CA2415808A1 - Transporters and ion channels - Google Patents

Abstract

The invention provides human transporters and ion channels (TRICH) and polynucleotides which identify and encode TRICH. The invention also provides expression vectors, host cells, antibodies, agonists, and antagonists. The invention also provides methods for diagnosing, treating, or preventing disorders associated with aberrant expression of TRICH.

Description

TRANSPORTERS AND ION CHANNELS
TECHNICAL FIELD
This invention relates to nucleic acid and amino acid sequences of transporters and ion channels and to the use of these sequences in the diagnosis, treatment, and prevention of transport, neurological, muscle, immunological, and cell proliferative disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of transpoiters and ion channels.
BACKGROUND OF THE INVENTION
Eukaryotic cells are surrounded and subdivided into functionally distinct organelles by hydrophobic lipid bilayer membranes which are highly impermeable to most polar molecules. Cells and organelles require transport proteins to import and export essential nutrients and metal ions including K+, NH4+, Pi, 5042-, sugars, and vitamins, as well as various metabolic waste products. Transport proteins also play roles in antibiotic resistance, toxin secretion, ion balance, synaptic neurotransmission, kidney function, intestinal absorption, tumor growth, and other diverse cell functions (Griffith, J. and C.
Sansom (1998) The Transporter Facts Book, Academic Press, San Diego CA, pp. 3-29). Transport can occur by a passive concentration-dependent mechanism, or can be linked to an energy source such as ATP hydrolysis or an ion gradient. Proteins that function in transport include Barrier proteins, which bind to a specific solute and undergo a conformational change that translocates the bound solute across the membrane, and channel proteins, which form hydrophilic pores that allow specific solutes to diffuse through the membrane down an electrochemical solute gradient.
Carrier proteins which transport a single solute from one side of the membrane to the other are called uniporters. In contrast, coupled transporters link the transfer of one solute with simultaneous or sequential transfer of a second solute, either in the same direction (symport) or in the opposite direction (antiport). For example, intestinal and kidney epithelium contains a variety of symporter systems driven by the sodium gradient that exists across the plasma membrane. Sodium moves into the cell down its electrochemical gradient and brings the solute into the cell with it. The sodium gradient that provides the driving force for solute uptake is maintained by the ubiquitous Na+/K+ ATPase system. Sodium-coupled transporters include the mammalian glucose transporter (SGLTl), iodide transporter (NIS), and multivitamin transporter (SMVT). All three transporters have twelve putative transmembrane segments, extracellular glycosylation sites, and cytoplasmically-oriented N- and C-termini. NIS plays a crucial role in the evaluation, diagnosis, and treatment of various thyroid pathologies because it is the molecular basis for radioiodide thyroid-imaging techniques and for specific targeting of radioisotopes to the thyroid gland (Levy, O. et al. (1997) Proc.
Natl. Acad. Sci. USA 94:5568-5573). SMVT is expressed in the intestinal mucosa, kidney, and placenta, and is implicated in the transport of the water-soluble vitamins, e.g., biotin and pantothenate (Prasad, P.D. et al. (1998) J. Biol. Chem. 273:7501-7506).
One of the largest families of transporters is the major facilitator superfamily (MFS), also called the uniporter-symporter-annporter family. MFS transporters are single polypepnde carriers that transport small solutes in response to ion gradients. Members of the MFS
are found in all classes of living organisms, and include transporters for sugars, oligosaccharides, phosphates, nitrates, nucleosides, monocarboxylates, and drugs. MFS transporters found in eukaryotes all have a structure comprising 12 transmembrane segments (Pao, S.S. et al. (1998) Microbiol.
Molec. Biol. Rev. 62:1-34). The largest family of MFS transporters is the sugar transporter family, which includes the seven glucose transporters (GLUT1-GLUT7) found in humans that are required for the transport of glucose and other hexose sugars. These glucose transport proteins have unique tissue distributions and physiological functions. GLUT1 provides many cell types with their basal glucose requirements and transports glucose across epithelial and endothelial barrier tissues; GLUT2 facilitates glucose uptake or efflux from the liver; GLUT3 regulates glucose supply to neurons; GLUT4 is responsible for insulin-regulated glucose disposal; and GLUTS regulates fructose uptake into skeletal muscle.
Defects in glucose transporters are involved in a recently identified neurological syndrome causing infantile seizures and developmental delay, as well as glycogen storage disease, Fanconi-Bickel syndrome, and non-insulin-dependent diabetes mellitus (Mueckler, M. (1994) Eur. J. Biochem.
219:713-725; Longo, N. and L.J. Elsas (1998) Adv. Pediatr. 45:293-313).
Monocarboxylate anion transporters are proton-coupled symporters with a broad substrate specificity that includes L-lactate, pyruvate, and the ketone bodies acetate, acetoacetate, and beta-hydroxybutyrate. At least seven isoforms have been identified to date.
The isoforms are predicted to have twelve transmembrane (TM) helical domains with a large intracellular loop between TM6 and TM7, and play a critical role in maintaining intracellular pH by removing the protons that are produced stoichiometrically with lactate during glycolysis. The best characterized H+-monocarboxylate transporter is that of the erythrocyte membrane, which transports L-lactate and a wide range of other aliphatic monocarboxylates. Other cells possess H+-linked monocarboxylate transporters with differing substrate and inhibitor selecnvines. In particular, cardiac muscle and tumor cells have transporters that differ in their Km values for certain substrates, including stereoselecnvity for L- over D-lactate, and in their sensitivity to inhibitors. There are Na+-monocarboxylate cotransporters on the luminal surface of intestinal and kidney epithelia, which allow the uptake of lactate, pyruvate, and ketone bodies in these tissues. In addition, there axe specific and selective transporters for organic canons and organic anions in organs including the kidney, intestine and liver. Organic anion transporters are selective for hydrophobic, charged molecules with electron-attracting side groups. Organic canon transporters, such as the ammonium transporter, mediate the secretion of a variety of drugs and endogenous metabolites, and contribute to the maintenance of intercellular pH (Poole, R.C. and A.P.
Halestrap (1993) Am. J.
Physiol. 264:C761-C782; Price, N.T. et al. (1998) Biochem. J. 329:321-328; and Martinelle, K. and I.
Haggstrom (1993) J. Biotechnol. 30:339-350).
ATP-binding cassette (ABC) transporters are members of a superfamily of membrane proteins that transport substances ranging from small molecules such as ions, sugars, amino acids, peptides, and phospholipids, to lipopeptides, large proteins, and complex hydrophobic drugs.
ABC transporters consist of four modules: two nucleotide-binding domains (NBD), which hydrolyze ATP to supply the energy required for transport, and two membrane-spanning domains (MSD), each containing six putative transmembrane segments. These four modules may be encoded by a single gene, as is the case for the cystic fibrosis transmembrane regulator (CFTR), or by separate genes.
When encoded by separate genes, each gene product contains a single NBD and MSD. These "half molecules" form homo- and heterodimers, such as Tap1 and Tap2, the endoplasmic reticulum-based major histocompatibility (MHC) peptide transport system. Several genetic diseases are attributed to defects in ABC transporters, such as the following diseases and their corresponding proteins: cystic fibxosis (CFTR, an ion channel), adrenoleukodystrophy (adrenoleukodystrophy protein, ALDP), Zellweger syndrome (peroxisomal membrane protein-70, PMP70), and hyperinsulinemic hypoglycemia (sulfonylurea receptor, SUR). Overexpression of the multidrug resistance (MDR) protein, another ABC transporter, in human cancer cells makes the cells resistant to a variety of cytotoxic drugs used in chemotherapy (Taglicht, D. and S. Michaelis (1998) Meth. Enzymol. 292:130-162).
A number of metal ions such as iron, zinc, copper, cobalt, manganese, molybdenum, selenium, nickel, and chromium are important as cofactors for a number of enzymes. For example, copper is involved in hemoglobin synthesis, connective tissue metabolism, and bone development, by acting as a cofactor in oxidoreductases such as superoxide dismutase, ferroxidase (ceruloplasmin), and lysyl oxidase. Copper and other metal ions must be provided in the diet, and are absorbed by transporters in the gastrointestinal tract. Plasma proteins transport the metal ions to the liver and other target organs, where specific transporters move the ions into cells and cellular organelles as needed. Imbalances in metal ion metabolism have been associated with a number of disease states (banks, D.M. (1986) J.
Med. Genet. 23:99-106).
Transport of fatty acids across~the plasma membrane can occur by diffusion, a high capacity, low affinity process. However, under normal physiological conditions a significant fraction of fatty acid transport appears to occur via a high affinity, low capacity protein-mediated transport process.

Fatty acid transport protein (FATP), an integral membrane protein with four transmembrane segments, is expressed in tissues exhibiting high levels of plasma membrane fatty acid flux, such as muscle, heart, and adipose. Expression of FATP is upregulated in 3T3-L1 cells during adipose conversion, and expression in COS7 fibroblasts elevates uptake of long-chain fatty acids (Hui, T.Y. et al. (1998) J.
Biol. Chem. 273:27420-27429).
Mitochondria) carrier proteins are transmembrane-spanning proteins which transport ions and charged metabolites between the cytosol and the mitochondria) matrix. Examples include the ADP, ATP carrier protein; the 2-oxoglutarate/malate carrier; the phosphate carriex protein; the pyruvate carrier; the dicarboxylate carrier which transports malate, succinate, fumarate, and phosphate; the tricarboxylate carrier wluch transports citrate and malate; and the Grave's disease carrier protein, a pxotein recognized by IgG in patients with active Grave's disease, an autoimmune disorder resulting in hyperthyroidism. Pxoteins in this family consist of three tandem repeats of an approximately 100 amino acid domain, each of which contains two transmembrane regions (Stryer, L.
(1995) Biochemistry, W.H.
Freeman and Company, New York NY, p. 551; PROSITE PDOC00189 Mitochondria) energy transfer proteins signature; Online Mendelian Inheritance in Man (OMIM) *275000 Graves Disease).
This class of transporters also includes the mitochondria) uncoupling proteins, which create proton leaks across the inner mitochondria) membrane, thus uncoupling oxidative phosphorylation from ATP synthesis. The result is energy dissipation in the form of heat.
Mitochondria) uncoupling proteins have been implicated as modulators of thermoregulation and metabolic rate, and have been proposed as potential targets for drugs against metabolic diseases such as obesity (Ricquier, D. et al. (1999) J. Int.
Med. 245:637-642).
Ion Channels The electrical potential of a cell is generated and maintained by controlling the movement of ions across the plasma membrane. The movement of ions requires ion channels, which form ion-selective pores within the membrane. There are two basic types of ion channels, ion transporters and gated ion channels. Ion transporters utilize the energy obtained from ATP
hydrolysis to actively transport an ion against the ion's concentration gradient. Gated ion channels allow passive flow of an ion down the ion's electrochemical gradient under restricted conditions.
Together, these types of ion channels generate, maintain, and utilize an electrochemical gradient that is used in 1) electrical impulse conduction down the axon of a nerve cell, 2) transport of molecules into cells against concentration gradients, 3) initiation of muscle contraction, and 4) endocrine cell secretion.
Ion Trans op rters Ion transporters generate and maintain the resting electrical potential of a cell. Utilizing the energy derived from ATP hydrolysis, they transport ions against the ion's concentration gradient.

These transmembrane ATPases are divided into three families. The phosphorylated (P) class ion transporters, including Na+-K~ ATPase, Ca2+-ATPase, and H+-ATPase, are activated by a phosphorylation event. P-class ion transporters are responsible for maintaining resting potential distributions such that cytosolic concentrations of Nay and Ca2+ are low and cytosolic concentration of K+ is high. The vacuolar (V) class of ion transporters includes H+ pumps on intracellular organelles, such as lysosomes and Golgi. V-class ion transporters are responsible for generating the low pH within the lumen of these organelles that is required for function. The coupling factor (F) class consists of H+
pumps in the mitochondria. F-class ion transporters utilize a proton gradient to generate ATP from ADP and inorganic phosphate (P;).
The P-ATPases are hexamers of a 100 kD subunit with ten transmembrane domains and several large cytoplasmic regions that may play a role in ion binding (Scarborough, G.A. (1999) Curr.
Opin. Cell Biol. 11:517-522). The V-ATPases are composed of two functional domains: the V 1 domain, a peripheral complex responsible for ATP hydrolysis; and the Vo domain, an integral complex responsible for proton translocation across the membrane. The F-ATPases are structurally and evolutionarily related to the V-ATPases. The F-ATPase Fo domain contains 12 copies of the c subunit, a highly hydrophobic protein composed of two transmembrane domains and containing a single buried carboxyl group in TM2 that is essential for proton transport.
The V-ATPase V o domain contains three types of homologous c subunits with four or five transmembrane domains and the essential carboxyl group in TM4 or TM3. Both types of complex also contain a single a subunit that may be involved in regulating the pH dependence of activity (Forgac, M. (1999) J. Biol. Chem.
274:12951-12954).
The resting potential of the cell is utilized in many processes involving carrier proteins and gated ion channels. Carrier proteins utilize the resting potential to transport molecules into and out of the cell. Amino acid and glucose transport into many cells is linked to sodium ion co-transport (symport) so that the movement of Na+ down an electrochemical gradient drives transport of the other molecule up a concentration gradient. Similarly, caxdiac muscle links transfer of Ca2+ out of the cell with transport of Na+ into the cell (antiport).
Gated Ion Channels Gated ion channels control ion flow by regulating the opening and closing of pores. The ability to control ion flux through various gating mechanisms allows ion channels to mediate such diverse signaling and homeostatic functions as neuronal and endocrine signaling, muscle contraction, fertilization, and regulation of ion and pH balance. Gated ion channels are categorized according to the manner of regulating the gating function. Mechanically-gated channels open their pores in response to mechanical stress; voltage-gated channels (e.g., Na+, K+, Ca2+, and Cl-channels) open their pores in response to changes in membrane potential; and ligand-gated channels (e.g., acetylcholine-, serotonin-, and glutamate-gated canon channels, and GABA- and glycine-gated chloride channels) open their pores in the presence of a specific ion, nucleotide, or neurotransmitter.
The gating properties of a particular ion channel (i.e., its threshold for and duration of opening and closing) are sometimes modulated by association with auxiliary channel proteins and/or post translational modifications, such as phosphorylation.
Mechanically-gated or mechanosensitive ion channels act as transducers for the senses of touch, hearing, and balance, and also play important roles in cell volume regulation, smooth muscle contraction, and cardiac rhythm generation. A stretch-inactivated channel (SIC) was recently cloned from rat kidney. The SIC channel belongs to a group of channels which are activated by pressure or stress on the cell membrane and conduct both Ca2+ and Na+ (Suzuki, M. et al.
(1999) J. Biol. Chem.
274:6330-6335).
The pore-forming subunits of the voltage-gated canon channels form a superfamily of ion channel proteins. The characteristic domain of these channel proteins comprises six transmembrane domains (S 1-S6), a pore-forming region (P) located between SS and S6, and intracellular amino and carboxy termini. In the Na+ and Ca2+ subfamilies, this domain is repeated four times, while in the K+
channel subfamily, each channel is formed from a tetramer of either identical or dissimilar subunits.
The P region contains information specifying the ion selectivity for the channel. In the case of K
channels, a GYG tripeptide is involved in this selectivity (Ishii, T.M. et al.
(1997) Proc. Natl. Acad.
Sci. USA 94:11651-11656).
Voltage-gated Nay and K+ channels are necessary for the function of electrically excitable cells, such as nerve and muscle cells. Action potentials, which lead to neurotransmitter release and muscle contraction, arise from large, transient changes in the permeability of the membrane to Na ~ and K+
ions. Depolarization of the membrane beyond the threshold level opens voltage-gated Na+ channels.
Sodium ions flow into the cell, further depolarizing the membrane and opening more voltage-gated Na+
channels, which propagates the depolarization down the length of the cell.
Depolarization also opens voltage-gated potassium channels. Consequently, potassium ions flow outward, which leads to repolarization of the membrane. Voltage-gated channels utilize charged residues in the fourth transmembrane segment (S4) to sense voltage change. The open state lasts only about 1 millisecond, at which time the channel spontaneously converts into an inactive state that cannot be opened irrespective of the membrane potential. Inactivation is mediated by the channel's N-terminus, which acts as a plug that closes the pore. The transition from an inactive to a closed state requires a return to resting potential.
Voltage-gated Na+ channels are heterotrimeric complexes composed of a 260 kDa pore-forming a subunit that associates with two smaller auxiliary subunits, j31 and ~i2.
The J32 subunit is a integral membrane glycoprotein that contains an extracellular Ig domain, and its association with a and (31 subunits correlates with increased functional expression of the channel, a change in its gating properties, as well as an increase in whole cell capacitance due to an increase in membrane surface area (Isom, L.L. et al. (1995) Cell 83:433-442).
Non voltage-gated Na+ channels include the members of the amiloride-sensitive Nay channel/degenerin (NaC/DEG) family. Channel subunits of this family axe thought to consist of two transmembrane domains flanking a long extracellular loop, with the amino and carboxyl termini located within the cell. The NaC/DEG family includes the epithelial Na+ channel (ENaC) involved in Na+
reabsorption in epithelia including the airway, distal colon, cortical collecting duct of the kidney, and exocrine duct glands. Mutations in ENaC result in pseudohypoaldosteronism type 1 and Liddle's syndrome (pseudohyperaldosteronism). The NaCIDEG family also includes the recently characterized H+-gated cation channels or acid-sensing ion channels (ASIC). ASIC subunits are expressed in the brain and form heteromultimeric Nay-permeable channels. These channels require acid pH fluctuations for activation. ASIC subunits show homology to the degenerins, a family of mechanically-gated channels originally isolated from C. elegans. Mutations in the degenerins cause neurodegeneration.
ASIC subunits may also have a role in neuronal function, or in pain perception, since tissue acidosis causes pain (Waldmann, R. and M. Lazdunski (1998) Curr. Opin. Neurobiol. 8:418-424; Eglen, R.M.
et al. (1999) Trends Pharmacol. Sci. 20:337-342).
K+ channels are located in all cell types, and may be regulated by voltage, ATP concentration, or second messengers such as Ca2+ and cAMP. In non-excitable tissue, K+
channels are involved in protein synthesis, control of endocrine secretions, and the maintenance of osmotic equilibrium across membranes. In neurons and other excitable cells, in addition to regulating action potentials and repolarizing membranes, K+ channels are responsible for setting resting membrane potential. The cytosol contains non-diffusible anions and, to balance this net negative charge, the cell contains a Na+-K+ pump and ion channels that provide the redistribution of Na+, K+, and Cl-.
The pump actively transports Na+ out of the cell and K+ into the cell in a 3:2 ratio. Ion channels in the plasma membrane allow K+ and Cl - to flow by passive diffusion. Because of the high negative charge within the cytosol, Cl- flows out of the cell. The flow of K+ is balanced by an electromotive force pulling K+ into the cell, and a K+ concentration gradient pushing K+ out of the cell. Thus, the resting membrane potential is primarily regulated by K+flow (Salkoff, L. and T. Jegla (1995) Neuron 15:489-492).
Potassium channel subunits of the Shaker-like superfamily all have the characteristic six transmembranell pore domain structure. Four subunits combine as homo- or heterotetramers to form functional K channels. These pore-forming subunits also associate with various cytoplasmic (3 subunits that alter channel inactivation kinetics. The Shaker-like channel family includes the voltage-gated K+ channels as well as the delayed rectifier type channels such as the human ether-a-go-go related gene (HERG) associated with long QT, a cardiac dysrythmia syndrome (Curran, M.E. (1998) Curr. Opin. Biotechnol. 9:565-572; Kaczorowski, G.J. and M.L. Garcia (1999) Curr. Opin. Chem.
Biol. 3:448-458).
A second superfamily of K+ channels is composed of the inward rectifying channels (Kir).
Kir channels have the property of preferentially conducting K'~ currents in the inward direction. These proteins consist of a single potassium selective pore domain and two transmembrane domains, which correspond to the fifth and sixth transmembrane domains of voltage-gated K+
channels. Kir subunits also assbciate as tetramers. The Kir family includes ROMK1, mutations in which lead to Bartter syndrome, a renal tubular disorder. Kir channels are also involved in regulation of cardiac pacemaker activity, seizures and epilepsy, and insulin regulation (Doupnik, C.A. et al.
(1995) Cmr. Opin.
Neurobiol. 5:268-277; Curran, supra).
The recently recognized TWIK K+ channel family includes the mammalian TWIK-1, and TASK proteins. Members of this family possess an overall structure with four transmembrane domains and two P domains. These proteins are probably involved in controlling the resting potential in a large set of cell types (Duprat, F. et al. (2997) EMBO J 16:5464-5471).
The voltage-gated Ca2+ channels have been classified into several subtypes based upon their electrophysiological and pharmacological characteristics. L-type Ca 2+
channels are predominantly expressed in heart and skeletal muscle where they play an essential role in excitation-contraction coupling. T-type channels are important for cardiac pacemaker activity, while N-type and P/Q-type channels are involved in the control of neurotransmitter release in the central and peripheral nervous system. The L-type and N-type voltage-gated Ca2+ channels have been purified and, though their functions differ dramatically, they have similar subunit compositions. The channels are composed of three subunits. The al subunit forms the membrane pore and voltage sensor, while the a28 and (3 subunits modulate the voltage-dependence, gating properties, and the current amplitude of the channel.
These subunits are encoded by at least six al, one aZb, and four (3 genes, A
fourth subunit, 'y, has been identified in skeletal muscle (Walker, D. et al. (1998) J. Biol. Chem.
273:2361-2367; McCleskey, E.W.
(1994) Curr. Opin. Neurobiol. 4:304-312).
The transient receptor family (Trp) of calcium ion channels are thought to mediate capacitative calcium entry (CCE). CCE is the Ca2+ influx into cells to resupply Ca2~ stores depleted by the action of inositol triphosphate (IP3) and other agents in response to numerous hormones and growth factors. Trp and Trp-like were first cloned from Drosophila and have similarity to voltage gated Ca2+ channels in the S3 through S6 regions. This suggests that Trp and/or related proteins may form mammalian CCC
entry channels (Zhu, X. et al. (1996) Cel185:661-671; Boulay, G. et al. (2997) J. Biol. Chem.

