgt ttaccagata tgatcttatc 720 aaccgtttca agattcctgt ttcttgccta atcacctttg cagaagcttt agaagttggt 780 tacagcaagt acaaaaatcc atatcacaat ttgattcatg cagctgatgt cactcaaact 840 gtgcattaca taatgcttca tacaggtatc atgcactggc tcactgaact ggaaatttta 900 gcaatggtct ttgctgctgc cattcatgat tatgagcata cagggacaac aaacaacttt 960 cacattcaga caaggtcaga tgttgccatt ttgtataatg atcgctctgt ccttgagaat 1020 caccacgtga gtgcagctta tcgacttatg caagaagaag aaatgaatat cttgataaat 1080 ttatccaaag atgactggag ggatcttcgg aacctagtga ttgaaatggt tttatctaca 1140 gacatgtcag gtcacttcca gcaaattaaa aatataagaa acagtttgca gcagcctgaa 1200 gggattgaca gagccaaaac catgtccctg attctccacg cagcagacat cagccaccca 1260 gccaaatcct ggaagctgca ttatcggtgg accatggccc taatggagga gtttttcctg 1320 cagggagata aagaagctga attagggctt ccattttccc cactttgtga tcggaagtca 1380 accatggtgg cccagtcaca aataggtttc atcgatttca tagtagagcc aacattttct 1440 cttctgacag actcaacaga gaaaattgtt attcctctta tagaggaagc ctcaaaagcc 1500 gaaacttctt cctatgtggc aagcagctca accaccattg tggggttaca cattgctgat 1560 gcactaagac gatcaaatac aaaaggctcc atgagtgatg ggtcctattc cccagactac 1620 tcccttgcag cagtggacct gaagagtttc aagaacaacc tggtggacat cattcagcag 1680 aacaaagaga ggtggaaaga gttagctgca caaggtgaat ctgatcttca taagaactca 1740 gaagacttag taaatgctga agaaaaacat gatgagacac attcataggc ccgaaacacc 1800 ttaaagactt ctgtcatttt aaacatgaga ggacaatgaa atcagcatga aaacatccta 1860 aattctcaac tttccacaaa gctatggctc ttctttcaac atagaattgg attgggccat 1920 tttaattgac tcctatacaa ggaattaaga agaacataaa ttttgagcta gtaactctgg 1980 ccaaataaat acactcaagt ttttatcaga gtttttggcc agtgcttctg ccattttttt 2040 ccctccacaa tttggccttc ttcaatcaag ccagataaat ttttgagaca aaagtcagac 2100 agtttttaat ttttcttgct ttgaaccctg tcataatgac tgtgcaatac atgtgcagaa 2160 gatgaggtat tttaaaattt acttccttgc actgtcttac acagagtgct ataactataa 2220 atttttcaag gtcttaaata aaaggaagca aaaacaaaat tattgaaaaa ttttttttgt 2280 tgtgctgggg aatatactat ttagattgtc cttcttattt taaatgcatg ggaacagaat 2340 gacagggggg atgctgagga gctggttgaa gcatcagagc aatgctacag tccaacaatg 2400 gagcattaga tccc 2414 27 2009 DNA Homo sapiens 27 gaattctgat gtgcttcagt gcacagaaca gtaacagatg agctgctttt ggggagagct 60 tgagtactca gtcggagcat catcatgggg tctagtgcca cagagattga agaattggaa 120 aacaccactt ttaagtatct tacaggagaa cagactgaaa aaatgtggca gcgcctgaaa 180 ggaatactaa gatgcttggt gaagcagctg gaaagaggtg atgttaacgt cgtcgactta 240 aagaagaata ttgaatatgc ggcatctgtg ctggaagcag tttatatcga tgaaacaaga 300 agacttctgg atactgaaga tgagctcagt gacattcaga ctgactcagt cccatctgaa 360 gtccgggact ggttggcttc tacctttaca cggaaaatgg ggatgacaaa aaagaaacct 420 gaggaaaaac caaaatttcg gagcattgtg catgctgttc aagctggaat ttttgtggaa 480 agaatgtacc gaaaaacata tcatatggtt ggtttggcat atccagcagc tgtcatcgta 540 acattaaagg atgttgataa atggtctttc gatgtatttg ccctaaatga agcaagtgga 600 gagcatagtc tgaagtttat gatttatgaa ctgtttacca gatatgatct tatcaaccgt 660 ttcaagattc ctgtttcttg cctaatcacc tttgcagaag ctttagaagt tggttacagc 720 aagtacaaaa atccatatca caatttgatt catgcagctg atgtcactca aactgtgcat 780 tacataatgc ttcatacagg tatcatgcac tggctcactg aactggaaat tttagcaatg 840 gtctttgctg ctgccattca tgattatgag catacaggga caacaaacaa ctttcacatt 900 cagacaaggt cagatgttgc cattttgtat aatgatcgct ctgtccttga gaatcaccac 960 gtgagtgcag cttatcgact tatgcaagaa gaagaaatga atatcttgat aaatttatcc 1020 aaagatgact ggagggatct tcggaaccta gtgattgaaa tggttttatc tacagacatg 1080 tcaggtcact tccagcaaat taaaaatata agaaacagtt tgcagcagcc tgaagggatt 1140 gacagagcca aaaccatgtc cctgattctc cacgcagcag acatcagcca cccagccaaa 1200 tcctggaagc tgcattatcg gtggaccatg gccctaatgg aggagttttt cctgcaggga 1260 gataaagaag ctgaattagg gcttccattt tccccacttt gtgatcggaa gtcaaccatg 1320 gtggcccagt cacaaatagg tttcatcgat ttcatagtag agccaacatt ttctcttctg 1380 acagactcaa cagagaaaat tgttattcct cttatagagg aagcctcaaa agccgaaact 1440 tcttcctatg tggcaagcag ctcaaccacc attgtggggt tacacattgc tgatgcacta 1500 agacgatcaa atacaaaagg ctccatgagt gatgggtcct attccccaga ctactccctt 1560 gcagcagtgg acctgaagag tttcaagaac aacctggtgg acatcattca gcagaacaaa 1620 gagaggtgga aagagttagc tgcacaagaa gcaagaacca gttcacagaa gtgtgagttt 1680 attcatcagt aaacaccttt aagtaaaacc tcgtgcatgg tggcagctct aatttgacca 1740 aaagacttgg agattttgat tatgcttgct ggaaatctac cctgtcctgt gtgagacagg 1800 aaatctattt ttgcagattg ctcaataagc atcatgagcc acataaataa cagctgtaaa 1860 ctccttaatt caccgggctc aactgctacc gaacagattc atctagtggc tacatcagca 1920 ccttgtgctt tcagatatct gtttcaatgg cattttgtgg catttgtctt taccgagtgc 1980 caataaattt tctttgagca gctaaaaaa 2009 28 2846 DNA Homo sapiens 28 aaatgcttga ggagagagag agagtaagga gccagccatg aatcctttcc agaaaaatga 60 gtccaaggaa actctttttt cacctgtctc cattgaagag gtaccacctc gaccacctag 120 ccctccaaag aagccatctc cgacaatctg tggctccaac tatccactga gcattgcctt 180 cattgtggtg aatgaattct gcgagcgctt ttcctattat ggaatgaaag ctgtgctgat 240 cctgtatttc ctgtatttcc tgcactggaa tgaagatacc tccacatcta tataccatgc 300 cttcagcagc ctctgttatt ttactcccat cctgggagca gccattgctg actcgtggtt 360 gggaaaattc aagacaatca tctatctctc cttggtgtat gtgcttggcc atgtgatcaa 420 gtccttgggt gccttaccaa tactgggagg acaagtggta cacacagtcc tatcattgat 480 cggcctgagt ctaatagctt tggggacagg aggcatcaaa ccctgtgtgg cagcttttgg 540 tggagaccag tttgaagaaa aacatgcaga ggaacggact agatacttct cagtcttcta 600 cctgtccatc aatgcaggga gcttgatttc tacatttatc acacccatgc tgagaggaga 660 tgtgcaatgt tttggagaag actgctatgc attggctttt ggagttccag gactgctcat 720 ggtaattgca cttgttgtgt ttgcaatggg aagcaaaata tacaataaac caccccctga 780 aggaaacata gtggctcaag ttttcaaatg tatctggttt gctatttcca atcgtttcaa 840 gaaccgttct ggagacattc caaagcgaca gcactggcta gactgggcgg ctgagaaata 900 tccaaagcag ctcattatgg atgtaaaggc actgaccagg gtactattcc tttatatccc 960 attgcccatg ttctgggctc ttttggatca gcagggttca cgatggactt tgcaagccat 1020 caggatgaat aggaatttgg ggttttttgt gcttcagccg gaccagatgc aggttctaaa 1080 tccccttctg gttcttatct tcatcccgtt gtttgacttt gtcatttatc gtctggtctc 1140 caagtgtgga attaacttct catcacttag gaaaatggct gttggtatga tcctagcatg 1200 cctggcattt gcagttgcgg cagctgtaga gataaaaata aatgaaatgg ccccagccca 1260 gccaggtccc caggaggttt tcctacaagt cttgaatctg gcagatgatg aggtgaaggt 1320 gacagtggtg ggaaatgaaa acaattctct gttgatagag tccatcaaat cctttcagaa 1380 aacaccacac tattccaaac tgcacctgaa aacaaaaagc caggattttc acttccacct 1440 gaaatatcac aatttgtctc tctacactga gcattctgtg caggagaaga actggtacag 1500 tcttgtcatt cgtgaagatg ggaacagtat ctccagcatg atggtaaagg atacagaaag 1560 cagaacaacc aatgggatga caaccgtgag gtttgttaac actttgcata aagatgtcaa 1620 catctccctg agtacagata cctctctcaa tgttggtgaa gactatggtg tgtctgctta 1680 tagaactgtg caaagaggag aataccctgc agtgcactgt agaacagaag ataagaactt 1740 ttctctgaat ttgggtcttc tagactttgg tgcagcatat ctgtttgtta ttactaataa 1800 caccaatcag ggtcttcagg cctggaagat tgaagacatt ccagccaaca aaatgtccat 1860 tgcgtggcag ctaccacaat atgccctggt tacagctggg gaggtcatgt tctctgtcac 1920 aggtcttgag ttttcttatt ctcaggctcc ctctggcatg aaatctgtgc tccaggcagc 1980 ttggctattg acaattgcag ttgggaatat catcgtgctt gttgtggcac agttcagtgg 2040 cctggtacag tgggccgaat tcattttgtt ttcctgcctc ctgctggtga tctgcctgat 2100 cttctccatc atgggctact actatgttcc tgtaaagaca gaggatatgc ggggtccagc 2160 agataagcac attcctcaca tccaggggaa catgatcaaa ctagagacca agaagacaaa 2220 actctgatga ctccctagat tctgtcctga ccccaattcc tggccctgtc ttgaagcatt 2280 ttttttcttc tactggatta gacaagagag atagcagcat atcagagctg atctcctcca 2340 cctttctcca atgacagaag ttccaggact ggttttccag tacatcttta aacaaggccc 2400 cagagactct atgtctgccc gtccatcagt gaactcatta aaacttgtgc agtgttgctg 2460 gagctggcct ggtgtctcca aatgaccatg aaaatacaca cgtataatgg agatcattct 2520 ctgtgggtat gcaaagttat gggaattcct ttataggtaa ctgccattta ggactgatgg 2580 ccctaatttt tgaggtgctg atttagaggc aaaattgcag aataacaaag aaatggtatt 2640 tcaagttttt ttttttataa gcaatgtaat tatgctattc acaggggcct caagaattgg 2700 tatgtatgat gtgatctggt ccagccaggg cctggcttgt cagctctcta ggtttgatat 2760 gactttagta aatttgtcaa tatagatggt aggaagcaga atgccatttt attaaaacac 2820 aggagaagtt aaaaaaaaaa aaaaaa 2846 29 21 DNA Artificial Sequence Synthetic oligonucleotide 29 ccgtttacgt ggagactcgc c 21 30 25 DNA Artificial Sequence Synthetic oligonucleotide 30 cccccacctt atatatattc tttcc 25 31 19 DNA Artificial Sequence Synthetic oligonucleotide 31 ccatgcctat ttctacagc

19 32 19 DNA Artificial Sequence Synthetic oligonucleotide 32 tcagtaacag ctcccagac 19 33 19 DNA Artificial Sequence Synthetic oligonucleotide 33 ccatgcctat ttctacagc 19 34 19 DNA Artificial Sequence Synthetic oligonucleotide 34 tcagtaacag ctcccagac 19 35 22 DNA Artificial Sequence Synthetic oligonucleotide 35 ggcaatagca ggttcacgta ca 22 36 22 DNA Artificial Sequence Synthetic oligonucleotide 36 cgataacagt cttgccccac tt 22 37 20 DNA Artificial Sequence Synthetic oligonucleotide 37 acggcacacc ctacgttacc 20 38 24 DNA Artificial Sequence Synthetic oligonucleotide 38 tgtgcaagga gagaacctct agct 24 39 19 DNA Artificial Sequence Synthetic oligonucleotide 39 ccaacactgt gcgcagctt 19 40 22 DNA Artificial Sequence Synthetic oligonucleotide 40 aagaatctcc gggttgtttt cc 22 41 24 DNA Artificial Sequence Synthetic oligonucleotide 41 cagtctcatc ctgaaagcat ctga 24 42 20 DNA Artificial Sequence Synthetic oligonucleotide 42 tttcccacac actccaccaa 20 43 23 DNA Artificial Sequence Synthetic oligonucleotide 43 tggagtgttt tacgctgaac gat 23 44 31 DNA Artificial Sequence Synthetic oligonucleotide 44 cctcttactg ctataccttt actctttatg g 31 45 21 DNA Artificial Sequence Synthetic oligonucleotide 45 tgccatcaaa gtcttctgca a 21 46 21 DNA Artificial Sequence Synthetic oligonucleotide 46 cgccatactc gaactggaat c 21 47 25 DNA Artificial Sequence Synthetic oligonucleotide 47 cactattatt ttggcacaac aggaa 25 48 24 DNA Artificial Sequence Synthetic oligonucleotide 48 agacacatat ttggcatggt tctg 24 49 24 DNA Artificial Sequence Synthetic oligonucleotide 49 caagggatcc agtctctcta tggt 24 50 24 DNA Artificial Sequence Synthetic oligonucleotide 50 ggataaggaa gggtcacatt tgtc 24 51 18 DNA Artificial Sequence Synthetic oligonucleotide 51 gctcggtgga gggtctca 18 52 21 DNA Artificial Sequence Synthetic oligonucleotide 52 ctgtgtggat ttctgcgatc a 21 53 23 DNA Artificial Sequence Synthetic oligonucleotide 53 catccatgac aactttggta tcg 23 54 21 DNA Artificial Sequence Synthetic oligonucleotide 54 agtcttctgg gtggcagtga t 21 55 919 PRT Homo sapiens 55 Met Gly Thr Thr Ala Pro Gly Pro Ile His Leu Leu Glu Leu Cys Asp 1 5 10 15 Gln Lys Leu Met Glu Phe Leu Cys Asn Met Asp Asn Lys Asp Leu Val 20 25 30 Trp Leu Glu Glu Ile Gln Glu Glu Ala Glu Arg Met Phe Thr Arg Glu 35 40 45 Phe Ser Lys Glu Pro Glu Leu Met Pro Lys Thr Pro Ser Gln Lys Asn 50 55 60 Arg Arg Lys Lys Arg Arg Ile Ser Tyr Val Gln Asp Glu Asn Arg Asp 65 70 75 80 Pro Ile Arg Arg Arg Leu Ser Arg Arg Lys Ser Arg Ser Ser Gln Leu 85 90 95 Ser Ser Arg Arg Leu Arg Ser Lys Asp Ser Val Glu Lys Leu Ala Thr 100 105 110 Val Val Gly Glu Asn Gly Ser Val Leu Arg Arg Val Thr Arg Ala Ala 115 120 125 Ala Ala Ala Ala Ala Ala Thr Met Ala Leu Ala Ala Pro Ser Ser Pro 130 135 140 Thr Pro Glu Ser Pro Thr Met Leu Thr Lys Lys Pro Glu Asp Asn His 145 150 155 160 Thr Gln Cys Gln Leu Val Pro Val Val Glu Ile Gly Ile Ser Glu Arg 165 170 175 Gln Asn Ala Glu Gln His Val Thr Gln Leu Met Ser Thr Glu Pro Leu 180 185 190 Pro Arg Thr Leu Ser Pro Thr Pro Ala Ser Ala Thr Ala Pro Thr Ser 195 200 205 Gln Gly Ile Pro Thr Ser Asp Glu Glu Ser Thr Pro Lys Lys Ser Lys 210 215 220 Ala Arg Ile Leu Glu Ser Ile Thr Val Ser Ser Leu Met Ala Thr Pro 225 230 235 240 Gln Asp Pro Lys Gly Gln Gly Val Gly Thr Gly Arg Ser Ala Ser Lys 245 250 255 Leu Arg Ile Ala Gln Val Ser Pro Gly Pro Arg Asp Ser Pro Ala Phe 260 265 270 Pro Asp Ser Pro Trp Arg Glu Arg Val Leu Ala Pro Ile Leu Pro Asp 275 280 285 Asn Phe Ser Thr Pro Thr Gly Ser Arg Thr Asp Ser Gln Ser Val Arg 290 295 300 His Ser Pro Ile Ala Pro Ser Ser Pro Ser Pro Gln Val Leu Ala Gln 305 310 315 320 Lys Tyr Ser Leu Val Ala Lys Gln Glu Ser Val Val Arg Arg Ala Ser 325 330 335 Arg Arg Leu Ala Lys Lys Thr Ala Glu Glu Pro Ala Ala Ser Gly Arg 340 345 350 Ile Ile Cys His Ser Tyr Leu Glu Arg Leu Leu Asn Val Glu Val Pro 355 360 365 Gln Lys Val Gly Ser Glu Gln Lys Glu Pro Pro Glu Glu Ala Glu Pro 370 375 380 Val Ala Ala Ala Glu Pro Glu Val Pro Glu Asn Asn Gly Asn Asn Ser 385 390 395 400 Trp Pro His Asn Asp Thr Glu Ile Ala Asn Ser Thr Pro Asn Pro Lys 405 410 415 Pro Ala Ala Ser Ser Pro Glu Thr Pro Ser Ala Gly Gln Gln Glu Ala 420 425 430 Lys Thr Asp Gln Ala Asp Gly Pro Arg Glu Pro Pro Gln Ser Ala Arg 435 440 445 Arg Lys Arg Ser Tyr Lys Gln Ala Val Ser Glu Leu Asp Glu Glu Gln 450 455 460 His Leu Glu Asp Glu Glu Leu Gln Pro Pro Arg Ser Lys Thr Pro Ser 465 470 475 480 Ser Pro Cys Pro Ala Ser Lys Val Val Arg Pro Leu Arg Thr Phe Leu 485 490 495 His Thr Val Gln Arg Asn Gln Met Leu Met Thr Pro Thr Ser Ala Pro 500 505 510 Arg Ser Val Met Lys Ser Phe Ile Lys Arg Asn Thr Pro Leu Arg Met 515 520 525 Asp Pro Lys Glu Lys Glu Arg Gln Arg Leu Glu Asn Leu Arg Arg Lys 530 535 540 Glu Glu Ala Glu Gln Leu Arg Arg Gln Lys Val Glu Glu Asp Lys Arg 545 550 555 560 Arg Arg Leu Glu Glu Val Lys Leu Lys Arg Glu Glu Arg Leu Arg Lys 565 570 575 Val Leu Gln Ala Arg Glu Arg Val Glu Gln Met Lys Glu Glu Lys Lys 580 585 590 Lys Gln Ile Glu Gln Lys Phe Ala Gln Ile Asp Glu Lys Thr Glu Lys 595 600 605 Ala Lys Glu Glu Arg Leu Ala Glu Glu Lys Ala Lys Lys Lys Ala Ala 610 615 620 Ala Lys Lys Met Glu Glu Val Glu Ala Arg Arg Lys Gln Glu Glu Asp 625 630 635 640 Ala Arg Arg Leu Arg Trp Leu Gln Gln Glu Glu Glu Glu Arg Arg His 645 650 655 Gln Glu Leu Leu Gln Lys Lys Lys Glu Glu Glu Gln Glu Arg Leu Arg 660 665 670 Lys Ala Ala Glu Ala Lys Arg Leu Ala Glu Gln Arg Glu Gln Glu Arg 675 680 685 Arg Glu Gln Glu Arg Arg Glu Gln Glu Arg Arg Glu Gln Glu Arg Arg 690 695 700 Glu Gln Glu Arg Arg Glu Gln Glu Arg Arg Glu Gln Glu Arg Gln Leu 705 710 715 720 Ala Glu Gln Glu Arg Arg Arg Glu Gln Glu Arg Leu Gln Ala Glu Arg 725 730 735 Glu Leu Gln Glu Arg Glu Lys Ala Leu Arg Leu Gln Lys Glu Gln Leu 740 745 750 Gln Arg Glu Leu Glu Glu Lys Lys Lys Lys Glu Glu Gln Gln Arg Leu 755 760 765 Ala Glu Arg Gln Leu Gln Glu Glu Gln Glu Lys Lys Ala Lys Glu Ala 770 775 780 Ala Gly Ala Ser Lys Ala Leu Asn Val Thr Val Asp Val Gln Ser Pro 785 790 795 800 Ala Cys Thr Ser Ser Pro Ile Thr Pro Gln Gly His Lys Ala Pro Pro 805 810 815 Gln Ile Asn Pro His Asn Tyr Gly Met Asp Leu Asn Ser Asp Asp Ser 820 825 830 Thr Asp Asp Glu Ala His Pro Arg Lys Pro Ile Pro Thr Trp Ala Arg 835 840 845 Gly Thr Pro Leu Ser Gln Ala Ile Ile His Gln Tyr Tyr Gln Pro Pro 850 855 860 Asn Leu Leu Glu Leu Phe Gly Thr Ile Leu Pro Leu Asp Leu Glu Asp 865 870 875 880 Ile Phe Lys Lys Ser Lys Pro Arg Tyr His Lys Arg Thr Ser Ser Ala 885 890 895 Val Trp Asn Ser Pro Pro Leu Gln Gly Ala Arg Val Pro Ser Ser Leu 900 905 910 Ala Tyr Ser Leu Lys Lys His 915 56 804 PRT Homo sapiens 56 Met Thr Asn Gln Glu Lys Trp Ala His Leu Ser Pro Ser Glu Phe Ser 1 5 10 15 Gln Leu Gln Lys Tyr Ala Glu Tyr Ser Thr Lys Lys Leu Lys Asp Val 20 25 30 Leu Glu Glu Phe His Gly Asn Gly Val Leu Ala Lys Tyr Asn Pro Glu 35 40 45 Gly Lys Gln Asp Ile Leu Asn Gln Thr Ile Asp Phe Glu Gly Phe Lys 50 55 60 Leu Phe Met Lys Thr Phe Leu Glu Ala Glu Leu Pro Asp Asp Phe Thr 65 70 75 80 Ala His Leu Phe Met Ser Phe Ser Asn Lys Phe Pro His Ser Ser Pro 85 90 95 Met Val Lys Ser Lys Pro Ala Leu Leu Ser Gly Gly Leu Arg Met Asn 100 105 110 Lys Gly Ala Ile Thr Pro Pro Arg Thr Thr Ser Pro Ala Asn Thr Cys 115 120 125 Ser Pro Glu Val Ile His Leu Lys Asp Ile Val Cys Tyr Leu Ser Leu 130 135 140 Leu Glu Arg Gly Arg Pro Glu Asp Lys Leu Glu Phe Met Phe Arg Leu 145 150 155 160 Tyr Asp Thr Asp Gly Asn Gly Phe Leu Asp Ser Ser Glu Leu Glu Asn 165 170 175 Ile Ile Ser Gln Met Met His Val Ala Glu Tyr Leu Glu Trp Asp Val 180 185 190 Thr Glu Leu Asn Pro Ile Leu His Glu Met Met Glu Glu Ile Asp Tyr 195 200 205 Asp His Asp Gly Thr Val Ser Leu Glu Glu Trp Ile Gln Gly Gly Met 210 215 220 Thr Thr Ile Pro Leu Leu Val Leu Leu Gly Leu Glu Asn Asn Val Lys 225 230 235 240 Asp Asp Gly Gln His Val Trp Arg Leu Lys His Phe Asn Lys Pro Ala 245 250 255 Tyr Cys Asn Leu Cys Leu Asn Met Leu Ile Gly Val Gly Lys Gln Gly 260 265 270 Leu Cys Cys Ser Phe Cys Lys Tyr Thr Val His Glu Arg Cys Val Ala 275 280 285 Arg Ala Pro Pro Ser Cys Ile Lys Thr Tyr Val Lys Ser Lys Arg Asn 290 295 300 Thr Asp Val Met His His Tyr Trp Val Glu Gly Asn Cys Pro Thr Lys 305 310 315 320 Cys Asp Lys Cys His Lys Thr Val Lys Cys Tyr Gln Gly Leu Thr Gly 325 330 335 Leu His Cys Val Trp Cys Gln Ile Thr Leu His Asn Lys Cys Ala Ser 340 345 350 His Leu Lys Pro Glu Cys Asp Cys Gly Pro Leu Lys Asp His Ile Leu 355 360 365 Pro Pro Thr Thr Ile Cys Pro Val Val Leu Gln Thr Leu Pro Thr Ser 370 375 380 Gly Val Ser Val Pro Glu Glu Arg Gln Ser Thr Val Lys Lys Glu Lys 385 390 395 400 Ser Gly Ser Gln Gln Pro Asn Lys Val Ile Asp Lys Asn Lys Met Gln 405 410 415 Arg Ala Asn Ser Val Thr Val Asp Gly Gln Gly Leu Gln Val Thr Pro 420 425 430 Val Pro Gly Thr His Pro Leu Leu Val Phe Val Asn Pro Lys Ser Gly 435 440 445 Gly Lys Gln Gly Glu Arg Ile Tyr Arg Lys Phe Gln Tyr Leu Leu Asn 450 455 460 Pro Arg Gln Val Tyr Ser Leu Ser Gly Asn Gly Pro Met Pro Gly Leu 465 470 475 480 Asn Phe Phe Arg Asp Val Pro Asp Phe Arg Val Leu Ala Cys Gly Gly 485 490 495 Asp Gly Thr Val Gly Trp Val Leu Asp Cys Ile Glu Lys Ala Asn Val 500 505 510 Gly Lys His Pro Pro Val Ala Ile Leu Pro Leu Gly Thr Gly Asn Asp 515 520 525 Leu Ala Arg Cys Leu Arg Trp Gly Gly Gly Tyr Glu Gly Glu Asn Leu 530 535 540 Met Lys Ile Leu Lys Asp Ile Glu Asn Ser Thr Glu Ile Met Leu Asp 545 550 555 560 Arg Trp Lys Phe Glu Val Ile Pro Asn Asp Lys Asp Glu Lys Gly Asp 565 570 575 Pro Val Pro Tyr Ser Ile Ile Asn Asn Tyr Phe Ser Ile Gly Val Asp 580 585 590 Ala Ser Ile Ala His Arg Phe His Ile Met Arg Glu Lys His Pro Glu 595 600 605 Lys Phe Asn Ser Arg Met Lys Asn Lys Phe Trp Tyr Phe Glu Phe Gly 610 615 620 Thr Ser Glu Thr Phe Ser Ala Thr Cys Lys Lys Leu His Glu Ser Val 625 630 635 640 Glu Ile Glu Cys Asp Gly Val Gln Ile Asp Leu Ile Asn Ile Ser Leu 645 650 655 Glu Gly Ile Ala Ile Leu Asn Ile Pro Ser Met His Gly Gly Ser Asn 660 665 670 Leu Trp Gly Glu Ser Lys Lys Arg Arg Ser His Arg Arg Ile Glu Lys 675 680 685 Lys Gly Ser Asp Lys Arg Thr Thr Val Thr Asp Ala Lys Glu Leu Lys 690 695 700 Phe Ala Ser Gln Asp Leu Ser Asp Gln Leu Leu Glu Val Val Gly Leu 705 710 715 720 Glu Gly Ala Met Glu Met Gly Gln Ile Tyr Thr Gly Leu Lys Ser Ala 725 730 735 Gly Arg Arg Leu Ala Gln Cys Ser Cys Val Val Ile Arg Thr Ser Lys 740 745 750 Ser Leu Pro Met Gln Ile Asp Gly Glu Pro Trp Met Gln Thr Pro Cys 755 760 765 Thr Ile Lys Ile Thr His Lys Asn Gln Ala Pro Met Leu Met Gly Pro 770 775 780 Pro Pro Lys Thr Gly Leu Phe Cys Ser Leu Val Lys Arg Thr Arg Asn 785 790 795 800 Arg Ser Lys Glu 57 773 PRT Homo sapiens 57 Met Thr Asn Gln Glu Lys Trp Ala His Leu Ser Pro Ser Glu Phe Ser 1 5 10 15 Gln Leu Gln Lys Tyr Ala Glu Tyr Ser Thr Lys Lys Leu Lys Asp Val 20 25 30 Leu Glu Glu Phe His Gly Asn Gly Val Leu Ala Lys Tyr Asn Pro Glu 35 40 45 Gly Lys Gln Asp Ile Leu Asn Gln Thr Ile Asp Phe Glu Gly Phe Lys 50 55 60 Leu Phe Met Lys Thr Phe Leu Glu Ala Glu Leu Pro Asp Asp Phe Thr 65 70 75 80 Ala His Leu Phe Met Ser Phe Ser Asn Lys Phe Pro His Ser Ser Pro 85 90 95 Met Val Lys Ser Lys Pro Ala Leu Leu Ser Gly Gly Leu Arg Met Asn 100 105 110 Lys Gly Ala Ile Thr Pro Pro Arg Thr Thr Ser Pro Ala Asn Thr Cys 115 120 125 Ser Pro Glu Val Ile His Leu Lys Asp Ile Val Cys Tyr Leu Ser Leu 130 135 140 Leu Glu Arg Gly Arg Pro Glu Asp Lys Leu Glu Phe Met Phe Arg Leu 145 150 155 160 Tyr Asp Thr Asp Gly Asn Gly Phe Leu Asp Ser Ser Glu Leu Glu Asn 165 170 175 Ile Ile Ser Gln Met Met His Val Ala Glu Tyr Leu Glu Trp Asp Val 180 185 190 Thr Glu Leu Asn Pro Ile Leu His Glu Met Met Glu Glu Ile Asp Tyr 195 200 205 Asp His Asp Gly Thr Val Ser Leu Glu Glu Trp Ile Gln Gly Gly Met 210 215 220 Thr Thr Ile Pro Leu Leu Val Leu Leu Gly Leu Glu Asn Asn Val Lys 225 230 235 240 Asp Asp Gly Gln His Val Trp Arg Leu Lys His Phe Asn Lys Pro Ala 245 250 255 Tyr Cys Asn Leu Cys Leu Asn Met Leu Ile Gly Val Gly Lys Gln Gly

