CA2441654A1 - Cytoskeleton-associated proteins - Google Patents

Abstract

The invention provides human cytoskeleton-associated proteins (CSAP) and polynucleotides which identify and encode CSAP. The invention also providing expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of CSAP.

Description

CYTOSKELETON-ASSOCIATED PROTEINS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of cytoskeleton-associated proteins and to the use of these sequences in the diagnosis, treatment, and prevention of cell proliferative disorders, viral infections, and neurological disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of cytoskeleton-associated proteins.
BACKGROUND OF THE INVENTION
Translocation of components within the cell is critical for maintaining cell structure and function. Cellular components such as proteins and membrane-bound organelles are transported along well-defined routes to specific subcellular compartments. Intracellular transport mechanisms utilize microtubules which are filamentous polymers that serve as tracks for directing the movement of molecules. Molecular transport is driven by the microtubule-based motor proteins, kinesin and dynein. These proteins use the energy derived from ATP hydrolysis to power their movement unidirectionally along microtubules and to transport molecular cargo to specific destinations.
The cytoskeleton is a cytoplasmic network of protein fibers that mediate cell shape, structure, and movement. The cytoskeleton supports the cell membrane and forms tracks along which organelles and other elements move in the cytosol. The cytoskeleton is a dynamic structure that allows cells to adopt various shapes and to carry out directed movements.
Major cytoskeletal fibers include the"microtubules, the microfilaments, and the intermediate filaments.
Motor proteins, including myosin, dynein, and kinesin, drive movement of or along the fibers.
The motor protein dynamin drives the formation of membrane vesicles. Accessory or associated proteins modify the structure or activity of the fibers while cytoskeletal membrane anchors connect the fibers to the cell membrane.
Microtubules and Associated Proteins Tubulins Microtubules, cytoskeletal fibers with a diameter of about 24 nm, have multiple roles in the cell. Bundles of microtubules form cilia and flagella, which are whip-like extensions of the cell membrane that are necessary for sweeping materials across an epithelium and for swimming of sperm, respectively. Marginal bands of microtubules in red blood cells and platelets are important for these cells' pliability. Organelles, membrane vesicles, and proteins are transported in the cell along tracks of microtubules. For example, microtubules run through nerve cell axons, allowing bi-directional transport of materials and membrane vesicles between the cell body and the nerve terminal. Failure to supply the nerve terminal with these vesicles blocks the transmission of neural signals. Microtubules are also critical to chromosomal movement during cell division. Both stable and short-lived populations of microtubules exist in the cell.
Microtubules are polymers of GTP-binding tubulin protein subunits. Each subunit is a heterodimer of a- and [3- tubulin, multiple isoforms of which exist. The hydrolysis of GTP is linked to the addition of tubulin subunits at the end of a microtubule. The subunits interact head to tail to form protofilaments; the protofilaments interact side to side to form a microtubule. A microtubule is polarized, one end ringed with a-tubulin and the other with ~3-tubulin, and the two ends differ in their rates of assembly. Generally, each microtubule is composed of 13 protofilaments although 11 or 15 protofilament-microtubules are sometimes found. Cilia and flagella contain doublet microtubules.
Microtubules grow from specialized structures known as centrosomes or microtubule-organizing centers (MTOCs). MTOCs may contain one or two centrioles, which are pinwheel arrays of triplet microtubules. The basal body, the organizing center located at the base of a cilium or flagellum, contains one centriole. Gamma tubulin present in the MTOC is important for nucleating the polymerization of a- and (3- tubulin heterodimers but does not polymerize into microtubules. The protein pericentrin is found in the MTOC and has a role in microtubule assembly.
Microtubule-Associated Proteins Microtubule-associated proteins (MAPS) have roles in the assembly and stabilization of microtubules. One major family of MAPS, assembly MAPS, can be identified in neurons as well as non-neuronal cells. Assembly MAPs are responsible for cross-linking microtubules in the cytosol.
These MAPS are organized into two domains: a basic microtubule-binding domain and an acidic projection domain. The projection domain is the binding site for membranes, intermediate filaments, or other microtubules. Based on sequence analysis, assembly MAPS can be further grouped into two types: Type I and Type II. Type I MAPs, which include MAP1A and MAP1B, are large, filamentous molecules that co-purify with microtubules and are abundantly expressed in brain and testes. Type I
MAPS contain several repeats of a positively-charged amino acid sequence motif that binds and neutralizes negatively charged tubulin, leading to stabilization of microtubules. MAPlA and MAP1B
are each derived from a single precursor polypeptide that is subsequently proteolytically processed to generate one heavy chain and one light chain.
Another light chain, LC3, is a 16.4 kDa molecule that binds MAP~lA, MAP1B, and microtubules. It is suggested that LC3 is synthesized from a source other than the MAP1A or MAP1B transcripts, and that the expression of LC3 may be important in regulating the microtubule binding activity of MAP1A and MAP1B during cell proliferation (Mann, S.S. et al. (1994) J. Biol.

Chem. 269:11492-11497).
Type II MAPS, which include MAP2a, MAP2b, MAP2c, MAP4, and Tau, are characterized by three to four copies of an 18-residue sequence in the microtubule-binding domain. MAP2a, MAP2b, and MAP2c are found only in dendrites, MAP4 is found in non-neuronal cells, and Tau is found in axons and dendrites of nerve cells. Alternative splicing of the Tau mRNA leads to the existence of multiple forms of Tau protein. Tau phosphorylation is altered in neurodegenerative disorders such as Alzheimer's disease, Pick's disease, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia and Parkinsonism linked to chromosome I7. The altered Tau phosphorylation leads to a collapse of the microtubule network and the formation of intraneuronal Tau aggregates (Spillantini, M.G. and M. Goedert (1998) Trends Neurosci. 21:428-433).
The cytoplasmic linker protein (CLIP-170) links endocytic vesicles to microtubules. CLIP-170 may also link microtubule ends to actin cables, thus playing a role in directional cell movement (Goode, B.L. et al. (2000) Curr. Opin. Cell Biol. 12:63-71). CLIP-170 proteins contain two copies of the CAP-Gly domain, a conserved, glycine-rich domain of about 42 residues found in several cytoskeleton-associated proteins (Prosite PDOC00660 CAP-GIy domain signature).
Another microtubule associated protein, STOP (stable tubule only polypeptide), is a calmodulin-regulated protein that regulates stability (Denarier, E. et al.
(1998) Biochem. Biophys.
Res. Commun. 24:791-796). In order for neurons to maintain conductive connections over great distances, they rely upon axodendritic extensions, which in turn are supported by microtubules.
STOP proteins function to stabilize the microtubular network. STOP proteins are associated with axonal microtubules, and are also abundant in neurons (Guillaud, L. et al.
(1998) J. Cell Biol.
142:167-179). STOP proteins are necessary for normal neurite formation, and have been observed to stabilize microtubules, in vitro, against cold-, calcium-, or drug-induced dissassembly (Margolis, R.L.
et al. (1990) EMBO 9:4095-502).
Microfilaments and Associated Proteins Actins Microfilaments, cytoskeletal filaments with a diameter of about 7-9 nm, are vital to cell locomotion, cell shape, cell adhesion, cell division, and muscle contraction.
Assembly and disassembly of the microfilaments allow cells to change their morphology.
Microfilaments are the polymerized form of actin, the most abundant intracellular protein in the eukaryotic cell. Human cells contain six isoforms of actin. The three a-actins are found in different kinds of muscle, nonmuscle (3-actin and nonmuscle y-actin are found in nonmuscle cells, and another y-actin is found in intestinal smooth muscle cells. G-actin, the monomeric form of actin, polymerizes into polarized, helical F-actin filaments, accompanied by the hydrolysis of ATP to ADP. Actin filaments associate to form bundles and networks, providing a framework to support the plasma membrane and determine cell shape. These bundles and networks are connected to the cell membrane. In muscle cells, thin filaments containing actin slide past thick filaments containing the motor protein myosin during contraction. A family of actin-related proteins exist that are not part of the actin cytoskeleton, but rather associate with microtubules and dynein.
Actin-Associated Proteins Actin-associated proteins have roles in cross-linking, severing, and stabilization of actin filaments and in sequestering actin monomers. Several of the actin-associated proteins have multiple functions. Bundles and networks of actin filaments are held together by actin cross-linking proteins.
These proteins have two actin-binding sites, one for each filament. Short cross-linking proteins promote bundle formation while longer, more flexible cross-linking proteins promote network formation. Actin-interacting proteins (AIPs) participate in the regulation of actin filament organization. Other actin-associated proteins such as TARA, a novel F-actin binding protein, function in a similar capacity by regulating actin cytoskeletal organization.
Calmodulin-like calcium-binding domains in actin cross-linking proteins allow calcium regulation of cross-linking. Group I
cross-linking proteins have unique actin-binding domains and include the 30 kD
protein, EF-la, fascin, and scrum. Group II cross-linking proteins have a 7,000-MW actin-binding domain and include villin and dematin. Group III cross-linking proteins have pairs of a 26,000-MW actin-binding domain and include fimbrin, spectrin, dystrophin, ABP 120, and filamin.
Severing proteins regulate the length of actin filaments by breaking them into short pieces or by blocking their ends. Severing proteins include gCAP39, severin (fragmin), gelsolin, and villin.
Capping proteins can cap the ends of actin filaments, but cannot break filaments. Capping proteins include CapZ and tropomodulin. The proteins thymosin and profilin sequester actin monomers in the cytosol, allowing a pool of unpolymerized actin to exist. The actin-associated proteins tropomyosin, troponin, and caldesmon regulate muscle contraction in response to calcium.
Microtubule and actin filament networks cooperate in processes such as vesicle and organelle transport, cleavage furrow placement, directed cell migration, spindle rotation, and nuclear migration.
lVlicrotubules and actin may coordinate to transport vesicles, organelles, and cell fate determinants, or transport may involve targeting and capture of microtubule ends at cortical actin sites. These cytoskeletal systems may be bridged by myosin-kinesin complexes, myosin-CLIf170 complexes, formin-homology (FIB proteins, dynein, the dynactin complex, I~ar9p, coronin, ERM proteins, and kelch repeat-containing proteins (for a review, see Goode, B.L. et al. (2000) Curr. Opin. Cell Biol.
12:63-71). The ketch repeat is a motif originally observed in the ketch protein, which is involved in formation of cytoplasmic bridges called ring canals. A variety of mammalian and other ketch family proteins have been identified. The ketch repeat domain is believed to mediate interaction with actin (Robinson, D.N. and L. Cooley (1997) J. Cell Biol. 138:799-810).
ADF/cofilins are a family of conserved 15-18 kDa actin-binding proteins that play a role in cytokinesis, endocytosis, and in development of embryonic tissues, as well as in tissue regeneration and in pathologies such as ischemia, oxidative or osmotic stress. LIM kinase 1 downregulates ADF
(Carlier, M.F. et al. (1999) J. Biol. Chem. 274:33827-33830).
The coronins are actin-binding proteins having a structure that contains five WD (Trp-Asp) repeats and is similar to the sequence of the ~i subunits of heterotrimeric G
proteins. Dictyostelium mutants lacking coronin are impaired in all actin-mediated processes, including cell locomotion, cytokinesis, phagocytosis, and macropinocytosis. In human neutrophils, coronin 1 accumulates with F-actin around endocytic vesicles, suggesting an evolutionarily conserved role for coronin in endocytosis. Other coronin proteins have specific activities such as promotion of actin polymerization, actin crosslinking, and binding to microtubules.
LIM is an acronym of three transcription factors, Lin-1 l, Isl-1, and Mec-3, in which the motif was first identified. The LIM domain is a double zinc-forger motif that mediates the protein-protein interactions of transcription factors, signaling, and cytoskeleton-associated proteins (Roof, D.J. et al.
(1997) J. Cell Biol. 138:575-588). These proteins are distributed in the nucleus, cytoplasm, or both (Brown, S. et al. (1999) J. Biol. Chem. 274:27083-27091). Recently, ALP
(actinin-associated LIM
protein) has been shown to bind alpha-actinin-2 (Bouju, S. et al. (1999) Neuromuscul. Disord. 9:3-10).
The Frabin protein is another example of an actin-filament binding protein (Obaishi, H. et al.
(1998) J. Biol. Chem. 273:18697-18700). Frabin (FGD1-related F-actin-binding protein) possesses one actin-filament binding (FAB) domain, one Dbl homology (DH) domain, two pleckstrin homology (PH) domains, and a single cysteine-rich FYVE ( Fablp, YOTB, Vaclp, and EEA1 (early endosomal antigen 1)) domain. Frabin has shown GDP/GTP exchange activity for Cdc42 small G protein (Cdc42), and indirectly induces activation of Rac small G protein (Rac) in intact cells. Through the activation of Cdc42 and Rac, Frabin is able to induce formation of both filopodia- and lamellipodia-like processes (Ono, Y. et al. (2000) Oncogene 19:3050-3058).
The Rho family of small GTP-binding proteins are important regulators of actin-dependent cell functions including cell shape change, adhesion, and motility. The Rho family consists of three major subfamilies: Cdc42, Rac, and Rho. Rho family members cycle between GDP-bound inactive and GTP-bound active forms by means of a GDP/GTP exchange factor (GEF) (Umikawa, M. et al.
(1999) J. Biol. Chem. 274:25197-25200). The Rho GEF family is crucial for microfilament organization.
Intermediate Filaments and Associated Proteins Intermediate filaments (IFs) are cytoskeletal fibers with a diameter of about 10 nm, intermediate between that of microfilaments and microtubules. IFs serve structural roles in the cell, reinforcing cells and organizing cells into tissues. IFs axe particularly abundant in epidermal cells and in neurons. IFs axe extremely stable, and, in contrast to microfilaments and microtubules, do not function in cell motility.
Five types of IF proteins are known in mammals. Type I and Type II proteins are the acidic and basic keratins, respectively. Heterodimers of the acidic and basic keratins are the building blocks of keratin IFs. Keratins are abundant in soft epithelia such as skin and cornea, hard epithelia such as nails and hair, and in epithelia that line internal body cavities. Mutations in keratin genes lead to epithelial diseases including epidermolysis bullosa simplex, bullous congenital ichthyosiform erythroderma (epidermolytic hyperkeratosis), non-epidermolytic and epidermolytic palmoplantar keratoderma, ichthyosis bullosa of Siemens, pachyonychia congenita, and white sponge nevus. Some of these diseases result in severe skin blistering. (See, e.g., Wawersik, M.
et al. (1997) J. Biol. Chem.
272:32557-32565; and Corden L.D. and W.H. McLean (1996) Exp. Dermatol. 5:297-307.) Type III IF proteins include desmin, glial fibrillary acidic protein, vimentin, and peripherin.
Desmin filaments in muscle cells link myofibrils into bundles and stabilize sarcomeres in contracting muscle. Glial fibrillaxy acidic protein filaments are found in the glial cells that surround neurons and astrocytes. Vimentin filaments are found in blood vessel endothelial cells, some epithelial cells, and mesenchymal cells such as fibroblasts, and are commonly associated with microtubules. Vimentin filaments may have roles in keeping the nucleus and other organelles in place in the cell. Type IV IFs include the neurofilaments and nestin. Neurofilaments, composed of three polypeptides, NF-L, NF-M, and NF-H, axe frequently associated with microtubules in axons.
Neurofilaments are responsible for the radial growth and diameter of an axon, and ultimately for the speed of nerve impulse transmission. Changes in phosphorylation and metabolism of neurofilaments are observed in neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson's disease, and Alzheimer's disease (Julien, J.P. and Mushynski, W.E. (1998) Prog. Nucleic Acid Res. Mol. Biol.
61:1-23). Type V IFs, the lamins, are found in the nucleus where they support the nuclear membrane.
IFs have a central a-helical rod region interrupted by short nonhelical linker segments. The rod region is bracketed, in most cases, by non-helical head and tail domains.
The rod regions of intermediate filament proteins associate to form a coiled-coil dimer. A highly ordered assembly process leads from the dimers to the lFs. Neither ATP nor GTP is needed for IF
assembly, unlike that of microfilaments and microtubules.

IF-associated proteins (lFAPs) mediate the interactions of IFs with one another and with other cell structures. lFAPs cross-link IFs into a bundle, into a network, or to the plasma membrane, and may cross-link 1Fs to the microfilament and microtubule cytoskeleton.
Microtubules and IFs are particularly closely associated. IFAPs include BPAG1, plakoglobin, desmoplakin I, desmoplakin II, plectin, ankyrin, filaggrin, and lamin B receptor.
Cytoskeletal-Membrane Anchors Cytoskeletal fibers are attached to the plasma membrane by specific proteins.
These attachments are important for maintaining cell shape and for muscle contraction. In erythrocytes, the spectrin-actin cytoskeleton is attached to the cell membrane by three proteins, band 4.1, ankyrin, and adducin. Defects in this attachment result in abnormally shaped cells which are more rapidly degraded by the spleen, leading to anemia. In platelets, the spectrin-actin cytoskeleton is also linked to the membrane by ankyrin; a second actin network is anchored to the membrane by filamin. In muscle cells the protein dystrophin links actin filaments to the plasma membrane; mutations in the dystrophin gene lead to Duchenne muscular dystrophy.
Focal adhesions Focal adhesions are specialized structures in the plasma membrane involved in the adhesion of a cell to a substrate, such as the extracellular matrix (ECM). Focal adhesions form the connection between an extracellular substrate and the cytoskeleton, and affect such functions as cell shape, cell motility and cell proliferation. Transmembrane integrin molecules form the basis of focal adhesions.
Upon ligand binding, integrins cluster in the plane of the plasma membrane.
Cytoskeletal linker proteins such as the actin binding proteins oc-actinin, talin, tensin, vinculin, paxillin, and filamin are recruited to the clustering site. Key regulatory proteins, such as Rho and Ras family proteins, focal adhesion kinase, and Src family members are also recruited. These events lead to the reorganization of actin filaments and the formation of stress fibers. These intracellular rearrangements promote further integrin-ECM interactions and integrin clustering. Thus, integrins mediate aggregation of protein complexes on both the cytosolic and extracellular faces of the plasma membrane, leading to the assembly of the focal adhesion. Many signal transduction responses are mediated via various adhesion complex proteins, including Sxc, FAK, paxillin, and tensin. (For a review, see Yamada, K.M. and B. Geiger, (1997) Curr. Opin. Cell Biol. 9:76-85.) IFs are also attached to membranes by cytoskeletal-membrane anchors. The nuclear lamina is attached to the inner surface of the nuclear membrane by the lamin B receptor.
Vimentin IFs are attached to the plasma membrane by ankyrin and plectin. Desmosome and hemidesmosome membrane junctions hold together epithelial cells of organs and skin. These membrane junctions allow shear forces to be distributed across the entire epithelial cell layer, thus providing strength and rigidity to the epithelium. IFs in epithelial cells are attached to the desmosome by plakoglobin and desmoplakins. The proteins that link IFs to hemidesmosomes are not known.
Desmin 1Fs surround the sarcomere in muscle and are linked to the plasma membrane by paranemin, synemin, and ankyrin.
Ank, Associations between the cytoskeleton and the lipid membranes bounding intercellular compartments involve spectrin, ankyrin, and integral membrane proteins.
Spectrin is a major component of the cytoskeleton and acts as a scaffolding protein. Similarly, ankyrin acts to tether the actin-spectrin moiety to membranes and to regulate the interaction between the cytoskeleton and membranous compartments. Different ankyrin isoforms are specific to different organelles and provide specificity for this interaction. Ankyrin also contains a regulatory domain that can respond to cellular signals, allowing remodeling of the cytoskeleton during the cell cycle and differentiation (Lambent, S. and Bennett, V. (1993) Eur. J. Biochem. 211:1-6).
Ankyrins have three basic structural components. The N-terminal portion of ankyrin consists of a repeated 33-amino acid motif, the ankyrin repeat, which is involved in specific protein-protein interactions. Variable regions within the motif are responsible for specific protein binding, such that different ankyrin repeats are involved in binding to tubulin, anion exchange protein, voltage-gated sodium channel, Na+/K~-ATPase, and neurofascin. The ankyrin motif is also found in transcription factors, such as NF-x-B, and in the yeast cell cycle proteins CDC10, SW14, and SW16. Proteins involved in tissue differentiation, such as Dros~phila Notch and C. elegans LIN-12 and GLP-l, also contain ankyrin-like repeats. Lux et al. (1990; Nature 344:36-42) suggest that ankyrin-like repeats function as 'built-in' ankyrins and form binding sites for integral membrane proteins, tubulin, and other proteins.
The central domain of ankyrin is required for binding spectrin. This domain consists of an acidic region, primarily responsible for binding spectrin, and a basic region.
Phosphorylation within the central domain may regulate spectrin binding. The C-terminal domain regulates ankyrin function.
The C-terminally-deleted ankyrin, protein 2.2, behaves as a constitutively active ankyrin, displaying increased membrane and spectrin binding. The C-terminal domain is divergent among ankyrin family members, and tissue-specific alternative splicing generates modified C-termini with acidic or basic characteristics (Lambent, supra).
Three ankyrin proteins, ANKl, ANK2, and ANK3, have been described which differ in their tissue-specific and subcellular localization patterns. ANK1, erythrocyte protein 2.1, is involved in protecting red cells from circulatory shear stresses and helping maintain the erythrocyte's unique biconcave shape. An ANK1 deficiency has been linked to hereditary hemolytic anemias, such as hereditary spherocytosis (HS), and a neurodegenerative disorder involving loss of Perkinje cells (Lambert, su ra). ANK2 is the major nervous tissue ankyrin. Two alternative splice variants are generated from the ANK2 gene. Brain ankyrin 1 (brankl), which is expressed in adults, is similar to ANKl in the N-terminal and central domains, but has an entirely dissimilar regulatory domain. An early neuronal form, brank2, includes an additional motif between the spectrin-binding and regulatory domain. An ankyrin homolog in C. elegans, uuc-44, produces alternative splice variants similar to ANK2. Mutations in the unc-44 gene affect the direction of axonal outgrowth (Otsuka, A.J. et al. (1995) J. Cell Biol. 129:1081-1092).
ANK3 consists of four ankyrin isoforms (G100, 6119, 6120, and G195), which localize to intracellular compartments and are implicated in vesicular transport. Ank~119 is associated with the Golgi, has a truncated N-terminal domain, and lacks a C-terminal regulatory domain. Ank~mo and ~CCioo associate with the late endolysosomes in macrophage, lack N-terminal ankyrin repeats, but contain both spectrin-binding and regulatory domains characteristic of ANKl and ANK2. Ankm9s is associated with the trans-Golgi network (TGN). These ankyrin isoforms are part of a spectrin complex which may mediate transport of proteins through the Golgi complex. A
spectrin-ankyrin-adapter protein trafficking system (SAATS) has been proposed for the selective sequestration of membrane proteins into vesicles destined for transport from the ER to the Golgi and beyond. In this model, infra-Golgi, TGN, and plasma membrane transport would involve exchange of SAATS
protein components, including ankyrin isoforms, to specify and distinguish the final destination for vesicular cargo (DeMatteis, M.A. and Morrow, J.S. (1998) Curr. Opin. Cell Biol. 10:542-549).
Motor Proteins Myosin-related Motor Proteins Myosins are actin-activated ATPases, found in eukaryotic cells, that couple hydrolysis of ATP with motion. Myosin provides the motor function for muscle contraction and intracellular movements such as phagocytosis and rearrangement of cell contents during mitotic cell division (cytokinesis). The contractile unit of skeletal muscle, termed the sarcomere, consists of highly ordered arrays of thin actin-containing filaments and thick myosin-containing filaments.
Crossbridges form between the thick and thin filaments, and the ATP-dependent movement of myosin heads within the thick filaments pulls the thin filaments, shortening the sarcomere and thus the muscle fiber.
Myosins are composed of one or two heavy chains and associated light chains.
Myosin heavy chains contain an amino-terminal motor or head domain, a neck that is the site of light-chain binding, and a carboxy-terminal tail domain. The tail domains may associate to form an a-helical coiled coil.
Conventional myosins, such as those found in muscle tissue, are composed of two myosin heavy-chain subunits, each associated with two light-chain subunits that bind at the neck region and play a regulatory role. Unconventional myosins, believed to function in intracellular motion, may contain either one or two heavy chains and associated light chains. There is evidence for about 25 myosin heavy chain genes in vertebrates, more than half of them unconventional.
Dynein-related Motor Proteins Dyneins are (-) end-directed motor proteins which act on microtubules. Two classes of dyneins, cytosolic and axonemal, have been identified. Cytosolic dyneins are responsible for translocation of materials along cytoplasmic microtubules, for example, transport from the nerve terminal to the cell body and transport of endocytic vesicles to lysosomes. As well, viruses often take advantage of cytoplasmic dyneins to be transported to the nucleus and establish a successful infection (Sodeik, B. et al. (1997) J. Cell Biol. 136:1007-1021). Virion proteins of herpes simplex virus l, for example, interact with the cytoplasmic dynein intermediate chain (Ye, G.J. et al. (2000) J. Virol.
74:1355-1363). Cytoplasmic dyneins are also reported to play a role in mitosis. Axonemal dyneins are responsible for the beating of flagella and cilia. Dynein on one microtubule doublet walks along the adjacent microtubule doublet. This sliding force produces bending that causes the flagellum or I5 cilium to beat. Dyneins have a native mass between 1000 and 2000 kDa and contain either two or three force-producing heads driven by the hydrolysis of ATP. The heads are linked via stalks to a basal domain which is composed of a highly variable number of accessory intermediate and light chains. Cytoplasmic dynein is the largest and most complex of the motor proteins.
Kinesin-related Motor Proteins Kinesins are (+) end-directed motor proteins which act on microtubules. The prototypical kinesin molecule is involved in the transport of membrane-bound vesicles and organelles. This function is particularly important for axonal transport in neurons. Kinesin is also important in all cell types for the transport of vesicles from the Golgi complex to the endoplasmic reticulum. This role is critical for maintaining the identity and functionality of these secretory organelles.
Kinesins define a ubiquitous, conserved family of over 50 proteins that can be classified into at least 8 subfamilies based on primary amino acid sequence, domain structure, velocity of movement, and cellular function. (Reviewed in Moore, J.D. and S.A. Endow (1996) Bioessays 18:207-219; and Hoyt, A.M. (1994) Curr. Opin. Cell Biol. 6:63-68.) The prototypical kinesin molecule is a heterotetramer comprised of two heavy polypeptide chains (KHCs) and two light polypeptide chains (KLCs). The KHC subunits are typically referred to as "kinesin." KHC is about 1000 amino acids in length, and KLC is about 550 amino acids in length. Two KHCs dimerize to form a rod-shaped molecule with three distinct regions of secondary structure. At one end of the molecule is a globular motor domain that functions in ATP hydrolysis and microtubule binding. Kinesin motor domains are highly conserved and share over 70% identity. Beyond the motor domain is an a-helical coiled-coil IO

region which mediates dimerization. At the other end of the molecule is a fan-shaped tail that associates with molecular cargo. The tail is formed by the interaction of the KHC C-termini with the two I~LCs.
Members of the more divergent subfamilies of kinesins are called kinesin-related proteins (KRPs), many of which function during mitosis in eukaryotes (Hoyt, supra).
Some KRPs are required for assembly of the mitotic spindle. In vivo and in vitro analyses suggest that these I~RPs exert force on microtubules that comprise the mitotic spindle, resulting in the separation of spindle poles.
Phosphorylation of KRP is required for this activity. Failure to assemble the mitotic spindle results in abortive mitosis and chromosomal aneuploidy, the latter condition being characteristic of cancer cells.
In addition, a unique KRP, centromere protein E, localizes to the kinetochore of human mitotic chromosomes and may play a role in their segregation to opposite spindle poles.
Dynamin-related Motor Proteins Dynamin is a large GTPase motor protein that functions as a "molecular pinchase,"
generating a mechanochemical force used to sever membranes. This activity is important in forming clathrin-coated vesicles from coated pits in endocytosis and in the biogenesis of synaptic vesicles in neurons. Binding of dynamin to a membrane leads to dynamin's self assembly into spirals that may act to constrict a flat membrane surface into a tubule. GTP hydrolysis induces a change in conformation of the dynamin polymer that pinches the membrane tubule, leading to severing of the membrane tubule and formation of a membrane vesicle. Release of GDP and inorganic phosphate leads to dynamin disassembly. Following disassembly the dynamin may either dissociate from the membrane or remain associated to the vesicle and be transported to another region of the cell. Three homologous dynamin genes have been discovered, in addition to several dynamin-related proteins.
Conserved dynamin regions are the N-terminal GTP-binding domain, a central pleckstrin homology domain that binds membranes, a central coiled-coil region that may activate dynamin's GTPase activity, and a C-terminal proline-rich domain that contains several motifs that bind SH3 domains on other proteins. Some dynamin-related proteins do not contain the pleckstrin homology domain or the proline-rich domain. (See McNiven, M.A. (1998) Cell 94:151-154; Scaife, R.M.
and R.L. Margolis (1997) Cell. Signal. 9:395-401.) The cytoskeleton is reviewed in Lodish, H. et al. (1995) Molecular Cell Biolo~y, Scientific American Books, New York NY.
Expression profiling Array technology can provide a simple way to explore the expression of a single polymorphic gene or the expression profile of a large number of related or unrelated genes. When the expression of a single gene is examined, arrays are employed to detect the expression of a specific gene or its variants. When an expression profile is examined, arrays provide a platform for identifying genes that are tissue specific, are affected by a substance being tested in a toxicology assay, are part of a signaling cascade, carry out housekeeping functions, or are specifically related to a particular genetic predisposition, condition, disease, or disorder.
Lung cancer is the leading cause of cancer death for men and the second leading cause of cancer death for women in the U.S. The vast majority of lung cancer cases are attributed to smoking tobacco, and increased use of tobacco products in third world countries is projected to lead to an epidemic of lung cancer in these countries. Exposure of the bronchial epithelium to tobacco smoke appears to result in changes in tissue morphology, which are thought to be precursors of cancer. Lung cancers are divided into four histopathologically distinct groups. Three groups (squamous cell carcinoma, adenocarcinoma, and large cell carcinoma) are classified as non-small cell lung cancers (NSCLCs). The fourth group of cancers is referred to as small cell lung cancer (SCLC).
Collectively, NSCLCs account for ~70% of cases while SCLCs account for ~18% of cases. The molecular and cellular biology underlying the development and progression of lung cancer are incompletely understood. Analysis of gene expression patterns associated with the development and progression of the disease will yield tremendous insight into the biology underlying this disease, and will lead to the development of improved diagnostics and therapeutics.
The discovery of new cytoskeleton-associated proteins, and the polynucleotides encoding them, satisfies a need in the art by providing new compositions which are useful in the diagnosis, prevention, and treatment of cell proliferative disorders, viral infections, and neurological disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of cytoskeleton-associated proteins.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, cytoskeleton-associated proteins, referred to collectively as "CSAP" and individually as "CSAP-l," "CSAP-2," "CSAP-3," "CSAP-4," "CSAP-5,"
"CSAP-6," "CSAP-7," "CSAP-8," "CSAP-9," "CSAP-10," "CSAP-I I," "CSAP-12,"
"CSAP-13,"
"CSAP-14," "CSAP-15," "CSAP-16," "CSAP-17," "CSAP-18," "CSAP-19," "CSAP-20,"
"CSAP-21," "CSAP-22," "CSAP-23," "CSAP-24," "CSAP-25," "CSAP-26," "CSAP-27," and "CSAP-28."
In one aspect, the invention provides an isolated polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ m NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ
ll~ NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group 12' consisting of SEQ >D NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D NO:1-28. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ >D N0:1-28.
The invention further provides an isolated polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ >D NO: l-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ
)D N0:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D NO: l-28.
In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ ID NO:1-28. In another alternative, the polynucleotide is selected from the group consisting of SEQ ID N0:29-56.
Additionally, the invention provides a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ll~ NO:1-2,8, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ )D NO:1-28. In one alternative, the invention provides a cell transformed with the recombinant polynucleotide. In another alternative, the invention provides a transgenic organism comprising the recombinant polynucleotide.
The invention also provides a method for producing a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ >D NO: l-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ )D NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO: l-28. The method comprises a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide encoding the polypeptide, and b) recovering the polypeptide so expressed.
Additionally, the invention provides an isolated antibody which specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ m NO: l-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ m NO: l-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ m NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ m NO:1-28.
The invention further provides an isolated polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ )D N0:29-56, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID
N0:29-56, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d).
In one alternative, the polynucleotide comprises at least 60 contiguous nueleotides.
Additionally, the invention provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynueleotide sequence selected from the group consisting of SEQ ID NO:29-56, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:29-56, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA
equivalent of a)-d). The method comprises a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and optionally, if present, the amount thereof. In one alternative, the probe comprises at least 60 contiguous nucleotides.
The invention further provides a method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide selected from the group consisting of a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:29-56, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ m N0:29-56, c) a polynucleotide complementary to the polynucleotide of a), d) a polynucleotide complementary to the polynucleotide of b), and e) an RNA equivalent of a)-d).
The method comprises a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.
The invention further provides a composition comprising an effective amount of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ m N0:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-28, and a pharmaceutically acceptable excipient. In one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID N0:1-28. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional CSAP, comprising administering to a patient in need of such treatment the composition.
The invention also provides a method for screening a compound for effectiveness as an agonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ~ NO:1-28. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting agonist activity in the sample. In one alternative, the invention provides a composition comprising an agonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with decreased expression of functional CSAP, comprising administering to a patient in need of such treatment the composition.
Additionally, the invention provides a method for screening a compound for effectiveness as an antagonist of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ >D NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ll~ NO:1-28. The method comprises a) exposing a sample comprising the polypeptide to a compound, and b) detecting antagonist activity in the sample.
In one alternative, the invention provides a composition comprising an antagonist compound identified by the method and a pharmaceutically acceptable excipient. In another alternative, the invention provides a method of treating a disease or condition associated with overexpression of functional CSAP, comprising administering to a patient in need of such treatment the composition.
The invention further provides a method of screening for a compound that specifically binds to a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ m NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90°lo identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected fxom the group consisting of SEQ m NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ >D NO:1-28. The method comprises a) combining the polypeptide with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide to the test compound, thereby identifying a compound that specifically binds to the polypeptide.
The invention further provides a method of screening for a compound that modulates the activity of a polypeptide selected from the group consisting of a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: l-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90% identical to an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-28, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ m NO:1-28. The method comprises a) combining the polypeptide with at least one test compound under conditions permissive for the activity of the polypeptide, b) assessing the activity of the polypeptide in the presence of the test compound, and c) comparing the activity of the polypeptide in the presence of the test compound with the activity of the polypeptide in the absence of the test compound, wherein a change in the activity of the polypeptide in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide.
The invention further provides a method for screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a polynucleotide sequence selected from the group consisting of SEQ ID N0:29-56, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.
The invention further provides a method for assessing toxicity of a test compound, said method comprising a) treating a biological sample containing nucleic acids with the test compound;
b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ
ID N0:29-56, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:29-56, iii) a polynucleotide having a sequence complementary to i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Hybridization occurs under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide selected from the group consisting of i) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ m N0:29-56, ii) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90%
identical to a polynucleotide sequence selected from the group consisting of SEQ ID N0:29-56, iii) a polynucleotide complementary to the polynucleotide of i), iv) a polynucleotide complementary to the polynucleotide of ii), and v) an RNA equivalent of i)-iv). Alternatively, the target polynucleotide comprises a fragment of a polynucleotide sequence selected from the group consisting of i)-v) above;
c) quantifying the amount of hybridization complex; and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.
BRIEF DESCRIPTION OF THE TABLES
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the present invention.
Table 2 shows the GenBank identification number and annotation of the nearest GenBank homolog for polypeptides of the invention. The probability scores for the matches between each polypeptide and its homolog(s) are also shown.
Table 3 shows structural features of polypeptide sequences of the invention, including predicted motifs and domains, along with the methods, algorithms, and searchable databases used for analysis of the polypeptides.
Table 4 lists the cDNA and/or genomic DNA fragments which were used to assemble polynucleotide sequences of the invention, along with selected fragments of the polynucleotide sequences.
Table 5 shows the representative cDNA library for polynucleotides of the invention.
Table 6 provides an appendix which describes the tissues and vectors used for construction of the cDNA libraries shown in Table 5.
Table 7 shows the tools, programs, and algorithms used to analyze the polynucleotides and polypeptides of the invention, along with applicable descriptions, references, and threshold parameters.
DESCRIPTION OF THE INVENTION
Before the present proteins, nucleotide sequences, and methods are described, it is understood that this invention is not limited to the. particular machines, materials and methods described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
It must be noted that as used herein and in the appended claims, the singular forms "a," "an,"
and "the" include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to "a host cell" includes a plurality of such host cells, and a reference to "an antibody" is a reference to one or more antibodies and equivalents thereof known to those skilled in the art, and so forth.
Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs.
Although any machines, materials, and methods similar or equivalent to those described herein can be used to practice or test the present invention, the preferred machines, materials and methods are now described. All publications mentioned herein are cited for the purpose of describing and disclosing the cell lines, protocols, reagents and vectors which are reported in the publications and which might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.
DEFINITIONS
"CSAP" refers to the amino acid sequences of substantially purred CSAP
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, marine, equine, and human, and from any source, whether natural, synthetic, semi-synthetic, or recombinant.

The term "agonist" refers to a molecule which intensifies or mimics the biological activity of CSAP. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of CSAP either by directly interacting with CSAP or by acting on components of the biological pathway in which CSAP
participates.
An "allelic variant" is an alternative form of the gene encoding CSAP. Allelic variants may result from at least one mutation in the nucleic acid sequence and may result in altered mRNAs or in polypeptides whose structure or function may or may not be altered. A gene may have none, one, or many allelic variants of its naturally occurring form. Common mutational changes which give rise to allelic variants are generally ascribed to natural deletions, additions, or substitutions of nucleotides.
Each of these types of changes may occur alone, or in combination with the others, one or more times in a given sequence.
"Altered" nucleic acid sequences encoding CSAP include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as CSAP or a polypeptide with at least one functional characteristic of CSAP. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding CSAP, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding CSAP. The encoded protein may also be "altered," and may contain deletions, insertions, or substitutions of amino acid residues which produce a silent change and result in a functionally equivalent CSAP. Deliberate amino acid substitutions may be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity, and/or the amphipathic nature of the residues, as long as the biological or immunological activity of CSAP is retained. For example, negatively charged amino acids may include aspartic acid and glutamic acid, and positively charged amino acids may include lysine and arginine. Amino acids with uncharged polar side chains having similar hydrophilicity values may include: asparagine and glutamine; and serine and threonine.
Amino acids with uncharged side chains having similar hydrophilicity values may include: leucine, isoleucine, and valine; glycine and alanine; and phenylalanine and tyrosine.
The terms "amino acid" and "amino acid sequence" refer to an oligopeptide, peptide, polypeptide, or protein sequence, or a fragment of any of these, and to naturally occurnng or synthetic molecules. Where "amino acid sequence" is recited to refer to a sequence of a naturally occurring protein molecule, "amino acid sequence" and like terms are not meant to limit the amino acid sequence to the complete native amino acid sequence associated with the recited protein molecule.
"Amplification" relates to the production of additional copies of a nucleic acid sequence.
Amplification is generally carried out using polymerase chain reaction (PCR) technologies well known in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of CSAP. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of CSAP either by directly interacting with CSAP or by acting on components of the biological pathway in which CSAP
participates.
The term "antibody" refers to intact immunoglobulin molecules as well as to fragments thereof, such as Fab, F(ab')2, and Fv fragments, which are capable of binding an epitopic determinant.
Antibodies that bind CSAP polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used to immunize an animal (e.g., a mouse, a rat, or a rabbit) can be derived from the translation of RNA, or synthesized chemically, and can be conjugated to a carrier protein if desired. Commonly used Garners that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KLH). The coupled peptide is then used to immunize the animal.
The term "antigenic determinant" refers to that region.of a molecule (i.e., an epitope) that makes contact with a particular antibody. When a protein or a fragment of a protein is used to immunize a host animal, numerous regions of the protein may induce the production of antibodies which bind specifically to antigenic determinants (particular regions or three-dimensional structures on the protein). An antigenic determinant may compete with the intact antigen (i.e., the immunogen used to elicit the immune response) fox binding to an antibody.
The term "aptamer" refers to a nucleic acid or oligonucleotide molecule that binds to a specific molecular target. Aptamers are derived from an in vitro evolutionary process (e.g., SELEX
(Systematic Evolution of Ligands by EXponential Enrichment), described in U.S.
Patent No.
5,270,163), which selects for target-specific aptamer sequences from large combinatorial libraries.
Aptamer compositions may be double-stranded or single-stranded, and may include deoxyribonucleotides, ribonucleotides, nucleotide derivatives, or other nucleotide-like molecules.
The nucleotide components of an aptamer may have modified sugar groups (e.g., the 2'-OH group of a ribonucleotide may be replaced by 2'-F or 2'-NHZ), which may improve a desired property, e.g., resistance to nucleases or longer lifetime in blood. Aptamers may be conjugated to other molecules, e.g., a high molecular weight carrier to slow clearance of the aptamer from the circulatory system.
Aptamers may be specifically cross-linked to their cognate ligands, e.g., by photo-activation of a cross-linker. (See, e.g., Brody, E.N. and L. Gold (2000) J. Biotechnol. 74:5-13.) The term "intramer" refers to an aptamer which is expressed in vivo. For example, a vaccinia virus-based RNA expres sion system has been used to express specific RNA
aptamers at high levels in the cytoplasm of leukocytes (Blind, M. et al. (1999) Proc. Natl Acad. Sci. USA
96:3606-3610).
The term "spiegelmer" refers to an aptamer which includes L-DNA, L-RNA, or other left-handed nucleotide derivatives or nucleotide-like molecules. Aptamers containing left-handed nucleotides are resistant to degradation by naturally occurring enzymes, which normally act on substrates containing right-handed nucleotides.
The term "antisense" refers to any composition capable of base-pairing with the "sense"
(coding) strand of a specific nucleic acid sequence. Antisense compositions may include DNA;
RNA; peptide nucleic acid (PNA); oligonucleotides having modified backbone linkages such as phosphorothioates, methylphosphonates, or benzylphosphonates; oligonucleotides having modified sugar groups such as 2'-methoxyethyl sugars or 2'-methoxyethoxy sugars; or oligonucleotides having modified bases such as 5-methyl cytosine, 2'-deoxyuracil, or 7-deaza-2'-deoxyguanosine. Antisense molecules may be produced by any method including chemical synthesis or transcription. Once introduced into a cell, the complementary antisense molecule base-pairs with a naturally occurring nucleic acid sequence produced by the cell to form duplexes which block either transcription or translation. The designation "negative" or "minus" can refer to the antisense strand, and the designation "positive" or "plus" can refer to the sense strand of a reference DNA molecule.
The term "biologically active" refers to a protein having structural, regulatory, or biochemical functions of a naturally occurring molecule. Likewise, "immunologically active" or "immunogenic"
refers to the capability of the natural, recombinant, or synthetic CSAP, or of any oligopeptide thereof, to induce a specific immune response in appropriate animals or cells and to bind with specific antibodies.
"Complementary" describes the relationship between two single-stranded nucleic acid sequences that anneal by base-pairing. For example, 5'-AGT-3' pairs with its complement, 3'-TCA-5'.
A "composition comprising a given polynucleotide sequence" and a "composition comprising a given amino acid sequence" refer broadly to any composition containing the given polynucleotide or amino acid sequence. The composition may comprise a dry formulation or an aqueous solution.
Compositions comprising polynucleotide sequences encoding CSAP or fragments of CSAP may be employed as hybridization probes. The probes may be stored in freeze-dried form and may be associated with a stabilizing agent such as a carbohydrate. In hybridizations, the probe may be deployed in an aqueous solution containing salts (e.g., NaCI), detergents (e.g., sodium dodecyl sulfate; SDS), and other components (e.g., Denhardt's solution, dry milk, salmon sperm DNA, etc.).
"Consensus sequence" refers to a nucleic acid sequence which has been subjected to repeated DNA sequence analysis to resolve uncalled bases, extended using the XL-PCR kit (Applied Biosystems, Foster City CA) in the 5' andlor the 3' direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genomic DNA fragments using a computer program for fragment assembly, such as the GELVIEW fragment assembly system (GCG, Madison WI) or Phrap (University of Washington, Seattle WA). Some sequences have been both extended and assembled to produce the consensus sequence.
"Conservative amino acid substitutions" are those substitutions that are predicted to least interfere with the properties of the original protein, i.e., the structure and especially the function of the protein is conserved and not significantly changed by such substitutions.
The table below shows amino acids which may be substituted for an original amino acid in a protein and which are regarded as conservative amino acid substitutions.
Original Residue Conservative Substitution Ala Gly, Ser Arg His, Lys Asn Asp, Gln, His Asp Asn, Glu Cys Ala, Ser Gln Asn, Glu, His Glu Asp, Gln, His Gly Ala His Asn, Arg, Gln, Glu Ile Leu, Val Leu Ile, Val Lys Arg, Gln, Glu Met ' Leu, Ile Phe His, Met, Leu, Trp, Tyr Ser Cys, Tllr Thr Ser, Val Trp Phe, Tyr Tyr His, Phe, Trp Val Ile, Leu, Thr Conservative amino acid substitutions generally maintain (a) the structure of the polypeptide backbone in the area of the substitution, for example, as a beta sheet or alpha helical conformation, (b) the charge or hydrophobicity of the molecule at the site of the substitution, and/or (c) the bulk of the side chain.
A "deletion" refers to a change in the amino acid or nucleotide sequence that results in the absence of one or more amino acid residues or nucleotides.
The term "derivative" refers to a chemically modified polynucleotide or polypeptide.
Chemical modifications of a polynucleotide can include, for example, replacement of hydrogen by an alkyl, acyl, hydroxyl, or amino group. A derivative polynucleotide encodes a polypeptide which retains at least one biological or immunological function of the natural molecule. A derivative polypeptide is one modified by glycosylation, pegylation, or any similar process that retains at least one biological or immunological function of the polypeptide from which it was derived.
A "detectable label" refers to a reporter molecule or enzyme that is capable of generating a measurable signal and is covalently or noncovalently joined to a polynucleotide or polypeptide.
"Differential expression" refers to increased or upregulated; or decreased, downregulated, or absent gene or protein expression, determined by comparing at least two different samples. Such comparisons may be carried out between, for example, a treated and an untreated sample, or a diseased and a normal sample.
"Exon shuffling" refers to the recombination of different coding regions (exons). Since an exon may represent a structural or functional domain of the encoded protein, new proteins may be assembled through the novel reassortment of stable substructures, thus allowing acceleration of the evolution of new protein functions.
A "fragment" is a unique portion of CSAP or the polynucleotide encoding CSAP
which is identical in sequence to but shorter in length than the parent sequence. A
fragment may comprise up to the entire length of the defined sequence, minus one nucleotide/amino acid residue. For example, a fragment may comprise from 5 to 1000 contiguous nucleotides or amino acid residues. A fragment used as a probe, primer, antigen, therapeutic molecule, or for other purposes, may be at least 5, 10, 15, 16, 20, 25, 30, 40, 50, 60, 75, 100, 150, 250 or at least 500 contiguous nucleotides or amino acid residues in length. Fragments may be preferentially selected from certain regions of a molecule. For example, a polypeptide fragment may comprise a certain length of contiguous amino acids selected from the first 250 or 500 amino acids (or first 25% or 50%) of a polypeptide as shown in a certain defined sequence. Clearly these lengths are exemplary, and any length that is supported by the specification, including the Sequence Listing, tables, and figures, may be encompassed by the present.
embodiments.
A fragment of SEQ m N0:29-56 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:29-56, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ )I~ N0:29-56 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ZD N0:29-56 from related polynucleotide sequences. The precise length of a fragment of SEQ
m N0:29-56 and the region of SEQ ID N0:29-56 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ 1D NO:1-28 is encoded by a fragment of SEQ ID N0:29-56. A
fragment of SEQ m NO:1-28 comprises a region of unique amino acid sequence that specifically identifies SEQ m NO:1-28. For example, a fragment of SEQ m NO: l-28 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ll~ NO:1-28.
The precise length of a fragment of SEQ m NO:1-28 and the region of SEQ ID N0:1-28 to which the fragment corresponds are routinely determinable by one of ordinary skill in the art based on the intended purpose for the fragment.
A "full length" polynucleotide sequence is one containing at least a translation initiation colon (e.g., methionine) followed by an open reading frame and a translation termination colon. A
"full length" polynucleotide sequence encodes a "full length" polypeptide sequence.
"Homology" refers to sequence similarity or, interchangeably, sequence identity, between two or more polynucleotide sequences or two or more polypeptide sequences.
The terms "percent identity" and "% identity," as applied to polynucleotide sequences, refer to the percentage of residue matches between at least two polynucleotide sequences aligned using a standardized algorithm. Such an algoritlun may insert, in a standardized and reproducible way, gaps in the sequences being compared in order to optimize alignment between two sequences, and therefore achieve a more meaningful comparison of the two sequences.
Percent identity between polynucleotide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program. This program is part of the LASERGENE software package, a suite of molecular biological analysis programs (DNASTAR, Madison WI). CLUSTAL V is described in Higgins, D.G. and P.M. Sharp (1989) CABIOS 5:151-153 and in Higgins, D.G. et al. (1992) CABIOS
8:189-191. For pairwise alignments of polynucleotide sequences, the default parameters are set as follows: Ktuple=2, gap penalty=5, window=4, and "diagonals saved"=4. The "weighted" residue weight table is selected as the default. Percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polynucleotide sequences.
Alternatively, a suite of commonly used and freely available sequence comparison algorithms is provided by the National Center for Biotechnology Information (NCBI) Basic Local Alignment Search Tool (BLAST) (Altschul, S.F. et al. (1990) J. Mol. Biol. 215:403-410), which is available from several sources, including the NCBI, Bethesda, MD, and on the Internet at http://www.ncbi.nlm.nih.gov/BLAST/. The BLAST software suite includes various sequence analysis programs including "blastn," that is used to align a known polynucleotide sequence with other polynucleotide sequences from a variety of databases. Also available is a tool called "BLAST 2 Sequences" that is used for direct pairwise comparison of two nucleotide sequences. "BLAST 2 Sequences" can be accessed and used interactively at http://www.ncbi.nlm.nih.gov/gorf/bl2.html.
The "BLAST 2 Sequences" tool can be used for both blastn and blastp (discussed below). BLAST
programs are commonly used with gap and other parameters set to default settings. For example, to compare two nucleotide sequences, one may use blastn with the "BLAST 2 Sequences" tool Version 2Ø12 (April-21-2000) set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Reward for fzzatch: 1 Penalty for mismatch: -2 Operz Gap: 5 arzd Extension Gap: 2 penalties Gap x drop-off. 50 Expect: 10 Word Size: I1 Filter: orz Percent identity may be measured over the length of an entire defined sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined sequence, for instance, a fragment of at Ieast 20, at least 30, at least 40, at Ieast 50, at Ieast 70, at least 100, or at least 200 contiguous nucleotides. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures, or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
Nucleic acid sequences that do not show a high degree of identity may nevertheless encode similar amino acid sequences due to the degeneracy of the genetic code. It is understood that changes in a nucleic acid sequence can be made using this degeneracy to produce multiple nucleic acid sequences that all encode substantially the same protein.
The phrases "percent identity" and "°Io identity," as applied to polypeptide sequences, refer to the percentage of residue matches between at least two polypeptide sequences aligned using a standardized algorithm. Methods of polypeptide sequence alignment are well-known. Some alignment methods take into account conservative amino acid substitutions.
Such conservative substitutions, explained in more detail above, generally preserve the charge and._hydrophobicity at the site of substitution, thus preserving the structure (and therefore function) of the polypeptide.
Percent identity between polypeptide sequences may be determined using the default parameters of the CLUSTAL V algorithm as incorporated into the MEGALIGN
version 3.12e sequence alignment program (described and referenced above). For pairwise alignments of polypeptide sequences using CLUSTAL V, the default parameters are set as follows: I~tuple=1, gap penalty=3, window=5, and "diagonals saved"=5. The PAM250 matrix is selected as the default residue weight table. As with polynucleotide alignments, the percent identity is reported by CLUSTAL V as the "percent similarity" between aligned polypeptide sequence pairs.

Alternatively the NCBI BLAST software suite may be used. For example, for a pairwise comparison of two polypeptide sequences, one may use the "BLAST 2 Sequences"
tool Version 2Ø12 (April-21-2000) with blastp set at default parameters. Such default parameters may be, for example:
Matrix: BLOSUM62 Open Gap: 11 and Extension Gap: 1 penalties Gap x drop-off.' S0 Expect: 10 Word Size: 3 Filter: on Percent identity may be measured over the length of an entire defined polypeptide sequence, for example, as defined by a particular SEQ ID number, or may be measured over a shorter length, for example, over the length of a fragment taken from a larger, defined polypeptide sequence, for instance, a fragment of at least 15, at least 20, at least 30, at least 40, at least 50, at least 70 or at least 150 contiguous residues. Such lengths are exemplary only, and it is understood that any fragment length supported by the sequences shown herein, in the tables, figures or Sequence Listing, may be used to describe a length over which percentage identity may be measured.
"Human artificial chromosomes" (HACs) are linear microchromosomes which may contain DNA sequences of about 6 kb to 10 Mb in size and which contain all of the elements required for chromosome replication, segregation and maintenance.
The term "humanized antibody" refers to an antibody molecule in which the amino acid sequence in the non-antigen binding regions has been altered so that the antibody more closely resembles a human antibody, and still retains its original binding ability.
"Hybridization" refers to the process by which a polynucleotide strand anneals with a complementary strand through base pairing under defined hybridization conditions. Specific hybridization is an indication that two nucleic acid sequences share a high degree of complementarity.
Specific hybridization complexes form under permissive annealing conditions and remain hybridized after the "washing" step(s). The washing steps) is particularly important in determining the stringency of the hybridization process, with more stringent conditions allowing less non-specific binding, i.e., binding between pairs of nucleic acid strands that are not perfectly matched. Permissive conditions for annealing of nucleic acid sequences are routinely determinable by one of ordinary skill in the art and may be consistent among hybridization experiments, whereas wash conditions may be varied among experiments to achieve the desired stringency, and therefore hybridization specificity.
Permissive annealing conditions occur, for example, at 68°C in the presence of about 6 x SSC, about 1 % (w/v) SDS, and about 100 ~tg/ml sheared, denatured salmon sperm DNA.
Generally, stringency of hybridization is expressed, in part, with reference to the temperature under which the wash step is carned out. Such wash temperatures are typically selected to be about 5°C to 20°C lower than the thermal melting point (Tin) for the specific sequence at a defined ionic strength and pH. The Tm is the temperature (under defined ionic strength and pH) at which 50% of the target sequence hybridizes to a perfectly matched probe. An equation for calculating Tm and conditions for nucleic acid hybridization are well known and can be found in Sambrook, J. et al.
(1989) Molecular Cloning A Laboratory Manual, 2°d ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; specifically see volume 2, chapter 9.
High stringency conditions for hybridization between polynucleotides of the present invention include wash conditions of 68°C in the presence of about 0.2 x SSC and about 0.1% SDS, for 1 hour. Alternatively, temperatures of about 65°C, 60°C, 55°C, or 42°C may be used. SSC
concentration may be varied from about 0.1 to 2 x SSC, with SDS being present at about 0.1%.
Typically, blocking reagents are used to block non-specific hybridization.
Such blocking reagents include, for instance, sheared and denatured salmon sperm DNA at about 100-200 ~.g/ml. Organic solvent, such as formamide at a concentration of about 35-50% vlv, may also be used under particular circumstances, such as for RNA:DNA hybridizations. Useful variations on these wash conditions will be readily apparent to those of ordinary skill in the art. Hybridization, particularly under high stringency conditions, may be suggestive of evolutionary similarity between the nucleotides. Such similarity is strongly indicative of a similar role for the nucleotides and their encoded polypeptides.
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., Cot or Rot 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 words "insertion" and "addition" refer to changes in an amino acid or nucleotide sequence resulting in the addition of one or more amino acid residues or nucleotides, respectively.
"Immune response" can refer to conditions associated with inflammation, trauma, immune disorders, or infectious or genetic disease, etc. These conditions can be characterized by expression of various factors, e.g., cytokines, chemokines, and other signaling molecules, which may affect cellular and systemic defense systems.
An "immunogenic fragment" is a polypeptide or oligopeptide fragment of CSAP
which is capable of eliciting an immune response when introduced into a living organism, for example, a mammal. The term "immunogenic fragment" also includes any polypeptide or oligopeptide fragment of CSAP which is useful in any of the antibody production methods disclosed herein or known in the art.
The term "microarray" refers to an arrangement of a plurality of polynucleotides, polypeptides, or other chemical compounds on a substrate.
The terms "element" and "array element" refer to a polynucleotide, polypeptide, or other chemical compound having a unique and defined position on a microarray.
The term "modulate" refers to a change in the activity of CSAP. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of CSAP.
The phrases "nucleic acid" and "nucleic acid sequence" refer to a nucleotide, oligonucleotide, polynucleotide, or any fragment thereof. These phrases also refer to DNA or RNA of genomic or synthetic origin which may be single-stranded or double-stranded and may represent the sense or the antisense strand, to peptide nucleic acid (PNA), or to any DNA-like or RNA-like material.
"Operably linked" refers to the situation in which a first nucleic acid sequence is placed in a functional relationship with a second nucleic acid sequence. For instance, a promoter is operably linked to a coding sequence if the promoter affects the transcription or expression of the coding sequence. Operably linked DNA sequences may be in close proximity or contiguous and, where necessary to join two protein coding regions, in the same reading frame.
"Peptide nucleic acid" (PNA) refers to an antisense molecule or anti-gene agent which comprises an oligonucleotide of at least about 5 nucleotides in length linked to a peptide backbone of amino acid residues ending in lysine. The terminal lysine confers solubility to the composition.
PNAs preferentially bind complementary single stranded DNA or RNA and stop transcript elongation, and may be pegylated to extend their lifespan in the cell.
"Post-translational modification" of an CSAP may involve lipidation, glycosylation, phosphorylation, acetylation, racemization, proteolytic cleavage, and other modifications known in the art. These processes may occur synthetically or biochemically. Biochemical modifications will vary by cell type depending on the enzymatic milieu of CSAP.
"Probe" refers to nucleic acid sequences encoding CSAP, their complements, or fragments thereof, which are used to detect identical, allelic or related nucleic acid sequences. Probes are isolated oligonucleotides or polynucleotides attached to a detectable label or reporter molecule.
Typical labels include radioactive isotopes, ligands, chemiluminescent agents, and enzymes.
"Primers" are short nucleic acids, usually DNA oligonucleotides, which may be annealed to a target polynucleotide by complementary base-pairing. The primer may then be extended along the target DNA strand by a DNA polymerase enzyme. Primer pairs can be used for amplification (and identification) of a nucleic acid sequence, e.g., by the polymerase chain reaction (PCR).
Probes and primers as used in the present invention typically comprise at least 15 contiguous nucleotides of a known sequence. In order to enhance specificity, longer probes and primers may also be employed, such as probes and primers that comprise at least 20, 25, 30, 40, 50, 60, 70, 80, 90, 100, or at least 150 consecutive nucleotides of the disclosed nucleic acid sequences. Pxobes and primers may be considerably longer than these examples, and it is understood that any length supported by the specification, including the tables, figures, and Sequence Listing, may be used.
Methods for preparing and using probes and primers are described in the references, for example Sambrook, J. et al. (1989) Molecular Cloning: A Laboratory Manual, 2°a ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; Ausubel, F.M. et al. (I987) Current Protocols in Molecular Bioloay, Greene Publ. Assoc. & Wiley-Intersciences, New York NY; Innis, M. et al. (1990) PCR
Protocols, A Guide to Methods and Applications, Academic Press, San Diego CA.
PCR primer pairs can be derived from a known sequence, for example, by using computer programs intended for that purpose such as Primer (Version 0.5, 1991, Whitehead Institute for Biomedical Research, Cambridge MA).
Oligonucleotides for use as primers are selected using software known in the art for such purpose. For example, OLIGO 4.06 software is useful for the selection of PCR
primer pairs of up to 100 nucleotides each, and for the analysis of oligonucleotides and larger polynucleotides of up to 5,000 nucleotides from an input polynucleotide sequence of up to 32 kilobases.
Similar primer selection programs nave incorporated additional features for expanded capabilities. For example, the PrimOU primer selection program (available to the public from the Genome Center at University of Texas South West Medical Center, Dallas TX) is capable of choosing specific primers from megabase sequences and is thus useful for designing primers on a genome-wide scope. The Primer3 primer selection program (available to the public from the Whitehead Institute/MIT Center for Genome Research, Cambridge MA) allows the user to input a "mispriming library," in which sequences to avoid as primer binding sites are user-specified. Primer3 is useful, in particular, for the selection of oligonucleotides for microarrays. (The source code for the latter two primer selection programs may also be obtained from their respective sources and modified to meet the user's specific needs.) The PrimeGen program (available to the public from the UK Human Genome Mapping Project Resource Centre, Cambridge UK) designs primers based on multiple sequence alignments, thereby allowing selection of primers that hybridize to either the most conserved or least conserved regions of aligned nucleic acid sequences. Hence, this program is useful for identification of both unique and conserved oligonucleotides and polynucleotide fragments. The oligonucleotides and polynucleotide fragments identified by any of the above selection methods are useful in hybridization technologies, for example, as PCR or sequencing primers, microarray elements, or specific probes to identify fully or partially complementary polynucleotides in a sample of nucleic acids. Methods of oligonucleotide selection are not limited to those described above.
A "recombinant nucleic acid" is a sequence that is not naturally occurring or has a sequence that is made by an artificial combination of two or more otherwise separated segments of sequence.
This artificial combination is often accomplished by chemical synthesis or, more commonly, by the artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, supra. The term recombinant includes nucleic acids that have been altered solely by addition, substitution, or deletion of a portion of the nucleic acid. Frequently, a recombinant nucleic acid may include a nucleic acid sequence operably linked to a promoter sequence. Such a recombinant nucleic acid may be part of a vector that is used, for example, to transform a cell.
Alternatively, such recombinant nucleic acids may be part of a viral vector, e.g., based on a vaccinia virus, that could be use to vaccinate a mammal wherein the recombinant nucleic acid is expressed, inducing a protective immunological response in the mammal.
A "regulatory element" refers to a nucleic acid sequence usually derived from untranslated regions of a gene and includes enhancers, promoters, introns, and 5' and 3' untranslated regions (UTRs). Regulatory elexxients interact with host or viral proteins which control transcription, translation, or RNA stability.
"Reporter molecules" are chemical or biochemical moieties used for labeling a nucleic acid, amino acid, or antibody. Reporter molecules include radionuclides; enzymes;
fluorescent, chemiluminescent, or chromogenic agents; substrates; cofactors; inhibitors;
magnetic particles; and other moieties known in the art.
An "RNA equivalent," in reference to a DNA sequence, is composed of the same linear sequence of nucleotides as the reference DNA sequence with the exception that all occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The term "sample" is used in its broadest sense. A sample suspected of containing CSAP, nucleic acids encoding CSAP, or fragments thereof may comprise a bodily fluid;
an extract from a cell, chromosome, organelle, or membrane isolated from a cell; a cell; genomic DNA, RNA, or cDNA, in solution or bound to a substrate; a tissue; a tissue print; etc.
The terms "specific binding" and "specifically binding" refer to that interaction between a protein or peptide and an agonist, an antibody, an antagonist, a small molecule, or any natural or synthetic binding composition. The interaction is dependent upon the presence of a particular structure of the protein, e.g., the antigenic determinant or epitope, recognized by the binding molecule. For example, if an antibody is specific for epitope "A," the presence of a polypeptide comprising the epitope A, or the presence of free unlabeled A, in a reaction containing free labeled A
and the antibody will reduce the amount of labeled A that binds to the antibody.
The term "substantially purified" refers to nucleic acid or amino acid sequences that are removed from their natural environment and are isolated or separated, and are at least 60% free, preferably at least 75% free, and most preferably at least 90% free from other components with which they are naturally associated.
A "substitution" refers to the replacement of one or more amino acid residues or nucleotides by different amino acid residues or nucleotides, respectively.
"Substrate" refers to any suitable rigid or semi-rigid support including membranes, filters, chips, slides, wafers, fibers, magnetic or nonmagnetic beads, gels, tubing, plates, polymers, microparticles and capillaries. The substrate can have a variety of surface forms, such as wells, trenches, pins, channels and pores, to which polynucleotides or polypeptides are bound.
A "transcript image" or "expression profile" refers to the collective pattern of gene expression by a particular cell type or tissue under given conditions at a given time.
"Transformation" describes a process by which exogenous DNA is introduced into a recipient cell. Transformation may occur under natural or artificial conditions according to various methods well known in the art, and may rely on any known method for the insertion of foreign nucleic acid sequences into a prokaryotic or eukaryotic host cell. The method for transformation is selected based on the type of host cell being transformed and may include, but is not limited to, bacteriophage or viral infection, electroporation, heat shock, lipofection, and particle bombardment. The term "transformed cells" includes stably transformed cells in which the inserted DNA is capable of replication either as an autonomously replicating plasmid or as part of the host chromosome, as well as transiently transformed cells which express the inserted DNA or RNA for limited periods of time.
A "transgenic organism," as used herein, is any organism, including but not limited to animals and plants, in which one or more of the cells of the organism contains heterologous nucleic acid introduced by way of human intervention, such as by transgenic techniques well known in the art. The nucleic acid is introduced into the cell, directly or indirectly by introduction into a precursor of the cell, by way of deliberate genetic manipulation, such as by microinjection or by infection with a recombinant virus. In one alternative, the nucleic acid can be introduced by infection with a recombinant viral vector, such as a lentiviral vector (Lois, C. et al. (2002) Science 295:868-872). The term genetic manipulation does not include classical cross-breeding, or in vitro fertilization, but rather is directed to the introduction of a recombinant DNA molecule. The transgenic organisms contemplated in accordance with the present invention include bacteria, cyanobacteria, fungi, plants and animals. The isolated DNA of the present invention can be introduced into the host by methods known in the art, for example infection, transfection, transformation or transconjugation. Techniques for transferring the DNA of the present invention into such organisms are widely known and provided in references such as Sambrook et al. (1989), supra.
A "variant" of a particular nucleic acid sequence is defined as a nucleic acid sequence having at least 40% sequence identity to the particular nucleic acid sequence over a certain length of one of the nucleic acid sequences using blastn with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of nucleic acids may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at Least 99% or greater sequence identity over a certain defined length. A variant may be described as, for example, an "allelic" (as defined above), "splice," "species," or "polymorphic" variant. A
splice variant may have significant identity to a reference molecule, but will generally have a greater or lesser number of polynucleotides due to alternate splicing of exons during mRNA processing. The corresponding polypeptide may possess additional functional domains or lack domains that are present in the reference molecule. Species variants are polynucleotide sequences that vary from one species to another. The resulting polypeptides will generally have significant amino acid identity relative to each other. A polymorphic variant is a variation in the polynucleotide sequence of a particular gene between individuals of a given species. Polymorphic variants also may encompass "single nucleotide polymorphisms" (SNPs) in which the polynucleotide sequence varies by one nucleotide base. The presence of SNPs may be indicative of, for example, a certain population, a disease state, or a propensity for a disease state.
A "variant" of a particular polypeptide sequence is defined as a polypeptide sequence having at least 40% sequence identity to the particular polypeptide sequence over a certain length of one of the polypeptide sequences using blastp with the "BLAST 2 Sequences" tool Version 2Ø9 (May-07-1999) set at default parameters. Such a pair of polypeptides may show, for example, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99%
or greater sequence identity over a certain defined length of one of the polypeptides.
THE INVENTION
The invention is based on the discovery of new human cytoskeleton-associated proteins (CSAP), the polynucleotides encoding CSAP, and the use of these compositions for the diagnosis, treatment, or prevention of cell proliferative disorders, viral infections, and neurological disorders.
Table 1 summarizes the nomenclature for the full length polynucleotide and polypeptide sequences of the invention. Each polynucleotide and its corresponding polypeptide are correlated to a single Incyte project identification number (Incyte Project ID). Each polypeptide sequence is denoted by both a polypeptide sequence identification number (Polypeptide SEQ >D NO:) and an Incyte polypeptide sequence number (Tncyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ 1D NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown. Column 6 shows the Incyte ID numbers of physical, full length clones corresponding to the polypeptide and polynucleotide sequences of the invention. The full length clones encode polypeptides which have at least 95% sequence identity to the polypeptide sequences shown in column 3.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns l and 2 show the polypeptide sequence identification number (Polypeptide SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide ID) for polypeptides of the invention. Column 3 shows the GenBank identification number (GenBank ID NO:) of the nearest GenBank homolog.
Column 4 shows the probability scores for the matches between each polypeptide and its homolog(s).
Column 5 shows the annotation of the GenBank homologs along with relevant citations where applicable, all of which are expressly incorporated by reference herein.
Table 3 shows various structural features of the polypeptides of the invention. Columns 1 and 2 show the polypeptide sequence identification number (SEQ ID NO:) and the corresponding Incyte polypeptide sequence number (Incyte Polypeptide TD) for each polypeptide of the invention.
Column 3 shows the number of amino acid residues in each polypeptide. Column 4 shows potential phosphorylation sites, and column 5 shows potential glycosylation sites; as determined by the MOTIFS program of the GCG sequence analysis software package (Genetics Computer Group, Madison WI). Column 6 shows amino acid residues comprising signature sequences, domains, and motifs. Column 7 shows analytical methods for protein structure/function analysis and in some cases, searchable databases to which the analytical methods were applied.
Together, Tables 2 and 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are cytoskeleton-associated proteins. For example, SEQ )D NO: l is 86% identical, from residue M1 to residue S459, to mouse c29 protein (GenBank ID
g3868802) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 1.4e-207, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:1 also contains an intermediate filament protein domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS and PROFILESCAN analyses provide further corroborative evidence that SEQ ID
NO:1 is a intermediate filament protein. In an alternative example, SEQ ID
N0:3 is 93% identical from residue M1 to residue D1107 and 42% identical from residue E470 to residue N1614, (that is, 74% identical over the length of the sequence) to Mus musculus Kif2la (GenBank ID g6561827) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score over the length of the sequence is 2.3e-199, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:3 also contains a kinesin motor domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains.
(See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide further corroborative evidence that SEQ ID N0:3 is a kinesin. In an alternative example, SEQ ID N0:7 is 95%
identical, from residue I125 to residue T1050, to rat ankyrin binding cell adhesion molecule neurofascin (GenBank ID g1842427) as determined by the Basic Local Alignment Search Tool (BLAST).
(See Table 2.) The BLAST probability score is 0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:7 also contains a fibronectin type III domain and an immunoglobulin domain as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS, MOTIFS, and PROFILESCAN analyses provide fuxther corroborative evidence that SEQ ID N0:7 is a cytoskeleton-associated protein. In an alternative example, SEQ ~
N0:9 is 95% identical, from residue M1 to residue D471, to rat coronin relative protein (GenBank ID
g15430628) as determined by the Basic Local Alignment Search Tool (BLAST).
(See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:9 also contains WD domains as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIMPS and MOTIFS
analyses provide further corroborative evidence that SEQ ID N0:9 is a coronin. In an alternative example, SEQ ID N0:14 is 99% identical, from residue M1 to residue 8523, to human keratin 6 irs (GenBank ID g6961277) as determined by the Basic Local Alignment Search Tool (BLAST).
The BLAST
probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:14 also contains intermediate filament protein domains as determined by searching for statistically significant matches in the hidden Markov model (I~VVIM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIIVVIPS, MOTIFS, and PROFILESCAN analyses provide further. corroborative evidence that SEQ ID N0:14 is an intermediate filament protein, which is a specific subtype of cytoskeletal protein. In an alternative example, SEQ ID N0:18 is 2039 residues in length and is 94% identical, from residue M1 to residue A2039, to mouse myosin containing PDZ domain (GenBank ID g7416032) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance.
SEQ 117 N0:18 also contains an IQ calmodulin-binding motif, a PDZ domain (also known as DHR or GLGF), and a myosin head (motor domain) as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BLIIVVIPS, MOTIFS, and additional BLAST
analyses provide further corroborative evidence that SEQ ll~ N0:18 is a cytoskeleton-associated protein. In an alternative example, SEQ ID N0:26 is 92% identical, from residue M1 to residue L1715, to rat ankyrin repeat-rich membrane-spanning protein (GenBank ~ g11321435) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 0.0, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ
ID N0:26 also contains eleven ankyrin repeat domains as determined by searching for statistically significant matches in the hidden Markov model (HMM)-based PFAM database of conserved protein family domains. (See Table 3.) Data from BL1MPS, MOTIFS, and PROFILESCAN
analyses provide further corroborative evidence that SEQ ID N0:26 is an ankyrin repeat-rich protein. Many ankyrin repeats have been shown to moderate protein-protein interactions, for example, in cytoskeletal proteins. SEQ ~ N0:2, SEQ ID N0:4-6, SEQ ID N0:8, SEQ ID N0:10-13, SEQ ID
N0:15-17, SEQ ff~ N0:19-25, and SEQ ID N0:27-28 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID N0:1-28 are described in Table 7.
As shown in Table 4, the full length polynucleotide sequences of the present invention were assembled using cDNA sequences or coding (axon) sequences derived from genomic DNA, or any combination of these two types of sequences. Column 1 lists the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:), the corresponding Incyte polynucleotide consensus sequence number (Incyte ID) for each polynucleotide of the invention, and the length of each polynucleotide sequence in basepairs. Column 2 shows the nucleotide start (5') and stop (3') positions of the cDNA and/or genomic sequences used to assemble the full length polynucleotide sequences of the invention, and of fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID
N0:29-56 or that distinguish between SEQ ID N0:29-56 and related polynucleotide sequences.