272:29672-29680). Melastatin is a gene isolated in both the mouse and human, and whose expression in melanoma cells is inversely correlated with melanoma aggressiveness in vivo. The human cDNA
transcript corresponds to a 1533-amino acid protein having homology to members of the Trp family. It has been proposed that the combined use of malastatin mRNA expression status and tumor thickness might allow for the determination of subgroups of patients at both low and high risk for developing metastatic disease (Duncan, L.M. et al (2001) J. Clin. Oncol. 19:568-576). ' Chloride channels are necessary in endocrine secretion and in regulation of cytosolic and organelle pH. In secretory epithelial cells, Cl- enters the cell across a basolateral membrane through an Na ~, K+/Cl' cotransporter, accumulating in the cell above its electrochemical equilibrium concentration.
Secretion of C1- from the apical surface, in response to hormonal stimulation, leads to flow of Na+ and water into the secretory lumen. The cystic fibrosis transmembrane conductance regulator (CFTR) is a chloride channel encoded by the gene for cystic fibrosis, a common fatal genetic disorder in humans.
CFTR is a member of the ABC transporter family, and is composed of two domains each consisting of six transmembrane domains followed by a nucleotide-binding site. Loss of CFTR
function decreases transepithelial water secretion and, as a result, the layers of mucus that coat the respiratory tree, pancreatic ducts, and intestine are dehydrated and difficult to clear. The resulting blockage of these sites leads to pancreatic insufficiency, "meconium ileus", and devastating "chronic obstructive pulmonary disease" (Al-Awqati, Q. et al. (1992) J. Exp. Biol. 172:245-266).
The voltage-gated chloride channels (CLC) are characterized by 10-12 transmembrane domains, as well as two small globular domains known as CBS domains. The CLC
subunits probably function as homotetramers. CLC proteins are involved in regulation of cell volume, membrane potential stabilization, signal transduction, and transepithelial transport.
Mutations in CLC-1, expressed predominantly in skeletal muscle, are responsible for autosomal recessive generalized myotonia and autosomal dominant myotonia congenita, while mutations in the kidney channel CLC-5 lead to kidney stones (Jentsch, T.J. (1996) Curr. Opin. Neurobiol. 6:303-310).
Ligand-gated channels open their pores when an extracellular or intracellular mediator binds to the channel. Neurotransmitter-gated channels are channels that open when a neurotransmitter binds to their extracellular domain. These channels exist in the postsynaptic membrane of nerve or muscle cells.
There are two types of neurotransmitter-gated channels. Sodium channels open in response to excitatory neurotransmitters, such as acetylcholine, glutamate, and serotonin.
This opening causes an influx of Na+ and produces the initial localized depolarization that activates the voltage-gated channels and starts the action potential. Chloride channels open in response to inhibitory neurotransmitters, such as 'y-aminobutyric acid (GABA) and glycine, leading to hyperpolarization of the membrane and the subsequent generation of an action potential. Neurotransmitter-gated ion channels have four transmembrane domains and probably function as pentamers (Jentsch, suura).
Amino acids in the second transmembrane domain appear to be important in determining channel permeation and selectivity (Sather, W.A. et al. (1994) Curr. Opin. Neurobiol. 4:313-323).
Ligand-gated channels can be regulated by intracellular second messengers. For example, calcium-activated K+ channels are gated by internal calcium ions. In nerve cells, an influx of calcium during depolarization opens K+ channels to modulate the magnitude of the action potential (Ishi et al., supra). The large conductance (BK) channel has been purified from brain and its subunit composition determined. The a, subunit of the BK channel has seven rather than six transmembrane domains in contrast to voltage-gated K+ channels. The extra transmembrane domain is located at the subunit N-terminus. A 28-amino-acid stretch in the C-terminal region of the subunit (the "calcium bowl" region) contains many negatively charged residues and is thought to be the region responsible for calcium binding. The ~i subunit consists of two transmembrane domains connected by a glycosylated extracellular loop, with intracellular N- and C-termini (Kaczorowski, supra;
Vergara, C. et al. (1998) Curr. Opin. Neurobiol. 8:321-329).
Cyclic nucleotide-gated (CNG) channels are gated by cytosolic cyclic nucleotides. The best examples of these are the cAMP-gated Na+ channels involved in olfaction and the cGMP-gated canon channels involved in vision. Both systems involve ligand-mediated activation of a G-protein coupled receptor which then alters the level of cyclic nucleotide within the cell. CNG
channels also represent a major pathway for Ca2+ entry into neurons, and play roles in neuronal development and plasticity.
CNG channels are tetraxners containing at least two types of subunits, an a subunit which can form functional homomeric channels, and a (3 subunit, which modulates the channel properties. All CNG
subunits have six transmembrane domains and a pore forming region between the fifth and sixth transmembrane domains, similar to voltage-gated K+ channels. A large C-terminal domain contains a cyclic nucleotide binding domain, while the N-terminal domain confers variation among channel subtypes (Zufall, F. et al. (1997) Curr. Opin. Neurobiol. 7:404-412).
The activity of other types of ion channel proteins may also be modulated by a variety of intracellular signalling proteins. Many channels have sites for phosphorylation by one or more protein kinases including protein kinase A, protein kinase C, tyrosine kinase, and casein kinase II, all of which regulate ion channel activity in cells. Kir channels are activated by the binding of the G~3~y subunits of heterotrimeric G-proteins (Reimann, F. and F.M. Ashcroft (1999) Curr. Opin. Cell. Biol.
11:503-508). Other proteins are involved in the localization of ion channels to specific sites in the cell membrane. Such proteins include the PDZ domain proteins known as MAGUKs (membrane-associated guanylate kinases) which regulate the clustering of ion channels at neuronal synapses (Craven, S.E. and D.S. Bredt (1998) Cell 93:495-498).

Disease Correlation The etiology of numerous human diseases and disorders can be attributed to defects in the transport of molecules across membranes. Defects in the trafficking of membrane-bound transporters and ion channels are associated with several disorders, e.g., cystic fibrosis, glucose-galactose malabsorption syndrome, hypercholesterolemia, von Gierke disease, and certain forms of diabetes mellitus. Single-gene defect diseases resultaing in an inability to transport small molecules across membranes include, e.g., cystinuria, iminoglycinuria, Hartup disease, and Fanconi disease (van't Hoff, W.G. (1996) Exp. Nephrol. 4:253-262; Talente, G.M. et al. (1994) Ann. Intern.
Med. 120:218-226;
and Chillon, M. et al. (1995) New Engl. J. Med. 332:1475-1480).
Human diseases caused by mutations in ion channel genes include disorders of skeletal muscle, cardiac muscle, and the central nervous system. Mutations in the pore-forming subunits of sodium and chloride channels cause myotonia, a muscle disorder in which relaxation after voluntary contraction is delayed. Sodium channel myotonias have been treated with channel blockers.
Mutations in muscle sodium and calcium channels cause forms of periodic paralysis, while mutations in the sarcoplasmic calcium release channel, T-tubule calcium channel, and muscle sodium channel cause malignant hyperthermia. Cardiac arrythmia disorders such as the long QT syndromes and idiopathic ventricular fibrillation are caused by mutations in potassium and sodium channels (Cooper, E.C. and L.Y. Jan (1998) Proc. Natl. Acad. Sci. USA 96:4759-4766). All four known human idiopathic epilepsy genes code for ion channel proteins (Berkovic, S.F. and LE. Scheffer (1999) Curr.
Opin. Neurology 12:177-182). Other neurological disorders such as ataxias, hemiplegic migraine and hereditary deafness can also result from mutations in ion channel genes (Jen, J. (1999) Curr. Opin.
Neurobiol. 9:274-280;
Cooper, suura).
Ion channels have been the target for many drug therapies. Neurotransmitter-gated channels have been targeted in therapies for treatment of insomnia, anxiety, depression, and schizophrenia.
Voltage-gated channels have been targeted in therapies for arrhythmia, ischemic stroke, head trauma, and neurodegenerative disease (Taylor, C.P. and L.S. Narasimhan (1997) Adv.
Pharmacol. 39:47-98).
Various classes of ion channels also play an important role in the perception of pain, and thus are potential targets for new analgesics. These include the vanilloid-gated ion channels, which are activated by the vanilloid capsaicin, as well as by noxious heat. Local anesthetics such as lidocaine and mexiletine which blockade voltage-gated Nay channels have been useful in the treatment of neuropathic pain (Eglen, supra).
Ion channels in the immune system have recently been suggested as targets for immunomodulation. T-cell activation depends upon calcium signaling, and a diverse set of T-cell specific ion channels has been characterized that affect this signaling process. Channel blocking agents can inhibit secretion of Iymphokines, cell proliferation, and killing of target cells. A peptide antagonist of the T-cell potassium channel Kvl.3 was found to suppress delayed-type hypersensitivity and allogenic responses in pigs, validating the idea of channel blockers as safe and efficacious immunosuppressants (Cahalan, M.D. and K.G. Chandy (1997) Curr. Opin.
Biotechnol. 8:749-756).
The discovery of new transporters and ion channels, 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 transport, neurological, muscle, immunological, and cell proliferative disorders, and in the assessment of the effects of exogenous compounds on the expression of nucleic acid and amino acid sequences of transporters and ion channels.
SUMMARY OF THE INVENTION
The invention features purified polypeptides, transporters and ion channels, referxed to collectively as "TRICH" and individually as "TRICH-1," "TRICH-2," "TRICH-3,"
"TRICH-4,"
"TRICH-5," "TRICH-6," "TRICH-7," "TRICH-8," "TRICH-9," "TRICH-10," "TRICH-11,"
"TRICH-12," "TRTCH-13," "TRICH-14," "TRICH-15," "TRICH-16," "TRICH-17," "TRICH-18,"
"TRICH-19," "TRICH-20," "TRICH-21," "TRICH-22," "TRICH-23," "TRICH-24," "TRICH-25,"
"TRICH-26," "TRICH-27," "TRICH-28," "TRICH-29," "TRICH-30," "TRICH-31," and "TRICH-32." 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 ID
N0:1-32, 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 N0:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32. In one alternative, the invention provides an isolated polypeptide comprising the amino acid sequence of SEQ ID N0:1-32.
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 ID NO:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32. In one alternative, the polynucleotide encodes a polypeptide selected from the group consisting of SEQ
ID NO:1-32. In another alternative, the polynucleotide is selected from the group consisting of SEQ ID N0:33-64. , 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 ID
NO:l-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32. 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 ID N0:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32. 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 ID N0:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32.
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 ID
N0:33-64, 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 N0:33-64, 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 nucleotides.

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 polynucleotide sequence selected from the group consisting of SEQ ID
N0:33-64, 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 N0:33-64, 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
N0:33-64, 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 N0:33-64, 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 N0:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-32, and a pharmaceutically acceptable excipient. In one embodiment, the composition comprises an amino acid sequence selected from the group consisting of SEQ ID N0:1-32. The invention additionally provides a method of treating a disease or condition associated with decreased expression of functional TRICH, 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 N0:1-32, 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 N0:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:l-32. 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 TRICH, 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 N0:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32. 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 TRICH, 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 ID N0:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-32. 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:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID N0:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
N0:1-32. 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 sequence selected from the group consisting of SEQ ID N0:33-64, the method comprising a) exposing a sample comprising the target polynucleotide to a compound, and b) detecting altered expression of the target polynucleotide.
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 N0:33-64, 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 N0:33-64, 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 ID
N0:33-64, 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 N0:33-64, 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 score for the match between each polypeptide and its GenBank homolog is 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 xeported 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
"TRICH" refers to the amino acid sequences of substantially purified TRICH
obtained from any species, particularly a mammalian species, including bovine, ovine, porcine, murine, 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 TRICH. Agonists may include proteins, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of TRICH either by directly interacting with TRICH or by acting on components of the biological pathway in which TRICH
participates.
An "allelic variant" is an alternative form of the gene encoding TRICH.
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 TRICH include those sequences with deletions, insertions, or substitutions of different nucleotides, resulting in a polypeptide the same as TRICH or a polypeptide with at least one functional characteristic of TRICH. Included within this definition are polymorphisms which may or may not be readily detectable using a particular oligonucleotide probe of the polynucleotide encoding TRICH, and improper or unexpected hybridization to allelic variants, with a locus other than the normal chromosomal locus for the polynucleotide sequence encoding TRICH.
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 TRICH.
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 TRICH 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 S 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 occurring 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 1S in the art.
The term "antagonist" refers to a molecule which inhibits or attenuates the biological activity of TRICH. Antagonists may include proteins such as antibodies, nucleic acids, carbohydrates, small molecules, or any other compound or composition which modulates the activity of TRICH either by directly interacting with TRICH or by acting on components of the biological pathway in which TRICH
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 TRICH polypeptides can be prepared using intact polypeptides or using fragments containing small peptides of interest as the immunizing antigen. The polypeptide or oligopeptide used 2S 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 carriers that are chemically coupled to peptides include bovine serum albumin, thyroglobulin, and keyhole limpet hemocyanin (KhH). 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) for binding to an antibody.

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 TRICH, 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-S'.
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 TRICH or fragments of TRICH 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., NaCl), 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 S' and/or the 3' direction, and resequenced, or which has been assembled from one or more overlapping cDNA, EST, or genoznic 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, Thr 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, aryl, 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.
A "fragment" is a unique portion of TRICH or the polynucleotide encoding TRICH
which is S 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 nuclebtide/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 S, 10, 15, 16, 20, 25, 30, 40, S0, 60, 7S, 100, 150, ZSO 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 S00 amino acids (or first 2S% or SO%) 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 1S embodiments.
A fragment of SEQ ID N0:33-64 comprises a region of unique polynucleotide sequence that specifically identifies SEQ ID N0:33-64, for example, as distinct from any other sequence in the genome from which the fragment was obtained. A fragment of SEQ ID N0:33-64 is useful, for example, in hybridization and amplification technologies and in analogous methods that distinguish SEQ ID N0:33-64 from related polynucleotide sequences. The precise length of a fragment of SEQ
ID N0:33-64 and the region of SEQ ID N0:33-64 to which the fragment corresponds are routinely deternunable by one of ordinary skill in the art based on the intended purpose for the fragment.
A fragment of SEQ ID N0:1-32 is encoded by a fragment of SEQ ID N0:33-64. A
fragment of SEQ ID N0:1-32 comprises a region of unique amino acid sequence that specifically identifies SEQ ID N0:1-32. For example, a fragment of SEQ ID N0:1-32 is useful as an immunogenic peptide for the development of antibodies that specifically recognize SEQ ID NO:1-32.
The precise length of a fragment of SEQ ID N0:1-32 and the region of SEQ ID N0:1-32 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 codon (e.g., methionine) followed by an open reading frame and a translation termination codon. 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.
3S 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 algorithm 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 VVI). 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.htxnl. 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 match: 1 Penalty for mismatch: -2 Open Gap: S afzd Exterasi.ofz Gap: 2 pefialties Gap x drop-off 50 Expect: 10 Word Size: 11 Filter: ofa 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 least 20, at least 30, at least 40, at least 50, at least 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" arid "% 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: Ktuple=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: 1l and Extension Gap: 1 penalties Gap x drop-off. 50 Expect: 1 D
Word Size: 3 Filter: ofa 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 % (wlv) SDS, and about 100 ~ g/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 carried out. Such wash temperatures are typically selected to be about 5°C to 20°C lower than the thermal melting point (T~ 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, 2nd 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 ~ ~ml. Organic solvent, such as formamide at a concentration of about 35-50% v/v, 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 TRICH
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 TRICH 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 TRICH. For example, modulation may cause an increase or a decrease in protein activity, binding characteristics, or any other biological, functional, or immunological properties of TRICH.
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 TRICH 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 TRICH.
"Probe" refers to nucleic acid sequences encoding TRICH, 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. Probes 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, 2nd ed., vol. 1-3, Cold Spring Harbor Press, Plainview NY; Ausubel, F.M. et al. (1987) Current Protocols in Molecular Bio- logy> 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).
S Oligonucleotides for use as primers are selected using software known in the art for such purpose. Fox 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 have incorporated additional features for expanded capabilities. For example, the PrimOU
20 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 InstituteJMIT Center for Genome Research, Cambridge MA) allows the user to input a "mispriming library," in which sequences to avoid as primer 15 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 20 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 oIigonucleotides 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 25 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 30 artificial manipulation of isolated segments of nucleic acids, e.g., by genetic engineering techniques such as those described in Sambrook, su ra. 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 elements interact with host or viral proteins which control transcription, translation, or RNA
stability.
"Reporter molecules" are chemical of 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 TRICH, nucleic acids encoding TRICH, 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" 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. 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), s-unra.
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 alternative 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 transporters and ion channels (TRICH), the polynucleotides encoding TRICH, and the use of these compositions for the diagnosis, treatment, or prevention of transport, neurological, muscle, immunological, and cell proliferative 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 ID NO:) and an Incyte polypeptide sequence number (Incyte Polypeptide ID) as shown. Each polynucleotide sequence is denoted by both a polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and an Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) as shown.
Table 2 shows sequences with homology to the polypeptides of the invention as identified by BLAST analysis against the GenBank protein (genpept) database. Columns 1 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 score for the match between each polypeptide and its GenBank homolog. Column 5 shows the annotation of the GenBank homolog 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 ID) 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 arid 3 summarize the properties of polypeptides of the invention, and these properties establish that the claimed polypeptides are transporters and ion channels. For example, SEQ
ID N0:5 is 83% identical to rat GABA receptor rho-3 subunit precursor (GenBank ID 81060975) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST
probability score is 1.7e-206, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:5 also contains a neurotransmitter-gated ion channel 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
N0:5 is a neurotransmitter-gated ion channel. In an alternate example, SEQ ID
N0:16 is 57%
identical to human Na+/glucose cotransporter (GenBank ID 8338055) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 2.4e-181, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID
NO:16 also contains a sodiumaolute symporter family 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 N0:16 is a Na+/glucose cotransporter. In an alternate example, SEQ ID N0:27 is 53% identical to human ATP-binding cassette transporter-2 (ABC-1) (GenBank ID 84128033) 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 N0:27 also contains an ABC transporter 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
N0:27 is an ABC transporter. In an alternate example, SEQ ID N0:12 is 45 %
identical to rat thyroid sodiumliodide symporter NIS (GenBank ID 81399954) as determined by the Basic Local Alignment Search Tool (BLAST). (See Table 2.) The BLAST probability score is 3.0e-143, which indicates the probability of obtaining the observed polypeptide sequence alignment by chance. SEQ ID N0:12 also contains a sodiumaolute symporter family 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 N0:12 is a sodiumaolute symporter. SEQ ID
NO:1-4, SEQ ID
N0:6-11, SEQ ID N0:13-15, SEQ ID N0:17-26, and SEQ ID N0:28-32 were analyzed and annotated in a similar manner. The algorithms and parameters for the analysis of SEQ ID
NO:1-32 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 (exon) sequences derived from genomic DNA, or any combination of these two types of sequences. Columns 1 and 2 list the polynucleotide sequence identification number (Polynucleotide SEQ ID NO:) and the corresponding Incyte polynucleotide consensus sequence number (Incyte Polynucleotide ID) for each polynucleotide of the invention.
Column 3 shows the length of each polynucleotide sequence in basepairs. Column 4 lists fragments of the polynucleotide sequences which are useful, for example, in hybridization or amplification technologies that identify SEQ ID N0:33-64 or that distinguish between SEQ ID
N0:33-64 and related polynucleotide sequences. Column 5 shows identification numbers corresponding to cDNA
sequences, coding sequences (exons) predicted from genomic DNA, and/or sequence assemblages comprised of both cDNA and genomic DNA. These sequences were used to assemble the full length polynucleotide sequences of the invention. Columns 6 and 7 of Table 4 show the nucleotide start (5') and stop (3') positions of the cDNA and/or genomic sequences in column 5 relative to their respective full length sequences.
The identification numbers in Column 5 of Table 4 may refer specifically, for example, to Incyte cDNAs along with their corresponding cDNA libxaries. For example, 6724643H1 is the identification number of an Incyte cDNA sequence, and LUNLTMT01 is the cDNA
library from which it is derived. Incyte cDNAs for which cDNA libraries are not indicated were derived from pooled cDNA libraries (e.8., 71495515V1). Alternatively, the identification numbers in column 5 may refer to GenBank cDNAs or ESTs (e.8., 85746200) which contributed to the assembly of the full length polynucleotide sequences. In addition, the identification numbers in column 5 may identify sequences derived from the ENSEMBL (The Sanger Centre, Cambridge, UK) database (i.e., those sequences including the designation "ENST"). Alternatively, the identification numbers in column S 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 identification numbers in column S may refer to S assemblages of both cDNA and Genscan-predicted exons brought together by an "exon stitching"
algorithm. For example, FL XXXXXX Nl NZ YYYYY N3 N~ represents a "stitched"
sequence in which XXXXXX is the identification number of the cluster of sequences to which the algorithm was applied, and YI'YYY 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 identification numbers in column S may refer to assemblages of exons brought together by an "exon-stretching" algorithm. Fox example, FLXXXXXX
gAAAAA_gBBBBB_1 N is the identification number of 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 1S NCBI RefSeq identification number of the nearest GenBank protein homolog, and N referring 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, 2S ENST for example, 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).