260 265 270 Leu Cys Cys Ser Phe Cys Lys Tyr Thr Val His Glu Arg Cys Val Ala 275 280 285 Arg Ala Pro Pro Ser Cys Ile Lys Thr Tyr Val Lys Ser Lys Arg Asn 290 295 300 Thr Asp Val Met His His Tyr Trp Val Glu Gly Asn Cys Pro Thr Lys 305 310 315 320 Cys Asp Lys Cys His Lys Thr Val Lys Cys Tyr Gln Gly Leu Thr Gly 325 330 335 Leu His Cys Val Trp Cys Gln Ile Thr Leu His Asn Lys Cys Ala Ser 340 345 350 His Leu Lys Pro Glu Cys Asp Cys Gly Pro Leu Lys Asp His Ile Leu 355 360 365 Pro Pro Thr Thr Ile Cys Pro Val Val Leu Gln Thr Leu Pro Thr Ser 370 375 380 Gly Val Ser Val Pro Glu Glu Arg Gln Ser Thr Val Lys Lys Glu Lys 385 390 395 400 Ser Gly Ser Gln Gln Pro Asn Lys Val Ile Asp Lys Asn Lys Met Gln 405 410 415 Arg Ala Asn Ser Val Thr Val Asp Gly Gln Gly Leu Gln Val Thr Pro 420 425 430 Val Pro Gly Thr His Pro Leu Leu Val Phe Val Asn Pro Lys Ser Gly 435 440 445 Gly Lys Gln Gly Glu Arg Ile Tyr Arg Lys Phe Gln Tyr Leu Leu Asn 450 455 460 Pro Arg Gln Val Tyr Ser Leu Ser Gly Asn Gly Pro Met Pro Gly Leu 465 470 475 480 Asn Phe Phe Arg Asp Val Pro Asp Phe Arg Val Leu Ala Cys Gly Gly 485 490 495 Asp Gly Thr Val Gly Trp Val Leu Asp Cys Ile Glu Lys Ala Asn Val 500 505 510 Gly Lys His Pro Pro Val Ala Ile Leu Pro Leu Gly Thr Gly Asn Asp 515 520 525 Leu Ala Arg Cys Leu Arg Trp Gly Gly Gly Tyr Glu Gly Glu Asn Leu 530 535 540 Met Lys Ile Leu Lys Asp Ile Glu Asn Ser Thr Glu Ile Met Leu Asp 545 550 555 560 Arg Trp Lys Phe Glu Val Ile Pro Asn Asp Lys Asp Glu Lys Gly Asp 565 570 575 Pro Val Pro Tyr Ser Ile Ile Asn Asn Tyr Phe Ser Ile Gly Val Asp 580 585 590 Ala Ser Ile Ala His Arg Phe His Ile Met Arg Glu Lys His Pro Glu 595 600 605 Lys Phe Asn Ser Arg Met Lys Asn Lys Phe Trp Tyr Phe Glu Phe Gly 610 615 620 Thr Ser Glu Thr Phe Ser Ala Thr Cys Lys Lys Leu His Glu Ser Val 625 630 635 640 Glu Ile Glu Cys Asp Gly Val Gln Ile Asp Leu Ile Asn Ile Ser Leu 645 650 655 Glu Gly Ile Ala Ile Leu Asn Ile Pro Ser Met His Gly Gly Ser Asn 660 665 670 Leu Trp Gly Glu Ser Lys Lys Arg Arg Ser His Arg Arg Ile Glu Lys 675 680 685 Lys Gly Ser Asp Lys Arg Thr Thr Val Thr Asp Ala Lys Glu Leu Lys 690 695 700 Phe Ala Ser Gln Asp Leu Ser Asp Gln Leu Leu Glu Val Val Gly Leu 705 710 715 720 Glu Gly Ala Met Glu Met Gly Gln Ile Tyr Thr Gly Leu Lys Ser Ala 725 730 735 Gly Arg Arg Leu Ala Gln Cys Ser Cys Val Val Ile Arg Thr Ser Lys 740 745 750 Ser Leu Pro Met Gln Ile Asp Gly Glu Pro Trp Met Gln Thr Pro Cys 755 760 765 Thr Val Ser Thr Glu 770 58 632 PRT Homo sapiens 58 Met Asn Arg Tyr Thr Thr Ile Arg Gln Leu Gly Asp Gly Thr Tyr Gly 1 5 10 15 Ser Val Leu Leu Gly Arg Ser Ile Glu Ser Gly Glu Leu Ile Ala Ile 20 25 30 Lys Lys Met Lys Arg Lys Phe Tyr Ser Trp Glu Glu Cys Met Asn Leu 35 40 45 Arg Glu Val Lys Ser Leu Lys Lys Leu Asn His Ala Asn Val Val 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 Ile Lys Glu Arg Asn Lys Leu 85 90 95 Phe Pro Glu Ser Ala 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 Leu 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 Ile Arg Ser Lys 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 Thr Asn 165 170 175 Tyr Ser Ser Pro Ile Asp Val Trp Ala Val Gly Cys Ile Met Ala Glu 180 185 190 Val Tyr Thr Leu Arg Pro Leu Phe Pro Gly Ala Ser Glu Ile Asp Thr 195 200 205 Ile Phe Lys Ile Cys Gln Val Leu Gly Thr Pro Lys Lys Thr Asp Trp 210 215 220 Pro Glu Gly Tyr Gln Leu Ser Ser Ala Met Asn Phe Arg Trp Pro Gln 225 230 235 240 Cys Val Pro Asn Asn Leu Lys Thr Leu Ile Pro Asn Ala Ser Ser Glu 245 250 255 Ala Val Gln Leu Leu Arg Asp Met Leu Gln Trp Asp Pro Lys Lys Arg 260 265 270 Pro Thr Ala Ser Gln Ala Leu Arg Tyr Pro Tyr Phe Gln Val Gly His 275 280 285 Pro Leu Gly Ser Thr Thr Gln Asn Leu Gln Asp Ser Glu Lys Pro Gln 290 295 300 Lys Gly Ile Leu Glu Lys Ala Gly Pro Pro Pro Tyr Ile Lys Pro Val 305 310 315 320 Pro Pro Ala Gln Pro Pro Ala Lys Pro His Thr Arg Ile Ser Ser Arg 325 330 335 Gln His Gln Ala Ser Gln Pro Pro Leu His Leu Thr Tyr Pro Tyr Lys 340 345 350 Ala Glu Val Ser Arg Thr Asp His Pro Ser His Leu Gln Glu Asp Lys 355 360 365 Pro Ser Pro Leu Leu Phe Pro Ser Leu His Asn Lys His Pro Gln Ser 370 375 380 Lys Ile Thr Ala Gly Leu Glu His Lys Asn Gly Glu Ile Lys Pro Lys 385 390 395 400 Ser Arg Arg Arg Trp Gly Leu Ile Ser Arg Ser Thr Lys Asp Ser Asp 405 410 415 Asp Trp Ala Asp Leu Asp Asp Leu Asp Phe Ser Pro Ser Leu Ser Arg 420 425 430 Ile Asp Leu Lys Asn Lys Lys Arg Gln Ser Asp Asp Thr Leu Cys Arg 435 440 445 Phe Glu Ser Val Leu Asp Leu Lys Pro Ser Glu Pro Val Gly Thr Gly 450 455 460 Asn Ser Ala Pro Thr Gln Thr Ser Tyr Gln Arg Arg Asp Thr Pro Thr 465 470 475 480 Leu Arg Ser Ala Ala Lys Gln His Tyr Leu Lys His Ser Arg Tyr Leu 485 490 495 Pro Gly Ile Ser Ile Arg Asn Gly Ile Leu Ser Asn Pro Gly Lys Glu 500 505 510 Phe Ile Pro Pro Asn Pro Trp Ser Ser Ser Gly Leu Ser Gly Lys Ser 515 520 525 Ser Gly Thr Met Ser Val Ile Ser Lys Val Asn Ser Val Gly Ser Ser 530 535 540 Ser Thr Ser Ser Ser Gly Leu Thr Gly Asn Tyr Val Pro Ser Phe Leu 545 550 555 560 Lys Lys Glu Ile Gly Ser Ala Met Gln Arg Val His Leu Ala Pro Ile 565 570 575 Pro Asp Pro Ser Pro Gly Tyr Ser Ser Leu Lys Ala Met Arg Pro His 580 585 590 Pro Gly Arg Pro Phe Phe His Thr Gln Pro Arg Ser Thr Pro Gly Leu 595 600 605 Ile Pro Arg Pro Pro Ala Ala Gln Pro Val His Gly Arg Thr Asp Trp 610 615 620 Ala Ser Lys Tyr Ala Ser Arg Arg 625 630 59 632 PRT Homo sapiens 59 Met Asn Arg Tyr Thr Thr Ile Arg Gln Leu Gly Asp Gly Thr Tyr Gly 1 5 10 15 Ser Val Leu Leu Gly Arg Ser Ile Glu Ser Gly Glu Leu Ile Ala Ile 20 25 30 Lys Lys Met Lys Arg Lys Phe Tyr Ser Trp Glu Glu Cys Met Asn Leu 35 40 45 Arg Glu Val Lys Ser Leu Lys Lys Leu Asn His Ala Asn Val Val 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 Ile Lys Glu Arg Asn Lys Leu 85 90 95 Phe Pro Glu Ser Ala 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 Leu 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 Ile Arg Ser Lys 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 Thr Asn 165 170 175 Tyr Ser Ser Pro Ile Asp Val Trp Ala Val Gly Cys Ile Met Ala Glu 180 185 190 Val Tyr Thr Leu Arg Pro Leu Phe Pro Gly Ala Ser Glu Ile Asp Thr 195 200 205 Ile Phe Lys Ile Cys Gln Val Leu Gly Thr Pro Lys Lys Thr Asp Trp 210 215 220 Pro Glu Gly Tyr Gln Leu Ser Ser Ala Met Asn Phe Arg Trp Pro Gln 225 230 235 240 Cys Val Pro Asn Asn Leu Lys Thr Leu Ile Pro Asn Ala Ser Ser Glu 245 250 255 Ala Val Gln Leu Leu Arg Asp Met Leu Gln Trp Asp Pro Lys Lys Arg 260 265 270 Pro Thr Ala Ser Gln Ala Leu Arg Tyr Pro Tyr Phe Gln Val Gly His 275 280 285 Pro Leu Gly Ser Thr Thr Gln Asn Leu Gln Asp Ser Glu Lys Pro Gln 290 295 300 Lys Gly Ile Leu Glu Lys Ala Gly Pro Pro Pro Tyr Ile Lys Pro Val 305 310 315 320 Pro Pro Ala Gln Pro Pro Ala Lys Pro His Thr Arg Ile Ser Ser Arg 325 330 335 Gln His Gln Ala Ser Gln Pro Pro Leu His Leu Thr Tyr Pro Tyr Lys 340 345 350 Ala Glu Val Ser Arg Thr Asp His Pro Ser His Leu Gln Glu Asp Lys 355 360 365 Pro Ser Pro Leu Leu Phe Pro Ser Leu His Asn Lys His Pro Gln Ser 370 375 380 Lys Ile Thr Ala Gly Leu Glu His Lys Asn Gly Glu Ile Lys Pro Lys 385 390 395 400 Ser Arg Arg Arg Trp Gly Leu Ile Ser Arg Ser Thr Lys Asp Ser Asp 405 410 415 Asp Trp Ala Asp Leu Asp Asp Leu Asp Phe Ser Pro Ser Leu Ser Arg 420 425 430 Ile Asp Leu Lys Asn Lys Lys Arg Gln Ser Asp Asp Thr Leu Cys Arg 435 440 445 Phe Glu Ser Val Leu Asp Leu Lys Pro Ser Glu Pro Val Gly Thr Gly 450 455 460 Asn Ser Ala Pro Thr Gln Thr Ser Tyr Gln Arg Arg Asp Thr Pro Thr 465 470 475 480 Leu Arg Ser Ala Ala Lys Gln His Tyr Leu Lys His Ser Arg Tyr Leu 485 490 495 Pro Gly Ile Ser Ile Arg Asn Gly Ile Leu Ser Asn Pro Gly Lys Glu 500 505 510 Phe Ile Pro Pro Asn Pro Trp Ser Ser Ser Gly Leu Ser Gly Lys Ser 515 520 525 Ser Gly Thr Met Ser Val Ile Ser Lys Val Asn Ser Val Gly Ser Ser 530 535 540 Ser Thr Ser Ser Ser Gly Leu Thr Gly Asn Tyr Val Pro Ser Phe Leu 545 550 555 560 Lys Lys Glu Ile Gly Ser Ala Met Gln Arg Val His Leu Ala Pro Ile 565 570 575 Pro Asp Pro Ser Pro Gly Tyr Ser Ser Leu Lys Ala Met Arg Pro His 580 585 590 Pro Gly Arg Pro Phe Phe His Thr Gln Pro Arg Ser Thr Pro Gly Leu 595 600 605 Ile Pro Arg Pro Pro Ala Ala Gln Pro Val His Gly Arg Thr Asp Trp 610 615 620 Ala Ser Lys Tyr Ala Ser Arg Arg 625 630 60 455 PRT Homo sapiens 60 Met Ile Cys Cys Ser Ala Leu Ser Pro Arg Ile His Leu Ser Phe His 1 5 10 15 Arg Ser Leu Thr Gly Ile Val Leu Ala Asn Ser Ser Leu Asp Ile Val 20 25 30 Leu His Asp Thr Tyr Tyr Val Val Ala His Cys Gly Gly Asn Val Arg 35 40 45 Arg Leu His Cys Gly Gly Pro Ala Ser Arg Glu Arg Thr Ala Met Gln 50 55 60 Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg Leu Leu Arg Asp His 65 70 75 80 Asn Leu Thr Arg Glu Gln Phe Ile Ala Leu Tyr Arg Leu Arg Pro Leu 85 90 95 Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala Lys Leu Ala Leu Val Leu 100 105 110 Thr Gly Val Leu Ile Phe Ala Leu Ala Leu Phe Gly Asn Ala Leu Val 115 120 125 Phe Tyr Val Val Thr Arg Ser Lys Ala Met Arg Thr Val Thr Asn Ile 130 135 140 Phe Ile Cys Ser Leu Ala Leu Ser Asp Leu Leu Ile Thr Phe Phe Cys 145 150 155 160 Ile Pro Val Thr Met Leu Gln Asn Ile Ser Asp Asn Trp Leu Gly Gly 165 170 175 Ala Phe Ile Cys Lys Met Val Pro Phe Val Gln Ser Thr Ala Val Val 180 185 190 Thr Glu Ile Leu Thr Met Thr Cys Ile Ala Val Glu Arg His Gln Gly 195 200 205 Leu Val His Pro Phe Lys Met Lys Trp Gln Tyr Thr Asn Arg Arg Ala 210 215 220 Phe Thr Met Leu Gly Val Val Trp Leu Val Ala Val Ile Val Gly Ser 225 230 235 240 Pro Met Trp His Val Gln Gln Leu Glu Ile Lys Tyr Asp Phe Leu Tyr 245 250 255 Glu Lys Glu His Ile Cys Cys Leu Glu Glu Trp Thr Ser Pro Val His 260 265 270 Gln Lys Ile Tyr Thr Thr Phe Ile Leu Ser Ser Ser Ser Ser Cys Leu 275 280 285 Leu Trp Lys Lys Lys Arg Ala Val Ile Met Met Val Thr Val Val Ala 290 295 300 Leu Phe Ala Val Cys Trp Ala Pro Phe His Val Val His Met Met Ile 305 310 315 320 Glu Tyr Ser Asn Phe Glu Lys Glu Tyr Asp Asp Val Thr Ile Lys Met 325 330 335 Ile Phe Ala Ile Val Gln Ile Ile Gly Phe Ser Asn Ser Ile Cys Asn 340 345 350 Pro Ile Val Tyr Ala Phe Met Asn Glu Asn Phe Lys Lys Asn Val Leu 355 360 365 Ser Ala Val Cys Tyr Cys Ile Val Asn Lys Thr Phe Ser Pro Ala Gln 370 375 380 Arg His Gly Asn Ser Gly Ile Thr Met Met Arg Lys Lys Ala Lys Phe 385 390 395 400 Ser Leu Arg Glu Asn Pro Val Glu Glu Thr Lys Gly Glu Ala Phe Ser 405 410 415 Asp Gly Asn Ile Glu Val Lys Leu Cys Glu Gln Thr Glu Glu Lys Lys 420 425 430 Lys Leu Lys Arg His Leu Ala Leu Phe Arg Ser Glu Leu Ala Glu Asn 435 440 445 Ser Pro Leu Asp Ser Gly His 450 455 61 431 PRT Homo sapiens 61 Met Gln Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg Leu Leu Arg 1 5 10 15 Asp His Asn Leu Thr Arg Glu Gln Phe Ile Ala Val His Arg Leu Arg 20 25 30 Pro Leu Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala Lys Leu Ala Leu 35 40 45 Val Leu Thr Gly Val Leu Ile Phe Ala Leu Ala Leu Phe Gly Asn Ala 50 55 60 Leu Val Phe Tyr Val Val Thr Arg Ser Lys Ala Met Arg Thr Val Thr 65 70 75 80 Asn Ile Phe Ile Cys Ser Leu Ala Leu Ser Asp Leu Leu Ile Thr Phe 85 90 95 Phe Cys Ile Pro Val Thr Met Leu Gln Asn Ile Ser Asp Asn Trp Leu 100 105 110 Gly Gly Ala Phe Ile Cys Lys Met Val Pro Phe Val Gln Ser Thr Ala 115 120 125 Val Val Thr Glu Ile Leu Thr Met Thr Cys Ile Ala Val Glu Arg His 130 135 140 Gln Gly Leu Val His Pro Phe Lys Met Lys Trp Gln Tyr Thr Asn Arg 145 150 155 160 Arg Ala Phe Thr Met Leu Gly Val Val Trp Leu Val Ala Val Ile Val 165 170 175 Gly Ser Pro Met Trp His Val Gln Gln Leu Glu Ile Lys Tyr Asp Phe 180 185 190 Leu Tyr Glu Lys Glu His Ile Cys Cys Leu Glu Glu Trp Thr Ser Pro 195 200 205 Val His Gln Lys Ile Tyr Thr Thr Phe Ile Leu Val Ile Leu Phe Leu 210