The polynucleotide fragments described in Column 2 of Table 4 may refer specifically, for example, to Incyte cDNAs derived from tissue-specific cDNA libraries or from pooled cDNA
libraries. Alternatively, the polynucleotide fragments described in column 2 may refer to GenBank cDNAs or ESTs which contributed to the assembly of the full length polynucleotide sequences. In addition, the polynucleotide fragments described in column 2 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation "ENST"). Alternatively, the polynucleotide fragments described in column 2 may be derived from the NCBI RefSeq Nucleotide Sequence Records Database (i.e., those sequences including the designation "NM" or "NT") or the NCBI RefSeq Protein Sequence Records (i.e., those sequences including the designation "NP"). Alternatively, the polynucleotide fragments described in column 2 may refer to assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching" algorithm. For example, a polynucleotide sequence identified as FL XXXXXX_NI 1Vz_YYYYY_N3 1V4 represents a "stitched" sequence in which XXXXXX
is the identification number of the cluster of sequences to which the algorithm was applied, and YYYYY is the number of the prediction generated by the algorithm, and N~,2,3..., if present, represent specific exons that may have been manually edited during analysis (See Example V).
Alternatively, the polynucleotide fragments in column 2 may refer to assemblages of exons brought together by an "exon-stretching" algorithm. For example, a polynucleotide sequence identified as FL~Y~YXXXXXX gAAAAA_gBBBBB_I N is a "stretched" sequence, with XXXXXX being the Incyte project identification number, gAAAAA being the GenBank identification number of the human genomic sequence to which the "exon-stretching" algorithm was applied, gBBBBB
being the GenBank identification number or NCBI RefSeq identification number of the nearest GenBank protein homolog, and Nreferring to specific exons (See Example V). In instances where a RefSeq sequence was used as a protein homolog for the "exon-stretching" algorithm, a RefSeq identifier (denoted by "NM," "NP," or "NT") may be used in place of the GenBank identifier (i.e., gBBBBB).
Alternatively, a prefix identifies component sequences that were hand-edited, predicted from genomic DNA sequences, or derived from a combination of sequence analysis methods. The following Table lists examples of component sequence prefixes and corresponding sequence analysis methods associated with the prefixes (see Example IV and Example V).
Prefix Type of analysis and/or examples of programs GNN, GFG, Exon prediction from genomic sequences using, for example, ENST GENSCAN (Stanford University, CA, USA) or FGENES

(Computer Genomics Group, The Sanger Centre, Cambridge, UK).

GBI Hand-edited analysis of genomic sequences.

FL Stitched or stretched genomic sequences (see Example V).

INCY Full length transcript and exon prediction from~mapping of EST

sequences to the genome. Genomic location and EST composition data are combined to predict the exons and resulting transcript.

In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in Table 4 was obtained to confirm the final consensus polynucleotide sequence, but the relevant Incyte cDNA
identification numbers are not shown.
Table 5 shows the representative cDNA libraries for those full length polynucleotide sequences which were assembled using Incyte cDNA sequences. The representative cDNA library is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and confirm the above polynucleotide sequences. The tissues and vectors which were used to construct the cDNA libraries shown in Table 5 are described in Table 6.
The invention also encompasses CSAP variants. A preferred CSAP variant is one which has at least about 80%, or alternatively at least about 90%, or even at least about 95% amino acid sequence identity to the CSAP amino acid sequence, and which contains at least one functional or structural characteristic of CSAP.
The invention also encompasses polynucleotides which encode CSAP. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:29-56, which encodes CSAP. The polynucleotide sequences of SEQ ID N0:29-56, as presented in the Sequence Listing, embrace the equivalent RNA
sequences, wherein occurrences of the nitrogenous base thymine are replaced with uracil, and the sugar backbone is composed of ribose instead of deoxyribose.
The invention also encompasses a variant of a polynucleotide sequence encoding CSAP. Tn particular, such a variant polynucleotide sequence will have at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to the polynucleotide sequence encoding CSAP. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ~
N0:29-56 which has at least about 70%, or alternatively at least about 85%, or even at least about 95% polynucleotide sequence identity to a nucleic acid sequence selected from the group consisting of SEQ ID N0:29-56. Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of CSAP.
In addition, or in the alternative, a polynucleotide variant of the invention is a splice variant of a polynucleotide sequence encoding CSAP. A splice variant may have portions which have significant sequence identity to the polynucleotide sequence encoding CSAP, but will generally have a greater or lesser number of polynucleotides due to additions or deletions of blocks of sequence arising from alternate splicing of exons during mRNA processing. A splice variant may have less than about 70%, or alternatively less than about 60%, or alternatively less than about 50%
polynucleotide sequence identity to the polynucleotide sequence encoding CSAP
over its entire length; however, portions of the splice variant will have at least about 70%, or alternatively at least about 85%, or alternatively at least about 95%, or alternatively 100%
polynucleotide sequence identity to portions of the polynucleotide sequence encoding CSAP. For example, a polynucleotide comprising a sequence of SEQ ID N0:31 is a splice variant of a polynucleotide comprising a sequence of SEQ ID N0:33. In an alternative example, a polynucleotide comprising a sequence of SEQ ID N0:34 is a splice variant of a polynucleotide comprising a sequence of SEQ ID N0:35. Any one of the splice variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of CSAP.
It will be appreciated by those skilled in the art that as a result of the degeneracy of the genetic code, a multitude of polynucleotide sequences encoding CSAP, some bearing minimal similarity to the polynucleotide sequences of any known and naturally occurring gene, may be produced. Thus, the invention contemplates each and every possible variation of polynucleotide sequence that could be made by selecting combinations based on possible codon choices. These combinations are made in accordance with the standard triplet genetic code as applied to the polynucleotide sequence of naturally occurring CSAP, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode CSAP and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring CSAP under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding CSAP or its derivatives possessing a substantially different codon usage, e.g., inclusion of non-naturally occurring codons. Codons may be selected to increase the rate at which expression of the peptide occurs in a particular prokaryotic or eukaryotic host in accordance with the frequency with which particular codons are utilized by the host. Other reasons for substantially altering the nucleotide sequence encoding CSAP and its derivatives without altering the encoded amino acid sequences include the production of RNA transcripts having more desirable properties, such as a greater half-life, than transcripts produced from the naturally occurring sequence.
The invention also encompasses production of DNA sequences which encode CSAP
and CSAP derivatives, or fragments thereof, entirely by synthetic chemistry. After production, the synthetic sequence may be inserted into any of the many available expression vectors and cell systems using reagents well known in the art. Moreover, synthetic chemistry may be used to introduce mutations into a sequence encoding CSAP or any fragment thereof.
Also encompassed by the invention are polynucleotide sequences that are capable of hybridizing to the claimed polynucleotide sequences, and, in particular, to those shown in SEQ ID
N0:29-56 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G.M. and S.L. Berger (1987) Methods Enzymol. 152:399-407; I~immel, A.R. (1987) Methods Enzymol.
152:507-511.) Hybridization conditions, including annealing and wash conditions, are described in "Definitions."
Methods for DNA sequencing axe well known in the art and may be used to practice any of the embodiments of the invention. The methods may employ such enzymes as the I~lenow fragment of DNA polymerase I, SEQUENASE (US Biochemical, Cleveland OH), Taq polymerase (Applied Biosystems), thermostable T7 polymerase (Amersham Pharmacia Biotech, Piscataway NJ), or combinations of polymerases and proofreading exonucleases such as those found in the ELONGASE
amplification system (Life Technologies, Gaithersburg MD). Preferably, sequence preparation is automated with machines such as the MICROLAB 2200 liquid transfer system (Hamilton, Reno NV), PTC200 thermal cycler (MJ Research, Watertown MA) and ABI CATALYST 800 thermal cycler (Applied Biosystems). Sequencing is then carried out using either the ABI 373 or 377 DNA
sequencing system (Applied Biosystems), the MEGABACE 1000 DNA sequencing system (Molecular Dynamics, Sunnyvale CA), or other systems known in the art. The resulting sequences are analyzed using a variety of algorithms which are well known in the art.
(See, e.g., Ausubel, F.M.
(1997) Short Protocols in Molecular Biolo~y, John Wiley & Sons, New York NY, unit 7.7; Meyers, R.A. (1995) Molecular Biolo~y and Biotechnology, Wiley VCH, New York NY, pp.
856-853.) The nucleic acid sequences encoding CSAP may be extended utilizing a partial nucleotide sequence and employing various PCR-based methods known in the art to detect upstream sequences, such as promoters and regulatory elements. For example, one method which may be employed, restriction-site PCR, uses universal and nested primers to amplify unknown sequence from genomic DNA within a cloning vector. (See, e.g., Sarkar, G. (1993) PCR Methods Applic.
2:318-322.) Another method, inverse PCR, uses primers that extend in divergent directions to amplify unknown sequence from a circularized template. The template is derived from restriction fragments comprising a known genomic locus and surrounding sequences. (See, e.g., Triglia, T. et al. (1988) Nucleic Acids Res. 16:8186.) A third method, capture PCR, involves PCR amplification of DNA
fragments adjacent to known sequences in human and yeast artificial chromosome DNA.
(See, e.g., Lagerstrom, M. et al. (1991) PCR Methods Applic. 1:111-119.) In this method, multiple restriction enzyme digestions and ligations may be used to insert an engineered double-stranded sequence into a region of unknown sequence before performing PCR. Other methods which may be used to retrieve unknown sequences are known in the art. (See, e.g., Parker, J.D. et al. (1991) Nucleic Acids Res.
19:3055-3060). Additionally, one may use PCR, nested primers, and PROMOTERFINDER libraries (Clontech, Palo Alto CA) to walk genomic DNA. This procedure avoids the need to screen libraries and is useful in fording intron/exon junctions. For all PCR-based methods, primers may be designed using commercially available software, such as OLIGO 4.06 primer analysis software (National Biosciences, Plymouth MN) or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the template at temperatures of about 68°C to 72°C.
When screening for full length cDNAs, it is preferable to use libraries that have been size-selected to include larger cDNAs. In addition, random-primed libraries, which often include sequences containing the 5' regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomic libraries may be useful for extension of sequence into 5' non-transcribed regulatory regions.
Capillary electrophoresis systems which are commercially available may be used to analyze the size or confirm the nucleotide sequence of sequencing or PCR products. In particular, capillary sequencing may employ flowable polymers for electrophoretic separation, four different nucleotide-specific, laser-stimulated fluorescent dyes, and a charge coupled device camera for detection of the emitted wavelengths. Output/light intensity may be converted to electrical signal using appropriate software (e.g., GENOTYPER and SEQUENCE NAVIGATOR, Applied Biosystems), and the entire process from loading of samples to computer analysis and electronic data display may be computer controlled. Capillary electrophoresis is especially preferable for sequencing small DNA fragments which may be present in limited amounts in a particular sample.
In another embodiment of the invention, polynucleotide sequences or fragments thereof which encode CSAP may be cloned in recombinant DNA molecules that direct expression of CSAP, or fragments or functional equivalents thereof, in appropriate host cells. Due to the inherent degeneracy of the genetic code, other DNA sequences which encode substantially the same or a functionally equivalent amino acid sequence may be produced and used to express CSAP.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter CSAP-encoding sequences for a variety of purposes including, but not limited to, modification of the cloning, processing, and/or expression of the gene product. DNA
shuffling by random fragmentation and PCR reassembly of gene fragments and synthetic oligonucleotides may be used to engineer the nucleotide sequences. For example, oligonucleotide-mediated site-directed mutagenesis may be used to introduce mutations that create new restriction sites, alter glycosylation patterns, change codon preference, produce splice variants, and so forth.
The nucleotides of the present invention may be subjected to DNA shuffling techniques such as MOLECULARBREEDING (Maxygen Inc., Santa Clara CA; described in U.S. Patent No.
5,837,458; Chang, C.-C. et al. (1999) Nat. Biotechnol. 17:793-797; Christians, F.C. et al. (1999) Nat.
Biotechnol. 17:259-264; and Crameri, A. et al. (1996) Nat. Biotechnol. 14:315-319) to alter or improve the biological properties of CSAP, such as its biological or enzymatic activity or its ability to bind to other molecules or compounds. DNA shuffling is a process by which a library of gene variants is produced using PCR-mediated recombination of gene fragments. The library is then subjected to selection or screening procedures that identify those gene variants with the desired properties. These preferred variants may then be pooled and further subjected to recursive rounds of DNA shuffling and selection/screening. Thus, genetic diversity is created through "artificial"
breeding and rapid molecular evolution. For example, fragments of a single gene containing random point mutations may be recombined, screened, and then reshuffled until the desired properties are optimized. Alternatively, fragments of a given gene may be recombined with fragments of homologous genes in the same gene family, either from the same or different species, thereby maximizing the genetic diversity of multiple naturally occurring genes in a directed and controllable manner.
In another embodiment, sequences encoding CSAP may be synthesized, in whole or in part, using chemical methods well known in the art. (See, e.g., Caruthers, M.H. et al. (1980) Nucleic Acids Symp. Ser. 7:215-223; and Horn, T. et al. (1980) Nucleic Acids Symp. Ser.

7:225-232.) Alternatively, CSAP itself or a fragment thereof may be synthesized using chemical methods. For example, peptide synthesis can be performed using various solution-phase or solid-phase techniques.
(See, e.g., Creighton, T. (1984) Proteins, Structures and Molecular Properties, WH Freeman, New York NY, pp. 55-60; and Roberge, J.Y, et al. (1995) Science 269:202-204.) Automated synthesis may be achieved using the ABI 431A peptide synthesizer (Applied Biosystems).
Additionally, the amino acid sequence of CSAP, or any part thereof, may be altered during direct synthesis and/or combined with sequences from other proteins, or any part thereof, to produce a variant polypeptide or a polypeptide having a sequence of a naturally occurring polypeptide.
The peptide may be substantially purified by preparative high performance liquid chromatography. (See, e.g., Chiez, R.M. and F.Z. Regnier (1990) Methods Enzymol. 182:392-421.) The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing. (See, e.g., Creighton, supra, pp. 28-53.) In order to express a biologically active CSAP, the nucleotide sequences encoding CSAP or derivatives thereof may be inserted into an appropriate expression vector, i.e., a vector which contains the necessary elements for transcriptional and translational control of the inserted coding sequence in a suitable host. These elements include regulatory sequences, such as enhancers, constitutive and inducible promoters, and 5' and 3' untranslated regions in the vector and in polynucleotide sequences encoding CSAP. Such elements may vary in their strength and specificity.
Specific initiation signals may also be used to achieve more efficient translation of sequences encoding CSAP. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding CSAP and its initiation codon and upstream regulatory sequences are inserted into the appropriate expression vector, no additional transcriptional or translational control signals may be needed. However, in cases where only coding sequence, or a fragment thereof, is inserted, exogenous translational control signals including an in-frame ATG initiation codon should be provided by the vector. Exogenous translational elements and initiation codons may be of various origins, both natural and synthetic. The efficiency of expression may be enhanced by the inclusion of enhancers appropriate for the particular host cell system used. (See, e.g., Scharf, D. et al. (1994) Results Probl. Cell Differ. 20:125-162.) Methods which are well known to those skilled in the art may be used to construct expression vectors containing sequences encoding CSAP and appropriate transcriptional and translational control elements. These methods include in vitro recombinant DNA techniques, synthetic techniques, and in vivo genetic recombination. (See, e.g., Sambrook, J. et al. (1989) Molecular Clonin,~, A Laboratory Manual, Cold Spring Harbor Press, Plainview NY, ch. 4, 8, and 16-17; Ausubel, F.M, et al. (1995) Current Protocols in Molecular Bioloay, John Wiley & Sons, New York NY, ch. 9, 13, and 16.) A variety of expression vector/host systems may be utilized to contain and express sequences encoding CSAP. These include, but are not limited to, microorganisms such as bacteria transformed with recombinant bacteriophage, plasmid, or cosmid DNA expression vectors;
yeast transformed with yeast expression vectors; insect cell systems infected with viral expression vectors (e.g., baculovirus);
plant cell systems transformed with viral expression vectors (e.g., cauliflower mosaic virus, CaMV, or tobacco mosaic virus, TMV) or with bacterial expression vectors (e.g., Ti or pBR322 plasmids); or animal cell systems. (See, e.g., Sambrook, supra; Ausubel, supra; Van Heeke, G. and S.M. Schuster (1989) J. Biol. Chem. 264:5503-5509; Engelhard, E.K. et al. (1994) Proc. Natl.
Acad. Sci. USA
91:3224-3227; Sandig, V. et al. (1996) Hum. Gene Ther. 7:1937-1945; Takamatsu, N. (1987) EMBO
J. 6:307-311; The McGraw Hill Yearbook of Science and Technolo~y (1992) McGraw Hill, New York NY, pp. 191-196; Logan, J. and T. Shenk (1984) Proc. Natl. Acad. Sci. USA
81:3655-3659; and Harrington, J.J. et al. (1997) Nat. Genet. 15:345-355.) Expression vectors derived fromretroviruses, adenoviruses, or herpes or vaccinia viruses, or from various bacterial plasmids, may be used for delivery of nucleotide sequences to the targeted organ, tissue, or cell population. (See, e.g., Di Nicoha, M. et al. (1998) Cancer Gen. Ther. 5(6):350-356; Yu, M. et al. (1993) Proc. Natl. Acad. Sci.
USA 90(13):6340-6344; Buller, R.M. et al. (1985) Nature 317(6040):813-815;
McGregor, D.P. et al.
(1994) Mol. Immunol. 31(3):219-226; and Verma, LM. and N. Somia (1997) Nature 389:239-242.) The invention is not limited by the host cell employed.
In bacterial systems, a number of cloning and expression vectors may be selected depending upon the use intended for polynucleotide sequences encoding CSAP. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding CSAP can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Johla CA) or PSPORTl plasmid (Life Teclmohogies). Ligation of sequences encoding CSAP into the vector's multiple cloning site disrupts the lacZ gene, allowing a cohorimetric screening procedure for identification of transformed bacteria containing recombinant molecules. In addition, these vectors may be useful for in vitro transcription, dideoxy sequencing, single strand rescue with helper phage, and creation of nested deletions in the cloned sequence. (See, e.g., Van Heeke, G. and S.M.
Schuster (1989) J. Biol.
Chem. 264:5503-5509.) When large quantities of CSAP are needed, e.g. for the production of antibodies, vectors which direct high level expression of CSAP may be used.
For example, vectors containing the strong, inducible SP6 or T7 bacteriophage promoter may be used.
Yeast expression systems may be used for production of CSAP. A number of vectors containing constitutive or inducible promoters, such as alpha factor, ahcohoh oxidase, and PGH
promoters, may be used in the yeast Saccharomyces cerevisiae or Pichia pastoris. In addition, such vectors direct either the secretion or intracellular retention of expressed proteins and enable integration of foreign sequences into the host genome for stable propagation.
(See, e.g., Ausubel, 1995, sue; Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) Bio/Technohogy 12:181-184.) Plant systems may also be used for expression of CSAP. Transcription of sequences encoding CSAP may be driven by viral promoters, e.g., the 35S and 195 promoters of CaMV used alone or in combination with the omega leader sequence from TMV (Takamatsu, N.
(1987) EMBO J.
6:307-311). Alternatively, plant promoters such as the small subunit of RUBISCO or heat shock promoters may be used. (See, e.g., Coruzzi, G. et a1. (1984) EMBO J. 3:1671-1680; Broglie, R. et a1.
(1984) Science 224:838-843; and Winter, J. et al. (1991) Results Probl. Cell Differ. 17:85-105.) These constructs can be introduced into plant cells by direct DNA
transformation or pathogen-mediated transfection. (See, e.g., The McGraw Hill Yearbook of Science and Teclmolo~y (1992) McGraw Hill, New York NY, pp. 191-196.) In mammalian cells, a number of viral-based expression systems may be utilized. In cases where an adenovirus is used as an expression vector, sequences encoding CSAP
may be ligated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insertion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses CSAP in host cells. (See, e.g., Logan, J. and T. Shenk (1984) Proc.
Natl. Acad. Sci. USA 81:3655-3659.) In addition, transcription enhancers, such as the Rous sarcoma virus (RSV) enhancer, may be used to increase expression in mammalian host cells. SV40 or EBV-based vectors may also be used for high-level protein expression.
Human artificial chromosomes (HACs) may also be employed to deliver larger fragments of DNA than can be contained in and expressed from a plasmid. HACs of about 6 kb to 10 Mb are constructed and delivered via conventional delivery methods (liposomes, polycationic amino IO polymers, or vesicles) for therapeutic purposes. (See, e.g., Harnngton, J.J. et aI. (1997) Nat. Genet.
15:345-355.) For Long term production of recombinant proteins in mammalian systems, stable expression of CSAP in cell lines is preferred. For example, sequences encoding CSAP can be transformed into cell Lines using expression vectors which may contain viral origins of replication and/or endogenous expression elements and a selectable marker gene on the same or on a separate vector. Following the introduction of the vector, cells may be allowed to grow for about 1 to 2 days in enriched media before being switched to selective media. The purpose of the selectable marker is to confer resistance to a selective agent, and its presence allows growth and recovery of cells which successfully express the introduced sequences. Resistant clones of stably transformed cells may be propagated using tissue culture techniques appropriate to the cell type.
Any number of selection systems may be used to recover transformed cell Lines.
These include, but are not limited to, the herpes simplex virus thymidine kinase and adenine phosphoribosyltransferase genes, fox use in tk- and apY cells, respectively.
(See, e.g., Wigler, M. et al. (1977) Cell 11:223-232; Lowy, I. et al. (1980) Cell 22:817-823.) Also, antimetabolite, antibiotic, or herbicide resistance can be used as the basis for selection. For example, dlzfr confers resistance to methotrexate; neo confers resistance to the aminoglycosides neomycin and G-418; and als and pat confer resistance to chlorsulfuron and phosphinotricin acetyltransferase, respectively. (See, e.g., Wigler, M. et a1. (1980) Proc. Natl. Acad. Sci. USA 77:3567-3570; Colbere-Garapin, F. et al. (1981) J. Mol. Biol. 150:1-14.) Additional selectable genes have been described, e.g., trpB and hisD, which alter cellular requirements for metabolites. (See, e.g., Hartman, S.C. and R.C. Mulligan (1988) Proc.
Natl. Acad. Sci. USA 85:8047-8051.) Visible markers, e.g., anthocyanins, green fluorescent proteins (GFP; Clontech),13 glucuronidase and its substrate 13-glucuronide, or luciferase and its substrate luciferin may be used. These markers can be used not only to identify transformants, but also to quantify the amount of transient or stable protein expression attributable to a specific vector system.
44.

(See, e.g., Rhodes, C.A. (1995) Methods Mol. Biol. 55:121-131.) Although the presencelabsence of marker gene expression suggests that the gene of interest is also present, the presence and expression of the gene may need to be confirmed. For example, if the sequence encoding CSAP is inserted within a marker gene sequence, transformed cells containing sequences encoding CSAP can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding CSAP under the control of a single promoter. Expression of the marker gene in response to induction or selection usually indicates expression of the tandem gene as well.
In general, host cells that contain the nucleic acid sequence encoding CSAP
and that express CSAP may be identified by a variety of procedures known to those of skill in the art. These procedures include, but are not limited to, DNA-DNA or DNA-RNA hybridizations, PCR
amplification, and protein bioassay or immunoassay techniques which include membrane, solution, or chip based technologies for the detection and/or quantification of nucleic acid or protein sequences.
Immunological methods for detecting and measuring the expression of CSAP using either specific polyclonal or monoclonal antibodies are known in the art. Examples of such techniques include enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), and fluorescence activated cell sorting (FACS). A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering epitopes on CSAP is preferred, but a competitive binding assay may be employed. These and other assays are well known in the art. (See, e.g., Hampton, R, et al. (1990) Serolo~,ical Methods, a Laboratory Manual, APS
Press, St. Paul MN, Sect. IV; Coligan, J.E. et al. (1997) Current Protocols in Immunolo~y, Greene Pub. Associates and Wiley-Interscience, New York NY; and Pound, J.D. ( 1990 Immunochemical Protocols, Humane Press, Totowa NJ.) A wide variety of labels and conjugation techniques are known by those skilled in the art and may be used in various nucleic acid and amino acid assays. Means for producing labeled hybridization or PCR probes for detecting sequences related to polynucleotides encoding CSAP
include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.
Alternatively, the sequences encoding CSAP, or any fragments thereof, may be cloned into a vector for the production of an mRNA probe. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by addition of an appropriate RNA polymerase such as T7, T3, or SP6 and labeled nucleotides. These procedures may be conducted using a variety of commercially available kits, such as those provided by Amersham Pharmacia Biotech, Promega (Madison WI), and US Biochemical. Suitable reporter molecules or labels which may be used for ease of detection include radionuclides, enzymes, fluorescent, chemiluminescent, or chromogenic agents, as well as substrates, cofactors, inhibitors, magnetic particles, and the Like.
Host cells transformed with nucleotide sequences encoding CSAP may be cultured under conditions suitable for the expression and recovery of the protein from cell culture. The protein produced by a transformed cell may be secreted or retained intracellularly depending on the sequence and/or the vector used. As will be understood by those of skill in the art, expression vectors containing polynucleotides which encode CSAP may be designed to contain signal sequences which direct secretion of CSAP through a prokaryotic or eukaryotic cell membrane.
In addition, a host cell strain may be chosen for its ability to modulate expression of the inserted sequences or to process the expressed protein in the desired fashion.
Such modifications of the polypeptide include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. Post-translational processing which cleaves a "prepro" or "pro" form of the protein may also be used to specify protein targeting, folding, and/or activity.
Different host cells which have specific cellular machinery and characteristic mechanisms for post-translational activities (e.g., CHO, HeLa, MDCK, HEK293, and WI38) are available from the American Type Culture Collection (ATCC, Manassas VA) and may be chosen to ensure the correct modification and processing of the foreign protein.
In another embodiment of the invention, natural, modified, or recombinant nucleic acid sequences encoding CSAP may be ligated to a heterologous sequence resulting in translation of a fusion protein in any of the aforementioned host systems. For example, a chimeric CSAP protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of CSAP activity.
Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but axe not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-myc, and hemagglutinin (HA). GST, MBP, Trx, CBP, and 6-His enable purification of their cognate fusion proteins on immobilized glutathione, maltose, phenylarsine oxide, calmodulin, and metal-chelate resins, respectively. FLAG, c-myc, and hemagglutinin (HA) enable immunoaffinity purification of fusion proteins using commercially available monoclonal and polyclonal antibodies that specifically recognize these epitope tags. A fusion protein may also be engineered to contain a proteolytic cleavage site located between the CSAP encoding sequence and the heterologous protein sequence, so that CSAP may be cleaved away from the heterologous moiety following purification.
Methods for fusion protein expression and purification are discussed in Ausubel (1995, supra, ch. 10).
A variety of commercially available kits may also be used to facilitate expression and purification of fusion proteins.

In a further embodiment of the invention, synthesis of radiolabeled CSAP may be achieved in vitro using the TNT rabbit reticulocyte lysate or wheat germ extract system (Promega). These systems couple transcription and translation of protein-coding sequences operably associated with the T7, T3, or SP6 promoters. Translation takes place in the presence of a radiolabeled amino acid precursor, for example, 35S-methionine.
CSAP of the present invention or fragments thereof may be used to screen for compounds that specifically bind to CSAP. At least one and up to a plurality of test compounds may be screened for specific binding to CSAP. Examples of test compounds include antibodies, oligonucleotides, proteins (e.g., receptors), or small molecules.
In one embodiment, the compound thus identified is closely related to the natural ligand of CSAP, e.g., a Iigand or fragment thereof, a natural substrate, a structural or functional mimetic, or a natural binding partner. (See, e.g., Coligan, J.E. et al. (1991) Current Protocols in Immunolo~y 1(2):
Chapter 5.) Similarly, the compound can be closely related to the natural receptor to which CSAP
binds, or to at least a fragment of the receptor, e.g., the ligand binding site. In either case, the compound can be rationally designed using known techniques. In one embodiment, screening for these compounds involves producing appropriate cells which express CSAP, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Drosophila, or E.
coli. Cells expressing CSAP or cell membrane fractions which contain CSAP are then contacted with a test compound and binding, stimulation, or inhibition of activity of either CSAP or the compound is analyzed.
An assay may simply test binding of a test compound to the polypeptide, wherein binding is detected by a fluorophore, radioisotope, enzyme conjugate, or other detectable label. For example, the assay may comprise the steps of combining at least one test compound with CSAP, either in solution or affixed to a solid support, and detecting the binding of CSAP to the compound.
Alternatively, the assay may detect or measure binding of a test compound in the presence of a labeled competitor. Additionally, the assay may be carried out using cell-free preparations, chemical libraries, or natural product mixtures, and the test compounds) may be free in solution or affixed to a solid support.
CSAP of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of CSAP. Such compounds may include agonists, antagonists, or partial or inverse agonists. In one embodiment, an assay is performed under conditions permissive for CSAP
activity, wherein CSAP is combined with at least one test compound, and the activity of CSAP in the presence of a test compound is compared with the activity of CSAP in the absence of the test compound. A change in the activity of CSAP in the presence of the test compound is indicative of a compound that modulates the activity of CSAP. Alternatively, a test compound is combined with an in vitro or cell-free system comprising CSAP under conditions suitable for CSAP activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of CSAP
may do so indirectly and need not come in direct contact with the test compound. At least one and up~
to a plurality of test compounds may be screened.
In another embodiment, polynucleotides encoding CSAP or their mammalian homologs may be "knocked out" in an animal model system using homologous recombination in embryonic stem (ES) cells. Such techniques are well known in the art and are useful for the generation of animal models of human disease. (See, e.g., U.S. Patent No. 5,175,383 and U.S. Patent No. 5,767,337.) For example, mouse ES cells, such as the mouse 129/SvJ cell line, are derived from the early mouse embryo and grown in culture. The ES cells are transformed with a vector containing the gene of interest disrupted by a marker gene, e.g., the neomycin phosphotransferase gene (neo; Capecchi, M.R.
(1989) Science 244:1288-1292). The vector integrates into the corresponding region of the host genome by homologous recombination. Alternatively, homologous recombination takes place using the Cre-loxP system to knockout a gene of interest in a tissue- or developmental stage-specific manner (Marth, J.D. (1996) Clin. Invest. 97:1999-2002; Wagner, K.U, et al.
(1997) Nucleic Acids Res. 25:4323-4330). Transformed ES cells are identified and microinjected into mouse cell blastocysts such as those from the C57BL/6 mouse strain. The blastocysts are surgically transferred to pseudopregnant dams, and the resulting chimeric progeny are genotyped and bred to produce heterozygous or homozygous strains. Transgenic animals thus generated may be tested with potential therapeutic or toxic agents.
Polynucleotides encoding CSAP may also be manipulated in vitro in ES cells derived from human blastocysts. Human ES cells have the potential to differentiate into at least eight separate cell lineages including endoderm, mesoderm, and ectodermal cell types. These cell lineages differentiate into, for example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J.A. et al.
(1998) Science 282:1145-1147).
Polynucleotides encoding CSAP can also be used to create "knockin" humanized animals (pigs) or transgenic animals (mice or rats) to model human disease. With knockin technology, a region of a polynucleotide encoding CSAP is injected into animal ES cells, and the injected sequence integrates into the animal cell genome. Transformed cells are injected into blastulae, and the blastulae are implanted as described above. Transgenic progeny or inbred lines are studied and treated with potential pharmaceutical agents to obtain information on treatment of a human disease.
Alternatively, a mammal inbred to overexpress CSAP, e.g., by secreting CSAP in its milk, may also serve as a convenient source of that protein (Janne, J. et al. (1998) Biotechnol. Annu. Rev. 4:55-74).

THERAPEUTICS
Chemical and structural similarity, e.g., in the context of sequences and motifs, exists between regions of CSAP and cytoskeleton-associated proteins. In addition, examples of tissues expressing CSAP are normal and cancerous lung tissues, and normal and cancerous breast tissues, and can also be found in Table 6. Therefore, CSAP appears to play a role in cell proliferative disorders, viral infections, and neurological disorders. In the treatment of disorders associated with increased CSAP expression or activity, it is desirable to decrease the expression or activity of CSAP.
In the treatment of disorders associated with decreased CSAP expression or activity, it is desirable to increase the expression or activity of CSAP.
Therefore, in one embodiment, CSAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of CSAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and a cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a viral infection such as those caused by adenoviruses (acute respiratory disease, pneumonia), arenaviruses (lymphocytic choriomeningitis), bunyaviruses (Hantavirus), coronaviruses (pneumonia, chronic bronchitis), hepadnaviruses (hepatitis), herpesviruses (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus), flaviviruses (yellow fever), orthomyxoviruses (influenza), papillomaviruses (cancer), paramyxoviruses (measles, mumps), picornoviruses (rhinovirus, poliovirus, coxsackie-virus), polyomaviruses (BK virus, JC virus), poxviruses (smallpox), reovirus (Colorado tick fever), retroviruses (human immunodeficiency virus, human T lymphotropic virus), rhabdoviruses (rabies), rotaviruses (gastroenteritis), and togaviruses (encephalitis, rubella); and a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, a prion disease including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, tuberous sclerosis, cerebelloretinal hemangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disoxders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder.
In another embodiment, a vector capable of expressing CSAP or a fragment or derivative thereof may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of CSAP including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified CSAP in conjunction with a suitable pharmaceutical carrier may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of CSAP including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of CSAP
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of CSAP including, but not limited to, those listed above.
In a further embodiment, an antagonist of CSAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of CSAP.
Examples of such disorders include, but are not limited to, those cell pxoliferative disorders, viral infections, and neurological disorders described above. In one aspect, an antibody which specifically binds CSAP
may be used directly as an antagonist or indirectly as a targeting or delivery mechanism for bringing a pharmaceutical agent to cells or tissues which express CSAP.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding CSAP may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of CSAP including, but not limited to, those described above.
In other embodiments, any of the proteins, antagonists, antibodies, agonists, complementary sequences, or vectors of the invention may be administered in combination with other appropriate therapeutic agents. Selection of the appropriate agents for use in combination therapy may be made by one of ordinary skill in the art, according to conventional pharmaceutical principles. The combination of therapeutic agents may act synergistically to effect the treatment or prevention of the various disorders described above. Using this approach, one may be able to achieve therapeutic efficacy with lower dosages of each agent, thus reducing the potential for adverse side effects.
An antagonist of CSAP may be produced using methods which are generally known in the art. In particular, purified CSAP may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind CSAP.
Antibodies to CSAP may also be generated using methods that are well known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, and single chain antibodies, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies (i.e., those which inhibit dimer formation) are generally preferred for therapeutic use. Single chain antibodies (e.g., from camels or llamas) may be potent enzyme inhibitors and may have advantages in the design of peptide mimetics, and in the development of immuno-adsorbents and biosensors (Muyldermans, S. (2001) J.
Biotechnol. 74:277-302).
For the production of antibodies, various hosts including goats, rabbits, rats, mice, camels, dromedaries, llamas, humans, and others may be immunized by injection with CSAP or with any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, KLH, and dinitrophenol.
Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to CSAP have an amino acid sequence consisting of at least about 5 amino acids, and generally will consist of at least about 10 amino acids. It is also preferable that these oligopeptides, peptides, or fragments are identical to a portion of the amino acid sequence of the natural protein. Short stretches of CSAP amino acids may be fused with those of another protein, such as KLH, and antibodies to the chimeric molecule may be produced.
Monoclonal antibodies to CSAP may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EB V-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D.
et aI. (1985) J.
Immunol. Methods 81:31-42; Cote, R.J. et al. (1983) Proc. Natl. Acad. Sci. USA
80:2026-2030; and Cole, S.P. et al. (1984) Mol. Cell Biol. 62:109-120.) In addition, techniques developed for the production of "chimeric antibodies,"
such as the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity, can be used. (See, e.g., Morrison, S.L. et al. (1984) Proc.

Natl. Acad. Sci. USA 81:6851-6855; Neuberger, M.S. et al. (1984) Nature 312:604-608; and Takeda, S. et al. (1985) Nature 314:452-454.) Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce CSAP-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries. (See, e.g., Burton, D.R. (1991) Proc. Natl. Acad. Sci. USA 88:10134-10137.) Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as disclosed in the literature. (See, e.g., Orlandi, R. et al. (1989) Proc. Natl.
Acad. Sci. USA
86:3833-3837; Winter, G. et al. (1991) Nature 349:293-299.) Antibody fragments which contain specific binding sites for CSAP may also be generated.
For example, such fragments include, but are not limited to, F(ab~2 fragments produced by pepsin digestion of the antibody molecule and Fab fragments generated by reducing the disulfide bridges of the F(ab'~2 fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity.
(See, e.g., Huse, W.D.
et al. (1989) Science 246:1275-1281.) Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificities are well known in the art. Such immunoassays typically involve the measurement of complex formation between CSAP and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering CSAP epitopes is generally used, but a competitive binding assay may also be employed (Pound, sacra).
Various methods such as Scatchard analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for CSAP. Affinity is expressed as an association constant, Ka, which is defined as the molar concentration of CSAP-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions.
The Ka determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple CSAP epitopes, represents the average affinity, or avidity, of the antibodies for CSAP. The Ka determined for a preparation of monoclonal antibodies, which are monospecific for a particular CSAP epitope, represents a true measure of affinity. High-affinity antibody preparations with Ka ranging from about 109 to 1012 L/mole are preferred for use in immunoassays in which the CSAP-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with Ka ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of CSAP, preferably in active form, from the antibody (Catty, D. (1988) Antibodies, Volume I: A Practical Approach, IRL
Press, Washington DC;
Liddell, J.E. and A. Cryer (1991) A Practical Guide to Monoclonal Antibodies, John Wiley & Sons, New York NY).
The titer and avidity of polyclonal antibody preparations may be further evaluated to determine the quality and suitability of such preparations for certain downstream applications. For example, a polyclonal antibody preparation containing at least 1-2 mg specific antibody/ml, preferably 5-10 mg specific antibody/ml, is generally employed in procedures requiring precipitation of CSAP-antibody complexes. Procedures for evaluating antibody specificity, titer, and avidity, and guidelines for antibody quality and usage in various applications, are generally available. (See, e.g., Catty, supra, and Coligan et al. supra.) In another embodiment of the invention, the polynucleotides encoding CSAP, or any fragment or complement thereof, may be used for therapeutic purposes. In one aspect, modifications of gene expression can be achieved by designing complementary sequences or antisense molecules (DNA, RNA, PNA, or modified oligonucleotides) to the coding or regulatory regions of the gene encoding CSAP. Such technology is well known in the art, and antisense oligonucleotides or larger fragments can be designed from various locations along the coding or control regions of sequences encoding CSAP. (See, e.g., Agrawal, S., ed. (1996) Antisense Therapeutics, Humana Press Inc., Totawa NJ.) In therapeutic use, any gene delivery system suitable for introduction of the antisense sequences into appropriate target cells can be used. Antisense sequences can be delivered intracellularly in the form of an expression plasmid which, upon transcription, produces a sequence complementary to at least a portion of the cellular sequence encoding the target protein. (See, e.g., Slater, J.E. et al. (1998) J. Allergy Clin. Immunol. 102(3):469-475; and Scanlon, I~.J. et al. (1995) 9(13):1288-1296.) Antisense sequences can also be introduced intracellularly through the use of viral vectors, such as retrovirus and adeno-associated virus vectors. (See, e.g., Miller, A.D. (1990) Blood 76:271; Ausubel, supra; Uckert, W. and W. Walther (1994) Pharmacol. Ther.
63(3):323-347.) Other gene delivery mechanisms include liposome-derived systems, artificial viral envelopes, and other systems known in the art. (See, e.g., Rossi, J.J. (1995) Br. Med. Bull.
51(1):217-225; Boado, R.J. et aI. (1998) J. Pharm. Sci. 87(11):I308-I3I5; and Morris, M.C. et al. (1997) Nucleic Acids Res.
25 ( 14):2730-2736.) In another embodiment of the invention, polynucleotides encoding CSAP may be used for somatic or germline gene therapy. Gene therapy may be performed to (i) correct a genetic deficiency (e.g., in the cases of severe combined immunodeficiency (SCID)-XI disease characterized by X-linked inheritance (Cavazzana-Calvo, M. et al. (2000) Science 288:669-672), severe combined immunodeficiency syndrome associated with an inherited adenosine deaminase (ADA) deficiency (Blaese, R.M. et al. (1995) Science 270:475-480; Bordignon, C. et al. (1995) Science 270:470-475), cystic fibrosis (Zabner, J. et al. (1993) Cell 75:207-216; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:643-666; Crystal, R.G. et al. (1995) Hum. Gene Therapy 6:667-703), thalassamias, familial hypercholesterolemia, and hemophilia resulting from Factor VIII or Factor IX
deficiencies (Crystal, R.G. (1995) Science 270:404-410; Verma, LM. and N. Somia (1997) Nature 389:239-242)), (ii) express a conditionally lethal gene product (e.g., in the case of cancers which result from unregulated cell proliferation), or (iii) express a protein which affords protection against intracellular parasites (e.g., against human retroviruses, such as human immunodeficiency virus (HIV) (Baltimore, D.
(1988) Nature 335:395-396; Poeschla, E. et al. (1996) Proc. Natl. Acad. Sci.
USA 93:11395-11399), hepatitis B or C virus (HBV, HCV); fungal parasites, such as Candida albicans and Paracoccidioides brasiliensis; and protozoan parasites such as Plasmodium falci~ and Trypanosoma cruzi). In the case where a genetic deficiency in CSAP expression or regulation causes disease, the expression of CSAP from an appropriate population of transduced cells may alleviate the clinical manifestations caused by the genetic deficiency.
In a further embodiment of the invention, diseases or disorders caused by deficiencies in CSAP are treated by constructing mammalian expression vectors encoding CSAP
and introducing these vectors by mechanical means into CSAP-deficient cells. Mechanical transfer technologies for use with cells in vivo or ex vitro include (i) direct DNA microinjection into individual cells, (ii) ballistic gold particle delivery, (iii) liposome-mediated transfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA transposons (Morgan, R.A. and W.F. Anderson (1993) Annu. Rev.
Biochem. 62:191-217; Ivics, Z. (1997) Cell 91:501-510; Boulay, J-L. and H.
Recipon (1998) Curr.
Opin. Biotechnol. 9:445-450).
Expression vectors that may be effective for the expression of CSAP include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX, PCR2-TOPOTA vectors (Invitrogen, Carlsbad CA), PCMV-SCRIPT, PCMV-TAG, PEGSH/PERV (Stratagene, La Jolla CA), and PTET-OFF, PTET-ON, PTRE2, PTRE2-LUC, PTK-HYG (Clontech, Palo Alto CA).
CSAP may be expressed using (i) a constitutively active promoter, (e.g., from cytomegalovirus (CMV), Rous sarcoma virus (RSV), SV40 virus, thymidine kinase (TK), or (3-actin genes), (ii) an inducible m promoter (e.g., the tetracycline-regulated promoter (Gossen, M. and H. Bujard (1992) Proc. Natl.
Acad. Sci. USA 89:5547-5551; Gossen, M. et al. (1995) Science 268:1766-1769;
Rossi, F.M.V. and H.M. Blau (1998) Curr. Opin. Biotechnol. 9:451-456), commercially available in the T-REX plasmid (Invitrogen)); the ecdysone-inducible promoter (available in the plasmids PVGRXR and PIND;

Invitrogen); the FK506lrapamycin inducible promoter; or the RU486lmifepristone inducible promoter (Rossi, F.M.V. and H.M. Blau, sue)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding CSAP from a normal individual.
Commercially available liposome transformation kits (e.g., the PERFECT LIPID
TRANSFECTION KTT, available from Invitrogen) allow one with ordinary skill in the art to deliver polynucleotides to target cells in culture and require minimal effort to optimize experimental parameters. In the alternative, transformation is performed using the calcium phosphate method (Graham, F.L. and A.J. Eb (1973) Virology 52:456-467), or by electroporation (Neumann, E. et al.
(1982) EMBO J. 1:841-845). The introduction of DNA to primary cells requires modification of these standardized mammalian transfection protocols.
In another embodiment of the invention, diseases or disorders caused by genetic defects with respect to CSAP expression axe treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding CSAP under the control of an independent promoter or the retrovirus long terminal repeat (LTR) promoter, (ii) appropriate RNA packaging signals, and (iii) a Rev-responsive element (RRE) along with additional retrovirus cis-acting RNA sequences and coding sequences required for efficient vector propagation. Retrovirus vectors (e.g., PFB and PFBNEO) are commercially available (Stratagene) and are based on published data (Riviere, I. et al. (1995) Proc.
Natl. Acad. Sci. USA 92:6733-6737), incorporated by reference herein. The vector is propagated in an appropriate vector producing cell line (VPCL) that expresses an envelope gene with a tropism for receptors on the target cells or a promiscuous envelope protein such as VSVg (Armentano, D. et al.
(1987) J. Virol. 61:1647-1650; Bender, M.A. et al. (1987) J. Virol. 61:1639-1646; Adam, M.A. and A.D. Miller (1988) J. Virol. 62:3802-3806; Dull, T. et al. (1998) J. Virol.
72:8463-8471; Zufferey, R.
et al. (1998) J. Virol. 72:9873-9880). U.S. Patent No. 5,910,434 to Rigg ("Method for obtaining retrovirus packaging cell lines producing high transducing efficiency retroviral supernatant") discloses a method for obtaining retrovirus packaging cell lines and is hereby incorporated by reference. Propagation of retrovirus vectors, transduction of a population of cells (e.g., CD4+ T-cells), and the return of transduced cells to a patient are procedures well known to persons skilled in the art of gene therapy and have been well documented (Ranga, U. et al. (1997) J. Virol. 71:7020-7029; Bauer, G. et al. (1997) Blood 89:2259-2267; Bonyhadi, M.L. (1997) J.
Virol. 71:4707-4716;
Ranga, U. et al. (1998) Proc. Natl. Acad. Sci. USA 95:1201-1206; Su, L. (1997) Blood 89:2283-2290).
In the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding CSAP to cells which have one or more genetic abnormalities with respect to the expression of CSAP. The construction and packaging of adenovirus-based vectors are well known to those with ordinary skill in the art. Replication defective adenovirus vectors have proven to be versatile for importing genes encoding immunoregulatory proteins into intact islets in the pancreas (Csete, M.E. et aI. (I995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Patent No. 5,707,618 to Armentano ("Adenovirus vectors for gene therapy"), hereby incorporated by reference. For adenoviral vectors, see also Antinozzi, P.A. et al. (1999) Annu. Rev. Nutr. 19:511-544 and Verma, LM. and N. Somia (1997) Nature 18:389:239-242, both incorporated by reference herein.
In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding CSAP to target cells which have one or more genetic abnormalities with respect to the expression of CSAP. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing CSAP to cells of the central nervous system, for which HSV has a tropism. The construction and packaging of herpes-based vectors are well known to those with ordinary skill in the art. A replication-competent herpes simplex virus (HSV) type 1-based vector has been used to deliver a reporter gene to the eyes of primates (Liu, X. et al.
(1999) Exp. Eye Res.
169:385-395). The construction of a HSV-1 virus vector has also been disclosed in detail in U.S.
Patent No. 5,804,413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U.S. Patent No. 5,804,413 teaches the use of recombinant HSV d92 which consists of a genome containing at least one exogenous gene to be transferred to a cell under the control of the appropriate promoter for purposes including human gene therapy.
Also taught by this patent are the construction and use of recombinant HSV strains deleted for ICP4, ICP27 and ICP22.
For HSV vectors, see also Goins, W.F. et al. (1999) J. Virol. 73:519-532 and Xu, H. et al. (1994) Dev. Biol. 163:152-161, hereby incorporated by reference. The manipulation of cloned herpesvirus sequences, the generation of recombinant virus following the transfection of multiple plasmids containing different segments of the large herpesvirus genomes, the growth and propagation of herpesvirus, and the infection of cells with herpesvirus are techniques well known to those of ordinary skill in the art.
In another alternative, an alphavirus (positive, single-stranded RNA virus) vector is used to deliver polynucleotides encoding CSAP to target cells. The biology of the prototypic alphavirus, Semliki Forest Virus (SFV), has been studied extensively and gene transfer vectors have been based on the SFV genome (Garoff, H. and I~.-J. Li (1998) Curr. Opin. Biotechnol.
9:464-469). During alphavirus RNA replication, a subgenomic RNA is generated that normally encodes the viral capsid proteins. This subgenomic RNA replicates to higher levels than the full length genomic RNA, resulting in the overproduction of capsid proteins relative to the viral proteins with enzymatic activity (e.g., protease and polymerase). Similarly, inserting the coding sequence for CSAP into the alphavirus genome in place of the capsid-coding region results in the production of a large number of CSAP-coding RNAs and the synthesis of high levels of CSAP in vector transduced cells. While alphavirus infection is typically associated with cell lysis within a few days, the ability to establish a persistent infection in hamster normal kidney cells (BHK-21) with a variant of Sindbis virus (SIN) indicates that the lytic replication of alphaviruses can be altered to suit the needs of the gene therapy application (Dryga, S.A. et al. (1997) Virology 228:74-83). The wide host range of alphaviruses will allow the introduction of CSAP into a variety of cell types. The specific transduction of a subset of cells in a population may require the sorting of cells prior to transduction.
The methods of manipulating infectious cDNA clones of alphaviruses, performing alphavirus cDNA and RNA
transfections, and performing alphavirus infections, are well known to those with ordinary skill in the art.
Oligonucleotides derived from the transcription initiation site, e.g., between about positions -10 and +10 from the start site, may also be employed to inhibit gene expression. Similarly, inhibition can be achieved using triple helix base-pairing methodology. Triple helix pairing is useful because it causes inhibition of the ability of the double helix to open sufficiently for the binding of polymerases, transcription factors, or regulatory molecules. Recent therapeutic advances using triplex DNA have been described in the literature. (See, e.g., Gee, J.E. et al. (1994) in Huber, B.E.
and B.I. Carr, Molecular and Immunolo~ic Approaches, Futura Publishing, Mt.
Kisco NY, pp. 163-177.) A complementary sequence or antisense molecule may also be designed to block translation of mRNA by preventing the transcript from binding to ribosomes.
Ribozymes, enzymatic RNA molecules, may also be used to catalyze the specific cleavage of RNA. The mechanism of ribozyme action involves sequence-specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleolytic cleavage.
For example, engineered hammerhead motif ribozyme molecules may specifically and efficiently catalyze endonucleolytic cleavage of sequences encoding CSAP.
Specific ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, including the following sequences: GUA, GUU, and GUC. Once identified, short RNA sequences of between 15 and 20 ribonucleotides, corresponding to the region of the target gene containing the cleavage site, may be evaluated for secondary structural features which may render the oligonucleotide inoperable.
The suitability of candidate targets may also be evaluated by testing accessibility to hybridization with complementary oligonucleotides using ribonuclease protection assays.
Complementary ribonucleic acid molecules and ribozymes of the invention may be prepared by any method known in the art for the synthesis of nucleic acid molecules.
These include techniques for chemically synthesizing oligonucleotides such as solid phase phosphoramidite chemical synthesis.
Alternatively, RNA molecules may be generated by in vitro and in vivo transcription of DNA
sequences encoding CSAP. Such DNA sequences may be incorporated into a wide variety of vectors with suitable RNA polymerase promoters such as T7 or SP6. Alternatively, these cDNA constructs that synthesize complementary RNA, constitutively or inducibly, can be introduced into cell lines, cells, or tissues.
RNA molecules may be modified to increase intracellular stability and half-life. Possible modifications include, but are not limited to, the addition of flanking sequences at the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2' O-methyl rather than phosphodiesterase linkages within the backbone of the molecule. This concept is inherent in the production of PNAs and can be extended in all of these molecules by the inclusion of nontraditional bases such as inosine, queosine, and wybutosine, as well as acetyl-, methyl-, thin-, and similarly modified forms of adenine, cytidine, guanine, thymine, and uridine which are not as easily recognized by endogenous endonucleases. ., An additional embodiment of the invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding CSAP. Compounds which may be effective in altering expression of a specific polynucleotide may include, but are not limited to, oligonucleotides, antisense oligonucleotides, triple helix-forming oligonucleotides, transcription factors and other polypeptide transcriptional regulators, and non-macromolecular chemical entities which are capable of interacting with specific polynucleotide sequences., Effective compounds may alter polynucleotide expression by acting as either inhibitors or promoters of polynucleotide expression. Thus, in the treatment of disorders associated with increased CSAP
expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding CSAP may be therapeutically useful, and in the treatment of disoxders associated with decreased CSAP expression or activity, a compound which specifically promotes expression of the polynucleotide encoding CSAP may be therapeutically useful.
At least one, and up to a plurality, of test compounds may be screened for effectiveness in altering expression of a specific polynucleotide. A test compound may be obtained by any method commonly known in the art, including chemical modification of a compound known to be effective in altering polynucleotide expression; selection from an existing, commercially-available or proprietary library of naturally-occurnng or non-natural chemical compounds; rational design of a compound based on chemical and/or structural properties of the target polynucleotide;
and selection from a library of chemical compounds created combinatorially or randomly. A sample comprising a polynucleotide encoding CSAP is exposed to at least one test compound thus obtained. The sample may comprise, for example, an intact or permeabilized cell, or an in vitro cell-free or reconstituted biochemical system. Alterations in the expression of a polynucleotide encoding CSAP are assayed by any method commonly known in the art. Typically, the expression of a specific nucleotide is detected by hybridization with a probe having a nucleotide sequence complementary to the sequence of the polynucleotide encoding CSAP. The amount of hybridization may be quantified, thus forming the basis fox a comparison of the expression of the polynucleotide both with and without exposure to one or more test compounds. Detection of a change in the expression of a polynucleotide exposed to a test compound indicates that the test compound is effective in altering the expression of the polynucleotide. A screen for a compound effective in altering expression of a specific polynucleotide can be carried out, for example, using a Schizosaccharomyces pombe gene expression system (Atkins, D. et al. (1999) U.S. Patent No. 5,932,435; Arndt, G.M. et al. (2000) Nucleic Acids Res.
28:E15) or a human cell line such as HeLa cell (Clarke, M.L. et al. (2000) Biochem. Biophys. Res.
Commun. 268:8-13). A particular embodiment of the present invention involves screening a combinatorial library of oligonucleotides (such as deoxyribonucleotides, ribonucleotides, peptide nucleic acids, and modified oligonucleotides) for antisense activity against a specific polynucleotide sequence (Bruice, T.W. et al. (1997) U.S. Patent No. 5,686,242; Bruice, T.W.
et al. (2000) U.S.
Patent No. 6,022,691).
Many methods for introducing vectors into cells or tissues are available and equally suitable for use in vivo, in vitro, and ex vivo. For ex vivo therapy, vectors may be introduced into stem cells taken from the patient and clonally propagated for autologous transplant back into that same patient.
Delivery by transfection, by liposome injections, or by polycationic amino polymers may be achieved using methods which are well known in the art. (See, e.g., Goldman, C.K. et al. (1997) Nat.
Biotechnol. 15:462-466.) Any of the therapeutic methods described above may be applied to any subject in need of such therapy, including, for example, mammals such as humans, dogs, cats, cows, horses, rabbits, and monkeys.
An additional embodiment of the invention relates to the administration of a composition which generally comprises an active ingredient formulated with a pharmaceutically acceptable excipient. Excipients may include, for example, sugars, starches, celluloses, gums, and proteins.
Various formulations are commonly known and are thoroughly discussed in the latest edition of Remin~ton's Pharmaceutical Sciences (Maack Publishing, Easton PA). Such compositions may consist of CSAP, antibodies to CSAP, and mimetics, agonists, antagonists, or inhibitors of CSAP.
The compositions utilized in this invention may be administered by any number of routes including, but not limited to, oral, intravenous, intramuscular, infra-arterial, intramedullary, intrathecal, intraventricular, pulmonary, transdermal, subcutaneous, intraperitoneal, intranasal, enteral, topical, sublingual, or rectal means.
Compositions for pulmonary administration may be prepared in liquid or dry powder form.
These compositions are generally aerosolized immediately prior to inhalation by the patient. In the case of small molecules (e.g. traditional low molecular weight organic drugs), aerosol delivery of fast-acting formulations is well-known in the art. In the case of macromolecules (e.g. larger peptides and proteins), recent developments in the field of pulmonary delivery via the alveolar region of the lung have enabled the practical delivery of drugs such as insulin to blood circulation (see, e.g., Patton, J.S. et al., U.S. Patent No. 5,997,848). Pulmonary delivery has the advantage of administration without needle injection, and obviates the need for potentially toxic penetration enhancers.
Compositions suitable fox use in the invention include compositions wherein the active ingredients are contained in an effective amount to achieve the intended purpose. The determination of an effective dose is well within the capability of those skilled in the art.
Specialized forms of compositions may be prepared for direct intracellular delivery of macromolecules comprising CSAP or fragments thereof. For example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, CSAP or a fragment thereof may be joined to a short cationic N-terminal portion from the HIV Tat-1 protein. Fusion proteins thus generated have been found to transduce into the cells of all tissues, including the brain, in a mouse model system (Schwarze, S.R. et al. (1999) Science 285:1569-1572).
For any compound, the therapeutically effective dose can be estimated initially either in cell culture assays, e.g., of neoplastic cells, or in animal models such as mice, rats, rabbits, dogs, monkeys, or pigs. An animal model may also be used to determine the appropriate concentration range and route of administration. Such information can then be used to determine useful doses and routes fox administration in humans.
A therapeutically effective dose refers to that amount of active ingredient, for example CSAP
or fragments thereof, antibodies of CSAP, and agonists, antagonists or inhibitors of CSAP, which . ameliorates the symptoms or condition. Therapeutic efficacy and toxicity may be determined by standard pharmaceutical procedures in cell cultures or with experimental animals, such as by calculating the EDSO (the dose therapeutically effective in 50% of the population) or LDSO (the dose lethal to 50% of the population) statistics. The dose ratio of toxic to therapeutic effects is the therapeutic index, which can be expressed as the LDso/EDSO ratio. Compositions which exhibit large therapeutic indices are preferred. The data obtained from cell culture assays and animal studies are used to formulate a range of dosage for human use. The dosage contained in such compositions is preferably within a range of circulating concentrations that includes the EDSO
with little or no toxicity.
The dosage varies within this range depending upon the dosage form employed, the sensitivity of the patient, and the route of administration.
The exact dosage will be determined by the practitioner, in light of factors related to the subject requiring treatment. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Factors which may be taken into account include the severity of the disease state, the general health of the subject, the age, weight, and gender of the subject, time and frequency of administration, drug combination(s), reaction sensitivities, and response to therapy. Long-acting compositions may be administered every 3 to 4 days, every week, or biweekly depending on the half life and clearance rate of the particular formulation.
Normal dosage amounts may vary from about O.l ,ug to 100,000 ,ug, up to a total dose of about 1 gram, depending upon the route of administration. Guidance as to particular dosages and methods of delivery is provided in the literature and generally available to practitioners in the art.
Those skilled in the art will employ different formulations for nucleotides than for proteins or their inhibitors. Similarly, delivery of polynucleotides or polypeptides will be specific to particular cells, conditions, locations, etc.
DIAGNOSTICS
In another embodiment, antibodies which specifically bind CSAP may be used for the diagnosis of disorders characterized by expression of CSAP, or in assays to monitor patients being treated with CSAP or agonists, antagonists, or inhibitors of CSAP. Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for CSAP include methods which utilize the antibody and a label to detect CSAP
in human body fluids or in extracts of cells or tissues. The antibodies may be used with or without modification, and may be labeled by covalent or non-covalent attachment of a reporter molecule.
A wide variety of reporter molecules, several of which are described above, are known in the art and may be used.
A variety of protocols for measuring CSAP, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of CSAP expression. Normal or standard values for CSAP expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to CSAP under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of CSAP
expressed in subject, control, and disease samples from biopsied tissues are compared with the standard values.
Deviation between standard and subject values establishes the parameters for diagnosing disease.
In another embodiment of the invention, the polynucleotides encoding CSAP may be used for diagnostic purposes. The polynucleotides which may be used include oligonucleotide sequences, complementary RNA and DNA molecules, and PNAs. The polynucleotides may be used to detect and quantify gene expression in biopsied tissues in which expression of CSAP
may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of CSAP, and to monitor regulation of CSAP levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding CSAP or closely related molecules may be used to identify nucleic acid sequences which encode CSAP. The specificity of the probe, whether it is made from a highly specific region, e.g., the 5'regulatory region, or from a less specific region, e.g., a conserved motif, and the stringency of the hybridization or amplification will determine whether the probe identifies only naturally occurring sequences encoding CSAP, allelic variants, or related sequences.
Probes may also be used for the detection of related sequences, and may have at least 50%
sequence identity to any of the CSAP encoding sequences. The hybridization probes of the subject invention may be DNA or RNA and may be derived from the sequence of SEQ ID
N0:29-56 or from genomic sequences including promoters, enhancers, and introns of the CSAP
gene.
Means for producing specific hybridization probes for DNAs encoding CSAP
include the cloning of polynucleotide sequences encoding CSAP or CSAP derivatives into vectors for the production of mRNA probes. Such vectors are known in the art, are commercially available, and may be used to synthesize RNA probes in vitro by means of the addition of the appropriate RNA
polymerases and the appropriate labeled nucleotides. Hybridization probes may be labeled by a variety of reporter groups, for example, by radionuclides such as 3'P or 355, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding CSAP may be used for the diagnosis of disorders associated with expression of CSAP. Examples of such disorders include, but are not limited to, a cell proliferative disorder such as actinic keratosis, arteriosclerosis, atherosclerosis, bursitis, cirrhosis, hepatitis, mixed connective tissue disease (MCTD), myelofibrosis, paroxysmal nocturnal hemoglobinuria, polycythemia vera, psoriasis, primary thrombocythemia, and a cancer including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, a cancer of the adrenal gland, bladder, bone, bone marrow, brain, breast, cervix, gall bladder, ganglia, gastrointestinal tract, heart, kidney, liver, lung, muscle, ovary, pancreas, parathyroid, penis, prostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus; a viral infection such as those caused by adenoviruses (acute respiratory disease, pneumonia), arenaviruses (lymphocytic choriomeningitis), bunyaviruses (Hantavirus),. coronaviruses (pneumonia, chronic bronchitis), hepadnaviruses (hepatitis), herpesviruses (herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, cytomegalovirus), flaviviruses (yellow fever), orthomyxoviruses (influenza), papillomaviruses (cancer), paramyxoviruses (measles, mumps), picornoviruses (rhinovirus, poliovirus, coxsackie-virus), polyomaviruses (BK virus, JC virus), poxviruses (smallpox), reovirus (Colorado tick fever), retroviruses'(human immunodeficiency virus, human T lymphotropic virus), rhabdoviruses (rabies), rotaviruses (gastroenteritis), and togaviruses (encephalitis, rubella); and a neurological disorder such as epilepsy, ischemic cerebrovascular disease, stroke, cerebral neoplasms, Alzheimer's disease, Pick's disease, Huntington's disease, dementia, Parkinson's disease and other extrapyramidal disorders, amyotrophic lateral sclerosis and other motor neuron disorders, progressive neural muscular atrophy, retinitis pigmentosa, hereditary ataxias, multiple sclerosis and other demyelinating diseases, bacterial and viral meningitis, brain abscess, subdural empyema, epidural abscess, suppurative intracranial thrombophlebitis, myelitis and radiculitis, viral central nervous system disease, a prion disease including kuru, Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, nutritional and metabolic diseases of the nervous system, neurofibromatosis, I5 tuberous sclerosis, cerebelloretinal hennangioblastomatosis, encephalotrigeminal syndrome, mental retardation and other developmental disorders of the central nervous system, cerebral palsy, neuroskeletal disorders, autonomic nervous system disorders, cranial nerve disorders, spinal cord diseases, muscular dystrophy and other neuromuscular disorders, peripheral nervous system disorders, dermatomyositis and polymyositis, inherited, metabolic, endocrine, and toxic myopathies, myasthenia gravis, periodic paralysis, mental disorders including mood, anxiety, and schizophrenic disorders, seasonal affective disorder (SAD), akathesia, amnesia, catatonia, diabetic neuropathy, tardive dyskinesia, dystonias, paranoid psychoses, postherpetic neuralgia, and Tourette's disorder.
The polynucleotide sequences encoding CSAP may be used in Southern or northern analysis, dot blot, or other membrane-based technologies; in PCR technologies; in dipstick, pin, and multiformat ELISA-like assays; and in microarrays utilizing fluids or tissues from patients to detect altered CSAP
expression. Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding CSAP may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding CSAP may be labeled by standard methods and added to a fluid or tissue sample from a patient under conditions suitable for the formation of hybridization complexes. After a suitable incubation period, the sample is washed and the signal is quantified and compared with a standard value. If the amount of signal in the patient sample is significantly altered in comparison to a control sample then the presence of altered levels of nucleotide sequences encoding CSAP in the sample indicates the presence of the associated disorder. Such assays may also be used to evaluate the efficacy of a particular therapeutic treatment regimen in animal studies, in clinical trials, or to monitor the treatment of an individual patient.
In order to provide a basis for the diagnosis of a disorder associated with expression of CSAP, a normal or standard profile for expression is established. This may be accomplished by S combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding CSAP, under conditions suitable for hybridization or amplification. Standard hybridization may be quantified by comparing the values obtained from normal subjects with values from an experiment in which a known amount of a substantially purified polynucleotide is used. Standard values obtained in this manner may be compared with values obtained from samples from patients who are symptomatic for a disorder.
Deviation from standard values is used to establish the presence of a disorder.
Once the presence of a disorder is established and a treatment protocol is initiated, hybridization assays may be repeated on a regular basis to determine if the level of expression in the patient begins to approximate that which is observed in the normal subject.
The results obtained from successive assays may be used to show the efficacy of treatment over a period ranging from several days to months.
With respect to cancer, the presence of an abnormal amount of transcript (either under- or overexpressed) in biopsied tissue from an individual may indicate a predisposition for the development of the disease, or may provide a means for detecting the disease prior to the appearance of actual clinical symptoms. A more definitive diagnosis of this type may allow health professionals to employ preventative measures or aggressive treatment earlier thereby preventing the development or further progression of the cancer.
Additional diagnostic uses for oligonucleotides designed from the sequences encoding CSAP
may involve the use of PCR. These oligomers may be chemically synthesized, generated enzymatically, or produced in vitro. Oligomers will preferably contain a fragment of a polynucleotide encoding CSAP, or a fragment of a polynucleotide complementary to the polynucleotide encoding CSAP, and will be employed under optimized conditions for identification of a specific gene or condition. Oligomers may also be employed under less stringent conditions for detection or quantification of closely related DNA or RNA sequences.
In a particular aspect, oligonucleotide primers derived from the polynucleotide sequences encoding CSAP may be used to detect single nucleotide polymorphisms (SNPs).
SNPs are substitutions, insertions and deletions that are a frequent cause of inherited or acquired genetic disease in humans. Methods of SNP detection include, but are not limited to, single-stranded conformation polymorphism (SSCP) and fluorescent SSCP (fSSCP) methods. In SSCP, oligonucleotide primers derived from the polynucleotide sequences encoding CSAP are used to amplify DNA using the polymerase chain reaction (PCR). The DNA may be derived, for example, from diseased or normal tissue, biopsy samples; bodily fluids, and the like.
SNPs in the DNA cause differences in the secondary and tertiary structures of PCR products in single-stranded form, and these differences are detectable using gel electrophoresis in non-denaturing gels. In fSCCP, the oligonucleotide primers are fluorescently labeled, which allows detection of the amplimers in high-throughput equipment such as DNA sequencing machines. Additionally, sequence database analysis methods, termed in silico SNP (isSNP), are capable of identifying polymorphisms by comparing the sequence of individual overlapping DNA fragments which assemble into a common consensus sequence. These computer-based methods filter out sequence variations due to laboratory preparation of DNA and sequencing errors using statistical models and automated analyses of DNA sequence chromatograms. In the alternative, SNPs may be detected and characterized by mass spectrometry using, for example, the high throughput MASSARRAY system (Sequenom, Inc., San Diego CA).
SNPs may be used to study the genetic basis of human disease. For example, at least 16 common SNPs have been associated with non-insulin-dependent diabetes mellitus.
SNPs are also useful for examining differences in disease outcomes in monogenic disorders, such as cystic fibrosis, sickle cell anemia, or chronic granulomatous disease. For example, variants in the mannose-binding lectin, MBL2, have been shown to be correlated with deleterious pulmonary outcomes in cystic fibrosis. SNPs also have utility in pharmacogenomics, the identification of genetic variants that influence a patient's response to a drug, such as.life-threatening toxicity.
For example, a variation in N-acetyl transferase is associated with a high incidence of peripheral neuropathy in response to the anti-tuberculosis drug isoniazid, while a variation in the core promoter of the ALOX5 gene results in diminished clinical response to treatment with an anti-asthma drug that targets the 5-lipoxygenase pathway. Analysis of the distribution of SNPs in different populations is useful for investigating genetic drift, mutation, recombination, and selection, as well as for tracing the origins of populations and their migrations. (Taylor, J.G. et al. (2001) Trends Mol. Med. 7:507-512;
Kwok, P.-Y. and Z. Gu (1999) Mol. Med. Today 5:538-543; Nowotny, P. et al. (2001) Curr. Opin.
Neurobiol. 11:637-641.) Methods which may also be used to quantify the expression of CSAP include radiolabeling or biotinylating nucleotides, coamplification of a control nucleic acid, and interpolating results from standard curves. (See, e.g., Melby, P.C. et al. (1993) J. Immunol. Methods 159:235-244; Duplaa, C.
et al. (1993) Anal. Biochem. 212:229-236.) The speed of quantitation of multiple samples may be accelerated by running the assay in a high-throughput format where the oligomer or polynucleotide of interest is presented in various dilutions and a spectrophotometric or colorimetric response gives rapid quantitation.