In some cases, Incyte cDNA coverage redundant with the sequence coverage shown in column S 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
Iibrary is the Incyte cDNA library which is most frequently represented by the Incyte cDNA sequences which were used to assemble and conf'~rm 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 TRICH variants. A preferred TRICH 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 TRICH amino acid sequence, and which contains at least one functional or structural characteristic of TRICH.
The invention also encompasses polynucleotides which encode TRICH. In a particular embodiment, the invention encompasses a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID N0:33-64, which encodes TRICH. The polynucleotide sequences of SEQ ID N0:33-64, 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 TRICH. In 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 TRICH. A particular aspect of the invention encompasses a variant of a polynucleotide sequence comprising a sequence selected from the group consisting of SEQ ID
N0:33-64 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 N0:33-64.
Any one of the polynucleotide variants described above can encode an amino acid sequence which contains at least one functional or structural characteristic of TRICH.
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 TRICH, 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 TRICH, and all such variations are to be considered as being specifically disclosed.
Although nucleotide sequences which encode TRICH and its variants are generally capable of hybridizing to the nucleotide sequence of the naturally occurring TRICH under appropriately selected conditions of stringency, it may be advantageous to produce nucleotide sequences encoding TRICH 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 TRICH 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 TRICH
and TRICH 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 TRICH 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
N0:33-64 and fragments thereof under various conditions of stringency. (See, e.g., Wahl, G.M. and S.L. Berger (1987) Methods Enzymol. 152:399-407; Kimmel, A.R. (1987) Methods Enzymol.
152:507-511.) Hybridization conditions, including annealing and wash conditions, are described in "Definitions."
Methods for DNA sequencing are 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 Klenow 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 Biology, John Wiley & Sons, New York NY, unit 7.7; Meyers, R.A.
(1995) Molecular Biology and Biotechnology, Wiley VCH, New York NY, pp. 856-853.) The nucleic acid sequences encoding TRICH 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., Saxkar, 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. I:1 I 1-119.) In this method, multiple restriction enzyme digestions and legations 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 es 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 S0% 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 additeon, random-primed libraries, which often include sequences contaening the 5' regions of genes, are preferable for situations in which an oligo d(T) library does not yield a full-length cDNA. Genomec 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 wavele baths. Outputllight 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 TRICH may be cloned in recombinant DNA molecules that direct expression of TRICH, 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 TRICH.
The nucleotide sequences of the present invention can be engineered using methods generally known in the art in order to alter TRICH-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 Number 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 TRICH, 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 TRICH 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, TRICH 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 TRICH, 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 (I990) Methods Enzymol. 182:392-42I.) The composition of the synthetic peptides may be confirmed by amino acid analysis or by sequencing.
(See, e.g., Creighton, s-u~ra, pp. 28-53.) In order to express a biologically active TRICH, the nucleotide sequences encoding TRICH 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 TRICH. Such elements may vary in their strength and specificity.
Specific initiation signals may also be used to achieve more efficient translation of sequences encoding TRICH. Such signals include the ATG initiation codon and adjacent sequences, e.g. the Kozak sequence. In cases where sequences encoding TRICH 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 TRICH 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 Cloning 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 Biolo~y, John Wiley & Sons, New York NY, ch. 9, 13, and 16.) A variety of expression vector/host systems maybe utilized to contain and express sequences encoding TRICH. 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, su ra; 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 from retxoviruses, 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 Nicola, 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 TRICH. For example, routine cloning, subcloning, and propagation of polynucleotide sequences encoding TRICH can be achieved using a multifunctional E. coli vector such as PBLUESCRIPT (Stratagene, La Jolla CA) or PSPORT1 plasmid (Life Technologies). Ligation of sequences encoding TRICH into the vector's multiple cloning site disrupts the lacZ gene, allowing a colorimetric 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 TRICH are needed, e.g. for the production of antibodies, vectors which direct high level expression of TRICH 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 TRICH. A number of vectors containing constitutive or inducible promoters, such as alpha factor, alcohol oxidase, and PGH
promoters, may be used in the yeast Saccharomvces 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, supra;
Bitter, G.A. et al. (1987) Methods Enzymol. 153:516-544; and Scorer, C.A. et al. (1994) Bio/Technology 12:181-184.) Plant systems may also be used for expression of TRICH. Transcription of sequences encoding TRICH may be driven by viral promoters, e.g., the 35S and 19S 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 al. (1984) EMBO J. 3:1671-1680; Brogue, R. et al. (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 Technolo~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 TRICH
may be ugated into an adenovirus transcription/translation complex consisting of the late promoter and tripartite leader sequence. Insextion in a non-essential E1 or E3 region of the viral genome may be used to obtain infective virus which expresses TRICH 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 polymers, or vesicles) for therapeutic purposes. (See, e.g., Harrington, J.J. et al.
(1997) Nat. Genet. 15:345-355.) For long term production of recombinant proteins in mammalian systems, stable expression of TRICH in cell lines is preferred. For example, sequences encoding TRICH 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, for use in tk and apr- 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 hexbicide resistance can be used as the basis for selection. For example, dl~ confers resistance to methotrexate; raeo 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 al. (1980) Pxoc. 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. (See, e.g., Rhodes, C.A.
(1995) Methods Mol. Biol. 55:121-131.) Although the presence/absence 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 TRICH is inserted witlun a marker gene sequence, transformed cells containing sequences encoding TRICH can be identified by the absence of marker gene function. Alternatively, a marker gene can be placed in tandem with a sequence encoding TRICH 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 TRICH
and that express TRICH 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 TRICH
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 TRICH 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) Serological 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. (1998) Immunochemical Protocols, Humana 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 TRICH include oligolabeling, nick translation, end-labeling, or PCR amplification using a labeled nucleotide.
Alternatively, the sequences encoding TRICH, 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 TRICH 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 TRICH may be designed to contain signal sequences which direct secretion of TRICH 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-txanslational activities (e.g., CHO, HeLa, MDCI~, 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 TRICH 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 TRICH protein containing a heterologous moiety that can be recognized by a commercially available antibody may facilitate the screening of peptide libraries for inhibitors of TRICH
activity. Heterologous protein and peptide moieties may also facilitate purification of fusion proteins using commercially available affinity matrices. Such moieties include, but are not limited to, glutathione S-transferase (GST), maltose binding protein (MBP), thioredoxin (Trx), calmodulin binding peptide (CBP), 6-His, FLAG, c-rnyc, 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 TRICH encoding sequence and the heterologous protein sequence, so that TRICH
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 TRICH 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.
TRICH of the present invention or fragments thereof may be used to screen for compounds that specifically bind to TRICH. At least one and up to a plurality of test compounds may be screened for specific binding to TRICH. 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 TRICH, e.g., a ligand 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 TRICH
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 TRICH, either as a secreted protein or on the cell membrane. Preferred cells include cells from mammals, yeast, Droso~hila, or E.
coli. Cells expressing TRICH or cell membrane fractions which contain TRICH
are then contacted with a test compound and binding, stimulation, or inhibition of activity of either TRICH 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 TRICH, either in solution or affixed to a solid support, and detecting the binding of TRICH 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.
TRICH of the present invention or fragments thereof may be used to screen for compounds that modulate the activity of TRICH. Such compounds may include agonists, antagonists, or partial 44.

or inverse agonists. In one embodiment, an assay is performed under conditions permissive for TRICH
activity, wherein TRICH is combined with at least one test compound, and the activity of TRICH in the presence of a test compound is compared with the activity of TRICH in the absence of the test compound. A change in the activity of TRICH in the presence of the test compound is indicative of a compound that modulates the activity of TRICH. Alternatively, a test compound is combined with an in vitro or cell-free system comprising TRICH under conditions suitable for TRICH activity, and the assay is performed. In either of these assays, a test compound which modulates the activity of TRICH
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.
I0 In another embodiment, polynucleotides encoding TRICH 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 Number 5,175,383 and U.S. Patent Number 5,767,337.) For example, mouse ES cells, such as the mouse 1291SvJ 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 axe identified and microinjected into mouse Bell 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 TRICH 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, fox example, neural cells, hematopoietic lineages, and cardiomyocytes (Thomson, J.A. et al. (1998) Science 282:1145-1147).
Polynucleotides encoding TRICH 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 TRICH 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 TRICH, e.g., by secreting TRICH 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 TRICH and transporters and ion channels. In addition, the expression of TRICH
is closely associated with adrenal, testicular, and prostate tumors, Crohn's disease, teratocarcinoma and dendritic cells, brain, lung, ileum, small intestine, uterine myometrial, colon, and pancreatic tissues. Therefore, TRICH appears to play a role in transport, neurological, muscle, immunological, and cell proliferative disorders. In the treatment of disorders associated with increased TRICH
expression or activity, it is desirable to decrease the expression or activity of TRICH. In the treatment of disorders associated with decreased TRICH expression or activity, it is desirable to increase the expression or activity of TRICH.
Therefore, in one embodiment, TRICH 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 TRICH. Examples of such disorders include, but are not limited to, a transport disorder such as akinesia, amyotrophic lateral sclerosis, ataxia telangiectasia, cystic fibrosis, Becker's muscular dystrophy, Bell's palsy, Charcot-Marie Tooth disease, diabetes mellitus, diabetes insipidus, diabetic neuropathy, Duchenne muscular dystrophy, hyperkalemic periodic paralysis, normokalemic periodic paralysis, Parkinson's disease, malignant hyperthermia, multidrug resistance, myasthenia gravis, myotonic dystrophy, catatonia, tardive dyskinesia, dystonias, peripheral neuropathy, cerebral neoplasms, prostate cancer, cardiac disorders associated with transport, e.g., angina, bradyarrythmia, tachyarrythmia, hypertension, Long QT syndrome, myocarditis, cardiomyopathy, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, thyrotoxic myopathy, ethanol myopathy, dermatomyositis, inclusion body myositis, infectious myositis, polymyositis, neurological disorders associated with transport, e.g., Alzheimer's disease, amnesia, bipolar disorder, dementia, depression, epilepsy, Tourette's disorder, paranoid psychoses, and schizophrenia, and other disorders associated with transport, e.g., neurofibromatosis, postherpetic neuralgia, trigeminal neuropathy, sarcoidosis, sickle cell anemia, Wilson's disease, cataracts, infertility, pulmonary artery stenosis, sensorineural autosomal deafness, hyperglycemia, hypoglycemia, Grave's disease, goiter, Cushing's disease, Addison's disease, glucose-galactose malabsorption syndrome, hypercholesterolemia, adrenoleukodystrophy, Zellweger syndrome, Menkes disease, occipital horn syndrome, von Gierke disease, cystinuria, iminoglycinuria, Hartup disease, and Fanconi disease; 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, prion diseases 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 including Down syndrome, 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, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a muscle disorder such as cardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker's muscular dystrophy, myotonic dystrophy, central core disease, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, infectious myositis, polymyositis, dermatomyositis, inclusion body myositis, thyrotoxic myopathy, ethanol myopathy, angina, anaphylactic shock, arrhythmias, asthma, cardiovascular shock, Cushing's syndrome, hypertension, hypoglycemia, myocardial infarction, migraine, pheochromocytoma, and myopathies including encephalopathy, epilepsy, Kearns-Sayre syndrome, lactic acidosis, myoclonic disorder, ophthalmoplegia, and acid maltase deficiency (AMD, also known as Pompe's disease); an immunological disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; and 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 cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocaxcinoma, and, in particular, cancers 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, pxostate, salivary glands, skin, spleen, testis, thymus, thyroid, and uterus.
In another embodiment, a vector capable of expressing TRICH 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 TRICH including, but not limited to, those described above.
In a further embodiment, a composition comprising a substantially purified TRICH in conjunction with a suitable pharmaceutical carrier may be administered to a subject to txeat or prevent a disorder associated with decreased expression or activity of TRICH including, but not limited to, those provided above.
In still another embodiment, an agonist which modulates the activity of TRICH
may be administered to a subject to treat or prevent a disorder associated with decreased expression or activity of TRICH including, but not limited to, those listed above.
In a further embodiment, an antagonist of TRICH may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of TRICH.
Examples of such disorders include, but are not limited to, those transport, neurological, muscle, immunological, and cell proliferative disorders described above. In one aspect, an antibody which specifically binds TRICH
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 TRICH.
In an additional embodiment, a vector expressing the complement of the polynucleotide encoding TRICH may be administered to a subject to treat or prevent a disorder associated with increased expression or activity of TRICH 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 TRICH may be produced using methods which axe generally known in the art.
In particular, purified TRICH may be used to produce antibodies or to screen libraries of pharmaceutical agents to identify those which specifically bind TRICH.
Antibodies to TRICH 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.
For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others may be immunized by injection with TRICH 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 Corvnebacteriumparvum are especially preferable.
It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to TRICH 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 TRICH 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 TRICH 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 EBV-hybridoma technique. (See, e.g., Kohler, G. et al. (1975) Nature 256:495-497; Kozbor, D.
et al. (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., Morxison, 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 TRICH-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. Acid. 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. Acid. Sci.
USA 86:3833-3837; Winter, G. et aI. (1991) Nature 349:293-299.) Antibody fragments which contain specific binding sites for TRICH 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 TRICH and its specific antibody. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering TRICH epitopes is generally used, but a competitive binding assay may also be employed (Pound, su ra).
Various methods such as Scatchaxd analysis in conjunction with radioimmunoassay techniques may be used to assess the affinity of antibodies for TRICH. Affinity is expressed as an association constant, I~, which is defined as the molar concentration of TRICH-antibody complex divided by the molar concentrations of free antigen and free antibody under equilibrium conditions. The I~ determined for a preparation of polyclonal antibodies, which are heterogeneous in their affinities for multiple TRICH epitopes, represents the average affinity, or avidity, of the antibodies for TRICH. The I~
determined for a preparation of monoclonal antibodies, which are monospecific for a particular TRICH
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 TRICH-antibody complex must withstand rigorous manipulations. Low-affinity antibody preparations with I~ ranging from about 106 to 10' L/mole are preferred for use in immunopurification and similar procedures which ultimately require dissociation of TRICH, 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 TRICH-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 TRICH, 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 TRICH.
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 TRICH.
(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, K.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, su ra; 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 al. (1998) J. Pharm. Sci. 87(11):1308-1315; and Morris, M.C. et al. (1997) Nucleic Acids Res.
25(14):2730-2736.) In another embodiment of the invention, polynucleotides encoding TRICH 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)-X1 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 deanninase (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) Cel175:207-216; 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 falc~arum and T~anosoma cruzi). In the case where a genetic deficiency in TRICH expression or regulation causes disease, the expression of TRICH 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 TRICH are treated by constructing mammalian expression vectors encoding TRICH
and introducing these vectors by mechanical means into TRICH-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 fransfection, (iv) receptor-mediated gene transfer, and (v) the use of DNA txansposons (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 TRICH include, but are not limited to, the PCDNA 3.1, EPITAG, PRCCMV2, PREP, PVAX 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). TRICH 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 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 FK506/rapamycin inducible promoter; or the RU486/mifepristone inducible promoter (Rossi, F.M.V.
and Blau, H.M. s_ upra)), or (iii) a tissue-specific promoter or the native promoter of the endogenous gene encoding TRICH from a normal individual.
Commercially available liposome transformation kits (e.g., the PERFECT LIPID
TRANSFECTION KIT, 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. 2:841-845). 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 TRICH expression are treated by constructing a retrovirus vector consisting of (i) the polynucleotide encoding TRICH 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) axe 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 Number 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 axe 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 89:22$3-2290).
In the alternative, an adenovirus-based gene therapy delivery system is used to deliver polynucleotides encoding TRICH to cells which have one or more genetic abnormalities with respect to the expression of TRICH. 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 al. (1995) Transplantation 27:263-268). Potentially useful adenoviral vectors are described in U.S. Patent Number 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 incarporated by reference herein.
In another alternative, a herpes-based, gene therapy delivery system is used to deliver polynucleotides encoding TRICH to target cells which have one or more genetic abnormalities with respect to the expression of TRICH. The use of herpes simplex virus (HSV)-based vectors may be especially valuable for introducing TRICH 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 Number 5,804,413 to DeLuca ("Herpes simplex virus strains for gene transfer"), which is hereby incorporated by reference. U.S. Patent Number 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 TCP22.
For HSV vectors, see also Goins, W.F. et al. (1999) J. Virol. 73:519-532 and Xu, H. et al, (1994) Dev.
Biol. 163:152-261, 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 TRICH 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 K.-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 TRICH
into the alphavirus genome in place of the capsid-coding region results in the production of a large number of TRICH-coding RNAs and the synthesis of high levels of TRICH 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 (STN) 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 TRICH 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 Immunoloyc 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 TRICH.
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 TRICH. 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 ofthe invention encompasses a method for screening for a compound which is effective in altering expression of a polynucleotide encoding TRICH.
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 TRICH expression or activity, a compound which specifically inhibits expression of the polynucleotide encoding TRICH may be therapeutically useful, and in the treatment of disorders associated with decreased TRICH expression or activity, a compound which specifically promotes expression of the polynucleotide encoding TRICH 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-occurring 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 TRICH 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 TRICH 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 TRICH. The amount of hybridization may be quantified, thus forming the basis for 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.
Biotechno1.15:462-466.) 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 TRICH, antibodies to TRICH, and mimetics, agonists, antagonists, or inhibitors of TRICH.
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 priox 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 for 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 TRICH or fragments thereof. Fox example, liposome preparations containing a cell-impermeable macromolecule may promote cell fusion and intracellular delivery of the macromolecule. Alternatively, TRICH 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 xoute of administration. Such information can then be used to determine useful doses and routes for administration in humans.
A therapeutically effective dose refers to that amount of active ingredient, for example TRICH
or fragments thereof, antibodies of TRICH, and agonists, antagonists or inhibitors of TRICH, 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 0.1 ~cg to 100,000 fig, 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 TRICH may be used for the diagnosis of disorders characterized by expression of TRICH, or in assays to monitor patients being treated with TRICH or agonists, antagonists, or inhibitors of TRICH.
Antibodies useful for diagnostic purposes may be prepared in the same manner as described above for therapeutics. Diagnostic assays for TRICH include methods which utilize the antibody and a label to detect TRICH 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 TRICH, including ELISAs, RIAs, and FACS, are known in the art and provide a basis for diagnosing altered or abnormal levels of TRICH expression. Normal or standard values for TRICH expression are established by combining body fluids or cell extracts taken from normal mammalian subjects, for example, human subjects, with antibodies to TRICH under conditions suitable for complex formation. The amount of standard complex formation may be quantitated by various methods, such as photometric means. Quantities of TRICH
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 TRICH 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 TRICH may be correlated with disease. The diagnostic assay may be used to determine absence, presence, and excess expression of TRICH, and to monitor regulation of TRICH levels during therapeutic intervention.
In one aspect, hybridization with PCR probes which are capable of detecting polynucleotide sequences, including genomic sequences, encoding TRICH or closely related molecules may be used to identify nucleic acid sequences which encode TRICH. 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 ox amplification will determine whether the probe identifies only naturally occurring sequences encoding TRICH, 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 TRICH encoding sequences. The hybridization probes of the subject invention may be DNA ox RNA and may be derived from the sequence of SEQ ID
N0:33-64 or from genomic sequences including promoters, enhancers, and introns of the TRICH
gene.
Means for producing specific hybridization probes for DNAs encoding TRICH
include the cloning of polynucleotide sequences encoding TRICH or TRICH 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 32P or 35S, or by enzymatic labels, such as alkaline phosphatase coupled to the probe via avidin/biotin coupling systems, and the like.
Polynucleotide sequences encoding TRICH may be used fox the diagnosis of disorders associated with expression of TRICH. Examples of such disorders include, but are not limited to, a transport disorder such as akinesia, amyotrophic lateral sclerosis, ataxia telangiectasia, cystic fibrosis, Becker's muscular dystrophy, Bell's palsy, Charcot-Marie Tooth disease, diabetes mellitus, diabetes insipidus, diabetic neuropathy, Duchenne muscular dystrophy, hyperkalemic periodic paralysis, normokalemic periodic paralysis, Parkinson's disease, malignant hyperthermia, multidrug resistance, myasthenia gravis, myotonic dystrophy, catatonia, tardive dyskinesia, dystonias, peripheral neuropathy, cerebral neoplasms, prostate cancer, cardiac disorders associated with transport, e.g., angina, bradyarrythmia, tachyarrythmia, hypertension, Long QT syndrome, myocarditis, cardiomyopathy, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, thyrotoxic myopathy, ethanol myopathy, dermatomyositis, inclusion body myositis, infectious myositis, polymyositis, neurological disorders associated with transport, e.g., Alzheimer's disease, amnesia, bipolar disorder, dementia, depression, epilepsy, Tourette's disorder, paranoid psychoses, and schizophrenia, and other disorders associated with transport, e.g., neurofibromatosis, postherpetic neuralgia, trigeminal neuropathy, sarcoidosis, sickle cell anemia, Wilson's disease, cataracts, infertility, pulmonary artery stenosis, sensorineural autosomal deafness, hyperglycemia, hypoglycemia, Grave's disease, goiter, Cushing's disease, Addison's disease, glucose-galactose malabsorption syndrome, hypercholesterolemia, adrenoleukodystrophy, Zellweger syndrome, Menkes disease, occipital horn syndrome, von Gierke disease, cystinuria, iminoglycinuxia, Hartup disease, and Fanconi disease; 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, priors diseases 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 including Down syndrome, 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, Tourette's disorder, progressive supranuclear palsy, corticobasal degeneration, and familial frontotemporal dementia; a muscle disorder such as cardiomyopathy, myocarditis, Duchenne's muscular dystrophy, Becker's muscular dystrophy, myotonic dystrophy, central core disease, nemaline myopathy, centronuclear myopathy, lipid myopathy, mitochondrial myopathy, infectious myositis, polymyositis, dermatomyositis, inclusion body myositis, thyrotoxic myopathy, ethanol myopathy, angina, anaphylactic shock, arrhythmias, asthma, cardiovascular shock, Cushing's syndrome, hypertension, hypoglycemia, myocardial infarction, migraine, pheochromocytoma, and myopathies including encephalopathy, epilepsy, Kearns-Sayre syndrome, lactic acidosis, myoclonic disorder, ophthalmoplegia, and acid maltase deficiency (AMD, also known as Pompe's disease); an immunological disorder such as acquired immunodeficiency syndrome (AIDS), Addison's disease, adult respiratory distress syndrome, allergies, ankylosing spondylitis, amyloidosis, anemia, asthma, atherosclerosis, autoimmune hemolytic anemia, autoimmune thyroiditis, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), bronchitis, cholecystitis, contact dermatitis, Crohn's disease, atopic dermatitis, dermatomyositis, diabetes mellitus, emphysema, episodic lymphopenia with lymphocytotoxins, erythroblastosis fetalis, erythema nodosum, atrophic gastritis, glomerulonephritis, Goodpasture's syndrome, gout, Graves' disease, Hashimoto's thyroiditis, hypereosinophilia, irritable bowel syndrome, multiple sclerosis, myasthenia gravis, myocardial or pericardial inflammation, osteoarthritis, osteoporosis, pancreatitis, polymyositis, psoriasis, Reiter's syndrome, rheumatoid arthritis, scleroderma, Sjogren's syndrome, systemic anaphylaxis, systemic lupus erythematosus, systemic sclerosis, thrombocytopenic purpura, ulcerative colitis, uveitis, Werner syndrome, complications of cancer, hemodialysis, and extracorporeal circulation, viral, bacterial, fungal, parasitic, protozoal, and helminthic infections, and trauma; and 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 cancers including adenocarcinoma, leukemia, lymphoma, melanoma, myeloma, sarcoma, teratocarcinoma, and, in particular, cancers 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.
The polynucleotide sequences encoding TRICH 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 TRICH expression.
Such qualitative or quantitative methods are well known in the art.
In a particular aspect, the nucleotide sequences encoding TRICH may be useful in assays that detect the presence of associated disorders, particularly those mentioned above. The nucleotide sequences encoding TRICH 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 TRICH 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 TRICH, a normal or standard profile for expression is established. This may be accomplished by combining body fluids or cell extracts taken from normal subjects, either animal or human, with a sequence, or a fragment thereof, encoding TRICH, 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 TRICH
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 TRICH, or a fragment of a polynucleotide complementary to the polynucleotide encoding TRICH, 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 TRICH 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 TRICH 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 tertiar y 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).
Methods which may also be used to quantify the expression of TRICH 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 spectrophotornetric 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 rnicroarray 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 his/her pharmacogenomic profile.
In another embodiment, TRICH, fragments of TRICH, or antibodies specific for TRICH 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 Number 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 arid refined 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://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 polynucleotides 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 biological 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 polypeptide 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 TRICH
to quantify the levels of TRICH 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 2U levels of protein bound to each array element (Lueking, A. et al. (1999) Anal. Biochem. 270:103-111;
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 S 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 W09S/2S 1116;
Shalom D. et al.
(1995) PCT application W095/35505; Heller, R.A. et al. (1997) Proc. Natl.
Acad. Sci. USA 94:2150-21SS; and Heller, M.J. et al. (1997) U.S. Patent No. S,60S,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 TRICH
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 multi-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 P1 2S 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, Larder, 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, su ra, pp. 96S-968.) Examples of genetic map data can be found in various scientific journals or at the Online Mendelian Inheritance in Man (OMIM) World Wide Web site. Correlation between the location of the gene encoding TRICH 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 11q22-23, 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, TRICH, 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 TRICH 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 W084/03564.) In this method, large numbers of different small test compounds are synthesized on a solid substrate. The test compounds are reacted with TRICH, or fragments thereof, and washed. Bound TRICH is then detected by methods well known in the art.
Purified TRICH 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 TRICH specifically compete with a test compound for binding TRICH.
In this manner, antibodies can be used to detect the presence of any peptide which shares one or more antigenic determinants with TRICH.
In additional embodiments, the nucleotide sequences which encode TRICH 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 limitative 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. 60/216,547, U.S. Ser. No. 60/21$,232, U.S. Ser. No.
60/220,112, and U.S.
Ser. No. 601221,839 are expressly incorporated by reference herein., are expressly incorporated by reference herein.
EXAMPLES
I. Construction of cDNA Libraries Incyte cDNAs were derived from cDNA libraries described in the LIFESEQ GOLD
database (Incyte Genomics, Palo Alto CA) and shown in Table 4, column 5. Some tissues were homogenized and lysed in guanidinium isothiocyanate, while others were homogenized and lysed in phenol or in a suitable mixture of denaturants, such as TRIZOL (Life Technologies), a monophasic solution of phenol and guanidine isothiocyanate. The resulting Iysates 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, s.~ra, 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), or pINCY (Incyte Genomics, Palo AIto CA), or derivatives thereof. Recombinant plasmids were transformed into competent E. coli cells including XL1-Blue, XLl-BlueMRF, or SOLR from Stratagene or DHSa, DH10B, 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. Biochem. 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 II 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, su ra, 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 algoritluns 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, and hidden Markov model (HMM)-based protein family databases such as PFAM.
(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, 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 Conned, 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, BLOCKS, PRINTS, DOMO, PRODOM, Prosite, and hidden Markov model (HMM)-based protein family databases such as PFAM. 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 ID
N0:33-64. Fragments from about 20 to about 4000 nucleotides which are useful in hybridization and amplification technologies are described in Table 4, column 4.
IV. Identification and Editing of Coding Sequences from Genomic DNA
Putative transporters and ion channels 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. Karlin (1997) J. Mol. Biol. 268:78-94, and Burge, C. and S. Karlin (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 transporters and ion channels, the encoded polypeptides were analyzed by querying against PFAM models for transporters and ion channels. Potential transporters and ion channels were also identified by homology to Incyte cDNA sequences that had been annotated as transporters and ion channels. 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 find 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" Seguences Partial cDNA sequences were extended with exons predicted by the Genscan gene identification program described in Example IV. 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 cDNA 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" Sequences Partial DNA sequences were extended to full length with an algorithm based on BLAST
analysis. First, partial cDNAs 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 in 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 homolog. 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 TRICH Encoding Polynucleotides The sequences which were used to assemble SEQ ID N0:33-64 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 N0:33-64 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/genemapn, 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 LIFESEQ (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 SO% overlap at one end, or 79% identity and 100% overlap.
Alternatively, polynucleotide sequences encoding TRICH 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 organltissue 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; unclassified/mixed; 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 disease/condition 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 TRICH. cDNA sequences and cDNA library/tissue information are found in the LIFESEQ
GOLD database (Incyte Genomics, Palo Alto CA).
VIII. Extension of TRICH 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 known 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 lmown 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)2S04, and 2-mercaptoethanol, Taq DNA polymerase (Amersham Pharmacia Biotech), ELONGASE enzyme (Life Technologies), and Pfu DNA polymerase (Stratagene), with the following parameters for 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, 1 S 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 ~1 PICOGREEN
quantitation reagent (0.25% (v/v) PICOGREEN; Molecular Probes, Eugene OR) dissolved in 1X TE
and 0.5 ~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 ~1 to 10 ~l 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 relegation into pUC 18 vectox (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 relegated using T4 ligase (New England Biolabs, Beverly MA) into pUC 18 vector (Amersham Pharmacia Biotech), treated with Pfu DNA polymerase (Stratagene) to fill-in restriction site overhangs, and transfected into competent E. cole 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 carb liquid media.
The cells were lysed, and DNA was amplified by PCR using Taq DNA polymerase (Amersham Phaxmacia Biotech) and Pfu DNA polymerase (Stratagene) with the following parameters: Step 1:
94°C, 3 min; Step 2: 94°C, 1S 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 wexe reaxnplified 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 S' regulatory sequences using the above procedure along with oligonucleotides designed for such extension, and an appropriate genomic library.
IX. Labeling and Use of Individual Hybridization Probes Hybridization probes derived from SEQ ID N0:33-64 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 ~CCi of [~
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 superfine 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.
X. 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 (SSTs), 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, Iaser 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/~Q oligo-(dT) primer (2lmer), 1X first strand buffer, 0.03 units/pl RNase inhibitor, 500 ~M dATP, 500 ~M dGTP, 500 ~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 girl 5X SSC/0.2% SDS.
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 fig. 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 Carporation (VWR), West Chester PA), washed extensively in distilled water, and coated with 0.05 % aminopxopyl 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 US
Patent No. 5,807,522, incorporated herein by reference. 1 Eal of the array element DNA, at an average concentration of 100 ng/Eil, 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) fox 30 minutes at 60°C
followed by washes in 0.2% SDS and distilled water as before.
Hybridization Hybridization reactions contain 9 ~.il of sample mixture consisting of 0.2 ~g each of Cy3 and Cy5 labeled cDNA synthesis pxoducts 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 Iarger 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 are 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 S6S nm for Cy3 and 6S0 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 fiuorophore, 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 fiuorophores and adding identical amounts of each to the hybridization mixture.
The output of the photomultiplier tube is digitized using a 12-bit RTI-83SH
analog-to-digital (A/D) conversion board (Analog Devices, Inc., Norwood MA) installed in an IBM-compatible PC
1S 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).
XI. Complementary Polynucleotides Sequences complementary to the TRICH-encoding sequences, or any parts thereof, are used to detect, decrease, or inhibit expression of naturally occurring TRICH. Although use of oligonucleotides comprising from about 1S 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 TRICH. To inhibit transcription, a complementary oligonucleotide is designed from the most unique S' 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 TRICH-encoding transcript.
XII. Expression of TRICH