215 220 Leu Pro Leu Met Val Met Leu Ile Leu Tyr Ser Lys Ile Gly Tyr Glu 225 230 235 240 Leu Trp Ile Lys Lys Arg Val Gly Asp Gly Ser Val Leu Arg Thr Ile 245 250 255 His Gly Lys Glu Met Ser Lys Ile Ala Arg Lys Lys Lys Arg Ala Val 260 265 270 Ile Met Met Val Thr Val Val Ala Leu Phe Ala Val Cys Trp Ala Pro 275 280 285 Phe His Val Val His Met Met Ile Glu Tyr Ser Asn Phe Glu Lys Glu 290 295 300 Tyr Asp Asp Val Thr Ile Lys Met Ile Phe Ala Ile Val Gln Ile Ile 305 310 315 320 Gly Phe Ser Asn Ser Ile Cys Asn Pro Ile Val Tyr Ala Phe Met Asn 325 330 335 Glu Asn Phe Lys Lys Asn Val Leu Ser Ala Val Cys Tyr Cys Ile Val 340 345 350 Asn Lys Thr Phe Ser Pro Ala Gln Arg His Gly Asn Ser Gly Ile Thr 355 360 365 Met Met Arg Lys Lys Ala Lys Phe Ser Leu Arg Glu Asn Pro Val Glu 370 375 380 Glu Thr Lys Gly Glu Ala Phe Ser Asp Gly Asn Ile Glu Val Lys Leu 385 390 395 400 Cys Glu Gln Thr Glu Glu Lys Lys Lys Leu Lys Arg His Leu Ala Leu 405 410 415 Phe Arg Ser Glu Leu Ala Glu Asn Ser Pro Leu Asp Ser Gly His 420 425 430 62 647 PRT Homo sapiens 62 Met Ala Glu Glu Glu Ala Pro Lys Lys Ser Arg Ala Ala Gly Gly Gly 1 5 10 15 Ala Ser Trp Glu Leu Cys Ala Gly Ala Leu Ser Ala Arg Leu Ala Glu 20 25 30 Glu Gly Ser Gly Asp Ala Gly Gly Arg Arg Arg Pro Pro Val Asp Pro 35 40 45 Arg Arg Leu Ala Arg Gln Leu Leu Leu Leu Leu Trp Leu Leu Glu Ala 50 55 60 Pro Leu Leu Leu Gly Val Arg Ala Gln Ala Ala Gly Gln Gly Pro Gly 65 70 75 80 Gln Gly Pro Gly Pro Gly Gln Gln Pro Pro Pro Pro Pro Gln Gln Gln 85 90 95 Gln Ser Gly Gln Gln Tyr Asn Gly Glu Arg Gly Ile Ser Val Pro Asp 100 105 110 His Gly Tyr Cys Gln Pro Ile Ser Ile Pro Leu Cys Thr Asp Ile Ala 115 120 125 Tyr Asn Gln Thr Ile Met Pro Asn Leu Leu Gly His Thr Asn Gln Glu 130 135 140 Asp Ala Gly Leu Glu Val His Gln Phe Tyr Pro Leu Val Lys Val Gln 145 150 155 160 Cys Ser Ala Glu Leu Lys Phe Phe Leu Cys Ser Met Tyr Ala Pro Val 165 170 175 Cys Thr Val Leu Glu Gln Ala Leu Pro Pro Cys Arg Ser Leu Cys Glu 180 185 190 Arg Ala Arg Gln Gly Cys Glu Ala Leu Met Asn Lys Phe Gly Phe Gln 195 200 205 Trp Pro Asp Thr Leu Lys Cys Glu Lys Phe Pro Val His Gly Ala Gly 210 215 220 Glu Leu Cys Val Gly Gln Asn Thr Ser Asp Lys Gly Thr Pro Thr Pro 225 230 235 240 Ser Leu Leu Pro Glu Phe Trp Thr Ser Asn Pro Gln His Gly Gly Gly 245 250 255 Gly His Arg Gly Gly Phe Pro Gly Gly Ala Gly Ala Ser Glu Arg Gly 260 265 270 Lys Phe Ser Cys Pro Arg Ala Leu Lys Val Pro Ser Tyr Leu Asn Tyr 275 280 285 His Phe Leu Gly Glu Lys Asp Cys Gly Ala Pro Cys Glu Pro Thr Lys 290 295 300 Val Tyr Gly Leu Met Tyr Phe Gly Pro Glu Glu Leu Arg Phe Ser Arg 305 310 315 320 Thr Trp Ile Gly Ile Trp Ser Val Leu Cys Cys Ala Ser Thr Leu Phe 325 330 335 Thr Val Leu Thr Tyr Leu Val Asp Met Arg Arg Phe Ser Tyr Pro Glu 340 345 350 Arg Pro Ile Ile Phe Leu Ser Gly Cys Tyr Thr Ala Val Ala Val Ala 355 360 365 Tyr Ile Ala Gly Phe Leu Leu Glu Asp Arg Val Val Cys Asn Asp Lys 370 375 380 Phe Ala Glu Asp Gly Ala Arg Thr Val Ala Gln Gly Thr Lys Lys Glu 385 390 395 400 Gly Cys Thr Ile Leu Phe Met Met Leu Tyr Phe Phe Ser Met Ala Ser 405 410 415 Ser Ile Trp Trp Val Ile Leu Ser Leu Thr Trp Phe Leu Ala Ala Gly 420 425 430 Met Lys Trp Gly His Glu Ala Ile Glu Ala Asn Ser Gln Tyr Phe His 435 440 445 Leu Ala Ala Trp Ala Val Pro Ala Ile Lys Thr Ile Thr Ile Leu Ala 450 455 460 Leu Gly Gln Val Asp Gly Asp Val Leu Ser Gly Val Cys Phe Val Gly 465 470 475 480 Leu Asn Asn Val Asp Ala Leu Arg Gly Phe Val Leu Ala Pro Leu Phe 485 490 495 Val Tyr Leu Phe Ile Gly Thr Ser Phe Leu Leu Ala Gly Phe Val Ser 500 505 510 Leu Phe Arg Ile Arg Thr Ile Met Lys His Asp Gly Thr Lys Thr Glu 515 520 525 Lys Leu Glu Lys Leu Met Val Arg Ile Gly Val Phe Ser Val Leu Tyr 530 535 540 Thr Val Pro Ala Thr Ile Val Ile Ala Cys Tyr Phe Tyr Glu Gln Ala 545 550 555 560 Phe Arg Asp Gln Trp Glu Arg Ser Trp Val Ala Gln Ser Cys Lys Ser 565 570 575 Tyr Ala Ile Pro Cys Pro His Leu Gln Ala Gly Gly Gly Ala Pro Pro 580 585 590 His Pro Pro Met Ser Pro Asp Phe Thr Val Phe Met Ile Lys Tyr Leu 595 600 605 Met Thr Leu Ile Val Gly Ile Thr Ser Gly Phe Trp Ile Trp Ser Gly 610 615 620 Lys Thr Leu Asn Ser Trp Arg Lys Phe Tyr Thr Arg Leu Thr Asn Ser 625 630 635 640 Lys Gln Gly Glu Thr Thr Val 645 63 258 PRT Homo sapiens 63 Met Leu Val Leu Tyr Gly His Ser Thr Gln Asp Leu Pro Glu Thr Asn 1 5 10 15 Ala Arg Val Val Gly Gly Thr Glu Ala Gly Arg Asn Ser Trp Pro Ser 20 25 30 Gln Ile Ser Leu Gln Tyr Arg Ser Gly Gly Ser Arg Tyr His Thr Cys 35 40 45 Gly Gly Thr Leu Ile Arg Gln Asn Trp Val Met Thr Ala Ala His Cys 50 55 60 Val Asp Tyr Gln Lys Thr Phe Arg Val Val Ala Gly Asp His Asn Leu 65 70 75 80 Ser Gln Asn Asp Gly Thr Glu Gln Tyr Val Ser Val Gln Lys Ile Val 85 90 95 Val His Pro Tyr Trp Asn Ser Asp Asn Val Ala Ala Gly Tyr Asp Ile 100 105 110 Ala Leu Leu Arg Leu Ala Gln Ser Val Thr Leu Asn Ser Tyr Val Gln 115 120 125 Leu Gly Val Leu Pro Gln Glu Gly Ala Ile Leu Ala Asn Asn Ser Pro 130 135 140 Cys Tyr Ile Thr Gly Trp Gly Lys Thr Lys Thr Asn Gly Gln Leu Ala 145 150 155 160 Gln Thr Leu Gln Gln Ala Tyr Leu Pro Ser Val Asp Tyr Ala Ile Cys 165 170 175 Ser Ser Ser Ser Tyr Trp Gly Ser Thr Val Lys Asn Thr Met Val Cys 180 185 190 Ala Gly Gly Asp Gly Val Arg Ser Gly Cys Gln Gly Asp Ser Gly Gly 195 200 205 Pro Leu His Cys Leu Val Asn Gly Lys Tyr Ser Val His Gly Val Thr 210 215 220 Ser Phe Val Ser Ser Arg Gly Cys Asn Val Ser Arg Lys Pro Thr Val 225 230 235 240 Phe Thr Gln Val Ser Ala Tyr Ile Ser Trp Ile Asn Asn Val Ile Ala 245 250 255 Ser Asn 64 2555 PRT Homo sapiens 64 Met Thr Ala Ile Thr His Gly Ser Pro Val Gly Gly Asn Asp Ser Gln 1 5 10 15 Gly Gln Val Leu Asp Gly Gln Ser Gln His Leu Phe Gln Gln Asn Gln 20 25 30 Thr Ser Ser Pro Asp Ser Ser Asn Glu Asn Ser Val Ala Thr Pro Pro 35 40 45 Pro Glu Glu Gln Gly Gln Gly Asp Ala Pro Pro Gln His Glu Asp Glu 50 55 60 Glu Pro Ala Phe Pro His Thr Glu Leu Ala Asn Leu Asp Asp Met Ile 65 70 75 80 Asn Arg Pro Arg Trp Val Val Pro Val Leu Pro Lys Gly Glu Leu Glu 85 90 95 Val Leu Leu Glu Ala Ala Ile Asp Leu Ser Val Lys Gly Leu Asp Val 100 105 110 Lys Ser Glu Ala Cys Gln Arg Phe Phe Arg Asp Gly Leu Thr Ile Ser 115 120 125 Phe Thr Lys Ile Leu Met Asp Glu Ala Val Ser Gly Trp Lys Phe Glu 130 135 140 Ile His Arg Cys Ile Ile Asn Asn Thr His Arg Leu Val Glu Leu Cys 145 150 155 160 Val Ala Lys Leu Ser Gln Asp Trp Phe Pro Leu Leu Glu Leu Leu Ala 165 170 175 Met Ala Leu Asn Pro His Cys Lys Phe His Ile Tyr Asn Gly Thr Arg 180 185 190 Pro Cys Glu Leu Ile Ser Ser Asn Ala Gln Leu Pro Glu Glu Glu Leu 195 200 205 Phe Ala Arg Ser Ser Asp Pro Arg Ser Pro Lys Gly Trp Leu Val Asp 210 215 220 Leu Ile Asn Lys Phe Gly Thr Leu Asn Gly Phe Gln Ile Leu His Asp 225 230 235 240 Arg Phe Phe Asn Gly Ser Ala Leu Asn Ile Gln Ile Ile Ala Ala Leu 245 250 255 Ile Lys Pro Phe Gly Gln Cys Tyr Glu Phe Leu Ser Gln His Thr Leu 260 265 270 Lys Lys Tyr Phe Ile Pro Val Ile Glu Ile Val Pro His Leu Leu Glu 275 280 285 Asn Leu Thr Asp Glu Glu Leu Lys Lys Glu Ala Lys Asn Glu Ala Lys 290 295 300 Asn Asp Ala Leu Ser Met Ile Ile Lys Ser Leu Lys Asn Leu Ala Ser 305 310 315 320 Arg Ile Ser Gly Gln Asp Glu Thr Ile Lys Asn Leu Glu Ile Phe Arg 325 330 335 Leu Lys Met Ile Leu Arg Leu Leu Gln Ile Ser Ser Phe Asn Gly Lys 340 345 350 Met Asn Ala Leu Asn Glu Ile Asn Lys Val Ile Ser Ser Val Ser Tyr 355 360 365 Tyr Thr His Arg His Ser Asn Pro Glu Glu Glu Glu Trp Leu Thr Ala 370 375 380 Glu Arg Met Ala Glu Trp Ile Gln Gln Asn Asn Ile Leu Ser Ile Val 385 390 395 400 Leu Gln Asp Ser Leu His Gln Pro Gln Tyr Val Glu Lys Leu Glu Lys 405 410 415 Ile Leu Arg Phe Val Ile Lys Glu Lys Ala Leu Thr Leu Gln Asp Leu 420 425 430 Asp Asn Ile Trp Ala Ala Gln Ala Gly Lys His Glu Ala Ile Val Lys 435 440 445 Asn Val His Asp Leu Leu Ala Lys Leu Ala Trp Asp Phe Ser Pro Gly 450 455 460 Gln Leu Asp His Leu Phe Asp Cys Phe Lys Ala Ser Trp Thr Asn Ala 465 470 475 480 Ser Lys Lys Gln Arg Glu Lys Leu Leu Glu Leu Ile Arg Arg Leu Ala 485 490 495 Glu Asp Asp Lys Asp Gly Val Met Ala His Lys Val Leu Asn Leu Leu 500 505 510 Trp Asn Leu Ala Gln Ser Asp Asp Val Pro Val Asp Ile Met Asp Leu 515 520 525 Ala Leu Ser Ala His Ile Lys Ile Leu Asp Tyr Ser Cys Ser Gln Asp 530 535 540 Arg Asp Ala Gln Lys Ile Gln Trp Ile Asp His Phe Ile Glu Glu Leu 545 550 555 560 Arg Thr Asn Asp Lys Trp Val Ile Pro Ala Leu Lys Gln Ile Arg Glu 565 570 575 Ile Cys Ser Leu Phe Gly Glu Ala Ser Gln Asn Leu Ser Gln Thr Gln 580 585 590 Arg Ser Pro His Ile Phe Tyr Arg His Asp Leu Ile Asn Gln Leu Gln 595 600 605 Gln Asn His Ala Leu Val Thr Leu Val Ala Glu Asn Leu Ala Thr Tyr 610 615 620 Met Asn Ser Ile Arg Leu Tyr Ala Gly Asp His Glu Asp Tyr Asp Pro 625 630 635 640 Gln Thr Val Arg Leu Gly Ser Arg Tyr Ser His Val Gln Glu Val Gln 645 650 655 Glu Arg Leu Asn Phe Leu Arg Phe Leu Leu Lys Asp Gly Gln Leu Trp 660 665 670 Leu Cys Ala Pro Gln Ala Lys Gln Ile Trp Lys Cys Leu Ala Glu Asn 675 680 685 Ala Val Tyr Leu Cys Asp Arg Glu Ala Cys Phe Lys Trp Tyr Ser Lys 690 695 700 Leu Met Gly Asp Glu Pro Asp Leu Asp Pro Asp Ile Asn Lys Asp Phe 705 710 715 720 Phe Glu Ser Asn Val Leu Gln Leu Asp Pro Ser Leu Leu Thr Glu Asn 725 730 735 Gly Met Lys Cys Phe Glu Arg Phe Phe Lys Ala Val Asn Cys Arg Glu 740 745 750 Arg Lys Leu Ile Ala Lys Arg Arg Ser Tyr Met Met Asp Asp Leu Glu 755 760 765 Leu Ile Gly Leu Asp Tyr Leu Trp Arg Val Val Ile Gln Ser Ser Asp 770 775 780 Glu Ile Ala Asn Arg Ala Ile Asp Leu Leu Lys Glu Ile Tyr Thr Asn 785 790 795 800 Leu Gly Pro Arg Leu Lys Ala Asn Gln Val Val Ile His Glu Asp Phe 805 810 815 Ile Gln Ser Cys Phe Asp Arg Leu Lys Ala Ser Tyr Asp Thr Leu Cys 820 825 830 Val Phe Asp Gly Asp Lys Asn Ser Ile Asn Cys Ala Arg Gln Glu Ala 835 840 845 Ile Arg Met Val Arg Val Leu Thr Val Ile Lys Glu Tyr Ile Asn Glu 850 855 860 Cys Asp Ser Asp Tyr His Lys Glu Arg Met Ile Leu Pro Met Ser Arg 865 870 875 880 Ala Phe Cys Gly Lys His Leu Ser Leu Ile Val Arg Phe Pro Asn Gln 885 890 895 Gly Arg Gln Val Asp Glu Leu Asp Ile Trp Phe His Thr Asn Asp Thr 900 905 910 Ile Gly Ser Val Arg Arg Cys Ile Val Asn Arg Ile Lys Ala Asn Val 915 920 925 Ala His Lys Lys Ile Glu Leu Phe Val Gly Gly Glu Leu Ile Asp Ser 930 935 940 Glu Asn Asp Arg Lys Leu Ile Gly Gln Leu Asn Leu Lys Asp Lys Ser 945 950 955 960 Leu Ile Thr Ala Lys Leu Thr Gln Ile Asn Phe Asn Met Pro Ser Ser 965 970 975 Pro Asp Ser Ser Ser Asp Ser Ser Thr Ala Ser Pro Gly Asn His Arg 980 985 990 Asn His Tyr Asn Asp Gly Pro Asn Leu Lys Val Glu Ser Cys Leu Pro 995 1000 1005 Gly Val Ile Met Ser Val His Pro Lys Tyr Ile Ser Phe Leu Trp 1010 1015 1020 Gln Phe Ala Asn Leu Gly Ser Asn Leu Asn Met Pro Pro Leu Lys 1025 1030 1035 Asn Gly Ala Arg Val Leu Met Lys Leu Met Pro Pro Asp Arg Thr 1040 1045 1050 Ala Val Glu Lys Leu Arg Thr Val Cys Leu Asp His Ala Asn Leu 1055 1060 1065 Gly Glu Gly Lys Leu Ser Pro Pro Leu Asp Ser Leu Phe Phe Gly 1070 1075 1080 Pro Ser Ala Ser Gln Val Leu Tyr Leu Thr Glu Val Val Tyr Ala 1085 1090 1095 Leu Leu Met Pro Ala Gly Val Pro Leu Thr Asp Gly Ser Ser Asp 1100 1105 1110 Phe Gln Val His Phe Leu Lys Ser Gly Gly Leu Pro Leu Val Leu 1115 1120 1125 Ser Met Leu Ile Arg Asn Asn Phe Leu Pro Asn Thr Asp Met Glu 1130 1135 1140 Thr Arg Arg Gly Ala Tyr Leu Asn Ala Leu Lys Ile Ala Lys Leu 1145 1150 1155 Leu Leu Thr Ala Ile Gly Tyr Gly His Val Arg Ala Val Ala Glu 1160 1165 1170 Ala Cys Gln Pro Val Val Asp Gly Thr Asp Pro Ile Thr Gln Ile 1175 1180 1185 Asn Gln Val Thr His Asp Gln Ala Val Val Leu Gln Ser Ala Leu 1190 1195 1200 Gln Ser Ile Pro Asn Pro Ser Ser Glu Cys Val Leu Arg Asn Glu 1205 1210 1215 Ser Ile Leu Leu Ala Gln Glu Ile Ser Asn Glu Ala Ser Arg Tyr 1220 1225 1230 Met Pro Asp Ile Cys Val Ile Arg Ala Ile Gln Lys Ile Ile Trp 1235 1240 1245 Ala Ser Ala Cys Gly Ala Leu Gly Leu Phe Phe Ser Pro Asn Glu 1250 1255 1260 Glu Ile Thr Lys Ile Tyr Gln Met Thr Thr Asn Gly Ser Asn Lys 1265 1270 1275 Leu Glu Val Glu Asp Glu Gln Val Cys Cys Glu Ala Leu Glu Val 1280 1285 1290 Met Thr Leu Cys Phe Ala Leu Leu Pro Thr Ala Leu Asp Ala Leu 1295 1300 1305 Ser Lys Glu Lys Ala Trp Gln Thr Phe Ile Ile Asp Leu Leu

Leu 1310 1315 1320 His Cys Pro Ser Lys Thr Val Arg Gln Leu Ala Gln Glu Gln Phe 1325 1330 1335 Phe Leu Met Cys Thr Arg Cys Cys Met Gly His Arg Pro Leu Leu 1340 1345 1350 Phe Phe Ile Thr Leu Leu Phe Thr Ile Leu Gly Ser Thr Ala Arg 1355 1360 1365 Glu Lys Gly Lys Tyr Ser Gly Asp Tyr Phe Thr Leu Leu Arg His 1370 1375 1380 Leu Leu Asn Tyr Ala Tyr Asn Gly Asn Ile Asn Ile Pro Asn Ala 1385 1390 1395 Glu Val Leu Leu Val Ser Glu Ile Asp Trp Leu Lys Arg Ile Arg 1400 1405 1410 Asp Asn Val Lys Asn Thr Gly Glu Thr Gly Val Glu Glu Pro Ile 1415 1420 1425 Leu Glu Gly His Leu Gly Val Thr Lys Glu Leu Leu Ala Phe Gln 1430 1435 1440 Thr Ser Glu Lys Lys Tyr His Phe Gly Cys Glu Lys Gly Gly Ala 1445 1450 1455 Asn Leu Ile Lys Glu Leu Ile Asp Asp Phe Ile Phe Pro Ala Ser 1460 1465 1470 Lys Val Tyr Leu Gln Tyr Leu Arg Ser Gly Glu Leu Pro Ala Glu 1475 1480 1485 Gln Ala Ile Pro Val Cys Ser Ser Pro Val Thr Ile Asn Ala Gly 1490 1495 1500 Phe Glu Leu Leu Val Ala Leu Ala Ile Gly Cys Val Arg Asn Leu 1505 1510 1515 Lys Gln Ile Val Asp Cys Leu Thr Glu Met Tyr Tyr Met Gly Thr 1520 1525 1530 Ala Ile Thr Thr Cys Glu Ala Leu Thr Glu Trp Glu Tyr Leu Pro 1535 1540 1545 Pro Val Gly Pro Arg Pro Pro Lys Gly Phe Val Gly Leu Lys Asn 1550 1555 1560 Ala Gly Ala Thr Cys Tyr Met Asn Ser Val Ile Gln Gln Leu Tyr 1565 1570 1575 Met Ile Pro Ser Ile Arg Asn Ser Ile Leu Ala Ile Glu Gly Thr 1580 1585 1590 Gly Ser Asp Leu His Asp Asp Met Phe Gly Asp Glu Lys Gln Asp 1595 1600 1605 Ser Glu Ser Asn Val Asp Pro Arg Asp Asp Val Phe Gly Tyr Pro 1610 1615 1620 His Gln Phe Glu Asp Lys Pro Ala Leu Ser Lys Thr Glu Asp Arg 1625 1630 1635 Lys Glu Tyr Asn Ile Gly Val Leu Arg His Leu Gln Val Ile Phe 1640 1645 1650 Gly His Leu Ala Ala Ser Gln Leu Gln Tyr Tyr Val Pro Arg Gly 1655 1660 1665 Phe Trp Lys Gln Phe Arg Leu Trp Gly Glu Pro Val Asn Leu Arg 1670 1675 1680 Glu Gln His Asp Ala Leu Glu Phe Phe Asn Ser Leu Val Asp Ser 1685 1690 1695 Leu Asp Glu Ala Leu Lys Ala Leu Gly His Pro Ala Ile Leu Ser 1700 1705 1710 Lys Val Leu Gly Gly Ser Phe Ala Asp Gln Lys Ile Cys Gln Gly 1715 1720 1725 Cys Pro His Arg Phe Glu Cys Glu Glu Ser Phe Thr Thr Leu Asn 1730 1735 1740 Val Asp Ile Arg Asn His Gln Asn Leu Leu Asp Ser Leu Glu Gln 1745 1750 1755 Tyr Ile Lys Gly Asp Leu Leu Glu Gly Ala Asn Ala Tyr His Cys 1760 1765 1770 Glu Lys Cys Asp Lys Lys Val Asp Thr Val Lys Arg Leu Leu Ile 1775 1780 1785 Lys Lys Leu Pro Arg Val Leu Ala Ile Gln Leu Lys Arg Phe Asp 1790 1795 1800 Tyr Asp Trp Glu Arg Glu Cys Ala Ile Lys Phe Asn Asp Tyr Phe 1805 1810 1815 Glu Phe Pro Arg Glu Leu Asp Met Gly Pro Tyr Thr Val Ala Gly 1820 1825 1830 Val Ala Asn Leu Glu Arg Asp Asn Val Asn Ser Glu Asn Glu Leu 1835 1840 1845 Ile Glu Gln Lys Glu Gln Ser Asp Asn Glu Thr Ala Gly Gly Thr 1850 1855 1860 Lys Tyr Arg Leu Val Gly Val Leu Val His Ser Gly Gln Ala Ser 1865 1870 1875 Gly Gly His Tyr Tyr Ser Tyr Ile Ile Gln Arg Asn Gly Lys Asp 1880 1885 1890 Asp Gln Thr Asp His Trp Tyr Lys Phe Asp Asp Gly Asp Val Thr 1895 1900 1905 Glu Cys Lys Met Asp Asp Asp Glu Glu Met Lys Asn Gln Cys Phe 1910 1915 1920 Gly Gly Glu Tyr Met Gly Glu Val Phe Asp His Met Met Lys Arg 1925 1930 1935 Met Ser Tyr Arg Arg Gln Lys Arg Trp Trp Asn Ala Tyr Ile Pro 1940 1945 1950 Phe Tyr Glu Gln Met Asp Met Ile Asp Glu Asp Asp Glu Met Ile 1955 1960 1965 Arg Tyr Ile Ser Glu Leu Thr Ile Ala Arg Pro His Gln Ile Ile 1970 1975 1980 Met Ser Pro Ala Ile Glu Arg Ser Val Arg Lys Gln Asn Val Lys 1985 1990 1995 Phe Met His Asn Arg Leu Gln Tyr Ser Leu Glu Tyr Phe Gln Phe 2000 2005 2010 Val Lys Lys Leu Leu Thr Cys Asn Gly Val Tyr Leu Asn Pro Ala 2015 2020 2025 Pro Gly Gln Asp Tyr Leu Leu Pro Glu Ala Glu Glu Ile Thr Met 2030 2035 2040 Ile Ser Ile Gln Leu Ala Ala Arg Phe Leu Phe Thr Thr Gly Phe 2045 2050 2055 His Thr Lys Lys Ile Val Arg Gly Pro Ala Ser Asp Trp Tyr Asp 2060 2065 2070 Ala Leu Cys Val Leu Leu Arg His Ser Lys Asn Val Arg Phe Trp 2075 2080 2085 Phe Thr His Asn Val Leu Phe Asn Val Ser Asn Arg Phe Ser Glu 2090 2095 2100 Tyr Leu Leu Glu Cys Pro Ser Ala Glu Val Arg Gly Ala Phe Ala 2105 2110 2115 Lys Leu Ile Val Phe Ile Ala His Phe Ser Leu Gln Asp Gly Ser 2120 2125 2130 Cys Pro Ser Pro Phe Ala Ser Pro Gly Pro Ser Ser Gln Ala Cys 2135 2140 2145 Asp Asn Leu Ser Leu Ser Asp His Leu Leu Arg Ala Thr Leu Asn 2150 2155 2160 Leu Leu Arg Arg Glu Val Ser Glu His Gly His His Leu Gln Gln 2165 2170 2175 Tyr Phe Asn Leu Phe Val Met Tyr Ala Asn Leu Gly Val Ala Glu 2180 2185 2190 Lys Thr Gln Leu Leu Lys Leu Asn Val Pro Ala Thr Phe Met Leu 2195 2200 2205 Val Ser Leu Asp Glu Gly Pro Gly Pro Pro Ile Lys Tyr Gln Tyr 2210 2215 2220 Ala Glu Leu Gly Lys Leu Tyr Ser Val Val Ser Gln Leu Ile Arg 2225 2230 2235 Cys Cys Asn Val Ser Ser Thr Met Gln Ser Ser Ile Asn Gly Asn 2240 2245 2250 Pro Pro Leu Pro Asn Pro Phe Gly Asp Leu Asn Leu Ser Gln Pro 2255 2260 2265 Ile Met Pro Ile Gln Gln Asn Val Leu Asp Ile Leu Phe Val Arg 2270 2275 2280 Thr Ser Tyr Val Lys Lys Ile Ile Glu Asp Cys Ser Asn Ser Glu 2285 2290 2295 Asp Thr Ile Lys Leu Leu Arg Phe Cys Ser Trp Glu Asn Pro Gln 2300 2305 2310 Phe Ser Ser Thr Val Leu Ser Glu Leu Leu Trp Gln Val Ala Tyr 2315 2320 2325 Ser Tyr Thr Tyr Glu Leu Arg Pro Tyr Leu Asp Leu Leu Phe Gln 2330 2335 2340 Ile Leu Leu Ile Glu Asp Ser Trp Gln Thr His Arg Ile His Asn 2345 2350 2355 Ala Leu Lys Gly Ile Pro Asp Asp Arg Asp Gly Leu Phe Asp Thr 2360 2365 2370 Ile Gln Arg Ser Lys Asn His Tyr Gln Lys Arg Ala Tyr Gln Cys 2375 2380 2385 Ile Lys Cys Met Val Ala Leu Phe Ser Ser Cys Pro Val Ala Tyr 2390 2395 2400 Gln Ile Leu Gln Gly Asn Gly Asp Leu Lys Arg Lys Trp Thr Trp 2405 2410 2415 Ala Val Glu Trp Leu Gly Asp Glu Leu Glu Arg Arg Pro Tyr Thr 2420 2425 2430 Gly Asn Pro Gln Tyr Ser Tyr Asn Asn Trp Ser Pro Pro Val Gln 2435 2440 2445 Ser Asn Glu Thr Ala Asn Gly Tyr Phe Leu Glu Arg Ser His Ser 2450 2455 2460 Ala Arg Met Thr Leu Ala Lys Ala Cys Glu Leu Cys Pro Glu Glu 2465 2470 2475 Glu Pro Asp Asp Gln Asp Ala Pro Asp Glu His Glu Pro Ser Pro 2480 2485 2490 Ser Glu Asp Ala Pro Leu Tyr Pro His Ser Pro Ala Ser Gln Tyr 2495 2500 2505 Gln Gln Asn Asn His Val His Gly Gln Pro Tyr Thr Gly Pro Ala 2510 2515 2520 Ala His His Leu Asn Asn Pro Gln Lys Thr Gly Gln Arg Thr Gln 2525 2530 2535 Glu Asn Tyr Glu Gly Asn Glu Glu Val Ser Ser Pro Gln Met Lys 2540 2545 2550 Asp Gln 2555 65 330 PRT Homo sapiens 65 Met Ser Gln Trp His His Pro Arg Ser Gly Trp Gly Arg Arg Arg Asp 1 5 10 15 Phe Ser Gly Arg Ser Ser Ala Lys Lys Lys Gly Gly Asn His Ile Pro 20 25 30 Glu Arg Trp Lys Asp Tyr Leu Pro Val Gly Gln Arg Met Pro Gly Thr 35 40 45 Arg Phe Ile Ala Phe Lys Val Pro Leu Gln Lys Ser Phe Glu Lys Lys 50 55 60 Leu Ala Pro Glu Glu Cys Phe Ser Pro Leu Asp Leu Phe Asn Lys Ile 65 70 75 80 Arg Glu Gln Asn Glu Glu Leu Gly Leu Ile Ile Asp Leu Thr Tyr Thr 85 90 95 Gln Arg Tyr Tyr Lys Pro Glu Asp Leu Pro Glu Thr Val Pro Tyr Leu 100 105 110 Lys Ile Phe Thr Val Gly His Gln Val Pro Asp Asp Glu Thr Ile Phe 115 120 125 Lys Phe Lys His Ala Val Asn Gly Phe Leu Lys Glu Asn Lys Asp Asn 130 135 140 Asp Lys Leu Ile Gly Val His Cys Thr His Gly Leu Asn Arg Thr Gly 145 150 155 160 Tyr Leu Ile Cys Arg Tyr Leu Ile Asp Val Glu Gly Val Arg Pro Asp 165 170 175 Asp Ala Ile Glu Leu Phe Asn Arg Cys Arg Gly His Cys Leu Glu Arg 180 185 190 Gln Asn Tyr Ile Glu Asp Leu Gln Asn Gly Pro Ile Arg Lys Asn Trp 195 200 205 Asn Ser Ser Val Pro Arg Ser Ser Asp Phe Glu Asp Ser Ala His Leu 210 215 220 Met Gln Pro Val His Asn Lys Pro Val Lys Gln Gly Pro Arg Tyr Asn 225 230 235 240 Leu His Gln Ile Gln Gly His Ser Ala Pro Arg His Phe His Thr Gln 245 250 255 Thr Gln Ser Leu Gln Gln Ser Val Arg Lys Phe Ser Glu Asn Pro His 260 265 270 Val Tyr Gln Arg His His Leu Pro Pro Pro Gly Pro Pro Gly Glu Asp 275 280 285 Tyr Ser His Arg Arg Tyr Ser Trp Asn Val Lys Pro Asn Ala Ser Arg 290 295 300 Ala Ala Gln Asp Arg Arg Arg Trp Tyr Pro Tyr Asn Tyr Ser Arg Leu 305 310 315 320 Ser Tyr Pro Ala Cys Trp Glu Trp Thr Gln 325 330 66 185 PRT Homo sapiens 66 Met Ser Gly Ser Phe Glu Leu Ser Val Gln Asp Leu Asn Asp Leu Leu 1 5 10 15 Ser Asp Gly Ser Gly Cys Tyr Ser Leu Pro Ser Gln Pro Cys Asn Glu 20 25 30 Val Thr Pro Arg Ile Tyr Val Gly Asn Ala Ser Val Ala Gln Asp Ile 35 40 45 Pro Lys Leu Gln Lys Leu Gly Ile Thr His Val Leu Asn Ala Ala Glu 50 55 60 Gly Arg Ser Phe Met His Val Asn Thr Asn Ala Asn Phe Tyr Lys Asp 65 70 75 80 Ser Gly Ile Thr Tyr Leu Gly Ile Lys Ala Asn Asp Thr Gln Glu Phe 85 90 95 Asn Leu Ser Ala Tyr Phe Glu Arg Ala Ala Asp Phe Ile Asp Gln Ala 100 105 110 Leu Ala Gln Lys Asn Gly Arg Val Leu Val His Cys Arg Glu Gly Tyr 115 120 125 Ser Arg Ser Pro Thr Leu Val Ile Ala Tyr Leu Met Met Arg Gln Lys 130 135 140 Met Asp Val Lys Ser Ala Leu Ser Ile Val Arg Gln Asn Arg Glu Ile 145 150 155 160 Gly Pro Asn Asp Gly Phe Leu Ala Gln Leu Cys Gln Leu Asn Asp Arg 165 170 175 Leu Ala Lys Glu Gly Lys Leu Lys Pro 180 185 67 1154 PRT Homo sapiens 67 Met Gln Tyr Leu Asn Ile Lys Glu Asp Cys Asn Ala Met Ala Phe Cys 1 5 10 15 Ala Lys Met Arg Ser Ser Lys Lys Thr Glu Val Asn Leu Glu Ala Pro 20 25 30 Glu Pro Gly Val Glu Val Ile Phe Tyr Leu Ser Asp Arg Glu Pro Leu 35 40 45 Arg Leu Gly Ser Gly Glu Tyr Thr Ala Glu Glu Leu Cys Ile Arg Ala 50 55 60 Ala Gln Ala Cys Arg Ile Ser Pro Leu Cys His Asn Leu Phe Ala Leu 65 70 75 80 Tyr Asp Glu Asn Thr Lys Leu Trp Tyr Ala Pro Asn Arg Thr Ile Thr 85 90 95 Val Asp Asp Lys Met Ser Leu Arg Leu His Tyr Arg Met Arg Phe Tyr 100 105 110 Phe Thr Asn Trp His Gly Thr Asn Asp Asn Glu Gln Ser Val Trp Arg 115 120 125 His Ser Pro Lys Lys Gln Lys Asn Gly Tyr Glu Lys Lys Lys Ile Pro 130 135 140 Asp Ala Thr Pro Leu Leu Asp Ala Ser Ser Leu Glu Tyr Leu Phe Ala 145 150 155 160 Gln Gly Gln Tyr Asp Leu Val Lys Cys Leu Ala Pro Ile Arg Asp Pro 165 170 175 Lys Thr Glu Gln Asp Gly His Asp Ile Glu Asn Glu Cys Leu Gly Met 180 185 190 Ala Val Leu Ala Ile Ser His Tyr Ala Met Met Lys Lys Met Gln Leu 195 200 205 Pro Glu Leu Pro Lys Asp Ile Ser Tyr Lys Arg Tyr Ile Pro Glu Thr 210 215 220 Leu Asn Lys Ser Ile Arg Gln Arg Asn Leu Leu Thr Arg Met Arg Ile 225 230 235 240 Asn Asn Val Phe Lys Asp Phe Leu Lys Glu Phe Asn Asn Lys Thr Ile 245 250 255 Cys Asp Ser Ser Val Ser Thr His Asp Leu Lys Val Lys Tyr Leu Ala 260 265 270 Thr Leu Glu Thr Leu Thr Lys His Tyr Gly Ala Glu Ile Phe Glu Thr 275 280 285 Ser Met Leu Leu Ile Ser Ser Glu Asn Glu Met Asn Trp Phe His Ser 290 295 300 Asn Asp Gly Gly Asn Val Leu Tyr Tyr Glu Val Met Val Thr Gly Asn 305 310 315 320 Leu Gly Ile Gln Trp Arg His Lys Pro Asn Val Val Ser Val Glu Lys 325 330 335 Glu Lys Asn Lys Leu Lys Arg Lys Lys Leu Glu Asn Lys Asp Lys Lys 340 345 350 Asp Glu Glu Lys Asn Lys Ile Arg Glu Glu Trp Asn Asn Phe Ser Phe 355 360 365 Phe Pro Glu Ile Thr His Ile Val Ile Lys Glu Ser Val Val Ser Ile 370 375 380 Asn Lys Gln Asp Asn Lys Lys Met Glu Leu Lys Leu Ser Ser His Glu 385 390 395 400 Glu Ala Leu Ser Phe Val Ser Leu Val Asp Gly Tyr Phe Arg Leu Thr 405 410 415 Ala Asp Ala His His Tyr Leu Cys Thr Asp Val Ala Pro Pro Leu Ile 420 425 430 Val His Asn Ile Gln Asn Gly Cys His Gly Pro Ile Cys Thr Glu Tyr 435 440 445 Ala Ile Asn Lys Leu Arg Gln Glu Gly Ser Glu Glu Gly Met Tyr Val 450 455 460 Leu Arg Trp Ser Cys Thr Asp Phe Asp Asn Ile Leu Met Thr Val Thr 465 470 475 480 Cys Phe Glu Lys Ser Glu Gln Val Gln Gly Ala Gln Lys Gln Phe Lys 485 490 495 Asn Phe Gln Ile Glu Val Gln Lys Gly Arg Tyr Ser Leu His Gly Ser 500 505 510 Asp Arg Ser Phe Pro Ser Leu Gly Asp Leu Met Ser His Leu Lys Lys 515 520 525 Gln Ile Leu Arg Thr Asp Asn Ile Ser Phe Met Leu Lys Arg Cys Cys 530 535 540 Gln Pro Lys Pro Arg Glu Ile Ser Asn Leu Leu Val Ala Thr Lys Lys 545 550 555 560 Ala Gln Glu Trp Gln Pro Val Tyr Pro Met Ser Gln Leu Ser Phe Asp 565 570 575 Arg Ile Leu Lys Lys Asp Leu Val Gln Gly Glu His Leu Gly Arg Gly 580 585 590 Thr Arg Thr His Ile Tyr Ser Gly Thr Leu Met Asp Tyr Lys Asp Asp 595 600 605 Glu Gly Thr Ser Glu Glu Lys Lys Ile Lys Val Ile Leu Lys Val Leu 610 615 620 Asp Pro Ser His Arg Asp Ile Ser Leu Ala Phe Phe Glu Ala Ala Ser 625 630 635 640 Met Met Arg Gln Val Ser His Lys His Ile Val Tyr Leu Tyr Gly Val 645 650