In further embodiments, oligonucleotides or longer fragments derived from any of the polynucleotide sequences described herein may be used as elements on a microarray. The microarray can be used in transcript imaging techniques which monitor the relative expression levels of large numbers of genes simultaneously as described below. The microarray may also be used to identify genetic variants, mutations, and polymorphisms. This information may be used to determine gene function, to understand the genetic basis of a disorder, to diagnose a disorder, to monitor progression/regression of disease as a function of gene expression, and to develop and monitor the activities of therapeutic agents in the treatment of disease. In particular, this information may be used to develop a pharmacogenomic profile of a patient in order to select the most appropriate and effective treatment regimen for that patient. For example, therapeutic agents which are highly effective and display the fewest side effects may be selected for a patient based on hislher pharmacogenomic profile.
In another embodiment, CSAP, fragments of CSAP, or antibodies specific for CSAP may be used as elements on a microarray. The microarray may be used to monitor or measure protein-protein interactions, drug-target interactions, and gene expression profiles, as described above.
A particular embodiment relates to the use of the polynucleotides of the present invention to generate a transcript image of a tissue or cell type. A transcript image represents the global pattern of gene expression by a particular tissue or cell type. Global gene expression patterns are analyzed by quantifying the number of expressed genes and their relative abundance under given conditions and at a given time. (See Seilhamer et al., "Comparative Gene Transcript Analysis,"
U.S. Patent No.
5,840,484, expressly incorporated by reference herein.) Thus a transcript image may be generated by hybridizing the polynucleotides of the present invention or their complements to the totality of transcripts or reverse transcripts of a particular tissue or cell type. In one embodiment, the hybridization takes place in high-throughput format, wherein the polynucleotides of the present invention or their complements comprise a subset of a plurality of elements on a microarray. The resultant transcript image would provide a profile of gene activity.
Transcript images may be generated using transcripts isolated from tissues, cell lines, biopsies, or other biological samples. The transcript image may thus reflect gene expression in vivo, as in the case of a tissue or biopsy sample, or in vitro, as in the case of a cell line.
Transcript images which profile the expression of the polynucleotides of the present invention may also be used in conjunction with in vitro model systems and preclinical evaluation of pharmaceuticals, as well as toxicological testing of industrial and naturally-occurring environmental compounds. All compounds induce characteristic gene expression patterns, frequently termed molecular fingerprints or toxicant signatures, which are indicative of mechanisms of action and toxicity (Nuwaysir, E.F. et al. (1999) Mol. Carcinog. 24:153-159; Steiner, S.
and N.L. Anderson (2000) Toxicol. Lett. 112-113:467-471, expressly incorporated by reference herein). If a test compound has a signature similar to that of a compound with known toxicity, it is likely to share those toxic properties. These fingerprints or signatures are most useful and refned when they contain expression information from a large number of genes and gene families.
Ideally, a genome-wide measurement of expression provides the highest quality signature. Even genes whose expression is not altered by any tested compounds are important as well, as the levels of expression of these genes are used to normalize the rest of the expression data. The normalization procedure is useful for comparison of expression data after treatment with different compounds. While the assignment of gene function to elements of a toxicant signature aids in interpretation of toxicity mechanisms, knowledge of gene function is not necessary for the statistical matching of signatures which leads to prediction of toxicity. (See, for example, Press Release 00-02 from the National Institute of Environmental Health Sciences, released February 29, 2000, available at http:l/www.niehs.nih.gov/oc/news/toxchip.htm.) Therefore, it is important and desirable in toxicological screening using toxicant signatures to include all expressed gene sequences.
In one embodiment, the toxicity of a test compound is assessed by treating a biological sample containing nucleic acids with the test compound. Nucleic acids that are expressed in the treated biological sample are hybridized with one or more probes specific to the pohynucleotides of the present invention, so that transcript levels corresponding to the polynucleotides of the present invention may be quantified. The transcript levels in the treated biological sample are compared with levels in an untreated biohogicah sample. Differences in the transcript levels between the two samples are indicative of a toxic response caused by the test compound in the treated sample.
Another particular embodiment relates to the use of the pohypeptide sequences of the present invention to analyze the proteome of a tissue or cell type. The term proteome refers to the global pattern of protein expression in a particular tissue or cell type. Each protein component of a proteome can be subjected individually to further analysis. Proteome expression patterns, or profiles, are analyzed by quantifying the number of expressed proteins and their relative abundance under given conditions and at a given time. A profile of a cell's proteome may thus be generated by separating and analyzing the polypeptides of a particular tissue or cell type.
In one embodiment, the separation is achieved using two-dimensional gel electrophoresis, in which proteins from a sample are separated by isoelectric focusing in the first dimension, and then according to molecular weight by sodium dodecyl sulfate slab gel electrophoresis in the second dimension (Steiner and Anderson, supra). The proteins are visualized in the gel as discrete and uniquely positioned spots, typically by staining the gel with an agent such ~as Coomassie Blue or silver or fluorescent stains. The optical density of each protein spot is generally proportional to the level of the protein in the sample. The optical densities of equivalently positioned protein spots from different samples, for example, from biological samples either treated or untreated with a test compound or therapeutic agent, are compared to identify any changes in protein spot density related to the treatment. The proteins in the spots are partially sequenced using, for example, standard methods employing chemical or enzymatic cleavage followed by mass spectrometry. The identity of the protein in a spot may be determined by comparing its partial sequence, preferably of at least 5 contiguous amino acid residues, to the polypeptide sequences of the present invention. In some cases, further sequence data may be obtained for definitive protein identification.
A proteomic profile may also be generated using antibodies specific for CSAP
to quantify the levels of CSAP expression. In one embodiment, the antibodies are used as elements on a microarray, and protein expression levels are quantified by exposing the microarray to the sample and detecting the levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem. 270:103-11 l; Mendoze, L.G. et al. (1999) Biotechniques 27:778-788). Detection may be performed by a variety of methods known in the art, for example, by reacting the proteins in the sample with a thiol-or amino-reactive fluorescent compound and detecting the amount of fluorescence bound at each array element.
Toxicant signatures at the proteome level are also useful for toxicological screening, and should be analyzed in parallel with toxicant signatures at the transcript level. There is a poor correlation between transcript and protein abundances for some proteins in some tissues (Anderson, N.L. and J. Seilhamer (1997) Electrophoresis 18:533-537), so proteome toxicant signatures may be useful in the analysis of compounds which do not significantly affect the transcript image, but which alter the proteomic profile. In addition, the analysis of transcripts in body fluids is difficult, due to rapid degradation of mRNA, so proteomic profiling may be more reliable and informative in such cases.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins that are expressed in the treated biological sample are separated so that the amount of each protein can be quantified. The amount of each protein is compared to the amount of the corresponding protein in an untreated biological sample. A difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample. Individual proteins are identified by sequencing the amino acid residues of the individual proteins and comparing these partial sequences to the polypeptides of the present invention.
In another embodiment, the toxicity of a test compound is assessed by treating a biological sample containing proteins with the test compound. Proteins from the biological sample are incubated with antibodies specific to the polypeptides of the present invention. The amount of protein recognized by the antibodies is quantified. The amount of protein in the treated biological sample is compared with the amount in an untreated biological sample. A
difference in the amount of protein between the two samples is indicative of a toxic response to the test compound in the treated sample.
Microarrays may be prepared, used, and analyzed using methods known in the art. (See, e.g., Brennan, T.M. et al. (1995) U.S. Patent No. 5,474,796; Schena, M. et al.
(1996) Proc. Natl. Acad. Sci.
USA 93:10614-10619; Baldeschweiler et al. (1995) PCT application W095/251116;
Shalom D. et al.
(1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA 94:2150-2155; and Heller, M.J. et al. (1997) U.S. Patent No. 5,605,662.) Various types of microarrays are well known and thoroughly described in DNA Microarrays: A Practical Approach, M. Schena, ed.
(1999) Oxford University Press, London, hereby expressly incorporated by reference.
In another embodiment of the invention, nucleic acid sequences encoding CSAP
may be used to generate hybridization probes useful in mapping the naturally occurring genomic sequence. Either coding or noncoding sequences may be used, and in some instances, noncoding sequences may be preferable over coding sequences. For example, conservation of a coding sequence among members of a mufti-gene family may potentially cause undesired cross hybridization during chromosomal mapping. The sequences may be mapped to a particular chromosome, to a specific region of a chromosome, or to artificial chromosome constructions, e.g., human artificial chromosomes (HACs), yeast artificial chromosomes (YACs), bacterial artificial chromosomes (BACs), bacterial Pl constructions, or single chromosome cDNA libraries. (See, e.g., Harrington, J.J. et al. (1997) Nat.
Genet. 15:345-355; Price, C.M. (1993) Blood Rev. 7:127-134; and Trask, B.J.
(1991) Trends Genet.
7:149-154.) Once mapped, the nucleic acid sequences of the invention may be used to develop genetic linkage maps, for example, which correlate the inheritance of a disease state with the inheritance of a particular chromosome region or restriction fragment length polymorphism (RFLP).
(See, for example, Lander, E.S. and D. Botstein (1986) Proc. Natl. Acad. Sci.
USA 83:7353-7357.) Fluorescent in situ hybridization (FISH) may be correlated with other physical and genetic map data. (See, e.g., Heinz-Ulrich, et al. (1995) in Meyers, supra, pp. 965-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OM1M) World Wide Web site. Correlation between the location of the gene encoding CSAP on a physical map and a specific disorder, or a predisposition to a specific disorder, may help define the region of DNA associated with that disorder and thus may further positional cloning efforts.
In situ hybridization of chromosomal preparations and physical mapping techniques, such as linkage analysis using established chromosomal markers, may be used for extending genetic maps.
Often the placement of a gene on the chromosome of another mammalian species, such as mouse, may reveal associated markers even if the exact chromosomal locus is not known. This information is valuable to investigators searching for disease genes using positional cloning or other gene discovery techniques. Once the gene or genes responsible for a disease or syndrome have been crudely localized by genetic linkage to a particular genomic region, e.g., ataxia-telangiectasia to l 1q22-23, any sequences mapping to that area may represent associated or regulatory genes for further investigation. (See, e.g., Gatti, R.A. et al. (1988) Nature 336:577-580.) The nucleotide sequence of the instant invention may also be used to detect differences in the chromosomal location due to translocation, inversion, etc., among normal, carrier, or affected individuals.
In another embodiment of the invention, CSAP, its catalytic or immunogenic fragments, or oligopeptides thereof can be used for screening libraries of compounds in any of a variety of drug screening techniques. The fragment employed in such screening may be free in solution, affixed to a solid support, borne on a cell surface, or located intracellularly. The formation of binding complexes between CSAP and the agent being tested may be measured.
Another technique for drug screening provides for high throughput screening of compounds having suitable binding affinity to the protein of interest. (See, e.g., Geysen, et al. (1984) PCT
application WO84/03564.) In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with CSAP, or fragments thereof, and washed. Bound CSAP is then detected by methods well known in the art.
Purified CSAP can also be coated directly onto plates for use in the aforementioned drug screening techniques.
Alternatively, non-neutralizing antibodies can be used to capture the peptide and immobilize it on a solid support.
In another embodiment, one may use competitive drug screening assays in which neutralizing antibodies capable of binding CSAP specifically compete with a test compound for binding CSAP. In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with CSAP.
In additional embodiments, the nucleotide sequences which encode CSAP may be used in any molecular biology techniques that have yet to be developed, provided the new techniques rely on properties of nucleotide sequences that are currently known, including, but not limited to, such properties as the triplet genetic code and specific base pair interactions.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. The following embodiments are, therefore, to be construed as merely illustrative, and not (imitative of the remainder of the disclosure in any way whatsoever.
The disclosures of all patents, applications, and publications mentioned above and below, including U.S. Ser. No. 60/280,508, U.S. Ser. No. 60/281,323, U.S. Ser. No.
60/283,769, U.S. Ser.
No. 60/288,609, U.S. Ser. No. 60/290,518, U.S. Ser. No. 60/291,870, and U.S.
Ser. No. 60/294,451, are hereby expressly incorporated by reference.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA). Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and Iysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting lysates were centrifuged over CsCI cushions or extracted with chloroform. RNA was precipitated from the lysates with either isopropanol or sodium acetate and ethanol, or by other routine methods.
Phenol extraction and precipitation of RNA were repeated as necessary to increase RNA
purity. In some cases, RNA was treated with DNase. For most libraries, poly(A)+ RNA was isolated using oligo d(T)-coupled paramagnetic particles (Promega), OLIGOTEX latex particles (QIAGEN, Chatsworth CA), or an OLIGOTEX mRNA purification kit (QIAGEN). Alternatively, RNA was isolated directly from tissue lysates using other RNA isolation kits, e.g., the POLY(A)PURE mRNA
purification kit (Ambion, Austin TX).
In some cases, Stratagene was provided with RNA and constructed the corresponding cDNA
libraries. Otherwise, cDNA was synthesized and cDNA libraries were constructed with the UNIZAP
vector system (Stratagene) or SUPERSCRIPT plasmid system (Life Technologies), using the recommended procedures or similar methods known in the art. (See, e.g., Ausubel, 1997, supra, units 5.1-6.6.) Reverse transcription was initiated using oligo d(T) or random primers. Synthetic oligonucleotide adapters were ligated to double stranded cDNA, and the cDNA
was digested with the appropriate restriction enzyme or enzymes. For most libraries, the cDNA was size-selected (300-1000 bp) using SEPHACRYL S 1000, SEPHAROSE CL2B, or SEPHAROSE CL4B column chromatography (Amersham Pharmacia Biotech) or preparative agarose gel electrophoresis. cDNAs were ligated into compatible restriction enzyme sites of the polylinker of a suitable plasmid, e.g., PBLUESCRIPT plasmid (Stratagene), PSPORTl plasmid (Life Technologies), PCDNA2.1 plasmid (Invitrogen, Carlsbad CA), PBK-CMV plasmid (Stratagene), PCR2-TOPOTA plasmid (Invitrogen), PCMV-ICIS plasmid (Stratagene), pIGEN (Incyte Genomics, Palo Alto CA), pRARE
(Incyte Genomics), or pINCY (Incyte Genomics), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL,l-Blue, XL1-BIueMRF, or SOLR from Stratagene or DHSa, DHlOB, or ElectroMAX DH10B from Life Technologies.
II. Isolation of cDNA Clones Plasmids obtained as described in Example I were recovered from host cells by in vivo excision using the UNIZAP vector system (Stratagene) or by cell lysis.
Plasmids were purified using at least one of the following: a Magic or WIZARD Minipreps DNA purification system (Promega); an AGTC Miniprep purification kit (Edge Biosystems, Gaithersburg MD); and QIAWELL

8 Plasmid, QIAWELL 8 Plus Plasmid, QIAWELL 8 Ultra Plasmid purification systems or the R.E.A.L. PREP 96 plasmid purification kit from QIAGEN. Following precipitation, plasmids were resuspended in 0.1 ml of distilled water and stored, with or without lyophilization, at 4°C.
Alternatively, plasmid DNA was amplified from host cell lysates using direct link PCR in a high-throughput format (Rao, V.B. (1994) Anal. Biochern. 216:1-14). Host cell lysis and thermal cycling steps were carried out in a single reaction mixture. Samples were processed and stored in 384-well plates, and the concentration of amplified plasmid DNA was quantified fluorometrically using PICOGREEN dye (Molecular Probes, Eugene OR) and a FLUOROSKAN If fluorescence scanner (Labsystems Oy, Helsinki, Finland).
III. Sequencing and Analysis Incyte cDNA recovered in plasmids as described in Example II were sequenced as follows.
Sequencing reactions were processed using standard methods or high-throughput instrumentation such as the ABI CATALYST 800 (Applied Biosystems) thermal cycler or the PTC-200 thermal cycler (MJ Research) in conjunction with the HYDRA microdispenser (Robbins Scientific) or the MICROLAB 2200 (Hamilton) liquid transfer system. cDNA sequencing reactions were prepared using reagents provided by Amersham Pharmacia Biotech or supplied in ABI
sequencing kits such as the ABI PRISM BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
Electrophoretic separation of cDNA sequencing reactions and detection of labeled polynucleotides were carried out using the MEGABACE 1000 DNA sequencing system (Molecular Dynamics); the ABI PRISM 373 or 377 sequencing system (Applied Biosystems) in conjunction with standard ABI
protocols and base calling software; or other sequence analysis.systems known in the art. Reading frames within the cDNA sequences were identified using standard methods (reviewed in Ausubel, 1997, suura, unit 7.7). Some of the cDNA sequences were selected for extension using the techniques disclosed in Example VIII.
The polynucleotide sequences derived from Incyte cDNAs were validated by removing vector, linker, and poly(A) sequences and by masking ambiguous bases, using algorithms and programs based on BLAST, dynamic programming, and dinucleotide nearest neighbor analysis. The Incyte cDNA sequences or translations thereof were then queried against a selection of public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases, and BLOCKS, PRINTS, DOMO, PRODOM; PROTEOME databases with sequences from Homo Sapiens, Rattus norve i~ cus, Mus musculus, Caenorhabditis eleg-ans, Saccharomyces cerevisiae, Schizosaccharo~ces pombe, and Candida albicans (Tncyte Genomics, Palo Alto CA); hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM (Haft, D.H. et al. (2001) Nucleic Acids Res. 29:41-43); and HMM-based protein domain databases such as SMART (Schultz et al. (1998) Proc. Natl. Acad. Sci. USA 95:5857-5864; Letunic, I. et al. (2002) Nucleic Acids Res. 30:242-244). (HMM is a probabilistic approach which analyzes consensus primary structures of gene families. See, for example, Eddy, S.R. (1996) Curr.
Opin. Struct. Biol.
6:361-365.) The queries were performed using programs based on BLAST, FASTA, BLIMPS, and HMMER. The Incyte cDNA sequences were assembled to produce full length polynucleotide sequences. Alternatively, GenBank cDNAs, GenBank ESTs, stitched sequences, stretched sequences, 1S or Genscan-predicted coding sequences (see Examples IV and V) were used to extend Incyte cDNA
assemblages to full length. Assembly was performed using programs based on Phred, Phrap, and Consed, and cDNA assemblages were screened for open reading frames using programs based on GeneMark, BLAST, and FASTA. The full length polynucleotide sequences were translated to derive the corresponding full length polypeptide sequences. Alternatively, a polypeptide of the invention may begin at any of the methionine residues of the full length translated polypeptide. Full length polypeptide sequences were subsequently analyzed by querying against databases such as the GenBank protein databases (genpept), SwissProt, the PROTEOME databases, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, hidden Markov model (HMM)-based protein family databases such as PFAM, INCY, and TIGRFAM; and HMM-based protein domain databases such as SMART.
Full length polynucleotide sequences are also analyzed using MACDNASIS PRO software (Hitachi Software Engineering, South San Francisco CA) and LASERGENE software (DNASTAR).
Polynucleotide and polypeptide sequence alignments are generated using default parameters specified by the CLUSTAL algorithm as incorporated into the MEGALIGN multisequence alignment program (DNASTAR), which also calculates the percent identity between aligned sequences.
Table 7 summarizes the tools, programs, and algorithms used for the analysis and assembly of Incyte cDNA and full length sequences and provides applicable descriptions, references, and threshold parameters. The first column of Table 7 shows the tools, programs, and algorithms used, the second column provides brief descriptions thereof, the third column presents appropriate references, all of which are incorporated by reference herein in their entirety, and the fourth column presents, where applicable, the scores, probability values, and other parameters used to evaluate the strength of a match between two sequences (the higher the score or the lower the probability value, the greater the identity between two sequences).
The programs described above for the assembly and analysis of full length polynucleotide and polypeptide sequences were also used to identify polynucleotide sequence fragments from SEQ
1D N0:29-56. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 2.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative cytoskeleton-associated proteins were initially identified by running the Genscan gene identification program against public genomic sequence databases (e.g., gbpri and gbhtg).
Genscan is a general-purpose gene identification program which analyzes genomic DNA sequences from a variety of organisms (See Burge, C. and S. Marlin (1997) J. Mol. Biol.
268:78-94, and Burge, C. and S. Marlin (1998) Curr. Opin. Struct. Biol. 8:346-354). The program concatenates predicted exons to form an assembled cDNA sequence extending from a methionine to a stop codon. The output of Genscan is a FASTA database of polynucleotide and polypeptide sequences. The maximum range of sequence for Genscan to analyze at once was set to 30 kb. To determine which of these Genscan predicted cDNA sequences encode cytoskeleton-associated proteins, the encoded polypeptides were analyzed by querying against PFAM models for cytoskeleton-associated proteins.
Potential cytoskeleton-associated proteins were also identified by homology to Incyte eDNA ' sequences that had been annotated as cytoskeleton-associated proteins. These selected Genscan-predicted sequences were then compared by BLAST analysis to the genpept and gbpri public databases. Where necessary, the Genscan-predicted sequences were then edited by comparison to the top BLAST hit from genpept to correct errors 'in the sequence predicted by Genscan, such as extra or omitted exons. BLAST analysis was also used to fmd any Incyte cDNA or public cDNA coverage of the Genscan-predicted sequences, thus providing evidence for transcription.
When Incyte cDNA
coverage was available, this information was used to correct or confirm the Genscan predicted sequence. Full length polynucleotide sequences were obtained by assembling Genscan-predicted coding sequences with Incyte cDNA sequences andlor public cDNA sequences using the assembly process described in Example III. Alternatively, full length polynucleotide sequences were derived entirely from edited or unedited Genscan-predicted coding sequences.
V. Assembly of Genomic Sequence Data with cDNA Sequence Data "Stitched" Seauences Partial eDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example 1V. Partial cDNAs assembled as described in Example III were mapped to genomic DNA and parsed into clusters containing related cDNAs and Genscan exon predictions from one or more genomic sequences. Each cluster was analyzed using an algorithm based on graph theory and dynamic programming to integrate eDNA and genomic information, generating possible splice variants that were subsequently confirmed, edited, or extended to create a full length sequence. Sequence intervals in which the entire length of the interval was present on more than one sequence in the cluster were identified, and intervals thus identified were considered to be equivalent by transitivity. For example, if an interval was present on a cDNA and two genomic sequences, then all three intervals were considered to be equivalent. This process allows unrelated but consecutive genomic sequences to be brought together, bridged by cDNA
sequence. Intervals thus identified were then "stitched" together by the stitching algorithm in the order that they appear along their parent sequences to generate the longest possible sequence, as well as sequence variants.
Linkages between intervals which proceed along one type of parent sequence (cDNA to cDNA or genomic sequence to genomic sequence) were given preference over linkages which change parent type (cDNA to genomic sequence). The resultant stitched sequences were translated and compared by BLAST analysis to the genpept and gbpri public databases. Incorrect exons predicted by Genscan were corrected by comparison to the top BLAST hit from genpept. Sequences were further extended with additional cDNA sequences, or by inspection of genomic DNA, when necessary.
"Stretched" Seauences Partial DNA sequences were extended to full length with an algorithm based on BLAST
analysis. First, partial eDNAs assembled as described in Example III were queried against public databases such as the GenBank primate, rodent, mammalian, vertebrate, and eukaryote databases using the BLAST program. The nearest GenBank protein homolog was then compared by BLAST
analysis to either Incyte cDNA sequences or GenScan exon predicted sequences described in1 Example IV. A chimeric protein was generated by using the resultant high-scoring segment pairs (HSPs) to map the translated sequences onto the GenBank protein homolog.
Insertions or deletions may occur in the chimeric protein with respect to the original GenBank protein hornolog. The GenBank protein homolog, the chimeric protein, or both were used as probes to search for homologous genomic sequences from the public human genome databases. Partial DNA sequences were therefore "stretched" or extended by the addition of homologous genomic sequences. The resultant stretched sequences were examined to determine whether it contained a complete gene.
VI. Chromosomal Mapping of CSAP Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:29-56 were compared with sequences from the Incyte LIFESEQ database and public domain databases using BLAST and other implementations of the Smith-Waterman algorithm. Sequences from these databases that matched SEQ ID N0:29-56 were assembled into clusters of contiguous and overlapping sequences using assembly algorithms such as Phrap (Table 7). Radiation hybrid and genetic mapping data available from public resources such as the Stanford Human Genome Center (SHGC), Whitehead Institute for Genome Research (WIGR), and Genethon were used to determine if any of the clustered sequences had been previously mapped. Inclusion of a mapped sequence in a cluster resulted in the assignment of all sequences of that cluster, including its particular SEQ ID NO:, to that map location.
Map locations are represented by ranges, or intervals, of human chromosomes.
The map position of an interval, in centiMorgans, is measured relative to the terminus of the chromosome's p-arm. (The centiMorgan (cM) is a unit of measurement based on recombination frequencies between chromosomal markers. On average, 1 cM is roughly equivalent to 1 megabase (Mb) of DNA in humans, although this can vary widely due to hot and cold spots of recombination.) The cM
distances are based on genetic markers mapped by Genethon which provide boundaries for radiation hybrid markers whose sequences were included in each of the clusters. Human genome maps and other resources available to the public, such as the NCBI "GeneMap'99" World Wide Web site (http://www.ncbi.nlm.nih.gov/genemap/), can be employed to determine if previously identified disease genes map within or in proximity to the intervals indicated above.
VII. Analysis of Polynucleotide Expression Northern analysis is a laboratory technique used to detect the presence of a transcript of a gene and involves the hybridization of a labeled nucleotide sequence to a membrane on which RNAs from a particular cell type or tissue have been bound. (See, e.g., Sambrook, supra, ch. 7; Ausubel (1995) supra, ch. 4 and 16.) Analogous computer techniques applying BLAST were used to search for identical or related molecules in cDNA databases such as GenBank or L1FESEQ (Incyte Genomics). This analysis is much faster than multiple membrane-based hybridizations. In addition, the sensitivity of the computer search can be modified to determine whether any particular match is categorized as exact or similar. The basis of the search is the product score, which is defined as:
BLAST Score x Percent Identity 5 x minimum { length(Seq. 1), length(Seq. 2) }
The product score takes into account both the degree of similarity between two sequences and the length of the sequence match. The product score is a normalized value between 0 and 100, and is calculated as follows: the BLAST score is multiplied by the percent nucleotide identity and the product is divided by (5 times the length of the shorter of the two sequences). The BLAST score is calculated by assigning a score of +5 for every base that matches in a high-scoring segment pair (HSP), and -4 for every mismatch. Two sequences may share more than one HSP
(separated by gaps). If there is more than one HSP, then the pair with the highest BLAST
score is used to calculate the product score. The product score represents a balance between fractional overlap and quality in a BLAST alignment. For example, a product score of 100 is produced only for 100%
identity over the entire length of the shorter of the two sequences being compared. A product score of 70 is produced either by 100% identity and 70% overlap at one end, or by 88% identity and 100% overlap at the other. A product score of 50 is produced either by 100% identity and 50%
overlap at one end, or 79%
identity and 100% overlap.
Alternatively, polynucleotide sequences encoding CSAP are analyzed with respect to the tissue sources from which they were derived. For example, some full length sequences are assembled, at least in part, with overlapping Incyte cDNA sequences (see Example III]. Each cDNA
sequence is derived from a cDNA library constructed from a human tissue. Each human tissue is classified into one of the following organ/tissue categories: cardiovascular system; connective tissue;
digestive system; embryonic structures; endocrine system; exocrine glands;
genitalia, female;
genitalia, male; germ cells; heroic and immune system; liver; musculoskeletal system; nervous system; pancreas; respiratory system; sense organs; skin; stomatognathic system; unclassifiedlmixed;
or urinary tract. The number of libraries in each category is counted and divided by the total number of libraries across all categories. Similarly, each human tissue is classified into one of the following diseaselcondition categories: cancer, cell line, developmental, inflammation, neurological, trauma, cardiovascular, pooled, and other, and the number of libraries in each category is counted and divided by the total number of libraries across all categories. The resulting percentages reflect the tissue- and disease-specific expression of cDNA encoding CSAP. cDNA sequences and cDNA
library/tissue information are found in the LIFESEQ GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of CSAP Encoding Polynucleotides Full length polynucleotide sequences were also produced by extension of an appropriate fragment of the full length molecule using oligonucleotide primers designed from this fragment. One primer was synthesized to initiate 5' extension of the lrnown fragment, and the other primer was synthesized to initiate 3' extension of the known fragment. The initial primers were designed using OLIGO 4.06 software (National Biosciences), or another appropriate program, to be about 22 to 30 nucleotides in length, to have a GC content of about 50% or more, and to anneal to the target sequence at temperatures of about 68 °C to about 72°C. Any stretch of nucleotides which would result in hairpin structures and primer-primer dimerizations was avoided.
Selected human cDNA libraries were used to extend the sequence. If more than one extension was necessary or desired-, additional or nested sets of primers were designed.
High fidelity amplification was obtained by PCR using methods well known in the art. PCR
was performed in 96-well plates using the PTC-200 thermal cycler (MJ Research, Inc.). The reaction mix contained DNA template, 200 nmol of each primer, reaction buffer containing Mg2+, (NH4)2504, and 2-mercaptoethanol, Taq DNA polymerise (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerise (Stratagene), with the following parameters fox primer pair PCI A and PCI B: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec;
Step 3: 60°C, 1 min; Step 4: 68°C, 2 min; Step 5: Steps 2, 3, and 4 repeated 20 times; Step 6: 68 °C, 5 min; Step 7: storage at 4°C. In the alternative, the parameters for primer pair T7 and SK+ were as follows: Step 1: 94°C, 3 min; Step 2:
94°C, 15 sec; Step 3: 57°C, 1 min; Step 4: 68°C, 2 min;
Step 5: Steps 2, 3, and 4 repeated 20 times;
Step 6: 68°C, 5 min; Step 7: storage at 4°C.
The concentration of DNA in each well was determined by dispensing 100 p,1 PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 p.1 of undiluted PCR product into each well of an opaque fluorimeter plate (Corning Costar, Acton MA), allowing the DNA to bind to the reagent. The plate was scanned in a Fluoroskan II
(Labsystems Oy, Helsinki, Finland) to measure the fluorescence of the sample and to quantify the concentration of DNA. A 5 ,u1 to 10 ,u1 aliquot of the reaction mixture was analyzed by electrophoresis on a 1 % agarose gel to determine which reactions were successful in extending the sequence.
The extended nucleotides were desalted and concentrated, transferred to 384-well plates, digested with CviJI cholera virus endonuclease (Molecular Biology Research, Madison WI), and sonicated or sheared prior to religation into pUC 18 vector (Amersham Pharmacia Biotech). For shotgun sequencing, the digested nucleotides were separated on low concentration (0.6 to 0.8%) agarose gels, fragments were excised, and agar digested with Agar ACE
(Promega). Extended clones were religated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerise (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. coli cells. Transformed cells were selected on antibiotic-containing media, and individual colonies were picked and cultured overnight at 37°C in 384-well plates in LB/2x curb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerise (Amersham Phannacia Biotech) and Pfu DNA polymerise (Stratagene) with the following parameters: Step 1: 94°C, 3 min; Step 2: 94°C, 15 sec; Step 3:
60°C, 1 min; Step 4: 72°C, 2 min;
Step 5: steps 2, 3, and 4 repeated 29 times; Step 6: 72°C, 5 min; Step 7: storage at 4°C. DNA was quantified by PICOGREEN reagent (Molecular Probes) as described above. Samples with low DNA

recoveries were reamplified using the same conditions as described above.
Samples were diluted with 20% dimethysulfoxide (1:2, v/v), and sequenced using DYENAMIC energy transfer sequencing primers and the DYENAMIC DIRECT kit (Amersham Pharmacia Biotech) or the ABI
PRISM
BIGDYE Terminator cycle sequencing ready reaction kit (Applied Biosystems).
In like manner, full length polynucleotide sequences are verified using the above procedure or are used to obtain 5'regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.
IX. Identification of Single Nucleotide Polymorphisms in CSAP Encoding Polynucleotides Common DNA sequence variants known as single nucleotide polymorphisms (SNPs) were identified in SEQ 1D N0:29-56 using the LIFESEQ database (Incyte Genomics).
Sequences from the same gene were clustered together and assembled as described in Example III, allowing the identification of all sequence variants in the gene. An algorithm consisting of a series of filters was used to distinguish SNPs from other sequence variants. Preliminary filters removed the majority of basecall errors by requiring a minimum Phred quality score of 15, and removed sequence alignment errors and errors resulting from improper trimming of vector sequences, chimeras, and splice variants. An automated procedure of advanced chromosome analysis analysed the original chromatogram files in the vicinity of the putative SNP. Clone error filters used statistically generated algorithms to identify errors introduced during laboratory processing, such as those caused by reverse transcriptase, polymerase, or somatic mutation. Clustering error filters used statistically generated algorithms to identify errors resulting from clustering of close homologs or pseudogenes, or due to contamination by non-human sequences. A final set of filters removed duplicates and SNPs found in immunoglobulins or T-cell receptors.
Certain SNPs were selected for further characterization by mass spectrometry using the high throughput MASSARRAY system (Sequenom, Inc.) to analyze allele frequencies at the SNP sites in four different human populations. The Caucasian population comprised 92 individuals (46 male, 46 female), including 83 from Utah, four French, three Venezualan, and two Amish individuals. The African population comprised 194 individuals (97 male, 97 female), all African Americans. The Hispanic population comprised 324 individuals (162 male, 162 female), all Mexican Hispanic. The Asian population comprised 126 individuals (64 male, 62 female) with a reported parental breakdown of 43% Chinese, 31% Japanese, 13% Korean, 5% Vietnamese, and 8% other Asian.
Allele frequencies were first analyzed in the Caucasian population; in some cases those SNPs which showed no allelic variance in this population were not further tested in the other three populations. .
X. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:29-56 are employed to screen cDNAs, genomic DNAs, or mRNAs. Although the labeling of oligonucleotides, consisting of about 20 base pairs, is specifically described, essentially the same procedure is used with larger nucleotide fragments. Oligonucleotides are designed using state-of the-art software such as OLIGO 4.06 software (National Biosciences) and labeled by combining 50 pmol of each oligomer, 250 ,uCi of [y 32P] adenosine triphosphate (Amersham Pharmacia Biotech), and T4 polynucleotide kinase (DuPont NEN, Boston MA). The labeled oligonucleotides are substantially purified using a SEPHADEX G-25 supe~ne size exclusion dextran bead column (Amersham Pharmacia Biotech).
An aliquot containing 10' counts per minute of the labeled probe is used in a typical membrane-based hybridization analysis of human genomic DNA digested with one of the following endonucleases:
Ase I, Bgl II, Eco RI, Pst I, Xba I, or Pvu II (DuPont NEN).
The DNA from each digest is fractionated on a 0.7% agarose gel and transferred to nylon membranes (Nytran Plus, Schleicher & Schuell, Durham NH). Hybridization is carried out for 16 hours at 40°C. To remove nonspecific signals, blots are sequentially washed at room temperature under conditions of up to, for example, 0.1 x saline sodium citrate and 0.5%
sodium dodecyl sulfate.
Hybridization patterns are visualized using autoradiography or an alternative imaging means and compared.
XI. Microarrays The linkage or synthesis of array elements upon a microarray can be achieved utilizing photolithography, piezoelectric printing (ink jet printing, See, e.g., Baldeschweiler, supra.), mechanical microspotting technologies, and derivatives thereof. The substrate in each of the aforementioned technologies should be uniform and solid with a non-porous surface (Schena (1999), supra). Suggested substrates include silicon, silica, glass slides, glass chips, and silicon wafers.
Alternatively, a procedure analogous to a dot or slot blot may also be used to arrange and link elements to the surface of a substrate using thermal, UV, chemical, or mechanical bonding procedures. A typical array may be produced using available methods and machines well known to those of ordinary skill in the art and may contain any appropriate number of elements. (See, e.g., Schena, M. et al. (1995) Science 270:467-470; Shalom D. et al. (1996) Genome Res. 6:639-645;
Marshall, A. and J. Hodgson (1998) Nat. Biotechnol. 16:27-31.) Full length cDNAs, Expressed Sequence Tags (ESTs), or fragments or oligomers thereof may comprise the elements of the microarray. Fragments or oligomers suitable for hybridization can be selected using software well known in the art such as LASERGENE software (DNASTAR). The array elements are hybridized with polynucleotides in a biological sample. The polynucleotides in the biological sample are conjugated to a fluorescent label or other molecular tag for ease of detection.
After hybridization, nonhybridized nucleotides from the biological sample are removed, and a fluorescence scanner is used to detect hybridization at each array element.
Alternatively, laser desorbtion and mass spectrometry may be used for detection of hybridization.
The degree of complementarity and the relative abundance of each polynucleotide which hybridizes to an element on the microarray may be assessed. In one embodiment, microarray preparation and usage is described in detail below.
Tissue or Cell Sample Preparation Total RNA is isolated from tissue samples using the guanidinium thiocyanate method and poly(A)+ RNA is purified using the oligo-(dT) cellulose method. Each poly(A)+
RNA sample is reverse transcribed using MMLV reverse-transcriptase, 0.05 pg/~,1 oligo-(dT) primer (2lmer), 1X
first strand buffer, 0.03 units/~.1 RNase inhibitor, 500 ~,M dATP, 500 ~.M
dGTP, 500 p,M dTTP, 40 ~,M dCTP, 40 ~.M dCTP-Cy3 (BDS) or dCTP-Cy5 (Amersham Pharmacia Biotech). The reverse transcription reaction is performed in a 25 ml volume containing 200 ng poly(A) ~ RNA with GEMBRIGHT kits (Incyte). Specific control poly(A)+ RNAs are synthesized by in vitro transcription from non-coding yeast genomic DNA. After incubation at 37° C for 2 hr, each reaction sample (one with Cy3 and another with Cy5 labeling) is treated with 2.5 ml of 0.5M sodium hydroxide and incubated for 20 minutes at 85° C to the stop the reaction and degrade the RNA. Samples are purified using two successive CHROMA SPIN 30 gel filtration spin columns (CLONTECH
Laboratories, Inc.
(CLONTECH), Palo Alto CA) and after combining, both reaction samples are ethanol precipitated using 1 ml of glycogen (1 mg/ml), 60 ml sodium acetate, and 300 ml of 100%
ethanol. The sample is then dried to completion using a SpeedVAC (Savant Instruments Inc., Holbrook NY) and resuspended in 14 ~,l 5X SSC/0.2% SDS.
For example, nonmalignant primary mammary epithelial cells and breast carcinoma cell lines are grown to 70-80% confluence prior to harvest. Gene expression profiles of nonmalignant primary mammary epithelial cells are compared to those of breast carcinoma cell lines at different stages of tumor progression.
Microarray Preparation Sequences of the present invention are used to generate array elements. Each array element is amplified from bacterial cells containing vectors with cloned cDNA inserts.
PCR amplification uses primers complementary to the vector sequences flanking the cDNA insert.
Array elements are amplified in thirty cycles of PCR from an initial quantity of 1-2 ng to a final quantity greater than 5 ,ug. Amplified array elements are then purified using SEPHACRYL-400 (Amersham Pharmacia Biotech).
Purified array elements are immobilized on polymer-coated glass slides. Glass microscope slides (Corning) are cleaned by ultrasound in 0.1% SDS and acetone, with extensive distilled water washes between and after treatments. Glass slides are etched in 4%
hydrofluoric acid (VWR
Scientific Products Corporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05% aminopropyl silane (Sigma) in 95% ethanol. Coated slides are cured in a 110°C oven.
Array elements are applied to the coated glass substrate using a procedure described in U.S.
Patent No. 5,807,522, incorporated herein by reference. 1 ~,l of the array element DNA, at an average concentration of 100 ng/pl, is loaded into the open capillary printing element by a high-speed-robotic apparatus. The apparatus then deposits about 5 n1 of array element sample per slide.
Microarrays are UV-crosslinked using a STRATALINKER UV-crosslinker (Stratagene).
Microarrays are washed at room temperature once in 0.2% SDS and three times in distilled water.
Non-specific binding sites are blocked by incubation of microarrays in 0.2%
casein in phosphate buffered saline (PBS) (Tropix, Inc., Bedford MA) for 30 minutes at 60°
C followed by washes im 0.2% SDS and distilled water as before.
Hybridization Hybridization reactions contain 9 ~,1 of sample mixture consisting of 0.2 ~,g each of Cy3 and Cy5 labeled cDNA synthesis products in 5X SSC, 0.2% SDS hybridization buffer.
The sample mixture is heated to 65° C for 5 minutes and is aliquoted onto the microarray surface and covered with an 1.8 cm2 coverslip. The arrays are transferred to a waterproof chamber having a cavity just slightly larger than a microscope slide. The chamber is kept at 100% humidity internally by the addition of 140 ~.l of 5X SSC in a corner of the chamber. The chamber containing the arrays is incubated for about 6.5 hours at 60° C. The arrays axe washed for 10 min at 45° C in a first wash buffer (1X SSC, 0.1% SDS), three times for 10 minutes each at 45° C in a second wash buffer (0.1X
SSC), and dried.
Detection Reporter-labeled hybridization complexes are detected with a microscope equipped with an Innova 70 mixed gas 10 W laser (Coherent, Inc., Santa Clara CA) capable of generating spectral lines at 488 nm for excitation of Cy3 and at 632 nm for excitation of CyS. The excitation laser light is focused on the array using a 20X microscope objective (Nikon, Inc., Melville NY). The slide containing the array is placed on a computer-controlled X-Y stage on the microscope and raster-scanned past the objective. The 1.8 cm x 1.8 cm array used in the present example is scanned with a resolution of 20 micrometers.
In two separate scans, a mixed gas multiline laser excites the two fluorophores sequentially.
Emitted light is split, based on wavelength, into two photomultiplier tube detectors (PMT 81477, Hamamatsu Photonics Systems, Bridgewater NJ) corresponding to the two fluorophores. Appropriate filters positioned between the array and the photomultiplier tubes are used to filter the signals. The emission maxima of the fluorophores used are 565 nm for Cy3 and 650 nm for CyS. Each array is typically scanned twice, one scan per fluorophore using the appropriate filters at the laser source, although the apparatus is capable of recording the spectra from both fluorophores simultaneously.
The sensitivity of the scans is typically calibrated using the signal intensity generated by a cDNA control species added to the sample mixture at a known concentration. A
specific location on the array contains a complementary DNA sequence, allowing the intensity of the signal at that location to be correlated with a weight ratio of hybridizing species of 1:100,000. When two samples from different sources (e.g., representing test and control cells), each labeled with a different fluorophore, are hybridized to a single array for the purpose of identifying genes that are differentially expressed, the calibration is done by labeling samples of the calibrating cDNA with the two fluorophores and adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-835H
analog-to-digital (AID) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-compatible PC
computer. The digitized data are displayed as an image where the signal intensity is mapped using a linear 20-color transformation to a pseudocolor scale ranging from blue (low signal) to red (high signal). The data is also analyzed quantitatively. Where two different fluorophores are excited and measured simultaneously, the data are first corrected for optical crosstalk (due to overlapping emission spectra) between the fluorophores using each fluorophore's emission spectrum.
A grid is superimposed over the fluorescence signal image such that the signal from each spot is centered in each element of the grid. The fluorescence signal within each element is then integrated to obtain a numerical value corresponding to the average intensity of the signal. The software used for signal analysis is the GEMTOOLS gene expression analysis program (Incyte).
For example, component 5504134_HGG3 of SEQ ID N0:31 and component 5504134 HGG3 of SEQ ID N0:33 showed differential expression in nonmalignant primary mammary epithelial cells versus breast carcinoma cell lines at different stages of tumor progression, as determined by microarray analysis. The expression of component 5504134 HGG3 was altered by at least a factor of 2 in breast carcinoma cell lines. Therefore, SEQ ID N0:31 and SEQ ID N0:33 are useful in diagnostic assays for cell proliferative disorders.
For example, SEQ ID N0:50 showed differential expression in human lung adenocarcinoma and squamous cell carcinoma versus normal lung tissue as determined by microarray analysis.
Matched normal and tumorigenic lung tissue samples were provided by the Roy Castle Lung Cancer Foundation, Liverpool, UK. The expression of SEQ ID N0:50 was decreased in lung tumor tissue at least two-fold over normal lung tissue from the same donor. Therefore, SEQ ID
N0:50 is useful in diagnostic assays for lung adenocarcinoma and squamous cell carcinoma.
XII. Complementary Polynucleotides Sequences complementary to the CSAP-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring CSAP. Although use of oligonucleotides comprising from about 15 to 30 base pairs is described, essentially the same procedure is used with smaller or with larger sequence fragments. Appropriate oligonucleotides are designed using OLIGO
4.06 software (National Biosciences) and the coding sequence of CSAP. To inhibit transcription, a complementary oligonucleotide is designed from the most unique 5' sequence and used to prevent promoter binding to the coding sequence. To inhibit translation, a complementary oligonucleotide is designed to prevent ribosomal binding to the CSAP-encoding transcript.
XIII. Expression of CSAP
Expression and purification of CSAP is achieved using bacterial or virus-based expression systems. For expression of CSAP in bacteria, cDNA is subcloned into an appropriate vector containing an antibiotic resistance gene and an inducible promoter that directs high levels of cDNA
transcription. Examples of such promoters include, but are not limited to, the trp-lac (tac) hybrid promoter and the TS or T7 bacteriophage promoter in conjunction with the lac operator regulatory element. Recombinant vectors are transformed into suitable bacterial hosts, e.g., BL21(DE3).
Antibiotic resistant bacteria express CSAP upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of CSAP in eukaryotic cells is achieved by infecting insect or mammalian cell lines with recombinant Auto.~raphica californica nuclear polyhedrosis virus (AcMNPV), commonly known as baculovirus. The nonessential polyhedrin gene of baculovirus is replaced with cDNA encoding CSAP by either homologous recombination or bacterial-mediated transposition involving transfer plasmid intermediates. Viral infectivity is maintained and the strong polyhedrin promoter drives high levels of cDNA transcription. Recombinant baculovirus is used to infect Spodoptera frugiperda (Sf9) insect cells in most cases, or human hepatocytes, in some cases.
Infection of the latter requires additional genetic modifications to baculovirus. (See Engelhard, E.I~.
et al. (1994) Proc. Natl. Acad.. Sci. USA 91:3224-3227; Sandig, V. et al.
(1996) Hum. Gene Ther.
7:1937-1945.) In most expression systems, CSAP is synthesized as a fusion protein with, e.g., glutathione S-transferase (GST) or a peptide epitope tag, such as FLAG or 6-His, permitting rapid, single-step, affinity-based purification of recombinant fusion protein from crude cell lysates. GST, a 26-kilodalton enzyme from Schistosoma iaponicum, enables the purification of fusion proteins on immobilized glutathione under conditions that maintain protein activity and antigenicity (Amersham Pharmacia Biotech). Following purification, the GST moiety can be proteolytically cleaved from CSAP at specifically engineered sites. FLAG, an 8-amino acid peptide, enables immunoaffinity purification using commercially available monoclonal and polyclonal anti-FLAG
antibodies (Eastman Kodak). 6-His, a stretch of six consecutive histidine residues, enables purification on metal-chelate resins (QIAGEN). Methods for protein expression and purification are discussed in Ausubel (1995, supra, ch. 10 and 16). Purified CSAP obtained by these methods can be used directly in the assays shown in Examples XVII and XVIII, where applicable.
XIV. Functional Assays CSAP function is assessed by expressing the sequences encoding CSAP at physiologically elevated levels in mammalian cell culture systems. cDNA is subcloned into a mammalian expression vector containing a strong promoter that drives high levels of cDNA
expression. Vectors of choice include PCMV SPORT (Life Technologies) and PCR3.1 (Invitrogen, Carlsbad CA), both of which contain the cytomegalovirus promoter. 5-10 ,ug of recombinant vector are transiently transfected into a human cell line, for example, an endothelial or hematopoietic cell line, using either liposome formulations or electroporation. 1-2 ,ug of an additional plasmid containing sequences encoding a marker protein are co-transfected. Expression of a marker protein provides a means to distinguish transfected cells from nontransfected cells and is a reliable predictor of cDNA expression from the recombinant vector. Marker proteins of choice include, e.g., Green Fluorescent Protein (GFP;
Clontech), CD64, or a CD64-GFP fusion protein. Flow cytometry (FCM), an automated, laser optics-based technique, is used to identify transfected cells expressing GFP or CD64-GFP and to evaluate the apoptotic state of the cells and other cellular properties. FCM detects and quantifies the uptake of fluorescent molecules that diagnose events preceding or coincident with cell death. These events include changes in nuclear DNA content as measured by staining of DNA with propidium iodide;
changes in cell size and granularity as measured by forward light scatter and 90 degree side light scatter; down-regulation of DNA synthesis as measured by decrease in bromodeoxyuridine uptake;
alterations in expression of cell surface and intracellular proteins as measured by reactivity with specific antibodies; and alterations in plasma membrane composition as measured by the binding of fluorescein-conjugated Annexin V protein to the cell surface. Methods in flow cytometry are discussed in Ormerod, M.G. (1994) Flow Cytometry, Oxford, New York NY.
The influence of CSAP on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding CSAP and either CD64 or CD64-GFP.
CD64 and CD64-GFP are expressed on the surface of transfected cells and bind to conserved regions of human immunoglobulin G (IgG). Transfected cells are efficiently separated from nontransfected cells using magnetic beads coated with either human IgG or antibody against CD64 (DYNAL, Lake Success NY). mRNA can be purified from the cells using methods well known by those of skill in the art.

Expression of mRNA encoding CSAP and other genes of interest can be analyzed by northern analysis or microarray techniques.
XV. Production of CSAP Specific Antibodies CSAP substantially purified using polyacrylamide gel electrophoresis (PAGE;
see, e.g., Harrington, M.G. (1990) Methods Enzymol. 182:488-495), or other purification techniques, is used to immunize animals (e.g., rabbits, mice, etc.) and to produce antibodies using standard protocols.
Alternatively, the CSAP amino acid sequence is analyzed using LASERGENE
software (DNASTAR) to determine regions of high immunogenicity, and a corresponding oligopeptide is synthesized and used to raise antibodies by means known to those of skill in the art. Methods for selection of appropriate epitopes, such as those near the C-terminus or in hydrophilic regions are well described in the art. (See, e.g., Ausubel, 1995, supra, ch. 11.) Typically, oligopeptides of about 15 residues in length are synthesized using an ABI 431A
peptide synthesizer (Applied Biosystems) using FMOC chemistry and coupled to KLH (Sigma-Aldrich, St. Louis MO) by reaction with N-maleimidobenzoyl-N-hydroxysuccinimide ester (MBS) to increase immunogenicity. (See, e.g., Ausubel, 1995, supra,.) Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-CSAP activity by, for example, binding the peptide or CSAP to a substrate, blocking with 1% BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XVI. Purification of Naturally Occurring CSAP Using Specific Antibodies Naturally occurring or recombinant CSAP is substantially purified by immunoaffinity chromatography using antibodies specific for CSAP. An immunoaffinity column is constructed by covalently coupling anti-CSAP antibody to an activated chromatographic resin, such as CNBr-activated SEPHAROSE (Amersham Pharmacia Biotech). After the coupling, the resin is blocked and washed according to the manufacturer's instructions.
Media containing CSAP are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of CSAP (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/CSAP binding (e.g., a buffer of pH 2 to pH 3, or a high concentration of a chaotrope, such as urea or thiocyanate ion), and CSAP is collected.
XVII. Identification of Molecules Which Interact with CSAP
CSAP, or biologically active fragments thereof, are labeled with'zsI Bolton-Hunter reagent.
(See, e.g., Bolton, A.E. and W.M. Hunter (1973) Biochem. J. 133:529-539.) Candidate molecules previously arrayed in the wells of a mufti-well plate are incubated with the labeled CSAP, washed, and any wells with labeled CSAP complex are assayed. Data obtained using different concentrations of CSAP are used to calculate values for the number, affinity, and association of CSAP with the candidate molecules.
Alternatively, molecules interacting with CSAP are analyzed using the yeast two-hybrid system as described in Fields, S. and O. Song (1989) Nature 340:245-246, or using commercially available kits based on the two-hybrid system, such as the MATCHMAKER system (Clontech).
CSAP may also be used in the PATHCALLING process (CuraGen Corp., New Haven CT) which employs the yeast two-hybrid system in a high-throughput manner to determine all interactions between the proteins encoded by two large libraries of genes (Nandabalan, K.
et al. (2000) U.S.
Patent No. 6,057,101).
XVIII. Demonstration of CSAP Activity A microtubule motility assay for CSAP measures motor protein activity. In this assay, recombinant CSAP is immobilized onto a glass slide or similar substrate. Taxol-stabilized bovine brain microtubules (commercially available) in a solution containing ATP and cytosolic extract are perfused onto the slide. Movement of microtubules as driven by CSAP motor activity can be visualized and quantified using video-enhanced light microscopy and image analysis techniques.
CSAP activity is directly proportional to the frequency and velocity of microtubule movement..
Alternatively, an assay for CSAP measures the formation of protein filaments in vitro. A
solution of CSAP at a concentration greater than the "critical concentration"
for polymer assembly is applied to carbon-coated grids. Appropriate nucleation sites may be supplied in the solution. The grids are negative stained with 0.7°l0 (w/v) aqueous uranyl acetate and examined by electron microscopy. The appearance of filaments of approximately 25 nm (nnicrotubules), 8 nm (actin), or 10 nm (intermediate filaments) is a demonstration of CSAP activity.
In another alternative, CSAP activity is measured by the binding of CSAP to protein filaments. 35S-Met labeled CSAP sample is incubated with the appropriate filament protein (actin, tubulin, or intermediate filament protein) and complexed protein is collected by immunoprecipitation using an antibody against the filament protein. The immunoprecipitate is then run out on SDS-PAGE
and the amount of CSAP bound is measured by autoradiography.
Various modifications and variations of the described methods and systems of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with certain embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention which are obvious to those skilled in molecular biology or related fields are intended to be within the scope of the following claims.