Expression and purification of TRICH is achieved using bacterial or virus-based expression systems. For expression of TRICH 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 TRICH upon induction with isopropyl beta-D-thiogalactopyranoside (IPTG). Expression of TRICH 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 TRICH 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 Spodo~tera 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.K. 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, TRICH is synthesized as a fusion protein with, e.g., glutathione S-txansferase (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 jaQonicum, 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 TRICH 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, su ra, ch. 10 and 16). Purified TRICH obtained by these methods can be used directly in the assays shown in Examples XVI, XVII, and XVIII where applicable.
XIII. Functional Assays TRICH function is assessed by expressing the sequences encoding TRICH 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. S-10 /.cg 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 ~cg 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 TRICH on gene expression can be assessed using highly purified populations of cells transfected with sequences encoding TRICH 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 TRICH and other genes of interest can be analyzed by northern analysis or microarray techniques.
XIV. Production of TRICK Specific Antibodies TRICH 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 rabbits and to produce antibodies using standard protocols.
Alternatively, the TRICH 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, ssupra.) Rabbits are immunized with the oligopeptide-KLH complex in complete Freund's adjuvant. Resulting antisera are tested for antipeptide and anti-TRICH activity by, for example, binding the peptide or TRICH to a substrate, blocking with 1 % BSA, reacting with rabbit antisera, washing, and reacting with radio-iodinated goat anti-rabbit IgG.
XV. Purification of Naturally Occurring TRICH Using Specific Antibodies Naturally occurring or recombinant TRICH is substantially purified by immunoaffinity chromatography using antibodies specific for TRICH. An immunoaffinity column is constructed by covalently coupling anti-TRICH 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 TRICH are passed over the immunoaffinity column, and the column is washed under conditions that allow the preferential absorbance of TRICH (e.g., high ionic strength buffers in the presence of detergent). The column is eluted under conditions that disrupt antibody/TRICH 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 TRICH is collected.
XVI. Identification of Molecules Which Interact with TRICH
Molecules which interact with TRICH may include transporter substrates, agonists or antagonists, modulatory proteins such as G~3~y proteins (Reimann, supra) or proteins involved in TRICH
localization or clustering such as MAGUKs (Craven, su ra). TRICH, or biologically active fragments thereof, are labeled with l2sl 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 multi-well plate are incubated with the labeled TRICH, washed, and any wells with labeled TRICH
complex are assayed. Data obtained using different concentrations of TRICH are used to calculate values for the number, affinity, and association of TRICH with the candidate molecules.
Alternatively, proteins that interact with TRICH axe isolated using the yeast 2-hybrid system (Fields, S. and O. Song (1989) Nature 340:245-246). TRICH, or fragments thereof, are expressed as fusion proteins with the DNA binding domain of Gal4 or lexA, and potential interacting proteins are expressed as fusion proteins with an activation domain. Interactions between the TRICH fusion protein and the TRICH interacting proteins (fusion proteins with an activation domain) reconstitute a transactivation function that is observed by expression of a reporter gene.
Yeast 2-hybrid systems are commercially available, and methods for use of the yeast 2-hybrid system with ion channel proteins are discussed in Niethammer, M. and M. Sheng (1998, Meth. Enzymol. 293:104-122).
TRICH 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 S between the proteins encoded by two large libraries of genes (Nandabalan, K, et al. (2000) U.S. Patent No. 6,0S7,101).
Potential TRICH agonists or antagonists may be tested for activation or inhibition of TRICH
ion channel activity using the assays described in section XVIII.
XVII. Demonstration of TRICH Activity Ion channel activity of TRICH is demonstrated using an electrophysiological assay for ion conductance. TRICH can be expressed by transforming a mammalian cell line such as COS7, HeLa or CHO with a eukaryotic expression vector encoding TRICH. Eukaryotic expression vectors are commercially available, and the techniques to introduce them into cells are well known to those .
skilled in the art. A second plasmid which expresses any one of a number of marker genes, such as 13-galactosidase, is co-transformed into the cells to allow rapid identification of those cells which have taken up and expressed the foreign DNA. The cells are incubated for 48-72 hours after transformation under conditions appropriate for the cell line to allow expression and accumulation of TRICH and 13-galactosidase.
Transformed cells expressing 13-galactosidase are stained blue when a suitable colorimetric substrate is added to the culture media under conditions that are well known in the art. Stained cells are tested for differences in membrane conductance by electrophysiological techniques that are well known in the art. Untransformed cells, andlor cells transformed with either vector sequences alone or 13-galactosidase sequences alone, are used as controls and tested in parallel.
Cells expressing TRICH
will have higher anion or canon conductance relative to control cells. The contribution of TRICH to conductance can be confirmed by incubating the cells using antibodies specific for TRICH. The antibodies will bind to the extracellular side of TRICH, thereby blocking the pore in the ion channel, and the associated conductance.
Alternatively, ion channel activity of TRICH is measured as current flow across a TRICH-containing Xenopus laevis oocyte membrane using the two-electrode voltage-clamp technique (Ishi et al., supra; Jegla, T. and L. Salkoff (1997) J. Neurosci. 17:32-44). TRICH is subcloned into an appropriate Xenopus oocyte expression vector, such as pBF, and O.S-S ng of mRNA is injected into mature stage IV oocytes. Injected oocytes are incubated at 18°C for 1-S
days. Inside-out macropatches are excised into an intracellular solution containing 116 mM K-gluconate, 4 mM KCI, and 10 mM Hepes (pH 7.2). The intracellular solution is supplemented with varying concentrations 3S of the TRICH mediator, such as CAMP, cGMP, or Ca+2 (in the form of CaCI~, where appropriate.

Electrode resistance is set at 2-5 MSS and electrodes are filled with the intracellular solution lacking mediator. Experiments are performed at room temperature from a holding potential of 0 mV. Voltage ramps (2.5 s) from -100 to 100 mV are acquired at a sampling frequency of 500 Hz. Current measured is proportional to the activity of TRICH in the assay.
In particular, the activities of TRICH-1, TRICH-2, and TRICH-10, are measured as K
conductance, the activities of TRICH-6 and TRICH-9 are measured as K*
conductance in the presence of membrane stretch or free fatty acids, the activities of TRICH-18, TRICH-25 and TRICH-31 are measured as voltage-gated K+ conductance, TRICH-5 activity is measured as CT
conductance in the presence of GABA, TRICH-11 activity is measured as canon conductance in the presence of heat, and the activity of TRICH-9, TRICH-28 is measured as Ca2+ conductance.
Transport activity of TRICH is assayed by measuring uptake of labeled substrates into Xenopus laevis oocytes. Oocytes at stages V and VI are injected with TRICH
mRNA (10 ng per oocyte) and incubated for 3 days at 18°C in OR2 medium (82.5mM NaCl, 2.5 mM KCl, 1mM CaCl2, 1mM MgCl2, 1mM Na2HP04, 5 mM Hepes, 3.8 mM NaOH , 50~ g/ml gentamycin, pH 7.8) to allow expression of TRICH. Oocytes are then transferred to standard uptake medium (100mM NaCI, 2 mM
KCl, 1mM CaCl2, 1mM MgCl2, 10 mM Hepes/Tris pH 7.5). Uptake of various substrates (e.g., amino acids, sugars, drugs, ions, and neurotransmitters) is initiated by adding labeled substrate (e.g.
radiolabeled with 3H, fluorescently labeled with rhodamine, etc.) to the oocytes. After incubating for 30 minutes, uptake is terminated by washing the oocytes three times in Na+-free medium, measuring the incorporated label, and comparing with controls. TRICH activity is proportional to the level of internalized labeled substrate. In particular, test substrates include pigment precursors and related molecules for TRICH-3, aminophospholipids for TRICH-4., fructose and glucose for TRICH-7 and TRICH-15, amino acids for TRICH-8, Nay and iodide for TRICH-12, Na+and H~for TRICH-13 and TRICH-21, Na+ and glucose for TRICH-16 and TRICH-19, and glucose for TRICH-23, TRICH-26, TRICH-29, TRICH-30, and TRICH-32.
ATPase activity associated with TRICH can be measured by hydrolysis of radiolabeled ATP-[Y 32P~~ separation of the hydrolysis products by chromatographic methods, and quantitation of the recovelred 32P using a scintillation counter. The reaction mixture contains ATP-['y-32P~ and varying amounts of TRICH in a suitable buffer incubated at 37 ° C for a suitable period of time. The reaction is terminated by acid precipitation with trichloroacetic acid and then neutralized with base, and an aliquot of the reaction mixture is subjected to membrane or filter paper-based chromatography to separate the reaction products. The amount of 32P liberated is counted in a scintillation counter. The amount of radioactivity recovered is proportional to the ATPase activity of TRICH in the assay.
XVIII. Identification of TRICH Agonists and Antagonists TRICH is expressed in a eukaryotic cell line such as CHO (Chinese Hamster Ovary) or HEK
(Human Embryonic Kidney) 293. Ion channel activity of the transformed cells is measured in the presence and absence of candidate agonists or antagonists. Ion channel activity is assayed using patch clamp methods well known in the art or as described in Example XVII.
Alternatively, ion channel activity is assayed using fluorescent techniques that measure ion flux across the cell membrane (Velicelebi, G. et al. (1999) Meth. Enzymol. 294:20-47; West, M.R. and C.R.
Molloy (1996) Anal.
Biochem. 241:51-58). These assays may be adapted for high-throughput screening using microplates.
Changes in internal ion concentration are measured using fluorescent dyes such as the Ca2+ indicator Fluo-4 AM, sodium-sensitive dyes such as SBFI and sodium green, ox the Cl-indicator MQAE (all available from Molecular Probes) in combination with the FLIPR fluorimetric plate reading system (Molecular Devices). In a more generic version of this assay, changes in membrane potential caused by ionic flux across the plasma membrane are measured using oxonyl dyes such as DiBAC4 (Molecular Probes). DiBAC4 equilibrates between the extracellular solution and cellular sites according to the cellular membrane potential. The dye's fluorescence intensity is 20-fold greater when bound to hydrophobic intracellular sites, allowing detection of DiBAC4 entry into the cell (Gonzalez, J.E. and P.A. Negulescu (1998) Curr. Opin. Biotechnol. 9:624-631). Candidate agonists or antagonists may be selected from known ion channel agonists or antagonists, peptide libraries, or combinatorial chemical libraries.
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 fox 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, .LNC.
RAUMANN, Brigitte E.
THORNTON, Michael l DING, Li YUE, Henry TANG, Y.Tom HARLAND, Lee BURFORD, Neil GREENE, Barrie D.
SANJANWALA, Madhu S.
BAUGHN, Mariah R.
YAO, Monique G.
YANG, Junming PATTERSON, Chandra GANDHI, Ameena R.
HAFALIA, April J.A.
TRIBOULEY, Catherine M.
WALIA, Narinder K.
AU-YOUNG, Janice WALSH, Roderick T.
RAMKUMAR, Jayala}ani LU, Yan LU, Dyung Aina M.
AZIMZAI, Yalda LAL, Preeti ELLIOTT, Vicki S.
NGUYEN, Danniel B.
XU, Yuming SEILHAMER, Jeffrey J.
BOROWSKY, Mark L.
KHAN, Farrah A.
KEARNEY, Liam THANGAVELU, Kavitha DAs, Debopriya POLICKY, Jennifer L.
<120> TRANSPORTERS AND ION CHANNELS
<130> PI-0149 PCT
<140> To Be Assigned <141> Herewith <150> 60/216,547; 60/218,232; 60/220,112; 60/221,839 <151> 2000-07-07; 2000-07-14; 2000-07-21; 2000-07-28 <160> 64 <170> PERL Program <210> 1 <211> 332 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3474673CD1 <400> 1 Met Tyr Arg Pro Arg Ala Arg Ala Ala Pro Glu Gly Arg Val Arg Gly Cys Ala Val Pro Ser Thr Val Leu Leu Leu Leu A1a Tyr Leu Ala Tyr Leu Ala Leu Gly Thr Gly Val Phe Trp Thr Leu Glu Gly Arg Ala Ala Gln Asp Ser Ser Arg Ser Phe Gln Arg Asp Lys Trp 1/g~