655 Cys Val Arg Asp Val Glu Asn Ile Met Val Glu Glu Phe Val Glu Gly 660 665 670 Gly Pro Leu Asp Leu Phe Met His Arg Lys Ser Asp Val Leu Thr Thr 675 680 685 Pro Trp Lys Phe Lys Val Ala Lys Gln Leu Ala Ser Ala Leu Ser Tyr 690 695 700 Leu Glu Asp Lys Asp Leu Val His Gly Asn Val Cys Thr Lys Asn Leu 705 710 715 720 Leu Leu Ala Arg Glu Gly Ile Asp Ser Glu Cys Gly Pro Phe Ile Lys 725 730 735 Leu Ser Asp Pro Gly Ile Pro Ile Thr Val Leu Ser Arg Gln Glu Cys 740 745 750 Ile Glu Arg Ile Pro Trp Ile Ala Pro Glu Cys Val Glu Asp Ser Lys 755 760 765 Asn Leu Ser Val Ala Ala Asp Lys Trp Ser Phe Gly Thr Thr Leu Trp 770 775 780 Glu Ile Cys Tyr Asn Gly Glu Ile Pro Leu Lys Asp Lys Thr Leu Ile 785 790 795 800 Glu Lys Glu Arg Phe Tyr Glu Ser Arg Cys Arg Pro Val Thr Pro Ser 805 810 815 Cys Lys Glu Leu Ala Asp Leu Met Thr Arg Cys Met Asn Tyr Asp Pro 820 825 830 Asn Gln Arg Pro Phe Phe Arg Ala Ile Met Arg Asp Ile Asn Lys Leu 835 840 845 Glu Glu Gln Asn Pro Asp Ile Val Ser Arg Lys Lys Asn Gln Pro Thr 850 855 860 Glu Val Asp Pro Thr His Phe Glu Lys Arg Phe Leu Lys Arg Ile Arg 865 870 875 880 Asp Leu Gly Glu Gly His Phe Gly Lys Val Glu Leu Cys Arg Tyr Asp 885 890 895 Pro Glu Asp Asn Thr Gly Glu Gln Val Ala Val Lys Ser Leu Lys Pro 900 905 910 Glu Ser Gly Gly Asn His Ile Ala Asp Leu Lys Lys Glu Ile Glu Ile 915 920 925 Leu Arg Asn Leu Tyr His Glu Asn Ile Val Lys Tyr Lys Gly Ile Cys 930 935 940 Thr Glu Asp Gly Gly Asn Gly Ile Lys Leu Ile Met Glu Phe Leu Pro 945 950 955 960 Ser Gly Ser Leu Lys Glu Tyr Leu Pro Lys Asn Lys Asn Lys Ile Asn 965 970 975 Leu Lys Gln Gln Leu Lys Tyr Ala Val Gln Ile Cys Lys Gly Met Asp 980 985 990 Tyr Leu Gly Ser Arg Gln Tyr Val His Arg Asp Leu Ala Ala Arg Asn 995 1000 1005 Val Leu Val Glu Ser Glu His Gln Val Lys Ile Gly Asp Phe Gly 1010 1015 1020 Leu Thr Lys Ala Ile Glu Thr Asp Lys Glu Tyr Tyr Thr Val Lys 1025 1030 1035 Asp Asp Arg Asp Ser Pro Val Phe Trp Tyr Ala Pro Glu Cys Leu 1040 1045 1050 Met Gln Ser Lys Phe Tyr Ile Ala Ser Asp Val Trp Ser Phe Gly 1055 1060 1065 Val Thr Leu His Glu Leu Leu Thr Tyr Cys Asp Ser Asp Ser Ser 1070 1075 1080 Pro Met Ala Leu Phe Leu Lys Met Ile Gly Pro Thr His Gly Gln 1085 1090 1095 Met Thr Val Thr Arg Leu Val Asn Thr Leu Lys Glu Gly Lys Arg 1100 1105 1110 Leu Pro Cys Pro Pro Asn Cys Pro Asp Glu Val Tyr Gln Leu Met 1115 1120 1125 Arg Lys Cys Trp Glu Phe Gln Pro Ser Asn Arg Thr Ser Phe Gln 1130 1135 1140 Asn Leu Ile Glu Gly Phe Glu Ala Leu Leu Lys 1145 1150 68 1142 PRT Homo sapiens 68 Met Ala Phe Cys Ala Lys Met Arg Ser Ser Lys Lys Thr Glu Val Asn 1 5 10 15 Leu Glu Ala Pro Glu Pro Gly Val Glu Val Ile Phe Tyr Leu Ser Asp 20 25 30 Arg Glu Pro Leu Arg Leu Gly Ser Gly Glu Tyr Thr Ala Glu Glu Leu 35 40 45 Cys Ile Arg Ala Ala Gln Ala Cys Arg Ile Ser Pro Leu Cys His Asn 50 55 60 Leu Phe Ala Leu Tyr Asp Glu Asn Thr Lys Leu Trp Tyr Ala Pro Asn 65 70 75 80 Arg Thr Ile Thr Val Asp Asp Lys Met Ser Leu Arg Leu His Tyr Arg 85 90 95 Met Arg Phe Tyr Phe Thr Asn Trp His Gly Thr Asn Asp Asn Glu Gln 100 105 110 Ser Val Trp Arg His Ser Pro Lys Lys Gln Lys Asn Gly Tyr Glu Lys 115 120 125 Lys Lys Ile Pro Asp Ala Thr Pro Leu Leu Asp Ala Ser Ser Leu Glu 130 135 140 Tyr Leu Phe Ala Gln Gly Gln Tyr Asp Leu Val Lys Cys Leu Ala Pro 145 150 155 160 Ile Arg Asp Pro Lys Thr Glu Gln Asp Gly His Asp Ile Glu Asn Glu 165 170 175 Cys Leu Gly Met Ala Val Leu Ala Ile Ser His Tyr Ala Met Met Lys 180 185 190 Lys Met Gln Leu Pro Glu Leu Pro Lys Asp Ile Ser Tyr Lys Arg Tyr 195 200 205 Ile Pro Glu Thr Leu Asn Lys Ser Ile Arg Gln Arg Asn Leu Leu Thr 210 215 220 Arg Met Arg Ile Asn Asn Val Phe Lys Asp Phe Leu Lys Glu Phe Asn 225 230 235 240 Asn Lys Thr Ile Cys Asp Ser Ser Val Ser Thr His Asp Leu Lys Val 245 250 255 Lys Tyr Leu Ala Thr Leu Glu Thr Leu Thr Lys His Tyr Gly Ala Glu 260 265 270 Ile Phe Glu Thr Ser Met Leu Leu Ile Ser Ser Glu Asn Glu Met Asn 275 280 285 Trp Phe His Ser Asn Asp Gly Gly Asn Val Leu Tyr Tyr Glu Val Met 290 295 300 Val Thr Gly Asn Leu Gly Ile Gln Trp Arg His Lys Pro Asn Val Val 305 310 315 320 Ser Val Glu Lys Glu Lys Asn Lys Leu Lys Arg Lys Lys Leu Glu Asn 325 330 335 Lys Asp Lys Lys Asp Glu Glu Lys Asn Lys Ile Arg Glu Glu Trp Asn 340 345 350 Asn Phe Ser Phe Phe Pro Glu Ile Thr His Ile Val Ile Lys Glu Ser 355 360 365 Val Val Ser Ile Asn Lys Gln Asp Asn Lys Lys Met Glu Leu Lys Leu 370 375 380 Ser Ser His Glu Glu Ala Leu Ser Phe Val Ser Leu Val Asp Gly Tyr 385 390 395 400 Phe Arg Leu Thr Ala Asp Ala His His Tyr Leu Cys Thr Asp Val Ala 405 410 415 Pro Pro Leu Ile Val His Asn Ile Gln Asn Gly Cys His Gly Pro Ile 420 425 430 Cys Thr Glu Tyr Ala Ile Asn Lys Leu Arg Gln Glu Gly Ser Glu Glu 435 440 445 Gly Met Tyr Val Leu Arg Trp Ser Cys Thr Asp Phe Asp Asn Ile Leu 450 455 460 Met Thr Val Thr Cys Phe Glu Lys Ser Glu Gln Val Gln Gly Ala Gln 465 470 475 480 Lys Gln Phe Lys Asn Phe Gln Ile Glu Val Gln Lys Gly Arg Tyr Ser 485 490 495 Leu His Gly Ser Asp Arg Ser Phe Pro Ser Leu Gly Asp Leu Met Ser 500 505 510 His Leu Lys Lys Gln Ile Leu Arg Thr Asp Asn Ile Ser Phe Met Leu 515 520 525 Lys Arg Cys Cys Gln Pro Lys Pro Arg Glu Ile Ser Asn Leu Leu Val 530 535 540 Ala Thr Lys Lys Ala Gln Glu Trp Gln Pro Val Tyr Pro Met Ser Gln 545 550 555 560 Leu Ser Phe Asp Arg Ile Leu Lys Lys Asp Leu Val Gln Gly Glu His 565 570 575 Leu Gly Arg Gly Thr Arg Thr His Ile Tyr Ser Gly Thr Leu Met Asp 580 585 590 Tyr Lys Asp Asp Glu Gly Thr Ser Glu Glu Lys Lys Ile Lys Val Ile 595 600 605 Leu Lys Val Leu Asp Pro Ser His Arg Asp Ile Ser Leu Ala Phe Phe 610 615 620 Glu Ala Ala Ser Met Met Arg Gln Val Ser His Lys His Ile Val Tyr 625 630 635 640 Leu Tyr Gly Val Cys Val Arg Asp Val Glu Asn Ile Met Val Glu Glu 645 650 655 Phe Val Glu Gly Gly Pro Leu Asp Leu Phe Met His Arg Lys Ser Asp 660 665 670 Val Leu Thr Thr Pro Trp Lys Phe Lys Val Ala Lys Gln Leu Ala Ser 675 680 685 Ala Leu Ser Tyr Leu Glu Asp Lys Asp Leu Val His Gly Asn Val Cys 690 695 700 Thr Lys Asn Leu Leu Leu Ala Arg Glu Gly Ile Asp Ser Glu Cys Gly 705 710 715 720 Pro Phe Ile Lys Leu Ser Asp Pro Gly Ile Pro Ile Thr Val Leu Ser 725 730 735 Arg Gln Glu Cys Ile Glu Arg Ile Pro Trp Ile Ala Pro Glu Cys Val 740 745 750 Glu Asp Ser Lys Asn Leu Ser Val Ala Ala Asp Lys Trp Ser Phe Gly 755 760 765 Thr Thr Leu Trp Glu Ile Cys Tyr Asn Gly Glu Ile Pro Leu Lys Asp 770 775 780 Lys Thr Leu Ile Glu Lys Glu Arg Phe Tyr Glu Ser Arg Cys Arg Pro 785 790 795 800 Val Thr Pro Ser Cys Lys Glu Leu Ala Asp Leu Met Thr Arg Cys Met 805 810 815 Asn Tyr Asp Pro Asn Gln Arg Pro Phe Phe Arg Ala Ile Met Arg Asp 820 825 830 Ile Asn Lys Leu Glu Glu Gln Asn Pro Asp Ile Val Ser Arg Lys Lys 835 840 845 Asn Gln Pro Thr Glu Val Asp Pro Thr His Phe Glu Lys Arg Phe Leu 850 855 860 Lys Arg Ile Arg Asp Leu Gly Glu Gly His Phe Gly Lys Val Glu Leu 865 870 875 880 Cys Arg Tyr Asp Pro Glu Asp Asn Thr Gly Glu Gln Val Ala Val Lys 885 890 895 Ser Leu Lys Pro Glu Ser Gly Gly Asn His Ile Ala Asp Leu Lys Lys 900 905 910 Glu Ile Glu Ile Leu Arg Asn Leu Tyr His Glu Asn Ile Val Lys Tyr 915 920 925 Lys Gly Ile Cys Thr Glu Asp Gly Gly Asn Gly Ile Lys Leu Ile Met 930 935 940 Glu Phe Leu Pro Ser Gly Ser Leu Lys Glu Tyr Leu Pro Lys Asn Lys 945 950 955 960 Asn Lys Ile Asn Leu Lys Gln Gln Leu Lys Tyr Ala Val Gln Ile Cys 965 970 975 Lys Gly Met Asp Tyr Leu Gly Ser Arg Gln Tyr Val His Arg Asp Leu 980 985 990 Ala Ala Arg Asn Val Leu Val Glu Ser Glu His Gln Val Lys Ile Gly 995 1000 1005 Asp Phe Gly Leu Thr Lys Ala Ile Glu Thr Asp Lys Glu Tyr Tyr 1010 1015 1020 Thr Val Lys Asp Asp Arg Asp Ser Pro Val Phe Trp Tyr Ala Pro 1025 1030 1035 Glu Cys Leu Met Gln Ser Lys Phe Tyr Ile Ala Ser Asp Val Trp 1040 1045 1050 Ser Phe Gly Val Thr Leu His Glu Leu Leu Thr Tyr Cys Asp Ser 1055 1060 1065 Asp Ser Ser Pro Met Ala Leu Phe Leu Lys Met Ile Gly Pro Thr 1070 1075 1080 His Gly Gln Met Thr Val Thr Arg Leu Val Asn Thr Leu Lys Glu 1085 1090 1095 Gly Lys Arg Leu Pro Cys Pro Pro Asn Cys Pro Asp Glu Val Tyr 1100 1105 1110 Gln Leu Met Arg Lys Cys Trp Glu Phe Gln Pro Ser Asn Arg Thr 1115 1120 1125 Ser Phe Gln Asn Leu Ile Glu Gly Phe Glu Ala Leu Leu Lys 1130 1135 1140 69 666 PRT Homo sapiens 69 Met Ala Cys Leu Met Ala Ala Phe Ser Val Gly Thr Ala Met Asn Ala 1 5 10 15 Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser 20 25 30 Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu 35 40 45 Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln 50 55 60 Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg 65 70 75 80 Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly 85 90 95 Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu 100 105 110 Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met 115 120 125 Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu 130 135 140 Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys 145 150 155 160 Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu 165 170 175 Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly 180 185 190 Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser 195 200 205 Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg 210 215 220 Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe 225 230 235 240 Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val 245 250 255 Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr 260 265 270 Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr 275 280 285 Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu 290 295 300 Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn 305 310 315 320 Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln 325 330 335 Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp 340 345 350 His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp 355 360 365 His Arg Pro Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser 370 375 380 Phe Ser Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr 385 390 395 400 Phe Leu Ser Ile Met Arg Asp Ser Val Leu Thr His Leu Arg Ile Thr 405 410 415 Ser His Ile Gly Ile Gly Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile 420 425 430 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly Phe Leu Phe Phe 435 440 445 Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr 450 455 460 Phe Pro Leu Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp 465 470 475 480 Tyr Ser Leu Lys Ala Tyr Tyr Leu Ala Lys Thr Met Ala Asp Val Pro 485 490 495 Phe Gln Ile Met Phe Pro Val Ala Tyr Cys Ser Ile Val Tyr Trp Met 500 505 510 Thr Ser Gln Pro Ser Asp Ala Val Arg Phe Val Leu Phe Ala Ala Leu 515 520 525 Gly Thr Met Thr Ser Leu Val Ala Gln Ser Leu Gly Leu Leu Ile Gly 530 535 540 Ala Ala Ser Thr Ser Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr 545 550 555 560 Ala Ile Pro Val Leu Leu Phe Ser Gly Phe Phe Val Ser Phe Asp Thr 565 570 575 Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr 580 585 590 Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp 595 600 605 Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln Lys Ser Glu Ala 610 615 620 Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe 625 630 635 640 Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe 645 650 655 Val Leu Arg Tyr Lys Ile Arg Ala Glu Arg 660 665 70 678 PRT Homo sapiens 70 Met Ala Cys Leu Met Ala Ala Phe Ser Val Gly Thr Ala Met Asn Ala 1 5 10 15 Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser 20 25 30 Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu 35 40 45 Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln 50 55 60 Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg 65 70 75 80 Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly 85 90 95 Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu 100 105 110 Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met 115

120 125 Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu 130 135 140 Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys 145 150 155 160 Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu 165 170 175 Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly 180 185 190 Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser 195 200 205 Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg 210 215 220 Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe 225 230 235 240 Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val 245 250 255 Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr 260 265 270 Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr 275 280 285 Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu 290 295 300 Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn 305 310 315 320 Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln 325 330 335 Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp 340 345 350 His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp 355 360 365 His Arg Pro Ser Glu Glu Val Lys Gln Thr Lys Arg Leu Lys Gly Leu 370 375 380 Arg Lys Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser 385 390 395 400 Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile 405 410 415 Met Arg Asp Ser Val Leu Thr His Leu Arg Ile Thr Ser His Ile Gly 420 425 430 Ile Gly Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile Gly Asn Glu Ala 435 440 445 Lys Lys Val Leu Ser Asn Ser Gly Phe Leu Phe Phe Ser Met Leu Phe 450 455 460 Leu Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr Phe Pro Leu Glu 465 470 475 480 Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu Lys 485 490 495 Ala Tyr Tyr Leu Ala Lys Thr Met Ala Asp Val Pro Phe Gln Ile Met 500 505 510 Phe Pro Val Ala Tyr Cys Ser Ile Val Tyr Trp Met Thr Ser Gln Pro 515 520 525 Ser Asp Ala Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr 530 535 540 Ser Leu Val Ala Gln Ser Leu Gly Leu Leu Ile Gly Ala Ala Ser Thr 545 550 555 560 Ser Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val 565 570 575 Leu Leu Phe Ser Gly Phe Phe Val Ser Phe Asp Thr Ile Pro Thr Tyr 580 585 590 Leu Gln Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly 595 600 605 Val Ile Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp Leu His Cys Asp 610 615 620 Ile Asp Glu Thr Cys His Phe Gln Lys Ser Glu Ala Ile Leu Arg Glu 625 630 635 640 Leu Asp Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe Ile Val Leu Gly 645 650 655 Ile Phe Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe Val Leu Arg Tyr 660 665 670 Lys Ile Arg Ala Glu Arg 675 71 677 PRT Homo sapiens 71 Met Arg Ile Ser Leu Pro Arg Ala Pro Glu Arg Asp Gly Gly Val Ser 1 5 10 15 Ala Ser Ser Leu Leu Asp Thr Val Thr Asn Ala Ser Ser Tyr Ser Ala 20 25 30 Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu Val Val 35 40 45 Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly His Leu 50 55 60 Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser Ser Leu 65 70 75 80 Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser Tyr Ser 85 90 95 Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr Leu Leu 100 105 110 Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala Ile Met 115 120 125 Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu Ala Gly 130 135 140 Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly Leu Pro 145 150 155 160 Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met Gln Asp 165 170 175 Asp Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met Val Ser 180 185 190 Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu Met Val 195 200 205 Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn Thr Arg 210 215 220 Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile Ala Leu 225 230 235 240 Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro Thr Ser 245 250 255 Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met Lys Gly 260 265 270 Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln Pro Ser 275 280 285 Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser Gln Gly 290 295 300 Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr Leu Arg 305 310 315 320 Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp Phe Val 325 330 335 Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg Leu Val 340 345 350 Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg Asp Leu 355 360 365 Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro Ser Glu 370 375 380 Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser Cys 385 390 395 400 Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile Met 405 410 415 Arg Asp Ser Val Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile 420 425 430 Gly Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile Gly Asn Glu Ala Lys 435 440 445 Lys Val Leu Ser Asn Ser Gly Phe Leu Phe Phe Ser Met Leu Phe Leu 450 455 460 Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr Phe Pro Leu Glu Met 465 470 475 480 Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu Lys Ala 485 490 495 Tyr Tyr Leu Ala Lys Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe 500 505 510 Pro Val Ala Tyr Cys Ser Ile Val Tyr Trp Met Thr Ser Gln Pro Ser 515 520 525 Asp Ala Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser 530 535 540 Leu Val Ala Gln Ser Leu Gly Leu Leu Ile Gly Ala Ala Ser Thr Ser 545 550 555 560 Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu 565 570 575 Leu Phe Ser Gly Phe Phe Val Ser Phe Asp Thr Ile Pro Thr Tyr Leu 580 585 590 Gln Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val 595 600 605 Ile Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp Leu His Cys Asp Ile 610 615 620 Asp Glu Thr Cys His Phe Gln Lys Ser Glu Ala Ile Leu Arg Glu Leu 625 630 635 640 Asp Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile 645 650 655 Phe Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe Val Leu Arg Tyr Lys 660 665 670 Ile Arg Ala Glu Arg 675 72 668 PRT Homo sapiens 72 Met Leu Gly Thr Gln Gly Trp Thr Lys Gln Arg Lys Pro Cys Pro Gln 1 5 10 15 Asn Ala Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys 20 25 30 Val Ser Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr 35 40 45 Asp Leu Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu 50 55 60 Ala Gln Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu 65 70 75 80 Phe Arg Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys 85 90 95 Lys Gly Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser 100 105 110 Gly Glu Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr 115 120 125 Leu Met Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala 130 135 140 Val Leu Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val 145 150 155 160 Ser Cys Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val 165 170 175 Gln Glu Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp 180 185 190 Glu Gly Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu 195 200 205 Leu Ser Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg 210 215 220 Lys Arg Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met 225 230 235 240 Phe Phe Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln 245 250 255 Val Val Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile 260 265 270 Cys Thr Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln 275 280 285 Leu Tyr Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys 290 295 300 Asn Leu Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr 305 310 315 320 His Asn Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly 325 330 335 Asp Gln Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp 340 345 350 Ser Asp His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe 355 360 365 Leu Trp His Arg Pro Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys 370 375 380 His Ser Phe Ser Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys 385 390 395 400 Arg Thr Phe Leu Ser Ile Met Arg Asp Ser Val Leu Thr His Leu Arg 405 410 415 Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile Gly Leu Leu Tyr Leu 420 425 430 Gly Ile Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly Phe Leu 435 440 445 Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro Thr Val 450 455 460 Leu Thr Phe Pro Leu Glu Met Gly Val Phe Leu Arg Glu His Leu Asn 465 470 475 480 Tyr Trp Tyr Ser Leu Lys Ala Tyr Tyr Leu Ala Lys Thr Met Ala Asp 485 490 495 Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys Ser Ile Val Tyr 500 505 510 Trp Met Thr Ser Gln Pro Ser Asp Ala Val Arg Phe Val Leu Phe Ala 515 520 525 Ala Leu Gly Thr Met Thr Ser Leu Val Ala Gln Ser Leu Gly Leu Leu 530 535 540 Ile Gly Ala Ala Ser Thr Ser Leu Gln Val Ala Thr Phe Val Gly Pro 545 550 555 560 Val Thr Ala Ile Pro Val Leu Leu Phe Ser Gly Phe Phe Val Ser Phe 565 570 575 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr Ile Ser Tyr Val 580 585 590 Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr Gly Leu Asp Arg 595 600 605 Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln Lys Ser 610 615 620 Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys Leu Tyr Leu 625 630 635 640 Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg Leu Ile Ala 645 650 655 Tyr Phe Val Leu Arg Tyr Lys Ile Arg Ala Glu Arg 660 665 73 644 PRT Homo sapiens 73 Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu Val Val Ser 1 5 10 15 Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly His Leu Lys 20 25 30 Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser Ser Leu Pro 35 40 45 Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser Tyr Ser Val 50 55 60 Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr Leu Leu Lys 65 70 75 80 Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala Ile Met Gly 85 90 95 Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu Ala Gly Tyr 100 105 110 Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly Leu Pro Arg 115 120 125 Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met Gln Asp Asp 130 135 140 Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met Val Ser Ala 145 150 155 160 His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu Met Val Lys 165 170 175 Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn Thr Arg Thr 180 185 190 Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile Ala Leu Glu 195 200 205 Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro Thr Ser Gly 210 215 220 Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met Lys Gly Leu 225 230 235 240 Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln Pro Ser Ala 245 250 255 Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser Gln Gly Gln 260 265 270 Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr Leu Arg Asp 275 280 285 Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp Phe Val Met 290 295 300 Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg Leu Val Arg 305 310 315 320 Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg Asp Leu Gly 325 330 335 Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro Ser Glu Glu 340 345 350 Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser Cys Leu 355 360 365 Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile Met Arg 370 375 380 Asp Ser Val Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly 385 390 395 400 Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile Gly Asn Glu Ala Lys Lys 405 410 415 Val Leu Ser Asn Ser Gly Phe Leu Phe Phe Ser Met Leu Phe Leu Met 420 425 430 Phe Ala Ala Leu Met Pro Thr Val Leu Thr Phe Pro Leu Glu Met Gly 435 440 445 Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu Lys Ala Tyr 450 455 460 Tyr Leu Ala Lys Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro 465 470 475 480 Val Ala Tyr Cys Ser Ile Val Tyr Trp Met Thr Ser Gln Pro Ser Asp 485 490 495 Ala Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu 500 505 510 Val Ala Gln Ser Leu Gly Leu Leu Ile Gly Ala Ala Ser Thr Ser Leu 515 520 525 Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu 530 535