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<110> INCYTE GENOMICS, INC. .
HAFALIA, April J.A.
TANG, Y. Tom YUE, Henry KHAN, Farrah A.
ISON, Craig H.
BAUGHN, Mariah R.
WARREN, Bridget A.
DUGGAN, Brendan M.
THANGAVELU, Kavitha HONCHELL, Cynthia D.
AZIMZAI, Yalda ELLIOTT, Vicki S.
BURFORD, Neil DING, Li YUE, Huibin BECHA, Shanya EMERLING, Brooke M.
RICHARDSON, Thomas W.
LEE, Soo Yeun BANDMAN, Olga LAL, Preeti G.
LEE, Sally' GIETZEN, Kimberly J.
WALIA, Narinder K.
GRIFFIN, Jennifer A.
LEE, Ernestine A.
~SWARNAKAR, Anita RING, Huijun Z.
JONES, Karen Anne <120> CYTOSKELETON-ASSOCIATED PROTEINS
<130> PF-0918 PCT
<140> To Be Assigned <141> Herewith <150> 60/280,508; 60/281,323; 60/283,769; 60/288,609; 60/290,518;
60/291,870; 60/294,451 <151> 2001-03-29; 2001-04-03; 2001-04-13; 2001-05-04; 2001-05-10;
2001-05-18; 2001-05-29 <160> 56 <170> PERL Program <210> 1 <211> 459 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6582721CD1 <400> 1 Met Ser Val Arg Phe Ser Ser Thr Ser Arg Arg Leu Gly Ser Cys Gly Gly Thr Gly Ser Val Arg Leu Ser Ser Gly Gly Ala Gly Phe Gly Ala Gly Asn Thr Cys Gly Val Pro Gly Ile Gly Ser Gly Phe Ser Cys Ala Phe Gly Gly Ser Ser Ser Ala Gly Gly Tyr G1y Gly Gly Leu Gly Gly Gly Ser Ala Ser Cys Ala Ala Phe Thr G1y Asn Glu His Gly Leu Leu Ser Gly Asn Glu Lys Val Thr Met Gln Asn Leu Asn Asp Arg Leu Ala Ser Tyr Leu Glu Asn Val Arg A1a Leu Glu Glu Ala Asn Ala Asp Leu Glu Gln Lys Ile Lys Gly Trp Tyr G1u Lys Phe G1y Pro Gly Ser Cys Arg Gly Leu Asp His Asp Tyr Ser Arg Tyr Phe Pro Ile Ile Asp Glu Leu Lys Asn Gln Ile Ile Ser Ala Thr Thr Ser Asn Ala His Val Val Leu Gln Asn Asp Asn Ala Arg Leu Thr Ala Asp Asp Phe Arg Leu Lys Phe Glu Asn Glu Leu Ala Leu His Gln Ser Val Glu Ala Asp Ile Asn Ser Leu Arg Arg Val Leu Asp Glu Leu Thr Leu Cys Arg Thr Asp Leu Glu Ile Gln Leu Glu Thr Leu Ser Glu Glu Leu A1a Tyr Leu Lys Lys Asn His Glu Glu Glu Met Lys Ala Leu Gln Cys Ala Ala Gly Gly Asn Val Asn Val Glu Met Asn Ala Ala Pro Gly Val Asp Leu Thr Val Leu Leu Asn Asn Met Arg Ala G1u Tyr G1u Ala Leu Ala Glu Gln Asn Arg Arg Asp Ala Glu Ala Trp Phe Asn Glu Lys Ser Ala Ser Leu G1n Gln Gln Ile Ser Asp Asp Ala Gly Ala Thr Thr Ser Ala Arg Asn Glu Leu Ile Glu Met Lys Arg Thr Leu Gln Thr Leu Glu Ile G1u Leu Gln Ser Leu Leu Ala Thr Lys His Ser Leu Glu Cys Ser Leu Thr Glu Thr Glu Ser Asn Tyr Cys Ala Gln Leu Ala Gln Ile Gln Ala Gln Ile Gly Ala Leu Glu Glu Gln Leu His Gln Val Arg Thr Glu Thr Glu Gly Gln Lys Leu Glu Tyr Glu Gln Leu Leu Asp Ile Lys Val His Leu Glu Lys Glu Ile Glu Thr Tyr Cys Leu Leu Ile Asp Gly Glu Asp Gly Ser Cys Ser Lys Ser Lys Gly Tyr Gly Gly Pro Gly Asn Gln Thr Lys Asp Ser Ser Lys Thr Thr I1e Val Lys Thr Val Val Glu Glu Ile Asp Pro Arg Gly Lys Va1 Leu Ser Ser Arg Val His Thr Val Glu Glu Lys Ser Thr Lys Val Asn Asn Lys Asn Glu Gln Arg Val Ser Ser <210> 2 <211> 669 <212> PRT
<213> Homo sapiens <220>

<221> misc_feature <223> Incyte ID No: 2828941CD1 <400> 2 Met Gly Glu Lys Asn Gly Asp Ala Lys Thr Phe Trp Met Glu Leu Glu Asp Asp Gly Lys Va1 Asp Phe Ile Phe Glu Gln Val Gln Asn Val Leu Gln Ser Leu Lys Gln Lys I1e Lys Asp Gly Ser Ala Thr Asn Lys Glu Tyr Ile Gln Ala Met I1e Leu Val Asn Glu Ala Thr Ile Ile Asn Ser Ser Thr Ser Ile Lys Asp Pro Met Pro Val Thr Gln Lys Glu Gln Glu Asn Lys Ser Asn Ala Phe Pro Ser Thr Ser Cys Glu Asn Ser Phe Pro Glu Asp Cys Thr Phe Leu Thr Thr Gly Asn Lys Glu Ile Leu Ser Leu Glu Asp Lys Val Val Asp Phe Arg Glu Lys Asp Ser Ser Ser Asn Leu Ser Tyr Gln Ser His Asp Cys Ser Gly Ala Cys Leu Met Lys Met Pro Leu Asn Leu Lys Gly Glu Asn Pro Leu Gln Leu Pro Ile Lys Cys His Phe G1n Arg Arg His Ala Lys Thr Asn Ser His Ser Ser Ala Leu His Val Ser Tyr Lys Thr Pro Cys Gly Arg Ser Leu Arg Asn Val Glu Glu Val Phe Arg Tyr Leu Leu Glu Thr Glu Cys Asn Phe Leu Phe Thr Asp Asn Phe Ser Phe Asn Thr Tyr Val G1n Leu Ala Arg Asn Tyr Pro Lys Gln Lys Glu Val Val Ser Asp Val Asp Ile Ser Asn G1y Val Glu Ser Val Pro Ile Ser Phe Cys Asn Glu Ile Asp Ser Arg Lys Leu Pro Gln Phe Lys Tyr Arg Lys Thr Val Trp Pro Arg Ala Tyr Asn Leu Thr Asn Phe Ser Ser Met Phe Thr Asp Ser Cys Asp Cys Ser Glu Gly Cys Ile Asp Ile Thr Lys Cys Ala Cys Leu Gln Leu Thr Ala Arg Asn Ala Lys Thr Ser Pro Leu Ser Ser Asp Lys Ile Thr Thr Gly Tyr Lys Tyr Lys Arg Leu Gln Arg Gln Ile Pro Thr Gly I12 Tyr Glu Cys Ser Leu Leu Cys Lys Cys Asn Arg Gln Leu Cys Gln Asn Arg Val Va1 Gln His G1y Pro Gln Val Arg Leu Gln Val Phe Lys Thr G1u Gln Lys Gly Trp Gly Val Arg Cys Leu Asp Asp Ile Asp Arg Gly Thr Phe Val Cys Ile Tyr Ser Gly Arg Leu Leu Ser Arg Ala Asn Thr Glu Lys Ser Tyr Gly Ile Asp Glu Asn Gly Arg Asp Glu Asn Thr Met Lys Asn Ile Phe Ser Lys Lys Arg Lys Leu Glu Val Ala Cys Ser Asp Cys Glu Val Glu Val Leu Pro Leu Gly Leu Glu Thr His Pro Arg Thr Ala Lys Thr Glu Lys Cys Pro Pro Lys Phe Ser Asn Asn Pro Lys Glu Leu Thr Val Glu Thr Lys Tyr Asp Asn Ile Ser Arg I1e G1n Tyr His Ser Val Ile Arg Asp Pro G1u Ser Lys Thr Ala Ile Phe Gln His Asn Gly Lys Lys Met Glu Phe Va1 Ser Ser Glu Ser Val Thr Pro Glu Asp Asn Asp Gly Phe Lys Pro Pro Arg Glu His Leu Asn Ser Lys Thr Lys Gly Ala Gln Lys Asp Ser Ser Ser Asn His Val Asp Glu Phe Glu Asp Asn Leu Leu Ile G1u Ser Asp Val I1e Asp Ile Thr Lys Tyr Arg Glu Glu Thr Pro Pro Arg Ser Arg Cys Asn Gln Ala Thr Thr Leu Asp Asn Gln Asn Ile Lys Lys Ala Ile Glu Val Gln Ile Gln Lys Pro Gln Glu Gly Arg Ser Thr Ala Cys Gln Arg Gln Gln Val Phe Cys Asp Glu Glu Leu Leu Ser Glu Thr Lys Asn Thr Ser Ser Asp Ser Leu Thr Lys Phe Asn Lys Gly Asn Val Phe Leu Leu Asp Ala Thr Lys Glu Gly Asn Va1 Gly Arg Phe Leu Asn Ser Leu Thr Leu Ser Pro Val Ala Gln Ser Gln Leu Thr Ala Thr Ser A1a Ser Gly Val Gln Ala Ile Leu Met Pro Arg Pro Pro Glu <210> 3 <211> 1614 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6260407CD1 <400> 3 Met Leu Gly Ala Pro Asp Glu Ser Ser Val Arg Val Ala Val Arg Ile Arg Pro Gln Leu Ala Lys Glu Lys Ile Glu Gly Cys His Ile Cys Thr Ser Val Thr Pro Gly Glu Pro Gln Val Phe Leu Gly Lys Asp Lys Ala Phe Thr Phe Asp Tyr Val Phe Asp Ile Asp Ser Gln Gln Glu Gln Ile Tyr Ile Gln Cys Ile Glu Lys Leu Ile Glu Gly Cys Phe Glu Gly Tyr Asn Ala Thr Val Phe Ala Tyr Gly Gln Thr Gly Ala Gly Lys Thr Tyr Thr Met Gly Thr Gly Phe Asp Val Asn Ile Val Glu Glu G1u Leu Gly Ile Ile Ser Arg Ala Val Lys His Leu Phe Lys Ser Ile Glu Glu Lys Lys His Ile Ala Ile Lys Asn Gly Leu Pro Ala Pro Asp Phe Lys Val Asn Ala Gln Phe Leu Glu Leu Tyr Asn Glu Glu Val Leu Asp Leu Phe Asp Thr Thr Arg Asp Ile Asp Ala Lys Ser Lys Lys Ser Asn Ile Arg Ile His Glu Asp Ser Thr Gly Gly Ile Tyr Thr Val Gly Val Thr Thr Arg Thr Va1 Asn Thr Glu Ser Glu Met Met Gln Cys Leu Lys Leu Gly Ala Leu Ser Arg Thr Thr Ala Ser Thr Gln Met Asn Val Gln Ser Ser Arg Ser His Ala Ile Phe Thr Ile His Val Cys Gln Thr Arg Val Cys Pro Gln Ile Asp Ala Asp Asn Ala Thr Asp Asn Lys Ile I1e Ser Glu Ser Ala Gln Met Asn Glu Phe Glu Thr Leu Thr Ala Lys Phe His Phe Val Asp Leu Ala Gly Ser Glu Arg Leu Lys Arg Thr Gly Ala Thr Gly Glu Arg Ala Lys Glu Gly Ile Ser Ile Asn Cys Gly Leu Leu Ala Leu Gly Asn Val Ile Ser Ala Leu Gly Asp Lys Ser Lys Arg Ala Thr His Val Pro Tyr Arg Asp Ser Lys Leu Thr Arg Leu Leu Gln Asp Ser Leu Gly Gly Asn Ser Gln Thr Ile Met Ile Ala Cys Val Ser Pro Ser Asp Arg Asp Phe Met Glu Thr Leu Asn Thr Leu Lys Tyr Ala Asn Arg Ala Arg Asn Ile Lys Asn Lys Val Met Val Asn Gln Asp Arg Ala Ser Gln Gln Ile Asn Ala Leu Arg Ser Glu Ile Thr Arg Leu Gln Met Glu Leu Met Glu Tyr Lys Thr G1y Lys Arg Ile Tle Asp Glu Glu Gly Val Glu Ser Ile Asn Asp Met Phe His Glu Asn Ala Met Leu Gln Thr Glu Asn Asn Asn Leu Arg Val Arg Ile Lys Ala Met Gln Glu Thr Val Asp Ala Leu Arg Ser Arg Ile Thr Gln Leu Val Ser Asp Gln Ala Asn His Val Leu Ala Arg Ala Gly Glu Gly Asn Glu Glu Ile Ser Asn Met Ile His Ser Tyr I1e Lys Glu Ile Glu Asp Leu Arg Ala Lys Leu Leu Glu Ser G1u Ala Val Asn Glu Asn Leu Arg Lys Asn Leu Thr Arg Ala Thr Ala Arg Ala Pro Tyr Phe Ser Gly Ser Ser Thr Phe Ser Pro Thr Ile Leu Ser Ser Asp Lys Glu Thr Ile Glu Ile Ile Asp Leu A1a Lys Lys Asp Leu Glu Lys Leu Lys Arg Lys Glu Lys Arg Lys Lys Lys Arg Leu Gln Lys Leu Glu Glu Ser Asn Arg Glu Glu Arg Ser Val Ala Gly Lys Glu Asp Asn Thr Asp Thr Asp Gln Glu Lys Lys G1u Glu Lys Gly Val Ser Glu Arg Glu Asn Asn Glu Leu Glu Val Glu Glu Ser Gln Glu Val Ser Asp His Glu Asp Glu Glu Glu Glu G1u Glu Glu Glu Glu Asp Asp Ile Asp Gly G1y Glu Ser Ser Asp Glu Ser Asp Ser Glu Ser Asp Glu Lys Ala Asn Tyr Gln Ala Asp Leu Ala Asn Ile Thr Cys Glu Ile A1a Ile Lys Gln Lys Leu Ile Asp Glu Leu Glu Asn Ser Gln Lys Arg Leu Gln Thr Leu Lys Lys Gln Tyr Glu Glu Lys Leu Met Met Leu Gln His Lys Ile Arg Asp Thr Gln Leu Glu Arg Asp Gln Val Leu Gln Asn Leu Gly Ser Val Glu Ser Tyr Ser Glu Glu Lys Ala Lys Lys Val Arg Ser Glu Tyr Glu Lys Lys Leu Gln Ala Met Asn Lys Glu Leu Gln Arg Leu Gln Ala Ala Gln Lys Glu His Ala Arg Leu Leu Lys Asn Gln Ser Gln Tyr Glu Lys Gln Leu Lys Lys Leu Gln Gln Asp Val Met G1u Met Lys Lys Thr Lys Val Arg Leu Met Lys Gln Met Lys Glu Glu Gln Glu Lys Ala Arg Leu Thr Glu Ser Arg Arg Asn Arg Glu Ile Ala Gln Leu Lys Lys Asp Gln Arg Lys Arg Asp His Gln Leu Arg Leu Leu Glu Ala Gln Lys Arg Asn Gln Glu Val Va1 Leu Arg Arg 8l5 820 825 Lys Thr Glu Glu Val Thr Ala Leu Arg Arg Gln Va1 Arg Pro Met Ser Asp Lys Val Ala Gly Lys Va1 Thr Arg Lys Leu Ser Ser Ser Asp Ala Pro Ala Gln Asp Thr Gly Ser Ser Ala Ala Ala Val Glu Thr Asp Ala Ser Arg Thr Gly Ala G1n Gln Lys Met Arg Ile Pro Val Ala Arg Val Gln Ala Leu Pro Thr Pro Ala Thr Asn Gly Asn Arg Lys Lys Tyr Gln Arg Lys Gly Leu Thr Gly Arg Val Phe Ile Ser Lys Thr Ala Arg Met Lys Trp G1n Leu Leu Glu Arg Arg Val Thr Asp Ile Ile Met Gln Lys Met Thr Ile Ser Asn Met Glu Ala Asp Met Asn Arg Leu Leu Lys Gln Arg Glu Glu Leu Thr Lys Arg Arg Glu Lys Leu Ser Lys Arg Arg Glu Lys Ile Val Lys Glu Asn Gly Glu G1y Asp Lys Asn Val Ala Asn Ile Asn Glu Glu Met Glu Ser Leu Thr Ala Asn Ile Asp Tyr Ile Asn Asp Ser Ile Ser Asp Cys Gln A1a Asn Ile Met Gln Met Glu G1u Ala Lys Glu Glu Gly Glu Thr Leu Asp Val Thr Ala Val Ile Asn Ala Cys Thr Leu Thr Glu Ala Arg~Tyr Leu Leu Asp His Phe Leu Ser Met Gly Ile Asn Lys Gly Leu Gln Ala Ala Gln Lys Glu A1a Gln Ile Lys Val Leu Glu Gly Arg Leu Lys Gln Thr G1u Ile Thr Ser Ala Thr Gln Asn Gln Leu Leu Phe His Met Leu Lys Glu Lys Ala Glu Leu Asn Pro Glu Leu Asp Ala Leu Leu Gly His Ala Leu Gln Asp Leu Asp Ser Val Pro Leu Glu Asn Val Glu Asp Ser Thr Asp Glu Asp Ala Pro Leu Asn Ser Pro Gly Ser G1u Gly Ser Thr Leu Ser Ser Asp Leu Met Lys Leu Cys Gly Glu Val Lys Pro Lys Asn Lys Ala Arg Arg Arg Thr Thr Thr Gln Met Glu Leu Leu Tyr Ala Asp Ser Ser Glu Leu Ala Ser Asp Thr Ser Thr Gly Asp Ala Ser Leu Pro G1y Pro Leu Thr Pro Val Ala Glu Gly Gln Glu Ile Gly Met Asn Thr Glu Thr Ser Gly Thr Ser Ala Arg Glu Lys G1u Leu Ser Pro Pro. Pro Gly Leu Pro Ser Lys Ile Gly Ser Ile Ser Arg Gln Ser Ser Leu Ser Glu Lys Lys Ile Pro G1u Pro Ser Pro Va1 Thr Arg Arg Lys Ala Tyr Glu Lys Ala Glu Lys Ser Lys Ala Lys Glu Gln Lys Gln Gly Ile Ile Asn Pro Phe Pro Ala Ser Lys Gly Ile Arg Ala Phe Pro Leu Gln Cys Ile His Ile Ala Glu Gly His Thr Lys Ala Val Leu Cys Val Asp Ser Thr Asp Asp Leu Leu Phe Thr Gly Ser Lys Asp Arg Thr Cys Lys Val Trp Asn Leu Val Thr G1y Gln Glu Ile Met Ser Leu Gly Gly His Pro Asn Asn Val Val Ser Val Lys Tyr Cys Asn Tyr Thr Ser Leu Val Phe Thr Val Ser Thr Ser Tyr Ile 1340 ~ 1345 1350 Lys Val Trp Asp Ile Arg Asp Ser Ala Lys Cys Ile Arg Thr Leu Thr Ser Ser Gly Gln Val Thr Leu Gly Asp Ala Cys Ser A1a Ser Thr Ser Arg Thr Val Ala Ile Pro Ser Gly Glu Asn Gln I1e Asn Gln Ile Ala Leu Asn Pro Thr Gly Thr Phe Leu Tyr Ala A1a Ser Gly Asn Ala Val Arg Met Trp Asp Leu Lys Arg Phe Gln Ser Thr Gly Lys Leu Thr Gly His Leu Gly Pro Val Met Cys Leu Thr Val Asp Gln Ile Ser Ser Gly Gln Asp Leu Ile Ile Thr Gly Ser Lys Asp His Tyr Ile Lys Met Phe Asp Val Thr Glu Gly Ala Leu Gly Thr Val Ser Pro Thr His Asn Phe Glu Pro Pro His Tyr Asp Gly Ile Glu Ala Leu Thr Ile Gln Gly Asp Asn Leu Phe Ser Gly Ser Arg Asp Asn Gly I1e Lys Lys Trp Asp Leu Thr Gln Lys Asp Leu Leu Gln Gln Val Pro Asn Ala His Lys Asp Trp Val Cys Ala Leu Gly Val Val Pro Asp His Pro Val Leu Leu Ser Gly Cys Arg Gly Gly Ile Leu Lys Val Trp Asn Met Asp Thr Phe Met Pro Val Gly Glu Met Lys Gly His Asp Ser Pro Ile Asn Ala Ile Cys Val Asn Ser Thr His Ile Phe Thr Ala Ala Asp Asp Arg Thr Val Arg Ile Trp Lys Ala Arg Asn Leu Gln Asp Gly Gln Ile Ser Asp Thr Gly Asp Leu Gly Glu Asp Ile Ala Ser Asn <210> 4 <211> 299 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7488258CD1 <400> 4 Met Thr Leu Ser Val Leu Ser Arg Lys Asp Lys Glu Arg Val Ile Arg Arg Leu Leu Leu Gln Ala Pro Pro G1y Glu Phe Va1 Asn Ala Phe Asp Asp Leu Cys Leu Leu Ile Arg Asp Glu Lys Leu Met His His Gln Gly Glu Cys A1a Gly His Gln His Cys Gln Lys Tyr Ser Val Pro Leu Cys Ile Asp Gly Asn Pro Val Leu Leu Ser His His Asn Val Met Gly Asp Tyr Arg Phe Phe Asp His Gln Ser Lys Leu Ser Phe Lys Tyr Asp Leu Leu Gln Asn Gln Leu Lys Asp Ile Gln Ser His Gly 21e Ile Gln Asn G1u Ala Glu Tyr Leu Arg Val Val Leu Leu Cys Ala Leu Lys Leu Tyr Val Asn Asp His Tyr Pro Lys Gly Asn Cys Asn Met Leu Arg Lys Thr Val Lys Ser Lys Glu Tyr Leu Ile Ala Cys Ile Glu Asp His Asn Tyr Glu Thr Gly Glu Cys Trp Asn Gly Leu Trp Lys Ser Lys Trp Ile Phe Gln Val Asn Pro Phe Leu Thr Gln Va1 Thr Gly Arg Ile Phe Val Gln Ala His Phe Phe Arg Cys Val Asn Leu His Ile Glu Ile Ser Lys Asp Leu Lys Glu Ser Leu Glu Ile Val Asn Gln Ala Gln Leu Ala Leu Ser Phe Ala Arg Leu Val Glu Glu Gln Glu Asn Lys Phe Gln Ala Ala Val 230 235 ' 240 Leu Glu Glu Leu Gln Glu Leu Ser Asn Glu A1a Leu Arg Lys I1e Leu Arg Arg Asp Leu Pro Val Thr Arg Thr Leu Ile Asp,Trp His Arg I1e Leu Ser Asp Leu Asn Leu Val Met Tyr Pro Lys Leu Gly Tyr Val I1e Tyr Ser Arg Ser Val Leu Cys Asn Trp Ile Ile <210> 5 <211> 1594 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7948948CD1 <400> 5 Met Leu Asp Ala Pro Asp Glu Ser Ser Val Arg Val Ala Val Arg Ile Arg Pro Gln Leu Ala Lys Glu Lys Ile Glu Gly Cys His Ile Cys Thr Ser Val Thr Pro Gly Glu Pro Gln Val Phe Leu Gly Lys Asp Lys Ala Phe Thr Phe Asp Tyr Val Phe Asp Ile Asp Ser Gln Gln Glu Gln Ile Tyr Ile Gln Cys Ile Glu Lys Leu Ile Glu Gly Cys Phe Glu Gly Tyr Asn Ala Thr Val Phe Ala Tyr Gly Gln Thr Gly Ala Gly Lys Thr Tyr Thr Met Gly Thr Gly Phe Asp Val Asn Ile Val Glu Glu Glu Leu Gly Ile Ile Ser Arg Ala Val Lys His Leu Phe Lys Ser Ile Glu Glu Lys Lys His Ile Ala Ile Lys Asn Gly Leu Pro Ala Pro Asp Phe Lys Val Asn Ala Gln Phe Leu Glu Leu Tyr Asn Glu Glu Val Leu Asp Leu Phe Asp Thr Thr Arg Asp Ile Asp Ala Lys Ser Lys Lys Ser Asn Ile Arg Ile His Glu Asp Ser Thr Gly Gly Ile Tyr Thr Val Gly Val Thr Thr Arg Thr Val Asn Thr Glu Ser Glu Met Met Gln Cys Leu Lys Leu Gly Ala Leu Ser Arg Thr Thr Ala Ser Thr Gln Met Asn Val Gln Ser Ser Arg Ser His Ala Ile Phe Thr Ile His Val Cys Gln Thr Arg Val Cys Pro Gln Ile Asp Ala Asp Asn Ala Thr Asp Asn Lys Ile Ile Ser Glu Ser Ala Gln Met Asn Glu Phe Glu Thr Leu Thr Ala Lys Phe His Phe Val Asp Leu Ala Gly Ser G1u Arg Leu Lys Arg Thr Gly Ala Thr Gly G1u Arg Ala Lys Glu Gly Ile Ser Ile Asn Cys Gly Leu Leu Ala Leu Gly Asn Val Ile Ser Ala Leu Gly Asp Lys Ser Lys Arg A1a Thr His Val Pro Tyr Arg Asp Ser Lys Leu Thr Arg Leu Leu Gln Asp Ser Leu Gly Gly Asn Ser Gln Thr Ile Met Ile Ala Cys Val Ser Pro Ser Asp Arg Asp Phe Met Glu Thr Leu Asn Thr Leu Lys Tyr Ala Asn Arg Ala Arg Asn Ile Lys Asn Lys Val Met Val Asn Gln Asp Arg Ala Ser Gln Gln Ile Asn Ala Leu Arg Ser G1u Ile Thr Arg Leu Gln Met Glu Leu Met Glu Tyr Lys Thr 395 400 ~ 405 Gly Lys Arg Ile Ile Asp Glu Glu Gly Val Glu Ser Ile Asn Asp Met Phe His Glu Asn Ala Met Leu Gln Thr Glu Asn Asn Asn Leu Arg Val Arg Ile Lys Ala Met Gln Glu Thr Val Asp Ala Leu Arg Ser Arg Ile Thr Gln Leu Val Ser Asp Gln Ala Asn His Val Leu Ala Arg Ala Gly Glu Gly Asn Glu Glu Ile Ser Asn Met Ile His Ser Tyr Ile Lys Glu Ile Glu Asp Leu Arg Ala Lys Leu Leu Glu Ser Glu Ala Va1 Asn Glu Asn Leu Arg Lys Asn Leu Thr Arg Ala Thr Ala Arg Ala Pro Tyr Phe Ser Gly Ser Ser Thr Phe Ser Pro Thr Ile Leu Ser Ser Asp Lys Glu Thr Ile Glu Ile Ile Asp Leu Ala Lys Lys Asp Leu Glu Lys Leu Lys Arg Lys Glu Lys Arg Lys Lys Lys Ser Val Ala Gly Lys Glu Asp Asn Thr Asp Thr Asp Gln Glu Lys Lys G1u Glu Lys Gly Val Ser Glu Arg Glu Asn Asn Glu Leu Glu Val Glu Glu Ser Gln Glu Val Ser Asp His Glu Asp Glu Glu Glu Glu Glu Glu Glu Glu Glu Asp Asp Ile Asp Gly Gly Glu Ser Ser Asp Glu Ser Asp Ser Glu Ser Asp Glu Lys Ala Asn Tyr Gln Ala Asp Leu Ala Asn Ile Thr Cys Glu Ile Ala Ile Lys Gln Lys Leu Ile Asp Glu Leu G1u Asn Ser Gln Lys Arg Leu Gln Thr Leu Lys Lys Gln Tyr Glu Glu Lys Leu Met Met Leu Gln His Lys Ile Arg Asp Thr Gln Leu Glu Arg Asp Gln Val Leu Gln Asn Leu Gly Ser Val Glu Ser Tyr Ser G1u Glu Lys Ala Lys Lys Val Arg Ser Glu Tyr Glu Lys Lys Leu G1n Ala Met Asn Lys Glu Leu Gln Arg Leu Gln Ala Ala Gln Lys Glu His Ala Arg Leu Leu Lys Asn Gln Ser Gln Tyr Glu Lys Gln Leu Lys Lys Leu Gln Gln Asp Val Met Glu Met Lys Lys Thr Lys Val Arg Leu Met Lys Gln Met Lys Glu Glu Gln Glu Lys Ala Arg Leu Thr Glu Ser Arg Arg Asn Arg Glu Ile Ala Gln Leu Lys Lys Asp Gln Arg Lys Arg Asp His Gln Leu Arg Leu Leu Glu Ala Gln Lys Arg Asn Gln Glu Val Val Leu Arg Arg Lys Thr Glu Glu Va1 Thr Ala Leu Arg Arg Gln Val Arg Pro Met Ser Asp Lys Val Ala Gly Lys Val Thr Arg Lys Leu Ser Ser Ser Asp Ala Pro Ala Gln Asp Thr Gly Ser Ser Ala Ala Ala Val Glu Thr Asp Ala Ser Arg Thr Gly Ala Gln Gln Lys Met Arg Ile Pro Val Ala Arg Val Gln Ala Leu Pro Thr Pro Ala Thr Asn Gly Asn Arg Lys Lys Tyr Gln Arg Lys Gly Leu Thr Gly Arg Val Phe Ile Ser Lys Thr Ala Arg Met Lys Trp Gln Leu Leu Glu Arg Arg Val Thr Asp Ile Ile Met Gln Lys Met Thr Ile Ser Asn Met Glu Ala Asp Met Asn Arg Leu Leu Lys Gln Arg Glu Glu Leu Thr Lys Arg Arg Glu Lys Leu Ser Lys Arg Arg Glu Lys Ile Val Lys Glu Asn Gly Glu Gly Asp Lys Asn Val Ala Asn Ile Asn Glu Glu Met Glu Ser Leu Thr Ala Asn Ile Asp Tyr Ile Asn Asp Ser Ile Ser Asp Cys Gln Ala Asn Ile Met Gln Met Glu Glu Ala Lys Glu Glu Gly Glu Thr Leu Asp Val Thr Ala Val Ile Asn Ala Cys Thr Leu Thr Glu Ala Arg Tyr Leu Leu Asp His Phe Leu Ser Met Gly Ile Asn Lys Gly Leu Gln Ala Ala G1n Lys Glu Ala Gln Ile Lys Val Leu G1u Gly Arg Leu Lys Gln Thr G1u Ile Thr Ser Ala Thr Gln Asn Gln Leu Leu Phe His Met Leu Lys Glu Lys Ala Glu Leu Asn Pro Glu Leu Asp Ala Leu Leu Gly His Ala Leu Gln Asp Asn Val Glu Asp Ser Thr Asp Glu Asp Ala Pro Leu Asn Ser Pro Gly Ser Glu Gly Ser Thr Leu Ser Ser Asp Leu Met Lys Leu Cys Gly Glu Val Lys Pro Lys Asn Lys Ala Arg Arg Arg Thr Thr Thr Gln Met Glu Leu Leu Tyr A1a Asp Ser Ser Glu Leu A1a Ser Asp Thr Ser Thr Gly Asp Ala Ser Leu Pro Gly Pro Leu Thr Pro Val Ala Glu Gly Gln Glu Ile Gly Met Asn Thr Glu Thr Ser G1y Thr Ser Ala Arg Glu Lys Glu Leu Ser Pro Pro Pro Gly Leu Pro Ser Lys 1190 1195 ~ 1200 Ile G1y Ser I1e Ser Arg Gln Ser Ser Leu Ser G1u Lys Lys Ile Pro G1u Pro Ser Pro Val Thr Arg Arg Lys A1a Tyr Glu Lys A1a Glu Lys Ser Lys Ala Lys Glu Gln Lys Gln Gly Ile Ile Asn Pro Phe Pro A1a Ser Lys Gly Ile Arg Ala Phe Pro Leu Gln Cys I1e His Ile A1a Glu Gly His Thr Lys Ala Val Leu Cys Val Asp Ser Thr Asp Asp Leu Leu Phe Thr Gly Ser Lys Asp Arg Thr Cys Lys Val Trp Asn Leu Val Thr Gly Gln Glu Ile Met Ser Leu Gly Gly His Pro Asn Asn Val Val Ser Val Lys Tyr Cys Asn Tyr Thr Ser Leu Val Phe Thr Val Ser Thr Ser Tyr Ile Lys Val Trp Asp Ile Arg Asp Ser Ala Lys Cys Ile Arg Thr Leu Thr Ser Ser Gly Gln Val Thr Leu Gly Asp Ala Cys Ser Ala Ser Thr Ser Arg Thr Val Ala Ile Pro Ser Gly G1u Asn Gln Ile Asn Gln Ile Ala Leu Asn 11!86 Pro Thr Gly Thr Phe Leu Tyr Ala Ala Ser Gly Asn Ala Val Arg Met Trp Asp Leu Lys Arg Phe Gln Ser Thr Gly Lys Leu Thr Gly His Leu Gly Pro Val Met Cys Leu Thr Val Asp Gln Ile Ser Ser Gly Gln Asp Leu Ile Ile Thr Gly Ser Lys Asp His Tyr Ile Lys Met Phe Asp Val Thr Glu Gly Ala Leu Gly Thr Val Ser Pro Thr His Asn Phe Glu Pro Pro His Tyr Asp Gly Ile Glu A1a Leu Thr Ile Gln Gly Asp Asn Leu Phe Ser Gly Ser Arg Asp Asn Gly Ile Lys Lys Trp Asp Leu Thr Gln Lys Asp Leu Leu Gln Gln Val Pro Asn A1a His Lys Asp Trp Val Cys Ala Leu Gly Val Val Pro Asp His Pro Val Leu Leu Ser Gly Cys Arg Gly Gly Ile Leu Lys Val Trp Asn Met Asp Thr Phe Met Pro Val Gly Glu Met Lys Gly His Asp Ser Pro Ile Asn Ala Ile Cys Val Asn Ser Thr His Ile Phe 1'550 1555 1560 Thr Ala Ala Asp Asp Arg Thr Val Arg Ile Trp Lys Ala Arg Asn Leu Gln Asp Gly Gln Ile Ser Asp Thr Gly Asp Leu Gly Glu Asp Ile Ala Ser Asn <210> 6 <211> 1267 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3467913CD1 <400> 6 Met Ala Arg Gln Pro Pro Pro Pro Trp Val His Ala Ala Phe Leu Leu Cys Leu Leu Ser Leu Gly Gly Ala Ile Glu Ile Pro Met Asp Pro Ser Ile G1n Asn Glu Leu Thr Gln Pro Pro Thr Ile Thr Lys Gln Ser Ala Lys Asp His I1e Val Asp Pro Arg Asp Asn Ile Leu Ile Glu Cys Glu Ala Lys Gly Asn Pro Ala Pro Ser Phe His Trp Thr Arg Asn Ser Arg Phe Phe Asn Ile Ala Lys Asp Pro Arg Val Ser Met Arg Arg Arg Ser Gly Thr Leu Val Ile Asp Phe Arg Ser Gly Gly Arg Pro Glu Glu Tyr Glu Gly Glu Tyr Gln Cys Phe Ala Arg Asn Lys Phe Gly Thr Ala Leu Ser Asn Arg Ile Arg Leu Gln Val Ser Lys Ser Pro Leu Trp Pro Lys Glu Asn Leu Asp Pro Val Val Val Gln Glu Gly Ala Pro Leu Thr Leu G1n Cys Asn Pro Pro Pro Gly Leu Pro Ser Pro Val Ile Phe Trp Met Ser Ser Ser Met Glu Pro Ile Thr Gln Asp Lys Arg Val Ser G1n Gly His Asn Gly Asp Leu Tyr Phe Ser Asn Va1 Met Leu Gln Asp Met Gln Thr Asp Tyr Ser Cys Asn A1a Arg Phe His Phe Thr His Thr Ile Gln Gln Lys Asn Pro Phe Thr Leu Lys Va1 Leu Thr Asn His Pro Tyr Asn Asp Ser Ser Leu Arg Asn His Pro Asp Met Tyr Ser Ala Arg Gly Val Ala Glu Arg Thr Pro Ser Phe Met Tyr Pro Gln Gly Thr Ala Ser Ser Gln Met Val Leu Arg G1y Met Asp Leu Leu Leu G1u Cys Ile Ala Ser Gly Val Pro Thr Pro Asp Ile Ala Trp Tyr Lys Lys Gly Gly Asp Leu Pro Ser Asp Lys Ala Lys Phe Glu Asn Phe Asn Lys Ala Leu Arg Ile Thr Asn Val Ser Glu Glu Asp Ser Gly Glu Tyr Phe Cys Leu Ala Ser Asn Lys Met Gly Ser Ile Arg His Thr Ile Ser Val Arg Val Lys Ala Ala Pro Tyr Trp Leu Asp Glu Pro Lys Asn Leu Ile Leu Ala Pro Gly Glu Asp Gly Arg Leu Val Cys Arg Ala Asn Gly Asn Pro Lys Pro Thr Val Gln Trp Met Val Asn Gly Glu Pro Leu Gln Ser Ala Pro Pro Asn Pro Asn Arg Glu Val Ala Gly Asp Thr Ile Ile Phe Arg Asp Thr Gln Ile Ser Ser Arg Ala Val Tyr Gln Cys Asn Thr Ser Asn Glu His Gly Tyr Leu Leu Ala Asn Ala Phe Val Ser Val Leu Asp Va1 Pro Pro Arg Met Leu Ser Pro Arg Asn Gln Leu Ile Arg Val Ile Leu Tyr Asn Arg Thr Arg Leu Asp Cys Pro Phe Phe Gly Ser Pro Ile Pro Thr Leu Arg Trp Phe Lys Asn Gly G1n Gly Ser Asn Leu Asp Gly Gly Asn Tyr His Val Tyr Glu Asn Gly Ser Leu Glu Ile Lys Met Ile Arg Lys G1u Asp Gln Gly Ile Tyr Thr Cys Val Ala Thr Asn Ile Leu Gly Lys Ala Glu Asn Gln Val Arg Leu Glu Val Lys Asp Pro Thr Arg Ile Tyr Arg Met Pro Glu Asp Gln Val Ala Arg Arg Gly Thr Thr Val Gln Leu Glu Cys Arg Val Lys His Asp Pro Ser Leu Lys Leu Thr Val Ser Trp Leu Lys Asp Asp Glu Pro Leu Tyr Ile G1y Asn Arg Met Lys Lys Glu Asp Asp Ser Leu Thr Ile Phe Gly Val Ala Glu Arg Asp Gln Gly Ser Tyr Thr Cys Val Ala Ser Thr Glu Leu Asp Gln Asp Leu Ala Lys Ala Tyr Leu Thr Val Leu A1a Asp G1n Ala Thr Pro Thr Asn Arg Leu Ala Ala Leu Pro Lys G1y Arg Pro 13rs6 Asp Arg Pro Arg Asp Leu Glu Leu Thr Asp Leu Ala Glu Arg Ser Val Arg Leu Thr Trp Ile Pro Gly Asp Ala Asn Asn Ser Pro Ile Thr Asp Tyr Va1 Va1 Gln Phe Glu Glu Asp Gln Phe Gln Pro Gly Val Trp His Asp His Ser Lys Tyr Pro Gly Ser Val Asn Ser Ala Val Leu Arg Leu Ser Pro Tyr Val Asn Tyr Gln Phe Arg Val Ile Ala Ile Asn Glu Val Gly Ser Ser His Pro Ser Leu Pro Ser Glu Arg Tyr Arg Thr Ser Gly Ala Pro Pro Glu Ser Asn Pro Gly Asp Val Lys Gly Glu Gly Thr Arg Lys Asn Asn Met Glu Ile Thr Trp Thr Pro Met Asn Ala Thr Ser Ala Phe Gly Pro Asn Leu Arg Tyr Ile Val Lys Trp Arg Arg Arg G1u Thr Arg Glu Ala Trp Asn Asn Val Thr Val Trp Gly Ser Arg Tyr Val Val Gly Gln Thr Pro Val Tyr Val Pro Tyr Glu Ile Arg Val Gln A1a Glu Asn Asp Phe Gly Lys Gly Pro Glu Pro Glu Ser Val Ile Gly Tyr Ser Gly Glu Asp Tyr Pro Arg Ala Ala Pro Thr Glu Val Lys Val Arg Val Met Asn Ser Thr Ala Ile Ser Leu Gln Trp Asn Arg Val Tyr Ser Asp Thr Val Gln Gly Gln Leu Arg Glu Tyr Arg Ala Tyr Tyr Trp Arg Glu Ser Ser Leu Leu Lys Asn Leu Trp Val Ser Gln Lys Arg Gln Gln Ala Ser Phe Pro Gly Asp Arg Leu Arg Gly Val Val Ser Arg Leu Phe Pro Tyr Ser Asn Tyr Lys Leu Glu Met Val Val Val Asn Gly Arg Gly Asp Gly Pro Arg Ser Glu Thr Lys Glu Phe Thr Thr Pro Glu Gly Val Pro Ser Ala Pro Arg Arg Phe Arg Va1 Arg Gln Pro Asn Leu Glu Thr I1e Asn Leu Glu Trp Asp His Pro Glu His Pro Asn Gly Ile Met Ile Gly Tyr Thr Leu Lys Tyr Val Ala Phe Asn Gly Thr Lys Val Gly Lys Gln Ile Val Glu Asn Phe Ser Pro Asn Gln Thr Lys Phe Thr Val Gln Arg Thr Asp Pro Val Ser Arg Tyr Arg Phe Thr Leu Ser Ala Arg Thr Gln Va1 Gly Ser Gly Glu Ala Val Thr Glu Glu Ser Pro Ala Pro Pro Asn Glu Ala Pro Pro Thr 1040 1045 ~ 1050 Leu Pro Pro Thr Thr Val Gly Ala Thr Gly Ala Val Ser Ser Thr Asp Ala Thr Ala Ile Ala Ala Thr Thr G1u Ala Thr Thr Val Pro 21e Ile Pro Thr Val Ala Pro Thr Thr Met Ala Thr Thr Thr Thr Val Ala Thr Thr Thr Thr Thr Thr Ala Ala Ala Thr Thr Thr Thr Glu Ser Pro Pro Thr Thr Thr Ser Gly Thr Lys Ile His Glu Ser Ala Tyr Thr Asn Asn Gln Ala Asp Ile Ala Thr Gln Gly Trp Phe Ile Gly Leu Met Cys Ala Ile Ala Leu Leu Val Leu Ile Leu Leu Ile Val Cys Phe Ile Lys Arg Ser Arg G1y Gly Asn Asp Glu Asp Asn Lys Pro Leu Gln Gly Ser Gln Thr Ser Leu Asp G1y Thr Ile Lys Gln Gln Val Arg Glu Lys Lys Asp Val Pro Leu Gly Pro Glu Asp Pro Lys Glu Glu Asp Gly Ser Phe Asp Tyr Arg Cys Ser Asp Asp Ser Leu Val Asp Tyr Gly Glu Gly Gly Glu Gly Gln Phe Asn Glu Asp Gly Ser Phe Ile Gly Gln Tyr Thr Val Lys Lys Asp Lys Glu Glu Thr Glu Gly Asn Glu Ser Ser Glu Ala Thr Ser Pro Val 1250 1255 ~ 1260 Asn Ala Ile Tyr Ser Leu Ala <210> 7 <211> 1359 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7495062CD1 <400> 7 Met Ala Arg Gln Pro Pro Pro Pro Trp Val His Ala Ala Phe Leu Leu Cys Leu Leu Ser Leu Gly Gly Ala Ile Glu Ile Pro Met Asp Pro Ser Ile Gln Asn Glu Leu Thr Gln Pro Pro Thr Tle Thr Lys Gln Ser Ala Lys Asp His Ile Val Asp Pro Arg Asp Asn Ile Leu Ile Glu Cys Glu Ala Lys Gly Asn Pro Ala Pro Ser Phe His Trp Thr Arg Asn Ser Arg Phe Phe Asn Ile Ala Lys Asp Pro Arg Val Ser Met Arg Arg Arg Ser Gly Thr Leu Val I1e Asp Phe Arg Ser Gly Gly Arg Pro Glu Glu Tyr Glu Gly Glu Tyr Gln Cys Phe Ala 110 . 115 120 Arg Asn Lys Phe Gly Thr Ala Leu Ser Asn Arg Ile Arg Leu Gln Val Ser Lys Ser Pro Leu Trp Pro Lys Glu Asn Leu Asp Pro Val Val Val Gln Glu G1y Ala Pro Leu Thr Leu Gln Cys Asn Pro Pro Pro Gly Leu Pro Ser Pro Val Ile Phe Trp Met Ser Ser Ser Met Glu Pro Ile Thr Gln Asp Lys Arg Val Ser G1n Gly His Asn Gly Asp Leu Tyr Phe Ser Asn Val Met Leu Gln Asp Met Gln Thr Asp Tyr Ser Cys Asn Ala Arg Phe His Phe Thr His Thr Ile Gln Gln 15!86 Lys Asn Pro Phe Thr Leu Lys Val Leu Thr Asn His Pro Tyr Asn Asp Ser Ser Leu Arg Asn His Pro Asp Met Tyr Ser Ala Arg Gly Val Ala Glu Arg Thr Pro Ser Phe Met Tyr Pro G1n Gly Thr Ala Ser Ser Gln Met Val Leu Arg Gly Met Asp Leu Leu Leu Glu Cys Ile Ala Ser Gly Val Pro Thr Pro Asp Ile Ala Trp Tyr Lys Lys Gly Gly Asp Leu Pro Ser Asp Lys Ala Lys Phe Glu Asn Phe Asn Lys Ala Leu Arg Ile Thr Asn Val Ser Glu Glu Asp Ser Gly Glu Tyr Phe Cys Leu A1a Ser Asn Lys Met Gly Ser Ile Arg His Thr Ile Ser Val Arg Val Lys Ala Ala Pro Tyr Trp Leu Asp Glu Pro Lys Asn Leu Ile Leu Ala Pro Gly Glu Asp Gly Arg Leu Val Cys Arg A1a Asn Gly Asn Pro Lys Pro Thr Val Gln Trp Met Val Asn Gly G1u Pro Leu Gln Ser Ala Pro Pro Asn Pro Asn Arg Glu Val Ala G1y Asp Thr Ile Ile Phe Arg Asp Thr Gln Ile Ser Ser Arg Ala Val Tyr Gln Cys Asn Thr Ser Asn Glu His Gly Tyr Leu Leu Ala Asn Ala Phe Val Ser Val Leu Asp Val Pro Pro Arg Met Leu Ser Pro Arg Asn Gln Leu Ile Arg Val Ile Leu Tyr Asn Arg Thr Arg Leu Asp Cys Pro Phe Phe Gly Ser Pro Ile Pro Thr Leu Arg Trp Phe Lys Asn Gly Gln Gly Ser Asn Leu Asp Gly Gly Asn Tyr His Val Tyr Glu Asn Gly Ser Leu Glu Ile Lys Met Ile Arg Lys Glu Asp Gln Gly Ile Tyr Thr Cys Val Ala Thr Asn Ile Leu Gly Lys Ala Glu Asn Gln Va1 Arg Leu Glu Val Lys Asp Pro Thr Arg Ile Tyr Arg Met Pro Glu Asp Gln Val Ala Arg Arg Gly Thr Thr Val Gln Leu G1u Cys Arg Val Lys His Asp Pro Ser Leu Lys Leu Thr Val Ser Trp Leu Lys Asp Asp Glu Pro Leu Tyr Ile Gly Asn Arg Met Lys Lys Glu Asp Asp Ser Leu Thr Ile Phe Gly Val Ala Glu Arg Asp Gln Gly Ser Tyr Thr Cys Val Ala Ser Thr Glu Leu Asp Gln Asp Leu Ala Lys Ala Tyr Leu Thr Val Leu Ala Asp Gln Ala Thr Pro Thr Asn Arg Leu Ala A1a Leu Pro Lys Gly Arg Pro Asp Arg Pro Arg Asp Leu Glu Leu Thr Asp Leu Ala G1u Arg Ser Val Arg Leu Thr Trp Ile Pro Gly Asp Ala Asn Asn Ser Pro Ile Thr Asp Tyr Val Val Gln Phe Glu Glu Asp Gln Phe Gln Pro Gly Va1 Trp His Asp His Ser Lys Tyr Pro Gly Ser Val Asn Ser Ala Va1 Leu Arg Leu Ser Pro Tyr Val Asn Tyr Gln Phe Arg Va1 21e Ala Ile Asn Glu Val Gly Ser Ser His Pro Ser Leu Pro Ser Glu Arg Tyr Arg Thr Ser Gly Ala Pro Pro Glu Ser Asn Pro Gly Asp 740 745 750 .
Val Lys Gly Glu Gly Thr Arg Lys Asn Asn Met Glu Ile Thr Trp Thr Pro Met Asn Ala Thr Ser Ala Phe Gly Pro Asn Leu Arg Tyr Ile Val Lys Trp Arg Arg Arg Glu Thr Arg Glu Ala Trp Asn Asn Val Thr Val Trp Gly Ser Arg Tyr Va1 Val Gly Gln Thr Pro Val 800 ~ 805 810 Tyr Val Pro Tyr Glu Ile Arg Val Gln Ala Glu Asn Asp Phe Gly 815 820 ~ 825 Lys Gly Pro Glu Pro Glu Ser Val Ile Gly Tyr Ser Gly Glu Asp Tyr Pro Arg Ala Ala Pro Thr Glu Val Lys Val Arg Val Met Asn Arg Thr Ala Ile Ser Leu Gln Trp Asn Arg Val Tyr Ser Asp Thr Val Gln Gly Gln Leu Arg Glu Tyr Arg Ala Tyr Tyr Trp Arg Glu Ser Ser Leu Leu Lys Asn Leu Trp Val Ser Gln Lys Arg Gln Gln Ala Ser Phe Pro Gly Asp Arg Leu Arg Gly Val Val Ser Arg Leu Phe Pro Tyr Ser Asn Tyr Lys Leu Glu Met Val Val Val Asn Gly Arg Gly Asp Gly Pro Arg Ser Glu Thr Lys Glu Phe Thr Thr Pro Glu Gly Val Pro Ser Ala Pro Arg Arg Phe Arg Val Arg Gln Pro Asn Leu Glu Thr I1e Asn Leu Glu Trp Asp His Pro Glu His Pro Asn Gly Ile Met Ile Gly Tyr Thr Leu Lys Tyr Va1 A1a Phe Asn Gly Thr Lys Val Gly Lys Gln Ile Val Glu Asn Phe Ser Pro Asn Gln Thr Lys Phe Thr Val Gln Arg Thr Asp Pro Val Ser Arg Tyr Arg Phe Thr Leu Ser A1a Arg Thr G1n Val Gly Ser G1y Glu Ala Val Thr Glu Glu Ser Pro Ala Pro Pro Asn Glu Ala Pro Pro Thr Leu Pro Pro Thr Thr Val Gly A1a Thr Gly Ala Val Ser Ser Thr Asp Ala Thr Ala Ile Ala Ala Thr Thr Glu Ala Thr Thr Val Pro Ile Ile Pro Thr Val Ala Pro Thr Thr Met Ala Thr Thr Thr Thr Val Ala Thr Thr Thr Thr Thr Thr Ala Ala Ala Thr Thr Thr Thr Glu Ser Pro Pro Thr Thr Thr Ser Gly Thr Lys Ile His Glu Ser Ala Pro Asp Glu Gln Ser Ile Trp Asn Va1 Thr Val Leu Pro Asn Ser Lys Trp Ala Asn Ile Thr Trp Lys His Asn Phe Gly Pro Gly Thr Asp Phe Val Val Glu Tyr Ile Asp Ser Asn His Thr Lys Lys Thr Val Pro Val Lys Ala Gln A1a Gln Pro Ile Gln Leu Thr Asp Leu Tyr Pro Gly Met Thr Tyr Thr Leu Arg Val Tyr Ser Arg Asp Asn Glu Gly Ile Ser Ser Thr Val Ile Thr Phe Met Thr Ser Thr Ala Tyr Thr Asn Asn Gln Ala Asp Ile Ala Thr Gln Gly Trp Phe Ile G1y Leu Met Cys Ala Ile Ala Leu Leu Val Leu Ile Leu Leu Ile Val Cys Phe Ile Lys Arg Ser Arg Gly Gly Lys Tyr Pro Val Arg Glu Lys Lys Asp Val Pro Leu Gly Pro Glu Asp Pro Lys Glu G1u Asp Gly Ser Phe Asp Tyr Ser Asp Glu Asp Asn Lys Pro Leu Gln Gly Ser Gln Thr Ser Leu Asp Gly Thr Ile Lys Gln Gln Glu Ser Asp Asp Ser Leu Val Asp Tyr Gly Glu Gly Gly Glu Gly Gln Phe Asn Glu Asp Gly Ser Leu Ile Gly Gln Tyr Thr Val Lys Lys Asp Lys Glu Glu Thr Glu Gly Asn Glu Ser Ser Glu Ala Thr Ser Pro Val Asn Ala Ile Tyr Ser Leu Ala <210> 8 <211> 452 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 284191CD1 <400> 8 Met Ser Ala Ser Leu Asn Tyr Lys Ser Phe Ser Lys Glu G1n Gln 1 5 10 ' 15 Thr Met Asp Asn Leu Glu Lys Gln Leu Ile Cys Pro Ile Cys Leu Glu Met Phe Thr Lys Pro Va1 Va1 Ile Leu Pro Cys G1n His Asn Leu Cys Arg Lys Cys Ala Ser Asp Ile Phe Gln Ala Ser Asn Pro Tyr Leu Pro Thr Arg Gly Gly Thr Thr Met Ala Ser Gly Gly Arg Phe Arg Cys Pro Ser Cys Arg His Glu Val Val Leu Asp Arg His Gly Val Tyr G1y Leu Gln Arg Asn Leu Leu Val Glu Asn Ile Ile Asp Ile Tyr Lys Gln Glu Ser Thr Arg Pro Glu Lys Lys Ser Asp Gln Pro Met Cys Glu Glu His Glu Glu Glu Arg Ile Asn Ile Tyr Cys Leu Asn Cys Glu Val Pro Thr Cys Ser Leu Cys Lys Val Phe Gly Ala His Lys Asp Cys Gln Val Ala Pro Leu Thr His Val Phe Gln Arg Gln Lys Ser Glu Leu Ser Asp Gly Ile Ala Ile Leu Val Gly Ser Asn Asp Arg Val Gln Gly Val Ile Ser Gln Leu Glu Asp Thr Cys Lys Thr Ile G1u Glu Cys Cys Arg Lys Gln Lys Gln Glu Leu Cys Glu Lys Phe Asp Tyr Leu Tyr Gly Ile Leu Glu Glu Arg Lys Asn Glu Met Thr G1n Val Ile Thr Arg Thr Gln Glu Glu Lys Leu Glu His Val Arg Ala Leu Ile Lys Lys Tyr Ser Asp His Leu Glu Asn Val Ser Lys Leu Val Glu Ser Gly Ile Gln Phe Met Asp Glu Pro Glu Met Ala Val Phe Leu Gln Asn Ala Lys Thr Leu Leu Lys Lys Ile Ser Glu Ala Ser Lys Ala Phe Gln Met Glu Lys Ile Glu His Gly Tyr Glu Asn Met Asn His Phe Thr Val Asn Leu Asn Arg Glu Glu Lys Ile Ile Arg Glu Ile Asp Phe Tyr Arg G1u Asp Glu Asp Glu Glu Glu Glu Glu G1y Gly Glu Gly Glu Lys G1u Gly Glu Gly Glu Val Gly Gly Glu Ala Val Glu Val Glu Glu Val Glu Asn Val Gln Thr Glu Phe Pro Gly Glu Asp Glu Asn Pro Glu Lys Ala Ser Glu Leu Ser Gln Val Glu Leu Gln Ala Ala Pro Gly Ala Leu Pro Va1 Ser Ser Pro Glu Pro Pro Pro A1a Leu Pro Pro Ala Ala Asp Ala Pro Val Thr Gln Ile Gly Phe G1u Ala Pro Pro Leu Gln Gly G1n Ala Ala Ala Pro Ala Ser Gly Ser Gly Ala Asp Ser Glu Pro Ala Arg His Ile Phe Ser Phe Ser Trp Leu Asn Ser Leu Asn Glu <210> 9 <211> 471 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2361681CD1 <400> 9 Met Ser Arg Arg Val Val Arg Gln Ser Lys Phe Arg His Val Phe Gly Gln Ala Ala Lys Ala Asp Gln Ala Tyr Glu Asp Ile Arg Va1 Ser Lys Val Thr Trp Asp Ser Ser Phe Cys A1a Val Asn Pro Lys Phe Leu Ala Ile Ile Val Glu Ala Gly Gly Gly Gly A1a Phe Ile Va1 Leu Pro Leu Ala Lys Thr Gly Arg Val Asp Lys Asn Tyr Pro Leu Val Thr Gly His Thr Ala Pro Val Leu Asp Ile Asp Trp Cys Pro His Asn Asp Asn Val Ile Ala Ser Ala Ser Asp Asp Thr Thr Ile Met Val Trp Gln Ile Pro Asp Tyr Thr Pro Met Arg Asn Ile Thr Glu Pro Ile Ile Thr Leu Glu Gly His Ser Lys Arg Val Gly Ile Leu Ser Trp His Pro Thr Ala Arg Asn Val Leu Leu Ser Ala G1y Gly Asp Asn Val Ile Tle Ile Trp Asn Val Gly Thr Gly Glu Val Leu Leu Ser Leu Asp Asp Met His Pro Asp Val Ile His Ser Val Cys Trp Asn Ser Asn Gly Ser Leu Leu Ala Thr Thr Cys Lys Asp Lys Thr Leu Arg Ile Ile Asp Pro Arg Lys Gly Gln Val Val A1a Glu Arg Phe Ala Ala His Glu Gly Met Arg Pro Met Arg Ala Val Phe Thr Arg Gln Gly His Ile Phe Thr Thr Gly Phe Thr Arg Met Ser Gln Arg Glu Leu Gly Leu Trp Asp Pro Asn Asn Phe Glu 245 ~ 250 255 G1u Pro Val Ala Leu Gln Glu Met Asp Thr Ser Asn Gly Val Leu Leu Pro Phe Tyr Asp Pro Asp Ser Ser Ile Val Tyr Leu Cys Gly Lys Gly Asp Ser Ser Ile Arg Tyr Phe Glu Ile Thr Asp Glu Pro Pro Phe Val His Tyr Leu Asn Thr Phe Ser Ser Lys Glu Pro Gln Arg Gly Met Gly Phe Met Pro Lys Arg Gly Leu Asp Val Ser Lys Cys G1u Ile Ala Arg Phe Tyr Lys Leu His Glu Arg Lys Cys Glu Pro Ile Ile Met Thr Val Pro Arg Lys Ser Asp Leu Phe Gln Asp Asp Leu Tyr Pro Asp Thr Pro Gly Pro Glu Pro Ala Leu Glu Ala Asp Glu Trp Leu Ser Gly Gln Asp Ala Glu Pro Val Leu Ile Ser Leu Arg Asp Gly Tyr Val Pro Pro Lys His Arg Glu Leu Arg Val Thr Lys Arg Asn Ile Leu Asp Val Arg Pro Pro Ser Gly Pro Arg Arg Ser Gln Ser Ala Ser Asp A1a Pro Leu Ser Gln His Thr Leu Glu Thr Leu Leu Glu Glu Ile Lys Ala Leu Arg Glu Arg Val Gln Ala Gln Glu Gln Arg Ile Thr Ala Leu Glu Asn Met Leu Cys Glu Leu Val Asp Gly Thr Asp <210> 10 <211> 705 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1683662CD1 <400> 10 Met Thr Ile Glu Asp Leu Pro Asp Phe Pro Leu Glu Gly Asn Pro Leu Phe Gly Arg Tyr Pro Phe I1e Phe Ser A1a Ser Asp Thr Pro Va1 Ile Phe Ser Ile Ser Ala Ala Pro Met Pro Ser Asp Cys Glu Phe Ser Phe Phe Asp Pro Asn Asp Ala Ser Cys Gln Glu I1e Leu Phe Asp Pro Lys Thr Ser Val Ser Glu Leu Phe Ala Ile Leu Arg Gln Trp Val Pro Gln Va1 Gln Gln Asn Ile Asp Ile Ile Gly Asn Glu Ile Leu Lys Arg Gly Cys Asn Val Asn Asp Arg Asp Gly Leu Thr Asp Met Thr Leu Leu His Tyr Thr Cys Lys Ser Gly Ala His Gly Ile Gly Asp Val Glu Thr Ala Val Lys Phe Ala Thr Gln Leu Ile Asp Leu Gly Ala Asp Ile Ser Leu Arg Ser Arg Trp Thr Asn Met Asn Ala Leu His Tyr Ala A1a Tyr Phe Asp Val Pro Glu Leu Ile Arg Val Ile Leu Lys Thr Ser Lys Pro Lys Asp Val Asp Ala Thr Cys Ser Asp Phe Asn Phe Gly Thr Ala Leu His Ile Ala Ala Tyr Asn Leu Cys Ala Gly Ala Val Lys Cys Leu Leu Glu Gln Gly Ala Asn Pro Ala Phe Arg Asn Asp Lys Gly Gln Ile Pro Ala Asp Val Val Pro Asp Pro Va1 Asp Met Pro Leu Glu Met Ala Asp Ala A1a Ala Thr Ala Lys Glu Ile Lys Gln Met Leu Leu Asp Ala Val Pro Leu Ser Cys Asn Ile Ser Lys Ala Met Leu Pro Asn Tyr Asp His Val Thr Gly Lys Ala Met Leu Thr Ser Leu Gly Leu Lys Leu Gly Asp Arg Val Val 2le Ala Gly Gln Lys Val Gly Thr Leu Arg Phe Cys Gly Thr Thr Glu Phe Ala Ser Gly Gln Trp Ala Gly Ile Glu Leu Asp Glu Pro Glu Gly Lys Asn Asn Gly Ser Val Gly Lys Val Gln Tyr Phe Lys Cys Ala Pro Lys Tyr Gly Ile Phe Ala Pro Leu Ser Lys Ile Ser Lys Ala Lys Gly Arg Arg Lys Asn Ile Thr His Thr Pro Ser Thr Lys Ala A1a Val Pro Leu Ile Arg Ser Gln Lys Ile Asp Val Ala His Val Thr Ser Lys Va1 Asn Thr Gly Leu Met Thr Ser Lys Lys Asp Ser Ala Ser Glu Ser Thr Leu Ser Leu Pro Pro Gly G1u G1u Leu Lys Thr Val Thr Glu Lys Asp Val Ala Leu Leu Gly Ser Val Ser Ser Cys Ser Ser Thr Ser Ser Leu Glu His Arg Gln Ser Tyr Pro Lys Lys Gln Asn Ala Ile Ser Ser Asn Lys Lys Thr Met Ser Lys Ser Pro Ser Leu Ser Ser Arg Ala Ser Ala Gly Leu Asn Ser Ser Ala Thr Ser Thr Ala Asn Asn Ser Arg Cys Glu Gly Glu Leu Arg Leu Gly Glu Arg Val Leu Val Val Gly Gln Arg Leu Gly Thr Ile Arg Phe Phe Gly Thr Thr Asn Phe Ala Pro Gly Tyr Trp Tyr Gly Ile G1u Leu Glu Lys Pro His Gly Lys Asn Asp Gly Ser Val G1y G1y Val Gln Tyr Phe Ser Cys Ser Pro Arg Tyr Gly Ile Phe Ala Pro Pro Ser Arg Val Gln Arg Val Thr Asp Ser Leu Asp Thr Leu Ser Glu Ile Ser Ser Asn Lys Gln Asn His Ser Tyr Pro Gly Phe Arg Arg Ser Phe Ser Thr Thr Ser Ala Ser Ser G1n Lys Glu Ile Asn Arg Arg Asn Ala Phe Ser Lys Ser Lys Ala Ala Leu Arg Arg Ser Trp Ser Ser Thr Pro Thr Ala Gly Gly Ile Glu Gly Ser Val Lys Leu His Glu Gly Ser Gln Val Leu Leu Thr Ser Ser Asn Glu Met Gly Thr Val Arg Tyr Val Gly Pro Thr Asp Phe Ala Ser Gly Ile Trp Leu Gly Leu Glu Leu Arg Ser Ala Lys Gly Lys Asn Asp Gly Ser Val Gly Asp Lys Arg Tyr Phe Thr Cys Lys Pro Asn His Gly Val Leu Val Arg Pro Ser Arg Val Thr Tyr Arg Gly Ile Asn Gly Ser Lys Leu Val Asp Glu Asn Cys <210> 11 <211> 997 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3750444CD1 <400> 11 Met Leu Asn Asn Ile Ser G1y Asp Val Leu Val Ala Ala Gly Phe Val Ala Tyr Leu Gly Pro Phe Thr Gly Gln Tyr Arg Thr Val Leu Tyr Asp Ser Trp Val Lys Gln Leu Arg Ser His Asn Val Pro His Thr Ser Glu Pro Thr Leu Ile G1y Thr Leu Gly Asn Pro Val Lys Ile Arg Ser Trp Gln Ile Ala G1y Leu Pro Asn Asp Thr Leu Ser Val Glu Asn Gly Val Ile Asn G1n Phe Ser Gln Arg Trp Thr His Phe Ile Asp Pro Gln Ser Gln A1a Asn Lys Trp Ile Lys Asn Met Glu Lys Asp Asn Gly Leu Asp Val Phe Lys Leu Ser Asp Arg Asp Phe Leu Arg Ser Met Glu Asn Ala Ile Arg Phe Gly Lys Pro Cys Leu Leu Glu Asn Val Gly Glu G1u Leu Asp Pro Ala Leu Glu Pro Val Leu Leu Lys Gln Thr Tyr Lys Gln Gln Gly Asn Thr Val Leu Lys Leu Gly Asp Thr Val Ile Pro Tyr His Glu Asp Phe Arg Met Tyr Ile Thr Thr Lys Leu Pro Asn Pro His Tyr Thr Pro Glu Ile Ser Thr Lys Leu Thr Leu Tle Asn Phe Thr Leu Ser Pro Ser Gly Leu Glu Asp Gln Leu Leu Gly Gln Val Val Ala Glu Glu Arg Pro Asp Leu Glu Glu Ala Lys Asn Gln Leu Ile Ile Ser Asn Ala Lys Met Arg Gln Glu Leu Lys Asp Ile Glu Asp Gln Ile Leu Tyr Arg Leu Ser Ser Ser Glu Gly Asn Pro Val Asp Asp Met Glu Leu Ile Lys Val Leu Glu Ala Ser Lys Met Lys Ala Ala Glu Ile Gln Ala Lys Val Arg Ile Ala Glu Gln Thr Glu Lys Asp Ile Asp Leu Thr Arg Met Glu Tyr Ile Pro Val Ala Ile Arg Thr Gln Ile Leu Phe Phe Cys Va1 Ser Asp Leu Ala Asn Val Asp Pro Met Tyr Gln Tyr Ser Leu Glu Trp Phe Leu Asn Ile Phe Leu Ser Gly Ile Ala Asn Ser Glu Arg Ala Asp Asn Leu Lys Lys Arg Ile Ser Asn Ile Asn Arg Tyr Leu Thr Tyr Ser Leu Tyr Ser Asn Val Cys Arg Ser Leu Phe Glu Lys His Lys Leu Met Phe Ala Phe Leu Leu Cys Val Arg Ile Met Met Asn Glu Gly Lys Ile Asn Gln Ser Glu Trp Arg Tyr Leu Leu Ser Gly Gly Ser Ile Ser Ile Met Thr Glu Asn Pro Ala Pro Asp Trp Leu Ser Asp Arg A1a Trp Arg Asp Ile Leu Ala Leu Ser Asn Leu Pro Thr Phe Ser Ser Phe Ser Ser Asp Phe Val Lys His Leu Ser Glu Phe Arg Val 21e Phe Asp Ser Leu Glu Pro His Arg Glu Pro Leu Pro Gly Ile Trp Asp Gln Tyr Leu Asp Gln Phe 470 ~ 475 480 Gln Lys Leu Leu Val Leu Arg Cys Leu Arg G1y Asp Lys Val Thr Asn Ala Met Gln Asp Phe Val Ala Thr Asn Leu Glu Pro Arg Phe Ile Glu Pro Gln Thr Ala Asn Leu Ser Val Val Phe Lys Asp Ser Asn Ser Thr Thr Pro Leu Ile Phe Val Leu Ser Pro Gly Thr Asp Pro Ala Ala Asp Leu Tyr Lys Phe A1a Glu Glu Met Lys Phe Ser Lys Lys Leu Ser Ala Ile Ser Leu G1y Gln G1y Gln Gly Pro Arg Ala Glu Ala Met Met Arg Ser Ser I1e Glu Arg Gly Lys Trp Val Phe Phe Gln Asn Cys His Leu Ala Pro Ser Trp Met Pro Ala Leu G1u Arg Leu Ile Glu His Ile Asn Pro Asp Lys Val His Arg Asp Phe Arg Leu Trp Leu Thr Ser Leu Pro Ser Asn Lys Phe Pro Va1 Ser Ile Leu Gln Asn Gly Ser Lys Met Thr Ile Glu Pro Pro Arg G1y Val Arg Ala Asn Leu Leu Lys Ser Tyr Ser Ser Leu Gly Glu Asp Phe Leu Asn Ser Cys His Lys Val Met Glu Phe Lys Ser Leu Leu Leu Ser Leu Cys Leu Phe His Gly Asn Ala Leu Glu Arg Arg Lys Phe Gly Pro Leu Gly Phe Asn Ile Pro Tyr Glu Phe Thr Asp Gly Asp Leu Arg Ile Cys Ile Ser Gln Leu Lys Met Phe Leu Asp Glu Tyr Asp Asp Ile Pro Tyr Lys Val Leu Lys Tyr Thr Ala Gly Glu I1e Asn Tyr Gly Gly Arg Val Thr Asp Asp Trp Asp Arg Arg Cys Ile Met Asn Ile Leu Glu Asp Phe Tyr Asn Pro Asp Val Leu Ser Pro Glu His Ser Tyr Ser Ala Ser Gly Ile Tyr His Gln Ile Pro Pro Thr Tyr Asp Leu His Gly Tyr Leu Ser Tyr Ile Lys Ser Leu Pro Leu Asn Asp Met Pro Glu Ile Phe Gly Leu His Asp Asn Ala Asn Ile Thr Phe Ala Gln Asn Glu Thr Phe Ala Leu Leu Gly Thr Ile Ile Gln Leu Gln Pro Lys Ser Ser Ser Ala Gly Ser Gln Gly Arg Glu Glu Ile Val Glu Asp Val Thr Gln Asn Ile Leu Leu Lys Val Pro Glu Pro Ile Asn Leu Gln Trp Val Met Ala Lys Tyr Pro Val Leu Tyr Glu Glu Ser Met Asn Thr Val Leu Val Gln Glu Val Ile Arg Tyr Asn Arg Leu Leu Gln Val Ile Thr Gln Thr Leu G1n Asp Leu Leu Lys Ala Leu Lys Gly Leu Val Val Met Ser Ser Gln Leu Glu Leu Met Ala A1a Ser Leu Tyr Asn Asn Thr Val Pro Glu Leu Trp Ser Ala Lys Ala Tyr Pro Ser Leu Lys Pro Leu Ser Ser Trp Val Met Asp Leu Leu Gln Arg Leu Asp Phe Leu Gln A1a Trp Ile Gln Asp Gly Ile Pro Ala Val Phe Trp Ile Ser G1y Phe Phe Phe Pro Gln Ala Cys Leu Asn Arg His Ser Ala Glu Phe Cys Pro Gln Ile Cys His Leu His <210> 12 <211> 1360 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5500608CD1 <400>