Glu Leu Leu Gln Asn Phe Thr Cys Leu Asp Arg Pro Ala Leu Asp Ser Leu Ile Arg Asp Val Val Gln A1a Tyr Lys Asn Gly Ala Ser Leu Leu Ser Asn Thr Thr Ser Met Gly Arg Trp Glu Leu Val Gly Ser Phe Phe Phe Ser Val Ser Thr Ile Thr Thr Ile Gly Tyr Gly Asn Leu Ser Pro Asn Thr Met Ala Ala Arg Leu Phe Cys Ile Phe Phe Ala Leu Val Gly I1e Pro Leu Asn Leu Val Val Leu Asn Arg Leu Gly His Leu Met Gln Gln Gly Val Asn His Trp Ala Ser Arg Leu Gly Gly Thr Trp Gln Asp Pro Asp Lys Ala Arg Trp Leu Ala Gly Ser Gly Ala Leu Leu Ser Gly Leu Leu Leu Phe Leu Leu Leu Pro Pro Leu Leu Phe Ser His Met G1u Gly Trp Ser Tyr Thr Glu Gly Phe Tyr Phe A1a Phe Ile Thr Leu her Thr Val G1y Phe Gly Asp Tyr Val Ile Gly Met Asn Pro Ser Gln Arg Tyr Pro Leu Trp Tyr Lys Asn Met Val Ser Leu Trp Ile Leu Phe Gly Met A1a Trp Leu Ala Leu Ile Ile Lys Leu Ile Leu Ser Gln Leu Glu Thr Pro G1y Arg Val Cys Ser Cys Cys His His Ser Ser Lys Glu Asp Phe Lys Ser Gln Ser Trp Arg Gln Gly Pro Asp Arg Glu Pro Glu Ser His Ser Pro Gln Gln Gly Cys Tyr Pro Glu Gly Pro Met G1y Ile Ile Gln His Leu Glu Pro Ser Ala His Ala Ala G1y Cys Gly Lys Asp Ser <210> 2 <211> .226 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4588877CD1 <400> 2 Met Val Glu Met Gly Trp Asp Trp Ala Asp Arg Lys Asp Met Arg His Arg Leu Gln Ala Gly Asn Leu Glu Asn Thr Asp Gln Val Lys Ser Pro Leu Leu Thr Gly Asp Ser Ser Gly Leu Pro Pro Ala Pro Ser Ala Pro Thr His Gly Val Lys Ala Ser Gly Gly Leu Gly Thr Ile Leu His Pro Gln Asp Pro Asp Lys Ala Arg Trp Leu Ala Gly Ser Gly Ala Leu Leu Ser Gly Leu Leu Leu Phe Leu Leu Leu Pro Pro Leu Leu Phe Ser His Met Glu Gly Trp Ser Tyr Thr Glu Gly Phe Tyr Phe Ala Phe Ile Thr Leu Ser Thr Val Gly Phe Gly Asp Tyr Val Ile G1y Met Asn Pro Ser Gln Arg Tyr Pro Leu Trp Tyr Lys Asn Met Val Ser Leu Trp I1e Leu Phe Gly Met Ala Trp Leu Ala Leu Ile Ile Lys Leu Ile Leu Ser Gln Leu G1u Thr Pro Gly Arg Val Cys Ser Cys Cys His His Ser Ser Lys Glu Asp Phe Lys Ser Gln Ser Trp Arg Gln Gly Pro Asp Arg Glu Pro Glu Ser His Ser Pro Gln Gln Gly Cys Tyr Pro Glu Gly Pro Met Gly Ile Ile Gln His Leu Glu Pro Ser Ala His Ala Ala GIy Cys Gly Lys Asp Ser <210> 3 <211> 646 <212 > PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Tncyte ID No: 7472214CD1 <400> 3 Met Ala Glu Lys Ala Leu Glu Ala Val G1y Cys Gly Leu Gly Pro Gly Ala Val Ala Met Ala Val Thr Leu Glu Asp Gly Ala Glu Pro Pro Val Leu Thr Thr His Leu Lys Lys Val Glu Asn His Ile Thr Glu Ala Gln Arg Phe Ser His Leu Pro Lys Arg Ser A1a Val Asp Ile Glu Phe Val Glu Leu Ser Tyr Ser Val Arg Glu Gly Pro Cys Trp Arg Lys Arg Gly Tyr Lys Thr Leu Leu Lys Cys Leu Ser Gly Lys Phe Cys Arg Arg Glu Leu Ile Gly I1e Met Gly Pro Ser Gly A1a Gly Lys Ser Thr Phe Met Asn Ile Leu Ala Gly Tyr Arg Glu Ser Gly Met Lys Gly Gln Ile Leu Val Asn Gly Arg Pro Arg Glu Leu Arg Thr Phe Arg Lys Met Ser Cys Tyr Ile Met Gln Asp Asp Met Leu Leu Pro His Leu Thr Val Leu Glu Ala Met Met Val Ser Ala Asn Leu Asn Leu Thr Glu Asn Pro Asp Val Lys Asn Asp Leu VaI Thr GIu Ile Leu Thr Ala Leu GIy Leu Met Ser Cys Ser His Thr Arg Thr Ala Leu Leu Ser Gly Gly Gln Arg Lys Arg Leu Ala Ile Ala Leu Glu Leu Val Asn Asn Pro Pro Val Met Phe Phe Asp Glu Pro Thr Ser Gly Leu Asp Ser Ala Ser Cys Phe Gln Val Val Ser Leu Met Lys Ser Leu Ala Gln Gly Gly Arg Thr Ile Ile Cys Thr IIe His Gln Pro Ser Ala Lys Leu Phe Glu Met Phe Asp Lys Leu Tyr Ile Leu Ser Gln Gly Gln Cys Ile Phe Lys Gly Val Val Thr Asn Leu Ile Pro Tyr Leu Lys Gly Leu Gly Leu His Cys Pro Thr Tyr His Asn Pro Ala Asp Phe Val Ile Glu Val Ala Ser Gly Glu Tyr Gly Asp Leu Asn Pro Met Leu Phe Arg Ala Val Gln Asn Gly Leu Cys Ala Met Ala Glu Lys Lys Ser Ser Pro Glu Lys Asn Glu Val Pro Ala Pro Cys Pro Pro Cys Pro Pro Glu Val Asp Pro Tle Glu Ser His Thr Phe Ala Thr Ser Thr Leu Thr Gln Phe Cys Tle Leu Phe Lys Arg Thr Phe Leu Ser Tle Leu Arg Asp Thr Val Leu Thr His Leu Arg Phe Met Ser His Val Val Ile Gly Val Leu Ile Gly Leu Leu Tyr Leu His Ile Gly Asp Asp Ala Ser Lys Val Phe Asn Asn Thr Gly Cys Leu Phe Phe Ser Met Leu Phe Leu Met Phe Ala Ala Leu Met Pro Thr Val Leu Thr Val Pro Leu Glu Met Ala Val Phe Met Arg Glu His Leu Asn Tyr Trp Tyr Ser Leu Lys Ala Tyr Tyr Leu A1a Lys Thr Met Ala Asp Val Pro Phe Gln Val Val Cys Pro Val Val Tyr Cys Ser Tle Val Tyr Trp Met Thr Gly Gln Pro Ala Glu Thr Ser Arg Phe Leu Leu Phe Ser Ala Leu Ala Thr Ala Thr Ala Leu Val Ala Gln Ser Leu Gly Leu Leu I1e Gly Ala Ala Ser Asn Ser Leu Gln Val Ala Thr Phe Val Gly Pro Val Thr Ala Ile Pro Val Leu Leu Phe Ser Gly Phe Phe Val Ser Phe Lys Thr Ile Pro Thr Tyr Leu Gln Trp Ser Ser Tyr Leu Ser Tyr Val Arg Tyr Gly Phe Glu Gly Val Ile Leu Thr Ile Tyr Gly Met Glu Arg Gly Asp Leu Thr Cys Leu Glu Glu Arg Cys Pro Phe Arg Glu Pro Gln Ser Ile Leu Arg Ala Leu Asp Val G1u Asp A1a Lys Leu Tyr Met Asp Phe Leu Val Leu Gly Ile Phe Phe Leu Ala Leu Arg Leu Leu Ala Tyr Leu Val Leu Arg Tyr Arg Val Lys Ser Glu Arg <210> 4 <211> 1190 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473053CD1 <400> 4 Met Ala Val Cys Ala Lys Lys Arg Pro Pro Glu Glu Glu Arg Arg Ala Arg Ala Asn Asp Arg Glu Tyr Asn Glu Lys Phe Gln Tyr Ala Ser, Asn Cys Ile Lys Thr Ser Lys Tyr Asn Ile Leu Thr Phe Leu Pro Val Asn Leu Phe Glu Gln Phe Gln Glu Val Ala Asn Thr Tyr Phe Leu Phe Leu Leu Ile Leu Gln Leu Ile Pro G1n Ile Ser Ser Leu Ser Trp Phe Thr Thr Ile Val Pro Leu Val Leu Val Leu Thr Ile Thr Ala Val Lys Asp Ala Thr Asp Asp Tyr Phe Arg His Lys Ser Asp Asn Gln Val Asn Asn Arg Gln Ser Gln Val Leu Ile Asn Gly Ile Leu Gln Gln Glu Gln Trp Met Asn Val Cys Val Gly Asp Ile Ile Lys Leu Glu Asn Asn GIn Phe Val Ala Ala Asp Leu Leu Leu Leu Ser Ser Ser Glu Pro His Gly Leu Cys Tyr Ile Glu Thr 155 l60 165 Ala Glu Leu Asp Gly Glu Thr Asn Met Lys Val Arg Gln Ala Ile Pro Val Thr Ser Glu Leu Gly Asp Ile Ser Lys Leu Ala Lys Phe Asp Gly Glu Val Ile Cys Glu Pro Pro Asn Asn Lys Leu Asp Lys Phe Ser G1y Thr Leu Tyr Trp Lys Glu Asn Lys Phe Pro Leu Ser Asn Gln Asn Met Leu Leu Arg Gly Cys Val Leu Arg Asn Thr Glu Trp Cys Phe Gly Leu Val Ile Phe Ala Gly Pro Asp Thr Lys Leu Met Gln Asn Ser Gly Arg Thr Lys Phe Lys Arg Thr Ser Ile Asp Arg Leu Met Asn Thr Leu Val Leu Trp Ile Phe G1y Phe Leu Val Cys Met G1y Val Ile Leu Ala Ile Gly Asn Ala Ile Trp Glu His Glu Val Gly Met Arg Phe Gln Val Tyr Leu Pro Trp Asp G1u Ala Val Asp Ser Ala Phe Phe Ser Gly Phe Leu Ser Phe Trp Ser Tyr Ile Ile I1e Leu Asn Thr Val Val Pro Ile Ser Leu Tyr Val Ser Val Glu Val Ile Arg Leu Gly His Ser Tyr Phe Tle Asn Trp Asp Lys Lys Met Phe Cys Met Lys Lys Arg Thr Pro Ala Glu Ala Arg Thr Thr Thr Leu Asn Glu G1u Leu Gly Gln Val Glu Tyr Ile Phe Ser Asp Lys Thr Gly Thr Leu Thr Gln Asn Ile Met Val Phe Asn Lys Cys Ser Ile Asn Gly His Ser Tyr Gly Asp Val Phe Asp Val Leu Gly His Lys Ala Glu Leu Gly Glu Arg Pro Glu Pro Val Asp Phe Ser Phe Asn Pro Leu Ala Asp Lys Lys Phe Leu Phe Trp Asp Pro Ser Leu Leu Glu Ala Val Lys Ile Gly Asp Pro His Thr His Glu Phe Phe Arg Leu Leu Ser Leu Cys His Thr Val Met Ser Glu Glu Lys Asn Glu Gly Glu Leu Tyr Tyr Lys Ala Gln Ser Pro Asp Glu Gly Ala Leu Val Thr A1a Ala Arg Asn Phe Gly Phe Va1 Phe Arg Ser Arg Thr Pro Lys Thr Ile Thr Val His Glu Met Gly Thr Ala Ile Thr Tyr Gln Leu Leu A1a Ile Leu Asp Phe Asn Asn Ile Arg Lys Arg Met Ser Val I1e Val Arg Asn Pro Glu Gly Lys Ile Arg Leu Tyr Cys Lys Gly Ala Asp Thr Tle Leu Leu Asp Arg Leu His His Ser Thr Gln Glu Leu Leu Asn Thr Thr Met Asp His Leu Asn Glu Tyr Ala Gly Glu Gly Leu Arg Thr Leu Val Leu Ala Tyr Lys Asp Leu Asp Glu Glu Tyr Tyr Glu Glu Trp Ala Glu Arg Arg Leu Gln Ala Ser Leu Ala Gln Asp Ser Arg Glu Asp Arg Leu Ala Ser Ile Tyr Glu G1u Val Glu Asn Asn Met Met Leu Leu Gly Ala Thr Ala Ile Glu Asp Lys Leu Gln Gln Gly Val Pro Glu Thr Ile 650 65'5 660 Ala Leu Leu Thr Leu Ala Asn Ile Lys Ile Trp Val Leu Thr Gly Asp Lys Gln Glu Thr AIa Val Asn Ile Gly Tyr Ser Cys Lys Met Leu Thr Asp Asp Met Thr Glu Val Phe Ile Val Thr Gly His Thr Val Leu Glu Val Arg Glu Glu Leu Arg Lys Ala Arg Glu Lys Met Met Asp Ser Ser Arg Ser Val Gly Asn Gly Phe Thr Tyr Gln Asp Lys Leu Ser Ser Ser Lys Leu Thr Ser Val Leu Glu Ala Val Ala Gly GIu Tyr Ala Leu Val Ile Asn Gly His Ser Leu Ala His Ala Leu Glu Ala Asp Met Glu Leu Glu Phe Leu Glu Thr Ala Cys Ala Cys Lys Ala Val Ile Cys,Cys Arg Val Thr Pro Leu Gln Lys Ala Gln Val Val Glu Leu Val Lys Lys Tyr Lys Lys Ala Val Thr Leu Ala Ile G1y Asp Gly Ala Asn Asp Val Ser Met Ile Lys Thr Ala His Ile Gly Val Gly Ile Ser Gly Gln Glu Gly Ile Gln Ala Val Leu Ala Ser Asp Tyr Ser Phe Ser Gln Phe Lys Phe Leu Gln Arg Leu Leu Leu Val His Gly Arg Trp Ser Tyr Leu Arg Met Cys Lys Phe Leu Cys Tyr Phe Phe Tyr Lys Asn Phe Ala Phe Thr Met Val His Phe Trp Phe Gly Phe Phe Cys Gly Phe Ser Ala Gln Thr Val Tyr Asp Gln Tyr Phe Ile Thr Leu Tyr Asn Tle Val Tyr Thr Ser Leu Pro Val Leu Ala Met Gly Val Phe Asp Gln Asp Val Pro Glu Gln Arg Ser Met Glu Tyr Pro Lys Leu Tyr Glu Pro Gly Gln Leu Asn Leu Leu Phe Asn Lys Arg Glu Phe Phe Ile Cys Ile Ala Gln Gly Ile Tyr Thr Ser Val Leu Met Phe Phe Ile Pro Tyr Gly Val Phe Ala Asp Ala Thr Arg Asp Asp Gly Thr Gln Leu Ala Asp Tyr Gln Ser Phe Ala Val Thr Val Ala Thr Ser Leu Val Ile Val Val Ser Val Gln Ile Gly Leu Asp Thr Gly Tyr Trp Thr Ala Ile Asn His Phe Phe Ile Trp Gly Ser Leu Ala Val Tyr Phe Ala Ile Leu Phe AIa Met His Ser Asn Gly Leu Phe Asp Met Phe Pro Asn Gln Phe Arg Phe Val Gly Asn Ala Gln Asn Thr Leu Ala Gln Pro Thr Val Trp Leu Thr Ile Va1 Leu Thr Thr Val Val Cys Ile Met Pro Val Va1 Ala Phe Arg Phe Leu Arg Leu Asn Leu Lys Pro Asp Leu Ser Asp Thr Val Arg Tyr Thr Gln Leu Val Arg Lys Lys Gln Lys Ala Gln His Arg Cys Met Arg Arg Val Gly Arg Thr Gly Ser Arg Arg Ser Gly Tyr Ala Phe Ser His Gln Glu Gly Phe Gly Glu Leu Ile Met Ser Gly Lys Asn Met Arg Leu Ser Ser Leu Ala Leu Ser Ser Phe Thr Thr Arg Ser Ser Ser Ser Trp Ile Glu Ser Leu Arg Arg Lys Lys Ser Asp Ser AIa Ser Ser Pro Ser Gly Gly Ala Asp Lys Pro Leu Lys Gly <210> 5 <211> 467 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473347CD1 <400> 5 Met Val Leu Ala Phe G1n Leu Val Ser Phe Thr Tyr Ile Trp Ile l 5 10 15 Ile Leu Lys Pro Asn Val Cys Ala Ala Ser Asn Ile Lys Met Thr His Gln Arg Cys Ser Ser Ser Met Lys Gln Thr Cys Lys Gln Glu Thr Arg Met Lys Lys Asp Asp Ser Thr Lys Ala Arg Pro Gln Lys Tyr Glu Gln Leu Leu His Ile Glu Asp Asn Asp Phe A1a Met Arg Pro Gly Phe Gly Gly Ser Pro Val Pro Val Gly Ile Asp Val His Val Glu Ser Ile Asp Ser Ile Ser G1u Thr Asn Met Asp Phe Thr Met Thr Phe Tyr Leu Arg His Tyr Trp Lys Asp Glu Arg Leu Ser Phe Pro Ser Thr Ala Asn Lys Ser Met Thr Phe Asp His Arg Leu Thr Arg Lys Ile Trp Val Pro Asp Ile Phe Phe Val His Ser Lys Arg Ser Phe Ile His Asp Thr Thr Met Glu Asn Ile Met Leu Arg Val His Pro Asp Gly Asn Val Leu Leu Ser Leu Arg Ile Thr Val Ser Ala Met Cys Phe Met Asp Phe Ser Arg Phe Pro Leu Asp Thr Gln Asn Cys Ser Leu Glu Leu Glu Ser Tyr Ala Tyr Asn Glu Asp Asp Leu Met Leu Tyr Trp Lys His Gly Asn Lys Ser Leu Asn Thr G1u Glu His Met Ser Leu Ser Gln Phe Phe Ile Glu Asp Phe Ser 230 ~ 235 240 Ala Ser Ser Gly Leu Ala Phe Tyr Ser Ser Thr Gly Trp Tyr Asn Arg Leu Phe Ile Ile Ser Val Leu Arg Arg His Val Phe Phe Phe Val Leu Pro Thr Tyr Tyr Pro Ala Ile Leu Met Val Met Leu Ser Trp Va1 Ser Phe Trp Ile Asp Arg Arg Ala Val Pro Ala Arg Val 7/$7 Ser Leu Gly Ile Thr Thr Val Leu Thr Met Ser Thr Ile Ile Thr Ala Val Ser Ala Ser Met Pro Gln Val Ser Tyr Leu Lys Ala Val Asp Val Tyr Leu Trp Val Ser Ser Leu Phe Val Phe Leu Ser Val Ile Glu Tyr Ala Ala Val Asn Tyr Leu Thr Thr Val Glu Glu Arg Lys Gln Phe Lys Lys Thr Gly Lys Ile Ser Arg Met Tyr Asn Ile Asp Ala Va1 Gln A1a Met Ala Phe Asp Gly Cys Tyr His Asp Ser Glu Ile Asp Met Asp Gln Thr Ser Leu Ser Leu Asn Ser GIu Asp Phe Met Arg Arg Lys Ser I1e Cys Ser Pro Ser Thr Asp Ser Ser Arg Ile Lys Arg Arg Lys Ser Leu Gly G1y His Val Gly Arg Ile Tle Leu Glu Asn Asn His Val Ile Asp Thr Tyr Ser Arg Ile Leu Phe Pro Tle Val Tyr Ile Leu Phe Asn Leu Phe Tyr Trp Gly Val Tyr Val <210> 6 <211> 1196 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474240CD1 <400> 6 Met Pro Val Arg Arg Gly His VaI Ala Pro Gln Asn Thr Phe Leu Gly Thr Ile Ile Arg Lys Phe G1u Gly Gln Asn Lys Lys Phe Ile Ile Ala Asn Ala Arg Va1 Gln Asn Cys Ala Ile Ile Tyr Cys Asn Asp Gly Phe Cys Glu Met Thr Gly Phe Ser Arg Pro Asp Val Met Gln Lys Pro Cys Thr Cys Asp Phe Leu His Gly Pro Glu Thr Lys Arg His Asp Ile Ala Gln Ile Ala Gln Ala Leu Leu Gly Ser G1u Glu Arg Lys Va1 Glu Val Thr Tyr Tyr His Lys Asn Gly Ser Thr Phe Ile Cys Asn Thr His Ile Tle Pro Val Lys Asn Gln Glu Gly Val Ala Met Met Phe Ile Ile Asn Phe Glu Tyr Va1 Thr Asp Asn Glu Asn Ala Ala Thr Pro G1u Arg Val Asn Pro Ile Leu Pro Ile Lys Thr Val Asn Arg Lys Phe Phe Gly Phe Lys Phe Pro Gly Leu Arg Val Leu Thr Tyr Arg Lys Gln Ser Leu Pro Gln Glu Asp Pro Asp Val Val Val Ile Asp Ser Ser Lys His Ser Asp Asp Ser Val Ala Met Lys His Phe Lys Ser Pro Thr Lys Glu Ser Cys Ser Pro Ser Glu Ala Asp Asp Thr Lys Ala Leu Ile Gln Pro Ser Lys Cys Ser Pro Leu Val Asn Ile Ser Gly Pro Leu Asp His Ser Ser Pro Lys Arg Gln Trp Asp Arg Leu Tyr Pro Asp Met Leu Gln Ser Ser Ser Gln Leu Ser His Ser Arg Ser Arg Glu Ser Leu Cys Ser Ile Arg Arg Ala Ser Ser Val His Asp Ile Glu Gly Phe Gly Val His Pro Lys Asn Ile Phe Arg Asp Arg His Ala Ser Glu Asp Asn G1y Arg Asn Val Lys Gly Pro Phe Asn His Ile Lys Ser Ser Leu Leu Gly Ser Thr Ser Asp Ser Asn Leu Asn Lys Tyr Ser Thr Ile Asn Lys Ile Pro Gln Leu Thr Leu Asn Phe Ser Glu Val Lys Thr Glu Lys Lys Asn Ser Ser Pro Pro Ser Ser Asp Lys Thr Ile Ile Ala Pro Lys Val Lys Asp Arg Thr His Asn Val Thr Glu Lys Val Thr Gln Val Leu Ser Leu Gly A1a Asp Val Leu Pro Glu Tyr Lys Leu Gln Thr Pro Arg Ile Asn Lys Phe Thr Ile Leu His Tyr Ser Pro Phe Lys Ala Val Trp Asp Trp Leu Ile Leu Leu Leu Val Ile Tyr Thr Ala Ile Phe Thr Pro Tyr Ser Ala Ala Phe Leu Leu Asn Asp Arg Glu Glu Gln Lys Arg Arg Glu Cys Gly Tyr Ser Cys Ser Pro Leu Asn Val Val Asp Leu Ile Val Asp Ile Met Phe Ile Ile Asp Ile Leu Ile Asn Phe Arg Thr Thr Tyr Val Asn Gln Asn Glu Glu Val Val Ser Asp Pro Ala Lys Ile Ala Ile His Tyr Phe Lys Gly Trp Phe Leu Ile Asp Met Val Ala Ala Ile Pro Phe Asp Leu Leu Ile Phe Gly Ser G1y Ser Asp Glu Thr Thr Thr Leu Ile Gly Leu Leu Lys Thr Ala Arg Leu Leu Arg Leu Val Arg Val Ala Arg Lys Leu Asp Arg Tyr Ser Glu Tyr Gly Ala Ala Val Leu Met Leu Leu Met Cys Ile Phe Ala Leu Ile Ala His Trp Leu Ala Cys Ile Trp Tyr Ala Ile Gly Asn Val Glu Arg Pro Tyr Leu Thr Asp Lys I1e Gly Trp Leu Asp Ser Leu Gly Gln Gln Ile Gly Lys Arg Tyr Asn Asp Ser Asp ser Ser Ser Gly Pro Ser Ile Lys Asp Lys Tyr Val Thr Ala Leu Tyr Phe Thr Phe Ser Ser Leu Thr Ser Val Gly Phe Gly Asn Val Ser Pro Asn Thr Asn Ser Glu Lys Ile Phe Ser Ile Cys Val Met Leu Ile Gly Ser Leu Met Tyr Ala Ser Ile Phe Gly Asn Val Ser Ala Ile Ile Gln Arg Leu Tyr Ser Gly Thr Ala Arg Tyr His Met Gln Met Leu Arg Val Lys Glu Phe Ile Arg Phe His Gln Ile Pro Asn Pro Leu Arg Gln Arg Leu Glu Glu Tyr Phe Gln His Ala Trp Thr Tyr Thr Asn Gly Ile Asp Met Asn Met Val Leu Lys Gly Phe Pro Glu Cys Leu Gln Ala Asp Ile Cys Leu His Leu Asn G1n Thr Leu Leu Gln Asn Cys Lys Ala Phe Arg Gly Ala Ser Lys Gly Cys Leu Arg Ala Leu Ala Met Lys Phe Lys Thr Thr His Ala Pro Pro Gly Asp Thr Leu Val His Cys Gly Asp Val Leu Thr Ala Leu Tyr Phe Leu Ser Arg Gly Ser Ile G1u Ile Leu Lys Asp Asp Ile Val Val Ala Ile Leu Gly Lys Asn Asp Ile Phe Gly Glu Met Val His Leu Tyr A1a Lys Pro Gly Lys Ser Asn Ala Asp Val Arg Ala Leu Thr Tyr Cys Asp Leu His Lys Ile Gln Arg Glu Asp Leu Leu Glu Val Leu Asp Met Tyr Pro Glu Phe Ser Asp His Phe Leu Thr Asn Leu Glu Leu Thr Phe Asn Leu Arg His G1u Ser Ala Lys Ala Asp Leu Leu Arg Ser Gln Ser Met Asn Asp Ser Glu Gly Asp Asn Cys Lys Leu Arg Arg Arg Lys Leu Ser Phe Glu Ser Glu Gly Glu Lys Glu Asn Ser Thr Asn Asp Pro Glu Asp Ser Ala Asp Thr Ile Arg His Tyr Gln Ser Ser Lys Arg His Phe Glu Glu Lys Lys Ser Arg Ser Ser Ser Phe Ile Ser Ser I1e Asp Asp Glu Gln Lys Pro Leu Phe Ser Gly Ile Val Asp Ser Ser Pro Gly Ile Gly Lys A1a Ser Gly Leu Asp Phe Glu Glu Thr Va1 Pro Thr Ser Gly 9&5 970 975 Arg Met His Ile Asp Lys Arg Ser His Ser Cys Lys Asp Ile Thr Asp Met Arg Ser Trp G1u Arg Glu Asn Ala His Pro Gln Pro Glu Asp Ser Ser Pro Ser Ala Leu Gln Arg Ala Ala Trp Gly Tle Ser G1u Thr Glu Ser Asp Leu Thr Tyr Gly Glu Val Glu Gln Arg Leu Asp Leu Leu G1n Glu Gln Leu Asn Arg Leu Glu Ser Gln Met Thr Thr Asp Ile Gln Thr Ile Leu Gln Leu Leu Gln Lys Gln Thr Thr Val Val Pro Pro Ala Tyr Ser Met Val Thr Ala Gly Ser Glu Tyr Gln Arg Pro Ile Ile Gln Leu Met Arg Thr Ser Gln Pro Glu Ala Ser Ile Lys Thr Asp Arg Ser Phe Ser Pro Ser Ser Gln Cys Pro Glu Phe Leu Asp Leu Glu Lys Ser Lys Leu Lys Ser Lys Glu Ser Leu Ser Ser Gly Val His Leu Asn Thr Ala Ser Glu Asp Asn Leu Thr Ser Leu Leu Lys Gln Asp Ser Asp Leu Ser Leu Glu Leu His Leu Arg Gln Arg Lys Thr Tyr Va1 His Pro Ile Arg His Pro Ser Leu Pro Asp Ser Ser Leu Ser Thr Val Gly Ile Val Gly Leu His Arg His Val Ser Asp Pro Gly Leu Pro Gly Lys <210> 7 <211> 512 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte TD No: 7475338CD1 <400> 7 Met G1u Asn Lys Glu Ala G1y Thr Pro Pro Pro I1e Pro Ser Arg Glu Gly Arg Leu Gln Pro Thr Leu Leu Leu Ala Thr Leu Ser Ala Ala Phe Gly Ser Ala Phe Gln Tyr G1y Tyr Asn Leu Ser Val Val Asn Thr Pro His Lys Val Phe Lys Ser Phe Tyr Asn Glu Thr Tyr Phe Glu Arg His Ala Thr Phe Met Asp Gly Lys Leu Met Leu Leu Leu Trp Ser Cys Thr Val Ser Met Phe Pro Leu Gly Gly Leu Leu Gly Ser Leu Leu Val Gly Leu Leu Val Asp Ser Cys Gly Arg Lys Gly Thr Leu Leu Tle Asn Asn Ile Phe Ala Ile Ile Pro Ala Ile Leu Met Gly Val Ser Lys Val Ala Lys Ala Phe Glu Leu Ile Val Phe Ser Arg Val Va1 Leu Gly Val Cys Ala Gly Tle Ser Tyr Ser Ala Leu Pro Met Tyr Leu Gly Glu Leu Ala Pro Lys Asn Leu Arg Gly Met Val Gly Thr Met Thr Glu Val Phe Val Ile Val Gly Val Phe Leu Ala Gln Ile Phe Ser Leu Gln Ala Ile Leu Gly Asn Pro Ala Gly Trp Pro Val Leu Leu Ala Leu Thr G1y Val Pro Ala Leu Leu Gln Leu Leu Thr Leu Pro Phe Phe Pro Glu Ser Pro Arg Tyr Ser Leu Ile Gln Lys Gly Asp Glu Ala Thr Ala Arg'GIn Ala Leu Arg Arg Leu Arg Gly His Thr Asp Met Glu Ala Glu Leu Glu Asp Met Arg Ala Glu Ala Arg Ala Glu Arg Ala Glu Gly His Leu Ser Val Leu His Leu Cys Ala Leu Arg Ser Leu Arg Trp Gln Leu Leu Ser Ile Ile Val Leu Met Ala Gly Gln Gln Leu Ser Gly I1e Asn Ala Ile Asn Tyr Tyr Ala Asp Thr Ile Tyr Thr Ser Ala Gly Val Glu Ala A1a His Ser Gln Tyr Val Thr Val Gly Ser Gly Val Val Asn Ile Val Met Thr Ile Thr Ser Ala Val Leu Val Glu Arg Leu Gly Arg Arg His Leu Leu Leu Ala Gly Tyr Gly Ile Cys Gly Ser Ala Cys Leu Val Leu Thr Val Val Leu Leu Phe G1n Asn Arg Val Pro Glu Leu Ser Tyr Leu Gly Ile Ile Cys Val Phe Ala Tyr Ile Ala Gly His Ser Ile Gly Pro Ser Pro Val Pro Ser Val Val Arg Thr Glu Ile Phe Leu Gln Ser Ser Arg Arg Ala Ala Phe Met Val Asp Gly Ala Val His Trp Leu Thr Asn Phe Ile Ile Gly Phe Leu Phe Pro Ser Ile Gln Glu Ala Ile Gly Ala Tyr Ser Phe Ile Ile Phe Ala Gly Ile Cys Leu Leu Thr Ala Ile Tyr Ile Tyr Val Val Ile Pro Glu Thr Lys Gly Lys Thr Phe Va1 Glu Ile Asn Arg Ile Phe Ala Lys Arg Asn Arg Val Lys Leu Pro Glu Glu Lys Glu Glu Thr Ile Asp Ala Gly Pro Pro Thr Ala Ser Pro Ala Lys Glu Thr Ser Phe <210> 8 <211> 568 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7476747CD1 <400> 8 Met Thr Ala Ser Thr Pro Glu Ala Thr Pro Asn Met Glu Leu Lys 1 5 l0 15 Ala Pro Ala Ala Gly Gly Leu Asn Ala Gly Pro Val Pro Pro Ala Ala Met Ser Thr Gln Arg Leu Arg Asn Glu Asp Tyr His Asp Tyr Ser Ser Thr Asp Val Ser Pro Glu Glu Ser Pro Ser Glu Gly Leu Asn Asn Leu Ser Ser Pro Gly Ser Tyr Gln Arg Phe Gly Gln Ser Asn Ser Thr Thr Trp Phe Gln Thr Leu Ile His Leu Leu Lys Gly Asn Ile Gly Thr Gly Leu Leu Gly Leu Pro Leu Ala Val Lys Asn Ala Gly Ile Val Met Gly Pro Ile Ser Leu Leu Ile I1e Gly I1e 110 1l5 120 VaI Ala Val His Cys Met Gly Ile Leu Val Lys Cys Ala His His Phe Cys Arg Arg Leu Asn Lys Ser Phe Val Asp Tyr Gly Asp Thr Val Met Tyr G1y Leu Glu Ser Ser Pro Cys Ser Trp Leu Arg Asn His Ala His Trp Gly Arg Arg Val Val Asp Phe Phe Leu Ile Val Thr Gln Leu Gly Phe Cys Cys Va1 Tyr Phe Val Phe Leu Ala Asp Asn Phe Lys Gln Val Ile Glu Ala Ala Asn Gly Thr Thr Asn Asn Cys His Asn Asn GIu Thr Val Ile Leu Thr Pro Thr Met Asp Ser Arg Leu Tyr Met Leu Ser Phe Leu Pro Phe Leu Val Leu Leu Val Phe Ile Arg Asn Leu Arg Ala Leu Ser Ile Phe Ser Leu Leu Ala Asn Ile Thr Met Leu Val Ser Leu Val Met Ile Tyr Gln Phe Ile Val Gln Arg Ile Pro Asp Pro Ser His Leu Pro Leu Val Ala Pro Trp Lys Thr Tyr Pro Leu Phe Phe Gly Thr Ala Ile Phe Ser Phe Glu G1y Ile Gly Met Val Leu Pro Leu Glu Asn Lys Met Lys Asp Pro Arg Lys Phe Pro Leu Ile Leu Tyr Leu Gly Met Val Ile Val Thr Ile Leu Tyr Ile Ser Leu Gly Cys Leu Gly Tyr Leu Gln Phe Gly Ala Asn Ile Gln Gly Ser Ile Thr Leu Asn Leu Pro Asn Cys 12l $7 Trp Leu Tyr Gln Ser Val Lys Leu Leu Tyr Ser Ile Gly Ile Phe Phe Thr Tyr Ala Leu Gln Phe Tyr Val Pro Ala Glu Tle Tle Ile Pro Phe Phe Val Ser Arg Ala Pro Glu Pro Cys Glu Leu Val Val Asp Leu Phe Val Arg Pro Val Leu Val Cys Leu Thr Ser Leu Ser Gly Ser Val Asp Asn Gly Trp Tyr Gly Thr Glu Ala Asp Gly Thr Ser Cys Gly Ser Ala Pro Leu Val Phe Val Ser Ser Ser Phe Leu Ala His Pro Trp Leu Ser Phe Arg Cys Glu Ser Gln Trp Val Ser Cys His Arg Asp Thr Val Val Val Trp Gly Phe Ala Arg Gly Ile Leu Ala Ile Leu Ile Pro Arg Leu Asp Leu Val Ile Ser Leu Val Gly Ser Val Ser Ser Ser Ala Leu Ala Leu Tle I1e Pro Pro Leu Leu Glu Val Thr Thr Phe Tyr Ser Glu Gly Met Ser Pro Leu Thr Ile Phe Lys Asp Ala Leu I1e Ser Ile Leu Gly Phe Val Gly Phe Val Val Gly Thr Tyr Glu Ala Leu Tyr Glu Leu Ile Gln Pro Ser Asn Ala Pro Ile Phe Ile Asn Ser Thr Cys Ala Phe Ile <210> 9 <211> 958 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477898CD1 <400> 9 Met Pro Val Arg Arg Gly His Val Ala Pro Gln Asn Thr Tyr Leu Asp Thr Ile Ile Arg Lys Phe Glu Gly Gln Ser Arg Lys Phe Leu I1e Ala Asn Ala Gln Met Glu Asn Cys Ala Ile Ile Tyr Cys Asn Asp Gly Phe Cys Glu Leu Phe Gly Tyr Ser Arg Val Glu Val Met Gln Gln Pro Cys Thr Cys Asp Phe Leu Thr Gly Pro Asn Thr Pro Ser Ser Ala Va1 Ser Arg Leu Ala Gln Ala Leu Leu Gly Ala Glu Glu Cys Lys Va1 Asp Ile Leu Tyr Tyr Arg Lys Asp Ala Ser Ser Phe Arg Cys Leu Val Asp Val Val Pro Val Lys Asn Glu Asp Gly Ala Val Ile Met Phe Ile Leu Asn Phe Glu Asp Leu Ala Gln Leu Leu Ala Lys Cys Ser Ser Arg Ser Leu Ser Gln Arg Leu Leu Ser Gln Ser Phe Leu Gly Ser Glu Gly Ser His Gly Arg Pro Gly Gly Pro Gly Pro Gly Thr Gly Arg Gly Lys Tyr Arg Thr Ile Ser Gln Ile Pro Gln Phe Thr Leu Asn Phe Val Glu Phe Asn Leu Glu Lys His Arg Ser Ser Ser Thr Thr Glu Ile Glu Tle Ile Ala Pro His Lys Val Val Glu Arg Thr G1n Asn Val Thr Glu Lys Val Thr Gln Val Leu Ser Leu Gly Ala Asp Val Leu Pro Glu Tyr Lys Leu Gln Ala Pro Arg Ile His Arg Trp Thr Ile Leu His Tyr Ser Pro Phe Lys Ala Val Trp Asp Trp Leu Ile Leu Leu Leu Val Ile Tyr Thr Ala Val Phe Thr Pro Tyr Ser Ala Ala Phe Leu Leu Ser Asp Gln Asp Glu Ser Arg Arg Gly A1a Cys Ser Tyr Thr Cys Ser Pro Leu Thr Val Val Asp Leu Ile Val Asp Ile Met Phe Val Val Asp I1e Val Ile Asn Phe Arg Thr Thr Tyr Val Asn Thr Asn Asp Glu Va1 Val Ser His Pro Arg Arg Ile Ala Val His Tyr Phe Lys Gly Trp Phe Leu Ile Asp Met Val Ala Ala Ile Pro Phe Asp Leu Leu Ile Phe Arg Thr Gly Ser Asp Glu Thr Thr Thr Leu Ile Gly Leu Leu Lys Thr Ala Arg Leu Leu Arg Leu Val Arg Val Ala Arg Lys Leu Asp Arg Tyr Ser Glu Tyr Gly Ala Ala Val Leu Phe Leu Leu Met Cys Thr Phe Pro Leu Ile Ala His Trp Leu Ala Cys Ile Trp Tyr A1a Ile Gly Asn Val Glu Arg Pro Tyr Leu Glu His Lys Ile Gly Trp Leu Asp Ser Leu Gly Val Gln Leu Gly Lys Arg Tyr Asn Gly Ser Asp Pro Ala Ser Gly Pro Ser Val Gln Asp Lys Tyr Val Thr Ala Leu Tyr Phe Thr Phe Ser Ser Leu Thr Ser Val Gly Phe Gly Asn Va1 Ser Pro Asn Thr Asn Ser Glu Lys Val Phe Ser Ile Cys Va1 Met Leu Ile Gly Ser Leu Met Tyr Ala Ser Ile Phe Gly Asn Val Ser Ala Ile Ile Gln Arg Leu Tyr Ser G1y Thr Ala Arg Tyr His Thr G1n Met Leu Arg Val Lys Glu Phe Ile Arg Phe His Gln Ile Pro Asn Pro Leu Arg Gln Arg Leu G1u Glu Tyr Phe Gln His Ala Trp Ser Tyr Thr Asn Gly Ile Asp Met Asn Ala Val Leu Lys Gly Phe Pro Glu Cys Leu Gln Ala Asp Ile Cys Leu His Leu His Arg Ala Leu Leu Gln His Cys Pro Ala Phe Ser Gly Ala Gly Lys Gly Cys Leu Arg Ala Leu Ala Val Lys Phe Lys Thr Thr His Ala Pro Pro Gly Asp Thr Leu Val His Leu Gly Asp Val Leu Ser Thr Leu Tyr Phe Ile Ser Arg Gly Ser Ile Glu Ile Leu Arg Asp Asp Va1 Val Val Ala Ile Leu Gly Lys Asn Asp Ile Phe Gly Glu Pro Val Ser Leu His Ala Gln Pro Gly Lys Ser Ser Ala Asp Val Arg Ala Leu Thr Tyr Cys Asp Leu His Lys Ile Gln Arg AIa Asp Leu Leu Glu Val Leu Asp Met Tyr Pro Ala Phe Ala Glu Ser Phe Trp Ser Lys Leu Glu Val Thr Phe Asn Leu Arg Asp Val Thr Gly Gly Leu His Ser Ser Pro Arg Gln Ala Pro Gly Ser Gln Asp His Gln 725f 730 735 Gly Phe Phe Leu Ser Asp Asn Gln Ser Asp Ala A1a Pro Pro Leu Ser Ile Ser Asp Ala Phe Trp Leu Trp Pro Glu Leu Leu Gln Glu Met Pro Pro Lys His Ser Pro Gln Ser Pro Gln Glu Asp Pro Asp Cys Trp Pro Leu Lys Leu Gly Ser Arg Leu Glu Gln Leu Gln Ala Gln Met Asn Arg Leu Glu Ser Arg Val Ser Ser Asp Leu Ser Arg Ile Leu Gln Leu Leu Gln Lys Pro Met Pro Gln Gly His Ala Ser Tyr Tle Leu Glu Ala Pro A1a Ser Asn Asp Leu Ala Leu Val Pro Ile Ala Ser Glu Thr Thr Ser Pro Gly Pro Arg Leu Pro Gln G1y Phe Leu Pro Pro Ala Gln Thr Pro Ser Tyr Gly Asp Leu Asp Asp Cys Ser Pro Lys His Arg Asn Ser Ser Pro Arg Met Pro His Leu Ala Val Ala Met Asp Lys Thr Leu Ala Pro Ser Ser Glu Gln G1u Gln Pro Glu Gly Leu Trp Pro Pro Leu Ala Ser Pro Leu His Pro Leu Glu Val Gln Gly Leu Ile Cys Gly Pro Cys Phe Ser Ser Leu Pro Glu His Leu Gly Ser Val Pro Lys Gln Leu Asp Phe Gln Arg His Gly Ser Asp Pro Gly Phe Ala Gly Ser Trp Gly His <210> 10 <211> 724 <212> PRT
<213> Homo Sapiens <220>
<221> misc_teature <223> Incyte ID No: 7472728CD1 <400> 10 Met Gly His Gln Gly Pro Phe Glu Glu Gly Asn Gly Gly Leu Arg Val Ile Ala Thr Trp Arg Arg Lys Glu A1a Trp Arg Arg Asp Cys Leu Leu Gly Ala Leu Pro Ser Val Ser Cys Gly Gly Trp Gly His Arg Gly Arg Gln Thr Tyr Gly Arg Ala Cys Gly Val Lys Glu Lys Pro Phe Ser Leu Leu Gly Pro G1n Ile Thr Val Tyr Ala Val Trp Pro Gln Ser Glu Gly Pro Gln Glu Gly Arg Leu Arg Val Asn Ser Ala Cys Leu Pro Pro Glu Arg Gly Leu Thr Asn Ala Cys Thr Asn His Glu Glu Leu Ser Leu Asp Cys Leu Leu Phe Glu Asn Val Asn Thr Leu Thr Leu Asp Phe Cys Leu Trp G1u Lys Thr Thr Ile Val Pro Gly Val Leu Pro Tyr Ala Gly Leu Thr Leu Gln Ser Lys Phe Leu Leu Gly Arg Ala Leu Leu Ala Gly Val His Val Ile Thr Leu Thr Pro GIu Arg Val Thr His His Val His Gly Trp Tyr Met Glu Asp Gly Phe Lys Gly Asp Arg Thr Glu Gly Cys Arg Ser Asp Ser Val Ala Val Pro Ala Ala Ala Pro Val Cys Gln Pro Lys Ser Ala Thr Asn Gly Gln Pro Pro Ala Pro Ala Pro Thr Pro Thr Pro Arg Leu Ser Ile Ser Ser Arg Ala Thr Val Val Ala Arg Met G1u Gly Thr Ser Gln Gly Gly Leu Gln Thr Val Met Lys Trp Lys Thr Val Val Ala Ile Phe Val Va1 Val Val Val Tyr Leu Val Thr G1y Gly Leu Val Phe Arg Ala Leu Glu Gln Pro Phe Glu Ser Ser Gln Lys Asn Thr Ile Ala Leu Glu Lys A1a Glu Phe Leu Arg Asp His Val Cys Val Ser Pro G1n Glu Leu Glu Thr Leu Ile Gln His Ala Leu Asp Ala Asp Asn Ala Gly Val Ser Pro Ile Gly Asn Ser Ser Asn Asn Ser Ser His Trp Asp Leu Gly Ser Ala Phe Phe Phe Ala Gly Thr Val Ile Thr Thr Met Tyr Gly Asn Ile Ala Pro Ser Thr Glu Gly Gly Lys Ile Phe Cys Ile Leu Tyr Ala Ile Phe Gly Ile Pro Leu Phe Gly Phe Leu Leu Ala Gly Ile Gly Asp Gln Leu Gly Thr Ile Phe Gly Lys Ser Ile Ala Arg Val Glu Lys Val Phe Arg Lys Lys Gln Val Ser Gln Thr Lys Ile Arg Val Ile Ser Thr Ile Leu Phe Ile Leu Ala Gly Cys Ile Val Phe Val Thr Ile Pro Ala Val Ile Phe Lys Tyr IIe Glu G1y Trp Thr AIa Leu Glu Ser Ile Tyr Phe Val Val Val Thr Leu Thr Thr Val Gly Phe Gly Asp Phe Val AIa Val Val Val Phe Arg Gly Asn Ala Gly Tle Asn Tyr Arg G1u Trp Tyr Lys Pro Leu Va1 Trp Phe Trp Ile Leu Val Gly Leu Ala Tyr Phe Ala Ala Val Leu Ser Met Ile Gly Asp Trp Leu Arg Val Leu Ser Lys Lys Thr Lys Glu Glu Val Gly G1u Ile Lys Ala His Ala Ala Glu Trp Lys Ala Asn Val Thr Ala Glu Phe Arg Glu Thr Arg Arg Arg Leu Ser Val Glu Ile His Asp Lys Leu Gln Arg Ala Ala Thr Ile Arg Ser Met Glu Arg Arg Arg Leu G1y Leu Asp Gln Arg Ala His Ser Leu Asp Met Leu Ser Pro Glu Lys Arg Ser Val Phe Ala Ala Leu Asp Thr Gly Arg Phe Lys Ala Ser Ser Gln Glu Ser Ile Asn Asn Arg Pro Asn Asn Leu Arg Leu Lys Gly Pro Glu Gln Leu Asn Lys His Gly Gln Gly Ala Ser Glu Asp Asn Ile Tle Asn~Lys Phe Gly Ser Thr Ser Arg Leu Thr Lys Arg Lys Asn Lys Asp Leu Lys Lys Thr Leu Pro Glu Asp Val Gln Lys Ile Tyr Lys Thr Phe Arg Asn Tyr Ser Leu Asp Glu Glu Lys Lys Glu Glu Glu Thr Glu Lys Met Cys Asn Ser Asp Asn Ser Ser Thr Ala Met Leu Thr Asp Cys Ile Gln Gln His A1a Glu Leu Glu Asn Gly Met Ile Pro Thr Asp Thr Lys Asp Arg Glu Pro Glu Asn Asn Ser Leu Leu Glu Asp Arg Asn <210> 11 <211> 470 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474322CD1 <220>
<221> unsure <222> 253 <223> unknown or other <400> 11 Met Tyr Asn Glu Ile Leu Met Leu Gly Ala Lys Leu His Pro Thr Leu Lys Leu Glu Glu Leu Thr Asn Lys Lys Gly Met Thr Pro Leu Ala Leu Ala Ala Gly Thr Gly Lys Ile Gly Asn Arg His Asp Met Leu Leu Val Glu Pro Leu Asn Arg Leu Leu Gln Asp Lys Trp Asp Arg Phe Val Lys Arg Ile Phe Tyr Phe Asn Phe Leu Val Tyr Cys Leu Tyr Met Ile Ile Phe Thr Met Ala Ala Tyr Tyr Arg Pro Val Asp Gly Leu Pro Pro Phe Lys Met G1u Lys Thr Gly Asp Tyr Phe Arg Val Thr Gly Glu Ile Leu Ser Val Leu Gly Gly Val Tyr Phe Phe Phe Arg Gly Ile Gln Tyr Phe Leu Gln Arg Arg Pro Ser Met Lys Thr Leu Phe Val Asp Ser Tyr Ser Glu Met Leu Leu Phe Leu Gln Ser Leu Phe Met Leu Ala Thr Val Val Leu Tyr Phe Ser His Leu Lys GIu Tyr Val Ala Ser Met Val Phe Ser Leu Ala Leu Gly Trp Thr Asn Met Leu Tyr Tyr Thr Arg Gly Phe Gln Gln Met Gly Ile Tyr Ala Val Met Ile Glu Lys Met Ile Leu Arg Asp Leu Cys Arg Phe Met Phe Val Tyr Ile Val Phe Leu Phe Gly Phe Ser Thr Ala Val Val Thr Leu Ile Glu Asp Gly Lys Asn Asp Ser Leu Pro Ser Glu Ser Thr Ser His Arg Trp Arg Gly Pro AIa Xaa Arg Pro Asn Ser Ser Tyr Asn Ser Leu Tyr Ser Thr Cys Leu Glu Leu Phe Lys Phe Thr Ile Gly Met Gly Asp Leu Glu Phe Thr Glu Asn Tyr Asp Phe Lys A1a Val Phe IIe Ile Leu Leu Leu Ala Tyr'Val Ile Leu Thr Tyr Ile Val Leu Leu Leu Asn Met Leu Ile Ala Leu Met Gly Glu Thr Val Glu Asn Val Ser Lys Glu Ser Glu Arg Ile Trp Arg Leu Gln Arg Ala Ile Thr Ile Leu Asp Thr Glu Lys Ser Phe Leu Lys Cys Met Arg Lys Ala Phe Arg Ser Gly Lys Leu Leu Gln Val Gly Tyr Thr Pro Asp Gly Lys Asp Asp Tyr Arg Trp Cys Phe Val Asp Glu Val Asn Trp Thr Thr Trp Asn Thr Asn Val G1y Ile Ile Asn Glu Asp Pro Gly Asn Cys Glu Gly Val Lys Arg Thr Leu Ser Phe Ser Leu Arg Ser Ser Arg Val Ser Gly Arg His Trp Lys Asn Phe Ala Leu Val Pro Leu Leu Arg Glu Ala Ser Ala Arg Asp Arg Gln Ser Ala Gln Pro Glu Glu Val Tyr Leu Arg Gln Phe Ser Gly Ser Leu Lys Pro Glu Asp Ala Glu Val Phe Lys Ser Pro Ala Ala Ser Gly Glu Lys <210> 12 <211> 618 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5455621CD1 <400> 12 Met Glu Va1 Lys Asn Phe Ala Val Trp Asp Tyr Val Val Phe Ala Ala Leu Phe°Phe Ile Ser Ser G1y Ile Gly Val Phe Phe Ala Ile Lys Glu Arg Lys Lys Ala Thr Ser Arg Glu Phe Leu Va1 G1y Gly Arg Gln Met Ser Phe Gly Pro Val Gly Leu Ser Leu Thr Ala Ser Phe Met Ser Ala Val Thr Val Leu Gly Thr Pro Ser Glu Val Tyr Arg Phe Gly Ala Ser Phe Leu Val Phe Phe Ile Ala Tyr Leu Phe Val Ile Leu Leu Thr Ser Glu Leu Phe Leu Pro Val Phe Tyr Arg Ser Gly Ile Thr Ser Thr Tyr Glu Tyr Leu Gln Leu Arg Phe Asn Lys Pro Val Arg Tyr Ala Ala Thr Val I1e Tyr Ile Va1 Gln Thr Ile Leu Tyr Thr Gly Val Val Val Tyr Ala Pro Ala Leu Ala Leu Asn Gln Val Thr Gly Phe Asp Leu Trp Gly Ser Val Phe Ala Thr Gly Ile Val Cys Thr Phe Tyr Cys Thr Leu Gly Gly Leu Lys Ala Val Val Trp Thr Asp Ala Phe Gln Met Val Val Met Ile Val Gly Phe Leu Thr Val Leu Ile Gln Gly Ser Thr His Ala Gly Gly Phe His Asn Val Leu G1u Gln Ser Thr Asn Gly Ser Arg Leu His Ile Phe Asp Phe Asp Val Asp Pro Leu Arg Arg His Thr Phe Trp Thr Ile Thr Val Gly Gly Thr Phe Thr Trp Leu Gly Ile Tyr Gly Val Asn Gln Ser Thr Ile Gln Arg Cys Ile Ser Cys Lys Thr Glu Lys His Ala Lys Leu Ala Leu Tyr Phe Asn Leu Leu Gly Leu Trp I1e Ile Leu Val Cys Ala Va1 Phe Ser Gly Leu Ile Met Tyr Ser His Phe Lys Asp Cys Asp Pro Trp Thr Ser Gly Ile Ile Ser Ala Pro Asp Gln Leu Met Pro Tyr Phe Val Met Glu Ile Phe Ala Thr Met Pro Gly Leu Pro Gly Leu Phe Val Ala Cys Ala Phe Ser Gly Thr Leu Ser Thr Val Ala Ser Ser Ile Asn Ala Leu Ala Thr Val Thr Phe Glu Asp Phe Val Lys Ser Cys Phe Pro His Leu Ser Asp Lys Leu Ser Thr Trp IIe Ser Lys Gly Leu Cys Leu Leu Phe G1y Val Met Cys Thr Ser Met Ala Val Ala Ala Ser Val Met Gly Gly Val Val Gln Ala Ser Leu Ser Ile His Gly Met Cys Gly Gly Pro Met Leu Gly Leu Phe Ser Leu Gly Ile Val Phe Pro Phe Val Asn Trp Lys Gly Ala Leu Gly Gly Leu Leu Thr G1y Ile Thr Leu Ser Phe Trp Val Ala Ile G1y Ala Phe Ile Tyr Pro Ala Pro Ala Ser Lys Thr Trp Pro Leu Pro Leu Ser Thr Asp Gln Cys Ile Lys Ser Asn Val Thr Ala Thr Gly Pro Pro Val Leu Ser Ser Arg Pro Gly I1e Ala Asp Thr Trp Tyr Ser Ile Ser Tyr Leu Tyr Tyr Ser Ala Leu G1y Cys Leu Gly Cys Ile Val A1a Gly Val Ile Ile Ser Leu Ile Thr Gly Arg Gln Arg Gly Glu Asp Ile Gln Pro Leu Leu Ile Arg Pro Val Cys Asn Leu Phe Cys Phe Trp Ser Lys Lys Tyr Lys Thr Leu Cys Trp Cys Gly Va1 Gln His Asp Ser Gly Thr Glu Gln Glu Asn Leu Glu Asn Gly Ser Ala Arg Lys Gln Gly Ala Glu Ser Val Leu G1n Asn Gly Leu Arg Arg Glu Ser Leu Val His Val Pro G1y Tyr Asp Pro Lys Asp Lys Ser Tyr Asn Asn Met Ala Phe Glu Thr Thr His Phe <210> 13 <211> 631 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477248CD1 <400> l3 Met Glu Arg Gln Ser Arg Val Met Ser G1u Lys Asp Glu Tyr Gln Phe Gln His Gln Gly Ala Val Glu Leu Leu Val Phe Asn Phe Leu Leu Ile Leu Thr Ile Leu Thr Tle Trp Leu Phe Lys Asn His Arg Phe Arg Phe Leu His Glu Thr Gly Gly Ala Met Val Tyr Gly Leu Ile Met Gly Leu Ile Leu Arg Tyr Ala Thr Ala Pro Thr Asp Ile Glu Ser Gly Thr Val Tyr Asp Cys Val Lys Leu Thr Phe Ser Pro Ser Thr Leu Leu Val Asn Ile Thr Asp Gln Va1 Tyr Glu Tyr Lys Tyr Lys Arg Glu Ile Ser Gln His Asn Ile Asn Pro His Gln Gly Asn Ala Ile Leu Glu Lys Met Thr Phe Asp Pro Glu Ile Phe Phe Asn Val Leu Leu Pro Pro Ile Tle Phe His Ala Gly Tyr Ser Leu 140 145 . 