540 Phe Ser Gly Phe Phe Val Ser Phe Asp Thr Ile Pro Thr Tyr Leu Gln 545 550 555 560 Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile 565 570 575 Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp Leu His Cys Asp Ile Asp 580 585 590 Glu Thr Cys His Phe Gln Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp 595 600 605 Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe 610 615 620 Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe Val Leu Arg Tyr Lys Ile 625 630 635 640 Arg Ala Glu Arg 74 663 PRT Homo sapiens 74 Met Ile Met Arg Leu Pro Gln Pro His Gly Thr Asn Ala Ser Ser Tyr 1 5 10 15 Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu 20 25 30 Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly 35 40 45 His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser 50 55 60 Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser 65 70 75 80 Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr 85 90 95 Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala 100 105 110 Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu 115 120 125 Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly 130 135 140 Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met 145 150 155 160 Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met 165 170 175 Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu 180 185 190 Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn 195 200 205 Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile 210 215 220 Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro 225 230 235 240 Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met 245 250 255 Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln 260 265 270 Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser 275 280 285 Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr 290 295 300 Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp 305 310 315 320 Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg 325 330 335 Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg 340 345 350 Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro 355 360 365 Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala 370 375 380 Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser 385 390 395 400 Ile Met Arg Asp Ser Val Leu Thr His Leu Arg Ile Thr Ser His Ile 405 410 415 Gly Ile Gly Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile Gly Asn Glu 420 425 430 Ala Lys Lys Val Leu Ser Asn Ser Gly Phe Leu Phe Phe Ser Met Leu 435 440 445 Phe Leu Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr Phe Pro Leu 450 455 460 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 465 470 475 480 Lys Ala Tyr Tyr Leu Ala Lys Thr Met Ala Asp Val Pro Phe Gln Ile 485 490 495 Met Phe Pro Val Ala Tyr Cys Ser Ile Val Tyr Trp Met Thr Ser Gln 500 505 510 Pro Ser Asp Ala Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met 515 520 525 Thr Ser Leu Val Ala Gln Ser Leu Gly Leu Leu Ile Gly Ala Ala Ser 530 535 540 Thr Ser Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro 545 550 555 560 Val Leu Leu Phe Ser Gly Phe Phe Val Ser Phe Asp Thr Ile Pro Thr 565 570 575 Tyr Leu Gln Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr Gly Phe Glu 580 585 590 Gly Val Ile Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp Leu His Cys 595 600 605 Asp Ile Asp Glu Thr Cys His Phe Gln Lys Ser Glu Ala Ile Leu Arg 610 615 620 Glu Leu Asp Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe Ile Val Leu 625 630 635 640 Gly Ile Phe Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe Val Leu Arg 645 650 655 Tyr Lys Ile Arg Ala Glu Arg 660 75 824 PRT Homo sapiens 75 Met Leu Ala Val Gln Gln Thr Glu His Leu Pro Ala Cys Pro Pro Ala 1 5 10 15 Arg Arg Trp Ser Ser Asn Phe Cys Pro Glu Ser Thr Glu Gly Gly Pro 20 25 30 Ser Leu Leu Gly Leu Arg Asp Met Val Arg Arg Gly Trp Ser Val Cys 35 40 45 Thr Ala Ile Leu Leu Ala Arg Leu Trp Cys Leu Val Pro Thr His Thr 50 55 60 Phe Leu Ser Glu Tyr Pro Glu Ala Ala Glu Tyr Pro His Pro Gly Trp 65 70 75 80 Val Tyr Trp Leu Gln Met Ala Val Ala Pro Gly His Leu Arg Ala Trp 85 90 95 Val Met Arg Asn Asn Val Thr Thr Asn Ile Pro Ser Ala Phe Ser Gly 100 105 110 Thr Leu Thr His Glu Glu Lys Ala Val Leu Thr Val Phe Thr Gly Thr 115 120 125 Ala Thr Ala Val His Val Gln Val Ala Ala Leu Ala Ser Ala Lys Leu 130 135 140 Glu Ser Ser Val Phe Val Thr Asp Cys Val Ser Cys Lys Ile Glu Asn 145 150 155 160 Val Cys Asp Ser Ala Leu Gln Gly Lys Arg Val Pro Met Ser Gly Leu 165 170 175 Gln Gly Ser Ser Ile Val Ile Met Pro Pro Ser Asn Arg Pro Leu Ala 180 185 190 Ser Ala Ala Ser Cys Thr Trp Ser Val Gln Val Gln Gly Gly Pro His 195 200 205 His Leu Gly Val Val Ala Ile Ser Gly Lys Val Leu Ser Ala Ala His 210 215 220 Gly Ala Gly Arg Ala Tyr Gly Trp Gly Phe Pro Gly Asp Pro Met Glu 225 230 235 240 Glu Gly Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser 245 250 255 Gly Glu Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr 260 265 270 Leu Met Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala 275 280 285 Val Leu Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val 290 295 300 Ser Cys Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val 305 310 315 320 Gln Glu Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp 325 330 335 Glu Gly Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu 340 345 350 Leu Ser Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg 355 360 365 Lys Arg Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met 370 375 380 Phe Phe Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln 385 390 395 400 Val Val Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile 405 410 415 Cys Thr Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln 420 425 430 Leu Tyr Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys 435 440 445 Asn Leu Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr 450 455 460 His Asn Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly 465 470 475 480 Asp Gln Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp 485 490 495 Ser Asp His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe 500 505 510 Leu Trp His Arg Pro Ser Glu Glu Val Lys Gln Thr Lys Arg Leu Lys 515 520 525 Gly Leu Arg Lys Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser 530 535 540 Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu 545 550 555 560 Ser Ile Met Arg Asp Ser Val Leu Thr His Leu Arg Ile Thr Ser His 565 570 575 Ile Gly Ile Gly Leu Leu Ile Gly Leu Leu Tyr Leu Gly Ile Gly Asn 580 585 590 Glu Ala Lys Lys Val Leu Ser Asn Ser Gly Phe Leu Phe Phe Ser Met 595 600 605 Leu Phe Leu Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr Phe Pro 610 615 620 Leu Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser 625 630 635 640 Leu Lys Ala Tyr Tyr Leu Ala Lys Thr Met Ala Asp Val Pro Phe Gln 645 650 655 Ile Met Phe Pro Val Ala Tyr Cys Ser Ile Val Tyr Trp Met Thr Ser 660 665 670 Gln Pro Ser Asp Ala Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr 675 680 685 Met Thr Ser Leu Val Ala Gln Ser Leu Gly Leu Leu Ile Gly Ala Ala 690 695 700 Ser Thr Ser Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile 705 710 715 720 Pro Val Leu Leu Phe Ser Gly Phe Phe Val Ser Phe Asp Thr Ile Pro 725 730 735 Thr Tyr Leu Gln Trp Met Ser Tyr Ile Ser Tyr Val Arg Tyr Gly Phe 740 745 750 Glu Gly Val Ile Leu Ser Ile Tyr Gly Leu Asp Arg Glu Asp Leu His 755 760 765 Cys Asp Ile Asp Glu Thr Cys His Phe Gln Lys Ser Glu Ala Ile Leu 770 775 780 Arg Glu Leu Asp Val Glu Asn Ala Lys Leu Tyr Leu Asp Phe Ile Val 785 790 795 800 Leu Gly Ile Phe Phe Ile Ser Leu Arg Leu Ile Ala Tyr Phe Val Leu 805 810 815 Arg Tyr Lys Ile Arg Ala Glu Arg 820 76 970 PRT Homo sapiens 76 Met Ala Gln Leu Glu Arg Ser Ala Ile Ser Gly Phe Ser Ser Lys Ser 1 5 10 15 Arg Arg Asn Ser Phe Ala Tyr Asp Val Lys Arg Glu Val Tyr Asn Glu 20 25 30 Glu Thr Phe Gln Gln Glu His Lys Arg Lys Ala Ser Ser Ser Gly Asn 35 40 45 Met Asn Ile Asn Ile Thr Thr Phe Arg His His Val Gln Cys Arg Cys 50 55 60 Ser Trp His Arg Phe Leu Arg Cys Val Leu Thr Ile Phe Pro Phe Leu 65 70 75 80 Glu Trp Met Cys Met Tyr Arg Leu Lys Asp Trp Leu Leu Gly Asp Leu 85 90 95 Leu Ala Gly Ile Ser Val Gly Leu Val Gln Val Pro Gln Gly Leu Thr 100 105 110 Leu Ser Leu Leu Ala Arg Gln Leu Ile Pro Pro Leu Asn Ile Ala Tyr 115 120 125 Ala Ala Phe Cys Ser Ser Val Ile Tyr Val Ile Phe Gly Ser Cys His 130 135 140 Gln Met Ser Ile Gly Ser Phe Phe Leu Val Ser Ala Leu Leu Ile Asn 145 150 155 160 Val Leu Lys Val Ser Pro Phe Asn Asn Gly Gln Leu Val Met Gly Ser 165 170 175 Phe Val Lys Asn Glu Phe Ser Ala Pro Ser Tyr Leu Met Gly Tyr Asn 180 185 190 Lys Ser Leu Ser Val Val Ala Thr Thr Thr Phe Leu Thr Gly Ile Ile 195 200 205 Gln Leu Ile Met Gly Val Leu Gly Leu Gly Phe Ile Ala Thr Tyr Leu 210 215 220 Pro Glu Ser Ala Met Ser Ala Tyr Leu Ala Ala Val Ala Leu His Ile 225 230 235 240 Met Leu Ser Gln Leu Thr Phe Ile Phe Gly Ile Met Ile Ser Phe His 245 250 255 Ala Gly Pro Ile Ser Phe Phe Tyr Asp Ile Ile Asn Tyr Cys Val Ala 260 265 270 Leu Pro Lys Ala Asn Ser Thr Ser Ile Leu Val Phe Leu Thr Val Val 275 280 285 Val Ala Leu Arg Ile Asn Lys Cys Ile Arg Ile Ser Phe Asn Gln Tyr 290 295 300 Pro Ile Glu Phe Pro Met Glu Leu Phe Leu Ile Ile Gly Phe Thr Val 305 310 315 320 Ile Ala Asn Lys Ile Ser Met Ala Thr Glu Thr Ser Gln Thr Leu Ile 325 330 335 Asp Met Ile Pro Tyr Ser Phe Leu Leu Pro Val Thr Pro Asp Phe Ser 340 345 350 Leu Leu Pro Lys Ile Ile Leu Gln Ala Phe Ser Leu Ser Leu Val Ser 355 360 365 Ser Phe Leu Leu Ile Phe Leu Gly Lys Lys Ile Ala Ser Leu His Asn 370 375 380 Tyr Ser Val Asn Ser Asn Gln Asp Leu Ile Ala Ile Gly Leu Cys Asn 385 390 395 400 Val Val Ser Ser Phe Phe Arg Ser Cys Val Phe Thr Gly Ala Ile Ala 405 410 415 Arg Thr Ile Ile Gln Asp Lys Ser Gly Gly Arg Gln Gln Phe Ala Ser 420 425 430 Leu Val Gly Ala Gly Val Met Leu Leu Leu Met Val Lys Met Gly His 435 440 445 Phe Phe Tyr Thr Leu Pro Asn Ala Val Leu Ala Gly Ile Ile Leu Ser 450 455 460 Asn Val Ile Pro Tyr Leu Glu Thr Ile Ser Asn Leu Pro Ser Leu Trp 465 470 475 480 Arg Gln Asp Gln Tyr Asp Cys Ala Leu Trp Met Met Thr Phe Ser Ser 485 490 495 Ser Ile Phe Leu Gly Leu Asp Ile Gly Leu Ile Ile Ser Val Val Ser 500 505 510 Ala Phe Phe Ile Thr Thr Val Arg Ser His Arg Ala Lys Ile Leu Leu 515 520 525 Leu Gly Gln Ile Pro Asn Thr Asn Ile Tyr Arg Ser Ile Asn Asp Tyr 530 535 540 Arg Glu Ile Ile Thr Ile Pro Gly Val Lys Ile Phe Gln Cys Cys Ser 545 550 555 560 Ser Ile Thr Phe Val Asn Val Tyr Tyr Leu Lys His Lys Leu Leu Lys 565 570 575 Glu Val Asp Met Val Lys Val Pro Leu Lys Glu Glu Glu Ile Phe Ser 580 585 590 Leu Phe Asn Ser Ser Asp Thr Asn Leu Gln Gly Gly Lys Ile Cys Arg 595 600 605 Cys Phe Cys Asn Cys Asp Asp Leu Glu Pro Leu Pro Arg Ile Leu Tyr 610 615 620 Thr Glu Arg Phe Glu Asn Lys Leu Asp Pro Glu Ala Ser Ser Ile Asn 625 630 635 640 Leu Ile His Cys Ser His Phe Glu Ser Met Asn Thr Ser Gln Thr Ala 645 650 655 Ser Glu Asp Gln Val Pro Tyr Thr Val Ser Ser Val Ser Gln Lys Asn 660 665 670 Gln Gly Gln Gln Tyr Glu Glu Val Glu Glu Val Trp Leu Pro Asn Asn 675 680 685 Ser Ser Arg Asn Ser Ser Pro Gly Leu Pro Asp Val Ala Glu Ser Gln 690 695 700 Gly Arg Arg Ser Leu Ile Pro Tyr Ser Asp Ala Ser Leu Leu Pro Ser 705 710 715 720 Val His Thr Ile Ile Leu Asp Phe Ser Met Val His Tyr Val Asp Ser 725 730 735 Arg Gly Leu Val Val Leu Arg Gln Ile Cys Asn Ala Phe Gln Asn Ala 740 745 750 Asn Ile Leu Ile Leu Ile Ala Gly Cys His Ser Ser Ile Val Arg Ala 755 760 765 Phe Glu Arg Asn Asp Phe Phe Asp Ala Gly Ile Thr Lys Thr Gln Leu 770 775 780 Phe Leu Ser Val His Asp Ala Val Leu Phe Ala Leu Ser Arg Lys Val 785 790 795 800 Ile Gly Ser Ser Glu Leu Ser Ile Asp Glu Ser Glu Thr Val Ile Arg 805 810 815 Glu Thr Tyr Ser Glu Thr Asp Lys Asn Asp Asn Ser Arg Tyr Lys Met 820 825 830 Ser Ser Ser Phe Leu Gly Ser Gln Lys Asn Val Ser Pro Gly Phe Ile 835 840 845 Lys Ile Gln Gln Pro Val Glu Glu Glu Ser Glu Leu Asp Leu Glu

Leu 850 855 860 Glu Ser Glu Gln Glu Ala Gly Leu Gly Leu Asp Leu Asp Leu Asp Arg 865 870 875 880 Glu Leu Glu Pro Glu Met Glu Pro Lys Ala Glu Thr Glu Thr Lys Thr 885 890 895 Gln Thr Glu Met Glu Pro Gln Pro Glu Thr Glu Pro Glu Met Glu Pro 900 905 910 Asn Pro Lys Ser Arg Pro Arg Ala His Thr Phe Pro Gln Gln Arg Tyr 915 920 925 Trp Pro Met Tyr His Pro Ser Met Ala Ser Thr Gln Ser Gln Thr Gln 930 935 940 Thr Arg Thr Trp Ser Val Glu Arg Arg Arg His Pro Met Asp Ser Tyr 945 950 955 960 Ser Pro Glu Gly Asn Ser Asn Glu Asp Val 965 970 77 225 PRT Homo sapiens 77 Met Thr Ser Glu Phe Phe Ser Ala Gln Leu Arg Ala Gln Ile Ser Asp 1 5 10 15 Asp Thr Thr His Pro Ile Ser Tyr Tyr Lys Pro Glu Phe Tyr Met Pro 20 25 30 Asp Asp Gly Gly Thr Ala His Leu Ser Val Val Ala Glu Asp Gly Ser 35 40 45 Ala Val Ser Ala Thr Ser Thr Ile Asn Leu Tyr Phe Gly Ser Lys Val 50 55 60 Arg Ser Pro Val Ser Gly Ile Leu Leu Asn Asn Glu Met Asp Asp Phe 65 70 75 80 Ser Ser Thr Ser Ile Thr Asn Glu Phe Gly Val Pro Pro Ser Pro Ala 85 90 95 Asn Phe Ile Gln Pro Gly Lys Gln Pro Leu Ser Ser Met Cys Pro Thr 100 105 110 Ile Met Val Gly Gln Asp Gly Gln Val Arg Met Val Val Gly Ala Ala 115 120 125 Gly Gly Thr Gln Ile Thr Met Ala Thr Ala Leu Ala Ile Ile Tyr Asn 130 135 140 Leu Trp Phe Gly Tyr Asp Val Lys Trp Ala Val Glu Glu Pro Arg Leu 145 150 155 160 His Asn Gln Leu Leu Pro Asn Val Thr Thr Val Glu Arg Asn Ile Asp 165 170 175 Gln Glu Val Thr Ala Ala Leu Glu Thr Arg His His His Thr Gln Ile 180 185 190 Thr Ser Thr Phe Ile Ala Val Val Gln Ala Ile Val Arg Met Ala Gly 195 200 205 Gly Trp Ala Ala Ala Ser Asp Ser Arg Lys Gly Gly Glu Pro Ala Gly 210 215 220 Tyr 225 78 225 PRT Homo sapiens 78 Met Thr Ser Glu Phe Phe Ser Ala Gln Leu Arg Ala Gln Ile Ser Asp 1 5 10 15 Asp Thr Thr His Pro Ile Ser Tyr Tyr Lys Pro Glu Phe Tyr Met Pro 20 25 30 Asp Asp Gly Gly Thr Ala His Leu Ser Val Val Ala Glu Asp Gly Ser 35 40 45 Ala Val Ser Ala Thr Ser Thr Ile Asn Leu Tyr Phe Gly Ser Lys Val 50 55 60 Arg Ser Pro Val Ser Gly Ile Leu Leu Asn Asn Glu Met Asp Asp Phe 65 70 75 80 Ser Ser Thr Ser Ile Thr Asn Glu Phe Gly Val Pro Pro Ser Pro Ala 85 90 95 Asn Phe Ile Gln Pro Gly Lys Gln Pro Leu Ser Ser Met Cys Pro Thr 100 105 110 Ile Met Val Gly Gln Asp Gly Gln Val Arg Met Val Val Gly Ala Ala 115 120 125 Gly Gly Thr Gln Ile Thr Met Ala Thr Ala Leu Ala Ile Ile Tyr Asn 130 135 140 Leu Trp Phe Gly Tyr Asp Val Lys Trp Ala Val Glu Glu Pro Arg Leu 145 150 155 160 His Asn Gln Leu Leu Pro Asn Val Thr Thr Val Glu Arg Asn Ile Asp 165 170 175 Gln Glu Val Thr Ala Ala Leu Glu Thr Arg His His His Thr Gln Ile 180 185 190 Thr Ser Thr Phe Ile Ala Val Val Gln Ala Ile Val Arg Met Ala Gly 195 200 205 Gly Trp Ala Ala Ala Ser Asp Ser Arg Lys Gly Gly Glu Pro Ala Gly 210 215 220 Tyr 225 79 225 PRT Homo sapiens 79 Met Thr Ser Glu Phe Phe Ser Ala Gln Leu Arg Ala Gln Ile Ser Asp 1 5 10 15 Asp Thr Thr His Pro Ile Ser Tyr Tyr Lys Pro Glu Phe Tyr Met Pro 20 25 30 Asp Asp Gly Gly Thr Ala His Leu Ser Val Val Ala Glu Asp Gly Ser 35 40 45 Ala Val Ser Ala Thr Ser Thr Ile Asn Leu Tyr Phe Gly Ser Lys Val 50 55 60 Arg Ser Pro Val Ser Gly Ile Leu Leu Asn Asn Glu Met Asp Asp Phe 65 70 75 80 Ser Ser Thr Ser Ile Thr Asn Glu Phe Gly Val Pro Pro Ser Pro Ala 85 90 95 Asn Phe Ile Gln Pro Gly Lys Gln Pro Leu Ser Ser Met Cys Pro Thr 100 105 110 Ile Met Val Gly Gln Asp Gly Gln Val Arg Met Val Val Gly Ala Ala 115 120 125 Gly Gly Thr Gln Ile Thr Met Ala Thr Ala Leu Ala Ile Ile Tyr Asn 130 135 140 Leu Trp Phe Gly Tyr Asp Val Lys Trp Ala Val Glu Glu Pro Arg Leu 145 150 155 160 His Asn Gln Leu Leu Pro Asn Val Thr Thr Val Glu Arg Asn Ile Asp 165 170 175 Gln Glu Val Thr Ala Ala Leu Glu Thr Arg His His His Thr Gln Ile 180 185 190 Thr Ser Thr Phe Ile Ala Val Val Gln Ala Ile Val Arg Met Ala Gly 195 200 205 Gly Trp Ala Ala Ala Ser Asp Ser Arg Lys Gly Gly Glu Pro Ala Gly 210 215 220 Tyr 225 80 545 PRT Homo sapiens 80 Met Gly Ser Ser Ala Thr Glu Ile Glu Glu Leu Glu Asn Thr Thr Phe 1 5 10 15 Lys Tyr Leu Thr Gly Glu Gln Thr Glu Lys Met Trp Gln Arg Leu Lys 20 25 30 Gly Ile Leu Arg Cys Leu Val Lys Gln Leu Glu Arg Gly Asp Val Asn 35 40 45 Val Val Asp Leu Lys Lys Asn Ile Glu Tyr Ala Ala Ser Val Leu Glu 50 55 60 Ala Val Tyr Ile Asp Glu Thr Arg Arg Leu Leu Asp Thr Glu Asp Glu 65 70 75 80 Leu Ser Asp Ile Gln Thr Asp Ser Val Pro Ser Glu Val Arg Asp Trp 85 90 95 Leu Ala Ser Thr Phe Thr Arg Lys Met Gly Met Thr Lys Lys Lys Pro 100 105 110 Glu Glu Lys Pro Lys Phe Arg Ser Ile Val His Ala Val Gln Ala Gly 115 120 125 Ile Phe Val Glu Arg Met Tyr Arg Lys Thr Tyr His Met Val Gly Leu 130 135 140 Ala Tyr Pro Ala Ala Val Ile Val Thr Leu Lys Asp Val Asp Lys Trp 145 150 155 160 Ser Phe Asp Val Phe Ala Leu Asn Glu Ala Ser Gly Glu His Ser Leu 165 170 175 Lys Phe Met Ile Tyr Glu Leu Phe Thr Arg Tyr Asp Leu Ile Asn Arg 180 185 190 Phe Lys Ile Pro Val Ser Cys Leu Ile Thr Phe Ala Glu Ala Leu Glu 195 200 205 Val Gly Tyr Ser Lys Tyr Lys Asn Pro Tyr His Asn Leu Ile His Ala 210 215 220 Ala Asp Val Thr Gln Thr Val His Tyr Ile Met Leu His Thr Gly Ile 225 230 235 240 Met His Trp Leu Thr Glu Leu Glu Ile Leu Ala Met Val Phe Ala Ala 245 250 255 Ala Ile His Asp Tyr Glu His Thr Gly Thr Thr Asn Asn Phe His Ile 260 265 270 Gln Thr Arg Ser Asp Val Ala Ile Leu Tyr Asn Asp Arg Ser Val Leu 275 280 285 Glu Asn His His Val Ser Ala Ala Tyr Arg Leu Met Gln Glu Glu Glu 290 295 300 Met Asn Ile Leu Ile Asn Leu Ser Lys Asp Asp Trp Arg Asp Leu Arg 305 310 315 320 Asn Leu Val Ile Glu Met Val Leu Ser Thr Asp Met Ser Gly His Phe 325 330 335 Gln Gln Ile Lys Asn Ile Arg Asn Ser Leu Gln Gln Pro Glu Gly Ile 340 345 350 Asp Arg Ala Lys Thr Met Ser Leu Ile Leu His Ala Ala Asp Ile Ser 355 360 365 His Pro Ala Lys Ser Trp Lys Leu His Tyr Arg Trp Thr Met Ala Leu 370 375 380 Met Glu Glu Phe Phe Leu Gln Gly Asp Lys Glu Ala Glu Leu Gly Leu 385 390 395 400 Pro Phe Ser Pro Leu Cys Asp Arg Lys Ser Thr Met Val Ala Gln Ser 405 410 415 Gln Ile Gly Phe Ile Asp Phe Ile Val Glu Pro Thr Phe Ser Leu Leu 420 425 430 Thr Asp Ser Thr Glu Lys Ile Val Ile Pro Leu Ile Glu Glu Ala Ser 435 440 445 Lys Ala Glu Thr Ser Ser Tyr Val Ala Ser Ser Ser Thr Thr Ile Val 450 455 460 Gly Leu His Ile Ala Asp Ala Leu Arg Arg Ser Asn Thr Lys Gly Ser 465 470 475 480 Met Ser Asp Gly Ser Tyr Ser Pro Asp Tyr Ser Leu Ala Ala Val Asp 485 490 495 Leu Lys Ser Phe Lys Asn Asn Leu Val Asp Ile Ile Gln Gln Asn Lys 500 505 510 Glu Arg Trp Lys Glu Leu Ala Ala Gln Gly Glu Ser Asp Leu His Lys 515 520 525 Asn Ser Glu Asp Leu Val Asn Ala Glu Glu Lys His Asp Glu Thr His 530 535 540 Ser 545 81 535 PRT Homo sapiens 81 Met Gly Ser Ser Ala Thr Glu Ile Glu Glu Leu Glu Asn Thr Thr Phe 1 5 10 15 Lys Tyr Leu Thr Gly Glu Gln Thr Glu Lys Met Trp Gln Arg Leu Lys 20 25 30 Gly Ile Leu Arg Cys Leu Val Lys Gln Leu Glu Arg Gly Asp Val Asn 35 40 45 Val Val Asp Leu Lys Lys Asn Ile Glu Tyr Ala Ala Ser Val Leu Glu 50 55 60 Ala Val Tyr Ile Asp Glu Thr Arg Arg Leu Leu Asp Thr Glu Asp Glu 65 70 75 80 Leu Ser Asp Ile Gln Thr Asp Ser Val Pro Ser Glu Val Arg Asp Trp 85 90 95 Leu Ala Ser Thr Phe Thr Arg Lys Met Gly Met Thr Lys Lys Lys Pro 100 105 110 Glu Glu Lys Pro Lys Phe Arg Ser Ile Val His Ala Val Gln Ala Gly 115 120 125 Ile Phe Val Glu Arg Met Tyr Arg Lys Thr Tyr His Met Val Gly Leu 130 135 140 Ala Tyr Pro Ala Ala Val Ile Val Thr Leu Lys Asp Val Asp Lys Trp 145 150 155 160 Ser Phe Asp Val Phe Ala Leu Asn Glu Ala Ser Gly Glu His Ser Leu 165 170 175 Lys Phe Met Ile Tyr Glu Leu Phe Thr Arg Tyr Asp Leu Ile Asn Arg 180 185 190 Phe Lys Ile Pro Val Ser Cys Leu Ile Thr Phe Ala Glu Ala Leu Glu 195 200 205 Val Gly Tyr Ser Lys Tyr Lys Asn Pro Tyr His Asn Leu Ile His Ala 210 215 220 Ala Asp Val Thr Gln Thr Val His Tyr Ile Met Leu His Thr Gly Ile 225 230 235 240 Met His Trp Leu Thr Glu Leu Glu Ile Leu Ala Met Val Phe Ala Ala 245 250 255 Ala Ile His Asp Tyr Glu His Thr Gly Thr Thr Asn Asn Phe His Ile 260 265 270 Gln Thr Arg Ser Asp Val Ala Ile Leu Tyr Asn Asp Arg Ser Val Leu 275 280 285 Glu Asn His His Val Ser Ala Ala Tyr Arg Leu Met Gln Glu Glu Glu 290 295 300 Met Asn Ile Leu Ile Asn Leu Ser Lys Asp Asp Trp Arg Asp Leu Arg 305 310 315 320 Asn Leu Val Ile Glu Met Val Leu Ser Thr Asp Met Ser Gly His Phe 325 330 335 Gln Gln Ile Lys Asn Ile Arg Asn Ser Leu Gln Gln Pro Glu Gly Ile 340 345 350 Asp Arg Ala Lys Thr Met Ser Leu Ile Leu His Ala Ala Asp Ile Ser 355 360 365 His Pro Ala Lys Ser Trp Lys Leu His Tyr Arg Trp Thr Met Ala Leu 370 375 380 Met Glu Glu Phe Phe Leu Gln Gly Asp Lys Glu Ala Glu Leu Gly Leu 385 390 395 400 Pro Phe Ser Pro Leu Cys Asp Arg Lys Ser Thr Met Val Ala Gln Ser 405 410 415 Gln Ile Gly Phe Ile Asp Phe Ile Val Glu Pro Thr Phe Ser Leu Leu 420 425 430 Thr Asp Ser Thr Glu Lys Ile Val Ile Pro Leu Ile Glu Glu Ala Ser 435 440 445 Lys Ala Glu Thr Ser Ser Tyr Val Ala Ser Ser Ser Thr Thr Ile Val 450 455 460 Gly Leu His Ile Ala Asp Ala Leu Arg Arg Ser Asn Thr Lys Gly Ser 465 470 475 480 Met Ser Asp Gly Ser Tyr Ser Pro Asp Tyr Ser Leu Ala Ala Val Asp 485 490 495 Leu Lys Ser Phe Lys Asn Asn Leu Val Asp Ile Ile Gln Gln Asn Lys 500 505 510 Glu Arg Trp Lys Glu Leu Ala Ala Gln Glu Ala Arg Thr Ser Ser Gln 515 520 525 Lys Cys Glu Phe Ile His Gln 530 535 82 729 PRT Homo sapiens 82 Met Asn Pro Phe Gln Lys Asn Glu Ser Lys Glu Thr Leu Phe Ser Pro 1 5 10 15 Val Ser Ile Glu Glu Val Pro Pro Arg Pro Pro Ser Pro Pro Lys Lys 20 25 30 Pro Ser Pro Thr Ile Cys Gly Ser Asn Tyr Pro Leu Ser Ile Ala Phe 35 40 45 Ile Val Val Asn Glu Phe Cys Glu Arg Phe Ser Tyr Tyr Gly Met Lys 50 55 60 Ala Val Leu Ile Leu Tyr Phe Leu Tyr Phe Leu His Trp Asn Glu Asp 65 70 75 80 Thr Ser Thr Ser Ile Tyr His Ala Phe Ser Ser Leu Cys Tyr Phe Thr 85 90 95 Pro Ile Leu Gly Ala Ala Ile Ala Asp Ser Trp Leu Gly Lys Phe Lys 100 105 110 Thr Ile Ile Tyr Leu Ser Leu Val Tyr Val Leu Gly His Val Ile Lys 115 120 125 Ser Leu Gly Ala Leu Pro Ile Leu Gly Gly Gln Val Val His Thr Val 130 135 140 Leu Ser Leu Ile Gly Leu Ser Leu Ile Ala Leu Gly Thr Gly Gly Ile 145 150 155 160 Lys Pro Cys Val Ala Ala Phe Gly Gly Asp Gln Phe Glu Glu Lys His 165 170 175 Ala Glu Glu Arg Thr Arg Tyr Phe Ser Val Phe Tyr Leu Ser Ile Asn 180 185 190 Ala Gly Ser Leu Ile Ser Thr Phe Ile Thr Pro Met Leu Arg Gly Asp 195 200 205 Val Gln Cys Phe Gly Glu Asp Cys Tyr Ala Leu Ala Phe Gly Val Pro 210 215 220 Gly Leu Leu Met Val Ile Ala Leu Val Val Phe Ala Met Gly Ser Lys 225 230 235 240 Ile Tyr Asn Lys Pro Pro Pro Glu Gly Asn Ile Val Ala Gln Val Phe 245 250 255 Lys Cys Ile Trp Phe Ala Ile Ser Asn Arg Phe Lys Asn Arg Ser Gly 260 265 270 Asp Ile Pro Lys Arg Gln His Trp Leu Asp Trp Ala Ala Glu Lys Tyr 275 280 285 Pro Lys Gln Leu Ile Met Asp Val Lys Ala Leu Thr Arg Val Leu Phe 290 295 300 Leu Tyr Ile Pro Leu Pro Met Phe Trp Ala Leu Leu Asp Gln Gln Gly 305 310 315 320 Ser Arg Trp Thr Leu Gln Ala Ile Arg Met Asn Arg Asn Leu Gly Phe 325 330 335 Phe Val Leu Gln Pro Asp Gln Met Gln Val Leu Asn Pro Leu Leu Val 340 345 350 Leu Ile Phe Ile Pro Leu Phe Asp Phe Val Ile Tyr Arg Leu Val Ser 355 360 365 Lys Cys Gly Ile Asn Phe Ser Ser Leu Arg Lys Met Ala Val Gly Met 370 375 380 Ile Leu Ala Cys Leu Ala Phe Ala Val Ala Ala Ala Val Glu Ile Lys 385 390 395 400 Ile Asn Glu Met Ala Pro Ala Gln Pro Gly Pro Gln Glu Val Phe Leu 405 410 415 Gln Val Leu Asn Leu Ala Asp Asp Glu Val Lys Val Thr Val Val Gly 420 425 430 Asn Glu Asn Asn Ser Leu Leu Ile Glu Ser Ile Lys Ser Phe Gln Lys 435 440 445 Thr Pro His Tyr Ser Lys Leu His Leu Lys Thr Lys Ser Gln Asp Phe 450 455 460 His Phe His Leu Lys Tyr His Asn Leu Ser Leu Tyr Thr Glu His Ser 465 470 475 480 Val Gln Glu Lys Asn Trp Tyr Ser Leu Val Ile Arg Glu Asp Gly Asn 485 490 495 Ser Ile Ser Ser Met Met Val Lys Asp Thr Glu Ser Arg Thr Thr Asn 500 505 510 Gly Met Thr Thr Val Arg Phe Val Asn Thr Leu His Lys Asp Val Asn 515 520 525 Ile Ser Leu Ser Thr Asp Thr Ser Leu Asn Val Gly Glu Asp Tyr Gly 530 535 540 Val Ser Ala Tyr Arg Thr Val Gln Arg Gly Glu Tyr Pro Ala Val His 545 550 555 560 Cys Arg Thr Glu Asp Lys Asn Phe Ser Leu