Met Ala Trp Ile Leu His Leu Asn Leu Ser Ser Lys Thr Ala His Leu Lys Leu Gln Gly Ser Tyr Tyr Leu Lys Leu Thr Ser Leu Thr Phe Asp I1e Lys Gly Tyr Leu Leu Lys Ser Ser Leu Glu Val Ser Tyr Lys Val Val Pro Val Ser Leu Ser Glu Val Tyr Leu Leu Gln Cys Asn Met Lys Phe Pro Thr Gln Ser Ser Phe Asp Arg Val Met Pro Leu Leu Asn Val A1a Val A1a Ser Leu His Pro Leu Thr Asp Glu His I1e Phe Gln Ala Ile Asn Ala Gly Ser Ile Glu Gly Thr Leu Glu Trp Glu Asp Phe Gln Gln Arg Met Glu Asn Leu Ser Met Phe Leu I1e Lys Arg Arg Asp Met Thr Arg Met Phe Val His Pro Ser Phe Arg Glu Trp Leu Ile Trp Arg Glu Glu G1y Glu Lys Thr Lys Phe Leu Cys Asp Pro Arg Ser Gly His Thr Leu Leu Ala Phe Trp Phe Ser Arg Gln Glu Gly Lys Leu Asn Arg Gln Gln Thr Ile 170 ' 175 180 Glu Leu G1y His His Ile Leu Lys Ala His Ile Phe Lys Gly Leu Ser Lys Lys Val Gly Val Ser Ser Ser Ile Leu Gln Gly Leu Trp Ile Ser Tyr Ser Thr Glu Gly Leu Ser Met Ala Leu Ala Ser Leu Arg Asn Leu Tyr Thr Pro Asn Ile Lys Val Ser Arg Leu Leu Ile Leu Gly Gly Ala Asn Ile Asn Tyr Arg Thr Glu Val Leu Asn Asn Ala Pro Ile Leu Cys Val Gln Ser His Leu Gly Tyr Thr Glu Met Val Ala Leu Leu Leu Glu Phe Gly Ala Asn Val Asp Ala Ser Ser Glu Ser Gly Leu Thr Pro Leu Gly Tyr A1a Ala Ala Ala Gly Tyr Leu Ser Ile Val Val Leu Leu Cys Lys Lys Arg Ala Lys Val Asp His Leu Asp Lys Asn Gly Gln Cys Ala Leu Val His Ala Ala Leu Arg Gly His Leu Glu Val Val Lys Phe Leu Ile Gln Cys Asp Trp Thr Met Ala Gly G1n Gln Gln Gly Val Phe Lys Lys Ser His Ala Ile G1n Gln Ala Leu Ile Ala Ala Ala Ser Met Gly Tyr Thr Glu Ile Val Ser Tyr Leu Leu Asp Leu Pro Glu Lys Asp Glu Glu Glu Val Glu Arg A1a Gln Ile Asn Ser Phe Asp Ser Leu Trp Gly Glu Thr Ala Leu Thr Ala A1a Ala Gly Arg Gly Lys Leu Glu Val Cys Arg Leu Leu Leu Glu Gln Gly Ala Ala Val Ala Gln Pro Asn Arg Arg Gly Ala Val Pro Leu Phe Ser Thr Val Arg Gln Gly His Trp Gln Ile Val Asp Leu Leu Leu Thr His Gly Ala Asp Val Asn Met Ala Asp Lys Gln Gly Arg Thr Pro Leu Met Met Ala Ala Ser Glu Gly His Leu Gly Thr Val Asp Phe Leu Leu Ala Gln Gly A1a Ser Ile Ala Leu Met Asp Lys Glu Gly Leu Thr Ala Leu Ser Trp Ala Cys Leu Lys Gly His Leu Ser Val Val Arg Ser Leu Val Asp Asn 5l5 520 525 Gly Ala Ala Thr Asp His Ala Asp Lys Asn Gly Arg Thr Pro Leu Asp Leu Ala Ala Phe Tyr Gly Asp Ala Glu Va1 Val Gln Phe Leu Val Asp His Gly Ala Met Ile Glu His Val Asp Tyr Ser Gly Met Arg Pro Leu Asp Arg Ala Val G1y Cys Arg Asn Thr Ser Val Val Val Thr Leu Leu Lys Lys Gly Ala Lys Ile Gly Pro Ala Thr Trp Ala Met Ala Thr Ser Lys Pro Asp Ile Met Ile Ile Leu Leu Ser Lys Leu Met Glu Glu Gly Asp Met Phe Tyr Lys Lys Gly Lys Val Lys Glu Ala Ala Gln Arg Tyr Gln Tyr Ala Leu Lys Lys Phe Pro Arg Glu Gly Phe Gly Glu Asp Leu Lys Thr Phe Arg Glu Leu Lys Val Ser Leu Leu Leu Asn Leu Ser Arg Cys Arg Arg Lys Met Asn Asp Phe Gly Met Ala Glu Glu Phe Ala Thr Lys Ala Leu Glu Leu Lys Pro Lys Ser Tyr Glu Ala Tyr Tyr Ala Arg Ala Arg Ala Lys Arg Ser Ser Arg Gln Phe Ala Ala Ala Leu Glu Asp Leu Asn Glu Ala I1e Lys Leu Cys Pro Asn Asn Arg Glu Ile Gln Arg Leu Leu Leu Arg Val Glu Glu Glu Cys Arg Gln Met Gln Gln Pro Gln Gln Pro Pro Pro Pro Pro Gln Pro Gln Gln Gln Leu Pro Glu Glu Ala Glu Pro Glu Pro Gln His Glu Asp Ile Tyr Ser Val Gln Asp Ile Phe Glu Glu Glu Tyr Leu Glu G1n Asp Val Glu Asn Val Ser Ile Gly Leu Gln Thr Glu Ala Arg Pro Ser G1n Gly Leu Pro Val Ile Gln Ser Pro Pro Ser Ser Pro Pro His Arg Asp Ser Ala Tyr Ile Ser Ser Ser Pro Leu Gly Ser His Gln Val Phe Asp Phe Arg Ser Ser Ser Ser Val Gly Ser Pro Thr Arg G1n Thr Tyr Gln Ser Thr Ser Pro Ala Leu Ser Pro Thr His Gln Asn Ser His Tyr Arg Pro Ser Pro Pro His Thr Ser Pro Ala His Gln Gly Gly Ser Tyr Arg Phe Ser Pro Pro Pro Val Gly Gly Gln Gly Lys Glu Tyr Pro Ser Pro Pro Pro Ser Pro Leu Arg Arg Gly Pro Gln Tyr Arg Ala Ser Pro Pro Ala Glu Ser Met Ser Val Tyr Arg Ser Gln Ser Gly Ser Pro Val Arg Tyr Gln Gln Glu Thr Ser Val Ser G1n Leu Pro Gly Arg Pro Lys Ser Pro Leu Ser Lys Met Ala Gln Arg Pro Tyr G1n Met Pro Gln Leu Pro Val Ala Val Pro Gln Gln Gly Leu Arg Leu Gln Pro A1a Lys Ala Gln Ile Val Arg Ser Asn Gln Pro Ser Pro Ala Val His Ser Ser Thr Val Ile Pro Thr Gly Ala Tyr Gly Gln Val Ala His Ser Met Ala Ser Lys Tyr Gln Ser Ser Gln Gly Asp Ile Gly Val Ser Gln Ser Arg Leu Val Tyr Gln Gly Ser Tle Gly Gly Ile Val Gly Asp Gly Arg Pro Val Gln His Val Gln Ala Ser Leu Ser Ala Gly Ala Ile Cys Gln His Gly Gly Leu Thr Lys Glu Asp Leu Pro Gln Arg Pro Ser Ser A1a Tyr Arg Gly Gly Val Arg Tyr Ser Gln Thr Pro G1n Ile Gly Arg Ser Gln Ser Ala Ser Tyr Tyr Pro Val Cys His Ser Lys Leu Asp Leu Glu Arg Ser Ser Ser Gln Leu Gly Ser Pro Asp Val Ser His Leu Ile Arg Arg Pro Ile Ser Val Asn Pro Asn Glu Ile Lys Pro His Pro Pro Thr Pro Arg Pro Leu Leu His Ser Gln Ser Val G1y Leu Arg Phe Ser Pro Ser Ser Asn Ser Ile Ser Ser Thr Ser Asn Leu Thr Pro Thr Phe Arg Pro Ser Ser Ser Ile Gln Gln Met Glu Ile Pro Leu Lys Pro Ala Tyr Glu Arg Ser Cys Asp Glu Leu Ser Pro Val Ser Pro Thr Gln Gly Gly Tyr Pro Ser Glu Pro Thr Arg Ser Arg Thr Thr Pro Phe Met Gly Ile Ile Asp Lys Thr Ala Arg Thr Gln Gln Tyr Pro His Leu His Gln Gln Asn Arg Thr Trp Ala Val Ser Ser Val Asp Thr Val Leu Ser Pro Thr Ser Pro G1y Asn Leu Pro Gln Pro Glu Ser Phe Ser Pro Pro Ser Ser Ile Ser Asn Ile Ala Phe Tyr Asn Lys Thr Asn Asn Ala Gln Asn Gly His Leu Leu Glu Asp Asp Tyr Tyr Ser Pro His Gly Met Leu Ala Asn Gly Ser Arg Gly Asp Leu Leu G1u Arg Val Ser Gln Ala Ser Ser Tyr Pro Asp Val Lys Val Ala Arg Thr Leu Pro Val Ala Gln Ala Tyr Gln Asp Asn Leu Tyr Arg Gln Leu Ser Arg Asp Ser Arg Gln G1y Gln Thr Ser Pro Ile Lys Pro Lys Arg Pro Phe Val Glu Ser Asn Val <210> 13 <211> 521 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2962837CD1 <400> 13 Met Leu Pro Arg Arg Pro Leu Ala Trp Pro Ala Trp Leu Leu Arg 27!86 Gly Ala Pro Gly Ala Ala Gly Ser Trp Gly Arg Pro Val Gly Pro Leu Ala Arg Arg_Gly Cys Cys Ser Ala Pro Gly Thr Pro Glu Val Pro Leu Thr Arg Glu Arg Tyr Pro Val Arg Arg Leu Pro Phe Ser Thr Val Ser Lys Gln Asp Leu Ala Ala Phe Glu Arg Ile Val Pro Gly Gly Val Val Thr Asp Pro Glu Ala Leu Gln Ala Pro Asn Val Asp Trp Leu Arg Thr Leu Arg Gly Cys Ser Lys Val Leu Leu Arg Pro Arg Thr Ser Glu Glu Val Ser His Ile Leu Arg His Cys His Glu Arg Asn Leu Ala Val Asn Pro Gln Gly Gly Asn Thr Gly Met Val G1y Gly Ser Val Pro Val Phe Asp Glu Ile Ile Leu Ser Thr Ala Arg Met Asn Arg Val Leu Ser Phe His Ser Val Ser Gly Ile Leu Val Cys Gln Ala Gly Cys Val Leu Glu Glu Leu Ser Arg Tyr Val Glu Glu Arg Asp Phe Ile Met Pro Leu Asp Leu Gly Ala Lys Gly Ser Cys His Ile Gly Gly Asn Val Ala Thr Asn Ala Gly Gly Leu Arg Phe Leu Arg Tyr Gly Ser Leu His Gly Thr Val Leu Gly Leu Glu Val Val Leu Ala Asp Gly Thr Val Leu Asp Cys Leu Thr Ser Leu Arg Lys Asp Asn Thr Gly Tyr Asp Leu Lys Gln Leu Phe Ile Gly Ser Glu Gly Thr Leu Gly Ile Ile Thr Thr Val Ser Ile Leu Cys Pro Pro Lys Pro Arg Ala Val Asn Val Ala Phe Leu Gly Cys Pro G1y Phe Ala Glu Val Leu Gln Thr Phe Ser Thr Cys Lys Gly Met Leu G1y Glu Ile Leu Ser Ala Phe Glu Phe Met Asp Ala 3 05 31'0 315 Val Cys Met Gln Leu Val Gly Arg His Leu His Leu Ala Ser Pro Val Gln Glu Ser Pro Phe Tyr Va1 Leu Ile Glu Thr Ser Gly Ser Asn Ala Gly His Asp Ala Glu Lys Leu G1y His Phe Leu Glu His Ala Leu Gly Ser Gly Leu Val Thr Asp Gly Thr Met Ala Thr Asp Gln Arg Lys Val Lys Met Leu Trp Ala Leu Arg Glu Arg I1e Thr Glu Ala Leu Ser Arg Asp Gly Tyr Val Tyr Lys Tyr Asp Leu Ser Leu Pro Val Glu Arg Leu Tyr Asp Ile Val Thr Asp Leu Arg Ala Arg Leu G1y Pro His Ala Lys His Val Val Gly Tyr Gly His Leu Gly Asp Gly Asn Leu His Leu Asn Val Thr Ala Glu Ala Phe Ser Pro Ser Leu Leu Ala Ala Leu Glu Pro His Val Tyr Glu Trp Thr Ala Gly Gln Gln Gly Ser Val Ser Ala Glu His Gly Val Gly Phe Arg Lys Arg Asp Val Leu Gly Tyr Ser Lys Pro Pro Gly Ala Leu Gln Leu Met Gln Gln Leu Lys Ala Leu Leu Asp Pro Lys Gly Ile Leu Asn Pro Tyr Lys Thr Leu Pro Ser Gln Ala <210> 14 <211> 523 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6961277CD1 <400> 14 Met Ser Arg Gln Phe Thr Cys Lys Ser Gly A1a Ala Ala Lys G1y Gly Phe Ser Gly Cys Ser Ala Val Leu Ser G1y Gly Ser Ser Ser 20 25 , 30 Ser Phe Arg Ala Gly Ser Lys Gly Leu Ser Gly Gly Leu Gly Ser Arg Ser Leu Tyr Ser Leu Gly Gly Va1 Arg Ser Leu Asn Va1 Ala Ser Gly Ser Gly Lys Ser Gly Gly Tyr Gly Phe Gly Arg Gly Arg Ala Ser Gly Phe Ala G1y Ser Met Phe Gly Ser Val Ala Leu Gly Pro Val Cys Pro Thr Val Cys Pro Pro Gly Gly Ile His Gln Val Thr Ile Asn Glu Ser Leu Leu Ala Pro Leu Asn Val Glu Leu Asp Pro Lys Ile Gln Lys Va1 Arg Ala Gln Glu Arg Glu Gln Tle Lys Ala Leu Asn Asn Lys Phe Ala Ser Phe Ile Asp Lys Val Arg Phe Leu Glu G1n Gln Asn Gln Val Leu Glu Thr Lys Trp Glu Leu Leu Gln Gln Leu Asp Leu Asn Asn Cys Lys Asn Asn Leu Glu Pro Ile Leu G1u Gly Tyr Ile Ser Asn Leu Arg Lys Gln Leu Glu Thr Leu Ser Gly Asp Arg Val Arg Leu Asp Ser Glu Leu Arg Asn Val Arg Asp Val Val Glu Asp Tyr Lys Lys Arg Tyr Glu Glu Glu Ile Asn Lys Arg Thr Ala Ala Glu Asn Glu Phe Val Leu Leu Lys Lys Asp Val Asp Ala Ala Tyr Ala Asn Lys Val G1u Leu Gln Ala Lys Val Glu.Ser Met Asp Gln Glu Ile Lys Phe Phe Arg Cys Leu Phe Glu Ala Glu Ile Thr G1n I1e Gln Ser His Ile Ser Asp Met Ser Val Ile Leu Ser Met Asp Asn Asn Arg Asn Leu Asp Leu Asp Ser Ile Ile Asp G1u Val Arg Thr Gln Tyr Glu Glu Ile Ala Leu Lys Ser Lys Ala Glu Ala Glu Ala Leu Tyr Gln Thr Lys Phe Gln Glu Leu Gln Leu Ala A1a Gly Arg His Gly Asp Asp Leu Lys Asn Thr Lys Asn G1u Ile Ser Glu Leu Thr Arg Leu Ile G1n Arg Ile Arg Ser Glu Ile Glu Asn Val Lys Lys Gln Ala Ser Asn Leu Glu Thr Ala Ile Ala Asp Ala Glu Gln Arg Gly Asp Asn Ala Leu Lys Asp A1a 380 385 .390 Arg Ala Lys Leu Asp Glu Leu Glu Gly Ala Leu His Gln Ala Lys Glu Glu Leu Ala Arg Met Leu Arg Glu Tyr Gln Glu Leu Met Ser Leu Lys Leu Ala Leu Asp Met Glu Ile Ala Thr Tyr Arg Lys Leu Leu Glu Ser Glu Glu Cys Arg Met Ser G1y Glu Phe Pro Ser Pro Val Ser Ile Ser Ile Ile Ser Ser Thr Ser Gly Gly Ser Val Tyr Gly Phe Arg Pro Ser Met Val Ser Gly Gly Tyr Val Ala Asn Ser Ser Asn Cys Ile Ser Gly Val Cys Ser Val Arg Gly Gly Glu Gly Arg Ser Arg Gly Ser A1a Asn Asp Tyr Lys Asp Thr Leu Gly Lys Gly Ser Ser Leu Ser Ala Pro Ser Lys Lys Thr Ser Arg <210> 15 <211> 615 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 56022622CD1 <400> 15 Met Gly Gly Trp Lys Gly Pro Gly G1n Arg Arg Gly Lys Glu Gly Pro Glu Ala Arg Arg Arg Ala A1a Glu Arg Gly Gly G1y Gly Gly Gly Gly Gly Val Pro Ala Pro Arg Ser Pro Ala Arg G1u Pro Arg Pro Arg Ser Cys Leu Leu Leu Pro Pro Pro Trp Gly A1a A1a Met Thr Pro Asp Leu Leu Asn Phe Lys Lys Gly Trp Met Ser T1e Leu Asp Glu Pro Gly G1u Pro Pro Ser Pro Ser Leu Thr Thr Thr Ser Thr Ser Gln Trp Lys Lys His Trp Phe Va1 Leu Thr Asp Ser Ser Leu Lys Tyr Tyr Arg Asp Ser Thr Ala G1u Glu Ala Asp Glu Leu Asp Gly G1u Ile Asp Leu Arg Ser Cys Thr Asp Va1 Thr Glu Tyr Ala Val G1n Arg Asn Tyr Gly Phe Gln Ile His Thr Lys Asp Ala Val Tyr Thr Leu Ser Ala Met Thr Ser Gly Ile Arg Arg Asn Trp Ile Glu Ala Leu Arg Lys Thr Val Arg Pro Thr Ser Ala Pro Asp Val Thr Lys Leu Ser Asp Ser Asn Lys G1u Asn Ala Leu His Ser Tyr Ser Thr Gln Lys Gly Pro Leu Lys Ala Gly Glu Gln Arg Ala Gly Ser Glu Val Ile Ser Arg Gly Gly Pro Arg Lys Ala Asp Gly Gln Arg Gln Ala Leu Asp Tyr Val Glu Leu Ser Pro Leu Thr Gln Ala Ser Pro Gln Arg Ala Arg Thr Pro A1a Arg Thr Pro Asp Arg Leu Ala Lys Gln Glu Glu Leu Glu Arg Asp Leu Ala Gln Arg Ser Glu Glu Arg Arg Lys Trp Phe Glu Ala Thr Asp Ser Arg Thr Pro Glu Val Pro Ala Gly Glu G1y Pro Arg Arg Gly Leu Gly Ala Pro Leu Thr Glu Asp Gln Gln Asn Arg Leu Ser Glu Glu Ile Glu Lys Lys Trp Gln Glu Leu Glu Lys Leu Pro Leu Arg Glu Asn Lys Arg Val Pro Leu Thr Ala Leu Leu Asn Gln Ser Arg Gly Glu Arg Arg Gly Pro Pro Ser Asp Gly His Glu Ala Leu Glu Lys Glu Glu Ala Cys Glu Arg Ser Leu Ala Glu Met Glu Ser Ser His Gln Gln Val Met Glu Glu Leu Gln Arg His His Glu Arg Glu Leu Gln Arg Leu Gln Gln Glu Lys Glu Trp Leu Leu Ala G1u Glu Thr Ala Ala Thr Ala Ser Ala Ile Glu A1a Met Lys Lys A1a Tyr Gln Glu Glu Leu Ser Arg Glu Leu Ser Lys Thr Arg Ser Leu Gln Gln Gly Pro Asp Gly Leu Arg Lys Gln His Gln Ser Asp Val Glu Ala Leu Lys Arg Glu Leu Gln Va1 Leu Ser Glu Gln Tyr Ser Gln Lys Cys Leu Glu Ile Gly Ala Leu Met Arg Gln Ala Glu Glu Arg Glu His Thr Leu 470 . 475 480 Arg Arg Cys Gln Gln Glu Gly Gln Glu Leu Leu Arg His Asn Gln Glu Leu His Gly Arg Leu Ser Glu Glu Ile Asp Gln Leu Arg G1y Phe Ile Ala Ser Gln Gly Met Gly Asn Gly Cys Gly Arg Ser Asn Glu Arg Ser Ser Cys Glu Leu Glu Val Leu Leu Arg Val Lys Glu Asn Glu Leu Gln Tyr Leu Lys Lys Glu Val Gln Cys Leu Arg Asp Glu Leu Gln Met Met Gln Lys Asp Lys Arg Phe Thr Ser Gly Lys Tyr Gln Asp Val Tyr Va1 Glu Leu Ser His Ile Lys Thr Arg Ser 575 580 . 585 Glu Arg Glu Ile Glu Gln Leu Lys Glu His Leu Arg Leu Ala Met Ala Ala Leu Gln Glu Lys Glu Ser Met Arg Asn Ser Leu Ala Glu <210> 16 <211> 875 <212> PRT
<213> Homo Sapiens <220>
<221> misc feature 31h6 <223> Incyte ID No: 542310CD1 <400> 16 Met Ser Arg His His Ser Arg Phe G1u Arg Asp Tyr Arg Val Gly Trp Asp Arg Arg Glu Trp Ser Val Asn Gly Thr His Gly Thr Thr Ser Ile Cys Ser Val Thr Ser Gly Ala Gly Gly Gly Thr Ala Ser Ser Leu Ser Val Arg Pro Gly Leu Leu Pro Leu Pro Val Val Pro Ser Arg Leu Pro Thr Pro A1a Thr Ala Pro Ala Pro Cys Thr Thr Gly Ser Ser Glu Ala Ile Thr Ser Leu Val Ala Ser Ser Ala Ser Ala Va1 Thr Thr Lys Ala Pro Gly Ile Ser Lys Gly Asp Ser Gln Ser Gln Gly Leu Ala Thr Ser Ile Arg Trp Gly Gln Thr Pro Ile Asn Gln Ser Thr Pro Trp Asp Thr Asp Glu Pro Pro Ser Lys Gln Met Arg Glu Ser Asp Asn Pro Gly Thr Gly Pro Trp Val Thr Thr Val Ala Ala Gly Asn Gln Pro Thr Leu Ile Ala His Ser Tyr Gly Val Ala Gln Pro Pro Thr Phe Ser Pro Ala Val Asn Val Gln Ala Pro Val Ile Gly Val Thr Pro Ser Leu Pro Pro His Val Gly Pro Gln Leu Pro Leu Met Pro Gly His Tyr Ser Leu Pro Gln Pro Pro Ser Gln Pro Leu Ser Ser Val Val Val Asn Met Pro Ala Gln Ala Leu Tyr Ala Ser Pro Gln Pro Leu Ala Val Ser Thr Leu Pro Gly Val Gly Gln Val Ala Arg Pro Gly Pro Thr Ala Va1 Gly Asn Gly His Met Ala Gly Pro Leu Leu Pro Pro Pro Pro Pro Ala Gln Pro Ser Ala Thr Leu Pro Ser Gly Ala Pro Ala Thr Asn Gly Pro Pro Thr Thr Asp Ser Ala His Gly Leu Gln Met Leu Arg Thr Ile Gly Val Gly Lys Tyr Glu Phe Thr Asp Pro Gly His Pro Arg G1u Met Leu Lys Glu Leu Asn Gln Gln Arg Arg Ala Lys Ala Phe Thr Asp Leu Lys I1e Val Val Glu Gly Arg Glu Phe Glu Val His Gln Asn Val Leu Ala Ser Cys Ser Leu Tyr Phe Lys Asp Leu Ile Gln Arg Ser Val Gln Asp Ser Gly Gln Gly G1y Arg Glu Lys Leu Glu Leu Val Leu Ser Asn Leu Gln Ala Asp Va1 Leu Glu Leu Leu Leu Glu Phe Val Tyr Thr Gly Ser Leu Val Ile Asp Ser Ala Asn Ala Lys Thr Leu Leu Glu Ala Ala Ser Lys Phe Gln Phe His Thr Phe Cys Lys Val Cys Val Ser Phe Leu Glu Lys G1n Leu Thr Ala Ser Asn Cys Leu Gly Val Leu Ala Met Ala Glu Ala Met Gln Cys Ser Glu Leu Tyr His Met Ala Lys Ala Phe Ala Leu Gln Ile Phe Pro G1u Val Ala Ala Gln Glu Glu Ile Leu Ser Ile Ser Lys Asp Asp Phe 470 475 . 480 Ile Ala Tyr Val Ser Asn Asp Ser Leu Asn Thr Lys Ala Glu G1u Leu Val Tyr Glu Thr Val Ile Lys Trp Ile Lys Lys Asp Pro A1a Thr Arg Thr Gln Tyr Ala Ala Glu Leu Leu Ala Val Val Arg Leu Pro Phe Ile His Pro Ser Tyr Leu Leu Asn Val Val Asp Asn Glu Glu Leu Ile Lys Ser Ser Glu Ala Cys Arg Asp Leu Val Asn Glu Ala Lys Arg Tyr His Met Leu Pro His A1a Arg Gln Glu Met Gln Thr Pro Arg Thr Arg Pro Arg Leu Ser A1a Gly Val Ala Glu Val Ile Val Leu Va1 G1y Gly Arg Gln Met Val Gly Met Thr Gln Arg Ser Leu Val Ala Val Thr Cys Trp Asn Pro Gln Asn Asn Lys Trp Tyr Pro Leu Ala Ser Leu Pro Phe Tyr.Asp Arg Glu Phe Phe Ser Val Val Ser Ala Gly Asp Asn Ile Tyr Leu Ser Gly Gly Met Glu Ser Gly Val Thr Leu Ala Asp Val Trp Cys Tyr Met Ser Leu Leu Asp Asn Trp Asn Leu Val Ser Arg Met Thr Val Pro Arg Cys Arg His Asn Ser Leu Val Tyr Asp Gly Lys Ile Tyr Thr Leu Gly Gly Leu Gly Val Ala Gly Asn Va1 Asp His Val Glu Arg Tyr Asp Thr Ile Thr Asn Gln Trp Glu Ala Val Ala Pro Leu Pro Lys Ala Val His Ser Ala Ala Ala Thr Va1 Cys Gly Gly Lys Ile Tyr Val Phe Gly Gly Val Asn Glu Ala Gly Arg Ala Ala Gly Val Leu Gln Ser Tyr Val Pro Gln Thr Asn Thr Trp Ser Phe Ile Glu Ser Pro Met I1e Asp Asn Lys Tyr Ala Pro A1a Val Thr Leu Asn Gly Phe Val 770 775 ~ 780 Phe Ile Leu Gly Gly Ala Tyr Ala Arg Ala Thr Thr Ile Tyr Asp Pro Glu Lys Gly Asn Ile Lys Ala Gly Pro Asn Met Asn His Ser Arg Gln Phe Cys Ser Ala Val Val Leu Asp Gly Lys Ile Tyr Ala Thr Gly G1y Ile Val Ser Ser G1u Gly Pro Ala Leu Gly Asn Met Glu Ala Tyr Glu Pro Thr Thr Asn Thr Trp Thr Leu Leu Pro His Met Pro Cys Pro Val Phe Arg His Gly Cys Val Val I1e Lys Lys Tyr Ile Gln Ser Gly <2~.0> 17 <211> 405 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1732825CD1 <400> 17 Met Asn Gly Ala Asn Leu Thr Ala Gln Asp Asp Arg Gly Cys Thr Pro Leu His Leu Ala Ala Thr His Gly His Ser Phe Thr Leu G1n Ile Met Leu Arg Ser Gly Val Asp Pro Ser Val Thr Asp Lys Arg Glu Trp Arg Pro Val His Tyr Ala Ala Phe His G1y Arg Leu Gly Cys Leu Gln Leu Leu Val Lys Trp Gly Cys Ser Ile Glu Asp Val Asp Tyr Asn Gly Asn Leu Pro Va1 His Leu Ala A1a Met G1u Gly His Leu His Cys Phe Lys Phe Leu Val Ser Arg Met Ser Ser Ala Thr Gln Val Leu Lys Ala Phe Asn Asp Asn Gly Glu Asn Val Leu Asp Leu Ala Gln Arg Phe Phe Lys Gln Asn Ile Leu G1n Phe Ile Gln Gly Ala Glu Tyr Glu Gly Lys Asp Leu Glu Asp Gln Glu Thr Leu Ala Phe Pro Gly His Val Ala Ala Phe Lys Gly Asp Leu Gly Met Leu Lys Lys Leu Val Glu Asp Gly Val Ile Asn Ile Asn Glu Arg Ala Asp Asn Gly Ser Thr Pro Met His Lys Ala A1a Gly Gln Gly His Ile Glu Cys Leu Gln Trp Leu Ile Lys Met Gly Ala Asp Ser Asn Ile Thr Asn Lys Ala Gly Glu Arg Pro Ser Asp Val Ala Lys Arg Phe Ala His Leu Ala A1a Val Lys Leu Leu Glu Glu Leu Gln Lys Tyr Asp Ile Asp Asp Glu Asn Glu Ile Asp Glu Asn Asp Val Lys Tyr Phe Ile Arg His Gly Val Glu Gly Ser Thr Asp Ala Lys Asp Asp Leu Cys Leu Ser Asp Leu Asp Lys Thr Asp Ala Arg Met Arg Ala Tyr Lys Lys Ile Val Glu Leu Arg His Leu Leu Glu Ile Ala Glu Ser Asn Tyr Lys His Leu Gly Gly Ile Thr Glu Glu Asp Leu Lys Gln Lys Lys Glu Gln Leu Glu Ser Glu Lys Thr Ile Lys Glu Leu Gln G1y Gln Leu Glu Tyr Glu Arg Leu Arg Arg Glu Lys Leu Glu Cys Gln Leu Asp Glu Tyr Arg Ala Glu Val Asp Gln Leu Arg Glu Thr Leu Glu Lys Ile Gln Val Pro Asn Phe Val Ala Met Glu Asp Ser Ala Ser Cys Glu Ser Asn Lys Glu Lys Arg Arg Va1 Lys Lys Lys Val Ser Ser Gly Gly Val Phe Va1 Arg Arg Tyr <210> 18 <211> 2039 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6170242CD1 <400> 18 Met Phe Asn Leu Met Lys Lys Asp Lys Asp Lys Asp Gly Gly Arg Lys Glu Lys Lys Glu Lys Lys Glu Lys Lys Glu Arg Met Ser Ala Ala Glu Leu Arg Ser Leu Glu Glu Met Ser Leu Arg Arg Gly Phe Phe Asn Leu Asn Arg Ser Ser Lys Arg Glu Ser Lys Thr Arg Leu Glu Ile Ser Asn Pro Ile Pro Ile Lys Val Ala Ser Gly Ser Asp Leu His Leu Thr Asp Ile Asp Ser Asp Ser Asn Arg G1y Ser Val Ile Leu Asp Ser Gly His Leu Ser Thr Ala Ser Ser Ser Asp Asp Leu Lys Gly Glu Glu Gly Ser Phe Arg Gly Ser Val Leu Gln Arg Ala Ala Lys Phe Gly Ser Leu Ala Lys Gln Asn Ser Gln Met Ile Val Lys Arg Phe Ser Phe Ser Gln Arg Ser Arg Asp Glu Ser Ala Ser Glu Thr Ser Thr Pro Ser Glu His Ser A1a A1a Pro Ser Pro Gln Val Glu Val Arg Thr Leu Glu Gly Gln Leu Val Gln His Pro Gly Pro Gly Ile Pro Arg Pro Gly His Arg Ser Arg A1a Pro Glu 185 190 ~ 195 Leu Val Thr Lys Lys Phe Pro Val Asp Leu Arg Leu Pro Pro Val Val Pro Leu Pro Pro Pro Thr Leu Arg Glu Leu Glu Leu Gln Arg Arg Pro Thr Gly Asp Phe Gly Phe Ser Leu Arg Arg Thr Thr Met Leu Asp Arg Gly Pro Glu Gly Gln Ala Cys Arg Arg Va1 Val His Phe Ala Glu Pro Gly Ala Gly Thr Lys Asp Leu Ala Leu Gly Leu Val Pro Gly Asp Arg Leu Val Glu I1e Asn Gly His Asn Val Glu Ser Lys Ser Arg Asp Glu Ile Val Glu Met Ile Arg Gln Ser Gly Asp Ser Val Arg Leu Lys Val G1n Pro Ile Pro Glu Leu Ser Glu Leu Ser Arg Ser Trp Leu Arg Ser Gly Glu Gly Pro Arg Arg Glu Pro Ser Asp A1a Lys Thr Glu Glu Gln Ile Ala Ala Glu G1u Ala Trp Asn Glu Thr Glu Lys Val Trp Leu Val His Arg Asp Gly Phe Ser Leu Ala Ser Gln Leu Lys Ser Glu Glu Leu Asn Leu Pro Glu 365 ' 370 375 Gly Lys Va1 Arg Val Lys Leu Asp His Asp G1y Ala Ile Leu Asp Val Asp Glu Asp Asp Val Glu Lys Ala Asn Ala Pro Ser Cys Asp Arg Leu Glu Asp Leu Ala Ser Leu Val Tyr Leu Asn Glu Ser Ser 35!86 Val Leu His Thr Leu Arg Gln Arg Tyr G1y Ala Ser Leu Leu His Thr Tyr Ala Gly Pro Ser Leu Leu Val Leu Gly Pro Arg Gly Ala Pro Ala Val Tyr Ser Glu Lys Val Met His Met Phe Lys Gly Cys Arg Arg Glu Asp Met Ala Pro His Ile Tyr Ala Val Ala Gln Thr Ala Tyr Arg Ala Met Leu Met Ser Arg Gln Asp Gln Ser Ile Ile Leu Leu Gly Ser Ser G1y Ser Gly Lys Thr Thr Ser Cys Gln His Leu Val Gln Tyr Leu Ala Thr Ile Ala Gly Ile Ser Gly Asn Lys Val Phe Ser Val Glu Lys Trp Gln Ala Leu Tyr Thr Leu Leu Glu Ala Phe Gly Asn Ser Pro Thr Ile Ile Asn Gly Asn Ala Thr Arg Phe Ser Gln Ile Leu Ser Leu Asp Phe Asp Gln Ala Gly Gln Val Ala Ser Ala Ser Ile Gln Thr Met Leu Leu Glu Lys Leu Arg Va1 Ala Arg Arg Pro Ala Ser Glu Ala Thr Phe Asn Val Phe Tyr Tyr Leu Leu Ala Cys Gly Asp Gly Thr Leu Arg Thr Glu Leu His Leu Asn His Leu Ala Glu Asn Asn Va1 Phe Gly Ile Va1 Pro Leu Ala Lys Pro Glu G1u Lys Gln Lys Ala Ala G1n Gln Phe Ser Lys Leu Gln A1a Ala Met Lys Val Leu Gly Ile Ser Pro Asp Glu Gln Lys Ala Cys Trp Phe Ile Leu Ala Ala Ile Tyr His Leu Gly Ala Ala Gly Ala Thr Lys Glu Ala Ala Glu Ala G1y Arg Lys Gln Phe Ala Arg His Glu Trp Ala Gln Lys Ala Ala Tyr Leu Leu Gly Cys Ser Leu Glu Glu Leu Ser Ser Ala Ile Phe Lys His Gln His Lys Gly Gly Thr Leu Gln Arg Ser Thr Ser Phe Arg G1n Gly Pro Glu Glu Ser Gly Leu Gly Asp Gly Thr Gly Pro Lys Leu Ser Ala Leu Glu Cys Leu Glu Gly Met Ala Ala Gly Leu Tyr Ser Glu Leu Phe Thr Leu Leu Val Ser Leu Val Asn Arg Ala Leu Lys Ser Ser Gln His Ser Leu Cys Ser Met Met Ile Val Asp Thr Pro G1y Phe Gln Asn Pro Glu Gln Gly Gly Ser Ala Arg Gly Ala Ser Phe Glu Glu Leu Cys His Asn Tyr Thr Gln Asp Arg Leu Gln Arg Leu Phe His Glu Arg Thr Phe Val Gln Glu Leu Glu Arg Tyr Lys Glu Glu Asn Ile Glu Leu Ala Phe Asp Asp Leu Glu Pro Pro Thr Asp Asp Ser Val Ala Ala Val Asp Gln Ala Ser His Gln Ser Leu Val Arg Ser Leu Ala Arg Thr Asp Glu Ala Arg Gly Leu Leu Trp Leu Leu Glu G1u Glu A1a Leu Val Pro Gly Ala Ser Glu Asp Thr Leu Leu Glu Arg Leu Phe Ser Tyr Tyr Gly Pro Gln Glu Gly Asp Lys Lys Gly Gln Ser Pro Leu Leu His Ser Ser Lys Pro His His Phe Leu Leu Gly His Ser His Gly Thr Asn Trp Val Glu Tyr Asn Val Thr Gly Trp Leu Asn Tyr Thr Lys Gln Asn Pro Ala Thr Gln Asn Val Pro Arg Leu Leu Gln Asp Ser Gln Lys Lys Ile Ile Ser Asn Leu Phe Leu Gly Arg A1a Gly Ser A1a Thr Val Leu Ser Gly Ser Ile Ala Gly Leu Glu Gly Gly Ser Gln Leu Ala Leu Arg Arg Ala Thr Ser Met Arg Lys Thr Phe Thr Thr Gly Met Ala Ala Val Lys Lys Lys Ser Leu Cys Ile Gln Met Lys Leu Gln Val Asp Ala Leu Ile Asp Thr Ile Lys Lys Ser Lys Leu His Phe Val His Cys Phe Leu Pro Val Ala Glu Gly Trp Ala Gly Glu Pro Arg Ser Ala Ser Ser Arg Arg Val Ser Ser Ser Ser Glu Leu Asp Leu Pro Ser Gly Asp His Cys Glu Ala Gly Leu Leu Gln Leu Asp Val Pro Leu Leu Arg Thr Gln 1085 1090 ' 1095 Leu Arg Gly Ser Arg Leu Leu Asp Ala Met Arg Met Tyr Arg Gln Gly Tyr'Pro Asp His Met Val Phe Ser Glu Phe Arg Arg Arg Phe Asp Val Leu Ala Pro His Leu Thr Lys Lys His Gly Arg Asn Tyr Ile Val Val Asp Glu Arg Arg Ala Val Glu Glu Leu Leu Glu Cys Leu Asp Leu Glu Lys Ser Ser Cys Cys Met Gly Leu Ser Arg Val Phe Phe Arg Ala Gly Thr Leu Ala Arg Leu Glu Glu Gln Arg Asp Glu Gln Thr Ser Arg Asn Leu Thr Leu Phe Gln Ala Ala Cys Arg Gly Tyr Leu Ala Arg Gln His Phe Lys Lys Arg Lys Ile Gln Asp Leu Ala Ile Arg Cys Va1 Gln Lys Asn Ile Lys Lys Asn Lys Gly Va1 Lys Asp Trp Pro Trp Trp Lys Leu Phe Thr Thr Val Arg Pro Leu Ile G1u Val Gln Leu Ser Glu Glu Gln Ile Arg Asn Lys Asp Glu Glu Ile Gln Gln Leu Arg Ser Lys Leu Glu Lys Ala Glu Lys Glu Arg Asn Glu Leu Arg Leu Asn Ser Asp Arg Leu G1u Ser Arg Ile Ser Glu Leu Thr Ser Glu Leu Thr Asp Glu Arg Asn Thr Gly Glu Ser Ala Ser Gln Leu Leu Asp Ala Glu Thr Ala Glu Arg Leu Arg Ala Glu Lys Glu Met Lys Glu Leu Gln Thr Gln Tyr Asp Ala Leu Lys Lys Gln Met Glu Val Met Glu Met Glu Val Met Glu Ala Arg Leu Ile Arg Ala Ala Glu Ile Asn Gly Glu Val Asp Asp Asp Asp Ala Gly Gly Glu Trp Arg Leu Lys Tyr Glu Arg Ala Val Arg Glu Val Asp Phe Thr Lys Lys Arg Leu Gln Gln Glu Phe G1u Asp Lys Leu Glu Va1 G1u Gln Gln Asn Lys Arg Gln Leu Glu Arg Arg Leu Gly Asp Leu Gln A1a Asp Ser Glu Glu Ser Gln Arg A1a Leu Gln Gln Leu Lys Lys Lys Cys Gln Arg Leu Thr Ala Glu Leu Gln Asp Thr Lys Leu His Leu Glu Gly Gln Gln Val Arg Asn His Glu Leu Glu Lys Lys Gln Arg Arg Phe Asp Ser Glu Leu Ser Gln Ala His Glu Glu Ala Gln Arg Glu Lys Leu Gln Arg Glu Lys Leu Gln Arg Glu Lys Asp Met Leu Leu Ala Glu Ala Phe Ser Leu Lys Gln Gln Leu Glu Glu Lys Asp Met Asp Ile Ala Gly Phe Thr Gln Lys Val Val Ser Leu G1u Ala Glu Leu Gln Asp Ile Ser Ser Gln Glu Ser Lys Asp Glu Ala Ser Leu Ala Lys Val Lys Lys Gln Leu Arg Asp Leu Glu Ala Lys Val Lys Asp Gln Glu Glu Glu Leu Asp Glu Gln Ala Gly Thr Ile Gln Met Leu Glu Gln Ala Lys Leu Arg Leu Glu Met Glu Met Glu Arg Met Arg Gln Thr His Ser Lys Glu Met 1580 ~ 1585 1590 Glu Ser Arg Asp Glu Glu Val Glu Glu Ala Arg Gln Ser Cys Gln Lys Lys Leu Lys Gln Met Glu Val G1n Leu Glu Glu Glu Tyr Glu Asp Lys Gln Lys Va1 Leu Arg Glu Lys Arg Glu Leu Glu Gly Lys Leu Ala Thr Leu Ser Asp Gln Val Asn Arg Arg Asp Phe Glu Ser Glu Lys Arg Leu Arg Lys Asp Leu Lys Arg Thr Lys Ala Leu Leu Ala Asp Ala Gln Leu Met Leu Asp His Leu Lys Asn Ser Ala Pro Ser Lys Arg Glu I1e Ala Gln Leu Lys Asn Gln Leu Glu Glu Ser Glu Phe Thr Cys A1a Ala Ala Val Lys Ala Arg Lys A1a Met Glu Val Glu Ile Glu Asp Leu His Leu Gln Ile Asp Asp Ile Ala Lys Ala Lys Thr Ala Leu Glu Glu Gln Leu Ser Arg Leu G1n Arg Glu Lys Asn Glu Ile Gln Asn Arg Leu G1u Glu Asp Gln G1u Asp Met Asn Glu Leu Met Lys Lys His Lys Ala Ala Val A1a G1n Ala Ser Arg Asp Leu Ala Gln Ile Asn Asp Leu Gln Ala Gln Leu Glu Glu Ala Asn Lys Glu Lys G1n Glu Leu Gln Glu Lys Leu Gln Ala Leu G1n Ser Gln Val Glu Phe Leu Glu Gln Ser Met Val Asp Lys Ser Leu Val Ser Arg Gln Glu Ala Lys Ile Arg Glu Leu Glu Thr Arg Leu Glu Phe Glu Arg Thr Gln Val Lys Arg Leu Glu Ser Leu Ala Ser Arg Leu Lys Glu Asn Met G1u Lys Leu Thr G1u Glu Arg Asp Gln Arg Ile A1a Ala Glu Asn Arg Glu Lys Glu Gln Asn Lys Arg Leu Gln Arg Gln Leu Arg Asp Thr Lys Glu G1u Met Gly Glu Leu Ala Arg Lys Glu Ala Glu Ala Ser Arg Lys Lys His Glu Leu Glu Met Asp Leu Glu Ser Leu Glu Ala Ala Asn Gln Ser Leu Gln Ala Asp Leu Lys Leu Ala Phe Lys Arg Ile Gly Asp Leu Gln Ala Ala Ile Glu Asp Glu Met Glu Ser Asp Glu Asn Glu Asp Leu Ile Asn Ser Glu G1y Asp Ser Asp Val Asp Ser Glu Leu Glu Asp Arg Val Asp Gly Val Lys Ser Trp Leu Ser Lys Asn Lys Gly Pro Ser Lys Ala Ala Ser Asp Asp Gly Ser Leu Lys Ser Ser Ser Pro Thr Ser Tyr Trp Lys Ser Leu Ala Pro Asp Arg Ser Asp Asp Glu His Asp Pro Leu Asp Asn Thr Ser Arg Pro Arg Tyr Ser His Ser Tyr Leu Ser Asp Ser Asp Thr Glu Ala Lys Leu Thr Glu Thr Asn Ala <210> 19 <211> 191 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2287640CD1 <400> 19 Met Gly I1e Leu Tyr Ser Glu Pro Ile Cys Gln Ala Ala Tyr Gln Asn Asp Phe Gly Gln Val Trp Arg Trp Val Lys Glu Asp Ser Ser Tyr Ala Asn Val Gln Asp Gly Phe Asn Gly Asp Thr Pro Leu Ile Cys Ala Cys Arg Arg Gly His Val Arg Ile Val Ser Phe Leu Leu Arg Arg Asn Ala Asn Val Asn Leu Lys Asn Gln Lys Glu Arg Thr Cys Leu His Tyr Ala Val Lys Lys Lys Phe Thr Phe Ile Asp Tyr Leu Leu Ile Ile Leu Leu Met Pro Val Leu Leu Ile Gly Tyr Phe Leu Met Val Ser Lys Thr Lys Gln Asn Glu Ala Leu Val Arg Met Leu Leu Asp Ala Gly Val Glu Val Asn Ala Thr Asp Cys Tyr Gly Cys Thr Ala Leu His Tyr Ala Cys Glu Met Lys Asn Gln Ser Leu Ile Pro Leu Leu Leu Glu Ala Arg A1a Asp Pro Thr Ile Lys Asn Lys His Gly Glu Ser Ser Leu Asp Ile Ala Arg Arg Leu Lys Phe Ser Gln Ile Glu Leu Met Leu Arg Lys A1a Leu <210> 20 <211> 887 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1990526CD1 <400> 20 Met Pro Ser Leu Pro Gln Glu Gly Val Ile Gln Gly Pro Ser Pro Leu Asp Leu Asn Thr Glu Leu Pro Tyr Gln Ser Thr Met Lys Arg Lys Val Arg Lys Lys Lys Lys Lys Gly Thr Ile Thr Ala Asn Val Ala Gly Thr Lys Phe Glu Ile Val Arg Leu Val Ile Asp Glu Met Gly Phe Met Lys Thr Pro Asp Glu Asp Glu Thr Ser Asn Leu I1e Trp Cys Asp Ser Ala Val Gln Gln Glu Lys Ile Ser Glu Leu Gln Asn Tyr Gln Arg Ile Asn His Phe Pro Gly Met Gly Glu Ile Cys Arg Lys Asp Phe Leu Ala Arg Asn Met Thr Lys Met Ile Lys Ser Arg Pro Leu Asp Tyr Thr Phe Val Pro Arg Thr Trp Ile Phe Pro Ala Glu Tyr Thr Gln Phe Gln Asn Tyr Val Lys Glu Leu Lys Lys Lys Arg Lys Gln Lys Thr Phe Ile Val Lys Pro Ala Asn Gly Ala Met Gly His Gly Ile Ser Leu I1e Arg Asn Gly Asp Lys Leu Pro Ser Gln Asp His Leu Ile Val Gln Glu Tyr Ile Glu Lys Pro Phe Leu Met Glu Gly Tyr Lys Phe Asp Leu Arg Ile Tyr Ile Leu Val Thr Ser Cys Asp Pro Leu Lys Ile Phe Leu Tyr His Asp Gly Leu Val Arg Met Gly Thr Glu Lys Tyr Ile Pro Pro Asn Glu Ser Asn Leu Thr Gln Leu Tyr Met His Leu Thr Asn Tyr Ser Val Asn Lys His Asn Glu His Phe Glu Arg Asp G1u Thr Glu Asn Lys Gly Ser Lys Arg Ser Ile Lys Trp Phe Thr Glu Phe Leu Gln Ala Asn Gln His Asp Val Ala Lys Phe Trp Ser Asp Ile Ser Glu Leu Val Val Lys Thr Leu Ile Val Ala Glu Pro His Val Leu His Ala Tyr Arg Met Cys Arg Pro Gly Gln Pro Pro Gly Ser Glu Ser Val Cys Phe Glu Val Leu Gly Phe Asp Ile Leu Leu Asp Arg Lys Leu Lys Pro Trp Leu Leu Glu Ile Asn Arg Ala Pro Ser Phe Gly Thr Asp Gln Lys Ile Asp Tyr Asp Val Lys Arg Gly Val Leu Leu Asn Ala Leu Lys Leu Leu Asn Ile Arg Thr Ser Asp Lys Arg Arg Asn Leu Ala Lys Gln Lys Ala Glu Ala Gln Arg Arg Leu Tyr Gly G1n Asn Ser Ile Lys Arg Leu Leu Pro Gly Ser Ser Asp Trp Glu Gln Gln Arg His Gln Leu Glu Arg Arg Lys Glu G1u Leu Lys Glu Arg Leu Ala Gln Val Arg Lys Gln Ile Ser Arg Glu Glu His Glu Asn Arg His Met Gly Asn Tyr Arg Arg Ile Tyr Pro Pro Glu Asp Lys Ala Leu Leu Glu Lys Tyr Glu Asn Leu Leu Ala Val Ala Phe Gln Thr Phe Leu Ser Gly Arg Ala Ala Ser Phe Gln Arg Glu Leu Asn Asn Pro Leu Lys Arg Met Lys Glu Glu Asp Ile Leu Asp Leu Leu Glu Gln Cys Glu Ile Asp Asp Glu Lys Leu Met Gly Lys Thr Thr Lys Thr Arg G1y Pro Lys Pro Leu Cys Ser Met Pro Glu Ser Thr Glu Ile Met Lys Arg Pro Lys Tyr Cys Ser Sex Asp Ser Ser Tyr Asp Ser Ser Ser Ser Ser Ser Glu Ser Asp Glu Asn Glu Lys Glu G1u Tyr Gln Asn Lys Lys Arg Glu Lys G1n Val Thr Tyr Asn Leu Lys Pro Ser Asn His Tyr Lys Leu Ile Gln Gln Pro Ser Ser Ile Arg Arg Ser Val Ser Cys Pro Arg Ser Ile Ser Ala Gln Ser Pro Ser Ser Gly Asp Thr Arg Pro Phe Ser Ala Gln Gln Met Ile Ser Val Ser Arg Pro Thr Ser Ala Ser Arg Ser His Ser Leu Asn Arg Ala Ser Ser Tyr Met Arg His Leu Pro His Ser Asn Asp Ala Cys Ser Thr Asn Ser Gln Val Ser Glu Ser Leu Arg Gln Leu Lys Thr Lys Glu Gln Glu Asp Asp Leu Thr Ser Gln Thr Leu Phe Val Leu Lys Asp Met Lys Ile Arg Phe Pro Gly Lys Ser Asp Ala Glu Ser Glu Leu Leu Ile Glu Asp Ile Ile Asp Asn Trp Lys Tyr His Lys Thr Lys Val Ala Ser Tyr Trp Leu Ile Lys Leu Asp Ser Val Lys Gln Arg 725 730 . 735 Lys Val Leu Asp Ile Val Lys Thr Ser Ile Arg Thr Val Leu Pro Arg Ile Trp Lys Val Pro Asp Val Glu Glu Va1 Asn Leu Tyr Arg Ile Phe Asn Arg Val Phe Asn Arg Leu Leu Trp Ser Arg Gly Gln Gly Leu Trp Asn Cys Phe Cys Asp Ser Gly Ser Ser Trp Glu Ser Ile Phe Asn Lys Ser Pro Glu Val Val Thr Pro Leu Gln Leu G1n Cys Cys Gln Arg Leu Val Glu Leu Cys Lys Gln Cys Leu Leu Val Val Tyr Lys Tyr A1a Thr Asp Lys Arg Gly Ser Leu Ser Gly Ile Gly Pro Asp Trp Gly Asn Ser Arg Tyr Leu Leu Pro Gly Ser Thr Gln Phe Phe Leu Arg Thr Pro Thr Tyr Asn Leu Lys Tyr Asn Ser Pro Gly Met Thr Arg Ser Asn Val Leu Phe Thr Ser Arg Tyr Gly His Leu <210> 21 <211> 423 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3742459CD1 <400> 21 Met Asn A1a Leu Leu Leu Ser Ala Trp Phe Gly His Leu Arg Ile Leu Gln Ile Leu Val Asn Ser Gly Ala Lys Ile His Cys Glu Ser Lys Asp Gly Leu Thr Leu Leu His Cys A1a Ala Gln Lys Gly His Val Pro Val Leu Ala Phe Ile Met Glu Asp Leu Glu Asp Val Ala Leu Asp His Val Asp Lys Leu Gly Arg Thr Ala Phe His Arg Ala Ala Glu His Gly Gln Leu Asp Ala Leu Asp Phe Leu Val Gly Ser G1y Cys Asp His Asn Val Lys Asp Lys Glu Gly Asn Thr Ala Leu His Leu Ala Ala Gly Arg Gly His Met Ala Val Leu Gln Arg Leu Val Asp Ile Gly Leu Asp Leu Glu Glu Gln Asn Ala Glu Gly Leu Thr Ala Leu His Ser Ala Ala Gly Gly Ser His Pro Asp Cys Val Gln Leu Leu Leu Arg Ala Gly Ser Thr Val Asn Ala Leu Thr G1n Lys Asn Leu Ser Cys Leu His Tyr Ala Ala Leu Ser Gly Ser Glu Asp Val Ser Arg Va1 Leu Ile His Ala G1y Gly Cys Ala Asn Val Val Asp His Gln Gly Ala Ser Pro Leu His Leu Ala Val Arg His Asn Phe Pro Ala Leu Val Arg Leu Leu Ile Asn Ser Asp Ser Asp Val Asn Ala Val Asp Asn Arg Gln Gln Thr Pro Leu His Leu Ala Ala Glu His Ala Trp G1n Asp 21e Ala Asp Met Leu Leu Ile Ala Gly Val Asp Leu Asn Leu Arg Asp Lys Gln Gly Lys Thr Ala Leu Ala Val Ala Val Arg Ser Asn His Val Ser Leu Val Asp Met Ile Ile Lys Ala Asp Arg Phe Tyr Arg Trp Glu Lys Asp His Pro Ser Asp Pro Ser Gly Lys Ser Leu Ser Phe Lys Gln Asp His Arg Gln Glu Thr Gln Gln Leu Arg Ser Val Leu Trp Arg Leu Ala Ser Arg Tyr Leu Gln Pro Arg Glu Trp Lys Lys Leu A1a Tyr Ser Trp Glu Phe Thr Glu Ala His Val Asp Ala Ile Glu Gln Gln Trp Thr Gly 350 355 , 360 Thr Arg Ser Tyr Gln Glu His Gly His Arg Met Leu Leu Ile Trp Leu His Gly Val Ala Thr Ala Gly Glu Asn Pro Ser Lys Ala Leu Phe G1u Gly Leu Va1 Ala Ile G1y Arg Arg Asp Leu A1a Glu Asn I1e Arg Lys Lys Ala Asn Ala Ala Pro Ser Ala Pro Arg Arg Cys Thr Ala Met <210> 22 <211> 916 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7468507CD1 <400> 22 Met Glu Val Glu Ser Leu Asn Lys Met Leu Glu Glu Leu Arg Leu Glu Arg Lys Lys Leu Ile Glu Asp Tyr Glu Gly Lys Leu Asn Lys Ala Gln Ser Phe Tyr Glu Arg Glu Leu Asp Thr Leu Lys Arg Ser Gln Leu Phe Thr Ala Glu Ser Leu Gln Ala Ser Lys G1u Lys Glu Ala Asp Leu Arg Lys Glu Phe Gln Gly Gln Glu Ala Ile Leu Arg Lys Thr Ile Gly Lys Leu Lys Thr Glu Leu Gln Met Val Gln Asp Glu Ala Gly Ser Leu Leu Asp Lys Cys Gln Lys Leu Gln Thr Ala Leu Ala Ile Ala Glu Asn Asn Val Gln Val Leu Gln Lys Gln Leu Asp Asp Ala Lys Glu Gly Glu Met Ala Leu Leu Ser Lys His Lys Glu Val Glu Ser Glu Leu Ala Ala Ala Arg Glu Arg Leu Gln Gln Gln Ala Ser Asp Leu Val Leu Lys Ala Ser His Ile Gly Met Leu Gln Ala Thr Gln Met Thr Gln G1u Val Thr Ile Lys Asp Leu Glu Ser Glu Lys Ser Arg Val Asn G1u Arg Leu Ser Gln Leu Glu Glu Glu Arg Ala Phe Leu Arg Ser Lys Thr Gln Ser Leu Asp Glu Glu Gln Lys Gln Gln Ile Leu Glu Leu Glu Lys Lys Val Asn Glu Ala Lys Arg Thr Gln Gln Glu Tyr Tyr Glu Arg Glu Leu Lys Asn Leu Gln Ser Arg Leu Glu Glu Glu Val Thr Gln Leu Asn Glu Ala His Ser Lys Thr Leu Glu Glu Leu Ala Trp Lys His His Met Ala Ile Glu Ala Val His Ser Asn Ala Ile Arg Asp Lys Lys Lys Leu Gln Met Asp Leu Glu Glu Gln His Asn Lys Asp Lys Leu Asn Leu G1u Glu Asp Lys Asn Gln Leu Gln Gln Glu Leu Glu Asn Leu Lys Glu Va1 Leu Glu Asp Lys Leu Asn Thr Ala Asn Gln Glu Ile Gly His Leu Gln Asp Met Val Arg Lys Ser Glu Gln Gly Leu Gly Ser Ala Glu Gly Leu Ile Ala Ser Leu Gln Asp Ser Gln Glu Arg Leu Gln Asn Glu Leu Asp Leu Thr Lys Asp Ser Leu Lys Glu Thr Lys Asp Ala Leu Leu Asn Val Glu Gly Glu Leu Glu Gln G1u Arg Gln Gln His Glu Glu Thr Ile Ala Ala Met Lys Glu Glu Glu Lys Leu Lys Val Asp Lys Met Ala His Asp Leu Glu Ile Lys Trp Thr Glu Asn Leu Arg Gln Glu Cys Ser Lys Leu Arg Glu Glu Leu Arg Leu G1n His Glu Glu Asp Lys Lys Ser Ala Met Ser Gln Leu Leu Gln Leu Lys Asp Arg Glu Lys Asn Ala Ala Arg Asp Ser Trp Gln Lys Lys Val Glu Asp Leu Leu Asn Gln Ile Ser Leu Leu Lys Gln Asn Leu Glu Ile Gln Leu Ser Gln Ser Gln Thr Ser Leu Gln Gln Leu Gln Ala Gln Phe Thr Gln Glu Arg Gln Arg Leu Thr Gln Glu Leu Glu Glu Leu Glu G1u Gln His Gln Gln Arg His Lys Ser Leu Lys Glu A1a His Val Leu Ala Phe Gln Thr Met Glu Glu Glu Lys Glu Lys Glu Gln Arg Ala Leu Glu Asn His Leu Gln Gln Lys His Ser Ala Glu Leu Gln Ser Leu Lys Asp Ala His Arg Glu Ser Met Glu Gly Phe Arg Ile Glu Met Glu Gln G1u Leu Gln Thr Leu Arg Phe Glu Leu Glu Asp Glu Gly Lys Ala Met Leu Ala Ser Leu Arg Ser Glu Leu Asn His Gln His A1a Ala Ala Ile Asp Leu Leu Arg His Asn His His Gln Glu Leu Ala A1a A1a Lys Met Glu Leu Glu Arg Ser Ile Asp Ile Ser Arg Arg Gln Ser Lys Glu His Ile Cys Arg Ile Thr Asp Leu Gln Glu Glu Leu Arg His Arg Glu His His Ile Ser Glu Leu Asp Lys Glu Val Gln His Leu His G1u Asn Ile Ser Ala Leu Thr Lys Glu Leu Glu Phe Lys Gly Lys Glu Ile Leu Arg Ile Arg Ser Glu Ser Asn Gln Gln I1e Arg Leu His Glu Gln Asp Leu Asn Lys Arg Leu Glu Lys Glu Leu Asp Val Met Thr Ala Asp His Leu Arg Glu Lys Asn Ile Met Arg Ala Asp Phe Asn Lys Thr Asn Glu Leu Leu Lys Glu Ile Asn Ala Ala Leu Gln Val Ser Leu Glu Glu Met Glu Glu Lys Tyr Leu Met Arg Glu Ser Lys Pro Glu Asp Ile Gln Met Ile Thr Glu Leu Lys Ala Met Leu Thr Glu Arg Asp Gln Ile Ile Lys Lys Leu Ile Glu Asp Asn Lys Phe Tyr Gln Leu Glu Leu Val Asn Arg Glu Thr Asn Phe Asn Lys Val Phe Asn Ser Ser Pro Thr Val Gly Val Ile Asn Pro Leu Ala Lys Gln Lys Lys Lys Asn Asp Lys Ser Pro Thr Asn Arg Phe Val Ser Val Pro Asn Leu Ser Ala Leu Glu Ser Gly Gly Val Gly Asn Gly His Pro Asn Arg Leu Asp Pro Ile Pro Asn Ser Pro Val His Asp Ile Glu Phe Asn Ser Ser Lys Pro Leu Pro Gln Pro Val Pro Pro Lys Gly Pro Lys Thr Phe Leu Ser Pro Ala Gln Ser Glu Ala Ser Pro Va1 Ala Ser Pro Asp Pro Gln Arg Gln Glu Trp Phe Ala Arg Tyr Phe Thr Phe <210> 23 <211> 399 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3049682CD1 <400> 23 Met Asp Ser Gln Arg Pro Glu Pro Arg Glu Glu Glu Glu Glu G1u Gln Glu Leu Arg Trp Met Glu Leu Asp Ser Glu Glu Ala Leu Gly Thr Arg Thr Glu Gly Pro Ser Val Val Gln Gly Trp Gly His Leu Leu Gln Ala Val Trp Arg G1y Pro A1a Gly Leu Val Thr Gln Leu Leu Arg Gln Gly Ala Ser Val Glu Glu Arg Asp His Ala Gly Arg Thr Pro Leu His Leu Ala Val Leu Arg Gly His Ala Pro Leu Val Arg Leu Leu Leu Gln Arg Gly Ala Pro Val Gly Ala Val Asp Arg Ala G1y Arg Thr Ala Leu His Glu Ala Ala Trp His Gly His Ser Arg Va1 Ala Glu Leu Leu Leu G1n Arg Gly Ala Ser Ala Ala Ala Arg Ser Gly Thr Gly Leu Thr Pro Leu His Trp Ala Ala Ala Leu Gly His Thr Leu Leu Ala Ala Arg Leu Leu Glu Ala Pro Gly Pro Gly Pro Ala Ala Ala Glu Ala Glu Asp Ala Arg G1y Trp Thr Ala 170 ~ 175 180 Ala His Trp Ala Ala Ala Gly Gly Arg Leu Ala Val Leu Glu Leu Leu Ala Ala Gly G1y Ala Gly Leu Asp Gly Ala Leu Leu Val Ala Ala Ala A1a Gly Arg Gly Ala Ala Leu Arg Phe Leu Leu Ala Arg Gly Ala Arg Val Asp Ala Arg Asp Gly A1a Gly Ala Thr Ala Leu Gly Leu Ala Ala Ala Leu Gly Arg Ser Gln Asp Ile Glu Val Leu Leu Gly His Gly Ala Asp Pro Gly Ile Arg Asp Arg His G1y Arg Ser Ala Leu His Arg Ala Ala Ala Arg Gly His Leu Leu Ala Val Gln Leu Leu Val Thr Gln Gly Ala Glu Val Asp Ala Arg Asp Thr Leu Gly Leu Thr Pro Leu His His Ala Ser Arg Glu Gly His Val Glu Val Ala Gly Cys Leu Leu Asp Arg Gly Ala Gln Val Asp Ala Thr Gly Trp Leu Arg Lys Thr Pro Leu His Leu Ala Ala Glu Arg Gly His Gly Pro Thr Va1 Gly Leu Leu Leu Ser Arg G1y Ala Ser Pro Thr Leu Arg Thr Gln Trp Ala Glu Val Ala Gln Met Pro Glu Gly Asp Leu Pro Gln Ala Leu Pro Glu Leu Gly Gly Gly Glu Lys Glu Cys Glu Gly Ile Glu Ser Thr Gly <210> 24 <211> 6l7 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 914468CD1 <400> 24 Met Ala Pro Gly Ala Ala Asp Ala Gln Ile Gly Thr Ala Asp Pro Gly Asp Phe Asp Gln Leu Thr Gln Cys Leu Ile Gln Ala Pro Ser Asn Arg Pro Tyr Phe Leu Leu Leu Gln Gly Tyr Gln Asp Ala Gln Asp Phe Val Val Tyr Val Met Thr Arg Glu Gln His Val Phe Gly Arg Gly Gly Asn Ser Ser Gly Arg Gly Gly Ser Pro Ala Pro Tyr Val Asp Thr Phe Leu Asn Ala Pro Asp Ile Leu Pro Arg His Cys Thr Val Arg Ala G1y Pro Glu His Pro Ala Met Val Arg Pro Ser Arg Gly A1a Pro Val Thr His Asn Gly Cys Leu Leu Leu Arg Glu A1a Glu Leu His Pro Gly Asp Leu Leu Gly Leu Gly Glu His Phe Leu Phe Met Tyr Lys Asp Pro Arg Thr Gly~Gly Ser G1y Pro Ala Arg Pro Pro Trp Leu Pro Ala Arg Pro Gly Ala Thr Pro Pro Gly Pro Gly Trp Ala Phe Ser Cys Arg Leu Cys Gly Arg Gly Leu Gln Glu Arg Gly Glu Ala Leu Ala Ala Tyr Leu Asp Gly Arg Glu Pro Val Leu Arg Phe Arg Pro Arg Glu Glu Glu Ala Leu Leu Gly Glu Ile Val Arg Ala Ala Ala Ala Gly Ser Gly Asp Leu Pro Pro Leu Gly Pro A1a Thr Leu Leu Ala Leu Cys Val Gln His Ser Ala Arg Glu Leu Glu Leu Gly His Leu Pro Arg Leu Leu Gly Cys Leu Ala Arg Leu Ile Lys Glu Ala Val Trp Glu Lys Ile Lys G1u Ile Gly Asp Arg Gln Pro Glu Asn His Pro Glu Gly Val Pro Glu Val Pro Leu Thr Pro Glu Ala Val Ser Val Glu Leu Arg Pro Leu Met Leu Trp Met Ala Asn Thr Thr Glu Leu Leu Ser Phe Val Gln Glu Lys Val Leu Glu Met Glu Lys Glu Ala Asp Gln Glu Asp Pro Gln Leu Cys Asn Asp Leu Glu Leu Cys Asp Glu A1a Met Ala Leu Leu Asp Glu Val Ile Met Cys Thr Phe~ Gln Gln Ser Val Tyr Tyr Leu Thr Lys Thr Leu Tyr Ser Thr Leu Pro Ala Leu Leu Asp Ser Asn Pro Phe Thr Ala Gly Ala Glu Leu Pro Gly Pro Gly Ala Glu Leu Gly Ala Met Pro Pro G1y Leu Arg Pro Thr Leu Gly Val Phe Gln Ala Ala Leu Glu Leu Thr Ser Gln Cys Glu Leu His Pro Asp Leu Val Ser Gln Thr Phe Gly Tyr Leu Phe Phe Phe Ser Asn Ala Ser Leu Leu Asn Ser Leu Met Glu Arg Gly Gln Gly Arg Pro Phe Tyr Gln Trp Ser Arg Ala Val Gln Ile Arg Thr Asn Leu Asp Leu Val Leu Asp Trp Leu Gln Gly A1a Gly Leu Gly Asp Ile Ala Thr Glu Phe 470 475. 480 Phe Arg Lys Leu Ser Met A1a Val Asn Leu Leu Cys Val Pro Arg Thr Ser Leu Leu Lys Ala Ser Trp Ser Ser Leu Arg Thr Asp His Pro Thr Leu Thr Pro Ala G1n Leu His His Leu Leu Ser His Tyr Gln Leu Gly Pro Gly Arg Gly Pro Pro Ala A1a Trp Asp Pro Pro Pro Ala Glu Arg Glu Ala Va1 Asp Thr Gly Asp Ile Phe G1u Ser Phe Ser Ser His Pro Pro Leu Ile Leu Pro Leu Gly Ser Ser Arg Leu Arg Leu Thr Gly Pro Val Thr Asp Asp Ala Leu His Arg Glu Leu Arg Arg Leu Arg Arg Leu Leu Trp Asp Leu Glu Gln Gln Glu Leu Pro Ala Asn Tyr Arg His Pro Gly Gly Pro Pro Val Ala Thr Ser Pro <2l0> 25 <211> 305 <212> PRT
<213> Homo Sapiens <220>