150 Lys Lys Arg His Phe Phe Gln Asn Leu Gly Ser Ile Leu Thr Tyr Ala Phe Leu Gly Thr Ala Ile Ser Cys Ile Val Ile Gly Leu Ile Met Tyr Gly Phe Val Lys Ala Met Ile His Ala Gly Gln Leu Lys Asn Gly Asp Phe His Phe Thr Asp Cys Leu Phe Phe Gly Ser Leu Met Ser Ala Thr Asp Pro Va1 Thr Val Leu Ala Ile Phe His Glu Leu His Val Asp Pro Asp Leu Tyr Thr Leu Leu Phe Gly Glu Ser Val Leu Asn Asp Ala Val Ala Ile Val Leu Thr Tyr Ser Ile Ser Ile Tyr Ser Pro Lys Glu Asn Pro Asn Ala Phe Asp Ala Ala Ala Phe Phe Gln Ser Val Gly Asn Phe Leu Gly Ile Phe Ala Gly Ser Phe Ala Met Gly Ser Ala Tyr Ala Ile Ile Thr Ala Leu Leu Thr Lys Phe Thr Lys Leu Cys Glu Phe Pro Met Leu Glu Thr Gly Leu Phe Phe Leu Leu Ser Trp Ser Ala Phe Leu Ser Ala Glu Ala Ala Gly Leu Thr Gly Ile Val Ala Val Leu Phe Cys Gly Val Thr Gln Ala His Tyr Thr Tyr Asn Asn Leu Ser Ser Asp Ser Lys Tle Arg Thr Lys Gln Leu Phe Glu Phe Met Asn Phe Leu Ala Glu Asn Val Ile Phe Cys Tyr Met Gly Leu Ala Leu Phe Thr Phe Gln Asn His Ile Phe Asn Ala Leu Phe Ile Leu Gly Ala Phe Leu Ala Ile Phe Val Ala Arg Ala Cys Asn Ile Tyr Pro Leu Ser Phe~Leu Leu Asn Leu Gly Arg Lys Gln Lys Ile Pro Trp Asn Phe Gln His Met Met Met Phe Ser Gly Leu Arg Gly Ala Ile Ala Phe Ala Leu Ala Ile Arg Asn Thr Glu Ser Gln Pro Lys Gln Met Met Phe Thr Thr Thr Leu Leu Leu Val Phe Phe Thr Val Trp Val Phe Gly Gly Gly Thr Thr Pro Met Leu Thr Trp Leu Gln Ile Arg Val Gly Val Asp Leu Asp Glu Asn Leu Lys Glu Asp Pro Ser Ser GIn His Gln Glu Ala Asn Asn Leu Asp Lys Asn Met Thr Lys Ala Glu Ser Ala Arg Leu Phe Arg Met Trp Tyr Ser Phe Asp His Lys Tyr Leu Lys Pro Ile Leu Thr His Ser Gly Pro Pro Leu Thr Thr Thr Leu Pro Glu Trp Cys Gly Pro Ile Ser Arg Leu Leu Thr Ser Pro Gln Ala Tyr Gly Glu Gln Leu Lys Glu Asp Asp Val Glu Cys Ile Val Asn Gln Asp Glu Leu Ala Ile Asn Tyr Gln Glu Gln Ala Ser Ser Pro Cys Ser Pro Pro AIa Arg Leu GIy Leu Asp Gln Lys Ala Ser Pro Gln Thr Pro Gly Lys Glu Asn Ile Tyr Glu Gly Asp Leu Gly Pro Gly Arg Leu <210> 14 <211> 1256 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 2944004CD1 <400> 14 Met Asp Arg Glu Glu Arg Lys Thr Ile Asn Gln Gly Gln Glu Asp Glu Met G1u Ile Tyr Gly Tyr Asn Leu Ser Arg Trp Lys Leu Ala Ile Val Ser Leu Gly Val Ile Cys Ser Gly Gly Val Ser Pro Pro Pro Leu Tyr Trp Met Pro Glu Trp Arg Val Lys Ala Thr Cys Val Arg Ala Ala IIe Lys Asp Cys Glu VaI Val Leu Leu Arg Thr Thr Asp Glu Phe Lys Met Trp Phe Cys Ala Lys Ile Arg Val Leu Ser Leu Glu Thr Tyr Pro Va1 Ser Ser Pro Lys Ser Met Ser Asn Lys Leu Ser Asn Gly His Ala Val Cys Leu Ile Glu Asn Pro Thr Glu Glu Asn Arg His Arg Ile Ser Lys Tyr Ser Gln Thr Glu Ser GIn Gln Ile Arg Tyr Phe Thr His His Ser Val Lys Tyr Phe Trp Asn Asp Thr Ile His Asn Phe Asp Phe Leu Lys Gly Leu Asp Glu Gly Val Ser Cys Thr Ser Ile Tyr Glu Lys His Ser Ala Gly Leu Thr Lys Gly Met His Ala Tyr Arg Lys Leu Leu Tyr Gly Val Asn Glu Ile Ala Val Lys Val Pro Ser Val Phe Lys Leu Leu Ile Lys Glu Val Leu Asn Pro Phe Tyr Ile Phe G1n Leu Phe Ser Val Ile Leu Trp Ser Thr Asp Glu Tyr Tyr Tyr Tyr Ala Leu Ala Ile Val Val Met Ser Ile Val Ser Ile Val Ser Ser Leu Tyr Ser Ile Arg Lys Gln Tyr Val Met Leu His Asp Met Val Ala Thr His Ser Thr Val Arg Val Ser Val Cys Arg Val Asn Glu Glu Ile G1u Glu Ile Phe Ser Thr Asp Leu Va1 Pro Gly Asp Val Met Val Ile Pro Leu Asn Gly Thr Ile Met Pro Cys Asp Ala Val Leu Ile Asn Gly Thr Cys Ile Val Asn Glu Ser Met Leu Thr Gly Glu Ser Val Pro Val Thr Lys Thr Asn Leu Pro Asn Pro Ser Val Asp Val Lys Gly Ile Gly Asp Glu Leu Tyr Asn Pro Glu Thr His Lys Arg His Thr Leu Phe Cys Gly Thr Thr Val Tle Gln Thr Arg Phe Tyr Thr Gly Glu Leu Val Lys Ala Ile Val Val Arg Thr Gly Phe Ser Thr Ser Lys Gly Gln Leu Val Arg Ser Ile Leu Tyr Pro Lys Pro Thr Asp Phe Lys Leu Tyr Arg Asp Ala Tyr Leu Phe Leu Leu Cys Leu Val Ala Val Ala Gly Ile Gly Phe Ile Tyr Thr Ile Ile Asn Ser I1e Leu Asn Glu Val Gln Val Gly Val Ile Ile Ile Glu Ser Leu Asp Ile Ile Thr Ile Thr Val Pro Pro Ala Leu Pro AIa Ala Met Thr Ala G1y Ile VaI Tyr Ala Gln Arg Arg Leu Lys Lys I1e Gly Ile Phe Cys I1e Ser Pro Gln Arg Ile Asn Ile Cys Gly Gln Leu Asn Leu Val Cys Phe Asp Lys Thr Gly Thr Leu Thr Glu Asp Gly Leu Asp Leu Trp Gly Ile Gln Arg Val G1u Asn Ala Arg Phe Leu Ser Pro Glu Glu Asn Val Cys Asn Glu Met Leu Val Lys Ser Gln Phe Val Ala Cys Met Ala Thr Cys His Ser Leu Thr Lys Ile Glu Gly Val Leu Ser Gly Asp Pro Leu Asp Leu Lys Met Phe Glu Ala Ile Gly Trp Ile Leu Glu Glu Ala Thr Glu Glu Glu Thr Ala Leu His Asn Arg Ile Met Pro Thr Val Val Arg Pro Pro Lys Gln Leu Leu Pro Glu Ser Thr Pro Ala Gly Asn Gln Glu Met Glu Leu Phe G1u Leu Pro Ala Thr Tyr Glu Ile GIy Ile Val Arg Gln Phe Pro Phe Ser Ser Ala Leu GIn Arg Met Ser Val Val Ala Arg Val Leu Gly Asp Arg Lys Met Asp A1a Tyr Met Lys Gly Ala Pro Glu Ala Ile A1a GIy Leu Cys Lys Pro G1u Thr Val Pro Val Asp Phe Gln Asn Val Leu Glu Asp Phe Thr Lys Gln Gly Phe Arg Val Ile Ala Leu Ala His Arg Lys Leu G1u Ser Lys Leu Thr Trp His Lys Val GIn Asn Ile Ser Arg Asp A1a Ile Glu Asn Asn Met Asp Phe Met Gly Leu Ile Ile Met Gln Asn Lys Leu Lys Gln Lys Thr Pro Ala Va1 Leu Glu Asp Leu His Lys Ala Asn Ile Arg Thr VaI Met Val Thr Gly Asp Ser Met Leu Thr Ala Val Ser Val Ala Arg Asp Cys GIy Met Ile Leu Pro Gln Asp Lys Va1 Ile Ile Ala Glu Ala Leu Pro Pro Lys Asp Gly Lys Val Ala Lys Ile Asn Trp His Tyr Ala Asp Ser Leu Thr Gln Cys Ser His Pro Ser Ala IIe Asp Pro Glu Ala Ile Pro Val Lys Leu Val His Asp Ser Leu Glu Asp Leu Gln Met Thr Arg Tyr His Phe Ala Met Asn Gly Lys Ser Phe Ser VaI Ile Leu GIu His Phe G1n Asp Leu Val Pro Lys Leu Met Leu His Gly Thr Val Phe Ala Arg Met Ala Pro Asp Gln Lys Thr Gln Leu Ile Glu Ala Leu Gln Asn Val Asp Tyr Phe Val Gly Met Cys Gly Asp Gly Ala Asn Asp Cys Gly Ala Leu Lys Arg Ala His Gly Gly I1e Ser Leu Ser Glu Leu Glu Ala Ser Val Ala Ser Pro Phe Thr Ser Lys Thr Pro Ser Ile Ser Cys Val Pro Asn Leu Ile Arg G1u Gly Arg Ala Ala Leu Ile Thr Ser Phe Cys Val Phe Lys Phe Met Ala Leu Tyr Ser Ile I1e Gln Tyr Phe Ser Val Thr Leu Leu Tyr Ser Ile Leu Ser Asn Leu Gly Asp Phe Gln Phe Leu Phe Ile Asp Leu Ala Ile 965 ~ 970 975 Ile Leu Val Val Val Phe Thr Met Ser Leu Asn Pro Ala Trp Lys Glu Leu Val Ala Gln Arg Pro Pro Ser G1y Leu Ile Ser Gly Ala Leu Leu Phe Ser Val Leu Ser Gln Ile Ile Ile Cys Ile Gly Phe Gln Ser Leu Gly Phe Phe Trp Val Lys Gln Gln Pro Trp Tyr Glu Val Trp His Pro Lys Ser Asp Ala Cys Asn Thr Thr Gly Ser Gly Phe Trp Asn Ser Ser His Val Asp Asn Glu Thr Glu Leu Asp Glu His Asn Ile Gln Asn Tyr Glu Asn Thr Thr Val Phe Phe Ile Ser Ser Phe G1n Tyr Leu Tle Val Ala Ile Ala Phe Ser Lys Gly Lys Pro Phe Arg Gln Pro Cys Tyr Lys Asn Tyr Phe Phe Val Phe Ser Val Ile Phe Leu Tyr Tle Phe Ile Leu Phe Ile Met Leu Tyr Pro Val Ala Ser Val Asp Gln Val Leu Gln Ile Val Cys Val Pro Tyr Gln Trp Arg Val Thr Met Leu Ile Ile Val Leu Val Asn Ala Phe Val Ser Ile Thr Val Glu Asn Phe Phe Leu Asp Met Val Leu Trp Lys Val Val Phe Asn Arg Asp Lys Gln Gly Glu Tyr Arg Phe Ser Thr Thr Gln Pro Pro Gln Glu Ser Val Asp Arg Trp Gly Lys Cys Cys Leu Pro Trp Ala Leu Gly Cys Arg Lys Lys Thr Pro Lys Ala Lys Tyr Met Tyr Leu Ala Gln Glu Leu Leu Val Asp Pro Glu Trp Pro Pro Lys Pro Gln Thr Thr Thr Glu Ala Lys Ala Leu Val Lys Glu Asn Gly Ser Cys Gln Ile Ile Thr Ile Thr <210> 15 <211> 499 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 3046849CD1 <400> 15 Met Leu His Ala Leu Leu Arg Ser Arg Thr Ile Gln Gly Arg Ile Leu Leu Leu Thr Ile Cys Ala Ala Gly Ile Gly Gly Thr Phe Gln Phe Gly Tyr Asn Leu Ser Ile Ile Asn Ala Pro Thr Leu His Ile Gln Glu Phe Thr Asn Glu Thr Trp Gln Ala Arg Thr Gly Glu Pro Leu Pro Asp His Leu Val Leu Leu Met Trp Ser Leu Ile Va1 Ser Leu Tyr Pro Leu Gly G1y Leu Phe Gly Ala Leu Leu Ala Gly Pro Leu Ala Ile Thr Leu Gly Arg Lys Lys Ser Leu Leu Val Asn Asn Ile Phe Val Val Ser Ala Ala Ile Leu Phe Gly Phe Ser Arg Lys Ala G1y Ser Phe Glu Met Ile Met Leu Gly Arg Leu Leu Val Gly Val Asn Ala Gly Val Ser Met Asn Ile Gln Pro Met Tyr Leu Gly G1u Ser Ala Pro Lys Glu Leu Arg Gly Ala Val Ala Met Ser Ser Ala I1e Phe Thr Ala Leu Gly Ile Val Met Gly Gln Val Val G1y Leu Arg Glu Leu Leu Gly Gly Pro Gln Ala Trp Pro Leu Leu Leu Ala Ser Cys Leu Val Pro Gly Ala Leu Gln Leu Ala Ser Leu Pro Leu Leu Pro Glu Ser Pro Arg Tyr Leu Leu Ile Asp Cys Gly Asp Thr Glu Ala Cys Leu Ala Ala Leu Arg Gln Leu Arg Gly Ser Gly Asp Leu A1a Gly Glu Leu Glu Glu Leu Glu Glu Glu Arg Ala Ala Cys Gln Gly Cys Arg A1a Arg Arg Pro Trp Glu Leu Phe Gln His Arg Ala Leu Arg Arg Gln Val Thr Ser Leu Val Val Leu Gly Ser Ala Met Glu Leu Cys Gly Asn Asp Ser Val Tyr Ala Tyr Ala Ser Ser Val Phe Arg Lys Ala Gly Va1 Pro Glu Ala Lys Ile Gln Tyr Ala Ile Ile Gly Thr Gly Ser Cys Glu Leu Leu Thr Ala Val Val Ser Cys Val Val Ile Glu Arg Val G1y Arg Arg Val Leu Leu Ile Gly Gly Tyr Ser Leu Met Thr Cys Trp Gly Ser Ile Phe Thr Val Ala Leu Cys Leu Gln Ser Ser Phe Pro Trp Thr Leu Tyr Leu Ala Met Ala Cys Ile Phe Ala Phe Ile Leu Ser Phe Gly Ile Gly Pro Ala Gly Val Thr Gly Ile Leu Ala Thr Glu Leu Phe Asp Gln Met Ala Arg Pro Ala Ala Cys Met Val Cys Gly Ala Leu Met Trp Ile Met Leu Ile Leu Val Gly Leu Gly Phe Pro Phe Ile Met Glu Ala Leu Ser His Phe Leu Tyr Val Pro Phe Leu Gly Val Cys Val Cys Gly Ala Ile Tyr Thr Gly Leu Phe Leu Pro Glu Thr Lys Gly Lys Thr Phe Gln Glu Ile Ser Lys Glu Leu His Arg Leu Asn Phe Pro Arg Arg Ala Gln Gly Pro Thr Trp Arg Ser Leu Glu Val Ile Gln Ser Thr Glu Leu <210> 16 <211> 596 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Tncyte ID No: 4538363CD1 <400> 16 Met Ala Ala Asn Ser Thr Ser Asp Leu His Thr Pro Gly Thr Gln Leu Ser Val Ala Asp Ile Ile Val I1e Thr Val Tyr Phe Ala Leu Asn Val Ala Val Gly Tle Trp Ser Ser Cys Arg Ala Ser Arg Asn Thr Val Asn Gly Tyr Phe Leu Ala Gly Arg Asp Met Thr Trp Trp Pro Tle Gly Ala Ser Leu Phe Ala Ser Ser Glu Gly Ser Gly Leu Phe Ile Gly Leu Ala Gly Ser Gly Ala Ala G1y G1y Leu Ala Val A1a Gly Phe Glu Trp Asn Ala Thr Tyr Val Leu Leu Ala Leu Ala Trp Val Phe Val Pro Ile Tyr Ile Ser Ser Glu Ile Val Thr Leu Pro Glu Tyr Ile Gln Lys Arg Tyr Gly Gly Gln Arg Ile Arg Met Tyr Leu Ser Val Leu Ser Leu Leu Leu Ser Va1 Phe Thr Lys Ile Ser Leu Asp Leu Tyr Ala Gly Ala Leu Phe Val His Ile Cys Leu Gly Trp Asn Phe Tyr Leu Ser Thr Ile Leu Thr Leu Gly Ile Thr Ala Leu Tyr Thr Ile Ala Gly Gly Leu Ala Ala Val Ile Tyr Thr Asp Ala Leu Gln Thr Leu I1e Met Val Val Gly Ala Val Ile Leu Thr Ile Lys Ala Phe Asp Gln Ile Gly Gly Tyr Gly Gln Leu Glu Ala Ala Tyr Ala Gln Ala Ile Pro Sex Arg Thr Ile Ala Asn Thr Thr Cys His Leu Pro Arg Thr Asp Ala Met His Met Phe Arg Asp Pro His Thr Gly Asp Leu Pro Trp Thr Gly Met Thr Phe Gly Leu Thr Ile Met Ala Thr Trp Tyr Trp Cys Thr Asp Gln Va1 Ile Val Gln Arg Ser Leu Ser Ala Arg Asp Leu Asn His Ala Lys Ala Gly Ser Ile Leu Ala Ser Tyr Leu Lys Met Leu Pro Met Gly Leu Ile Ile Met Pro Gly Met Ile Ser Arg Ala Leu Phe Pro Asp Asp Val Gly Cys Val Val Pro Ser Glu Cys Leu Arg Ala Cys Gly Ala Glu Val Gly Cys Ser Asn Ile Ala Tyr Pro Lys Leu Val Met Glu Leu Met Pro Ile Gly Leu Arg Gly Leu Met Ile Ala Val Met Leu Ala Ala Leu Met Ser Ser Leu Thr Ser Ile Phe Asn Ser Ser Ser Thr Leu Phe Thr Met Asp Ile Trp Arg Arg Leu Arg Pro Arg Ser Gly Glu Arg Glu Leu Leu Leu Va1 Gly Arg Leu Val Ile Val Ala Leu Ile Gly Val Ser Val Ala Trp Ile Pro Val Leu Gln Asp Ser Asn Ser Gly Gln Leu Phe Ile Tyr Met Gln Ser Val Thr Ser Ser Leu Ala Pro Pro Val Thr Ala Val Phe Val Leu Gly Val Phe Trp Arg Arg Ala Asn Glu Gln Gly Ala Phe Trp Gly Leu Tle Ala Gly Leu Val Val Gly Ala Thr Arg Leu Val Leu Glu Phe Leu Asn Pro Ala Pro Pro Cys Gly Glu Pro Asp Thr Arg Pro Ala Val Leu Gly Ser Ile His Tyr Leu His Phe Ala Val Ala Leu Phe Ala Leu Ser Gly Ala Val Val Val Ala Gly Ser Leu Leu Thr Pro Pro Pro Gln Ser Va1 Gln Ile Glu Asn Leu Thr Trp Trp Thr Leu Ala Gln Asp Val Pro Leu Gly Thr Lys A1a Gly Asp Gly Gln Thr Pro Gln Lys His Ala Phe Trp Ala Arg Val Cys Gly Phe Asn Ala Ile Leu Leu Met Cys Val Asn Ile Phe Phe Tyr Ala Tyr Phe Ala <210> 17 <211> 1192 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 6427460CD1 <400> 17 Met Asp Cys Ser Leu Val Arg Thr Leu Val His Arg Tyr Cys A1a Gly Glu Glu Asn Trp Va1 Asp Ser Arg Thr Ile Tyr Val Gly His Arg Glu Pro Pro Pro Gly Ala Glu Ala Tyr I1e Pro Gln Arg Tyr Pro Asp Asn Arg Ile Val Ser Ser Lys Tyr Thr Phe Trp Asn Phe Ile Pro Lys Asn Leu Phe Glu Gln Phe Arg Arg Val Ala Asn Phe Tyr Phe Leu Ile Ile Phe Leu Val Gln Leu Ile Ile Asp Thr Pro Thr Ser Pro Val Thr Ser Gly Leu Pro Leu Phe Phe Val Ile Thr Val Thr Ala Ile Lys Gln Gly Tyr Glu Asp Trp Leu Arg His Lys Ala Asp Asn Ala Met Asn Gln Cys Pro Val His Phe Ile Gln His Gly Lys Leu Val Arg Lys Gln Ser Arg Lys Leu Arg Val Gly Asp Ile Val Met Val Lys Glu Asp Glu Thr Phe Pro Cys Asp Leu Ile Phe Leu Ser Ser Asn Arg G1y Asp Gly Thr Cys His Val Thr Thr Ala Ser Leu Asp Gly Glu Ser Ser His Lys Thr His Tyr Ala Val Gln Asp Thr Lys Gly Phe His Thr Glu Glu Asp Ile Gly Gly Leu His Ala Thr Ile Glu Cys Glu Gln Pro Gln Pro Asp Leu Tyr Lys Phe Val Gly Arg Ile Asn Val Tyr Ser Asp Leu Asn Asp Pro Val Va1 Arg Pro Leu Gly Ser Glu Asn Leu Leu Leu Arg Gly Ala Thr Leu Lys Asn Thr Glu Lys Ile Phe Gly Val Ala Ile Tyr Thr Gly Met Glu Thr Lys Met Ala Leu Asn Tyr Gln Ser Lys Ser Gln Lys Arg Ser AIa Val Glu Lys Ser Met Asn AIa Phe Leu Ile Val Tyr Leu Cys Ile Leu Ile Ser Lys Ala Leu Tle Asn Thr Val Leu Lys Tyr Val Trp Gln Ser Glu Pro Phe Arg Asp Glu Pro Trp Tyr Asn Gln Lys Thr Glu Ser Glu Arg Gln Arg Asn Leu Phe Leu Lys Ala Phe Thr Asp Phe Leu Ala Phe Met Val Leu Phe Asn Tyr Ile Tle Pro Val Ser Met Tyr Val Thr Val Glu Met Gln Lys Phe Leu Gly Ser Tyr Phe Ile Thr Trp Asp Glu Asp Met Phe Asp Glu Glu Thr Gly GIu Gly Pro Leu Val Asn Thr Ser Asp Leu Asn Glu Glu Leu Gly Gln VaI Glu Tyr Ile Phe Thr Asp Lys Thr Gly Thr Leu Thr 410 4l5 420 Glu Asn Asn Met Glu Phe Lys Glu Cys Cys Ile Glu Gly His Val Tyr Val Pro His Val Ile Cys Asn Gly Gln Val Leu Pro Glu Ser Ser G1y Tle Asp Met Ile Asp Ser Ser Pro Ser Val Asn Gly Arg Glu Arg Glu Glu Leu Phe Phe Arg Ala Leu Cys Leu Cys His Thr Val Gln Val Lys Asp Asp Asp Ser Val Asp Gly Pro Arg Lys Ser Pro Asp Gly Gly Lys Ser Cys Val Tyr Ile Ser Ser Ser Pro Asp Glu Val Ala Leu Val Glu Gly Val Gln Arg Leu Gly Phe Thr Tyr Leu Arg Leu Lys Asp Asn Tyr Met Glu Ile Leu Asn Arg Glu Asn His Ile Glu Arg Phe Glu Leu Leu Glu Ile Leu Ser Phe Asp Ser Val Arg Arg Arg Met Ser Val Ile Val Lys Ser Ala Thr Gly Glu Ile Tyr Leu Phe Cys Lys GIy Ala Asp Ser Ser Ile Phe Pro Arg Val Ile G1u Gly Lys Val Asp Gln Ile Arg Ala Arg Val Glu Arg Asn Ala Val Glu Gly Leu Arg Thr Leu Cys Val Ala Tyr Lys Arg Leu Ile Gln Glu Glu Tyr Glu Gly Ile Cys Lys Leu Leu Gln Ala Ala Lys Val Ala Leu Gln Asp Arg Glu Lys Lys Leu A1a Glu Ala Tyr G1u Gln Ile Glu Lys Asp Leu Thr Leu Leu Gly A1a Thr Ala Val Glu Asp Arg Leu Gln Glu Lys Ala Ala Asp Thr Ile Glu A1a Leu Gln Lys Ala Gly Ile Lys Val Trp Val Leu Thr Gly Asp Lys Met Glu Thr AIa Ala Ala Thr Cys Tyr Ala Cys Lys Leu Phe Arg Arg Asn Thr Gln Leu Leu Glu Leu Thr Thr Lys Arg Ile Glu Glu G1n Ser Leu His Asp Val Leu Phe Glu Leu Ser Lys Thr Val Leu Arg His Ser Gly Ser Leu Thr Arg Asp Asn Leu Ser Gly Leu Ser Ala Asp Met Gln Asp Tyr Gly Leu Ile Ile Asp Gly Ala Ala Leu Ser Leu Ile Met Lys Pro Arg Glu Asp Gly Ser Ser Gly Asn Tyr Arg Glu Leu Phe Leu Glu Ile Cys Arg Ser Cys Ser Ala Val Leu Cys Cys Arg Met Ala Pro Leu Gln Lys Ala Gln Ile Val Lys Leu Ile Lys Phe Ser Lys Glu His Pro Ile Thr Leu Ala Ile Gly Asp 8l5 820 825 Gly Ala Asn Asp Val Ser Met Ile Leu Glu Ala His Val Gly Ile Gly Val Ile Gly Lys Glu Gly Arg Gln Ala Ala Arg Asn Ser Asp Tyr Ala Ile Pro Lys Phe Lys His Leu Lys Lys Met Leu Leu Val 860 865° 870 His Gly His Phe Tyr Tyr Ile Arg Ile Ser Glu Leu Val Gln Tyr Phe Phe Tyr Lys Asn Val Cys Phe Ile Phe Pro Gln Phe Leu Tyr Gln Phe Phe Cys Gly Phe Ser Gln Gln Thr Leu Tyr Asp Thr Ala Tyr Leu Thr Leu Tyr Asn Ile Ser Phe Thr Ser Leu Pro Ile Leu Leu Tyr Ser Leu Met Glu Gln His Val Gly Ile Asp Val Leu Lys Arg Asp Pro Thr Leu Tyr Arg Asp Val Ala Lys Asn Ala Leu Leu Arg Trp Arg Val Phe Ile Tyr Trp Thr Leu Leu G1y Leu Phe Asp Ala Leu Val Phe Phe Phe Gly Ala Tyr Phe Val Phe Glu Asn Thr Thr Val Thr Ser Asn Gly Gln Ile Phe Gly Asn Trp Thr Phe Gly Thr Leu Val Phe Thr Val Met Val Phe Thr Val Thr Leu Lys Leu Ala Leu Asp Thr His Tyr Trp Thr Trp Ile Asn His Phe Val Ile Trp Gly Ser Leu Leu Phe Tyr Val Val Phe Ser Leu Leu Trp Gly Gly Val Ile Trp Pro Phe Leu Asn Tyr Gln Arg Met Tyr Tyr Val Phe Ile Gln Met Leu Ser Ser Gly Pro Ala Trp Leu Ala Ile Val Leu Leu Val Thr Ile Ser Leu Leu Pro Asp Val Leu Lys Lys Val Leu Cys Arg Gln Leu Trp Pro Thr Ala Thr Glu Arg Val Gln Gln Asn Gly Cys Ala Gln Pro Arg Asp Arg Asp Ser Glu Phe Thr Pro Leu Ala S2r Leu Gln Ser Pro Gly Tyr Gln Ser Thr Cys Pro Ser Ala Ala Trp Tyr Ser Ser His Ser Gln Gln Val Thr Leu Ala Ala Trp Lys Glu Lys Val Ser Thr Glu Pro Pro Pro Ile Leu Gly Gly Ser His His His Cys Ser Ser Ile Pro Ser His Ser Cys Pro Arg Ser Arg Va1 G1y Met Leu Val <210> 18 <211> 638 <212> PRT