Asn Leu Gly Leu Leu Asp 565 570 575 Phe Gly Ala Ala Tyr Leu Phe Val Ile Thr Asn Asn Thr Asn Gln Gly 580 585 590 Leu Gln Ala Trp Lys Ile Glu Asp Ile Pro Ala Asn Lys Met Ser Ile 595 600 605 Ala Trp Gln Leu Pro Gln Tyr Ala Leu Val Thr Ala Gly Glu Val Met 610 615 620 Phe Ser Val Thr Gly Leu Glu Phe Ser Tyr Ser Gln Ala Pro Ser Gly 625 630 635 640 Met Lys Ser Val Leu Gln Ala Ala Trp Leu Leu Thr Ile Ala Val Gly 645 650 655 Asn Ile Ile Val Leu Val Val Ala Gln Phe Ser Gly Leu Val Gln Trp 660 665 670 Ala Glu Phe Ile Leu Phe Ser Cys Leu Leu Leu Val Ile Cys Leu Ile 675 680 685 Phe Ser Ile Met Gly Tyr Tyr Tyr Val Pro Val Lys Thr Glu Asp Met 690 695 700 Arg Gly Pro Ala Asp Lys His Ile Pro His Ile Gln Gly Asn Met Ile 705 710 715 720 Lys Leu Glu Thr Lys Lys Thr Lys Leu 725 83 8 RNA Artificial Sequence Synthetic oligonucleotide 83 uugcuaua 8 84 19 DNA Artificial Sequence Synthetic oligonucleotide 84 ttccatggta atggtgtgc 19 85 19 DNA Artificial Sequence Synthetic oligonucleotide 85 ccgaagcaag gaataatcc 19 86 19 DNA Artificial Sequence Synthetic oligonucleotide 86 tatgtttcgc ctttatgac 19 87 19 DNA Artificial Sequence Synthetic oligonucleotide 87 ggattcaagg aggaatgac 19 88 19 DNA Artificial Sequence Synthetic oligonucleotide 88 ctccctcttg catcaagac 19 89 19 DNA Artificial Sequence Synthetic oligonucleotide 89 aaatcctcgt caggtttac 19 90 19 DNA Artificial Sequence Synthetic oligonucleotide 90 agtgccttac agtatcatc 19 91 19 DNA Artificial Sequence Synthetic oligonucleotide 91 cctgaatgtg actgtggac 19 92 19 DNA Artificial Sequence Synthetic oligonucleotide 92 gactgactgg cctgaaggc 19 93 19 DNA Artificial Sequence Synthetic oligonucleotide 93 gcagcactat ttgaagcac 19 94 19 DNA Artificial Sequence Synthetic oligonucleotide 94 gcctgagaac ctcctctgc 19 95 19 DNA Artificial Sequence Synthetic oligonucleotide 95 acagctagtc aggcacttc 19 96 19 DNA Artificial Sequence Synthetic oligonucleotide 96 tataagaaat ggcatactc 19 97 19 DNA Artificial Sequence Synthetic oligonucleotide 97 ctaatccatg gtctagttc 19 98 19 DNA Artificial Sequence Synthetic oligonucleotide 98 gtctgctata aggaatatc 19 99 19 DNA Artificial Sequence Synthetic oligonucleotide 99 aagtactcct gaggtctac 19 100 19 DNA Artificial Sequence Synthetic oligonucleotide 100 aggcaccagg gacttgtgc 19 101 19 DNA Artificial Sequence Synthetic oligonucleotide 101 gatctacacc accttcatc 19 102 19 DNA Artificial Sequence Synthetic oligonucleotide 102 tggtgttcta cgtggtgac 19 103 19 DNA Artificial Sequence Synthetic oligonucleotide 103 tgttaggcgc ctgcattgc 19 104 19 DNA Artificial Sequence Synthetic oligonucleotide 104 caacatcttt atctgctcc 19 105 19 DNA Artificial Sequence Synthetic oligonucleotide 105 cgaagggctt tcacaatgc 19 106 19 DNA Artificial Sequence Synthetic oligonucleotide 106 gtactacgtt gtagcccac 19 107 19 DNA Artificial Sequence Synthetic oligonucleotide 107 tgcaggcgct taacattac 19 108 19 DNA Artificial Sequence Synthetic oligonucleotide 108 ggtgtatggg ctcatgtac 19 109 19 DNA Artificial Sequence Synthetic oligonucleotide 109 catcgtcatc gcctgctac 19 110 19 DNA Artificial Sequence Synthetic oligonucleotide 110 gctcatggtg cgcattggc 19 111 19 DNA Artificial Sequence Synthetic oligonucleotide 111 gtaccttatg acgctgatc 19 112 19 DNA Artificial Sequence Synthetic oligonucleotide 112 acctggtatg ggtttggcc 19 113 19 DNA Artificial Sequence Synthetic oligonucleotide 113 atgtgtgcag gtctactgc 19 114 19 DNA Artificial Sequence Synthetic oligonucleotide 114 ttatttaggg cggtttaac 19 115 19 DNA Artificial Sequence Synthetic oligonucleotide 115 taatgtcatc gcctccaac 19 116 19 DNA Artificial Sequence Synthetic oligonucleotide 116 agaactgggt gatgacagc 19 117 19 DNA Artificial Sequence Synthetic oligonucleotide 117 caacagtccc tgctacatc 19 118 19 DNA Artificial Sequence Synthetic oligonucleotide 118 gatcgtggtg catccatac 19 119 19 DNA Artificial Sequence Synthetic oligonucleotide 119 gcgtggatta ccagaagac 19 120 19 DNA Artificial Sequence Synthetic oligonucleotide 120 taacaacagt ccctgctac 19 121 19 DNA Artificial Sequence Synthetic oligonucleotide 121 ccattgcttg gtgaatggc 19 122 19 DNA Artificial Sequence Synthetic oligonucleotide 122 attctctcca tggagtgac 19 123 19 DNA Artificial Sequence Synthetic oligonucleotide 123 atgaactctg tgatccagc 19 124 19 DNA Artificial Sequence Synthetic oligonucleotide 124 aggttggcta gtggatctc 19 125 19 DNA Artificial Sequence Synthetic oligonucleotide 125 aagtgggtaa ttcctgctc 19 126 19 DNA Artificial Sequence Synthetic oligonucleotide 126 cgaatggcag aatggatac 19 127 19 DNA Artificial Sequence Synthetic oligonucleotide 127 tctggcaggt tgcatattc 19 128 19 DNA Artificial Sequence Synthetic oligonucleotide 128 ctgcaagttt catatctac 19 129 19 DNA Artificial Sequence Synthetic oligonucleotide 129 atagcatcag attgtatgc 19 130 19 DNA Artificial Sequence Synthetic oligonucleotide 130 tttacacgat gatatgttc 19 131 19 DNA Artificial Sequence Synthetic oligonucleotide 131 cagaggattt gccagaaac 19 132 19 DNA Artificial Sequence Synthetic oligonucleotide 132 ttggaattcc agtgtaccc 19 133 19 DNA Artificial Sequence Synthetic oligonucleotide 133 cagagacacc atctccctc 19 134 19 DNA Artificial Sequence Synthetic oligonucleotide 134 acccagaccc aaagtttgc 19 135 19 DNA Artificial Sequence Synthetic oligonucleotide 135 aaggtggaaa gactatctc 19 136 19 DNA Artificial Sequence Synthetic oligonucleotide 136 tataaaccag aggatttgc 19 137 19 DNA Artificial Sequence Synthetic oligonucleotide 137 gtataatcta catcagatc 19 138 19 DNA Artificial Sequence Synthetic oligonucleotide 138 ccacatgttt accagagac 19 139 19 DNA Artificial Sequence Synthetic oligonucleotide 139 gctagttatc gcctacctc 19 140 19 DNA Artificial Sequence Synthetic oligonucleotide 140 gacacacagg agttcaacc 19 141 19 DNA Artificial Sequence Synthetic oligonucleotide 141 gctgcagaaa ctaggcatc 19 142 19 DNA Artificial Sequence Synthetic oligonucleotide 142 tgccaacttc tacaaggac 19 143 19 DNA Artificial Sequence Synthetic oligonucleotide 143 cgacacacag gagttcaac 19 144 19 DNA Artificial Sequence Synthetic oligonucleotide 144 gatggacgtc aagtctgcc 19 145 19 DNA Artificial Sequence Synthetic oligonucleotide 145 acaggagttc aacctcagc 19 146 19 DNA Artificial Sequence Synthetic oligonucleotide 146 ttggcatgga accaacgac 19 147 19 DNA Artificial Sequence Synthetic oligonucleotide 147 cctctttgcc ctgtatgac 19 148 19 DNA Artificial Sequence Synthetic oligonucleotide 148 agattccaga tgcaacccc 19 149 19 DNA Artificial Sequence Synthetic oligonucleotide 149 catgagccag ctgagtttc 19 150 19 DNA Artificial Sequence Synthetic oligonucleotide 150 gtggaagtga tcttctatc 19 151 19 DNA Artificial Sequence Synthetic oligonucleotide 151 tggctgtcat ggtccaatc 19 152 19 DNA Artificial Sequence Synthetic oligonucleotide 152 ccgctgcatg aactatgac 19 153 19 DNA Artificial Sequence Synthetic oligonucleotide 153 ttggagactt cggtttaac 19 154 19 DNA Artificial Sequence Synthetic oligonucleotide 154 tgtgattcag attctagtc 19 155 19 DNA Artificial Sequence Synthetic oligonucleotide 155 agtggatgtc ctacatctc 19 156 19 DNA Artificial Sequence Synthetic oligonucleotide 156 atcatgcagg atgacatgc 19 157 19 DNA Artificial Sequence Synthetic oligonucleotide 157 ctgaactact ggtacagcc 19 158 19 DNA Artificial Sequence Synthetic oligonucleotide 158 cagctttacg tcctgagtc 19 159 19 DNA Artificial Sequence Synthetic oligonucleotide 159 tcagaccaca agagagacc 19 160 19 DNA Artificial Sequence Synthetic oligonucleotide 160 gtacctacag tggatgtcc 19 161 19 DNA Artificial Sequence Synthetic oligonucleotide 161 tggtcaagga gatactgac 19 162 19 DNA Artificial Sequence Synthetic oligonucleotide 162 ccctccagtc atgttcttc 19 163 19 DNA Artificial Sequence Synthetic oligonucleotide 163 ttctgcaact gtgatgatc 19 164 19 DNA Artificial Sequence Synthetic oligonucleotide 164 gtacactacg tggattcac 19 165 19 DNA Artificial Sequence Synthetic oligonucleotide 165 gcgaattcca ccagcattc 19 166 19 DNA Artificial Sequence Synthetic oligonucleotide 166 tcttccagtg ctgcagctc 19 167 19 DNA Artificial Sequence Synthetic oligonucleotide 167 tcagaacaag aggctgggc 19 168 19 DNA Artificial Sequence Synthetic oligonucleotide 168 gaagattgcc agtcttcac 19 169 19 DNA Artificial Sequence Synthetic oligonucleotide 169 gattcctcct ctcaacatc 19 170 19 DNA Artificial Sequence Synthetic oligonucleotide 170 gcattctagt atttctaac 19 171 19 DNA Artificial Sequence Synthetic oligonucleotide 171 ttacagtgtc aattccaac 19 172 19 DNA Artificial Sequence Synthetic oligonucleotide 172 tgattatcgg gagatcatc 19 173 19 DNA Artificial Sequence Synthetic oligonucleotide 173 gaatggatgt gtatgtatc 19 174 19 DNA Artificial Sequence Synthetic oligonucleotide 174 tgacatgatt ccttatagc 19 175 19 DNA Artificial Sequence Synthetic oligonucleotide 175 tctacacact gccaaatgc 19 176 19 DNA Artificial Sequence Synthetic oligonucleotide 176 actggccatc atctacaac 19 177 19 DNA Artificial Sequence Synthetic oligonucleotide 177 tgctcacctg tctgtggtc 19 178 19 DNA Artificial Sequence Synthetic oligonucleotide 178 acattgacca ggaagtgac 19 179 19 DNA Artificial Sequence Synthetic oligonucleotide 179 tggatgactt cagctctac 19 180 19 DNA Artificial Sequence Synthetic oligonucleotide 180 ctacaacctc tggttcggc 19 181 19 DNA Artificial Sequence Synthetic oligonucleotide 181 cacgacagtg gagagaaac 19 182 19 DNA Artificial Sequence Synthetic oligonucleotide 182 gttctacatg ccggatgac 19 183 19 DNA Artificial Sequence Synthetic oligonucleotide 183 aggtatcatg cactggctc 19 184 19 DNA Artificial Sequence Synthetic oligonucleotide 184 gaagctgaat tagggcttc 19 185 19 DNA Artificial Sequence Synthetic oligonucleotide 185 ctggtggaca tcattcagc 19 186 19 DNA Artificial Sequence Synthetic oligonucleotide 186 tttgtgatcg gaagtcaac 19 187 19 DNA Artificial Sequence Synthetic oligonucleotide 187 attgctgatg cactaagac 19 188 19 DNA Artificial Sequence Synthetic oligonucleotide 188 cagatatgat cttatcaac 19 189 19 DNA Artificial Sequence Synthetic oligonucleotide 189 actgtgcatt acataatgc 19 190 19 DNA Artificial Sequence Synthetic oligonucleotide 190 cacgtgagtg cagcttatc 19 191 19 DNA Artificial Sequence Synthetic oligonucleotide 191 agtcctatca ttgatcggc 19 192 19 DNA Artificial Sequence Synthetic oligonucleotide 192 gaagccatct ccgacaatc 19 193 19 DNA Artificial Sequence Synthetic oligonucleotide 193 atggctgttg gtatgatcc 19 194 19 DNA Artificial Sequence Synthetic oligonucleotide 194 ccgtgaggtt tgttaacac 19 195 19 DNA Artificial Sequence Synthetic oligonucleotide 195 ttgggtgcct taccaatac 19 196 19 DNA Artificial Sequence Synthetic oligonucleotide 196 ctccaagtgt ggaattaac 19 197 19 DNA Artificial Sequence Synthetic oligonucleotide 197 gcatgatggt aaaggatac 19 198 109 PRT Homo sapiens 198 Met Ile Cys Cys Ser Ala Leu Ser Pro Arg Ile His Leu Ser Phe His 1 5 10 15 Arg Ser Leu Thr Gly Ile Val Leu Ala Asn Ser Ser Leu Asp Ile Val 20 25 30 Leu His Asp Thr Tyr Tyr Val Val Ala His Cys Gly Gly Asn Val Arg