<221> misc_feature <223> Incyte ID No: 2673631CD1 <400> 25 Met Asp Phe Ile Ser Ile Gln Gln Leu Val Ser Gly G1u Arg Val Glu Gly Lys Val Leu Gly Phe Gly His Gly Val Pro Asp Pro Gly Ala Trp Pro Ser Asp Trp Arg Arg Gly Pro Gln Glu Ala Val Ala Arg Glu Lys Leu Lys Leu Glu Glu Glu Lys Lys Lys Lys Leu G1u Arg Phe Asn Ser Thr Arg Phe Asn Leu Asp Asn Leu Ala Asp Leu Glu Asn Leu Val Gln Arg Arg Lys Lys Arg Leu Arg His Arg Val Pro Pro Arg Lys Pro Glu Pro Leu Val Lys Pro Gln Ser Gln Ala Gln Val Glu Pro Val Gly Leu Glu Met Phe Leu Lys Ala Ala Ala Glu Asn Gln Glu Tyr Leu Ile Asp Lys Tyr Leu Thr Asp Gly Gly Asp Pro Asn Ala His Asp Lys Leu His Arg Thr Ala Leu His Trp 140 ' 145 150 Ala Cys Leu Lys Gly His Ser Gln Leu Val Asn Lys Leu Leu Val Ala Gly Ala Thr Val Asp Ala Arg Asp Leu Leu Asp Arg Thr Pro Val Phe Trp Ala Cys Arg Gly Gly His Leu Val Ile Leu Lys Gln Leu Leu Asn Gln Gly Ala Arg Val Asn A1a Arg Asp Lys Ile Gly Ser Thr Pro Leu His Val Ala Val Arg Thr Arg His Pro Asp Cys Leu Glu His Leu Ile Glu Cys Gly A1a His Leu Asn Ala Gln Asp Lys Glu Gly Asp Thr Ala Leu His Glu Ala Val Arg His Gly Ser Tyr Lys Ala Met Lys Leu Leu Leu Leu Tyr Gly Ala Glu Leu Gly Val Arg Asn Ala Ala Ser Val Thr Pro Val Gln Leu Ala Arg Asp Trp Gln Arg G1y Ile Arg Glu Ala Leu Gln Ala His Val Ala His Pro Arg Thr Arg Cys <210> 26 <211> 1715 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2755454CD1 <400> 26 Met Ser Val Leu Ile Ser Gln Ser Val Ile Asn Tyr Val Glu Glu Glu Asn Ile Pro Ala Leu Lys A1a Leu Leu Glu Lys Cys Lys Asp Val Asp Glu Arg Asn Glu Cys G1y Gln Thr Pro Leu Met Ile Ala Ala Glu Gln Gly Asn Leu Glu Ile Val Lys Glu Leu Ile Lys Asn Gly Ala Asn Cys Asn Leu Glu Asp Leu Asp Asn Trp Thr Ala Leu Ile Ser Ala Ser Lys G1u Gly His Val His Ile Val Glu Glu Leu Leu Lys Cys G1y Val Asn Leu Glu His Arg Asp Met Gly Gly Trp Thr Ala Leu Met Trp Ala Cys Tyr Lys Gly Arg Thr Asp Val Val Glu Leu Leu Leu Ser His Gly Ala Asn Pro Ser Val Thr Gly Leu Gln Tyr Ser Val Tyr Pro Ile Ile Trp Ala Ala Gly Arg Gly His A1a Asp Ile Val His Leu Leu Leu Gln Asn Gly Ala Lys Va1 Asn Cys Ser Asp Lys Tyr Gly Thr Thr Pro Leu Val Trp A1a Ala Arg Lys Gly His Leu Glu Cys Val Lys His Leu Leu Ala Met Gly Ala Asp Val Asp Gln Glu Gly Ala Asn Ser Met Thr Ala Leu Ile Val Ala Val Lys Gly Gly Tyr Thr Gln Ser Val Lys Glu Ile Leu Lys Arg Asn Pro Asn Val Asn Leu Thr Asp Lys Asp Gly Asn Thr Ala Leu Met Ile Ala Ser Lys Glu Gly His Thr Glu Ile Val Gln Asp Leu Leu Asp A1a Gly Thr Tyr Va1 Asn Ile Pro Asp Arg Ser Gly Asp Thr Val Leu Tle Gly Ala Val Arg Gly Gly His Val Glu Ile Val Arg Ala Leu Leu Gln Lys Tyr Ala Asp Ile Asp Ile Arg Gly Gln Asp Asn Lys Thr Ala Leu Tyr Trp Ala Val Glu Lys Gly Asn Ala Thr Met Val Arg Asp Ile Leu Gln Cys Asn Pro Asp Thr Glu Ile Cys Thr Lys Asp Gly Glu Thr Pro Leu Ile Lys Ala Thr Lys Met Arg Asn Ile Glu Val Val Glu Leu Leu Leu Asp Lys Gly Ala Lys Val Ser Ala Va1 Asp Lys Lys Gly Asp Thr Pro Leu His Ile Ala Ile Arg Gly Arg Ser Arg Lys Leu Ala Glu Leu Leu Leu Arg Asn Pro Lys Asp Gly Arg Leu Leu Tyr Arg Pro Asn Lys Ala Gly Glu Thr Pro Tyr Asn Ile Asp Cys Ser His Gln Lys Ser Ile Leu Thr Gln Ile Phe Gly Ala Arg His Leu Ser Pro Thr Glu Thr Asp Gly Asp Met Leu Gly Tyr Asp Leu Tyr Ser Ser Ala Leu Ala Asp Ile Leu Ser Glu Pro Thr Met Gln Pro Pro Ile Cys Val Gly Leu Tyr Ala G1n Trp Gly Ser Gly Lys Ser Phe Leu Leu Lys Lys Leu Glu Asp Glu Met Lys Thr Phe Ala Gly Gln Gln Ile Glu Pro Leu Phe Gln Phe Ser Trp Leu Ile Val Phe Leu Thr Leu Leu Leu Cys Gly Gly Leu Gly Leu Leu Phe Ala Phe Thr Val His Pro Asn Leu 515 ' 520 525 Gly Ile A1a Val Ser Leu Ser Phe Leu Ala Leu Leu Tyr Ile Phe Phe Ile Val Ile Tyr Phe Gly Gly Arg Arg Glu Gly Glu Ser Trp Asn Trp Ala Trp Val Leu Ser Thr Arg Leu Ala Arg His Ile Gly Tyr Leu Glu Leu Leu Leu Lys Leu Met Phe Val Asn Pro Pro Glu Leu Pro Glu Gln Thr Thr Lys Ala Leu Pro Val Arg Phe Leu Phe Thr Asp Tyr Asn Arg Leu Ser Ser Val Gly Gly Glu Thr Ser Leu Ala G1u Met Ile Ala Thr Leu Ser Asp Ala Cys Glu Arg Glu Phe Gly Phe Leu Ala Thr Arg Leu Phe Arg Val Phe Lys Thr Glu Asp Thr Gln Gly Lys Lys Lys Trp Lys Lys Thr Cys Cys Leu Pro Ser Phe Val Ile Phe Leu Phe Ile Ile Gly Cys Ile Ile Ser Gly Ile Thr Leu Leu A1a Ile Phe Arg Val Asp Pro Lys His Leu Thr Va1 Asn Ala Val Leu Ile Ser Ile Ala Ser Val Val Gly Leu A1a Phe Val Leu Asn Cys Arg Thr Trp Trp Gln Val Leu Asp Ser Leu Leu Asn Ser Gln Arg Lys Arg Leu His Asn Ala Ala Ser Lys Leu His Lys Leu Lys Ser Glu Gly Phe Met Lys Val Leu Lys Cys Glu Val Glu Leu Met Ala Arg Met Ala Lys Thr Ile Asp Ser Phe Thr Gln Asn G1n Thr Arg Leu Val Val Ile Ile Asp Gly Leu Asp Ala Cys Glu Gln Asp Lys Val Leu Gln Met Leu Asp Thr Val Arg Val Leu Phe Ser Lys Gly Pro Phe Ile Ala Ile Phe Ala Ser Asp Pro His Ile Ile Ile Lys Ala Ile Asn Gln Asn Leu Asn Ser Val Leu Arg Asp Ser Asn Ile Asn Gly His Asp Tyr Met Arg Asn Ile Val His Leu Pro Val Phe Leu Asn Ser Arg Gly Leu Ser Asn Ala Arg Lys Phe Leu Val Thr Ser Ala Thr Asn Gly Asp Val Pro Cys Ser Asp Thr Thr Gly Ile Gln Glu Asp Ala Asp Arg Arg Val Ser G1n Asn Ser Leu Gly Glu Met Thr Lys Leu Gly Ser Lys Thr Ala Leu Asn Arg Arg Asp Thr Tyr Arg Arg Arg Gln Met Gln Arg Thr Ile Thr Arg Gln Met Ser Phe Asp Leu Thr Lys Leu Leu Val Thr Glu Asp Trp Phe Ser Asp Ile Ser Pro Gln Thr Met Arg Arg Leu Leu Asn Ile Val Ser Val Thr Gly Arg Leu Leu Arg Ala Asn Gln Ile Ser 950 955 ~ 960 Phe Asn Trp Asp Arg Leu Ala Ser Trp Ile Asn Leu Thr Glu Gln Trp Pro Tyr Arg Thr Ser Trp Leu Ile Leu Tyr Leu Glu Glu Thr Glu Gly I1e Pro Asp Gln Met Thr Leu Lys Thr Ile Tyr Glu Arg Ile Ser Lys Asn Ile Pro Thr Thr Lys Asp Val Glu Pro Leu Leu Glu Ile Asp Gly Asp Ile Arg Asn Phe Glu Val Phe Leu Ser Ser Arg Thr Pro Val Leu Val Ala Arg Asp Val Lys Val Phe Leu Pro Cys Thr Val Asn Leu Asp Pro Lys Leu Arg Glu Ile Ile Ala Asp Val Arg Ala Ala Arg Glu Gln Ile Ser Ile Gly Gly Leu Ala Tyr Pro Pro Leu Pro Leu His Glu Gly Pro Pro Arg Ala Pro Ser Gly Tyr Ser Gln Pro Pro Ser Val Cys Ser Ser Thr Ser Phe Asn Gly Pro Phe Ala Gly Gly Val Val Ser Pro Gln Pro His Ser Ser Tyr Tyr Ser Gly Met Thr Gly Pro Gln His Pro Phe Tyr Asn Arg Gly Ser Gly Pro Ala Pro Gly Pro Val Val Leu Leu Asn Ser Leu Asn Val Asp Ala Val Cys Glu Lys Leu Lys Gln Ile Glu Gly Leu Asp Gln Ser Met Leu Pro Gln Tyr Cys Thr Thr Ile Lys Lys Ala Asn Ile Asn Gly Arg Val Leu Ala Gln Cys Asn Ile Asp Glu Leu Lys Lys Glu Met Asn Met Asn Phe Gly Asp Trp His Leu Phe Arg Ser Thr Val Leu Glu Met Arg Asn Ala Glu Ser His Val Val Pro Glu Asp Pro Arg Phe Leu Ser Glu Ser Ser Ser Gly Pro Ala Pro His Gly Glu Pro Ala Arg Arg Ala Ser His Asn Glu Leu Pro His Thr Glu Leu Ser Ser Gln Thr Pro Tyr Thr Leu Asn Phe Ser Phe Glu Glu Leu Asn Thr Leu Gly Leu Asp Glu Gly Ala Pro Arg His Ser Asn Leu Ser Trp Gln Ser Gln Thr Arg Arg Thr Pro Ser Leu Ser Ser Leu Asn Ser Gln Asp Ser Ser Ile Glu Ile Ser Lys Leu Thr Asp Lys Val Gln Ala Glu Tyr Arg Asp Ala Tyr Arg Glu Tyr Ile Ala Gln Met Ser Gln Leu Glu Gly Gly Pro Gly Ser Thr Thr Ile Ser Gly Arg Ser Ser Pro His Ser Thr Tyr Tyr Met Gly Gln Ser Ser Ser Gly Gly Ser Ile His Ser Asn Leu Glu Gln Glu Lys Gly Lys Asp Ser Glu Pro Lys Pro Asp Asp Gly Arg Lys Ser Phe Leu Met Lys Arg Gly Asp Val Ile Asp Tyr Ser Ser Ser Gly Val~Ser Thr Asn Asp Ala Ser Pro Leu Asp Pro Ile Thr Glu Glu Asp Glu Lys Ser Asp Gln Ser Gly Ser Lys Leu Leu Pro Gly Lys Lys Ser Ser Glu Arg Ser Ser Leu Phe Gln Thr Asp Leu Lys Leu Lys Gly Ser Gly Leu Arg Tyr Gln Lys Leu Pro Ser Asp Glu Asp Glu Ser Gly Thr Glu Glu Ser Asp Asn Thr Pro Leu Leu Lys Asp Asp Lys Asp Arg Lys Ala Glu Gly Lys Val Glu Arg Val Pro Lys Ser Pro Glu His Ser Ala Glu Pro Ile Arg Thr Phe Ile Lys Ala Lys Glu Tyr Leu Ser Asp Ala Leu Leu Asp Lys Lys Asp Ser Ser Asp Ser Gly Val Arg Ser Ser Glu Ser Ser Pro Asn His Ser Leu His Asn Glu Val Ala Asp Asp Ser Gln Leu Glu Lys Ala Asn Leu Ile Glu Leu Glu Asp Asp Ser His Ser Gly Lys Arg Gly Ile Pro His Ser Leu Ser Gly Leu Gln Asp Pro Ile Ile Ala Arg Met Ser Ile Cys Ser Glu Asp Lys Lys Ser Pro Ser Glu Cys Ser Leu Ile Ala Ser Ser Pro Glu Glu Asn Trp Pro Ala Cys Gln Lys Ala Tyr Asn Leu Asn Arg Thr Pro Ser Thr Val Thr Leu Asn Asn Asn Ser Ala Pro Ala Asn Arg Ala Asn Gln Asn Phe Asp Glu Met G1u Gly Ile Arg Glu Thr Ser Gln Val I1e Leu Arg Pro Ser Ser Ser Pro Asn Pro Thr Thr I1e Gln Asn Glu Asn Leu Lys Ser Met Thr His Lys Arg Ser Gln Arg Ser Ser Tyr Thr Arg Leu Ser Lys Asp Pro Pro Glu 1685 1690 ~ 1695 Leu His Ala Ala A1a Ser Ser Glu Ser Thr Gly Phe G1y Glu Glu Arg Glu Ser Ile Leu <210> 27 <211> 1392 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5868348CD1 <400> 27 Met Ala Ser Val Lys Val Ala Val Arg Val Arg Pro Met Asn Arg Arg Glu Lys Asp Leu Glu Ala Lys Phe Ile Ile Gln Met Glu Lys Ser Lys Thr Thr Ile Thr Asn Leu Lys Ile Pro Glu Gly Gly Thr Gly Asp Ser Gly Arg Glu Arg Thr Lys Thr Phe Thr Tyr Asp Phe Ser Phe Tyr Ser Ala Asp Thr Lys Ser Pro Asp Tyr Val Ser Gln Glu Met Val Phe Lys Thr Leu Gly Thr Asp Val Va1 Lys Ser Ala .80 85 90 Phe Glu Gly Tyr Asn Ala Cys Val Phe Ala Tyr Gly Gln Thr Gly Ser Gly Lys Ser Tyr Thr Met Met Gly Asn Ser Gly Asp Ser Gly Leu Ile Pro Arg Ile Cys Glu~Gly Leu Phe Ser Arg Ile Asn Glu Thr Thr Arg Trp Asp Glu Ala Ser Phe Arg Thr Glu Val Ser Tyr Leu Glu I1e Tyr Asn Glu Arg Val Arg Asp Leu Leu Arg Arg Lys Ser Ser Lys Thr Phe Asn Leu Arg Val Arg Glu His Pro Lys Glu Gly Pro Tyr Val Glu Asp Leu Ser Lys His Leu Val Gln Asn Tyr Gly Asp Val Glu Glu Leu Met Asp Ala G1y Asn Ile Asn Arg Thr Thr Ala Ala Thr Gly Met Asn Asp Val Ser Ser Arg Ser His Ala Ile Phe Thr Ile Lys Phe Thr Gln Ala Lys Phe Asp Ser Glu Met 230 ' 235 240 Pro Cys Glu Thr Val Ser Lys Ile His Leu Val Asp Leu Ala Gly Ser Glu Arg Ala Asp Ala Thr Gly A1a Thr Gly Val Arg Leu Lys Glu Gly Gly Asn Ile Asn Lys Ser Leu Val Thr Leu Gly Asn Val Ile Ser Ala Leu Ala Asp Leu Ser Gln Asp Ala Ala Asn Thr Leu Ala Lys Lys Lys Gln Val Phe Val Pro Tyr Arg Asp Ser Val Leu Thr Trp Leu Leu Lys Asp Ser Leu Gly Gly Asn Ser Lys Thr Ile Met I1e Ala Thr Ile Ser Pro Ala Asp Val Asn Tyr Gly Glu Thr Leu Ser Thr Leu Arg Tyr A1a Asn Arg Ala Lys Asn Ile Ile Asn Lys Pro Thr Ile Asn Glu Asp Ala Asn Val Lys Leu Ile Arg Glu Leu Arg Ala Glu Ile Ala Arg Leu Lys Thr Leu Leu Ala Gln Gly 380 . 385 390 Asn Gln Ile Ala Leu Leu Asp Ser Pro Thr Ala Leu Ser Met Glu Glu Lys Leu Gln Gln Asn Glu Ala Arg Val Gln Glu Leu Thr Lys Glu Trp Thr Asn Lys Trp Asn Glu Thr Gln Asn Ile Leu Lys Glu Gln Thr Leu Ala Leu Arg Lys Glu Gly Ile Gly Val Val Leu Asp Ser Glu Leu Pro His Leu I1e Gly Ile Asp Asp Asp Leu Leu Ser Thr Gly Ile Ile Leu Tyr His Leu Lys Glu Gly Gln Thr Tyr Val Gly Arg Asp Asp Ala Ser Thr Glu Gln Asp Tle Val Leu His Gly Leu Asp Leu Glu Ser Glu His Cys Ile Phe Glu Asn Ile Gly Gly Thr Val Thr Leu Ile Pro Leu Ser Gly Ser Gln Cys Ser Val Asn Gly Val Gln Ile Val Glu Ala Thr His Leu Asn Gln Gly Ala Val Ile Leu Leu Gly Arg Thr Asn Met Phe Arg Phe Asn His Pro Lys Glu A1a Ala Lys Leu Arg Glu Lys Arg Lys Ser Gly Leu Leu Ser Ser Phe Ser Leu Ser Met Thr Asp Leu Ser Lys Ser Arg Glu Asn Leu Ser Ala Va1 Met Leu Tyr Asn Pro Gly Leu Glu Phe Glu Arg Gln Gln Arg Glu Glu Leu Glu Lys Leu Glu Ser Lys Arg Lys Leu Ile Glu Glu Met Glu Glu Lys G1n Lys Ser Asp Lys Ala Glu Leu Glu Arg Met Gln Gln Glu Val Glu Thr Gln Arg Lys Glu Thr Glu Ile Val Gln Leu Gln Ile Arg Lys Gln Glu Glu Ser Leu Lys Arg Arg Ser Phe His Ile Glu Asn Lys Leu Lys Asp Leu Leu Ala Glu Lys Glu Lys Phe Glu Glu Glu Arg Leu Arg Glu Gln Gln Glu Ile Glu ~Leu Gln Lys Lys Arg Gln Glu Glu Glu Thr Phe Leu Arg Val Gln Glu Glu Leu Gln Arg Leu Lys Glu Leu Asn Asn Asn Glu Lys Ala Glu Lys Phe Gln Ile Phe Gln Glu Leu Asp Gln Leu Gln Lys Glu Lys Asp Glu Gln Tyr Ala Lys Leu Glu Leu Glu Lys Lys Arg Leu Glu Glu Gln Glu Lys Glu Gln Val Met Leu Val Ala His Leu G1u Glu Gln Leu Arg Glu Lys Gln Glu Met Ile Gln Leu Leu Arg Arg Gly Glu Val Gln Trp Val Glu Glu Glu Lys Arg Asp Leu Glu Gly I1e Arg Glu Ser Leu Leu Arg Va1 Lys Glu Ala Arg Ala Gly Gly Asp Glu Asp Gly Glu Glu Leu Glu Lys Ala Gln Leu Arg Phe Phe Glu Phe Lys Arg Arg Gln Leu Val Lys Leu Val Asn Leu Glu 830 835 ~ 840 Lys Asp Leu Val Gln G1n Lys Asp Ile Leu Lys Lys Glu Val Gln Glu Glu Gln Glu Ile Leu Glu Cys Leu Lys Cys Glu His Asp Lys Glu Ser Arg Leu Leu Glu Lys His Asp G1u Ser Val Thr Asp Val Thr G1u Val Pro Gln Asp Phe Glu Lys I1e Lys Pro Val Glu Tyr Arg Leu Gln Tyr Lys Glu Arg Gln Leu Gln Tyr Leu Leu Gln Asn His Leu Pro Thr Leu Leu Glu Glu Lys Gln Arg Ala Phe Glu I1e Leu Asp Arg Gly Pro Leu Ser Leu Asp Asn Thr Leu Tyr Gln Val Glu Lys Glu Met Glu Glu Lys Glu G1u Gln Leu Ala Gln Tyr Gln Ala Asn Ala Asn Gln Leu Gln Lys Leu Gln Ala Thr Phe Glu Phe Thr Ala Asn Ile Ala Arg Gln Glu Glu Lys Val Arg Lys Lys Glu Lys Glu Ile Leu Glu Ser Arg Glu Lys Gln Gln Arg Glu Ala Leu Glu Arg Ala Leu Ala Arg Leu Glu Arg Arg His Ser Ala Leu Gln Arg His Ser Thr Leu Gly Thr Glu Ile Glu Glu G1n Arg Gln Lys Leu Ala Ser Leu Asn Ser Gly Ser Arg Glu Gln Ser Gly Leu Gln Ala Ser Leu Glu Ala Glu Gln Glu Ala Leu Glu Lys Asp Gln Glu Arg Leu Glu Tyr Glu Ile Gln Gln Leu Lys Gln Lys Ile Tyr Glu Val Asp Gly Val Gln Lys Asp His His Gly Thr Leu Glu Gly Lys Val Ala Ser Ser Ser Leu Pro Val Ser Ala Glu Lys Ser His Leu Val Pro Leu Met Asp Ala Arg Ile Asn Ala Tyr Ile Glu Glu Glu Val Gln Arg Arg Leu Gln Asp Leu His Arg Val Ile Ser Glu Gly Cys Ser Thr Ser AIa Asp Thr Met Lys Asp Asn Glu Lys Leu His Lys Gly Thr Ile Gln Arg Lys Leu Lys Tyr Glu Leu Cys Arg Asp Leu Leu Cys Val Leu Met Pro Glu Pro Asp Ala Ala Ala Cys A1a Asn His Pro Leu Leu Gln Gln Asp Leu Val Gln Leu Ser Leu Asp Trp Lys Thr Glu Ile Pro Asp Leu Val Leu Pro Asn Gly Val Gln Val Ser Ser Lys Phe Gln Thr Thr Leu VaI Asp Met Ile Tyr Phe Leu His Gly Asn Met Glu Val Asn Val Pro Ser Leu A1a Glu Val Gln Leu Leu Leu Tyr Thr Thr Val Lys Val Met Gly Asp Ser Gly His Asp Gln Cys Gln Ser Leu Val Leu Leu Asn Thr His Ile Ala Leu Val Lys Glu Asp Cys Val Phe Tyr Pro Arg Ile Arg Ser Arg Asn Ile Pro Pro Pro Gly Ala Gln Phe Asp Val Ile Lys Cys His A1a Leu Ser Glu Phe Arg Cys Val Val Val Pro Glu Lys Lys Asn Val Ser Thr Val Glu Leu Val Phe Leu G1n Lys Leu Lys Pro Ser Val Gly Ser Arg Asn Ser Pro Pro Glu His Leu Gln Glu Ala Pro Asn Val Gln Leu Phe Thr Thr Pro Leu Tyr Leu Gln Gly Ser Gln Asn Val Ala Pro Glu Val Trp Lys Leu Thr Phe Asn Ser Gln Asp Glu Ala Leu Trp Leu Ile Ser His Leu Thr Arg Leu <210> 28 <211> 337 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2055455CD1 <400> 28 Met Ala Glu Gly Gly Ser Pro Asp Gly Arg Ala G1y Pro Gly Leu Arg Ser Ala Gly Arg Asn Leu Lys Glu Trp Leu Arg Glu Gln Phe Cys Asp His Pro Leu Glu His Cys Glu Asp Thr Arg Leu His Asp Ala Ala Tyr Val Gly Asp Leu Gln Thr Leu Arg Ser Leu Leu Gln Glu Glu Ser Tyr Arg Ser Arg Ile Asn Glu Lys Ser Val Trp Cys 55!86 Cys Gly Trp Leu Pro Cys Thr Pro Leu Arg Ile Ala Ala Thr Ala G1y His Gly Ser Cys Val Asp Phe Leu Ile Arg Lys Gly Ala Glu Val Asp Leu Val Asp Val Lys Gly Gln Thr Ala Leu Tyr Val Ala Val Val Asn Gly His Leu Glu Ser Thr Gln Ile Leu Leu Glu Ala Gly Ala Asp Pro Asn Gly Ser Arg His His Arg Ser Thr Pro Val Tyr His Ala Ser Arg Val Gly Arg Ala Asp Ile Leu Lys Ala Leu Ile Arg Tyr Gly Ala Asp Val Asp Val Asn His His Leu Thr Pro Asp Val Gln Pro Arg Phe Ser Arg Arg Leu Thr Ser Leu Val Val Cys Pro Leu Tyr Ile Ser Ala Ala Tyr His Asn Leu Gln Cys Phe Arg Leu Leu Leu Leu Ala Gly Ala Asn Pro Asp Phe Asn Cys Asn Gly Pro Val Asn Thr Gln Gly Phe Tyr Arg Gly Ser Pro Gly Cys Val Met Asp Ala Val Leu Arg His Gly Cys Glu Ala Ala Phe Val Ser Leu Leu Val Glu Phe Gly Ala Asn Leu Asn Leu Val Lys Trp Glu Ser Leu Gly Pro Glu Ser Arg Gly Arg Arg Lys Val Asp Pro Glu Ala Leu Gln Val Phe Lys Glu Ala Arg Ser Val Pro Arg Thr Leu Leu Cys Leu Cys Arg Val Ala Val Arg Arg Ala Leu Gly Lys His Arg Leu His Leu Ile Pro Ser Leu Pro Leu Pro Asp Pro Ile Lys Lys Phe Leu Leu His G1u <210> 29 <211> 1685 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6582721CB1 <400> 29 accctaataa tgtgtatata aaggcaaacc aagctgtttg agtaggccgt tcaccatcag 60 agcatcaccg cagaaacaaa ggctccagcc tccggacacc atgtctgtgc gcttttcttc 120 tacctccagg agacttggct cttgcggggg cactggctct gtgaggctct ctagtggggg 180 agcaggcttt ggggctggaa acacatgcgg tgtgccaggc attggaagtg gcttctcttg 240 tgcttttggg ggcagctcat ctgcaggagg ctatggcgga ggtctgggcg ggggaagtgc 300 ttcctgtgct gccttcacag ggaatgagca cggcctcctc tctggcaatg agaaggtgac 360 catgcagaac ctcaacgacc gcttggcctc ctacctggag aatgttcgag ccctagagga 420 ggccaacgct gacttggagc agaagatcaa ggggtggtat gagaaatttg gacctggttc 480 ttgccgtggc cttgatcatg attacagcag atatttccca attattgacg aacttaagaa 540 ccagataatt tctgcaacta ccagtaatgc ccatgttgtc ctgcaaaatg ataatgcaag 600 actaacagct gatgacttca gactaaagtt tgaaaacgag ctagcgcttc accagagcgt 660 ggaggcggac atcaatagtt tgcgaagagt cctggatgag ctgaccttgt gcagaacgga 720 cctggagatc cagctggaaa ctctcagtga ggagctcgct tacctcaaga agaatcatga 780 ggaggaaatg aaagctcttc agtgcgcggc tggaggcaac gtgaacgtgg agatgaacgc 840 ggcccccggg gtagacctca cggttctgct gaacaatatg cgagctgagt acgaagccct 900 cgcagagcag aaccgcaggg acgcggaggc ctggttcaac gaaaagagcg cctcgctgca 960 gcagcagatc tctgacgacg ctggcgccac cacctcagcc cggaatgagc ttatcgagat 1020 gaaacgcact cttcaaaccc ttgagattga acttcagtcc ctcttagcaa cgaaacactc 1080 cctggagtgc tccttgacag agaccgagag taactactgt gcacagctgg cacagatcca 2140 ggctcagatc ggggccctgg aggagcagct gcaccaggtc agaaccgaga ccgagggcca 1200 gaagctcgag tatgagcagc tccttgacat caaggtccac ctggaaaaag aaattgagac 1260 ctactgcctc ctgatagatg gagaagatgg ctcctgttct aaatcaaaag gctatggagg 1320 cccaggaaat caaacaaaag attcatctaa aaccaccatt gtcaaaacag ttgttgaaga 1380 gatagatcct cgtggcaaag ttctctcatc cagagttcac actgtggaag agaaatccac 1440 caaagtcaac aacaagaatg aacagagggt gtcttcctga actccagcct ctgagacaga 1500 atggccccca aattaaaata ccaaaatgaa gctagtttcc taaataaggg tccccttatt 1560 tttctgcttt tcttccaatg aattaagaca agttattttt agaatagtac catttctttg 1620 gctttttctc tatggtggtg tttcaataaa agttcttcct gttgcaagtc aaaaaaaaaa 1680 aaaaa 1685 <210> 30 <211> 3147 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2828941CB1 <400> 30 ggcggaggtt acgccttccc tcatccccgg tagaggcagg gcgggactgt tgtggttgag 60 atgaaggcta gtaaatggtg aagtacttcc cggccagagg gcacctgcgc tcgggaggtt 120 tgggcggctt ggcgtcggag gagagcccca cccgcggagg aacccagcct tgccaacgga 180 gctggcggag ctcactcctc aggtcaggcg ggcggcgtag aaaacgcagc ggagccaggt 240 gaaaccaagg caccgccgtg gctggccccc gacagttcct ctagccggga ggttggagga 300 gctgaaaacg ccgcggagcc ctcggccgcc cgagcagggg ctggacccca gcccttgcag 360 cctcccttct cctggcaccc aagtgcagtc ctggctgcag aaggggccgc gggcgcactg 420 agtttccaac ctccatttca gcctgtctgt ctcagggtgc agccttaatg agaggtgatt 480 cctaagctgc tgggaacctg aggttgtcaa aggggcggca ggaaatggac agcagtataa 540 aacccagaag cagaacttga aggttaaacc actagcccat ttcacagaat gtttcatcca 600 tttgtggacc aaaagatgga gttggttttt atttttaaaa agataatgtt aatgatctga 660 taccactaca aatatttacg tgagaagatt catggacttg tcttttggtt ggactgtcac 720 tcatttctga aagtttcttc agccacaatt tctatttgaa aattcaagta tcaaaggata 780 ccaggtttag aatggtataa tgatgtattt tgtctgagga ctgcaaattt tatagagacc 840 acagttggat tccagtgata ttctgcaatc aaagtgattt gataaaccta attttgaagc 900 attttatatt tataagcgac atcaaaagat gggagaaaaa aatggcgatg caaaaacttt 960 ctggatggag ctagaagatg atggaaaagt ggacttcatt tttgaacaag tacaaaatgt 1020 gctgcagtca ctgaaacaaa agatcaaaga tgggtctgcc accaataaag aatacatcca 1080 agcaatgatt ctagtgaatg aagcaactat aattaacagt tcaacatcaa taaaggatcc 1140 tatgcctgtg actcagaagg aacaggaaaa caaatccaat gcatttccct ctacatcatg 1200 tgaaaactcc tttccagaag actgtacatt tctaacaaca ggaaataagg aaattctctc 1260 tcttgaagat aaagttgtag actttagaga aaaagactca tcttcgaatt tatcttacca 1320 aagtcatgac tgctctggtg cttgtctgat gaaaatgcca ctgaacttga agggagaaaa 1380 ccctctgcag ctgccaatca aatgtcactt ccaaagacga catgcaaaga caaactctca 1440 ttcttcagca ctccacgtga gttataaaac cccttgtgga aggagtctac gaaacgtgga 1500 ggaagttttt cgttacctgc ttgagacaga gtgtaacttt ttatttacag ataacttttc 1560 tttcaatacc tatgttcagt tggctcggaa ttacccaaag caaaaagaag ttgtttctga 1620 tgtggatatt agcaatggag tggaatcagt gcccatttct ttctgtaatg aaattgacag 1680 tagaaagctc ccacagttta agtacagaaa gactgtgtgg cctcgagcat ataatctaac 1740 caacttttcc agcatgttta ctgattcctg tgactgctct gagggctgca tagacataac 1800 aaaatgtgca tgtcttcaac tgacagcaag gaatgccaaa acttccccct tgtcaagtga 1860 caaaataacc actggatata aatataaaag actacagaga cagattccta ctggcattta 1920 tgaatgcagc cttttgtgca aatgtaatcg acaattgtgt caaaaccgag ttgtccaaca 1980 tggtcctcaa gtgaggttac aggtgttcaa aactgagcag aagggatggg gtgtacgctg 2040 tctagatgac attgacagag ggacatttgt ttgcatttat tcaggaagat tactaagcag 2100 agctaacact gaaaaatctt atggtattga tgaaaacggg agagatgaga atactatgaa 2160 aaatatattt tcaaaaaaga ggaaattaga agttgcatgt tcagattgtg aagttgaagt 2220 tctcccatta ggattggaaa cacatcctag aactgctaaa actgagaaat gtccaccaaa 2280 57!86 gttcagtaat aatcccaagg agcttactgt ggaaacgaaa tatgataata tttcaagaat 2340 tcaatatcat tcagttatta gagatcctga atccaagaca gccatttttc aacacaatgg 2400 gaaaaaaatg gaatttgttt cctcggagtc tgtcactcca gaagataatg atggatttaa 2460 accaccccga gagcatctga actctaaaac caagggagca caaaaggact caagttcaaa 2520 ccatgttgat gagtttgaag ataatctgct gattgaatca gatgtgatag atataactaa 2580 atatagagaa gaaactccac caaggagcag atgtaaccag gcgaccacat tggataatca 2640 gaatattaaa aaggcaattg aggttcaaat tcagaaaccc caagagggac gatctacagc 2700 atgtcaaaga cagcaggtat tttgtgatga agagttgcta agtgaaacca agaatacttc 2760 atctgattct ctaacaaagt tcaataaagg gaatgtgttt ttattggatg ccacaaaaga 2820 aggaaatgtc ggccgcttcc ttaatagtct cactttgtca ccagtggcac aatctcagct 2880 cactgcaacc tccgcttctg gggttcaagc aattctcatg cctcggcctc ctgagtagct 2940 gagattacag gcgttaatga atcacatgat gaatgtgtgg agatggcggc tagtgggcaa 3000 cagagcaata ctggaatagt gctaatatga ggaaatggta tcatctattt agaagcctcg 3060 gaacgacgat acataatgac tatcttcagc aaagaaattt gttgcttaca atatctcctc 3120 tccaaaaggc ttgtttgtta cagtgat 3147 <210> 31 <211> 5322 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6260407CB1 <400> 31 cggctcgagg,gccgctggcg gcctgttggc ttctccacag gcgcgctcgc cgttcaagcg 60 cgctttgtcc ccgccccaga tcctgggggg tgagcggtgg agaaggggcg ggcgcccgcg 120 agccgtgaat cacctcctcc tcttgctgcc tcagcgccgc cgccaccttt ccattcagtc 180 gcccaacatg gctggagcgc ggcggaggtg agccggccgc ccgcccgcag acgccccagc 240 ctactgcgcc cgagtcccgc ggccccagtg gcgcctcagc tctgcggtgc cgaggcccaa 300 cggctcgatc gctgcccgcc gccagcatgt tgggcgeccc ggacgagagc tccgtgcggg 360 tggctgtcag aataagacca cagcttgcca aagagaagat tgaaggatgc catatttgta 420 catctgtcac accaggagag cctcaggtct tcctagggaa agataaggct tttacttttg 480 actatgtatt tgacattgac tcccagcaag agcagatcta cattcaatgt atagaaaaac 540 taattgaagg ttgctttgaa ggatacaatg ctacagtttt tgcttatgga caaactggag 600 ctggtaaaac atacacaatg ggaacaggat ttgatgttaa cattgttgag gaagaactgg 660 gtattatttc tcgagctgtt aaacaccttt ttaagagtat tgaagaaaaa aaacacatag 720 caattaaaaa tgggcttcct gctccagatt ttaaagtgaa tgcccaattc ttagagctct 780 ataatgaaga ggtccttgac ttatttgata ccactcgtga tattgatgca aaaagtaaaa 840 aatcaaatat aagaattcat gaagattcaa ctggaggaat ttatactgtg ggcgttacaa 900 cacgtactgt gaatacagaa tcagagatga tgcagtgttt gaagttgggt gctttatccc 960 ggacaactgc cagtacccag atgaatgttc agagctctcg ttcacatgcc atttttacca 1020 ttcatgtgtg tcaaaccaga gtgtgtcccc aaatagatgc tgacaatgca actgataata 1080 aaattatttc tgaatcagca cagatgaatg aatttgaaac cctgactgca aagttccatt 1140 ttgttgatct cgcaggatct gaaagactga agegtactgg agctacaggc gagagggcaa 1200 aagaaggcat ttctatcaac tgtggacttt tggcacttgg caatgtaata agtgccttgg 1260 gagacaagag caagagggcc acacatgtec cctatagaga ttccaagcta acaagactac 1320 tacaggattc cctcgggggt aatagccaaa caatcatgat agcatgtgtc agcccttcag 1380 acagagactt tatggaaacg ttaaacaccc tgaaatacgc caatcgagct agaaatatca 1440 agaataaggt gatggtcaat caggacagag ctagtcagca aatcaatgca cttcgtagtg 1500 aaatcacacg acttcagatg gagctcatgg agtacaaaac aggtaaaaga ataattgacg 1560 aagagggtgt ggaaagcatc aatgacatgt ttcatgagaa tgctatgcta cagactgaaa 1620 ataataacct gcgtgtaaga attaaagcca tgcaagagac ggttgatgca ttgaggtcca 1680 gaattacaca gcttgttagt gatcaggcca accatgttct tgccagagca ggtgaaggaa 1740 atgaggagat tagtaatatg attcatagtt atataaaaga aatcgaagat ctcagggcaa 1800 aattattaga aagtgaagca gtgaatgaga accttcgaaa aaacttgaca agagccacag 1860 caagagcgcc atatttcagc ggatcatcaa ctttttctcc taccatacta tcctcagaca 1920 aagaaaccat tgaaattata gacctagcaa aaaaagattt agagaagttg aaaagaaaag 1980 aaaagaggaa gaaaaaaagg ctacagaaac ttgaggaaag caatcgagaa gaaagaagtg 2040 tggctggtaa agaggataat acagacactg accaagagaa gaaagaagaa aagggtgttt 2100 cggaaagaga aaacaatgaa ttagaagtgg aagaaagtca agaagtgagt gatcatgagg 2160 atgaagaaga ggaggaggag gaggaggaag atgacattga tgggggtgaa agttctgatg 2220 aatcagattc tgaatcagat gaaaaagcca attatcaagc agacttggca aacattactt 2280 gtgaaattgc aattaagcaa aagctgattg atgaactaga aaacagccag aaaagactgc 2340 agactctgaa aaagcagtat gaagagaagc taatgatgct gcaacataaa attcgggata 2400 ctcagcttga aagagaccag gtgcttcaaa acttaggctc ggtagaatct tactcagaag 2460 aaaaagcaaa aaaagttagg tctgaatatg aaaagaaact ccaagccatg aacaaagaac 2520 tgcagagact tcaagcagct caaaaagaac atgcaaggtt gcttaaaaat cagtctcagt 2580 atgaaaagca attgaagaaa ttgcagcagg atgtgatgga aatgaaaaaa acaaaggttc 2640 gcctaatgaa acaaatgaaa gaagaacaag agaaagccag actgactgag tctagaagaa 2700 acagagagat tgctcagttg aaaaaggatc aacgtaaaag agatcatcaa cttagacttc 2760 tggaagccca aaaaagaaac caagaagtgg ttctacgtcg caaaactgaa gaggttacgg 2820 ctcttcgtcg gcaagtaaga cccatgtcag ataaagtggc tgggaaagtt actcggaagc 2880 tgagttcatc tgatgcacct gctcaggaca caggttccag tgcagctgct gtcgaaacag 2940 atgcatcaag gacaggagcc cagcagaaaa tgagaattcc tgtggcgaga gtccaggcct 3000 taccaacgcc ggcaacaaat ggaaacagga aaaaatatca gaggaaagga ttgactggcc 3060 gagtgtttat ttccaagaca gctcgcatga agtggcagct ccttgagcgc agggtcacag 3120 acatcatcat gcagaagatg accatttcca acatggaggc agatatgaat agactcctca 3180 agcaacggga ggaactcaca aaaagacgag agaaactttc aaaaagaagg gagaagatag 3240 tcaaggagaa tggagaggga gataaaaatg tggctaatat caatgaagag atggagtcac 3300 tgactgctaa tatcgattac atcaatgaca gtatttctga ttgtcaggcc aacataatgc 3360 agatggaaga agcaaaggaa gaaggtgaga cattggatgt tactgcagtc attaatgcct 3420 gcacccttac agaagcccga tacctgctag atcacttcct gtcaatgggc atcaataagg 3480 gtcttcaggc tgcccagaaa gaggctcaaa ttaaagtact ggaaggtcga ctcaaacaaa 3540 cagaaataac cagtgctacc caaaaccagc tcttattcca tatgttgaaa gagaaggcag 3600 aattaaatcc tgagctagat gctttactag gccatgcttt acaagatcta gatagcgtac 3660 cattagaaaa tgtagaggat agtactgatg aggatgctcc tttaaacagc ccaggatcag 3720 aaggaagcac gctgtcttca gatctcatga agctttgtgg tgaagtgaaa cctaagaaca 3780 aggcccgaag gagaaccacc actcagatgg aattgctgta tgcagatagc agtgaactag 3840 cttcagacac tagtacagga gatgcctcct tgcctggccc tctcacacct gttgcagaag 3900 ggcaagagat tggaatgaat acagagacaa gtggtacttc tgctagggaa aaagagctct 3960 CtCCCCCaCC tggcttacct tctaagatag gcagcatttc caggcagtca tctctatcag 4020 aaaaaaaaat tccagagcct tctcctgtaa caaggagaaa ggcatatgag aaagcagaaa 4080 aatcaaaggc caaggaacaa aagcagggca taatcaaccc atttcctgct tcaaaaggaa 4140 tcagagcttt tccacttcag tgtattcaca tagctgaagg gcatacaaaa gctgtgctct 4200 gtgtggattc tactgatgat ctcctcttca ctggatcaaa agatcgtact tgtaaagtat 4260 ggaatctggt gactgggcag gaaataatgt cactgggggg tcatcccaac aatgtcgtgt 4320 ctgtaaaata ctgtaattat accagtttgg tcttcactgt atcaacatct tatattaagg 4380 tgtgggatat cagagattca gcaaagtgca ttcgaacact aacgtcttca ggtcaagtta 4440 ctcttggaga tgcttgttct gcaagtacca gtcgaacagt agctattcct tctggagaga 4500 accagatcaa tcaaattgcc ctaaacccaa ctggcacctt cctctatgct gcttctggaa 4560 atgctgtcag gatgtgggat cttaaaaggt ttcagtctac aggaaagtta acaggacacc 4620 taggccctgt tatgtgcctt actgtggatc agatttccag tggacaagat ctaatcatca 4680 ctggctccaa ggatcattac atcaaaatgt ttgatgttac agaaggagct cttgggactg 4740 tgagtcccac ccacaatttt gaaccccctc attatgatgg catagaagca ctaaccattc 4800 aaggggataa cctatttagt gggtctagag ataatggaat caagaaatgg gacttaactc 4860 aaaaagacct tcttcagcaa gttccaaatg cacataagga ttgggtctgt gccttgggag 4920 tggtgccaga ccacccagtt ttgctcagtg gctgcagagg gggcattttg aaagtctgga 4980 acatggatac ttttatgcca gtgggagaga tgaagggtca tgatagtcct atcaatgcca 5040 tatgtgttaa ttccacccac atttttactg cagctgatga tcgaactgtg agaatttgga 5100 aggctcgcaa tttgcaagat ggtcagatct ctgacacagg agatctgggg gaagatattg 5160 ccagtaatta aacatgaatg aagataggtt gtaaactgaa tgctgtgata atactctgta 5220 ttctttatgg aaatgttgtc ctgtacttac taggccaacg tttaatcggt taccggactt 5280 ttcgtcccgg cgcatttagg tctaaacccg tctccttgtc ct 5322 <210> 32 <211> 931 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte TD No: 7488258CB1 <400> 32 gttgcaacca aacatgacac ttagcgtgct gagcaggaag gacaaggaaa gagtaattcg 60 cagactgtta ttacaggccc ctccagggga atttgtaaat gcctttgatg atctctgtct 120 gcttatccgt gatgaaaaac ttatgcacca ccaaggtgag tgtgcaggcc accaacactg 180 ccaaaaatat tctgtaccac tctgcatcga tggaaatcca gtactcttgt ctcaccacaa 240 tgtaatgggc gactaccgat tttttgacca tcaaagcaaa ctttctttca aatatgacct 300 gcttcaaaat cagctgaaag acatccaaag tcatggtatc attcagaatg aggcagaata 360 cctgagagtt gttcttctgt gcgccttaaa actgtatgtg aatgaccact atccaaaagg 420 aaattgcaac atgctgagaa aaactgtcaa aagtaaggag tacttgatag cttgcattga 480 agatcacaac tatgaaacag gagagtgctg gaacggactt tggaaatcta aatggatttt 540 ccaagttaac ccatttctaa cccaagtaac gggaagaata tttgtgcaag ctcacttctt 600 caggtgtgtc aaccttcata ttgaaatatc caaggacctg aaagaaagct tggaaatagt 660 taaccaagct caactggctc taagttttgc aaggcttgtg gaagagcaag agaacaaatt 720 tcaagctgca gtcttggaag aattacagga gttatccaat gaagccctga gaaaaattct 780 acgaagggat cttccagtga cccgcactct tattgactgg cacaggatac tctctgactt 840 gaatctggtg atgtatccta aattaggata tgtcatttat tcaagaagtg tgttgtgcaa 900 ctggataata taaagaattg ctcctggtaa a 931 <210> 33 <211> 5299 <212> DNA
<213> Homo Sapiens <220>
<221> misc_teature <223> Incyte ID No: 7948948CB1 <400> 33 tagcctgtac gatcactata gcggaaacgc tgatacgcct gtcggtaccg gtcccgaatt 60 cctgggtcga cggggggaga aggggcgggc gcccgcgagc cggtgaatca cctcctcctc 120 ttgctgcctc agcgccgccg ccacctttcc attcagtcgc ccaacatggc tggagcgcgg 180 cggaggtgag CCggCCgCCC gcccgcagac gccccagcct actgcgcccg agtcccgcgg 240 ccccagtggc gcctcagctc tgcggtgccg aggcccaacg gctcgatcgc tgcccgccgc 300 cagcatgttg gacgccccgg acgagagctc cgtgcgggtg gctgtcagaa taagaccaca 360 gcttgccaaa gagaagattg aaggatgcca tatttgtaca tctgtcacac caggagagcc 420 tcaggtcttc ctagggaaag ataaggcttt tacttttgac tatgtatttg acattgactc 480 ccagcaagag cagatctaca ttcaatgtat agaaaaacta attgaaggtt gctttgaagg 540 atacaatgct acagtttttg cttatggaca aactggagct ggtaaaacat acacaatggg 600 aacaggattt gatgttaaca ttgttgagga agaactgggt attatttctc gagctgttaa 660 acaccttttt aagagtattg aagaaaaaaa acacatagca attaaaaatg ggcttcctgc 720 tccagatttt aaagtgaatg cccaattctt agagctctat aatgaagagg tccttgactt 780 atttgatacc actcgtgata ttgatgcaaa aagtaaaaaa tcaaatataa gaattcatga 840 agattcaact ggaggaattt atactgtggg cgttacaaca cgtactgtga atacagaatc 900 agagatgatg cagtgtttga agttgggtgc tttatcccgg acaactgcca gtacccagat 960 gaatgttcag agctctcgtt cacatgccat ttttaccatt catgtgtgtc aaaccagagt 1020 gtgtccccaa atagatgctg acaatgcaac tgataataaa attatttctg aatcagcaca 1080 gatgaatgaa tttgaaaccc tgactgcaaa gttccatttt gttgatctcg caggatctga 1140 aagactgaag cgtactggag ctacaggcga gagggcaaaa gaaggcattt ctatcaactg 1200 tggacttttg gcacttggca atgtaataag tgccttggga gacaagagca agagggccac 1260 acatgtcccc tatagagatt ccaagctaac aagactacta caggattccc tcgggggtaa 1320 tagccaaaca atcatgatag catgtgtcag cccttcagac agagacttta tggaaacgtt 1380 a~aacaccctg aaatacgcca atcgagctag aaatatcaag aataaggtga tggtcaatca 1440 ggacagagct agtcagcaaa tcaatgcact tcgtagtgaa atcacacgac ttcagatgga 1500 gctcatggag tacaaaacag gtaaaagaat aattgacgaa gagggtgtgg aaagcatcaa 1560 tgacatgttt catgagaatg ctatgctaca gactgaaaat aataacctgc gtgtaagaat 1620 taaagccatg caagagacgg ttgatgcatt gaggtccaga attacacagc ttgttagtga 1680 tcaggccaac catgttcttg ccagagcagg tgaaggaaat gaggagatta gtaatatgat 1740 tcatagttat ataaaagaaa tcgaagatct cagggcaaaa ttattagaaa gtgaagcagt 1800 gaatgagaac cttcgaaaaa acttgacaag agccacagca agagcgccat atttcagcgg 1860 atcatcaact ttttctccta ccatactatc ctcagacaaa gaaaccattg aaattataga 1920 cctagcaaaa aaagatttag agaagttgaa aagaaaagaa aagaggaaga aaaaaagtgt 1980 ggctggtaaa gaggataata cagacactga ccaagagaag aaagaagaaa agggtgtttc 2040 ggaaagagaa aacaatgaat tagaagtgga agaaagtcaa gaagtgagtg atcatgagga 2100 tgaagaagag gaggaggagg aggaggaaga tgacattgat gggggtgaaa gttctgatga 2160 atcagattct gaatcagatg aaaaagccaa ttatcaagca gacttggcaa acattacttg 2220 tgaaattgca attaagcaaa agctgattga tgaactagaa aacagccaga aaagactgca 2280 gactctgaaa aagcagtatg aagagaagct aatgatgctg caacataaaa ttcgggatac 2340 tcagcttgaa agagaccagg tgcttcaaaa cttaggctcg gtagaatctt actcagaaga 2400 aaaagcaaaa aaagttaggt ctgaatatga aaagaaactc caagccatga acaaagaact 2460 gcagagactt caagcagctc aaaaagaaca tgcaaggttg cttaaaaatc agtctcagta 2520 tgaaaagcaa ttgaagaaat tgcagcagga tgtgatggaa atgaaaaaaa caaaggttcg 2580 cctaatgaaa caaatgaaag aagaacaaga gaaagccaga ctgactgagt ctagaagaaa 2640 cagagagatt gctcagttga aaaaggatca acgtaaaaga gatcatcaac ttagacttct 2700 ggaagcccaa aaaagaaacc aagaagtggt tctacgtcgc aaaactgaag aggttacggc 2760 tcttcgtcgg caagtaagac ccatgtcaga taaagtggct gggaaagtta ctcggaagct 2820 gagttcatct gatgcacctg ctcaggacac aggttccagt gcagctgctg tcgaaacaga 2880 tgcatcaagg acaggagccc agcagaaaat gagaattcct gtggcgagag tccaggcctt 2940 accaacgccg gcaacaaatg gaaacaggaa aaaatatcag aggaaaggat tgactggccg 3000 agtgtttatt tccaagacag ctcgcatgaa gtggcagctc cttgagcgca gggtcacaga 3060 catcatcatg cagaagatga ccatttccaa catggaggca gatatgaata gactcctcaa 3120 gcaacgggag gaactcacaa aaagacgaga gaaactttca aaaagaaggg agaagatagt 3180 caaggagaat ggagagggag ataaaaatgt ggctaatatc aatgaagaga tggagtcact 3240 gactgctaat atcgattaca tcaatgacag tatttctgat tgtcaggcca acataatgca 3300 gatggaagaa gcaaaggaag aaggtgagac attggatgtt actgcagtca ttaatgcctg 3360 cacccttaca gaagcccgat acctgctaga tcacttcctg tcaatgggca tcaataaggg 3420 tcttcaggct gcccagaaag aggctcaaat taaagtactg gaaggtcgac tcaaacaaac 3480 agaaataacc agtgctaccc aaaaccagct cttattccat atgttgaaag agaaggcaga 3540 attaaatcct gagctagatg ctttactagg ccatgcttta caagataatg tagaggatag 3600 tactgatgag gatgctcctt taaacagccc aggatcagaa ggaagcacgc tgtcttcaga 3660 tctcatgaag ctttgtggtg aagtgaaacc taagaacaag gcccgaagga gaaccaccac 3720 tcagatggaa ttgctgtatg cagatagcag tgaactagct tcagacacta gtacaggaga 3780 tgcctccttg cctggccctc tcacacctgt tgcagaaggg caagagattg gaatgaatac 3840 agagacaagt ggtacttctg ctagggaaaa agagctctct cccccacctg gcttaccttc 3900 taagataggc agcatttcca ggcagtcatc tctatcagaa aaaaaaattc cagagccttc 3960 tcctgtaaca aggagaaagg catatgagaa agcagaaaaa tcaaaggcca aggaacaaaa 4020 gcagggcata atcaacccat ttcctgcttc aaaaggaatc agagcttttc cacttcagtg 4080 tattcacata gctgaagggc atacaaaagc tgtgctctgt gtggattcta ctgatgatct 4140 cctcttcact ggatcaaaag atcgtacttg taaagtatgg aatctggtga ctgggcagga 4200 aataatgtca ctggggggtc atcccaacaa tgtcgtgtct gtaaaatact gtaattatac 4260 cagtttggtc ttcactgtat caacatctta tattaaggtg tgggatatca gagattcagc 4320 aaagtgcatt cgaacactaa cgtcttcagg tcaagttact cttggagatg cttgttctgc 4380 aagtaccagt cgaacagtag ctattccttc tggagagaac cagatcaatc aaattgccct 4440 aaacccaact ggcaccttcc tctatgctgc ttctggaaat gctgtcagga tgtgggatct 4500 taaaaggttt cagtctacag gaaagttaac aggacaccta ggccctgtta tgtgccttac 4560 tgtggatcag atttccagtg gacaagatct aatcatcact ggctccaagg atcattacat 4620 caaaatgttt gatgttacag aaggagctct tgggactgtg agtcccaccc acaattttga 4680 accccctcat tatgatggca tagaagcact aaccattcaa ggggataacc tatttagtgg 4740 gtctagagat aatggaatca agaaatggga cttaactcaa aaagaccttc ttcagcaagt 4800 tccaaatgca cataaggatt gggtctgtgc cttgggagtg gtgccagacc acccagtttt 4860 gctcagtggc tgcagagggg gcattttgaa agtctggaac atggatactt ttatgccagt 4920 gggagagatg aagggtcatg atagtcctat caatgccata tgtgttaatt ccacccacat 4980 ttttactgca gctgatgatc gaactgtgag aatttggaag gctcgcaatt tgcaagatgg 5040 tcagatctct gacacaggag atctggggga agatattgcc agtaattaaa catgaatgaa 5100 gataggttgt aaactgaatg ctgtgataat actctgtatt ctttatggaa aatgttgtcc 5160 tgtacttact aggcaaaacg tatgaatcgg attaactgga aaatatatct gaattcactg 5220 ctgactataa atggtattct aataaaattg tgtactatcc tgtgtgctta gtttaaatcc 5280 tttccgcctg accgctgcg 5299 <210> 34 <221> 4080 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3467913CB1 <400> 34 tccaagctgg tcgagctcca tcactgatag cggccgcagt gtgctggaaa gagggccgga 60 gcccgagccc ttggaggttg attgacttat gtgcaatttg ggacgctgga gtttaccttc 120 cctccgcagc ctggaacaga gcctcctctg gtgttgcaag gaagaggctg aatgaggcag 180 agaagctgag tgctgtccag gaggcccagt taaagcggct cgaggtgaca agaccccgag 240 tgctggggag cagggagcag ggccaggtgc cgaggatggc caggcagcca ccgccgccct 300 gggtccatgc agccttcctc ctctgcctcc tcagtcttgg cggagccatc gaaattccta 360 tggatccaag cattcagaat gagctgacgc agccgccaac catcaccaag cagtcagcga 420 aggatcacat cgtggacccc cgtgataaca tcctgattga gtgtgaagca aaagggaacc 480 ctgcccccag cttccactgg acacgaaaca gcagattctt caacatcgcc aaggaccccc 540 gggtgtccat gaggaggagg tctgggaccc tggtgattga cttccgcagt ggcgggcggc 600 cggaggaata tgagggggaa tatcagtgct tcgcccgcaa caaatttggc acggccctgt 660 ccaataggat ccgcctgcag gtgtctaaat ctcctctgtg gcccaaggaa aacctagacc 720 ctgtcgtggt ccaagagggc gctcctttga cgctccagtg caaccccccg cctggacttc 780 catccccggt catcttctgg atgagcagct ccatggagcc catcacccaa gacaaacgtg 840 tctctcaggg ccataacgga gacctatact tctccaacgt gatgctgcag gacatgcaga 900 ccgactacag ttgtaacgcc cgcttccact tcacccacac catccagcag aagaaccctt 960 tcaccctcaa ggtcctcacc aaccaccctt ataatgactc gtccttaaga aaccaccctg 1020 acatgtacag tgcccgagga gttgcagaaa gaacaccaag cttcatgtat ccccagggca 1080 ccgcgagcag ccagatggtg cttcgtggca tggacctcct gctggaatgc atcgcctccg 1140 gggtcccaac accagacatc gcatggtaca agaaaggtgg ggacctccca tctgataagg 1200 ccaagtttga gaactttaat aaggccctgc gtatcacaaa tgtctctgag gaagactccg 1260 gggagtattt ctgcctggcc tccaacaaga tgggcagcat ccggcacacg atctcggtga 1320 gagtaaaggc tgctccctac tggctggacg aacccaagaa ccttattctg gctcctggcg 1380 aggatgggag actggtgtgt cgagccaatg gaaaccccaa acccactgtc cagtggatgg 1440 tgaatgggga acctttgcaa tcggcaccac ctaacccaaa ccgtgaggtg gccggagaca 1500 ccatcatctt ccgggacacc cagatcagca gcagggctgt gtaccagtgc aacacctcca 1560 acgagcatgg ctacctgctg gccaacgcct ttgtcagtgt gctggatgtg ccgcctcgga 1620 tgctgtcgcc ccggaaccag ctcattcgag tgattcttta caaccggacg cggctggact 1680 gCCCtttCtt tgggtCtCCC atCCCCaCaC tgcgatggtt taagaatggg caaggaagca 1740 acctggatgg tggcaactac catgtttatg agaacggcag tctggaaatt aagatgatcc 1800 gcaaagagga ccagggcatc tacacctgtg tcgccaccaa catcctgggc aaagctgaaa 1860 accaagtccg cctggaggtc aaagacccca ccaggatcta ccggatgccc gaggaccagg 1920 tggccagaag gggcaccacg gtgcagctgg agtgtcgggt gaagcacgac ccctccctga 1980 aactcaccgt ctcctggctg aaggatgacg agccgctcta tattggaaac aggatgaaga 2040 aggaagacga ctccctgacc atctttgggg tggcagagcg ggaccagggc agttacacgt 2100 gtgtcgccag caccgagcta gaccaagacc tggccaaggc ctacctcacc gtgctagctg 2160 atcaggccac tccaactaac cgtttggctg ccctgcccaa aggacggcca gaccggcccc 2220 gggacctgga gctgaccgac ctggccgaga ggagcgtgcg gctgacctgg atccccgggg 2280 atgctaacaa cagccccatc acagactacg tcgtccagtt tgaagaagac cagttccaac 2340 ctggggtctg gcatgaccat tccaagtacc ccggcagcgt taactcagcc gtcctccggc 2400 tgtccccgta tgtcaactac cagttccgtg tcattgccat caacgaggtt gggagcagcc 2460 accccagcct cccatccgag cgctaccgaa ccagtggagc tccccccgag tccaatcctg 2520 gtgacgtgaa gggagagggg accagaaaga acaacatgga gatcacgtgg acgcccatga 2580 atgccacctc ggcctttggc cccaacctgc gctacattgt caagtggagg cggagagaga 2640 ctcgagaggc ctggaacaac gtcacagtgt ggggctctcg ctacgtggtg gggcagaccc 2700 cagtctacgt gccctatgag atccgagtcc aggctgaaaa tgacttcggg aagggccctg 2760 agccagagtc cgtcatcggt tactccggag aagattatcc cagggctgcg cccactgaag 2820 ttaaagtccg agtcatgaac agcacagcca tcagccttca gtggaaccgc gtctactccg 2880 acacggtcca gggccagctc agagagtacc gagcctacta ctggagggag agcagcttgc 2940 tgaagaacct gtgggtgtct cagaagagac agcaagccag CttCCCtggt gaCCgCCtCC 3000 gtggcgtggt gtcccgcctc ttcccctaca gtaactacaa gctggagatg gttgtggtca 3060 atgggagagg tgatgggcct cgcagtgaga ccaaggagtt caccaccccg gaaggagtac 3120 ccagtgcccc taggcgtttc cgagtccggc agcccaacct ggagacaatc aacctggaat 3180 gggatcatcc tgagcatcca aatgggatca tgattggata cactctcaaa tatgtggcct 3240 ttaacgggac caaagtagga aagcagatag tggaaaactt ctctcccaat cagaccaagt 3300 tcacggtgca aagaacggac cccgtgtcac gctaccgctt taccctcagc gccaggacgc 3360 aggtgggctc tggggaagcc gtcacagagg agtcaccagc acccccgaat gaagctcctc 3420 ccacattgcc cccgactacc gtgggtgcga cgggcgctgt gagcagtacc gatgctactg 3480 ccattgctgc caccaccgaa gccacaacag tccccatcat cccaactgtc gcacctacca 3540 ccatggccac caccaccacc gtcgccacaa ctactacaac cactgctgcc gccaccacca 3600 ccacggagag tcctcccacc accacctccg ggactaagat acacgaatcc gcttacacca 3660 acaaccaagc ggacatcgcc acccagggct ggttcattgg gcttatgtgc gccatcgccc 3720 tcctggtgct gatcctgctc atcgtctgtt tcatcaagag gagtcgcggc ggcaatgatg 3780 aggacaacaa gcccctgcag ggcagtcaga catctctgga cggcaccatc aagcagcagg 3840 tacgagaaaa gaaggatgtt ccccttggcc ctgaagaccc caaggaagag gatggctcat 3900 ttgactatag gtgcagtgac gacagcctgg tggactatgg cgagggtggc gagggtcagt 3960 tcaatgaaga cggctccttc atcggccagt acacggtcaa aaaggacaag gaggaaacag 4020 agggcaacga aagctcagag gccacgtcac ctgtcaatgc tatctactct ctggcctaac 4080 <210> 35 <211> 4360 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7495062CB1 <400> 35 tccaagctgg tcgagctcca tcactgatag cggccgcagt gtgctggaaa gagggccgga 60 gcccgagccc ttggaggttg attgacttat gtgcaatttg ggacgctgga gtttaccttc 220 cctccgcagc ctggaacaga gcctcctctg gtgttgcaag gaagaggctg aatgaggcag 180 agaagctgag tgctgtccag gaggcccagt taaagcggct cgaggtgaca agaccccgag 240 tgctggggag cagggagcag ggccaggtgc cgaggatggc caggcagcca ccgccgccct 300 gggtccatgc agccttcctc ctctgcctcc tcagtcttgg cggagccatc gaaattccta 360 tggatccaag cattcagaat gagctgacgc agccgccaac catcaccaag cagtcagcga 420 aggatcacat cgtggacccc cgtgataaca tcctgattga gtgtgaagca aaagggaacc 480 ctgcccccag cttccactgg acacgaaaca gcagattctt caacatcgcc aaggaccccc 540 gggtgtccat gaggaggagg tctgggaccc tggtgattga cttccgcagt ggcgggcggc 600 cggaggaata tgagggggaa tatcagtgct tcgcccgcaa caaatttggc acggccctgt 660 ccaataggat ccgcctgcag gtgtctaaat ctcctctgtg gcccaaggaa aacctagacc 720 ctgtcgtggt ccaagagggc gctcctttga cgctccagtg caaccccccg cctggacttc 780 catccccggt catcttctgg atgagcagct ccatggagcc catcacccaa gacaaacgtg 840 tctctcaggg ccataacgga gacctatact tctccaacgt gatgctgcag gacatgcaga 900 ccgactacag ttgtaacgcc cgcttccact tcacccacac catccagcag aagaaccctt 960 tcaccctcaa ggtcctcacc aaccaccctt ataatgactc gtccttaaga aaccaccctg 1020 acatgtacag tgcccgagga gttgcagaaa gaacaccaag cttcatgtat ccccagggca 1080 ccgcgagcag ccagatggtg cttcgtggca tggacctcct gctggaatgc atcgcctccg 1140 gggtcccaac accagacatc gcatggtaca agaaaggtgg ggacctccca tctgataagg 1200 ccaagtttga gaactttaat aaggccctgc gtatcacaaa tgtctctgag gaagactccg 1260 gggagtattt ctgcctggcc tccaacaaga tgggcagcat ccggcacacg atctcggtga 1320 gagtaaaggc tgctccctac tggctggacg aacccaagaa ccttattctg gctcctggcg 1380 aggatgggag actggtgtgt cgagccaatg gaaaccccaa acccactgtc cagtggatgg 1440 tgaatgggga acctttgcaa tcggcaccac ctaacccaaa ccgtgaggtg gccggagaca 1500 ccatcatctt ccgggacacc cagatcagca gcagggctgt gtaccagtgc aacacctcca 1560 acgagcatgg ctacctgctg gccaacgcct ttgtcagtgt gctggatgtg ccgcctcgga 1620 tgctgtcgcc ccggaaccag ctcattcgag tgattcttta caaccggacg cggctggact 1680 gccctttctt tgggtctccc atccccacac tgcgatggtt taagaatggg caaggaagca 1740 acctggatgg tggcaactac catgtttatg agaacggcag tctggaaatt aagatgatcc 1800 gcaaagagga ccagggcatc tacacctgtg tcgccaccaa catcctgggc aaagctgaaa 1860 accaagtccg cctggaggtc aaagacccca ccaggatcta ccggatgccc gaggaccagg 1920 tggccagaag gggcaccacg gtgcagctgg agtgtcgggt gaagcacgac ccctccctga 1980 aactcaccgt ctcctggctg aaggatgacg agccgctcta tattggaaac aggatgaaga 2040 aggaagacga ctccctgacc atctttgggg tggcagagcg ggaccagggc agttacacgt 2100 gtgtcgccag caccgagcta gaCCaagacc tggccaaggc ctacctcacc gtgctagctg 2160 atcaggccac tccaactaac cgtttggctg ccctgcccaa aggacggcca gaccggcccc 2220 gggacctgga gctgaccgac ctggccgaga ggagcgtgcg gctgacctgg atccccgggg 2280 atgctaacaa cagccccatc acagactacg tcgtccagtt tgaagaagac cagttccaac 2340 ctggggtctg gcatgaccat tccaagtacc ccggcagcgt taactcagcc gtcctccggc 2400 tgtccccgta tgtcaactac cagttccgtg tcattgccat caacgaggtt gggagcagcc 2460 accccagcct cccatccgag cgctaccgaa ccagtggagc accccccgag tccaatcctg 2520 gtgacgtgaa gggagagggg accagaaaga acaacatgga gatcacgtgg acgcccatga 2580 atgccacctc ggcctttggc cccaacctgc gctacattgt caagtggagg cggagagaga 2640 ctcgagaggc ctggaacaac gtcacagtgt ggggctctcg ctacgtggtg gggcagaccc 2700 cagtctacgt gccctatgag atccgagtcc aggctgaaaa tgacttcggg aagggccctg 2760 agccagagtc cgtcatcggt tactccggag aagattatcc cagggctgcg cccactgaag 2820 ttaaagtccg agtcatgaac aggacagcca tcagccttca gtggaaccgc gtctactccg 2880 acacggtcca gggccagctc agagagtacc gagcctacta ctggagggag agcagcttgc 2940 tgaagaacct gtgggtgtct cagaagagac agcaagccag cttccctggt gaccgcctcc 3000 gtggcgtggt gtcccgcctc ttcccctaca gtaactacaa gctggagatg gttgtggtca 3060 atgggagagg tgatgggcct cgcagtgaga ccaaggagtt caccaccccg gaaggagtac 3120 ccagtgcccc taggcgtttc cgagtccggc agcccaacct ggagacaatc aacctggaat 3180 gggatcatcc tgagcatcca aatgggatca tgattggata cactctcaaa tatgtggcct 3240 ttaacgggac caaagtagga aagcagatag tggaaaactt ctctcccaat cagaccaagt 3300 tcacggtgca aagaacggac cccgtgtcac gctaccgctt taccctcagc gccaggacgc 3360 aggtgggctc tggggaagcc gtcacagagg agtcaccagc acccccgaat gaagctcctc 3420 ccacattgcc cccgactacc gtgggtgcga cgggcgctgt gagcagtacc gatgctactg 3480 ccattgctgc caccaccgaa gccacaacag tccccatcat cccaactgtc gcacctacca 3540 ccatggccac caccaccacc gtcgccacaa ctactacaac cactgctgcc gccaccacca 3600 ccacggagag tcctcccacc accacctccg ggactaagat acacgaatcc gcccctgatg 3660 agcagtccat atggaacgtc acggtgctcc ccaacagtaa atgggccaac atcacctgga 3720 agcacaattt cgggcccgga actgactttg tggttgagta catcgacagc aaccatacga 3780 aaaaaactgt cccagttaag gcccaggctc agcctataca gctgacagac ctctatcccg 3840 ggatgacata cacgttgcgg gtttattccc gggacaacga gggcatcagc agtaccgtca 3900 tcacctttat gaccagtaca gcttacacca acaaccaagc ggacatcgcc acccagggct 3960 ggttcattgg gcttatgtgc gccatcgccc tcctggtgct gatcctgctc atcgtctgtt 4020 tcatcaagag gagtcgcggc ggcaagtacc cagtacgaga aaagaaggat gttccccttg 4080 gccctgaaga ccccaaggaa gaggatggct catttgacta tagtgatgag gacaacaagc 4140 ccctgcaggg cagtcagaca tctctggacg gcaccatcaa gcagcaggag agtgacgaca 4200 gcctggtgga ctatggcgag ggtggcgagg gtcagttcaa tgaagacggc tCCCtCatCg 4260 gccagtacac ggtcaaaaag gacaaggagg aaacagaggg caacgaaagc tcagaggcca 4320 cgtcacctgt caatgctatc tactctctgg cctaacggag 4360 <210> 36 <211> 2434 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 284191CB1 <400> 36 ggaccgcagg ctgctaaaaa cagctccagc acccactcca aaccaggcct gaaacaatgt 60 cctccaccga gagaaacgta aaggacactt gatcacacaa tccctggaat aatatccagg 120 aaacacttgc tggagccact cgcagcaccc ttccctggca gcacacttgg ggacagcgag 180 gagatgagcg catctctgaa ttacaaatct ttttccaaag agcagcagac catggataac 240 ttagagaagc aactcatctg tcccatctgc ttagagatgt tcacgaaacc tgtggtgatt 300 ctcccttgtc agcacaacct gtgtaggaaa tgtgccagtg atattttcca ggcctctaac 360 ccgtatttgc ccacaagagg aggtaccacc atggcatcag ggggccgatt ccgctgccca 420 tcctgtagac atgaagtggt tttggataga catggggtat atggacttca gaggaacctg 480 ctggtggaaa atatcattga catctacaag caggagtcca ccaggccaga aaagaaatcc 540 gaccagccca tgtgcgagga acatgaagag gagcgcatca acatctactg tctgaactgc 600 gaagtaccca cctgctctct gtgcaaggtg tttggtgcac acaaagactg ccaggtggct 660 cccctcactc atgtgttcca gagacagaag tctgagctca gtgatggcat cgccatcctc 720 gtgggcagca acgatcgagt ccagggagtg atcagccagc tggaagacac ctgcaaaact 780 atcgaggaat gttgcagaaa acagaaacaa gagctttgtg agaagtttga ttacctgtat 840 ggcattttgg aggagaggaa gaatgaaatg acccaagtca ttacccgaac ccaagaggag 900 aaactggaac atgtccgtgc tctgatcaaa aagtattctg atcatttgga gaacgtctca 960 aagttggttg agtcaggaat tcagtttatg gatgagccag aaatggcagt gtttctgcag 1020 aatgccaaaa ccctgctaaa aaaaatctcg gaagcatcaa aggcatttca gatggagaaa 1080 atagaacatg gctatgagaa catgaaccac ttcacagtca acctcaatag agaagaaaag 1140 ataatacgtg aaattgactt ttacagagaa gatgaagatg aagaagaaga agaaggcgga 1200 gaaggagaaa aagaaggaga aggagaagtg ggaggagaag cagtagaagt ggaagaggta 1260 gaaaatgttc aaacagagtt tccaggagaa gatgaaaacc cagaaaaagc ttcagagctc 1320 tctcaggtgg agctgcaggc tgcccctggg gcacttccag tttcctctcc agagccacct 1380 ccagccctgc cacctgctgc ggatgcccct gtgacacaga ttggatttga ggctcctccc 1440 ctccagggac aggctgcagc tccagcgagt ggcagtggag ctgattctga gccagctcgc 1500 catatcttct ccttttcctg gttgaactcc ctaaatgaat gatattcatt ccaactgctg 1560 cccctctgtc tgcctggctg agatgcatgt gggcagcagg aagcccaagt gaaattaata 1620 ttatgcagat gatgaaaggg acctctgaac aggatttctg caaaaatagc cccaaactgc 1680 aattccatat gacttatcta acatcttggg gggaaagaat attttgagaa aatagttgca 1740 gaaagcactg gaaataataa acttgatctt atacaaatct tctattgtgt ggaaaatgtt 1800 gtgaagggtg tgtaggtgtg gtacatgtgt atgtcactaa caagtggcaa atggtgaaaa 1860 aagtggtcac tatgcttttg tctctcatag gcactgactt tttgttatta tattatggta 1920 gctttcattt cctttactct ttaacagtgc aggtggtcag tgaaaatcag tgtcaactca 1980 gaagtgactg atttatcaat acatggacaa aaagtaaatc attgaccaaa gctatgaaat 2040 gtttcacaaa gttttcctct tttgcataac agatgtcact ggatgtacat tcagaaatgt 2100 tctttgaatt tggtgacact ttcatggtcc agaaagctga aggcctgggc atctcttgtg 2160 acatttttct aatattagtt ttagattttc acgtattagg cactttagtt gaatcttcca 2220 gcaaaagctg tctactttct cttttattca ctgtggcacc aatctggtaa attgtagaac 2280 aattgcatgt gtttaaatat atatacaaac atatcacaca ttaaatatat atatatttaa 2340 atcatgcttt gttaatattt gtcccaccat aatgcctcct tcagaacata agtgtaactt 2400 tatatgaact cttaaataaa tgatgttttt aaaa ' 2434 <210> 37 <211> 2688 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2361681CB1 <400> 37 ggcagcggca gctggggctg cagcggcgcc gggctctaga gagccgcagg atcggccaga 60 gtgcggagct ggacacccgg gtcccagata ctacagacac ccggagaggt ggctccttcg 120 ccctgaagcc ttcctcggcc ccctacgcac tcgggcccct tccgcagagg attcgcagcg 180 tgagcgcccc gcagcccgct caggaccagc tcacaggact aaggaccaaa ggcatttctg 240 ggcactgaga tcctacctct ctgcctgcag ctatgagcag acgtgtggtt cggcaaagca 300 agttccgcca tgtgtttggg caggcagcaa aggccgacca ggcctacgag gacatccgtg 360 tgtccaaggt cacatgggac agctccttct gtgccgtcaa ccccaaattc ctggccatta 420 ttgtggaggc tggaggcggg ggtgccttca tcgtcctgcc tctggccaag acagggcgag 480 tggataagaa ctacccactg gtcactgggc acactgcccc tgtgctggat attgactggt 540 gtccacacaa tgacaacgtt atcgccagtg cctcagacga caccaccatc atggtgtggc 600 agattccaga ctataccccc atgcgcaaca ttacggaacc tatcatcaca cttgagggcc 660 actccaagcg tgtgggcatc ctctcctggc accctactgc caggaatgtc ctgctcagtg 720 caggtggtga caatgtgatc atcatctgga atgtgggcac cggggaggtg ctgctgagcc 780 tggatgatat gcacccagac gtcatccaca gtgtgtgctg gaacagcaac ggtagcctgc 840 tagccaccac ctgcaaggac aagaccttgc gcatcattga ccccagaaaa ggccaagtgg 900 tggcggagag gtttgcggcc cacgagggga tgaggcccat gcgggccgtc ttcacgcgcc 960 agggccatat cttcaccacg ggcttcaccc gcatgagcca gcgagagctg ggcctgtggg 1020 acccgaacaa cttcgaggag ccagtggcac tgcaggagat ggacacaagc aacggggtcc 1080 tattgccctt ttacgatccc gactccagca tcgtctacct gtgtggcaag ggcgacagca 1140 gcattcggta ctttgagatt accgacgagc cgcctttcgt gcactacctg aacacgttca 1200 gcagcaaaga gccgcagcgg ggcatgggtt tcatgcccaa aaggggactg gatgtcagca 1260 agtgtgagat cgcccggttc tacaagctac acgaaagaaa gtgtgaacct atcatcatga 1320 ctgtgccccg caagtcagac ctcttccagg acgatctgta cccggatacg ccaggcccgg 1380 agccggccct agaagcggac gaatggctat ccggccagga cgccgaaccc gtgctcattt 1440 cgctgaggga cggctatgtg ccccccaagc accgcgagct ccgggtcacg aagcgcaaca 1500 tcctggacgt gcgcccgccc tccggccccc gccgcagcca gtcggccagc gacgccccct 1560 tgtcgcagca caccctggag acgctgctgg aagagatcaa ggccctccgc gagcgggtgc 1620 aggcccagga gcagcgcatc acggctctgg agaacatgct gtgcgagctg gtggacggca 1680 cggactagcc ccgcgcgcca ggcaggcgga gcggggcggg gcgcacaagc tcggccccgc 1740 cccggctttt agtcccgaac tccggacccc gccttcttgg gctgggcccg ggggcgggac 1800 tggggaggga actccgcccc tcgcgggaga ccagaactct tggagcttag gggagaccca 1860 cgtcgctcca gcggaggctg gactgcgagc ctcgtctggg actcggctgg agctggccta 2920 gggaggcctg gggtaacctg gggggctcag caatggtgct gcacggcgag gtggtgtccc 1980 cctttgtcct ccgcccaggg cagggaaagt gcttagtatt agcgtgatgc ttggggttat 2040 tggagcctga gcttgacctc aaacgggtgg cgatttgatg ggtaccccca ggctggggaa 2100 aatgacagcg cttctcctaa tcagctcact ggattccatc accctgagcg gtaaaccaga 2160 tgggcgtcac cccagttctg cagacacata cacaacccgt ttgctgcaga gccggaccca 2220 gtggctacac ccacagcggt ctgtggtaga gaactctctt ccttctttcc accgacaggg 2280 gcgagggctg cttcctcgcg gcagcccccg cgaagaaatc tcgagagaac tggcatgagg 2340 agttaggttc atcacaaata cacacacact gcccccaacc ctctgccgtt gcctctctca 2400 gaaaaacaag acgtactgaa tgaaatattt tactaagcgt tcagtctgtg cctcctgcat 2460 gggtgggagt gaggggaacg agacccccag cctctgcaaa tgctaccccc aggctcctgg 2520 gagacctggc gatgcactcc tgggctcagg gtccatcagg cagcctctta ccctagagct 2580 ctctccactc tgaggttcag aaggacccca acccacaccg taggcgttcc ccccaagtaa 2640 agttaggtag caaaagcaaa aaaaaaaaaa aaaaaaaaaa aaaaaaaa 2688 <210> 38 <211> 4264 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1683662CB1 <400> 38 cgcgccgccc ggccgcctgc actgcgcgcg cgcccacccc gcgtgggagg cagcgggagg 60 ggcccggaga ggtgtggagc ggcgcggcgg gaggctccgt gggcggccac gggagacagc 120 gccggcggga gcgcgcctct cggcctttcc tCCgC(,aCCCC CgCgtCCCCa gccggccgct 180 ccgagaggac ccggaggagg caggtggctt tctagaagat gaccatagag gaccttccag 240 attttccatt agaaggaaat cctttgtttg gaagataccc atttatattt tctgcttctg 300 ataccccagt tatcttttcc atttctgcag caccaatgcc ttcagactgt gaattttctt 360 tctttgatcc taatgatgca tcatgccagg aaattctttt tgatcccaaa acttcagttt 420 cagaattatt tgccattttg agacagtggg ttcctcaggt ccaacaaaac attgacatta 480 ttggaaatga gattcttaag agaggttgca atgtgaatga tagagatgga ttgacagata 540 tgactctttt acattatacc tgcaaatctg gagctcatgg tattggtgat gtggaaacag 600 ctgtaaaatt tgcaactcag cttattgacc tcggagcaga cattagtttg cggagtcgct 660 ggacaaacat gaatgctttg cattatgctg cttattttga tgtccctgaa cttataagag 720 tgattttgaa aacatcgaaa ccaaaagatg tggatgccac ttgcagtgat tttaattttg 780 gaacagcttt gcatattgca gcatacaact tgtgtgcagg tgctgtgaag tgcctcttgg 840 agcagggagc aaatcctgca tttaggaatg acaaaggaca gatccctgct gatgttgttc 900 cagacccagt agatatgccg ttagagatgg ctgacgccgc agccactgct aaggaaatca 960 agcagatgct tctagatgcg gtgcctctgt catgtaacat ctcaaaggcc atgctcccaa 1020 attatgatca tgtcactggc aaggcaatgc ttacgtcact tggcctgaag ttgggggatc 1080 gtgttgttat tgcaggacag aaggttggta cattaagatt ttgtggaaca actgaatttg 1140 caagtgggca gtgggctggc attgaactgg atgaaccaga aggaaaaaat aatggaagtg 1200 ttggaaaagt ccagtacttt aaatgtgccc ccaagtatgg tatttttgca cctctttcaa 1260 agataagtaa agcaaaaggt cgaaggaaga atataacaca cactccttct acaaaagctg 1320 ctgtacctct catcaggtcc cagaaaattg acgtagctca tgtgacgtca aaagtaaata 1380 ctggattaat gacatcaaaa aaagatagtg cttctgagtc aacactttca ttgcctcctg 1440 gtgaagaact taaaactgtg acagagaaag atgttgccct gcttggatct gtcagcagct 1500 gctcctctac atcttctttg gaacacagac agagctaccc caagaaacag aatgcaatca 1560 gcagtaacaa gaagacaatg agcaaaagcc cttccctttc atccagagcc agtgctggtt 1620 tgaattcctc agcaacatct acagcaaata atagccgttg cgagggggaa ctccgcctcg 1680 gagagagagt gttagtggta ggacagagac tgggcaccat taggttcttt gggacaacaa 1740 acttcgctcc aggatattgg tatggtatag agcttgaaaa accccatggc aagaatgatg 1800 gttcagttgg aggtgtgcag tattttagct gttctccaag atatggaata tttgctcccc 1860 catccagggt gcaaagagta acagattccc tggataccct ttcagaaatt tcttcaaata 1920 aacagaacca ttcttatcct ggttttagga gaagttttag cacaacttct gcttcttccc 1980 aaaaggagat taacagaaga aatgcttttt ccaaatcgaa agctgctttg cgtcgcagtt 2040 ggagcagcac ccccaccgca ggtggcattg aagggagcgt gaagctgcac gaggggtctc 2100 aggtcctgct cacgagctcc aatgagatgg gtactgttag gtatgtgggc cccactgact 2160 ttgcttcagg tatctggctt ggacttgagc tccgaagcgc caagggaaaa aatgatgggt 2220 cagtgggtga caagcgctat ttcacctgta agccgaacca tggagtctta gttcgaccga 2280 gcagagtgac ctatcgggga attaatgggt caaaacttgt ggatgagaat tgttaagctt 2340 ctaaaatatt aaataagctc aaatatatat atttggtgta aataaagagt ccatggtaaa 2400 tggtttactt tatttagcca tattaaaatt ttgaaaatat agttatcttc ttaaaaacca 2460 ttataacaat tcagagagag ttctttacaa agccatgaat atgaactatg gggaatcatg 2520 gttcttttaa agcaattttc aaaataagta ccaattaaag ctttaggttc caagaagatt 2580 ctgggactca ggaagaaaaa gtgccatcag gtgaccagct gttgcatttc ttgcttattc 2640 tgttttgttt ttgcacatca taatggattt ttcttagtgc cctaattgtg aagggtttct 2700 ctagctttgg ttatgtgtaa tgttcacgtg accttttttt tgtcaatcat ttttggaatt 2760 tttctttctt tctgtgcttt attactaata agtccaatga gtgagtagta gctagatgac 2820 tagtatgtag ttttatattt tggtaaaatt atttgccctt tcagaaatgc ctcatctaaa 2880 gatacatgat aattttggag ttggaagggg ccttagaggc tctccagctc tgcttcttgc 2940 ccattgccaa atactgaaat ggaagcccgt cttacctggg gtcactaact ggttggttaa 3000 ctgagctaag aatagactgt gggtctcctc acttgtggcc cagtgctctt tctgctatac 3060 aaaatgtcta atctcagatt tttcttctgc tgcttgactg cttcatctgg atgaactaca 3120 aaaaacccat gattaaggtt tatgaattca agtaataatt agattttttt tgcacagact 3280 tacttaactt ccttattgga tatgtttgta acacataaac acaaagcact tttcaaacat 3240 gatgcacttt tatctttgtg aataatttac tgtcctttcc tcctgggata tgagaaacat 3300 tttaaaaaac gtatttaaca gaagagagca aataaagata tatcaggaag gatgtattag 3360 ttatttactt aaatgtttat aatatctgga ttttttttgt tttgttactc atagaactgg 3420 tgttgtttgc tgtttttatt tctctaattg ttgcagagtt ctgcctgtta caaagctaca 3480 gaactgtatt gtttttattt tccttcttga gcacatgtta acaaactaag cttcacatta 3540 gagtgatgtc ataatgtaaa atgtttgcat tgtggttagg tattgaagtt tatgtcctgt 3600 ctgtgtaaag attcatcttt tattgtaaat atttagactt taccacagaa atattggaac 3660 agtttgcttt ataagattaa aaagcatcct tcagaatgga gcttgccttg tgcttagaaa 3720 taatatgttg aactattttg caatatacta ttttaaatct aaattctgtc acttcgctgc 3780 ctttttaaaa tagtgtggta tttcaaatat tgctagagct attttcctga aatacatttg 3840 caaaataagg ctgctttgta atcaaggaat atttttattg attgaaggaa atgactgtac 3900 tgcgattcaa aagtaaactt attttattat acagattatt tcttaaaaac tctatttata 3960 ccttaacatg aaatccatga ccacaccaaa cttggttatt cataattttt cctgttaaat 4020 ataaaacact gtaagttaaa aacagtaatg ccaacattga atttattttt gaggtcaaag 4080 aaccagttgt tctctttata tttagatgag gatgattgag tccatatact atgtatgttt 4140 acatatacta tacatgcaca ttaggtgttt tcatttgtgt tttgcttatg aaatgtcatt 4200 taaagttcac ttcttgagca tcaataaaaa gggaagctgt gtggttttgg aaaaaaaaaa 4260 aagg 4264 <210> 39 <211> 3930 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3750444CB1 <400> 39 gttccaaggt cgaaaccgcc ggtgagatcg acctgcaggt ttcagacctg caatcctgaa 60 gcttcaggtg aaagacacat tggaattgtt tcaaccatca gcgacatcga taatgaagag 120 ttccacccac caccatgcca ggtgtccagc ttgcaccctc ccatctccca gtgggtgcgc 180 ccatgcacaa gtaccacttt gtgccaagcc gtggagccca acggcaagcc tgctggaggc 240 ccaggatgac ctgggggtga cacagaggat cctggatgag gcaaaacagc gccttcgtga 300 ggtggaggac ggcatcgcca caatgcaggc taagtaccgg gaatgcatta ccaagaagga 360 ggagctggag ctgaagtgtg agcagtgtga gcagcggctg ggccgagctg gcaaggtgcg 420 caccctcctc ctgcaaggcc tgcaagcggg cccggcccag acaggggcca gaaaggacca 480 gggcgccggt gggtcctggg gtggctgtcc acaccccctt cctggcaacc ccaggtgcca 540 cagtgggtag ggccagcccc aggcccctag cccagcctcc cagagcccac cccacggggc 600 tgcccctcca gctcatcaac gggctgtcgg atgagaaggt gcgctggcag gagacggtgg 660 agaacctgca gtacatgctc aacaacatct ccggcgatgt cctggtggcc gctggctttg 720 tggcctacct gggccccttc acgggccagt accgcacggt gctctacgac agctgggtca 780 agcagctcag gagccacaat gtcccacaca cctccgagcc cacgctaatc gggacgctgg 840 ggaaccctgt gaagatccga tcgtggcaga tcgctggcct ccccaacgac acactgtcag 900 tggagaacgg ggtcatcaac cagttttccc agcgctggac ccacttcatt gaccctcaga 960 gccaggccaa caaatggatc aagaacatgg agaaggacaa tgggctggat gtgttcaagt 1020 tgagtgaccg cgacttcctg cgcagcatgg agaacgccat ccgctttggc aagccatgtc 1080 tcctggagaa cgtgggcgag gagctagacc cagccctgga gccagtgctg ctcaagcaga 1140 cgtacaagca gcagggaaac acggtgctga agctggggga cacggtgatc ccctaccatg 1200 aggacttcag gatgtacatc accaccaagc tgcccaaccc acactacacg cccgagatct 1260 ccaccaaact caccctcatc aacttcaccc tgtcgcccag tggcctagag gaccagctac 1320 tgggccaggt agtggcagag gagcgacccg acctggagga ggccaagaac cagctgatta 1380 67!86 tcagtaatgc caagatgcgc caggagctga aggacattga ggaccagatc ctgtaccggc 1440 tcagctcctc cgagggcaac cctgtagatg acatggaact catcaaggtg ctggaagcct 1500 ccaagatgaa ggctgctgag atccaggcca aagtcaggat tgcagagcag acggagaagg 1560 acatcgacct gacgcgcatg gagtacatac ccgtggccat ccgcacccag atcctcttct 1620 tctgtgtgtc cgacctggcc aacgtggacc ccatgtacca gtactccctt gagtggtttc 1680 tcaacatctt cctctcgggc atcgccaact cagagagagc agacaacctg aagaagcgca 1740 tctccaacat caaccgctac ctgacctaca gcctctacag caacgtctgc cgcagcctct 1800 ttgagaagca caagctgatg tttgccttcc tgctgtgtgt tcgcatcatg atgaacgagg 1860 gcaaaatcaa ccagagtgag tggcgatacc tcctgtctgg gggctccatc tcgatcatga 1920 ctgagaatcc ggcaccggac tggctgtcag accgggcttg gcgagacatc ctagcactct 1980 cgaacctgcc aaccttttcc tccttctctt ccgacttcgt gaagcacctc tcagaattcc 2040 gggtcatctt cgacagcctt gagccccacc gggagccttt gcctggcatc tgggaccagt 2100 acctagacca gttccagaag ctgctagtcc tccgctgcct gcgtggggac aaggttacca 2160 acgccatgca ggactttgtg gccaccaacc tggagccacg cttcattgaa ccccagacag 2220 ccaatctgtc agtggtgttc aaagactcca actccaccac acccctcatc tttgtgctgt 2280 cacccggcac agaccctgct gccgacctct acaagtttgc cgaagaaatg aagttctcca 2340 aaaagctctc tgccatctcc ctgggccagg ggcagggccc tcgggcagaa gccatgatgc 2400 gcagctccat agagaggggc aaatgggtct tcttccagaa ctgccacctg gcaccaagct 2460 ggatgccagc cctagaacgc ctcatcgagc acatcaaccc cgacaaggta cacagggact 2520 tccgcctctg gctcaccagc ctgcccagca acaagttccc agtgtccatc ctgcagaacg 2580 gctccaagat gaccattgag ccgccacgcg gtgtcagggc caacctgctg aagtcctata 2640 gtagccttgg tgaagacttc ctcaactcct gccacaaggt gatggagttc aagtctctgc 2700 tgctgtctct gtgcttgttc catgggaacg ccctggagcg ccgtaagttt gggcccctgg 2760 gcttcaacat cccctatgag ttcacggatg gagatctgcg catctgcatc agccagctca 2820 agatgttcct ggacgaatat gatgacatcc cctacaaggt cctcaagtac acggcagggg 2880 agatcaatta cgggggccgt gtcactgatg actgggaccg gcgctgcatc atgaacatct 2940 tggaggactt ctacaaccct gacgtgctct cccctgagca cagctacagc gcctcgggca 3000 tctaccacca gatcccgcct acctacgacc tccacggcta cctctcctac atcaagagcc 3060 tcccactcaa tgatatgcct gagatctttg gcctgcatga caatgccaac atcacctttg 3120 cccagaacga gacgttcgcc ctcctgggca ccatcatcca gctgcaaccc aaatcatctt 3180 ctgcaggcag ccagggccgg gaggagatag tggaggacgt cacccaaaac attctgctca 3240 aggtgcctga gcctatcaac ttgcaatggg tgatggccaa gtacccagtg ctgtatgagg 3300 aatcaatgaa cacagtacta gtacaagagg tcattaggta caatcggctg ctgcaggtga 3360 tcacacagac actgcaagac ctactcaagg cactcaaggg gctggtagtg atgtcctctc 3420 agctggagct gatggctgcc agcctgtaca acaatactgt gcctgagctc tggagtgcca 3480 aggcctaccc atcgctcaag cctctgtcat catgggtcat ggacctgctg caacgcctgg 3540 actttctgca ggcctggatc caagatggca tcccagctgt cttctggatc agtggattct 3600 tcttccccca ggcatgtctt aacaggcact ctgcagaatt ttgcccgcaa atttgtcatc 3660 tccattgaca ccatctcctt tgatttcaag gtctgggcac agccagggcc aggtcaggtg 3720 acaggctagg gtacagccca gggaggagag gctctgaggc cacggttggt tggcagttgg 3780 gggaccccta agecagggca tggaaagacc caagecagaa gaggccatga gtcccaggaa 3840 cgggtctggg ctgggtccat cagaaatcca caggggcagg gcacagacca caggccatgg 3900 gctaaagtgg taggtacgtg atgatgggca 3930 <210> 40 <211> 5204 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5500608CB1 <400> 40 caccttcagc ccactcatct atcaccagtg gaagctgccc aggaactccg gaaatgcgca 60 ggcggcagga ggaggctatg cgaagactag cctcgcaggt ggttgcctat cactattgtc 120 aagcagataa tgcctacact tgcttggtgc cagaatttgt ccacaatgtt gctgccttgc 180 tctgccgctc acctcagctg acagcctatc gggagcagct tcttcgggaa cctcacctgc 240 agagcatgct gagccttcgt tcctgtgttc aagaccccat ggcctccttc cggaggggag 300 ttctggagcc actagaaaat ctccataaag agagaaaaga tcccagatga agatttcatc 360 attttaattg atggattaaa tgaagcagaa tttcacaaac cggattatgg ggatacaatt 420 gtatcgtttc tgagtaaaat gatcggaaag tttccttctt ggctcaaact aattgtaaca 480 gttaggacca gtttacagga aattaccaag ctgctgcctt tccataggat ttttttggat 540 cgactagaag agaatgaagc catagaccag gacctgcagg cttacatcct gcaccggata 600 cacagcagct cagagatcca gaataacatt tcacttaatg gcaaaatgga caatactaca 660 tttggcaaac ctcagttctc atctcaagac cctcagtcaa gggtcctatc tatatctgaa 720 acttacattt gacctcatag agaaaggcta tctagtgtta aagagctcta gctacaaagt 780 agttcctgtt tcgctctcag aggtttattt actccagtgc aatatgaagt tcccaaccca 840 gtcttccttt gaccgggtga tgcctctcct gaatgtggca gtggcctctc tccacccact 900 gactgatgag catatcttcc aggccatcaa tgctgggagc attgaaggca cactagaatg 960 ggaggatttt cagcagagaa tggagaacct ctccatgttc ctaatcaagc gcagagacat 1020 gactcgtatg tttgtacatc cttcttttcg agaatggctt atctggagag aagaaggaga 1080 gaaaaccaaa tttctctgtg atccgaggag tggtcacacg ttacttgcct tctggttttc 1140 ccgccaagag ggaaaactaa accgacagca gactattgaa ctgggacatc acatcctcaa 1200 agcacacatt tttaagggtt tgagtaaaaa agttggtgta tcatcctcca tcctccaagg 1260 tctctggatc tcttatagca cagaaggtct ttccatggca ctggcgtctt tacgaaatct 1320 ctacactcca aatataaagg tcagccgact gctgattttg ggaggtgcca atattaatta 1380 ccggacagag gttttaaata atgctccaat tctatgtgtt cagtcccatc ttggttacac 1440 agaaatggta gccctgctgc tggagttcgg ggccaacgtg gatgcctctt ctgaaagtgg 1500 cctgactccc ctgggatatg ctgcagcagc agggtacctg agcattgtgg tgctgctgtg 1560 caagaaacgg gccaaggtgg atcatttgga taagaacggg cagtgtgctt tggttcatgc 1620 tgcactccga ggtcatctgg aggttgtcaa gtttttgatt cagtgtgact ggacgatggc 1680 cggccagcag caaggagtat ttaagaagag ccatgccatc caacaggccc tcattgctgc 1740 agccagcatg ggttatactg agattgtctc ctacctactt gatcttccag aaaaagatga 1800 agaggaagta gagcgagcac agatcaacag ctttgacagt ctctggggag agacagccct 1860 aacagctgca gccggaaggg