35 40 45 Arg Leu His Cys Gly Gly Pro Ala Ser Arg Glu Arg Thr Ala Met Gln 50 55 60 Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg Leu Leu Arg Asp His 65 70 75 80 Asn Leu Thr Arg Glu Gln Phe Ile Ala Leu Tyr Arg Leu Arg Pro Leu 85 90 95 Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala Lys Leu Ala 100 105 199 23 PRT Homo sapiens 199 Leu Val Leu Thr Gly Val Leu Ile Phe Ala Leu Ala Leu Phe Gly Asn 1 5 10 15 Ala Leu Val Phe Tyr Val Val 20 200 11 PRT Homo sapiens 200 Thr Arg Ser Lys Ala Met Arg Thr Val Thr Asn 1 5 10 201 23 PRT Homo sapiens 201 Ile Phe Ile Cys Ser Leu Ala Leu Ser Asp Leu Leu Ile Thr Phe Phe 1 5 10 15 Cys Ile Pro Val Thr Met Leu 20 202 14 PRT Homo sapiens 202 Gln Asn Ile Ser Asp Asn Trp Leu Gly Gly Ala Phe Ile Cys 1 5 10 203 23 PRT Homo sapiens 203 Lys Met Val Pro Phe Val Gln Ser Thr Ala Val Val Thr Glu Ile Leu 1 5 10 15 Thr Met Thr Cys Ile Ala Val 20 204 20 PRT Homo sapiens 204 Glu Arg His Gln Gly Leu Val His Pro Phe Lys Met Lys Trp Gln Tyr 1 5 10 15 Thr Asn Arg Arg 20 205 23 PRT Homo sapiens 205 Ala Phe Thr Met Leu Gly Val Val Trp Leu Val Ala Val Ile Val Gly 1 5 10 15 Ser Pro Met Trp His Val Gln 20 206 48 PRT Homo sapiens 206 Gln Leu Glu Ile Lys Tyr Asp Phe Leu Tyr Glu Lys Glu His Ile Cys 1 5 10 15 Cys Leu Glu Glu Trp Thr Ser Pro Val His Gln Lys Ile Tyr Thr Thr 20 25 30 Phe Ile Leu Ser Ser Ser Ser Ser Cys Leu Leu Trp Lys Lys Lys Arg 35 40 45 207 23 PRT Homo sapiens 207 Ala Val Ile Met Met Val Thr Val Val Ala Leu Phe Ala Val Cys Trp 1 5 10 15 Ala Pro Phe His Val Val His 20 208 19 PRT Homo sapiens 208 Met Met Ile Glu Tyr Ser Asn Phe Glu Lys Glu Tyr Asp Asp Val Thr 1 5 10 15 Ile Lys Met 209 23 PRT Homo sapiens 209 Ile Phe Ala Ile Val Gln Ile Ile Gly Phe Ser Asn Ser Ile Cys Asn 1 5 10 15 Pro Ile Val Tyr Ala Phe Met 20 210 96 PRT Homo sapiens 210 Asn Glu Asn Phe Lys Lys Asn Val Leu Ser Ala Val Cys Tyr Cys Ile 1 5 10 15 Val Asn Lys Thr Phe Ser Pro Ala Gln Arg His Gly Asn Ser Gly Ile 20 25 30 Thr Met Met Arg Lys Lys Ala Lys Phe Ser Leu Arg Glu Asn Pro Val 35 40 45 Glu Glu Thr Lys Gly Glu Ala Phe Ser Asp Gly Asn Ile Glu Val Lys 50 55 60 Leu Cys Glu Gln Thr Glu Glu Lys Lys Lys Leu Lys Arg His Leu Ala 65 70 75 80 Leu Phe Arg Ser Glu Leu Ala Glu Asn Ser Pro Leu Asp Ser Gly His 85 90 95 211 47 PRT Homo sapiens 211 Met Gln Ala Leu Asn Ile Thr Pro Glu Gln Phe Ser Arg Leu Leu Arg 1 5 10 15 Asp His Asn Leu Thr Arg Glu Gln Phe Ile Ala Val His Arg Leu Arg 20 25 30 Pro Leu Val Tyr Thr Pro Glu Leu Pro Gly Arg Ala Lys Leu Ala 35 40 45 212 23 PRT Homo sapiens 212 Leu Val Leu Thr Gly Val Leu Ile Phe Ala Leu Ala Leu Phe Gly Asn 1 5 10 15 Ala Leu Val Phe Tyr Val Val 20 213 11 PRT Homo sapiens 213 Thr Arg Ser Lys Ala Met Arg Thr Val Thr Asn 1 5 10 214 23 PRT Homo sapiens 214 Ile Phe Ile Cys Ser Leu Ala Leu Ser Asp Leu Leu Ile Thr Phe Phe 1 5 10 15 Cys Ile Pro Val Thr Met Leu 20 215 14 PRT Homo sapiens 215 Gln Asn Ile Ser Asp Asn Trp Leu Gly Gly Ala Phe Ile Cys 1 5 10 216 23 PRT Homo sapiens 216 Lys Met Val Pro Phe Val Gln Ser Thr Ala Val Val Thr Glu Ile Leu 1 5 10 15 Thr Met Thr Cys Ile Ala Val 20 217 20 PRT Homo sapiens 217 Glu Arg His Gln Gly Leu Val His Pro Phe Lys Met Lys Trp Gln Tyr 1 5 10 15 Thr Asn Arg Arg 20 218 23 PRT Homo sapiens 218 Ala Phe Thr Met Leu Gly Val Val Trp Leu Val Ala Val Ile Val Gly 1 5 10 15 Ser Pro Met Trp His Val Gln 20 219 28 PRT Homo sapiens 219 Gln Leu Glu Ile Lys Tyr Asp Phe Leu Tyr Glu Lys Glu His Ile Cys 1 5 10 15 Cys Leu Glu Glu Trp Thr Ser Pro Val His Gln Lys 20 25 220 23 PRT Homo sapiens 220 Ile Tyr Thr Thr Phe Ile Leu Val Ile Leu Phe Leu Leu Pro Leu Met 1 5 10 15 Val Met Leu Ile Leu Tyr Ser 20 221 34 PRT Homo sapiens 221 Lys Ile Gly Tyr Glu Leu Trp Ile Lys Lys Arg Val Gly Asp Gly Ser 1 5 10 15 Val Leu Arg Thr Ile His Gly Lys Glu Met Ser Lys Ile Ala Arg Lys 20 25 30 Lys Lys 222 23 PRT Homo sapiens 222 Arg Ala Val Ile Met Met Val Thr Val Val Ala Leu Phe Ala Val Cys 1 5 10 15 Trp Ala Pro Phe His Val Val 20 223 19 PRT Homo sapiens 223 His Met Met Ile Glu Tyr Ser Asn Phe Glu Lys Glu Tyr Asp Asp Val 1 5 10 15 Thr Ile Lys 224 23 PRT Homo sapiens 224 Met Ile Phe Ala Ile Val Gln Ile Ile Gly Phe Ser Asn Ser Ile Cys 1 5 10 15 Asn Pro Ile Val Tyr Ala Phe 20 225 97 PRT Homo sapiens 225 Met Asn Glu Asn Phe Lys Lys Asn Val Leu Ser Ala Val Cys Tyr Cys 1 5 10 15 Ile Val Asn Lys Thr Phe Ser Pro Ala Gln Arg His Gly Asn Ser Gly 20 25 30 Ile Thr Met Met Arg Lys Lys Ala Lys Phe Ser Leu Arg Glu Asn Pro 35 40 45 Val Glu Glu Thr Lys Gly Glu Ala Phe Ser Asp Gly Asn Ile Glu Val 50 55 60 Lys Leu Cys Glu Gln Thr Glu Glu Lys Lys Lys Leu Lys Arg His Leu 65 70 75 80 Ala Leu Phe Arg Ser Glu Leu Ala Glu Asn Ser Pro Leu Asp Ser Gly 85 90 95 His 226 320 PRT Homo sapiens 226 Met Ala Glu Glu Glu Ala Pro Lys Lys Ser Arg Ala Ala Gly Gly Gly 1 5 10 15 Ala Ser Trp Glu Leu Cys Ala Gly Ala Leu Ser Ala Arg Leu Ala Glu 20 25 30 Glu Gly Ser Gly Asp Ala Gly Gly Arg Arg Arg Pro Pro Val Asp Pro 35 40 45 Arg Arg Leu Ala Arg Gln Leu Leu Leu Leu Leu Trp Leu Leu Glu Ala 50 55 60 Pro Leu Leu Leu Gly Val Arg Ala Gln Ala Ala Gly Gln Gly Pro Gly 65 70 75 80 Gln Gly Pro Gly Pro Gly Gln Gln Pro Pro Pro Pro Pro Gln Gln Gln 85 90 95 Gln Ser Gly Gln Gln Tyr Asn Gly Glu Arg Gly Ile Ser Val Pro Asp 100 105 110 His Gly Tyr Cys Gln Pro Ile Ser Ile Pro Leu Cys Thr Asp Ile Ala 115 120 125 Tyr Asn Gln Thr Ile Met Pro Asn Leu Leu Gly His Thr Asn Gln Glu 130 135 140 Asp Ala Gly Leu Glu Val His Gln Phe Tyr Pro Leu Val Lys Val Gln 145 150 155 160 Cys Ser Ala Glu Leu Lys Phe Phe Leu Cys Ser Met Tyr Ala Pro Val 165 170 175 Cys Thr Val Leu Glu Gln Ala Leu Pro Pro Cys Arg Ser Leu Cys Glu 180 185 190 Arg Ala Arg Gln Gly Cys Glu Ala Leu Met Asn Lys Phe Gly Phe Gln 195 200 205 Trp Pro Asp Thr Leu Lys Cys Glu Lys Phe Pro Val His Gly Ala Gly 210 215 220 Glu Leu Cys Val Gly Gln Asn Thr Ser Asp Lys Gly Thr Pro Thr Pro 225 230 235 240 Ser Leu Leu Pro Glu Phe Trp Thr Ser Asn Pro Gln His Gly Gly Gly 245 250 255 Gly His Arg Gly Gly Phe Pro Gly Gly Ala Gly Ala Ser Glu Arg Gly 260 265 270 Lys Phe Ser Cys Pro Arg Ala Leu Lys Val Pro Ser Tyr Leu Asn Tyr 275 280 285 His Phe Leu Gly Glu Lys Asp Cys Gly Ala Pro Cys Glu Pro Thr Lys 290 295 300 Val Tyr Gly Leu Met Tyr Phe Gly Pro Glu Glu Leu Arg Phe Ser Arg 305 310 315 320 227 23 PRT Homo sapiens 227 Thr Trp Ile Gly Ile Trp Ser Val Leu Cys Cys Ala Ser Thr Leu Phe 1 5 10 15 Thr Val Leu Thr Tyr Leu Val 20 228 12 PRT Homo sapiens 228 Asp Met Arg Arg Phe Ser Tyr Pro Glu Arg Pro Ile 1 5 10 229 20 PRT Homo sapiens 229 Ile Phe Leu Ser Gly Cys Tyr Thr Ala Val Ala Val Ala Tyr Ile Ala 1 5 10 15 Gly Phe Leu Leu 20 230 27 PRT Homo sapiens 230 Glu Asp Arg Val Val Cys Asn Asp Lys Phe Ala Glu Asp Gly Ala Arg 1 5 10 15 Thr Val Ala Gln Gly Thr Lys Lys Glu Gly Cys 20 25 231 23 PRT Homo sapiens 231 Thr Ile Leu Phe Met Met Leu Tyr Phe Phe Ser Met Ala Ser Ser Ile 1 5 10 15 Trp Trp Val Ile Leu Ser Leu 20 232 20 PRT Homo sapiens 232 Thr Trp Phe Leu Ala Ala Gly Met Lys Trp Gly His Glu Ala Ile Glu 1 5 10 15 Ala Asn Ser Gln 20 233 23 PRT Homo sapiens 233 Tyr Phe His Leu Ala Ala Trp Ala Val Pro Ala Ile Lys Thr Ile Thr 1 5 10 15 Ile Leu Ala Leu Gly Gln Val 20 234 23 PRT Homo sapiens 234 Asp Gly Asp Val Leu Ser Gly Val Cys Phe Val Gly Leu Asn Asn Val 1 5 10 15 Asp Ala Leu Arg Gly Phe Val 20 235 23 PRT Homo sapiens 235 Leu Ala Pro Leu Phe Val Tyr Leu Phe Ile Gly Thr Ser Phe Leu Leu 1 5 10 15 Ala Gly Phe Val Ser Leu Phe 20 236 20 PRT Homo sapiens 236 Arg Ile Arg Thr Ile Met Lys His Asp Gly Thr Lys Thr Glu Lys Leu 1 5 10 15 Glu Lys Leu Met 20 237 23 PRT Homo sapiens 237 Val Arg Ile Gly Val Phe Ser Val Leu Tyr Thr Val Pro Ala Thr Ile 1 5 10 15 Val Ile Ala Cys Tyr Phe Tyr 20 238 42 PRT Homo sapiens 238 Glu Gln Ala Phe Arg Asp Gln Trp Glu Arg Ser Trp Val Ala Gln Ser 1 5 10 15 Cys Lys Ser Tyr Ala Ile Pro Cys Pro His Leu Gln Ala Gly Gly Gly 20 25 30 Ala Pro Pro His Pro Pro Met Ser Pro Asp 35 40 239 23 PRT Homo sapiens 239 Phe Thr Val Phe Met Ile Lys Tyr Leu Met Thr Leu Ile Val Gly Ile 1 5 10 15 Thr Ser Gly Phe Trp Ile Trp 20 240 25 PRT Homo sapiens 240 Ser Gly Lys Thr Leu Asn Ser Trp Arg Lys Phe Tyr Thr Arg Leu Thr 1 5 10 15 Asn Ser Lys Gln Gly Glu Thr Thr Val 20 25 241 409 PRT Homo sapiens 241 Met Ala Cys Leu Met Ala Ala Phe Ser Val Gly Thr Ala Met Asn Ala 1 5 10 15 Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser 20 25 30 Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu 35 40 45 Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln 50 55 60 Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg 65 70 75 80 Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly 85 90 95 Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu 100 105 110 Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met 115 120 125 Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu 130 135 140 Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys 145 150 155 160 Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu 165 170 175 Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly 180 185 190 Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser 195 200 205 Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg 210 215 220 Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe 225 230 235 240 Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val 245 250 255 Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr 260 265 270 Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr 275 280 285 Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu 290 295 300 Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn 305 310 315 320 Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln 325 330 335 Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp 340 345 350 His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp 355 360 365 His Arg Pro Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser 370 375 380 Phe Ser Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr 385 390 395 400 Phe Leu Ser Ile Met Arg Asp Ser Val 405 242 23 PRT Homo sapiens 242 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 243 12 PRT Homo sapiens 243 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 244 23 PRT Homo sapiens 244 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 245 23 PRT Homo sapiens 245 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 246 23 PRT Homo sapiens 246 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 247 6 PRT Homo sapiens 247 Ser Gln Pro Ser Asp Ala 1 5 248 23 PRT Homo sapiens 248 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 249 9 PRT Homo sapiens 249 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 250 23 PRT Homo sapiens 250 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 251 12 PRT Homo sapiens 251 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 252 18 PRT Homo sapiens 252 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 253 31 PRT Homo sapiens 253 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 254 23 PRT Homo sapiens 254 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 255 8 PRT Homo sapiens 255 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 256 421 PRT Homo sapiens 256 Met Ala Cys Leu Met Ala Ala Phe Ser Val Gly Thr Ala Met Asn Ala 1 5 10 15 Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser 20 25 30 Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu 35 40 45 Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln 50 55 60 Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg 65 70 75 80 Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly 85 90

95 Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu 100 105 110 Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met 115 120 125 Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu 130 135 140 Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys 145 150 155 160 Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu 165 170 175 Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly 180 185 190 Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser 195 200 205 Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg 210 215 220 Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe 225 230 235 240 Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val 245 250 255 Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr 260 265 270 Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr 275 280 285 Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu 290 295 300 Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn 305 310 315 320 Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln 325 330 335 Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp 340 345 350 His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp 355 360 365 His Arg Pro Ser Glu Glu Val Lys Gln Thr Lys Arg Leu Lys Gly Leu 370 375 380 Arg Lys Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser 385 390 395 400 Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile 405 410 415 Met Arg Asp Ser Val 420 257 23 PRT Homo sapiens 257 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 258 12 PRT Homo sapiens 258 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 259 23 PRT Homo sapiens 259 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 260 23 PRT Homo sapiens 260 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 261 23 PRT Homo sapiens 261 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 262 6 PRT Homo sapiens 262 Ser Gln Pro Ser Asp Ala 1 5 263 23 PRT Homo sapiens 263 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 264 9 PRT Homo sapiens 264 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 265 23 PRT Homo sapiens 265 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 266 12 PRT Homo sapiens 266 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 267 18 PRT Homo sapiens 267 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 268 31 PRT Homo sapiens 268 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 269 23 PRT Homo sapiens 269 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 270 8 PRT Homo sapiens 270 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 271 420 PRT Homo sapiens 271 Met Arg Ile Ser Leu Pro Arg Ala Pro Glu Arg Asp Gly Gly Val Ser 1 5 10 15 Ala Ser Ser Leu Leu Asp Thr Val Thr Asn Ala Ser Ser Tyr Ser Ala 20 25 30 Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu Val Val 35 40 45 Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly His Leu 50 55 60 Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser Ser Leu 65 70 75 80 Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser Tyr Ser 85 90 95 Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr Leu Leu 100 105 110 Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala Ile Met 115 120 125 Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu Ala Gly 130 135 140 Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly Leu Pro 145 150 155 160 Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met Gln Asp 165 170 175 Asp Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met Val Ser 180 185 190 Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu Met Val 195 200 205 Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn Thr Arg 210 215 220 Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile Ala Leu 225 230 235 240 Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro Thr Ser 245 250 255 Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met Lys Gly 260 265 270 Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln Pro Ser 275 280 285 Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser Gln Gly 290 295 300 Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr Leu Arg 305 310 315 320 Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp Phe Val 325 330 335 Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg Leu Val 340 345 350 Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg Asp Leu 355 360 365 Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro Ser Glu 370 375 380 Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser Cys 385 390 395 400 Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile Met 405 410 415 Arg Asp Ser Val 420 272 23 PRT Homo sapiens 272 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 273 12 PRT Homo sapiens 273 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 274 23 PRT Homo sapiens 274 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 275 23 PRT Homo sapiens 275 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 276 23 PRT Homo sapiens 276 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 277 6 PRT Homo sapiens 277 Ser Gln Pro Ser Asp Ala 1 5 278 23 PRT Homo sapiens 278 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 279 9 PRT Homo sapiens 279 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 280 23 PRT Homo sapiens 280 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 281 12 PRT Homo sapiens 281 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 282 18 PRT Homo sapiens 282 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 283 31 PRT Homo sapiens 283 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 284 23 PRT Homo sapiens 284 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 285 8 PRT Homo sapiens 285 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 286 411 PRT Homo sapiens 286 Met Leu Gly Thr Gln Gly Trp Thr Lys Gln Arg Lys Pro Cys Pro Gln 1 5 10 15 Asn Ala Ser Ser Tyr Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys 20 25 30 Val Ser Val Asp Glu Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr 35 40 45 Asp Leu Leu Asn Gly His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu 50 55 60 Ala Gln Arg Phe Ser Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu 65 70 75 80 Phe Arg Asp Leu Ser Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys 85 90 95 Lys Gly Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser 100 105 110 Gly Glu Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr 115 120 125 Leu Met Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala 130 135 140 Val Leu Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val 145 150 155 160 Ser Cys Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val 165 170 175 Gln Glu Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp 180 185 190 Glu Gly Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu 195 200 205 Leu Ser Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg 210 215 220 Lys Arg Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met 225 230 235 240 Phe Phe Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln 245 250 255 Val Val Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile 260 265 270 Cys Thr Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln 275 280 285 Leu Tyr Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys 290 295 300 Asn Leu Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr 305 310 315 320 His Asn Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly 325 330 335 Asp Gln Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp 340 345 350 Ser Asp His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe 355 360 365 Leu Trp His Arg Pro Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys 370 375 380 His Ser Phe Ser Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys 385 390 395 400 Arg Thr Phe Leu Ser Ile Met Arg Asp Ser Val 405 410 287 23 PRT Homo sapiens 287 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 288 12 PRT Homo sapiens 288 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 289 23 PRT Homo sapiens 289 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 290 23 PRT Homo sapiens 290 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 291 23 PRT Homo sapiens 291 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 292 6 PRT Homo sapiens 292 Ser Gln Pro Ser Asp Ala 1 5 293 23 PRT Homo sapiens 293 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 294 9 PRT Homo sapiens 294 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 295 23 PRT Homo sapiens 295 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 296 12 PRT Homo sapiens 296 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 297 18 PRT Homo sapiens 297 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 298 31 PRT Homo sapiens 298 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 299 23 PRT Homo sapiens 299 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 300 8 PRT Homo sapiens 300 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 301 387 PRT Homo sapiens 301 Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu Val Val Ser 1 5 10 15 Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly His Leu Lys 20 25 30 Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser Ser Leu Pro 35 40 45 Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser Tyr Ser Val 50 55 60 Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr Leu Leu Lys 65 70 75 80 Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala Ile Met Gly 85 90 95 Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu Ala Gly Tyr 100 105 110 Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly Leu Pro Arg 115 120 125 Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met Gln Asp Asp 130 135 140 Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met Val Ser Ala 145 150 155 160 His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu Met Val Lys 165 170 175 Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn Thr Arg Thr 180 185 190 Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile Ala Leu Glu 195 200 205 Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro Thr Ser Gly 210 215 220 Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met Lys Gly Leu 225 230 235 240 Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln Pro Ser Ala 245 250 255 Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser Gln Gly Gln 260 265 270 Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr Leu Arg Asp 275 280 285 Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp Phe Val Met 290 295 300 Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg Leu Val Arg 305 310 315 320 Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg Asp Leu Gly 325 330 335 Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro Ser Glu Glu 340 345 350 Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala Ser Cys Leu 355 360 365 Thr Gln Phe

Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser Ile Met Arg 370 375 380 Asp Ser Val 385 302 23 PRT Homo sapiens 302 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 303 12 PRT Homo sapiens 303 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 304 23 PRT Homo sapiens 304 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 305 23 PRT Homo sapiens 305 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 306 23 PRT Homo sapiens 306 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 307 6 PRT Homo sapiens 307 Ser Gln Pro Ser Asp Ala 1 5 308 23 PRT Homo sapiens 308 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 309 9 PRT Homo sapiens 309 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 310 23 PRT Homo sapiens 310 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 311 12 PRT Homo sapiens 311 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 312 18 PRT Homo sapiens 312 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 313 31 PRT Homo sapiens 313 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 314 23 PRT Homo sapiens 314 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 315 8 PRT Homo sapiens 315 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 316 406 PRT Homo sapiens 316 Met Ile Met Arg Leu Pro Gln Pro His Gly Thr Asn Ala Ser Ser Tyr 1 5 10 15 Ser Ala Glu Met Thr Glu Pro Lys Ser Val Cys Val Ser Val Asp Glu 20 25 30 Val Val Ser Ser Asn Met Glu Ala Thr Glu Thr Asp Leu Leu Asn Gly 35 40 45 His Leu Lys Lys Val Asp Asn Asn Leu Thr Glu Ala Gln Arg Phe Ser 50 55 60 Ser Leu Pro Arg Arg Ala Ala Val Asn Ile Glu Phe Arg Asp Leu Ser 65 70 75 80 Tyr Ser Val Pro Glu Gly Pro Trp Trp Arg Lys Lys Gly Tyr Lys Thr 85 90 95 Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser Gly Glu Leu Val Ala 100 105 110 Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr Leu Met Asn Ile Leu 115 120 125 Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala Val Leu Ile Asn Gly 130 135 140 Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val Ser Cys Tyr Ile Met 145 150 155 160 Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Gln Glu Ala Met Met 165 170 175 Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp Glu Gly Arg Arg Glu 180 185 190 Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu Leu Ser Cys Ala Asn 195 200 205 Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile 210 215 220 Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro 225 230 235 240 Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met 245 250 255 Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile Cys Thr Ile His Gln 260 265 270 Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln Leu Tyr Val Leu Ser 275 280 285 Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys Asn Leu Val Pro Tyr 290 295 300 Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr His Asn Pro Ala Asp 305 310 315 320 Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly Asp Gln Asn Ser Arg 325 330 335 Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp Ser Asp His Lys Arg 340 345 350 Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe Leu Trp His Arg Pro 355 360 365 Ser Glu Glu Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser Ala 370 375 380 Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu Ser 385 390 395 400 Ile Met Arg Asp Ser Val 405 317 23 PRT Homo sapiens 317 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 318 12 PRT Homo sapiens 318 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 319 23 PRT Homo sapiens 319 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 320 23 PRT Homo sapiens 320 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 321 23 PRT Homo sapiens 321 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 322 6 PRT Homo sapiens 322 Ser Gln Pro Ser Asp Ala 1 5 323 23 PRT Homo sapiens 323 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 324 9 PRT Homo sapiens 324 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 325 23 PRT Homo sapiens 325 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 326 12 PRT Homo sapiens 326 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 327 18 PRT Homo sapiens 327 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 328 31 PRT Homo sapiens 328 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 329 23 PRT Homo sapiens 329 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 330 8 PRT Homo sapiens 330 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 331 567 PRT Homo sapiens 331 Met Leu Ala Val Gln Gln Thr Glu His Leu Pro Ala Cys Pro Pro Ala 1 5 10 15 Arg Arg Trp Ser Ser Asn Phe Cys Pro Glu Ser Thr Glu Gly Gly Pro 20 25 30 Ser Leu Leu Gly Leu Arg Asp Met Val Arg Arg Gly Trp Ser Val Cys 35 40 45 Thr Ala Ile Leu Leu Ala Arg Leu Trp Cys Leu Val Pro Thr His Thr 50 55 60 Phe Leu Ser Glu Tyr Pro Glu Ala Ala Glu Tyr Pro His Pro Gly Trp 65 70 75 80 Val Tyr Trp Leu Gln Met Ala Val Ala Pro Gly His Leu Arg Ala Trp 85 90 95 Val Met Arg Asn Asn Val Thr Thr Asn Ile Pro Ser Ala Phe Ser Gly 100 105 110 Thr Leu Thr His Glu Glu Lys Ala Val Leu Thr Val Phe Thr Gly Thr 115 120 125 Ala Thr Ala Val His Val Gln Val Ala Ala Leu Ala Ser Ala Lys Leu 130 135 140 Glu Ser Ser Val Phe Val Thr Asp Cys Val Ser Cys Lys Ile Glu Asn 145 150 155 160 Val Cys Asp Ser Ala Leu Gln Gly Lys Arg Val Pro Met Ser Gly Leu 165 170 175 Gln Gly Ser Ser Ile Val Ile Met Pro Pro Ser Asn Arg Pro Leu Ala 180 185 190 Ser Ala Ala Ser Cys Thr Trp Ser Val Gln Val Gln Gly Gly Pro His 195 200 205 His Leu Gly Val Val Ala Ile Ser Gly Lys Val Leu Ser Ala Ala His 210 215 220 Gly Ala Gly Arg Ala Tyr Gly Trp Gly Phe Pro Gly Asp Pro Met Glu 225 230 235 240 Glu Gly Tyr Lys Thr Leu Leu Lys Gly Ile Ser Gly Lys Phe Asn Ser 245 250 255 Gly Glu Leu Val Ala Ile Met Gly Pro Ser Gly Ala Gly Lys Ser Thr 260 265 270 Leu Met Asn Ile Leu Ala Gly Tyr Arg Glu Thr Gly Met Lys Gly Ala 275 280 285 Val Leu Ile Asn Gly Leu Pro Arg Asp Leu Arg Cys Phe Arg Lys Val 290 295 300 Ser Cys Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val 305 310 315 320 Gln Glu Ala Met Met Val Ser Ala His Leu Lys Leu Gln Glu Lys Asp 325 330 335 Glu Gly Arg Arg Glu Met Val Lys Glu Ile Leu Thr Ala Leu Gly Leu 340 345 350 Leu Ser Cys Ala Asn Thr Arg Thr Gly Ser Leu Ser Gly Gly Gln Arg 355 360 365 Lys Arg Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met 370 375 380 Phe Phe Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln 385 390 395 400 Val Val Ser Leu Met Lys Gly Leu Ala Gln Gly Gly Arg Ser Ile Ile 405 410 415 Cys Thr Ile His Gln Pro Ser Ala Lys Leu Phe Glu Leu Phe Asp Gln 420 425 430 Leu Tyr Val Leu Ser Gln Gly Gln Cys Val Tyr Arg Gly Lys Val Cys 435 440 445 Asn Leu Val Pro Tyr Leu Arg Asp Leu Gly Leu Asn Cys Pro Thr Tyr 450 455 460 His Asn Pro Ala Asp Phe Val Met Glu Val Ala Ser Gly Glu Tyr Gly 465 470 475 480 Asp Gln Asn Ser Arg Leu Val Arg Ala Val Arg Glu Gly Met Cys Asp 485 490 495 Ser Asp His Lys Arg Asp Leu Gly Gly Asp Ala Glu Val Asn Pro Phe 500 505 510 Leu Trp His Arg Pro Ser Glu Glu Val Lys Gln Thr Lys Arg Leu Lys 515 520 525 Gly Leu Arg Lys Asp Ser Ser Ser Met Glu Gly Cys His Ser Phe Ser 530 535 540 Ala Ser Cys Leu Thr Gln Phe Cys Ile Leu Phe Lys Arg Thr Phe Leu 545 550 555 560 Ser Ile Met Arg Asp Ser Val 565 332 23 PRT Homo sapiens 332 Leu Thr His Leu Arg Ile Thr Ser His Ile Gly Ile Gly Leu Leu Ile 1 5 10 15 Gly Leu Leu Tyr Leu Gly Ile 20 333 12 PRT Homo sapiens 333 Gly Asn Glu Ala Lys Lys Val Leu Ser Asn Ser Gly 1 5 10 334 23 PRT Homo sapiens 334 Phe Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro 1 5 10 15 Thr Val Leu Thr Phe Pro Leu 20 335 23 PRT Homo sapiens 335 Glu Met Gly Val Phe Leu Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu 1 5 10 15 Lys Ala Tyr Tyr Leu Ala Lys 20 336 23 PRT Homo sapiens 336 Thr Met Ala Asp Val Pro Phe Gln Ile Met Phe Pro Val Ala Tyr Cys 1 5 10 15 Ser Ile Val Tyr Trp Met Thr 20 337 6 PRT Homo sapiens 337 Ser Gln Pro Ser Asp Ala 1 5 338 23 PRT Homo sapiens 338 Val Arg Phe Val Leu Phe Ala Ala Leu Gly Thr Met Thr Ser Leu Val 1 5 10 15 Ala Gln Ser Leu Gly Leu Leu 20 339 9 PRT Homo sapiens 339 Ile Gly Ala Ala Ser Thr Ser Leu Gln 1 5 340 23 PRT Homo sapiens 340 Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe 1 5 10 15 Ser Gly Phe Phe Val Ser Phe 20 341 12 PRT Homo sapiens 341 Asp Thr Ile Pro Thr Tyr Leu Gln Trp Met Ser Tyr 1 5 10 342 18 PRT Homo sapiens 342 Ile Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Ser Ile Tyr 1 5 10 15 Gly Leu 343 31 PRT Homo sapiens 343 Asp Arg Glu Asp Leu His Cys Asp Ile Asp Glu Thr Cys His Phe Gln 1 5 10 15 Lys Ser Glu Ala Ile Leu Arg Glu Leu Asp Val Glu Asn Ala Lys 20 25 30 344 23 PRT Homo sapiens 344 Leu Tyr Leu Asp Phe Ile Val Leu Gly Ile Phe Phe Ile Ser Leu Arg 1 5 10 15 Leu Ile Ala Tyr Phe Val Leu 20 345 8 PRT Homo sapiens 345 Arg Tyr Lys Ile Arg Ala Glu Arg 1 5 346 90 PRT Homo sapiens 346 Met Ala Gln Leu Glu Arg Ser Ala Ile Ser Gly Phe Ser Ser Lys Ser 1 5 10 15 Arg Arg Asn Ser Phe Ala Tyr Asp Val Lys Arg Glu Val Tyr Asn Glu 20 25 30 Glu Thr Phe Gln Gln Glu His Lys Arg Lys Ala Ser Ser Ser Gly Asn 35 40 45 Met Asn Ile Asn Ile Thr Thr Phe Arg His His Val Gln Cys Arg Cys 50 55 60 Ser Trp His Arg Phe Leu Arg Cys Val Leu Thr Ile Phe Pro Phe Leu 65 70 75 80 Glu Trp Met Cys Met Tyr Arg Leu Lys Asp 85 90 347 23 PRT Homo sapiens 347 Trp Leu Leu Gly Asp Leu Leu Ala Gly Ile Ser Val Gly Leu Val Gln 1 5 10 15 Val Pro Gln Gly Leu Thr Leu 20 348 5 PRT Homo sapiens 348 Ser Leu Leu Ala Arg 1 5 349 23 PRT Homo sapiens 349 Gln Leu Ile Pro Pro Leu Asn Ile Ala Tyr Ala Ala Phe Cys Ser Ser 1 5 10 15 Val Ile Tyr Val Ile Phe Gly 20 350 6 PRT Homo sapiens 350 Ser Cys His Gln Met Ser 1 5 351 20 PRT Homo sapiens 351 Ile Gly Ser Phe Phe Leu Val Ser Ala Leu Leu Ile Asn Val Leu Lys 1 5 10 15 Val Ser Pro Phe 20 352 29 PRT Homo sapiens 352 Asn Asn Gly Gln Leu Val Met Gly Ser Phe Val Lys Asn Glu Phe Ser 1 5 10 15 Ala Pro Ser Tyr Leu Met Gly Tyr Asn Lys Ser Leu Ser 20 25 353 23 PRT Homo sapiens 353 Val Val Ala Thr Thr Thr Phe Leu Thr Gly Ile Ile Gln Leu Ile Met 1 5 10 15 Gly Val Leu Gly Leu Gly Phe 20 354 12 PRT Homo sapiens 354 Ile Ala Thr Tyr Leu Pro Glu Ser Ala Met Ser Ala 1 5 10 355 23 PRT Homo sapiens 355 Tyr Leu Ala Ala Val Ala Leu His Ile Met Leu Ser Gln Leu Thr Phe 1 5 10 15 Ile Phe Gly Ile Met Ile Ser 20 356 14 PRT Homo sapiens 356 Phe His Ala Gly Pro Ile Ser Phe Phe Tyr Asp Ile Ile Asn 1 5 10 357 23 PRT Homo sapiens 357 Tyr Cys Val Ala Leu Pro Lys Ala Asn Ser Thr Ser Ile Leu Val Phe 1 5 10 15 Leu Thr Val Val Val Ala Leu 20 358 20 PRT Homo sapiens 358 Arg Ile Asn Lys Cys Ile Arg Ile Ser Phe Asn Gln Tyr Pro Ile Glu 1 5 10 15 Phe Pro Met Glu 20 359 18 PRT Homo sapiens 359 Leu Phe Leu Ile Ile Gly Phe Thr Val Ile Ala Asn Lys Ile Ser Met 1 5 10 15 Ala Thr 360 27 PRT Homo sapiens 360 Glu Thr Ser Gln Thr Leu Ile Asp Met Ile Pro Tyr Ser Phe Leu Leu 1 5 10 15 Pro Val Thr Pro Asp Phe Ser Leu Leu Pro Lys 20 25 361 20 PRT Homo sapiens 361 Ile Ile Leu Gln Ala Phe Ser Leu Ser Leu Val Ser Ser Phe Leu Leu 1 5 10 15 Ile Phe Leu Gly 20 362 53 PRT Homo sapiens 362 Lys Lys Ile Ala Ser Leu His Asn Tyr Ser Val Asn Ser Asn Gln Asp 1 5 10 15 Leu Ile Ala Ile Gly Leu Cys Asn Val Val Ser Ser Phe Phe Arg Ser 20 25 30 Cys Val Phe Thr Gly Ala Ile Ala Arg Thr Ile Ile Gln Asp Lys Ser 35 40 45 Gly Gly Arg Gln Gln 50 363 23 PRT Homo sapiens 363 Phe Ala Ser Leu Val Gly Ala Gly Val Met Leu Leu Leu Met Val Lys 1 5 10 15 Met Gly His Phe Phe Tyr Thr 20 364 4 PRT Homo sapiens 364 Leu Pro Asn Ala 1 365 20 PRT Homo sapiens 365 Val Leu Ala Gly Ile Ile Leu Ser Asn Val Ile Pro Tyr Leu Glu Thr 1 5 10 15 Ile Ser Asn Leu

20 366 20 PRT Homo sapiens 366 Pro Ser Leu Trp Arg Gln Asp Gln Tyr Asp Cys Ala Leu Trp Met Met 1 5 10 15 Thr Phe Ser Ser 20 367 23 PRT Homo sapiens 367 Ser Ile Phe Leu Gly Leu Asp Ile Gly Leu Ile Ile Ser Val Val Ser 1 5 10 15 Ala Phe Phe Ile Thr Thr Val 20 368 451 PRT Homo sapiens 368 Arg Ser His Arg Ala Lys Ile Leu Leu Leu Gly Gln Ile Pro Asn Thr 1 5 10 15 Asn Ile Tyr Arg Ser Ile Asn Asp Tyr Arg Glu Ile Ile Thr Ile Pro 20 25 30 Gly Val Lys Ile Phe Gln Cys Cys Ser Ser Ile Thr Phe Val Asn Val 35 40 45 Tyr Tyr Leu Lys His Lys Leu Leu Lys Glu Val Asp Met Val Lys Val 50 55 60 Pro Leu Lys Glu Glu Glu Ile Phe Ser Leu Phe Asn Ser Ser Asp Thr 65 70 75 80 Asn Leu Gln Gly Gly Lys Ile Cys Arg Cys Phe Cys Asn Cys Asp Asp 85 90 95 Leu Glu Pro Leu Pro Arg Ile Leu Tyr Thr Glu Arg Phe Glu Asn Lys 100 105 110 Leu Asp Pro Glu Ala Ser Ser Ile Asn Leu Ile His Cys Ser His Phe 115 120 125 Glu Ser Met Asn Thr Ser Gln Thr Ala Ser Glu Asp Gln Val Pro Tyr 130 135 140 Thr Val Ser Ser Val Ser Gln Lys Asn Gln Gly Gln Gln Tyr Glu Glu 145 150 155 160 Val Glu Glu Val Trp Leu Pro Asn Asn Ser Ser Arg Asn Ser Ser Pro 165 170 175 Gly Leu Pro Asp Val Ala Glu Ser Gln Gly Arg Arg Ser Leu Ile Pro 180 185 190 Tyr Ser Asp Ala Ser Leu Leu Pro Ser Val His Thr Ile Ile Leu Asp 195 200 205 Phe Ser Met Val His Tyr Val Asp Ser Arg Gly Leu Val Val Leu Arg 210 215 220 Gln Ile Cys Asn Ala Phe Gln Asn Ala Asn Ile Leu Ile Leu Ile Ala 225 230 235 240 Gly Cys His Ser Ser Ile Val Arg Ala Phe Glu Arg Asn Asp Phe Phe 245 250 255 Asp Ala Gly Ile Thr Lys Thr Gln Leu Phe Leu Ser Val His Asp Ala 260 265 270 Val Leu Phe Ala Leu Ser Arg Lys Val Ile Gly Ser Ser Glu Leu Ser 275 280 285 Ile Asp Glu Ser Glu Thr Val Ile Arg Glu Thr Tyr Ser Glu Thr Asp 290 295 300 Lys Asn Asp Asn Ser Arg Tyr Lys Met Ser Ser Ser Phe Leu Gly Ser 305 310 315 320 Gln Lys Asn Val Ser Pro Gly Phe Ile Lys Ile Gln Gln Pro Val Glu 325 330 335 Glu Glu Ser Glu Leu Asp Leu Glu Leu Glu Ser Glu Gln Glu Ala Gly 340 345 350 Leu Gly Leu Asp Leu Asp Leu Asp Arg Glu Leu Glu Pro Glu Met Glu 355 360 365 Pro Lys Ala Glu Thr Glu Thr Lys Thr Gln Thr Glu Met Glu Pro Gln 370 375 380 Pro Glu Thr Glu Pro Glu Met Glu Pro Asn Pro Lys Ser Arg Pro Arg 385 390 395 400 Ala His Thr Phe Pro Gln Gln Arg Tyr Trp Pro Met Tyr His Pro Ser 405 410 415 Met Ala Ser Thr Gln Ser Gln Thr Gln Thr Arg Thr Trp Ser Val Glu 420 425 430 Arg Arg Arg His Pro Met Asp Ser Tyr Ser Pro Glu Gly Asn Ser Asn 435 440 445 Glu Asp Val 450 369 57 PRT Homo sapiens 369 Met Asn Pro Phe Gln Lys Asn Glu Ser Lys Glu Thr Leu Phe Ser Pro 1 5 10 15 Val Ser Ile Glu Glu Val Pro Pro Arg Pro Pro Ser Pro Pro Lys Lys 20 25 30 Pro Ser Pro Thr Ile Cys Gly Ser Asn Tyr Pro Leu Ser Ile Ala Phe 35 40 45 Ile Val Val Asn Glu Phe Cys Glu Arg 50 55 370 18 PRT Homo sapiens 370 Phe Ser Tyr Tyr Gly Met Lys Ala Val Leu Ile Leu Tyr Phe Leu Tyr 1 5 10 15 Phe Leu 371 9 PRT Homo sapiens 371 His Trp Asn Glu Asp Thr Ser Thr Ser 1 5 372 23 PRT Homo sapiens 372 Ile Tyr His Ala Phe Ser Ser Leu Cys Tyr Phe Thr Pro Ile Leu Gly 1 5 10 15 Ala Ala Ile Ala Asp Ser Trp 20 373 6 PRT Homo sapiens 373 Leu Gly Lys Phe Lys Thr 1 5 374 23 PRT Homo sapiens 374 Ile Ile Tyr Leu Ser Leu Val Tyr Val Leu Gly His Val Ile Lys Ser 1 5 10 15 Leu Gly Ala Leu Pro Ile Leu 20 375 3 PRT Homo sapiens 375 Gly Gly Gln 1 376 23 PRT Homo sapiens 376 Val Val His Thr Val Leu Ser Leu Ile Gly Leu Ser Leu Ile Ala Leu 1 5 10 15 Gly Thr Gly Gly Ile Lys Pro 20 377 20 PRT Homo sapiens 377 Cys Val Ala Ala Phe Gly Gly Asp Gln Phe Glu Glu Lys His Ala Glu 1 5 10 15 Glu Arg Thr Arg 20 378 20 PRT Homo sapiens 378 Tyr Phe Ser Val Phe Tyr Leu Ser Ile Asn Ala Gly Ser Leu Ile Ser 1 5 10 15 Thr Phe Ile Thr 20 379 14 PRT Homo sapiens 379 Pro Met Leu Arg Gly Asp Val Gln Cys Phe Gly Glu Asp Cys 1 5 10 380 20 PRT Homo sapiens 380 Tyr Ala Leu Ala Phe Gly Val Pro Gly Leu Leu Met Val Ile Ala Leu 1 5 10 15 Val Val Phe Ala 20 381 61 PRT Homo sapiens 381 Met Gly Ser Lys Ile Tyr Asn Lys Pro Pro Pro Glu Gly Asn Ile Val 1 5 10 15 Ala Gln Val Phe Lys Cys Ile Trp Phe Ala Ile Ser Asn Arg Phe Lys 20 25 30 Asn Arg Ser Gly Asp Ile Pro Lys Arg Gln His Trp Leu Asp Trp Ala 35 40 45 Ala Glu Lys Tyr Pro Lys Gln Leu Ile Met Asp Val Lys 50 55 60 382 19 PRT Homo sapiens 382 Ala Leu Thr Arg Val Leu Phe Leu Tyr Ile Pro Leu Pro Met Phe Trp 1 5 10 15 Ala Leu Leu 383 29 PRT Homo sapiens 383 Asp Gln Gln Gly Ser Arg Trp Thr Leu Gln Ala Ile Arg Met Asn Arg 1 5 10 15 Asn Leu Gly Phe Phe Val Leu Gln Pro Asp Gln Met Gln 20 25 384 23 PRT Homo sapiens 384 Val Leu Asn Pro Leu Leu Val Leu Ile Phe Ile Pro Leu Phe Asp Phe 1 5 10 15 Val Ile Tyr Arg Leu Val Ser 20 385 11 PRT Homo sapiens 385 Lys Cys Gly Ile Asn Phe Ser Ser Leu Arg Lys 1 5 10 386 18 PRT Homo sapiens 386 Met Ala Val Gly Met Ile Leu Ala Cys Leu Ala Phe Ala Val Ala Ala 1 5 10 15 Ala Val 387 250 PRT Homo sapiens 387 Glu Ile Lys Ile Asn Glu Met Ala Pro Ala Gln Pro Gly Pro Gln Glu 1 5 10 15 Val Phe Leu Gln Val Leu Asn Leu Ala Asp Asp Glu Val Lys Val Thr 20 25 30 Val Val Gly Asn Glu Asn Asn Ser Leu Leu Ile Glu Ser Ile Lys Ser 35 40 45 Phe Gln Lys Thr Pro His Tyr Ser Lys Leu His Leu Lys Thr Lys Ser 50 55 60 Gln Asp Phe His Phe His Leu Lys Tyr His Asn Leu Ser Leu Tyr Thr 65 70 75 80 Glu His Ser Val Gln Glu Lys Asn Trp Tyr Ser Leu Val Ile Arg Glu 85 90 95 Asp Gly Asn Ser Ile Ser Ser Met Met Val Lys Asp Thr Glu Ser Arg 100 105 110 Thr Thr Asn Gly Met Thr Thr Val Arg Phe Val Asn Thr Leu His Lys 115 120 125 Asp Val Asn Ile Ser Leu Ser Thr Asp Thr Ser Leu Asn Val Gly Glu 130 135 140 Asp Tyr Gly Val Ser Ala Tyr Arg Thr Val Gln Arg Gly Glu Tyr Pro 145 150 155 160 Ala Val His Cys Arg Thr Glu Asp Lys Asn Phe Ser Leu Asn Leu Gly 165 170 175 Leu Leu Asp Phe Gly Ala Ala Tyr Leu Phe Val Ile Thr Asn Asn Thr 180 185 190 Asn Gln Gly Leu Gln Ala Trp Lys Ile Glu Asp Ile Pro Ala Asn Lys 195 200 205 Met Ser Ile Ala Trp Gln Leu Pro Gln Tyr Ala Leu Val Thr Ala Gly 210 215 220 Glu Val Met Phe Ser Val Thr Gly Leu Glu Phe Ser Tyr Ser Gln Ala 225 230 235 240 Pro Ser Gly Met Lys Ser Val Leu Gln Ala 245 250 388 23 PRT Homo sapiens 388 Ala Trp Leu Leu Thr Ile Ala Val Gly Asn Ile Ile Val Leu Val Val 1 5 10 15 Ala Gln Phe Ser Gly Leu Val 20 389 4 PRT Homo sapiens 389 Gln Trp Ala Glu 1 390 23 PRT Homo sapiens 390 Phe Ile Leu Phe Ser Cys Leu Leu Leu Val Ile Cys Leu Ile Phe Ser 1 5 10 15 Ile Met Gly Tyr Tyr Tyr Val 20 391 32 PRT Homo sapiens 391 Pro Val Lys Thr Glu Asp Met Arg Gly Pro Ala Asp Lys His Ile Pro 1 5 10 15 His Ile Gln Gly Asn Met Ile Lys Leu Glu Thr Lys Lys Thr Lys Leu 20 25 30 392 19 DNA Artificial Sequence Synthetic oligonucleotide 392 ataagcggtt atcactgcc 19 393 19 DNA Artificial Sequence Synthetic oligonucleotide 393 gctgggattc caagtggac 19 394 19 DNA Artificial Sequence Synthetic oligonucleotide 394 aactgtgcag ggcctctcc 19 395 19 DNA Artificial Sequence Synthetic oligonucleotide 395 gctgctggat gtcattcac 19 396 19 DNA Artificial Sequence Synthetic oligonucleotide 396 agagacacag tgcccatcc 19 397 19 DNA Artificial Sequence Synthetic oligonucleotide 397 actgaacctc cgaaatgcc 19 398 19 DNA Artificial Sequence Synthetic oligonucleotide 398 gtgctggagt gcttccatc 19 399 19 DNA Artificial Sequence Synthetic oligonucleotide 399 ttcagaccta ccttcagtc 19 400 19 DNA Artificial Sequence Synthetic oligonucleotide 400 gagtcacaca gagatgagc 19 401 19 DNA Artificial Sequence Synthetic oligonucleotide 401 cgatgtgcct tcaagattc 19 402 19 DNA Artificial Sequence Synthetic oligonucleotide 402 cagtggtttg ggaatctgc 19 403 19 DNA Artificial Sequence Synthetic oligonucleotide 403 gtgactacac aaggactcc 19 404 19 DNA Artificial Sequence Synthetic oligonucleotide 404 gactgattcg ctctttgcc 19 405 19 DNA Artificial Sequence Synthetic oligonucleotide 405 agtgcagcct tgtgggttc 19 406 19 DNA Artificial Sequence Synthetic oligonucleotide 406 taacactcac tgcacctgc 19 407 19 DNA Artificial Sequence Synthetic oligonucleotide 407 taactgaaac tcagctagc 19 408 19 DNA Artificial Sequence Synthetic oligonucleotide 408 actgaagtag ccctccttc 19 409 19 DNA Artificial Sequence Synthetic oligonucleotide 409 agtgcagtac agcgatgac 19 410 19 DNA Artificial Sequence Synthetic oligonucleotide 410 ttcacatcgc tgagcaccc 19 411 19 DNA Artificial Sequence Synthetic oligonucleotide 411 agccagcaac gacatgtac 19 412 19 DNA Artificial Sequence Synthetic oligonucleotide 412 gctgctgggc atgtccttc 19 413 19 DNA Artificial Sequence Synthetic oligonucleotide 413 tgtgatcgtc atcacagtc 19 414 19 DNA Artificial Sequence Synthetic oligonucleotide 414 aacatgatat gtgctggac 19 415 19 DNA Artificial Sequence Synthetic oligonucleotide 415 ctgagaaggc ttccactgc 19 416 19 DNA Artificial Sequence Synthetic oligonucleotide 416 tgatacgtgg atccaggcc 19 417 19 DNA Artificial Sequence Synthetic oligonucleotide 417 ctacagtgac aaggctaac 19 418 19 DNA Artificial Sequence Synthetic oligonucleotide 418 gaactggata gccctcatc 19 419 19 DNA Artificial Sequence Synthetic oligonucleotide 419 ccctggtaaa gctgcattc 19 420 19 DNA Artificial Sequence Synthetic oligonucleotide 420 gatgaaggct tcgggcttc 19 421 19 DNA Artificial Sequence Synthetic oligonucleotide 421 tgtaaagctg gaaagggac 19 422 19 DNA Artificial Sequence Synthetic oligonucleotide 422 ctgaagaagc tggagttgc 19 423 19 DNA Artificial Sequence Synthetic oligonucleotide 423 tccttgcagc aggcacatc 19 424 19 DNA Artificial Sequence Synthetic oligonucleotide 424 tctgtgcgtg gactggaac 19 425 19 DNA Artificial Sequence Synthetic oligonucleotide 425 ctttgctcgg aagacgttc 19 426 19 DNA Artificial Sequence Synthetic oligonucleotide 426 gaaggctttg gaaagtgtc 19 427 19 DNA Artificial Sequence Synthetic oligonucleotide 427 gtgaactctg ctgcgactc 19 428 19 DNA Artificial Sequence Synthetic oligonucleotide 428 gacaaggcta tgatgctgc 19 429 19 DNA Artificial Sequence Synthetic oligonucleotide 429 ggatgtgtgg tgctgtcac 19 430 19 DNA Artificial Sequence Synthetic oligonucleotide 430 ctctgtgttc cacttcggc 19 431 19 DNA Artificial Sequence Synthetic oligonucleotide 431 cagcaatgca gagtgtgac 19 432 19 DNA Artificial Sequence Synthetic oligonucleotide 432 caaagctggc tactactac 19 433 19 DNA Artificial Sequence Synthetic oligonucleotide 433 cagtgcaaag agcccaaac 19 434 19 DNA Artificial Sequence Synthetic oligonucleotide 434 gtattctgta caccctggc 19 435 19 DNA Artificial Sequence Synthetic oligonucleotide 435 gtgatcgaca ggattgctc 19 436 19 DNA Artificial Sequence Synthetic oligonucleotide 436 cacagtgaaa ccttcctgc 19 437 19 DNA Artificial Sequence Synthetic oligonucleotide 437 atctgtgaca ctggatcgc 19 438 19 DNA Artificial Sequence Synthetic oligonucleotide 438 agagactgga gttgtcagc 19 439 19 DNA Artificial Sequence Synthetic oligonucleotide 439 cctgagttga atgtcatac 19 440 19 DNA Artificial Sequence Synthetic oligonucleotide 440 ctgaactagt gactatccc 19 441 19 DNA Artificial Sequence Synthetic oligonucleotide 441 ataagcaccg tgagcgacc 19 442 19 DNA Artificial Sequence Synthetic oligonucleotide 442 cattgggcca cagacctac 19 443 19 DNA Artificial Sequence Synthetic oligonucleotide 443 gatgaagaca gcaaccaac 19 444 19 DNA Artificial Sequence Synthetic oligonucleotide 444 agcatatgat gaccttggc 19 445 19 DNA Artificial Sequence Synthetic oligonucleotide 445 attccactac tacagctgc 19 446 19 DNA Artificial Sequence Synthetic oligonucleotide 446 gaaactgtgg caggctaac 19 447 19 DNA Artificial Sequence Synthetic oligonucleotide 447 ctgatgaagg ccttcgacc 19 448 19 DNA Artificial Sequence Synthetic oligonucleotide 448 ttgaaacaag aggaagtcc 19 449 19 DNA Artificial Sequence Synthetic oligonucleotide 449 tgaacttgct ctgagctgc 19 450 19 DNA Artificial Sequence Synthetic

oligonucleotide 450 atctgtaacc tcagcacac 19 451 19 DNA Artificial Sequence Synthetic oligonucleotide 451 gaagctaagc ctcggttac 19 452 19 DNA Artificial Sequence Synthetic oligonucleotide 452 taaccgtggc atctacctc 19 453 19 DNA Artificial Sequence Synthetic oligonucleotide 453 tgaccacctg gagtatcac 19 454 19 DNA Artificial Sequence Synthetic oligonucleotide 454 gtggacatct ttgagcttc 19 455 19 DNA Artificial Sequence Synthetic oligonucleotide 455 gctgagaagt acttccacc 19 456 19 DNA Artificial Sequence Synthetic oligonucleotide 456 agactactgc aagggcggc 19 457 19 DNA Artificial Sequence Synthetic oligonucleotide 457 gagtatttgc tggcattcc 19 458 19 DNA Artificial Sequence Synthetic oligonucleotide 458 ggagacacgg aataaactc 19 459 19 DNA Artificial Sequence Synthetic oligonucleotide 459 ccgagaccac ctcaatgtc 19 460 19 DNA Artificial Sequence Synthetic oligonucleotide 460 atggacatct ccacgggac 19 461 19 DNA Artificial Sequence Synthetic oligonucleotide 461 tatcctgacc ttcctgcgc 19 462 19 DNA Artificial Sequence Synthetic oligonucleotide 462 cacatgatca agctaggtc 19 463 19 DNA Artificial Sequence Synthetic oligonucleotide 463 gaagccaggc atcttcatc 19 464 19 DNA Artificial Sequence Synthetic oligonucleotide 464 gctgaagtta tccagtctc 19 465 19 DNA Artificial Sequence Synthetic oligonucleotide 465 agcattggac cagttgatc 19 466 19 DNA Artificial Sequence Synthetic oligonucleotide 466 gtgatctacg tgaactggc 19 467 19 DNA Artificial Sequence Synthetic oligonucleotide 467 gccgacagtg gtgcactac 19 468 19 DNA Artificial Sequence Synthetic oligonucleotide 468 aacatgatgg ctcagaacc 19 469 19 DNA Artificial Sequence Synthetic oligonucleotide 469 tacagtgatg gatcatagc 19 470 19 DNA Artificial Sequence Synthetic oligonucleotide 470 accaatatgc ctaccttcc 19 471 19 DNA Artificial Sequence Synthetic oligonucleotide 471 actgtatccc agcagtccc 19 472 19 DNA Artificial Sequence Synthetic oligonucleotide 472 aagctgaaca taaccttgc 19 473 19 DNA Artificial Sequence Synthetic oligonucleotide 473 ttgaatagct cggtgtccc 19 474 19 DNA Artificial Sequence Synthetic oligonucleotide 474 gtggaaggca agatcttcc 19 475 19 DNA Artificial Sequence Synthetic oligonucleotide 475 tgtatggctg gtcgatcac 19 476 19 DNA Artificial Sequence Synthetic oligonucleotide 476 gctgcgacaa cttctgttc 19 477 19 DNA Artificial Sequence Synthetic oligonucleotide 477 gcccacggtc ttccactac 19 478 19 DNA Artificial Sequence Synthetic oligonucleotide 478 gactgaatca ggccttccc 19

Claims

1. Method for identifying a compound that induces chondrocyte anabolic stimulation, comprising contacting a compound with a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82 and 198-391; and measuring a compound-polypeptide property related to the anabolic stimulation of chondrocytes.

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

3. The method according to claim 2, wherein said polypeptide is present in a mammalian cell.

4. The method of claim 1, wherein said property is a binding affinity of said compound to said polypeptide.

5. The method of claim 3, wherein said property is activation of a biological pathway producing a biochemical marker indicative of the anabolic stimulation of chondrocytes.

6. The method of claim 5 wherein said indicator is selected from the group consisting of collagen type II, alpha-1 (col2.alpha.1) and aggrecan.

7. The method of claim 6 wherein said polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82.

8. 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: 55-82 and 198-391.

9. The method according to claim 2, wherein said compound is a peptide in a phage display library or an antibody fragment library.

10. An agent for inducing the anabolic stimulation of chondrocytes, 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 encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82 and 198-391.

11. The agent according to claim 10, wherein polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82.

12. The agent according to claim 11, wherein a vector in a mammalian cell expresses said agent.

13. The agent according to claim 12, wherein said vector is an adenoviral, retroviral, adeno-associated viral, lentiviral, a herpes simplex viral or a sendaiviral vector.

14. The agent according to claim 10, 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 encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82.

15. The agent according to claims 14, wherein said siRNA further comprises said sense strand.

16. The agent according to claim 15, 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: 1-28.

17. The agent according to claim 16, wherein said siRNA further comprises a loop region connecting said sense and said antisense strand.

18. The agent according to claim 17, wherein said loop region comprises a nucleic acid sequence defined of SEQ ID NO: 83.

19. The agent according to claim 18, wherein said agent is an antisense polynucleotide, ribozyme, or siRNA comprising a nucleic acid sequence complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 84-197.

20. A chondrocyte anabolic stimulation enhancing pharmaceutical composition comprising a therapeutically effective amount of an agent of claim 10 in admixture with a pharmaceutically acceptable carrier.

21. A method of treating and/or preventing a disease involving a systemic or local decrease in cartilege in a subject suffering from or susceptible to the disease, comprising administering to said subject a pharmaceutical composition according to claim 20.

22. The method according to claim 21 wherein the disease is selected from the group consisting of osteoarthritis, rheumatoid arthritis, psoriatic arthritis, juvenile rheumatoid arthritis, gouty arthritis, septic or infectious arthritis, reactive arthritis, reflex sympathetic dystrophy, algodystrophy, Tietze syndrome or costal chondritis, fibromyalgia, osteochondritis, neurogenic or neuropathic arthritis, arthropathy, osteoarthritis deformans endemica, Mseleni disease, Handigodu disease, degeneration resulting from fibromyalgia, systemic lupus erythematosus, scleroderma, ankylosing spondylitis, hereditary chondrolysis, chondrodysplasias, pseudoachondrodysplasias, microtia, anotia, and metaphyseal chondrodysplasia.

23. The method according to claim 22, wherein the disease is osteoarthritis.

24. Use of an agent according to claims 10-19 in the manufacture of a medicament for the treatment and/or prevention of a disease involving a decrease in mean cartilage thickness.

25. Use according to claim 24, wherein the disease is selected from the group consisting of osteoartnritis, hypercalcemia of malignancy, multiple myelomatosis, hyperparathyroidism, and hyperthyroidism.

26. Use according to claim 25, wherein the disease is osteoarthritis.

27. A method for in vitro production of cartilage tissue, comprising contacting de-differentiated chondrocyte cells with a polynucleotide sequence comprising a nucleic acid sequence complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 1-28 for a time sufficient to re-differentiate the chondrocytes, thereby producing a cartilaginous matrix.

28. A method according to claim 27, comprising: applying a mixture of chondrocytes and de-differentiated chondrocytes on a substrate to form a cellular substrate, and contacting said cells with a polynucleotide sequence comprising a nucleic acid sequence complementary to a polynucleotide selected from the group consisting of SEQ ID NO: 84-197, thereby producing a continuous cartilaginous matrix.

29. A method for diagnosing a pathological condition involving a systemic or local decrease in mean cartilage thickness or a susceptibility to the condition in a subject, comprising determining a first amount of polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 55-82 and 198-391 present in a biological sample obtained from said subject, and comparing said first amount with the ranges of amounts of the polypeptide determined in a population of healthy subjects, wherein an increase of the amount of polypeptide in said biological sample compared to the range of amounts determined for healthy subjects is indicative of the presence of the pathological condition.

30. A method for diagnosing a pathological condition involving chondrocyte de-differentiation, said method comprising the steps of: determining the nucleic acid sequence of any one of the genes of SEQ. ID NOS. 1-28 in a genomic DNA sample; comparing the sequence from step (a) with the nucleic acid sequence of a healthy subject; and identifying any difference(s) related to the pathological condition.

31. A method for diagnosing a pathological condition involving chondrocyte de-differentiation, said method comprising the steps of: determining the amount of any one of the polypeptides of SEQ ID NOS. 55-82 in a sample; and comparing the amount determined in step (a) with the amount of said polypeptide in a sample from a healthy individual; wherein an increase as compared to the sample of the healthy individual is indicative for the onset or presence of said pathological condition.

32. Method according to claim 31, wherein the pathological condition is osteoarthritis.