gcaaactgga ggtgtgccgt ttgctcttgg aacaaggggc 1920 ggcagtggcc cagccaaacc gccgaggagc agtgccacta ttcagcacag tgcgccaggg 1980 ccactggcag attgttgatc ttttactcac ccatggagct gatgtcaaca tggcagacaa 2040 gcagggccgc actcccctga tgatggctgc ttccgaaggc catctaggaa ccgtggactt 2100 tctgcttgca caaggtgcct ccattgctct tatggacaaa gaaggattga cagccctcag 2160 ctgggcttgt ttgaagggcc atctctcagt agtacgttct ctggtggata acggagctgc 2220 cacagaccat gctgacaaga atggccgtac cccactggat ctggcagctt tctatggcga 2280 tgctgaggtg gtccagttcc tggtagatca tggggccatg atcgagcacg ttgactacag 2340 tggaatgcgc cctttggata gggcagtggg gtgccggaac acttctgttg ttgtcactct 2400 tctgaagaaa ggagccaaga taggtccagc cacatgggcg atggccacct ccaagccaga 2460 catcatgatc atcctgttga gcaagctgat ggaagagggg gacatgtttt ataagaaagg 2520 taaagtaaag gaagctgccc agcgctacca gtacgccctg aagaagttcc ctagagaagg 2580 gtttggtgag gacttgaaaa ctttccggga actaaaggtg tctctcctcc tcaacctctc 2640 tcggtgtcgc aggaaaatga acgattttgg aatggcggag gaatttgcta ctaaggccct 2700 ggagctgaaa ccgaaatctt atgaagctta ctatgcgaga gcaagggcaa aacgcagcag 2760 cagacagttc gcagcagcct tagaggacct gaacgaggcc atcaagctgt gtcccaacaa 2820 ccgtgagatc cagagacttc tgctgagagt ggaagaagag tgtagacaga tgcagcagcc 2880 acagcagcca ccgccgccac cgcagcctca gcagcagttg ccggaagaag cagaacctga 2940 gccacagcat gaagacatat actctgtaca ggatatattc gaggaggagt acctggaaca 3000 ggatgttgaa aatgtttcca ttggcctcca gacagaggcc cggcccagcc aggggctccc 3060 ggtcatccag agcccaccct CCtCtCCCCC gcatcgggac tcagcctaca tctccagctc 3120 acctcttggc tctcatcagg tttttgactt ccggtccagt agttctgtag gctctcccac 3180 tagacagacc tatcagtcca cctcacctgc cctttctcca actcatcaga actcacatta 3240 CaggCCtagC CCaCC3CaCa CttCCCCggC tCatCaggga ggatcttacc gtttcagccc 3300 ccctcctgtg ggaggacagg gcaaagaata cccaagccct cccccttccc ctctccggag 3360 aggccctcag tatcgggcca gccctccagc tgaaagtatg agtgtctata gatcccagtc 3420 tggttcaccc gtgcgctatc agcaggaaac aagcgtcagt cagcttcctg gcagacccaa 3480 atctccatta tccaaaatgg cccagcggcc ctaccagatg cctcagctcc ctgtggcagt 3540 tccccagcaa gggctcaggc tacagcctgc caaggcccag attgtgagaa gtaaccagcc 3600 cagcccagcc gtccattcaa gcaccgtcat ccccacagga gcctatggcc aagtagccca 3660 ttcaatggcc agtaaatacc agtcttcaca aggagacata ggagtcagcc agagccggtt 3720 ggtttatcaa gggtcaattg ggggaatcgt aggggatgga aggccggtgc agcatgtcca 3780 agccagcctg agtgcaggcg ccatctgtca gcatggagga ttgaccaaag aggatcttcc 3840 acagcgacct tcctcagcat accgaggtgg cgtgagatac agccagacac cacagatcgg 3900 acgcagccag tcagcatcct attacccagt ctgtcactca aaactagatc tggagcgctc 3960 ctccagccaa ctaggttccc ctgatgtgtc gcatttaatc agaagaccta tcagtgtcaa 4020 ccctaacgaa atcaaaccgc acccgccaac tcccaggccg ttgctgcatt cccaaagtgt 4080 aggccttcgc ttctctccat ctagcaatag tatctcctcc acctccaacc taactccgac 4140 cttccggcca tcttcttcca tccagcaaat ggagatccca ctgaaacctg catatgagag 4200 gtcatgtgac gagctgtcgc cagtgtctcc aactcaagga ggttacccca gtgagcccac 4260 ccgatccagg accacaccat tcatggggat catagataaa acagcacgga ctcagcagta 4320 cccccacctc caccagcaga atcggacctg ggcagtgtca tctgtggaca ccgtcctcag 4380 tcccacgtct ccaggcaacc tgcctcagcc tgagtccttc agtccaccat catccatcag 4440 caacattgcc ttttataaca aaaccaacaa tgcacagaat ggccatttgc tggaggacga 4500 ttattacagc ccccatggga tgctggctaa cgggtctcgt ggagacctct tggagcgagt 4560 cagccaggcc tcctcctatc ccgacgtgaa ggtagctcgg actctacctg tggctcaggc 4620 ataccaggac aacctgtaca ggcagctgtc ccgagactct cggcaagggc agacatcccc 4680 tatcaaacca aagagaccgt tcgtggagtc taatgtttaa aagacgtttt gttggagtga 4740 gacccatatg ttttcactgc acattttcag gcttggtttc cacattcgag gtagttctct 4800 ggcttaattt ctcatgtagt ttctgtgtgg tgttcagagg tggcagccca catgctgaaa 4860 tcctttgcat gcagccgact gggaagcggc ctcccgggag ccaggacttc agtttctctt 4920 gtctgtgccc agccacatgc tctctccctc tcttcagatg ccaacgagga gattttcgtg 4980 ctgtgtgctt taacccaggg agatcagaca cactggtcag ctttttccag gagacaatcg 5040 ctttcactga tgttcttgtt gtgtaattgt ctttttcctt ttttaaaaaa taaggtgttc 5100 ttgttcgttt tcttctagaa actttagaaa gagtgcgatg cccctttgcc tttgcatcct 5160 tagccagtgt cacccacaca gccagccgca gcgcattctc atgc 5204 <210> 41 <211> 2271 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2962837CB1 <400> 41 ggcaaggtcc cggcgaggcc gccgcgagcc tgcgcgtcgc taagtccagg cctgctgcgt 60 ggggcttcgc gcgctcgcgg ggttgcggcc cgggcagggg gagggcccgg gtgctcggag 120 CCttCCCttC gctgccctcc tgCCCCCtCC CtgCttCtgC aagCgtgttt caatttgtac 180 aacgtgcata aaacatgaaa ttacccttgg ccacttccag gcgcgcagcc agcggctccc 240 tgCCCttCCC CtCCgggCCC tgagtaccgg ccccccacca aggaggagcc cgaggtctcc 300 gtcccggcgg cgatgctgcc ccgtcggcct ctggcgtggc ccgcgtggct gttgcggggt 360 gctccgggag ccgcgggttc ttggggtcgg ccggttggcc ccctggcccg cagaggctgc 420 tgctccgccc cggggacccc cgaggtgccg ctgacccggg agcgctaccc cgtgcggcgc 480 ttgccgttct ccacggtgtc taagcaggac ctggccgcct ttgagcgcat cgtgcccggc 540 ggggtcgtca cggacccgga agcgctgcag gctcccaacg tggactggtt gcggacgctg 600 cgaggctgta gcaaggtgct gctgaggcca cggacgtcgg aggaggtgtc ccacatcctc 660 aggcactgcc acgagaggaa cctggccgtg aacccacagg ggggcaacac aggcatggtg 720 ggtggcagcg tccccgtctt tgacgagatc atcctctcca ctgcccgcat gaaccgggtc 780 ctcagcttcc acagcgtgtc tggaattctg gtttgccagg cgggctgcgt cctggaggag 840 ctgagccggt atgtggagga acgggacttc atcatgccgc tggacttagg agccaagggc 900 agctgccaca tcgggggaaa cgtggcaacc aacgctggag gcctgcggtt tcttcgatat 960 ggctcactgc atgggactgt cctgggcctg gaagtggtgc tggccgacgg cactgtcctg 1020 gactgcctga cctccctgag gaaggacaac acgggctatg acctgaagca gctgttcatc 1080 gggtcggagg gcactttggg gatcatcacc acggtgtcca tcttgtgtcc acccaagccc 1140 agggctgtga acgtggcttt cctcggctgc ccaggctttg ctgaggttct gcagaccttc 1200 agcacctgca aggggatgct gggtgagatc ctgtctgcat tcgagttcat ggatgctgtg 1260 tgcatgcagc tggtcgggcg ccatctccac ctggccagcc cggtgcaaga gagtccgttt 1320 tacgtcctca tcgagacttc aggctccaac gcaggccatg acgctgagaa gctgggccac 1380 ttcctggagc acgcgctggg ctccggcctg gtgaccgatg ggaccatggc caccgaccag 1440 aggaaagtca agatgctgtg ggccctgagg gaaaggatca cagaggcgct gagccgggat 1500 ggctacgtgt acaagtacga cctctccctc cctgtggagc ggctctacga catcgtgact 1560 gacctgcgcg cccgcctcgg cccgcacgcc aagcacgtgg tgggctatgg ccaccttgga 1620 gatggtaacc tgcacctcaa tgtgacggcg gaggccttca gcccctcgct cctggctgcc 1680 ctggagcccc acgtgtacga gtggacggcc gggcagcagg gcagcgtcag cgcggagcac 1740 ggagtgggct tcaggaagag ggacgtcctg ggctacagca agccaccggg ggccctgcag 1800 ctcatgcagc agctcaaggc cctgctggac cccaagggca tcctcaaccc ctacaagacg 1860 ctgcccagcc aggcctgacg gccactcctg ctgctgccaa ggcccactgg gggtcggcgg 1920 gtggctctcg ggcgggggtg ttgcggtggc tctgagggat gagccggcag tgggcagggg 1980 accaggcacc tggttgaagg gactgggagc ccgcactggg gaactgccgg acgcatgtgc 2040 cctcggtgca gggagcatct ggcagagtgg ggggctgtgg caggcaccct cctttgcagg 2100 gcgaggtggg gcctctgcag ccatcctgga caggccgggg tgtgcggcag cttttgccca 2160 cgtggaagcg gggtgggtct cacttgcgtg gtggccctgt gccatcttgc ctgctgcggc 2220 tgggagcagg cgctgggtgt tggttctgct gttgtgctcg tcccgggatc g 2271 <210> 42 <211> 2270 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6961277CB1 <400> 42 cggctcgaga tttgccttcc tCCCtCCCgC atCtgagCtt gtCtCCaCCa gcaacatgag 60 ccgccaattc acctgcaagt cgggagctgc cgccaagggg ggcttcagtg gctgctcagc 120 tgtgctctca gggggcagct catcctcctt ccgggcaggg agcaaagggc tcagtggggg 180 gcttggcagc cggagcctct acagcctggg gggtgtccgg agcctcaatg tggccagtgg 240 cagcgggaag agtggaggct atggatttgg Ccggggccgg gccagtggct ttgctggaag 300 catgtttggc agtgtggccc tggggcctgt gtgcccaact gtatgcccac ctggaggcat 360 ccaccaggtt accatcaatg agagcctcct ggcccccctc aacgtggagc tggaccccaa 420 gatccagaaa gtgcgtgccc aggagcgaga gcagatcaag gctctgaaca acaagttcgc 480 ctccttcatc gacaaggtgc ggttcctgga gcagcagaac caggtactgg agaccaagtg 540 ggagctgctg cagcagctgg acctgaacaa ctgcaagaac aacctggagc ccatcctcga 600 gggctacatc agcaacctgc ggaagcagot ggagacgctg tctggggaca gggtgaggct 660 ggactcggag ctgaggaatg tgcgggacgt agtggaggac tacaagaaga ggtatgagga 720 ggaaatcaac aagcggacag cagcagagaa cgagtttgtg ctgctcaaga aggatgtgga 780 tgctgcttac gccaataagg tggaactgca ggccaaggtg gaatccatgg accaggagat 840 caagttcttc aggtgtctct ttgaagccga gatcactcag atccagtccc acatcagtga 900 catgtctgtc atcctgtcca tggacaacaa ccggaaccta gacctggaca gcatcattga 960 cgaagtccgc acccagtatg aggagattgc cttgaagagt aaggccgagg ctgaggccct 1020 gtaccagacc aagttccaag agcttcagct ggcagctggc aggcatgggg acgacctcaa 1080 aaacaccaag aatgaaatct cggagctcac tcggctcatc cagagaatcc gctcagagat 1140 cgagaacgtg aagaagcagg cttccaacct ggagacagcc atcgctgatg ctgagcagcg 1200 gggagacaac gccctgaagg atgcccgggc caagctggac gagctggagg gcgccctgca 1260 ccaggccaag gaggagctgg cgcggatgct gcgcgagtac caggagctca tgagcctgaa 1320 gctggccctg gacatggaga tcgccaccta tcgcaagcta ctggagagcg aggagtgcag 1380 gatgtcagga gaatttccct cccctgtcag catctccatc atcagcagca ccagtggcgg 1440 cagtgtctat ggcttccggc ccagcatggt cagcggtggc tatgtggcca acagcagcaa 1500 ctgcatctct ggagtgtgca gcgtgagagg cggggagggc aggagccggg gcagtgccaa 1560 cgattacaaa gacaccctgg ggaagggttc cagcctgagt gcaccctcca agaaaaccag 1620 tcggtagaga agactgcccc gggccccgcc tcattccatg acccggctct ggatcccaca 1680 ctgtacttcc cacagcccac tctcagctcc atctccaccc tgctggtcct gctcccatac 1740 aCCtggCaCt ggCCttggCC aCCCaCttCt CCCagCCtgt gtCttCCtga tcctgggaag 1800 gcctggatga ccaagcttgg tgaaattcct ccctgtacac accctattaa ctccttggct 1860 gtggtccccc agctacacca ccagcccagg tcctggctgc cagctttcct cctctgcccg 1920 gcctctagcg cagtcgctaa ctactctgct gggctccctg ggtctctgcc caaggccccg 1980 cacacactgg ggcctagcat agttcctgcc tatgccagga gctggctctg tgtttaagaa 2040 aaggaggact gaaggacaaa caaccaagag tggcccagtc cccaccccca catctagctc 2100 agtctcaaat ctgagtggga ccaagtgcaa ttcagggcct ttttctccac tcacctgcac 2160 ccagaagcag agaaaagcag gcactgttca cttttccttt attcttaatg gccttcctct 2220 gttgcaacct caataaacag cacaatctca aaaaaaaaaa aaaaaaagat 2270 <210> 43 <211> 2629 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> 2ncyte ID No: 56022622CB1 <400> 43 ggcccgctcg ggtcctccca ggaagtttga aaaaaaaaaa aaaaaagttt tatgggcgga 60 tggaaggggc cggggcagcg tcggggaaag gaagggccgg aggcgcggcg gcgggcggcc 120 gagaggggcg gcggcggcgg cggcggcggg gttcccgcgc cgcggagccc ggcccgagag 180 ccgcgtccac gttcctgcct CCtgCtCCCg CCgCCCtggg gcgccgccat gacgcccgat 240 ctgctcaact tcaagaaggg atggatgtcg atcttggacg agcctggaga gcctccctcc 300 ccctcgctca ccaccacctc tacttcgcag tggaagaaac attggtttgt gctgacagat 360 tcaagtctca aatattacag agactccact gctgaggagg cagatgagct ggatggtgag 420 atcgacctgc gttcctgcac ggatgtcact gagtacgcgg tgcagcgcaa ctatggcttc 480 cagatccaca ccaaggatgc tgtctatacc ttgtcggcca tgacctcagg catccggcgg 540 aactggatcg aggctctgag aaagaccgta cgtccaactt cagccccaga tgtcaccaag 600 ctctcggact ctaacaagga gaacgcgctg cacagctaca gcacccagaa gggccccctg 660 aaggcagggg agcagcgggc gggctctgag gtcatcagcc ggggtggccc tcggaaggcg 720 gacgggcagc gtcaggcctt ggactacgtg gagctctcgc cgctgaccca ggcttccccg 780 cagcgggccc gCdCCCCagC CCgCdCtCCt gaCCgCCtgg ccaagcagga ggagctggag 840 cgggacctgg cccagcgctc cgaggagcgg cgcaagtggt ttgaggccac agacagcagg 900 accccagagg tgcctgctgg tgaggggccg cgccggggcc tgggtgcccc cctgactgag 960 gaccagcaaa accggcttag tgaggagatc gagaagaagt ggcaggagct ggagaagctg 1020 cccctgcggg agaataagcg ggtgcccctc actgccctgc tcaaccaaag ccgcggagag 1080 cgccgagggc ccccaagtga cggccacgag gcactggaga aggaggaggc atgtgagcgc 1140 agcctggcag agatggagtc ctcgcaccag caggtgatgg aggagctgca gcggcaccac 1200 gagcgggagc tgcagcgcct gcagcaggag aaggagtggc tcctggctga ggagacggca 1260 gccacggcct cagccattga agccatgaag aaggcctacc aggaagagct gagccgagag 1320 ctgagcaaaa cacggagtct ccagcagggc ccggatggcc tccggaagca gcaccagtca 1380 gatgtggagg cactgaagcg agagctgcag gtgctatcgg agcagtactc gcagaagtgc 1440 ctggagattg gggcactcat gcggcaggct gaggagcgcg agcacacgct gcgccgctgc 1500 cagcaggagg gccaggagct gctgcgccac aaccaggagc tgcatggccg cctgtcagag 1560 gagatagacc agctgcgcgg cttcattgcc tcgcagggca tgggcaatgg ctgcgggcgc 1620 agcaacgagc ggagttcctg cgagctagag gtgctgcttc gcgtaaaaga aaacgaactc 1680 cagtacctaa agaaggaggt gcagtgcctc cgggacgagc tccagatgat gcagaaggac 1740 aagcgcttca cctcgggaaa gtaccaggac gtctatgtgg agctgagcca catcaagaca 1800 cggtctgagc gggagatcga gcagctgaag gagcacctgc gtcttgccat ggccgccctc 1860 caggagaagg agtcgatgcg caacagcctg gctgagtaga ggtcccgccc agctgcagac 2920 cctccaggct ggaggaccag ccgccctcct tccctcctgg atggaagtaa aaagccaagc 1980 tttCtCCCCa CCCtCtgtgg gCCaCa.Cgtg CaCttgCa.CC CaCCaCaCaC aCaCaCaCa.C 2040 acacacacac acacacagac acacagacac atacgcacac acgtgcacac atgtacacac 2100 ggatacacac acacacacac acactgcata tctgagcgcg cccctcgcac tgggtctcac 2160 cttgcacctt cttcaggatt ttatatgtga agagattttt atatagattt ttttcctttt 2220 tttccaaaac actttatact ttaaaaaaaa aaaaaaaaag caattcctgg tggctgtgtg 2280 CCtCCaaCCC tggtccccct ctgtctccag ccaccctctg cttgggcttc tgagctggtg 2340 gccctggccc agaggtctgg cggaggccca ggcagcagcc atggcggggt gtctctacag 2400 gggagaggcg ggagcctgcc accctcttcc tgccctacct CCtactaaca cttcctgccc 2460 catttggacc cgtaccatgg ggctcaggac agagggagct agcagctggc ctccatggcc 2520 ccacagcctc cttcgaggct gtgctgggtg cagaaccgcc agagccaccc aaaaggtgtt 2580 tctcttctgc tccctgaacc tcttaactta ataaaacgtt ccagcagct 2629 <210> 44 <211> 5062 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 542310CB1 <400> 44 gatgagagcc gcgccgcacc gctcatagcc gcacaggtgt acaggcagga ggaccgactt 60 CCCtCtCCCg ggCatCCtCC CtgggCtgCC gggacggcgt gcggcccgag gaggaggagg 120 aacgagggga gaaggcggag agcaggaacg cgaggaggag gacctggatc cgtttcctcc 180 ggccaggacc cgagcggccc cagccaccgc tacccgccgg cgctgtccgc tctccatcag 240 ccctcctgcg cccacccgcg accccgggct ctctgcgcgt cgggccgggg ccggagccgc 300 gcggccggag actatctggc ttcctggtga tgctcacgct ttgctaagtg ttggcggcca 360 tcgtggtttt cgcatcctgg ggacgaatcc tgagcttgcc agagacgggc ggcgcaaggt 420 ccgggctctg tttccctgtg agaagccgcc tcggcccacc gagatgtccc ggcaccatag 480 ccgcttcgaa agagattacc gggtgggctg ggaccgccgc gaatggagcg tcaacgggac 540 gcatgggacc accagcatct gcagtgtcac ctcgggggcc ggtggcggca cagccagcag 600 cctcagcgtc cggcccggcc tcctgccgct gcccgtggtg ccctcccggc tgcccacccc 660 ggctacagct cctgctccct gcaccaccgg cagcagcgag gccatcacca gcctcgtggc 720 cagctctgcg tctgcggtca ccaccaaggc tCCCggcatc tccaaagggg acagtcagtc 780 ccagggactg gcgaccagca tccggtgggg gcagacgcct atcaatcagt ccacaccctg 840 ggacactgat gagccaccct ccaaacagat gagagagagt gacaatccag gcacagggcc 900 atgggtgacc acggtggccg ccgggaacca gcccaccctg atcgcacact cctatggagt 960 ggcccagcct cccaccttca gcccggctgt gaacgtccag gccccggtca ttggggtgac 1020 cccctcactg cctccccacg tggggcccca gctcccgctg atgccaggcc actactcgct 1080 ccctcagccg ccctctcagc cactgagcag cgtggtggtc aacatgcctg cccaggccct 1140 gtatgccagc cctcagcccc tggccgtgtc cacactgccc ggtgtggggc aggtggcccg 1200 cccaggaccc accgctgtgg gcaacggcca catggcaggg cccctgctgc ctccaccgcc 1260 gccagcccag ccgtccgcca ctctccccag tggtgcccct gccaccaatg ggccccccac 1320 aaccgactcg gcccacgggc tgcagatgct gcggaccatt ggcgtgggga agtatgagtt 1380 caccgacccg gggcacccca gagaaatgtt gaaggaattg aaccagcaac gcagagcgaa 1440 agcgtttaca gacctgaaaa ttgttgttga aggcagagag tttgaagtcc accaaaatgt 1500 tctagcttcc tgcagcttgt atttcaagga cctgattcaa aggtccgtgc aagacagcgg 1560 ccagggcggc cgggagaagc tggagctcgt cctgtcgaac ctgcaggcag acgtcctgga 1620 gttgctgctg gagtttgtct acacgggctc cctggtcatc gactcggcca acgccaagac 1680 actgctggag gcggccagca agttccagtt ccacaccttc tgcaaagtct gcgtgtcctt 1740 tctcgagaag cagctgacgg ccagcaactg cctgggcgtg ctggccatgg ccgaggccat 1800 gcagtgcagc gagctctacc acatggccaa ggccttcgcg ctgcagatct tccccgaggt 1860 ggccgcccag gaggagatcc tcagcatctc caaggacgac ttcatcgcct acgtctccaa 1920 cgacagcctc aacaccaagg ctgaggagct ggtgtacgag acagtcatca agtggatcaa 1980 gaaggacccc gcgacacgca cacagtacgc ggctgagctc ctggccgtgg tccgcctccc 2040 cttcatccac cccagctacc tgctcaatgt ggttgacaat gaagagctga tcaagtcatc 2100 agaagcctgc cgggacctgg tgaacgaggc caaacgctac catatgctgc cccacgcccg 2160 ccaggagatg cagacgcccc gaacccggcc gcgcctctct gcaggtgtgg ctgaggtcat 2220 cgtcttggtt gggggccgtc agatggtggg gatgacccag cgctcgctgg tggccgtcac 2280 ctgctggaac ccgcagaaca acaagtggta ccccttggcc tcgctgccct tctatgaccg 2340 cgagttcttc agtgtagtga gtgcagggga caacatctac ctctcaggtg ggatggaatc 2400 aggggtgacg ctggctgatg tctggtgcta catgtccctg cttgataact ggaacctcgt 2460 ctccagaatg acagtccccc gctgtcggca caatagcctc gtctacgatg ggaagattta 2520 caccctcggg ggacttggcg tggcaggcaa cgtggaccac gtggagaggt acgacaccat 2580 caccaaccaa tgggaggcgg tggcccctct gcccaaggca gtacactctg ctgcagccac 2640 agtgtgtggc ggcaagatct acgtgtttgg tggggtgaac gaggcaggcc gagctgccgg 2700 cgtcctccag tcttacgttc ctcagaccaa cacgtggagc ttcatcgagt ccccaatgat 2760 tgacaacaag tatgcccccg ctgtcacgct caatggcttc gttttcatcc tgggcggggc 2820 ttatgccaga gccaccacca tctacgaccc tgagaaagga aacattaagg cgggcccaaa 2880 catgaaccac tctcgccagt tctgcagtgc tgtggtgctt gatggcaaga tttatgcaac 2940 tggaggtatt gtcagcagtg aagggcccgc gctgggcaac atggaggcct acgagcccac 3000 aaCCaaCaca tggaccctcc tCCCCCaCat gCCCtgCCCt gtgttcagac acggctgcgt 3060 cgtgataaag aaatatattc aaagcggctg acatcagcag aaagcccacg ataagactgt 3220 ggacaagtct ggtgaggcaa gtgccacgca atgataattt tccagcgaca ccaacaagag 3180 gccaacaaaa cacaatcaag gaactcactg cgctcaacat gttgaatatt ctctacattg 3240 aatgtagaaa atcatcctcg cctttggatg aaacggaggc accgcgcttg gagccgcagg 3300 aaccacgatc ccgccatggg gctggctgcc tcctgaacag gggcgctcgc tctgccaggt 3360 gcaatagagt ttcacgtatt tttcaactgg gagagagaag ctgttttttc cttcctgcag 3420 agcaagcttg atccctaaac aaccatagat cagttatctt atgacaacat taggcatcag 3480 gctctcttgg aataagatca aagtgtcctt atcactttga ttcctacttt tgttttttaa 3540 ccgatctaca ctttcagtgg ccgacagaaa acgagggaca atactgtgca tcacaaggcc 3600 taggaggctg ctggtcccca ctggggctga agagaagccc agctgcccac gcggagccag 3660 gggtggcagc tgtgggacag ccggggagca gggacagcgg tctgtccttc acaggttttt 3720 ctactgtgtt tttgctggag aaggacagtg attgcgctag ctttctctta cccggtatga 3780 attatttaga tttctgaggc attttcttga taaacaaaag gctattttta agtactgaga 3840 ggaggagcag gccacaagag ggataatgtt gtgggaattc ccaaagctct ttgtaggtag 3900 tgccagaggg gggcttttgc tctcattttt ctatgtgcag aatagaggat ctctcctggg 3960 gtgggcgatg cccccatttt atttttagaa aaagtaactc ccagacagcc ccataaaagc 4020 tgtgcccaag gaagaagagt ctgctctaga aggagcccgg ttctggctca ggacaccggc 4080 ccagctccct ccatgaggtc aagctgagga ccaggccagt gggaagggaa ggagggagaa 4140 ttagcgtcta taaagcacag gagactattt ttgatattca tagctatata ttaaggcacc 4200 tgccacaaga gctctcagga tggggacagc cttcttagtg gagccatggc agcaaggcct 4260 gagggcatga acagaaccac tcttcttgtc acatacgaac ctgagaaaag ggaagccagg 4320 agggaggtca caccatggct caaaagggaa aggccttccc acttgtcctt agcccctcaa 4380 acctcacacg gtcaacagtt tccattccag ggcaggagaa tgctgecgcc actgcgctgt 4440 tgagttgaag ttggtaccaa atacacattt accactttta tatctgggaa gtcaacttgc 4500 catcgtttca tgataacaac catttataag agaaaaagac aggacacgct ttccatcgtt 4560 cagtatttga tgacacaaaa ttccagttct aacgttgggc atcaacttct agcactacga 4620 gtgtggctcc cacttggaca agataccgag cttcgttatg cagtttttaa tattatttat 4680 tattttaaaa agtaataagc acaaaactac atacattgta tgtcatttaa agtatttatg 4740 tcaaacaggg tgcaagtgtg aacccaagga ctggagcaca aattcctaac tgcctggggc 4800 agggctaatg ttagcattgg tgtgcgtctg cctccaaagg aggttctagt tgtcagcgag 4860 actcaacaca gatgacattg aaattcgttt Ctctcctcat ctatcacact ggagcaaaac 4920 tggctatttc tgtgaatgat ataaaacagg gttctctgta atggtattgt acatagtata 4980 tgtttactgt taagttcttg ttatattata ataaatatat ttatagatct agacttggaa 5040 aaaaaaaaaa aaaaaaaagg gg 5062 <210> 45 <211> 1839 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1732825CB1 <400> 45 gtgacgacgg agaagagggc cgctgccgct gcagtggctc gtgggtgaga gcaagtgaag 60 accgccgcag catcaggggc ctggactcaa ctcctcccca gagtcggagg tgttgcgcca 120 tgcccggggt ggccaattca ggcccctcca cttcctctag ggagactgca aacccctgtt 180 ccaggaagaa ggtgcatttt ggcagcatac atgatgcagt acgagctgga gatgtaaagc 240 agctttcaga aatagtggta cgtggagcca gcattaatga acttgatgtt ctccataagt 300 ttaccccttt acattggcag cacattctgg aagtttggag tgtcttcatt ggctgctctg 360 gcatggagct gatatcacac acgtaacaac gagaggttgg acagcatctc acatagctgc 420 aatcaggggt caggatgctt gtgtacaggc tcttataatg aatggagcaa atctgacagc 480 ccaggatgac cggggatgca ctcctttaca tcttgctgca actcatggac attctttcac 540 tttacaaata atgctccgaa gtggagtgga tcccagtgtg actgataaga gagaatggag 600 acctgtgcat tatgcagctt ttcatgggcg gcttggctgc ttgcaacttc ttgttaaatg 660 gggttgtagc atagaagatg tggactacaa tggaaacctt ccagttcact tagcagccat 720 ggaaggccac cttcactgtt tcaaattcct agtcagtaga atgagcagtg cgacgcaagt 780 tttaaaagct ttcaatgata atggagaaaa tgtactggat ttggcccaga ggttcttcaa 840 gcagaacatt ttacagttta tccagggggc tgagtatgaa ggaaaagacc tagaggatca 900 ggaaacttta gcatttccag gtcatgtggc tgcctttaag ggtgatttgg ggatgcttaa 960 gaaattagtg gaagatggag taatcaatat taatgagcgt gctgataatg gatcaactcc 1020 tatgcataaa gctgctggac aaggccacat agagtgtttg cagtggttaa ttaaaatggg 1080 agcagacagt aatattacca a~aaagcagg ggagagacec agtgatgtgg caaagaggtt 1140 tgcccatttg gcagcagtga agctgttaga ggagctacag aaatatgata tagatgacga 1200 aaatgaaatt gatgaaaatg atgtgaaata ttttataaga catggtgttg agggaagcac 2260 tgatgccaag gatgatttat gtctgagtga cttggataaa acagatgcca gaatgagagc 1320 ttacaagaaa attgtagaat tgagacacct cctggaaatt gccgagagca actataaaca 1380 cttgggaggc ataacagaag aagatttaaa gcagaagaaa gaacagcttg agtctgaaaa 1440 gaccatcaaa gaactgcagg gccagctgga gtatgaacga ctacgtagag aaaaattaga 1500 atgtcagctt gatgaatatc gagcagaagt tgatcaactc agggaaacac tggaaaaaat 2560 tcaagtccca aactttgtgg ctatggaaga cagcgcttct tgtgagtcaa acaaagagaa 1620 gaggcgagta aaaaaaaagg tttcttctgg aggggtgttt gtgagaaggt actaatcagt 1680 gaaataacta aattgacctg ctagattttt ctctttcatt agaaaaattg atataaatgt 1740 gagtctatac aaactatctc agaattactc tgatatgctt ctgttccaat tctgatggca 1800 gaaatgttat attaaagaga tttagagatt ttttaaatg 1839 <210> 46 <211> 7557 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6170242CB1 attatttaga tttctgaggc attttcttga taaacaaaag gctattttta agtac <400> 46 ctggagacac atgaggctct gttcgaataa cctttctctc tgtgtgtttc tgtttgcagc 60 agcaaagtgg ggcaccaagg ccctgtgcta agcactcata atcctctggg ggtgctaccc 120 ctacaaacag cacccccacc atgtttaacc taatgaagaa agacaaggac aaagatggcg 180 ggcggaagga gaagaaggag aaaaaggaga aaaaggagcg gatgtcagcg gcagagcttc 240 ggagcctgga ggagatgagc ctgcgacgtg gcttcttcaa cctgaaccgc tcctccaagc 300 gtgaatccaa gacgcgcctg gaaatctcca accccatccc catcaaggtg gccagcggct 360 ctgacctgca cctgactgac attgactccg atagtaaccg gggcagcgtc atcctggact 420 cgggccacct aagtacagcc agctccagcg atgacctcaa gggtgaggag ggtagcttcc 480 gtggctcggt gctgcagcgg gcagccaagt tcggctcact ggccaagcag aactcacaga 540 tgattgtcaa gcgcttttcc ttctcccagc gtagccggga tgagagcgcc tcagaaacct 600 CgaCgCCCtC agagCaCtCt gCCgCCCCCt cgccacaggt ggaggtgagg actctagagg 660 gacagctggt gcagcatcct ggcccaggca tccctcgacc agggcaccga tcccgagccc 720 ctgagctagt gactaaaaag ttcccagtcg aCCtgCgCCt gCCCCCCgtg gtgCCCCtgC 780 ccccacctac cctccgggag ctggagctgc aacgacggcc cactggagac tttggcttct 840 ccctgcggcg cacaaccatg ctggatcggg gccccgaggg ccaggcctgt cggcgtgtgg 900 tccactttgc tgagcctggt gcaggcacca aggacctggc cctggggctg gtgccaggag 960 atcgactggt ggagattaat gggcacaatg tggagagcaa gtccagggat gagattgtgg 1020 agatgatccg gcagtcaggg gacagcgtgc ggctcaaggt gcagcccatt ccagagctca 1080 gcgagctcag caggagctgg ctgcggagcg gcgagggacc tcgcagggag ccatccgatg 1140 cgaaaacaga agaacagatt gcagcagaag aggcctggaa tgagacggag aaggtgtggc 1200 tggtccatag ggacggcttc tcactggcca gtcaactcaa atctgaggag ctcaacttgc 1260 ctgaggggaa ggtgcgtgtg aagctggacc acgatggggc catcctggat gtggatgagg 1320 atgacgttga gaaggctaat gctccctcct gcgaccgtct ggaggatctg gcctcactgg 1380 tgtacctcaa tgagtccagc gtcctgcaca ccttgcgcca gcgctatggc gctagcctgc 1440 tgcacacgta tgctggcccc agcctgctgg ttcttggccc ccgtggggcc cctgctgtgt 1500 actctgagaa ggtgatgcac atgttcaagg gttgtcggcg ggaggacatg gcaccccaca 1560 tctatgcagt ggcccagacc gcatacaggg cgatgctgat gagccgtcag gatcagtcaa 1620 tcatcctcct gggcagtagt ggcagtggca agaccaccag ctgccagcat ctggtgcagt 1680 acctggccac catcgcgggc atcagcggga acaaggtgtt ttctgtggag aagtggcagg 1740 ctctgtacac cctcctggaa gcctttggga acagccccac catcattaat ggcaatgcca 1800 cccgcttctc ccagatcctc tccctggact ttgaccaagc tggccaggtg gcctcagcct 1860 ccattcagac aatgcttctg gagaagctgc gtgtggctcg gcgcccagcc agtgaagcca 1920 cattcaacgt cttctactac ctgctggcct gtggggatgg caccctcagg acagagctcc 1980 acctcaacca cttggcagag aacaatgtgt ttgggattgt gccactggcc aagcctgagg 2040 aaaagcagaa ggcagctcag cagtttagta agctgcaggc ggccatgaag gtgctgggca 2100 tctcccccga tgaacagaag gcctgctggt tcattctggc tgccatctac cacctggggg 2160 ctgcgggagc caccaaagaa gctgctgaag ctgggcgcaa gcagtttgcc cgccatgagt 2220 gggcccagaa ggctgcgtac ctactgggct gcagcctgga ggagctgtcc tcagccatct 2280 tcaagcacca gcacaagggt ggcaccctgc agcgctccac ctccttccgc cagggccccg 2340 aggagagtgg cctgggagat gggacaggcc cgaaactgag tgcactggag tgccttgagg 2400 gcatggcggc cggcctctac agcgagctct tcacccttct cgtctccctg gtgaataggg 2460 ctctcaagtc cagccagcac tcactctgct ccatgatgat tgtcgacacc ccgggcttcc 2520 agaaccctga gcagggtggg tcagcccgcg gagcctcctt tgaggagctg tgccacaact 2580 acacccaaga ccggctgcag aggctcttcc acgagcgcac cttcgtgcag gagttggaaa 2640 gatacaagga ggagaacatc gagctggcgt ttgacgactt ggaacccccc acggatgact 2700 ctgtggctgc tgtggaccag gcctcccatc agtccctggt ccgctcgctg gcccgcacag 2760 acgaggcgag gggcctgctc tggctattgg aagaggaggc tctggtgcca ggggccagtg 2820 aggacaccct cctggagcgc cttttctcct attatggccc ccaggaaggt gacaaaaaag 2880 gccaaagccc ccttctgcac agcagcaaac cacaccactt tctcctgggc cacagccatg 2940 gcaccaactg ggtagagtac aatgtgactg gctggctgaa ctacaccaag cagaacccag 3000 ccacccagaa tgtcccccgg ctcctgcagg actcccagaa aaaaatcatc agcaacctgt 3060 ttctgggccg cgcaggcagt gccacggtgc tctctggctc catcgcgggc ctggagggcg 3120 gctcgcagct ggcactgcgc cgggccacca gcatgcggaa aacctttacc acaggcatgg 3180 cggctgtcaa aaagaagtca ctgtgcatcc agatgaagct acaggtggac gccctcatcg 3240 acaccatcaa gaagtcaaag ctgcattttg tgcactgctt cctgcctgta gctgagggct 3300 gggctgggga gccccgttcc gcctcctccc gccgagtcag cagcagcagt gagctggacc 3360 tgccctcggg agaccactgc gaggctgggc tcctgcagct cgacgtgccc ctgctccgca 3420 cccagctccg cggctcccgc ctgctcgatg ccatgcgcat gtaccgccaa ggttaccctg 3480 accacatggt gttttccgag ttccgccgcc gctttgatgt cctggccccg cacctgacca 3540 agaaacacgg gcgtaactac atcgtggtgg atgaaaggcg ggcagtggag gagctgctgg 3600 agtgcttgga tctggagaag agcagctgct gcatgggcct gagccgggtg ttcttccggg 3660 cgggcacctt ggcacggctg gaggagcagc gggatgaaca aaccagcagg aacctaaccc 3720 tgttccaagc agcctgcagg ggctacctgg cccgccagca cttcaagaag agaaagatcc 3780 aggacctggc cattcgctgt gtacagaaga acatcaagaa gaacaaaggg gtgaaggact 3840 ggccctggtg gaagcttttt accacagtga ggcccctcat cgaagtacag ctgtcagagg 3900 agcagatccg gaacaaagac gaggagatcc agcagctgcg gagcaagctc gagaaggcgg 3960 agaaggagag gaacgagctg cggctcaaca gtgaccggct ggagagccgg atctcagagc 4020 tgacatcgga gctgacagat gagcgtaaca caggagagtc cgcctcccag ctgctggacg 4080 cggagacagc agagaggctc cgggctgaga aggagatgaa ggaactgcag acccagtacg 4140 atgcactgaa gaagcagatg gaggttatgg aaatggaggt gatggaggcc cgtctcatcc 4200 gggcagcgga gatcaacggg gaagtggatg atgatgatgc aggtggcgag tggcggctga 4260 agtatgagcg ggctgtgcgg gaggtggact tcaccaagaa acggctccag caggagtttg 4320 aggacaagct ggaggtggag cagcagaaca agaggcagct ggaacggcgg ctcggggacc 4380 tgcaggcaga tagtgaggag agtcagcggg ctctgcagca gctcaagaag aagtgccagc 4440 gactgacggc tgagctgcaa gacaccaagc tgcacctgga gggccagcag gtccgcaacc 4500 acgaactgga gaagaagcag aggaggtttg acagtgagct ctcgcaggcg catgaggagg 4560 cccagcggga gaagctgcag cgggagaagc tgcagcggga gaaggacatg ctcctcgctg 4620 aggctttcag cctgaagcag caactagagg aaaaagacat ggacattgca gggttcaccc 4680 agaaggttgt gtctctagag gcagagctcc aggacatttc ttcccaagag tccaaggatg 4740 aggcttctct ggccaaggtc aagaaacagc tccgggacct ggaggccaaa gtcaaggatc 4800 aggaagaaga gctggatgag caggcaggga ccatccagat gctggaacag gccaagctgc 4860 gtctggagat ggagatggag cggatgagac agacccattc taaggagatg gagagtcggg 4920 atgaggaggt ggaggaggcc cggcagtcgt gtcagaagaa gttaaaacag atggaggtgc 4980 agctagagga agagtatgag gacaagcaga aggttctgcg agagaagcgg gagctggagg 5040 gcaagctcgc caccctcagc gaccaggtga accggcggga ctttgagtca gagaagcggc 5100 tgcggaagga cctgaagcgc accaaggccc tgctggcaga tgcccagctc atgctggacc 5160 acctgaagaa cagtgctccc agcaagcgag agattgccca gctcaagaac cagctggagg 5220 agtcagagtt cacctgtgcg gcagccgtga aagcacggaa agcaatggag gtggagatcg 5280 aagacctgca cctgcagatt gatgacatcg ccaaagccaa gacagcgctg gaggagcagc 5340 tgagccgcct tcagcgtgag aagaatgaga tccagaaccg gctggaggaa gatcaggaag 5400 acatgaacga attgatgaag aagcacaagg ctgccgtggc tcaggcttcc cgggacctgg 5460 ctcagataaa tgatctccaa gctcagctag aagaagccaa caaagagaag caggagctgc 5520 aggagaagct acaagccctc cagagccagg tggagttcct ggagcagtcc atggtggaca 5580 agtccctggt gagcaggcag gaagctaaga tacgggagct ggagacacgc ctggagtttg 5640 aaaggacgca agtgaaacgg ctggagagcc tggctagccg tctcaaggaa aacatggaga 5700 agctgactga ggagcgggat cagcgcattg cagccgagaa ccgggagaag gaacagaaca 5760 agcggctaca gaggcagctc cgggacacca aggaggagat gggcgagatt gccaggaagg 5820 aggccgaggc gagccgcaag aagcacgaac tggagatgga tctagaaagc ctggaggctg 5880 ctaaccagag cctgcaggct gacctaaagt tggcattcaa gcgcatcggg gacctgcagg 5940 ctgccattga ggatgagatg gagagtgatg agaatgagga cctcatcaac agtgagggag 6000 actctgatgt ggactcggag ctggaggacc gtgttgacgg ggtcaagtcc tggttgtcaa 6060 aaaacaaggg accttccaag gcagcttctg atgatggcag cttaaagagt tccagcccca 6120 ccagctactg gaagtccctt gcccctgatc ggtcagatga tgagcacgac cctctcgaca 6180 acacctccag accgcgatac tcccacagtt atctgagtga cagcgacaca gaggccaagc 6240 tgacggagac taacgcatag cccaggggag tggttggcag ccctctcacc ccagggcctg 6300 tggctgcctg ggcacctctc ccaggaagtg gtggggcacc ggtCtCCCCC aCCCgaCtgC 6360 tgatctgcat gggaaacacc ctgaccttct tctgtcaggg gcactttcca ggctatgggt 6420 gtctgatgtc tccacgtgga agaggtgggg gaaagaggag tttctgaaga gaactttttg 6480 C'tCCtCtgtC tcaaaatgcc agactettgg cttctaccct gtgtcaccgt gggcagtggc 6540 aggtggCCtg gcactgcatg gagccagcac gttgacctcc etctcagctc cctgctcagg 6600 gacggtggac aggttgccta ctgggacact ctaggttgct gggtccatgg ggaggattgg 6660 gggaggagaa gcagtgcctt ccctctcgtg tggggtgggg gctctctctt cttggtgcct 6720 gctgtctttc tactttttaa tttaaatacc caacctctcc atcacagctg catccctgag 6780 agtgggaggg ggctgtagtg gtagctgggg ctcccaagaa cgactcggga atgtcatctc 6840 catcttcacc cttcagagag cagtcctttc tctgtgcagc tggagacgct ggtgaggaga 6900 gccgggtcca ggttcttaag aatgaggtgc ggaggggctc tccggtgctg ctgggctggg 6960 ttgagcaagc ctacgcagac aagtgtgtgt gtggaccatc cgcacctcca gcccccaccc 7020 caccctcttt gtctcagcgt gttatgtgca atgacctatt taaggtaaac ccattccaac 7080 tacagcagtt cagggctgat ccaagcactg cctccctcct gctctgtcca ggtggtctgg 7140 accataaact caacttgaga gggaaggctt ggggttgagg acttgtgatc agaaaaactg 7200 aagatggaag ttttggccgg tgctcattag acatgagtcc tcactctgtg tcctgagccc 7260 gtgtcattct tccaacctcc ctgcccccac acacttatcc cagacacaac accatgtggt 7320 ctggaggtcc cagcccccac cctaaaaagg ttatccctga gaactccacc agacttggga 7380 gcccaagtgc agtgcctggt gctgctccca tctgccgccc cccttctctc ctgcaattgg 7440 tttgtactca ctgggctgtg ctctcccctg tttacccgat gtatggaaat aaaggccctt 7500 ttcctcctga aaaaaaaaaa aaaaaaaaaa gggcagccgc tcgcgatcta gaactag 7557 <210> 47 <211> 1118 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2287640CB1 <400> 47 cggacggtgg gcggacgcgt gggctggcag agcaaatatg actcagaaac cggctcctca 60 gggttgtaac attagatgat acaggcttgg gtcgttacac atgacaccag tgcctttgtt 120 tcattgggct gggctctctg gaaggtgtgc tgctgcctga gctgctggaa aagcactgac 280 aggtgtttgc tagaaaagca ctcctggagc ttgccaccag cttggacttc tagggacttt 240 cctctcagcc aggaaggatt ttgatattca tcagaaatac ctccagaaga ttcaaggagc 300 tgtagaggtg aagtaagcct gtgaaggacc agcatgggaa tcctatactc tgagcccatc 360 tgccaagcag cctatcagaa tgactttgga caagtgtggc ggtgggtgaa agaagacagc 420 agctatgcca acgttcaaga tggctttaat ggagacacgc ccctgatctg tgcttgcagg 480 cgagggcatg tgagaatcgt ttccttcctt ttaagaagaa atgctaatgt caacctcaaa 540 aaccagaaag agagaacctg cttgcattat gctgtgaaga aaaaatttac cttcattgat 600 tatctactaa ttatcctctt aatgcctgtt ctgcttattg ggtatttcct catggtatca 660 aagacaaagc agaatgaggc tcttgtacga atgctacttg atgctggcgt cgaagttaat 720 gctacagatt gttatggctg taccgcatta cattatgcct gtgaaatgaa aaaccagtct 780 cttatccctc tgctcttgga agcccgtgca gaccccacaa taaagaataa gcatggtgag 840 agctcactgg atattgcacg gagattaaaa ttttcccaga ttgaattaat gctaaggaaa 900 gcattgtaat ccttgtgacc acaccgatgg agatacagaa aaagttaacg actggattct 960 atcttcattt tagacttttg gtctgtgggc catttaacct ggatgccacc attttatggg 1020 gataatgatg cttaccatgg ttaatgtttt ggaagagctt tttatttata gcattgttta 1080 ctcagtcaag ttcaccatgg gggaagttgc actgcgat 1118 <210> 48 <211> 3340 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1990526CB1 <400> 48 ccacggggaa gctgcgaggc gcgggagcac ctgggggacc gcttgcagcg gggacgcgag 60 gacccgggct gggctttcct cacccgggta ccttgttatc ccataacttt ggtatcctga 120 aatctgagga ttccaccaag ataatatgat aagaactttc agtgatttgg ggccatatcc 180 tacttagact aatgtggaat ttccagattt cctgagagct tggtacagca gcacacactg 240 cttgctaatc agcacaggca ataatgccat ctctgcctca agaaggagtt attcagggac 300 cctctcccct ggatttgaat acagaattac cttatcaaag cacaatgaaa aggaaagtca 360 gaaagaagaa aaagaaggga accattacag caaatgttgc cgggacaaag tttgaaattg 420 ttcgtttagt aatagatgaa atgggattta tgaaaactcc agatgaggat gaaacaagta 480 atcttatatg gtgtgattct gctgttcagc aggagaaaat ttcagagctg caaaattatc 540 agaggatcaa ccattttcca ggaatggggg agatctgtag gaaggatttc ttagcaagaa 600 atatgaccaa aatgatcaag tctcggcctc tggattatac ctttgttcct cgaacttgga 660 tctttcctgc tgaatatact caattccaaa attatgtgaa agaattgaag aaaaaacgga 720 agcagaaaac ttttatagtg aaaccagcta atggtgcaat gggtcatggg atttctttga 780 taagaaatgg tgacaaactt ccatctcagg atcatttgat tgttcaagaa tacattgaaa 840 agcctttcct aatggaaggt tacaagtttg acttacgaat ttatattctg gttacatcgt 900 gtgatccact aaaaatattt ctctaccatg atgggcttgt gcgaatgggt acagagaagt 960 acattccacc taatgagtcc aatttgaccc agttatacat gcatctgaca aactactccg 1020 tgaacaagca taatgagcat tttgaacggg atgaaactga gaacaaaggc agcaaacgtt 1080 ccatcaaatg gtttacagaa ttccttcaag caaatcaaca tgatgttgct aagttttgga 1140 gtgatatttc agaattggtg gtaaagaccc tgattgtagc agaacctcat gtcctgcatg 1200 cctatcgaat gtgtagacct ggtcaacctc caggaagcga aagtgtctgc tttgaagtcc 1260 tgggatttga tattttgttg gatagaaaac taaagccatg gcttctggag attaaccgag 1320 ccccaagctt tggaactgat cagaaaatag actatgatgt aaaaagggga gtgctgctaa 1380 atgcgttgaa gctactaaac ataaggacca gtgacaaaag aagaaacttg gccaaacaaa 1440 aagctgaggc tcaaaggagg ctctatggtc aaaattcaat taaaaggctc ttaccaggct 1500 cctcagactg ggaacagcag agacaccagt tggagaggcg gaaagaagag ttgaaagaga 1560 gactcgctca agtacgaaag cagatctcac gagaagaaca tgaaaatcga catatgggga 1620 attatagacg aatttatcct cctgaagata aagcattact tgaaaagtat gaaaatttgt 1680 tagctgttgc ctttcagacc ttcctttcag gaagagcagc ttcattccag cgagagttga 1740 ataatccttt gaaaaggatg aaggaagaag atattttgga tcttctggag caatgtgaaa 1800 ttgatgatga aaagttgatg ggaaaaacta ccaagactcg aggaccaaag cctctgtgtt 1860 ctatgcctga gagtactgag ataatgaaaa gaccaaagta ctgcagcagt gacagcagtt 1920 atgatagtag cagcagctct tcagaatctg acgaaaatga aaaagaagag taccaaaata 1980 agaaaagaga aaagcaagtt acatataatc ttaaaccctc caaccactac aaattaattc 2040 aacaacccag ctccataaga cgttcagtca gctgccctcg gtccatctct gctcaatcac 2100 cttccagtgg ggacacccgc ccattttctg ctcaacaaat gatatctgtt tcacggccaa 2160 cttctgcatc tcggtcacat tccttaaacc gtgcttcctc ctacatgagg catctgcctc 2220 acagtaatga tgcctgctct accaactctc aagtgagtga gtctttgcgg caactgaaaa 2280 caaaagaaca agaagatgat ctaacaagtc agaccttatt tgttctcaaa gacatgaaga 2340 tccggtttcc aggaaagtca gatgcagaat cagaacttct gatagaagat atcattgata 2400 actggaagta tcataaaacc aaagtggctt catattggct cataaaattg gactctgtaa 2460 aacaacgaaa agttttggac atagtgaaaa caagtattcg tacagttctt ccacgcatct 2520 ggaaggtgcc tgatgttgaa gaagtaaatt tatatcggat tttcaaccgg gtttttaatc 2580 gcttactctg gagtcgtggc caagggctgt ggaactgttt ctgtgattca ggatcctctt 2640 gggagagtat attcaataaa agcccggagg tggtgactcc tttgcagctc cagtgttgcc 2700 agcgcctagt ggagctttgt aaacagtgcc tgctagtggt ttacaaatat gcaactgaca 2760 aaagaggatc actttcaggc attggtcctg actggggtaa ttccaggtat ttactaccag 2820 ggagcaccca attcttcttg agaacaccaa cctacaactt gaagtacaat tcacctggaa 2880 tgactcgctc caatgttttg tttacatcca gatatggcca tctgtgaaac agaagggaag 2940 atcgccattg gttatacata acagcaattc atttttttcc tctgaagttg aacatgcaaa 3000 gaacatgacc attaagtgct gttttatgta tataagacat atatatgtgt gaaaatatat 3060 gcacatatgc accctaataa catatattta ttatattaaa tgatatatga aagaagaatt 3120 agcagaaaat ggaatataag acttaacctt tctggaaacg taataaacca tgttaaaatt 3180 gtttaaaaaa aaaaaaataa aaaggggact aattaggccg ggggtgtttt gtcaatttta 3240 actaaacaaa aggggcggcc cgcctcaagg ggctcccagc tttacgtacg cgggtcattg 3300 ccggggttta ggcccccccc aagggggccc ccaaaatttc 3340 <210> 49 <211> 2230 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte TD No: 3742459CB1 <400> 49 gcgccctgga gcatgtgaca cgggaccggg tgcgaggggg ccagcgacgc cggccaccaa 60 cgagagtcca cctgaaggag tgcttcctct ggagaggcag ctccacgagg ccgcccgcca 120 gaacaatgtc ggcaggatgc aggagctgat tgggaggagg gttaacacca gggccagaaa 180 ccacgtgggc agggtggccc tgcactgggc tgcaggtgca gggcacgagc aggctgtgcg 240 tctgcttctg gagcacgagg ctgctgtgga cgaggaggat gcggtagggg ccctcacaga 300 ggcccttggt CCtCtCCttg CCttggCCCC agCCtCtgCt tCCCtCCtCt ctccagtgct 360 gtccttgtct gcaccacccg cctcctgcct ccaaattccc gcctgtttct aaagcaaagc 420 agtgcaactc tctttggatg ctcgggagcc tgctgatcat ttgggatgaa tgcgcttctc 480 ctgtctgcct ggttcggcca cttacgaatc ctccagatct tggtaaactc aggggccaag 540 atccactgtg agagcaagga tggcctgacc ttactgcact gcgcagccca aaaaggccat 600 gtgcctgtgc tggcgttcat aatggaggac ctggaggatg tggccctgga ccacgtagac 660 aagctgggga ggacggcgtt tcacagggca gctgagcacg ggcagctgga tgctctggac 720 ttcctcgtgg gctctggctg tgaccacaat gtcaaagaca aggaggggaa cactgccctt 780 catctggctg ctggtcgggg ccatatggct gtgctgcagc gacttgtgga catcgggctg 840 gacctggagg agcagaatgc ggaaggtctg actgccctgc attcggctgc tggaggatcc 900 caccctgact gtgtgcagct cctcctcagg gctgggagca ccgtgaatgc cctcacccag 960 aaaaacctaa gctgccttca ctatgcagcc ctcagtggct cggaggatgt gtctcgggtc 1020 ctcatccacg caggaggctg cgccaacgtg gttgatcatc agggtgcctc tcctctgcac 1080 ctcgctgtga ggcacaactt ccctgccttg gtccggctcc tcatcaactc cgacagtgac 1140 gtgaatgccg tggacaatag gcagcagacg ccccttcacc tggctgcaga gcacgcctgg 1200 caggacatag cagatatgct cctcattgct ggggttgact taaacctgag agataagcag 1260 ggaaaaaccg ccctggcagt ggctgtccgc agcaaccatg tcagcctggt ggacatgatc 1320 ataaaagctg atcgtttcta cagatgggag aaggaccacc ccagtgatcc ctctgggaag 1380 agcttgtcct ttaagcagga ccatcggcag gaaacacagc agctccgttc tgtgctgtgg 1440 cggctggcct ccaggtatct gcagccccgt gagtggaaga agctggcata ttcctgggag 1500 ttcacggagg cacatgtcga cgccatcgag caacagtgga caggcaccag gagctatcag 1560 gagcacggcc accgaatgct gctcatttgg ctgcatggcg tggccacggc tggtgagaac 1620 cccagcaaag cgctgttcga gggcctcgtg gccattggca ggagggacct ggctgaaaat 2680 atcaggaaga aagcaaacgc agccccgagt gcccccagga ggtgcacagc catgtaaccg 1740 gaggggccag accttcaggc acgtgggacc tcagcgtgtg gagccacctg aacagaagat 1800 gaccatcatt taagggcttt ttaaaaaatc actgttaaca gacctccagg tgattctgct 1860 gaaatgcaca gtcatgcaga gcccaggagg caaatgtttg tacactgatc tttttcatga 1920 ggatgggtcc aagggcctgt aatcccgtcc aacaggctgg agtacaatgg cgagatctca 1980 gCtCaCggCa aCCtCCgCCt cccgggttca°aatgattctc gtgcctcagc ctCCCgagta 2040 gctgggatta caggtgcatg ccatcacagc tggctaattt ttgtattttt agtagagatg 2100 gggtttggcc atgatggcca ggctggaaaa ttgaaacata atttcacatt attccttttt 2160 ccaccttaaa taataagagt agaatacttt ctgtgttttt atctatacac atgaataaat 2220 gctatggctt <210> 50 <211> 3257 <222> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7468507CB1 <400> 50 tccaacgcat agtgaccatg tctagagaag tcgaagagat tagaaggaaa ttgaagaaaa 60 attacggagc tttggacaac ttcaagtaca gtttgaaaaa gacaaacgat tggcattgga 120 agacttgcaa gctgctcaca gacgggagat acaagagcta ttgaagtcac agcaggatca 180 cagtgcctca gtaaataaag gccaggaaaa ggcagaggaa ctacacagaa tggaggtgga 240 gtccctaaac aaaatgcttg aggagctaag acttgaacgg aagaaactaa ttgaggatta 300 tgaaggcaag ttgaataaag ctcagtcctt ttatgaacgt gagcttgata ctttgaaaag 360 gtcacagctt tttacagcag aaagcctaca ggccagcaaa gaaaaggaag ctgatcttag 420 aaaagaattt cagggacaag aagcaatttt acgaaaaact ataggaaaat taaagacaga 480 gttacagatg gtacaggatg aagctggaag tcttcttgac aaatgccaaa agcttcagac 540 ggcacttgcc atagcagaga acaatgttca ggttcttcaa aaacagcttg atgatgccaa 600 ggagggagaa atggccctat taagcaagca caaagaagtg gaaagtgagc tagcagctgc 660 cagagaacgt ttacaacagc aagcttcaga tcttgtcctc aaagctagtc atattggaat 720 gcttcaagca actcaaatga cccaggaagt tacaattaaa gatttagaat cagaaaaatc 780 gagagtcaat gagagattat ctcaacttga agaggaaaga gcttttttgc gaagcaaaac 840 ccaaagtctg gatgaagagc agaagcaaca gattctagaa ctggagaaga aagtaaatga 900 agcaaagaga actcagcaag aatattatga aagggaactt aaaaacctgc aaagtagatt 960 ggaagaggag gtgactcaat taaacgaggc ccattctaag actttggaag aattagcttg 1020 gaagcaccat atggcaattg aagctgtcca cagtaatgca attagggata agaaaaaact 1080 gcaaatggat ttggaagaac aacataacaa agataaacta aacctggaag aggataaaaa 1140 tcagcttcaa caagagctag aaaacctaaa ggaagtactg gaagacaagt tgaatacagc 1200 caatcaagag attggccacc tccaagatat ggtaaggaaa agtgaacaag gtcttggctc 1260 tgcagaagga cttattgcta gtcttcagga ctcccaggaa aggcttcaga atgagcttga 1320 cttgactaaa gacagcctaa aggagaccaa ggatgctcta ttaaatgtgg agggtgagct 1380 agaacaagaa aggcaacagc atgaagaaac aattgctgcc atgaaagaag aagagaagct 1440 caaagtggac aaaatggccc atgacttaga aattaagtgg actgaaaatc ttagacaaga 1500 gtgttctaaa cttcgtgaag agttaaggct tcaacatgaa gaggataaga agtcagcaat 1560 gtctcaactt ttgcagttga aagatcgaga gaaaaatgca gcaagagatt catggcagaa 1620 gaaagtagaa gatctcttaa accagatttc cttgctgaaa cagaatctgg agatacagct 1680 ttcccagtct cagacttctt tgcaacaact gcaagcccag tttacgcaag aacgacagcg 1740 gcttacgcaa gagcttgaag aattagagga gcaacatcag caaagacaca aatcattaaa 1800 agaagcacat gtccttgcat ttcaaactat ggaagaggaa aaggaaaagg agcaaagagc 1860 tcttgaaaat catttacaac agaagcattc tgcagagctt caatcactaa aagatgcaca 1920 cagagagtca atggagggct tccggataga aatggaacag gaacttcaga ctcttcggtt 1980 tgaattagaa gatgaaggaa aggctatgct tgcttccttg cgctcagaac tcaaccatca 2040 acatgcagct gcaattgatt tgttacggca taatcatcat caagaattgg cagctgctaa 2100 aatggaatta gagagaagca tagacatcag cagaagacag agtaaggagc acatatgtag 2160 aattacagat.ctacaagagg aattaagaca cagagagcat cacatctctg aattggataa 2220 ggaggttcag caccttcatg agaatataag tgccctaacc aaagaactgg aatttaaggg 2280 gaaagaaatt ctcagaatac gaagtgaatc taaccaacag ataaggttgc atgaacaaga 2340 tttaaacaag agacttgaaa aagagttgga tgtcatgaca gcagaccacc tcagagagaa 2400 aaatatcatg cgggcagatt ttaataagac taacgagcta ctcaaggaaa taaatgccgc 2460 tttacaagtg tcattagaag aaatggaaga aaaatatcta atgagagaat caaaaccaga 2520 agatatacag atgattacag aattaaaagc catgcttaca gaaagagacc agatcataaa 2580 gaaactaatt gaggataata agttttatca gctggaatta gtcaatcgag aaactaactt 2640 caacaaagtg tttaactcaa gtcctactgt tggtgttatt aatccattgg ctaagcaaaa 2700 gaagaagaat gataaatcac caacaaacag gtttgtgagt gttcccaatc taagtgctct 2760 ggaatctggt ggagtgggca atggacatcc taaccgcctg gatcccattc ctaattctcc 2820 agtccacgat attgagttca acagcagcaa accacttcca cagccagtgc cacctaaagg 2880 gcccaagaca tttttgagtc ctgctcagag tgaagcttct ccagtggctt ctccagatcc 2940 ccagcgccag gagtggtttg cccggtactt cacattctga aagaattgtg ttggcacagc 3000 tctgtataga ctgttactaa gagcatgact ttatacagat tgttatgtaa ataggctttc 3060 ctatgtcaaa cactgtgaat gagaaagtat ttgtctctcc aacttgaaaa tgcactgtat 3120 ttcctgtgat atttattgga atcattctat aaggtactat attatgtgtg taattataac 3180 tgttattttt atttgagatg gaagagtctt taacctttgt aattactgca taataaattt 3240 tgttagaatc aaaaaaa 3257 <210> 51 <211> 2031 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3049682CB1 <400> 51 cagcttttca gcagcagaca ctccacccca aagcctgcag aagggatttt gtgaagaggg 60 tcaccaggct gagcctcggc cagaacccgt ctacagagga ccctcagcca gagcagaaag 120 ctcctgagcc agctcccttg gatggactcc cagaggcctg agcccagaga ggaggaggag 180 gaggaacagg aactgcggtg gatggagctg gactccgaag aggccctggg aaccaggaca 240 gaggggccta gtgttgtcca gggctggggg cacctgctcc aggccgtgtg gaggggccct 300 gcaggcctgg tgacgcagct gctgcggcaa ggtgccagcg tggaggagag.ggaccacgca 360 ggccggaccc cgctccacct ggccgtgctg cggggccacg cgcccctggt gcgtctcctg 420 ctgcagcgag gggccccggt gggcgcggtg gaccgggcgg ggcgcaccgc gctgcacgag 480 gccgcctggc acggacactc gcgggtggcc gagctgctgc tgcagcgcgg ggcctcggcg 540 gcggctcgct ccgggacggg cctcacgccg ctgcactggg ccgctgccct gggccacacg 600 ctgctggccg cgcgcctgct ggaggctccg ggcccgggac ccgcggcagc ggaggcggag 660 gacgcgcgcg gctggacggc ggcgcactgg gcggccgcgg gcgggcggct ggcggtgctg 720 gagctgctgg cggccggcgg cgcgggcctg gacggcgccc tgctcgtggc tgccgctgcg 780 gggcgcgggg cggcgctgcg cttcctcctg gcgcgcgggg cgcgggtgga cgcccgggat 840 ggcgcggggg ccacagcgct gggtctggcg gccgccctag gccgctccca ggacattgag 900 gtgctgctgg gccacggggc agacccaggc atcagggaca ggcatggccg ctctgcgctg 960 cacagggctg ccgcccgagg acacctgctt gccgtccagt tgctggtcac ccagggggcc 1020 gaggtggatg CgCgggaCaC CCtgggCCtC aCaCCCCtgC atCaCCJCCtC tcgggaaggc 1080 cacgtggagg ttgccggctg cctgctggac aggggtgccc aggtggatgc taccggctgg 1140 ctccgaaaga cccccctaca cctggctgca gagcgagggc atgggcctac cgtggggctt 1200 ctgctgagcc gaggggccag ccccaetctg cggacgcagt gggccgaggt ggcccagatg 1260 cctgaggggg acctgcccca ggcgctgcct gaacttggag ggggggagaa ggagtgtgag 1320 ggcatagagt ccacgggctg agccagacag caggctccag gctccaccgc cccagtgatt 1380 tccaggctct ctggctgagg ctgcctgcct ggaggggaca tcagggaaga ggcttccgga~1440 ggaggggatg ggagaaagta ggggatgtgg cttgagctgc agtcacaggc cttggctgga 1500 ccagggatgg cccccagctc ccaggagggc ccactgaccc tgcagctcca gccttctcca 1560 tacttcaaca aagaatgagt tgtggcaatg agggaagaga gaccctctca tagtgtttta 1620 tactcagtac ctgttttaag aaaaaacaac aaggaagtaa aaccaaagac aggcaggcag 1680 cctggcgcta ggcccgaaac caggcctgcg cctgcctggc ctaaacccag tagttgaaaa 1740 tcaattcata acttagaaac cgatgttatt catagattcc agacattgta tagaagaaca 1800 tttgtgaaac tccctgccgt gttctgtttc tctctgaccg ccggtgcatg cagcccctgt 1860 cacgtaccgc ctgcttgctc aaatcaatga cgaccctttc atgtgaaatc ttcggtgttg 1920 tgagccctta aaagggacag aaattgtgca cttggggagc tcggatttta aggcagtagc 1980 ttgccgatgc tcccagctga ataaagccct tccttctaaa aaaaaaaaaa a 2031 <210> 52 <211> 2576 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 914468CB1 <400> 52 tacgtattga aataaaaaaa aaaaagaaga agaacaaatg attcaatgga aaggaatgaa 60 tgaaattcct gagctgaaaa ctgcaagatg ggtattaatc aggacagaaa ggtgttccac 120 gcacagggaa cagaatatgc aaaagcctaa atcctaaatg tgggaagcag cctcacctct 180 ctgcaaccag ttctttgtct cataatctgc agctctgtgt ctatccctgt ctttccaggc 240 tcagcctcac tgttctccat ctctccgcag gcaccggcgc cccttcgtgg cggcacagaa 300 gaaccgctcc cgggcggcgt cgggtggggc agcgctggcc agtcctggcc cggggaccgg 360 atcaggggcc ccagctgggt ctggaggcaa ggagcgctca gaaaacttgt ctttgcggcg 420 cagcgtgtcg gagcttagcc ttcaggggcg gcggcggcgg cagcaggagc ggagacagca 480 ggcacttagc atggccccag gggcagccga cgcccaaatc ggaactgcag accccgggga 540 cttcgatcag ttgactcagt gcctcatcca ggCCCCCagC aaCCJCCCCt acttcctgct 600 gctccagggc taccaggacg cccaggactt tgtggtgtat gtgatgacgc gagagcagca 660 cgtgtttggg cgaggtggga actcgtctgg ccgcgggggg tccccggctc cctatgtgga 720 caccttcctc aacgccccgg acatcctgcc gcgtcactgc acagtgcgcg cgggccctga 780 gcacccggcc atggtgcgcc cgtcccgggg cgccccagtc acgcacaacg ggtgcctcct 840 gctgcgggag gctgagctgc acccgggcga cctcctgggg ctgggcgagc acttcctgtt 900 catgtacaag gacccccgca ctgggggctc ggggcctgcg aggccgccgt ggctgcccgc 960 gcgccccggg gccacgccgc caggccctgg ctgggccttc tcctgtcgcc tgtgcggccg 1020 cggcctgcag gagcgcggcg aggcactggc cgcctacctg gacggccgtg agccagtcct 1080 gcgcttccgg ccgcgcgagg aggaggcgct gctgggcgag atcgtgcgcg ccgcagccgc 1140 cggctcggga gaCCtgCCgC CCCtCgggCC CgCCaCCjCtg ctggcgctgt gcgtgcagca 1200 ttccgcccgt gagctggagc tgggccacct gccacgactg ctgggctgcc tggcccggct 1260 catcaaggag gccgtctggg aaaagattaa ggaaattgga gaccgtcagc cagaaaacca 1320 ccctgagggg gtccccgagg tgcccctgac tcctgaagct gtgtctgtgg agctgcggcc 1380 actcatgctg tggatggcca acaccacgga gctgcttagc tttgtgcagg agaaggtgct 1440 ggaaatggag aaggaggctg accaagagga cccacagctc tgcaatgact tggaattatg 1500 tgatgaggcc atggccctcc tggatgaggt catcatgtgt accttccagc agtctgtcta 1560 ctacctcacc aagactctct attcaacgct gcctgctctc ctggatagta accctttcac 1620 agctggtgca gagctgccgg ggcctggcgc ggagctgggg gccatgcctc caggattgag 1680 acctaccctg ggcgtgttcc aggcagcctt ggagctgacc agccagtgcg agctgcaccc 1740 tgacctcgtg tctcagactt ttggctactt gttcttcttc tccaacgcat cccttctcaa 1800 ctcgctgatg gaacgaggtc aaggccggcc tttctatcaa tggtcccgag ctgttcaaat 1860 ccgaaccaac ctggacctcg tcttggactg gctacaggga gctgggctgg gcgacattgc 1920 cactgagttc ttccggaaac tctccatggc tgtgaacctg ctctgtgtgc cccgcacttc 1980 cctgctcaag gcttcatgga gcagcctaag aaccgaccac cccaccttga cccccgccca 2040 gctgcaccat ctgctcagcc actatcagct gggccctggc cgcgggccgc cagccgcgtg 2100 ggaccctccc cctgcagagc gggaggctgt ggacacaggg gacatcttcg aaagcttctc 2160 ctcgcacccg cccctcatcc tccccctggg gagctcgcgc ctgcgcctca ctggtccagt 2220 gacggacgat gccttgcacc gtgaactccg taggctccgc cgcctcctct gggatcttga 2280 gcagcaggag ctgccagcca attatcgcca tgggcctccc gtggccacgt ctccttgaga 2340 accaatacca aacgagcgcg cgaaccttga aatgtcacgg gcttctacgg acaggagccc 2400 gcctgagcgc aaagctttct gggagttgta gttcttatcc cgcgtggaat gttgggagat 2460 tgagttttcg ggaagtagcg gatgggacgg tgggagcatg ggcttaggat gtgaatgcca 2520 gggagcaata aaggtatccg tggtatcggc aaaaaaaaaa aaaaaaaaaa aaaaaa 2576 <210> 53 <211> 1534 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2673631CB1 <400> 53 gactgggggg tgtgaggaac aggggggacc atggacttca tcagcattca gcagttggta 60 agtggagaaa gagttgaagg gaaagtgttg ggatttggac atggagttcc tgaccctgga 120 gcctggccta gtgactggag gaggggcccc caagaggctg tggcccggga gaagctgaaa 180 ttggaagaag agaagaagaa gaaacttgaa agatttaaca gtaccagatt taatctggat 240 aacctggctg acttggaaaa cttggttcaa agacggaaaa agcgactgag acacagagtc 300 ccccccagga aacctgagcc cctggttaag ccgcagtccc aggcccaggt ggagcctgtg 360 ggcctggaga tgttcctgaa ggcagctgct gagaaccagg agtacctgat tgacaagtac 420 ttgacagacg gaggggaccc caatgcccat gacaagctcc accgcaccgc cttgcactgg 480 gcctgtctga agggtcacag ccagctggtg aacaagctgc tggtggcagg tgccacagtg 540 gacgcgcgag acttgctgga caggacacct gtgttctggg cctgccgcgg aggacatctg 600 gtcatcctca aacagctgct taaccaggga gcccgggtca atgcccggga caagatcggg 660 agcaccccec tgcacgtggc agtgcgcacc cggcaccccg actgcctgga gcacctcatc 720 gagtgtggcg cccacctgaa cgcacaggat aaggaagggg acacggctct gcacgaggcc 780 gtgcggcacg gcagctacaa agccatgaag ctactgctgc tctatggggc cgagctgggg 840 gtgcggaacg cggcctccgt gaccccggtg cagctggctc gagactggca gcgcggcatc 900 cgggaggccc tgcaggccca cgtggcgcat ccccgcaccc ggtgctgacc gcagcaccgc 960 CCCCCCJCCgC gCCtttCgCa CtgCCaCCat tccatcctgt gccccgcccc cgcgtctgca 1020 cctctgtggt tcctgccctc agccctggtt cctccctctc tggcctgtgc cgcctcagca 1080 gccctggcag aactgaagag cggcaccggg cccagcaggc aaagagagag gcctccctgg 1140 cttcgagtgt caggggagcc gcgttccctc ccagggctgg agcagaggac cacaaggcag 1200 cagaaagcgc gggtccagat gagggccagg aaggggagga gagtgagggc caagaacgag 1260.
ccttaaggga gcagtcccaa gctggagcca cccagggctg ggtctgggag tcctcagtgt 1320 ccacttgtcc cagaggatcc acctggttca tgaaccctcc ctcactgctc tctgcacatc 1380 acggccacac agcacctgca gggaggctgt ggggaggtgt ggagcaggtg caacaggcag 1440 ctactctcct gggggccaca cggcgggaga gaggattcga tgcagcatga cgatcccttc 1500 ctcccaggca tgacctcttc tcagaacaca gggc 1534 <210> 54 <211> 5633 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2755454CB1 <400> 54 gCggagaggg aagaatatgg ccgccgggtg tggtgagggc gacgcgcttg cagtcgccgt 60 ctcttgcttc cccgtcctct gacatcgcct gcagccgagc gggcccgttc cgccggagct 120 gaggaccagg tattcaaata aagttaattg cagctttctg tgaaaatgtc agttttgata 280 tcacagagcg tcataaatta tgtagaggaa gaaaacattc ctgctctgaa agctcttctt 240 gaaaaatgca aagatgtaga tgagagaaat gagtgtggcc agactccact gatgatagct 300 gccgaacaag gcaatctgga aatagtgaag gaattaatta agaatggagc taactgcaat 360 ctggaagatt 'tggataattg gacagcactt atatctgcat cgaaagaagg gcatgtgcac 420 atcgtagagg aactactgaa atgtggggtt aacttggagc accgtgatat gggaggatgg 480 acagctctta tgtgggcatg ttacaaaggc cgtactgacg tagtagagtt gcttctttct 540 catggtgcca atccaagtgt cactggtctg cagtacagtg tttacccaat catttgggca 600 gcagggagag gccatgcaga tatagttcat cttttactgc aaaatggtgc taaagtcaac 660 tgctctgata agtatggaac caccccttta gtttgggctg cacgaaaggg tcatttggaa 720 tgtgtgaaac atttattggc catgggagct gatgtggatc aagaaggagc taattcaatg 780 actgcactta ttgtggcagt gaaaggaggt tacacacagt cagtaaaaga aattttgaag 840 aggaatccaa atgtaaactt aacagataaa gatggaaata cagctttgat gattgcatca 900 aaggagggac atacggagat tgtgcaggat ctgctcgacg ctggaacata tgtgaacata 960 cctgacagga gtggggatac tgtgttgatt ggcgctgtca gaggtggtca tgttgaaatt 1020 gttcgagcgc ttctccaaaa atatgctgat atagacatta gaggacagga taataaaact 1080 gctttgtatt gggctgttga gaaaggaaat gcaacaatgg tgagagatat cttacagtgc 1140 aatcctgaca ctgaaatatg cacaaaggat ggtgaaacgc cacttataaa ggctaccaag 1200 atgagaaaca ttgaagtggt ggagctgctg ctagataaag gtgctaaagt gtctgctgta 1260 gataagaaag gagatactcc cttgcatatt gctattcgtg gaaggagccg gaaactggca 1320 gaactgcttt taagaaatcc caaagatggg cgattacttt ataggcccaa caaagcaggc 1380 gagactcctt ataatattga ctgtagccat cagaagagta ttttaactca aatatttgga 1440 gccagacact tgtctcctac tgaaacagac ggtgacatgc ttggatatga tttatatagc 1500 agtgccctgg cagatattct cagtgagcct accatgcagc cacccatttg tgtggggtta 1560 tatgcacagt ggggaagtgg gaaatctttc ttactcaaga aactagaaga cgaaatgaaa 1620 accttcgccg gacaacagat tgagcctctc tttcagttct catggctcat agtgtttctt 1680 accctgctac tttgtggagg gcttggttta ttgtttgCCt tCaCggtCCa CCCaaatCtt 1740 ggaatagcag tgtcactgag cttcttggct ctcttatata tattctttat tgtcatttac 1800 tttggtggac gaagagaagg agagagttgg aattgggcct gggtcctcag cactagattg 1860 gcaagacata ttggatattt ggaactcctc cttaaattga tgtttgtgaa tccacctgag 1920 ttgccagagc agactactaa agctttacct gtgaggtttt tgtttacaga ttacaataga 1980 ctgtccagtg taggtggaga aacttctctg gctgaaatga ttgcaaccct ctcggatgct 2040 tgtgaaagag agtttggctt tttggcaacc aggctttttc gagtattcaa gactgaagat 2100 actcagggta aaaagaaatg gaaaaaaaca tgttgtctcc catcttttgt catcttcctt 2160 tttatcattg gctgcattat atctggaatt actcttctgg ctatatttag agttgaccca 2220 aagcatctga ctgtaaatgc tgtcctcata tcaatcgcat ctgtagtggg attggccttt 2280 gtgttgaact gtcgtacatg gtggcaagtg ctggactcgc tcctgaattc ccaaagaaaa 2340 cgcctccata atgcagcctc caaactgcac aaattgaaaa gtgaaggatt catgaaagtt 2400 cttaaatgtg aagtggaatt gatggccagg atggcaaaaa ccattgacag cttcactcag 2460 aatcagacaa ggctggtggt catcatcgat ggattagatg cctgtgagca ggacaaagtc 2520 cttcagatgc tggacactgt ccgagttctg ttttcaaaag gcccgttcat tgccattttt 2580 gcaagtgatc cacatattat cataaaggca attaaccaga acctcaatag tgtgcttcgg 2640 gattcaaata taaatggcca tgactacatg cgcaacatag tccacttgcc tgtgttcctt 2700 aatagtcgtg gactaagcaa tgcaagaaaa tttctcgtaa cttcagcaac aaatggagac 2760 gttccatgct cagatactac agggatacag gaagatgctg acagaagagt ttcacagaac 2820 agccttgggg agatgacaaa acttggtagc aagacagccc tcaatagacg ggacacttac 2880 cgaagaaggc agatgcagag gaccatcact cgccagatgt cctttgatct tacaaaactg 2940 ctggttaccg aggactggtt cagtgacatc agtccccaga ccatgagaag attacttaat 3000 attgtttctg tgacaggacg attactgaga gccaatcaga ttagtttcaa ctgggacagg 3060' cttgctagct ggatcaacct tactgagcag tggccatacc ggacttcatg gctcatatta 3120 tatttggaag agactgaagg tattccagat caaatgacat taaaaaccat ctacgaaaga 3180 atatcaaaga atattccaac aactaaggat gttgagccac ttcttgaaat tgatggagat 3240 ataagaaatt ttgaagtgtt tttgtcttca aggaccccag ttcttgtggc tcgagatgta 3300 aaagtctttt tgccatgcac tgtaaaccta gatcccaaac tacgggaaat tattgcagat 3360 gttcgtgctg ccagagagca gatcagtatt ggaggactgg cgtacccccc gctccctcta 3420 catgagggtc ctcctagggc gccatcaggg tacagccagc ccccatccgt gtgctcttcc 3480 acgtccttca atgggccctt cgcaggtgga gtggtgtcac cacagcctca cagcagctat 3540 tacagcggca tgacgggccc tcagcatccc ttctacaaca gggggtcagg cccagcccca 3600 ggcccagtgg tattactgaa ttcactgaat gtggatgcag tatgtgagaa gctgaaacaa 3660 atagaagggc tggaccagag tatgctgcct cagtattgta ccacgatcaa aaaggcaaac 3720 ataaatggcc gtgtgttagc tcagtgtaac attgatgagc tgaagaaaga gatgaatatg 3780 aattttggag actggcacct tttcagaagc acagtactag aaatgagaaa cgcagaaagc 3840 cacgtggtcc ctgaagaccc acgtttcctc agtgagagca gcagtggccc agccccgcac 3900 ggtgagcctg ctcgccgcgc ttcccacaac gagctgcctc acaccgagct ctccagccag 3960 acgccctaca cactcaactt cagcttcgaa gagctgaaca cgcttggcct ggatgaaggt 4020 gcccctcgtc acagtaatct aagttggcag tcacaaactc gcagaacccc aagtctttcg 4080 agtctcaatt cccaggattc cagtattgaa atttcaaagc ttactgataa ggtgcaggcc 4140 gagtatagag atgcctatag agaatacatt gctcagatgt cccagttaga agggggcccc 4200 gggtctacaa ccattagtgg cagatcttct ccacatagca catattacat gggtcagagt 4260 tcatcagggg gctctattca ttcaaaccta gagcaagaaa aggggaagga tagtgaacca 4320 aagcccgatg atgggaggaa gtcctttcta atgaagaggg gagatgttat cgattattca 4380 tcatcagggg tttccaccaa cgatgcttcc cccctggatc ctatcactga agaagatgaa 4440 aaatcagatc agtcaggcag taagcttctc ccaggcaaga aatcttccga aaggtcaagc 4500 ctcttccaga cagatttgaa gcttaaggga agtgggctgc gctatcaaaa actcccaagt 4560 gacgaggatg aatctggcac agaagaatca gataacactc cactgctcaa agatgacaaa 4620 gacagaaaag ccgaagggaa agtagagaga gtgccgaagt ctCCagaaca cagtgctgag 4680 ccgatcagaa ccttcattaa agccaaagag tatttatcgg atgcgctcct tgacaaaaag 4740 gattcatcgg attcaggagt gagatccagt gaaagttctc ccaatcactc tctgcacaat 4800 gaagtggcgg atgactccca gcttgaaaag gcaaatctca tagagctgga agatgacagt 4860 cacagcggaa agcggggaat cccacatagc ctgagtggcc tgcaagatcc aattatagct 4920 cggatgtcca tttgttcaga agacaagaaa agcccttccg aatgcagctt gatagccagc 4980 agccctgaag aaaactggcc tgcatgccag aaagcctaca acctgaaccg aactcccagc 5040 accgtgactc tgaacaacaa tagtgctcca gccaacagag ccaatcaaaa tttcgatgag 5100 atggagggaa ttagggagac ttctcaagtc attttgaggc ctagttccag tcccaaccca 5160 accactattc agaatgagaa tctaaaaagc atgacacata agcgaagcca acgttcaagt 5220 tacacaaggc tctccaaaga tcctccggag ctccatgcag cagcctcttc tgagagcaca 5280 ggctttggag aagaaagaga aagcattctt tgagaaaaac aagcaaaagg agaagagtgt 5340 tactgtaccc ttatgacaga attgtcctgg attttgactc catccacgcc catcaccttt 5400 ctacattttg ctgacagata actaaccgat gatgagggcc gagggtacaa cacgagacat 5460 cttgccgtgt gacagaaggg agcatgaaaa gccatggttc acacaaggca agcttctgtg 5520 ggctttgtat tagaagcttt cgaactccac taatatatct gtggctttca ttggggcctt 5580 tccccataaa attttttgag accaggggcg accggggatt aaacaacggg cca 5633 <210> 55 <211> 4587 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5868348CB1 <400> 55 gcgatctgag tagccagcgt cgccggcgac cgcggagttc tgggctagtg ggaccccgcg 60 cgggctggtt cgggatgagc gatggcatcg gtcaaggtgg ccgtgagggt ccggcccatg 120 aatcgcaggg aaaaggactt ggaggccaag ttcattattc agatggagaa aagcaaaacg 180 acaatcacaa acttaaagat accagaagga ggcactgggg actcaggaag agaacggacc 240 aagaccttca cctatgactt ttctttttat tctgctgata caaaaagccc agattacgtt 300 tcacaagaaa tggttttcaa aaccctcggc acagatgtcg tgaagtctgc atttgaaggt 360 tataatgctt gtgtctttgc atatgggcaa actggatctg gaaagtcata cactatgatg 420 ggaaattctg gagattctgg cttaatacct cggatctgtg aaggactctt cagtcggata 480 aatgaaacca ccagatggga tgaagcttct tttcgaactg aagtcagcta cttagaaatt 540 tataacgaac gtgtgagaga tctacttcgg cggaagtcat ctaaaacctt caatttgaga 600 gtccgtgagc atcccaaaga aggcccttat gttgaggatt tatccaaaca tttagtacag 660 aattatggtg acgtagaaga acttatggat gcgggcaata tcaaccggac caccgcagcg 720 actgggatga acgacgtcag tagcaggtct catgccatct tcaccatcaa gttcactcag 780 gctaaatttg attctgaaat gccatgtgaa accgtcagta agatccactt ggttgatctt 840 gccggaagtg agcgtgcaga tgccaccgga gccaccgggg ttaggctaaa ggaaggggga 900 aatattaaca agtccctcgt gactctgggg aacgtcattt ctgccttagc tgatttatct 960 caggatgctg caaatactct tgcaaagaag aagcaagttt tcgtgcctta cagggattct 1020 gtgttgactt ggttgttaaa agatagcctt ggaggaaact ctaaaactat catgattgcc 1080 accatttcac ctgctgatgt caattatgga gaaaccctaa gtactcttcg ctatgcaaat 1140 agagccaaaa acatcatcaa caagcctacc attaatgagg atgccaacgt caaacttatc 1200 cgtgagctgc gagctgaaat agccagactg aaaacgctgc ttgctcaagg gaatcagatt 2260 gccctcttag actcccccac agctttaagt atggaggaaa aacttcagca gaatgaagca 1320 agagttcaag aattgaccaa ggaatggaca aataagtgga atgaaaccca aaatattttg 1380 aaagaacaaa ctctagccct caggaaagaa gggattggag ttgttttgga ttctgaactg 1440 cctcatttga ttggcatcga tgatgacctt ttgagtactg gaatcatctt atatcattta 1500 aaggaaggtc agacatacgt tggtagagac gatgcttcca cggagcaaga tattgttctt 2560 catggccttg acttggagag tgagcattgc atctttgaaa atatcggggg gacagtgact 1620 ctgatacccc tgagtgggtc ccagtgctct gtgaatggtg ttcagatcgt ggaggccaca 1680 catctaaatc aaggtgctgt gattctcttg ggaagaacca atatgtttcg ctttaaccat 1740 ccaaaggaag ccgccaagct cagggagaag aggaagagtg gccttctgtc ctccttcagc 1800 ttgtccatga ccgacctctc gaagtcccgt gagaacctgt ctgcagtcat gttgtataac 1860 cccggacttg aatttgagag gcaacagcgt gaagaacttg aaaaattaga aagtaaaagg 1920 aaactcatag aagaaatgga ggaaaagcag aaatcagaca aggctgaact ggagcggatg 1980 cagcaggagg tggagaccca gcgcaaggag acagaaatcg tgcagctcca gattcgcaag 2040 caggaggaga gcctcaaacg ccgcagcttc cacatcgaga acaagctaaa ggatttactt 2100 gcggagaagg aaaaatttga agaggagagg ctgagggaac agcaggaaat cgagctgcag 2160 aagaagagac aagaagaaga gacctttctc cgcgtccaag aagaactcca acgactcaaa 2220 gaactcaaca acaacgagaa ggctgagaag tttcagatat ttcaagaact ggaccagctc 2280 caaaaggaaa aagatgaaca gtatgccaag cttgaactgg aaaaaaagag actagaggag 2340 caggagaagg agcaggtcat gctcgtggcc catctggaag agcagctccg agagaagcag 2400 gagatgatcc agctcctgcg gcgtggggag gtacagtggg tggaagagga gaagagggac 2460 ctggaaggca ttcgggaatc cctcctgcgg gtgaaggagg ctcgtgccgg aggggatgaa 2520 gatggcgagg agttagaaaa ggctcaactg cgtttcttcg aattcaagag aaggcagctt 2580 gtcaagctag tgaacttgga gaaggacctg gttcagcaga aagacatcct gaaaaaagaa 2640 gtccaagaag aacaggagat cctagagtgt ttaaaatgtg aacatgacaa agaatctaga 2700 ttgttggaaa aacatgatga gagtgtcaca gatgtcacgg aagtgcctca agatttcgag 2760 aaaataaagc cagtggagta caggctgcaa tataaagaac gccagctaca gtacctcctg 2820 cagaatcact tgccaactct gttggaagaa aagcagagag catttgaaat tcttgacaga 2880 ggcCCtctca gcttagacaa cactctttat caagtagaaa aggaaatgga agaaaaagaa 2940 gaacagcttg cacagtacca ggccaatgca aaccagctgc aaaagctcca agccaccttt 3000 gaattcactg ccaacattgc acgtcaggag gaaaaagtga ggaaaaagga aaaggagatt 3060 ttggagtcca gagagaagca gcagagagag gcgctggagc gggccctggc caggctggag 3120 aggagacatt ctgcgctgca gaggcactcc accctgggca cggagattga agagcagagg 3180 cagaaacttg ccagtctgaa cagtggcagc agagagcagt cagggctcca ggctagcctg 3240 gaggctgagc aggaagccct ggagaaggac caggagaggt tagaatatga aatccagcag 3300 ctgaaacaga agatttatga ggtcgatggt gttcaaaaag atcatcatgg gaccctggaa 3360 gggaaggtgg cttcttccag cttgccagtc agtgctgaaa aatcacacct ggttcccctc 3420 atggatgcca ggatcaatgc ttacattgaa gaagaagtcc aaagacgcct tcaggatttg 3480 catcgtgtga ttagtgaagg ctgcagtaca tctgcagaca cgatgaagga taatgagaaa 3540 cttcacaagg gcaccattca acgtaaacta aaatatgagc tgtgtcgtga cctcctgtgt 3600 gtcctgatgc cagagcctga tgccgctgcc tgcgctaatc atcccttgct ccagcaagat 3660 ctggttcagc tttctcttga ttggaaaaca gaaatccctg atttagtttt gccaaatgga 3720 gttcaggtgt catccaaatt ccagactacc ttggttgaca tgatttactt tcttcatgga 3780 aatatggaag tcaatgtccc ttccctggca gaagttcagt tactgctcta cacaacagtg 3840 aaagtcatgg gtgactctgg ccatgaccag tgccagtcgc tagtccttct gaacacccac 3900 attgcactgg tgaaggaaga ctgtgttttt tatccacgca ttcgatctcg aaacatacct 3960 cctccgggtg cacaatttga tgtgatcaaa tgccatgctt taagtgaatt caggtgtgtt 4020 gttgttccag aaaagaaaaa tgtgtcaaca gtagaactag tcttcttaca gaaactcaaa 4080 ccttcagtgg gttcCagaaa tagtccacct gagcaccttc aggaagcccc aaatgtccag 4140 ttgttcacca ccccattgta tcttcaaggc agtcagaatg tcgcacctga ggtctggaaa 4200 cttactttca attctcaaga tgaggctctt tggctaatct cacatttgac aagactctaa 4260 ggaggagacc tttaaagatg cactacatgt tttttgagat cattaataaa ataagcattg 4320 tgaaaacagt caaggcaata tgaatatctc cgtgtagcta attgaattgg aactggaaaa 4380 atgcagacct ctaaaattga aaatgtaaat attttaaata tctacaataa aataaaaaca 4440 gctaatagca gagccccaat aaaatatctt tatcatcacc ttgcttcatt ttcttgaaac 4500 tcaggcttgt aaatttgtgc ctgcttcatt atttgtgagg tgattaaagc atttctgatt 4560 gttaaacaaa acaaaaaagg gggggcg 4587 <210> 56 <211> 1509 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2055455CB1 <400> 56 eggaagcatc catggcggag ggcggcagcc cagacgggcg ggcagggccg gggctccgca 60 gtgcaggtcg taatctgaag gagtggctga gggagcaatt ttgtgatcat ccgctggagc 120 actgtgagga cacgaggctc catgatgcag cttacgtcgg ggacctccag accctcagga 180 gcctattgca agaggagagc taccggagcc gcatcaacga gaagtctgtc tggtgctgtg 240 gctggctccc ctgcacaccg ttgcgaatcg cggccactgc aggccatggg agctgtgtgg 300 acttcctcat ccggaagggg gccgaggtgg atctggtgga cgtaaaagga cagacggccc 360 tgtatgtggc tgtggtgaac gggcacctag agagtaccca gatccttctc gaagctggcg 420 cggaccccaa cggaagccgg caccatcgca gcacccctgt ctaccacgcc tctcgcgtgg 480 gccgggcaga catcctgaag gccctcatca ggtacggggc tgatgttgac gtcaaccacc 540 acctgactcc tgatgtccag cctcgattct cccggcggct cacctccttg gtggtctgcc 600 ccttgtacat cagcgcagcc taccacaacc tccagtgctt ccggctgctc ctcctggctg 660 gcgcgaaccc .tgacttcaac tgcaatggtc ctgtcaacac acagggattc tacaggggct 720 cccctgggtg cgtcatggat gctgttctgc gccacggctg tgaggcagcc ttcgtgagcc 780 tgctggtaga atttggagcc aacctgaatc tagtgaagtg ggaatcgctg ggcccagagt 840 cgagaggaag aagaaaagtg gaccctgagg ccttgcaggt ctttaaagag gccagaagtg 900 ttcccagaac cttgctgtgt ctgtgccgtg tggctgtgag aagagctctt ggcaaacacc 960 ggcttcatct gattccttcg ctgcctctgc cagaccccat aaagaagttt ctactccatg 1020 agtagactcc aagtgctgcg gttgattcca gtgagggaga aagtgatctg cagggaggtg 1080 gacaccgagc cctgagtgct gtgctgctgc tggtctcctg atggctgttg ctgcagaaga 1140 tgtcctcgta gactgtcatt gctcctcagg tgcctgggcc gctgaacagt ccttgggtca 1200 ttgtcagctg agaggcttat actaaagtta ttattgtttt tcccaaaaaa aaaaaaaaaa 1260 aaaaaaaaaa aaaaaagatg acaaaaaaaa agaagggggg ggccgccacc caataggtgt 1320 gtaccctcgc tgcacacgcg gagttattta ttctcgggca gcgatacttt cgagaggtgt 1380 gtggagagat attatgatat aactttttta agaacggacc accaccagga ggggggcccc 1440 gagatcacaa tgttcgcctt aatgtgtgat tttataacgc gcccactgtg gcggtgttaa 1500 aaagtgtgt 1509

Claims (111)

What is claimed is:

1. An isolated polypeptide selected from the group consisting of:
a) a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, b) a polypeptide comprising a naturally occurring amino acid sequence at least 90%
identical to an amino acid sequence selected from the group consisting of SEQ
ID
NO:1-3, SEQ ID NO:5-13, SEQ ID NO:16-17, and SEQ ID NO:19-28, c) a polypeptide comprising a naturally occurring amino acid sequence at least 92%
identical to an amino acid sequence selected from the group consisting of SEQ
ID
NO:4, SEQ ID NO:14, and SEQ ID NO:15, d) a polypeptide comprising a naturally occurring amino acid sequence at least 95%
identical to the amino acid sequence of SEQ ID NO:18, e) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, and f) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

2. An isolated polypeptide of claim 1 comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

3. An isolated polynucleotide encoding a polypeptide of claim 1.

4. An isolated polynucleotide encoding a polypeptide of claim 2.

5. An isolated polynucleotide of claim 4 comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:29-56.

6. A recombinant polynucleotide comprising a promoter sequence operably linked to a polynucleotide of claim 3.

7. A cell transformed with a recombinant polynucleotide of claim 6.

8. A transgenic organism comprising a recombinant polynucleotide of claim 6.

9. A method of producing a polypeptide of claim 1, the method comprising:
a) culturing a cell under conditions suitable for expression of the polypeptide, wherein said cell is transformed with a recombinant polynucleotide, and said recombinant polynucleotide comprises a promoter sequence operably linked to a polynucleotide encoding the polypeptide of claim 1, and b) recovering the polypeptide so expressed.

10. A method of claim 9, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

11. An isolated antibody which specifically binds to a polypeptide of claim 1.

12. An isolated polynucleotide selected from the group consisting of:
a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID NO:29-56, b) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 90% identical to a polynucleotide sequence selected from the group consisting of SEQ ID NO:29-31 and SEQ ID NO:33-56, c) a polynucleotide comprising a naturally occurring polynucleotide sequence at least 92% identical to the polynucleotide sequence of SEQ ID NO:32, d) a polynucleotide complementary to a polynucleotide of a), e) a polynucleotide complementary to a polynucleotide of b), f) a polynucleotide complementary to a polynucleotide of c), and g) an RNA equivalent of a)-f).

13. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 12.

14. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising:
a) hybridizing the sample with a probe comprising at least 20 contiguous nucleotides comprising a sequence complementary to said target polynucleotide in the sample, and which probe specifically hybridizes to said target polynucleotide, under conditions whereby a hybridization complex is formed between said probe and said target polynucleotide or fragments thereof, and b) detecting the presence or absence of said hybridization complex, and, optionally, if present, the amount thereof.

15. A method of claim 14, wherein the probe comprises at least 60 contiguous nucleotides.

16. A method of detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 12, the method comprising:
a) amplifying said target polynucleotide or fragment thereof using polymerase chain reaction amplification, and b) detecting the presence or absence of said amplified target polynucleotide or fragment thereof, and, optionally, if present, the amount thereof.

17. A composition comprising a polypeptide of claim 1 and a pharmaceutically acceptable excipient.

18. A composition of claim 17, wherein the polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

19. A method for treating a disease or condition associated with decreased expression of functional CSAP, comprising administering to a patient in need of such treatment the composition of claim 17.

20. A method of screening a compound for effectiveness as an agonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting agonist activity in the sample.

21. A composition comprising an agonist compound identified by a method of claim 20 and a pharmaceutically acceptable excipient.

22. A method for treating a disease or condition associated with decreased expression of functional CSAP, comprising administering to a patient in need of such treatment a composition of claim 21.

23. A method of screening a compound for effectiveness as an antagonist of a polypeptide of claim 1, the method comprising:
a) exposing a sample comprising a polypeptide of claim 1 to a compound, and b) detecting antagonist activity in the sample.

24. A composition comprising an antagonist compound identified by a method of claim 23 and a pharmaceutically acceptable excipient.

25. A method for treating a disease or condition associated with overexpression of functional CSAP, comprising administering to a patient in need of such treatment a composition of claim 24.

26. A method of screening for a compound that specifically binds to the polypeptide of claim 1, the method comprising:
a) combining the polypeptide of claim 1 with at least one test compound under suitable conditions, and b) detecting binding of the polypeptide of claim 1 to the test compound, thereby identifying a compound that specifically binds to the polypeptide of claim 1.

27. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, the method comprising:
a) combining the polypeptide of claim 1 with at least one test compound under conditions permissive for the activity of the polypeptide of claim 1, b) assessing the activity of the polypeptide of claim 1 in the presence of the test compound, and c) comparing the activity of the polypeptide of claim 1 in the presence of the test compound with the activity of the polypeptide of claim 1 in the absence of the test compound, wherein a change in the activity of the polypeptide of claim 1 in the presence of the test compound is indicative of a compound that modulates the activity of the polypeptide of claim 1.

28. A method of screening a compound for effectiveness in altering expression of a target polynucleotide, wherein said target polynucleotide comprises a sequence of claim 5, the method comprising:
a) exposing a sample comprising the target polynucleotide to a compound, under conditions suitable for the expression of the target polynucleotide, b) detecting altered expression of the target polynucleotide, and c) comparing the expression of the target polynucleotide in the presence of varying amounts of the compound and in the absence of the compound.

29. A method of assessing toxicity of a test compound, the method comprising:
a) treating a biological sample containing nucleic acids with the test compound, b) hybridizing the nucleic acids of the treated biological sample with a probe comprising at least 20 contiguous nucleotides of a polynucleotide of claim 12 under conditions whereby a specific hybridization complex is formed between said probe and a target polynucleotide in the biological sample, said target polynucleotide comprising a polynucleotide sequence of a polynucleotide of claim 12 or fragment thereof, c) quantifying the amount of hybridization complex, and d) comparing the amount of hybridization complex in the treated biological sample with the amount of hybridization complex in an untreated biological sample, wherein a difference in the amount of hybridization complex in the treated biological sample is indicative of toxicity of the test compound.

30. A diagnostic test for a condition or disease associated with the expression of CSAP in a biological sample, the method comprising:
a) combining the biological sample with an antibody of claim 11, under conditions suitable for the antibody to bind the polypeptide and form an antibody:polypeptide complex, and b) detecting the complex, wherein the presence of the complex correlates with the presence of the polypeptide in the biological sample.

31. The antibody of claim 11, wherein the antibody is:
a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a F(ab')2 fragment, or e) a humanized antibody.

32. A composition comprising an antibody of claim 11 and an acceptable excipient.

33. A method of diagnosing a condition or disease associated with the expression of CSAP in a subject, comprising administering to said subject an effective amount of the composition of claim 32.

34. A composition of claim 32, wherein the antibody is labeled.

35. A method of diagnosing a condition or disease associated with the expression of CSAP in a subject, comprising administering to said subject an effective amount of the composition of claim 34.

36. A method of preparing a polyclonal antibody with the specificity of the antibody of claim 11, the method comprising:
a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibodies from said animal, and c) screening the isolated antibodies with the polypeptide, thereby identifying a polyclonal antibody which specifically binds to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

37. A polyclonal antibody produced by a method of claim 36.

38. A composition comprising the polyclonal antibody of claim 37 and a suitable carrier.

39. A method of making a monoclonal antibody with the specificity of the antibody of claim 11, the method comprising:
a) immunizing an animal with a polypeptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NO:1-28, or an immunogenic fragment thereof, under conditions to elicit an antibody response, b) isolating antibody producing cells from the animal, c) fusing the antibody producing cells with immortalized cells to form monoclonal antibody-producing hybridoma cells, d) culturing the hybridoma cells, and e) isolating from the culture monoclonal antibody which specifically binds to a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28.

40. A monoclonal antibody produced by a method of claim 39.

41. A composition comprising the monoclonal antibody of claim 40 and a suitable carrier.

42. The antibody of claim 11, wherein the antibody is produced by screening a Fab expression library.

43. The antibody of claim 11, wherein the antibody is produced by screening a recombinant immunoglobulin library.

44. A method of detecting a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28 in a sample, the method comprising:
a) incubating the antibody of claim 11 with a sample under conditions to allow specific binding of the antibody and the polypeptide, and b) detecting specific binding, wherein specific binding indicates the presence of a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28 in the sample.

45. A method of purifying a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO:1-28 from a sample, the method comprising:
a) incubating the antibody of claim 11 with a sample under conditions to allow specific binding of the antibody and the polypeptide, and b) separating the antibody from the sample and obtaining the purified polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID
NO:1-28.

46. A microarray wherein at least one element of the microarray is a polynucleotide of claim 13.

47. A method of generating an expression profile of a sample which contains polynucleotides, the method comprising:

a) labeling the polynucleotides of the sample, b) contacting the elements of the microarray of claim 46 with the labeled polynucleotides of the sample under conditions suitable for the formation of a hybridization complex, and c) quantifying the expression of the polynucleotides in the sample.

48. An array comprising different nucleotide molecules affixed in distinct physical locations on a solid substrate, wherein at least one of said nucleotide molecules comprises a first oligonucleotide or polynucleotide sequence specifically hybridizable with at least 30 contiguous nucleotides of a target polynucleotide, and wherein said target polynucleotide is a polynucleotide of claim 12.

49. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 30 contiguous nucleotides of said target polynucleotide.

50. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to at least 60 contiguous nucleotides of said target polynucleotide.

51. An array of claim 48, wherein said first oligonucleotide or polynucleotide sequence is completely complementary to said target polynucleotide.

52. An array of claim 48, which is a microarray.

53. An array of claim 48, further comprising said target polynucleotide hybridized to a nucleotide molecule comprising said first oligonucleotide or polynucleotide sequence.

54. An array of claim 48, wherein a linker joins at least one of said nucleotide molecules to said solid substrate.

55. An array of claim 48, wherein each distinct physical location on the substrate contains multiple nucleotide molecules, and the multiple nucleotide molecules at any single distinct physical location have the same sequence, and each distinct physical location on the substrate contains nucleotide molecules having a sequence which differs from the sequence of nucleotide molecules at another distinct physical location on the substrate.

56. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:1.

57. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:2.

58. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:3.

59. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:4.

60. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:5.

61. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:6.

62. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:7.

63. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:8.

64. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:9.

65. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:10.

66. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:11.

67. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:12.

68. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:13.

69. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:14.

70. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:15.

71. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:16.

72. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:17.

73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:18.

74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:19.

75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:20.

76. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:21.

77. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:22.

78. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:23.

79. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:24.

80. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:25.

81. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:26.

82. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:27.

83. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:28.

84. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:29.

85. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:30.

86. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:31.

87. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:32.

88. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:33.

89. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:34.

90. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:35.

91. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:36.

92. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:37.

93. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:38.

94. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:39.

95. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:40.

96. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:41.

97. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:42.

98. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:43.

99. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID

NO:44.

100. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:45.

101. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:46.

102. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:47.

103. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:48.

104. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:49.

105. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:50.

106. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:51.

107. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:52.

108. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:53.

109. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:54.

110. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:55.

111. A polynucleotide of claim 12, comprising the polynucleotide sequence of SEQ ID
NO:56.