<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474127CD1 <400> 18 Met Gly Lys Ile Glu Asn Asn Glu Arg Val Ile Leu Asn Val Gly Gly Thr Arg His Glu Thr Tyr Arg Ser Thr Leu Lys Thr Leu Pro Gly Thr Arg Leu Ala Leu Leu Ala Ser Ser Glu Pro Pro Gly Asp Cys Leu Thr Thr Ala Gly Asp Lys Leu Gln Pro Ser Pro Pro Pro Leu Ser Pro Pro Pro Arg Ala Pro Pro Leu Ser Pro Gly Pro Gly Gly Cys Phe Glu Gly Gly Ala Gly Asn Cys Ser Ser Arg Gly Gly Arg Ala Ser Asp His Pro Gly Gly Gly Arg Glu Phe Phe Phe Asp Arg His Pro Gly Val Phe Ala Tyr Val Leu Asn Tyr Tyr Arg Thr G1y Lys Leu His Cys Pro Ala Asp Val Cys Gly Pro Leu Phe Glu Glu Glu Leu Ala Phe Trp Gly Ile Asp Glu Thr Asp Val Glu Pro Cys Cys Trp Met Thr Tyr Arg Gln His Arg Asp Ala Glu Glu Ala Leu Asp Ile Phe Glu Thr Pro Asp Leu Ile Gly Gly Asp Pro G1y Asp Asp Glu Asp Leu Ala Ala Lys Arg Leu Gly Ile Glu Asp Ala Ala Gly Leu Gly Gly Pro Asp Gly Lys Ser Gly Arg Trp Arg Arg Leu Gln Pro Arg Met Trp Ala Leu Phe G1u Asp Pro Tyr Ser Ser Arg Ala Ala Arg Phe Ile Ala Phe Ala Ser Leu Phe Phe Ile Leu Val Ser I1e Thr Thr Phe Cys Leu Glu Thr His Glu Ala Phe Asn Ile Val Lys Asn Lys Thr Glu Pro Val I1e Asn Gly Thr Ser Val Val Leu Gln Tyr G1u Ile G1u Thr Asp Pro A1a Leu Thr Tyr Val Glu Gly Val Cys Val Val Trp Phe Thr Phe Glu Phe Leu Val Arg Ile Val Phe Ser Pro Asn Lys Leu Glu Phe Ile Lys Asn Leu Leu Asn Ile Ile Asp Phe Val Ala Ile Leu Pro Phe Tyr Leu Glu Val Gly Leu Ser Gly Leu Ser Ser Lys Ala A1a Lys Asp Val Leu Gly Phe Leu Arg Val Val Arg Phe Val Arg Ile Leu Arg Ile Phe Lys Leu Thr Arg His Phe Val Gly Leu Arg Val Leu Gly His Thr Leu Arg Ala Ser Thr Asn Glu Phe Leu Leu Leu Ile Ile Phe Leu Ala Leu Gly Val Leu Ile Phe Ala Thr Met Ile Tyr Tyr Ala Glu Arg Val Gly Ala Gln Pro Asn Asp Pro Ser Ala Ser Glu His Thr G1n Phe Lys Asn I1e Pro Ile Gly Phe Trp Trp Ala Val Val Thr Met Thr Thr Leu Gly Tyr Gly Asp Met Tyr Pro Gln Thr Trp Ser Gly Met Leu Val Gly Ala Leu Cys Ala Leu Ala Gly Val Leu Thr Ile Ala Met Pro Val Pro Val Ile Val Asn Asn Phe Gly Met Tyr Tyr Ser Leu Ala Met Ala Lys Gln Lys Leu Pro Arg Lys Arg Lys Lys His Tle Pro Pro Ala Pro Gln Ala Ser Ser Pro Thr Phe Cys Lys Thr Glu Leu Asn Met A1a Cys Asn Ser Thr Gln Ser Asp Thr Cys Leu Gly Lys Asp Asn Arg Leu Leu Glu His Asn Arg Ser Val Leu Ser Gly Asp Asp Ser Thr Gly Ser Glu Pro Pro Leu Ser Pro Pro Glu Arg Leu Pro Ile Arg Arg Ser Ser Thr Arg Asp Lys Asn Arg Arg Gly Glu Thr Cys Phe Leu Leu Thr Thr Gly Asp Tyr Thr Cys Ala Ser Asp Gly Gly Ile Arg Lys Gly Tyr Glu Lys Ser Arg Ser Leu Asn Asn Ile Ala Gly Leu Ala Gly Asn Ala Leu Arg Leu Ser Pro Val Thr Ser Pro Tyr Asn Ser Pro Cys Pro Leu Arg Arg Ser Arg Ser Pro I1e Pro Ser Ile Leu <210> 19 <211> 681 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7476949CD1 <400> 19 Met Ser Lys Asp Leu Ala Ala Met Gly Pro Gly Ala Ser G1y Asp Gly Val Arg Thr Glu Thr Ala Pro His Ile Ala Leu Asp Ser Arg Val Gly Leu His Ala Tyr Asp Tle Ser Val Val Val Ile Tyr Phe Val Phe Val Ile Ala Val Gly Ile Trp Ser Ser Tle Arg Ala Ser Arg Gly Thr Ile Gly Gly Tyr Phe Leu Ala G1y Arg Sex Met Ser Trp Trp Pro Ile Gly Ala Ser Leu Met Ser Ser Asn Val Gly Ser Gly Leu Phe Ile Gly Leu Ala Gly Thr Gly Ala Ala Gly Gly Leu Ala Val G1y Gly Phe Glu Trp Asn Ala Thr Trp Leu Leu Leu A1a Leu Gly Trp Val Phe Val Pro Val Tyr Ile Ala Ala Gly Val Val Thr Met Pro Gln Tyr Leu Lys Lys Arg Phe Gly Gly Gln Arg Ile Gln Val Tyr Met Ser Val Leu Ser Leu Ile Leu Tyr Ile Phe Thr Lys Ile Ser Thr Asp Ile Phe Ser Gly Ala Leu Phe Ile Gln Met Ala Leu Gly Trp Asn Leu Tyr Leu Ser Thr Gly I1e Leu Leu Val Val Thr A1a Val Tyr Thr Ile Ala Gly Gly Leu Met Ala Val Ile Tyr Thr Asp A1a Leu Gln Thr Val Ile Met Val Gly Gly Ala Leu Val Leu Met Phe Leu Gly Phe Gln Asp Val Gly Trp Tyr Pro Gly Leu G1u Gln Arg Tyr Arg Gln Ala Ile Pro Asn Val Thr Val Pro Asn Thr Thr Cys His Leu Pro Arg Pro Asp Ala Phe His Ile Leu 260 ~ 265 270 Arg Asp Pro Val Ser Gly Asp Ile Pro Trp Pro Gly Leu Ile Phe Gly Leu Thr Val Leu Ala Thr Trp Cys Trp Cys Thr Asp Gln Val Ile Val Gln Arg Ser Leu Ser Ala Lys Ser Leu Ser His Ala Lys Gly Gly Ser Val Leu Gly Gly Tyr Leu Lys I1e Leu Pro Met Phe Phe Ile Val Met Pro Gly Met Ile Ser Arg Ala Leu Phe Pro Asp Glu Val Gly Cys Val Asp Pro Asp Val Cys Gln Arg Ile Cys Gly Ala Arg Val Gly Cys Ser Asn Ile Ala Tyr Pro Lys Leu Val Met Ala Leu Met Pro Val Gly Leu Arg Gly Leu Met Ile Ala Val Ile Met Ala Ala Leu Met Ser Ser Leu Thr Ser Ile Phe Asn Ser Ser Ser Thr Leu Phe Thr Ile Asp Val Trp Gln Arg Phe Arg Arg Lys Ser Thr Glu Gln Glu Leu Met Val Val Gly Arg Val Phe Val Val Phe Leu Val Val Ile Ser Ile Leu Trp Ile Pro Ile Ile Gln Ser Ser Asn Ser Gly Gln Leu Phe Asp Tyr Ile Gln Ala Val Thr Ser 455 460 ' 465 Tyr Leu Ala Pro Pro Ile Thr Ala Leu Phe Leu Leu Ala Ile Phe Cys Lys Arg Val Thr Glu Pro Gly Ala Phe Trp Gly Leu Val Phe Gly Leu Gly Val Gly Leu Leu Arg Met Ile Leu Glu Phe Ser Tyr Pro Ala Pro Ala Cys Gly Glu Val Asp Arg Arg Pro Ala Val Leu Lys Asp Phe His Tyr Leu Tyr Phe Ala Ile Leu Leu Cys Gly Leu Thr Ala Ile Val Ile Va1 Ile Val Ser Leu Cys Thr Thr Pro Ile Pro Glu Glu Gln Leu Thr Arg Leu Thr Trp Trp Thr Arg Asn Cys Pro Leu Ser Glu Leu Glu Lys Glu Ala His Glu Ser Thr Pro Glu Ile Ser Glu Arg Pro Ala Gly Glu Cys Pro Ala Gly Gly Gly Ala Ala Glu Asn Ser Ser Leu Gly Gln Glu Gln Pro Glu Ala Pro Ser Arg Ser Trp Gly Lys Leu Leu Trp Ser Trp Phe Cys Gly Leu Ser Gly Thr Pro Glu Gln Ala Leu Ser Pro Ala Glu Lys Ala Ala Leu Glu G1n Lys Leu Thr Ser Ile Glu Glu Glu Pro Leu Trp Arg His VaI Cys Asn Ile Asn Ala Val Leu Leu Leu Ala IIe Asn Ile Phe Leu Trp Gly Tyr Phe Ala <210> 20 <211> 1096 <212> PRT
<223> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477249CD1 <400> 20 Met Trp Arg Trp Ile Arg Gln Gln Leu Gly Phe Asp Pro Pro His G1n Ser Asp Thr Arg Thr Ile Tyr Val Ala Asn Arg Phe Pro Gln Asn Gly Leu Tyr Thr Pro Gln Lys Phe Ile Asp Asn Arg Ile Ile Ser Ser Lys Tyr Thr Val Trp Asn Phe Va1 Pro Lys Asn Leu Phe Glu Gln Phe Arg Arg Val Ala Asn Phe Tyr Phe Leu Ile Ile Phe Leu VaI Gln Leu Met Ile Asp Thr Pro Thr Ser Pro Val Thr Ser Gly Leu Pro Leu Phe Phe Val Ile Thr Val Thr Ala Ile Lys Gln Gly Tyr Glu Asp Trp Leu Arg His Asn Ser Asp Asn Glu Va1 Asn Gly Ala Pro Val Tyr Val Val Arg Ser Gly Gly Leu Val Lys Thr Arg Ser Lys Asn Ile Arg Val Gly Asp Ile Val Arg Ile Ala Lys Asp G1u Ile Phe Pro Ala Asp Leu Val Leu Leu Ser Ser Asp Arg Leu Asp Gly Ser Cys His Val Thr Thr Ala Ser Leu Asp Gly Glu Thr Asn Leu Lys Thr His Val Ala Val Pro Glu Thr Ala Leu Leu Gln Thr Va1 Ala Asn Leu Asp Thr Leu Va1 Ala Val Ile Glu Cys Gln Gln Pro Glu Ala Asp Leu Tyr Arg Phe Met Gly Arg Met I1e Ile Thr Gln Gln Met Glu Glu Ile Val Arg Pro Leu Gly Pro Glu Ser Leu Leu Leu Arg Gly Ala Arg Leu Lys Asn Thr Lys Glu Ile Phe Gly Val Ala Val Tyr Thr Gly Met Glu Thr Lys Met A1a Leu Asn Tyr Lys Ser Lys Ser Gln Lys Arg Ser Ala Val Glu Lys Ser Met Asn Thr Phe Leu Ile Ile Tyr Leu Val Ile Leu Ile Ser Glu Ala Val Ile Ser Thr Ile Leu Lys Tyr Thr Trp Gln Ala Glu Glu Lys Trp Asp Glu Pro Trp Tyr Asn Gln Lys Thr Glu His Gln Arg Asn Ser Ser Lys Val Glu Tyr Val Phe Thr Asp Lys Thr Gly Thr Leu Thr Glu Asn Glu Met Gln Phe Arg Glu Cys Ser Ile Asn Gly Met Lys Tyr Gln Glu Ile Asn Gly Arg Leu Val Pro Glu Gly Pro Thr Pro Asp Ser Ser Glu Gly Asn Leu Ser Tyr Leu Ser Ser Leu Ser His Leu Asn Asn Leu Ser His Leu Thr Thr Ser Ser Ser Phe Arg Thr Ser Pro Glu Asn Glu Thr Glu Leu Ile Lys GIu His Asp 410 415 ~ 420 Leu Phe Phe Lys Ala Val Ser Leu Cys His Thr Val Gln Ile Ser Asn Val Gln Thr Asp Cys Thr Gly Asp Gly Pro Trp Gln Ser Asn Leu Ala Pro Ser Gln Leu Glu Tyr Tyr Ala Ser Ser Pro Asp G1u Lys Ala Leu Val Glu Ala Ala Ala Arg Tle Gly Ile Val Phe Ile Gly Asn Ser Glu Glu Thr Met Glu Val Lys Thr Leu Gly Lys Leu Glu Arg Tyr Lys Leu Leu His Ile Leu G1u Phe Asp Ser Asp Arg Arg Arg Met Ser Val Ile Val Gln Ala Pro Ser Gly Glu Lys Leu Leu Phe Ala Lys Gly Ala Glu Ser Ser Ile Leu Pro Lys Cys Ile Gly Gly Glu I1e Glu Lys Thr Arg Ile His Val Asp Glu Phe Ala Leu Lys Gly Leu Arg Thr Leu Cys Ile Ala Tyr Arg Lys Phe Thr Ser Lys Glu Tyr G1u Glu I1e Asp Lys Arg Ile Phe Glu Ala Arg Thr Ala Leu Gln Gln Arg Glu Glu Lys Leu Ala Ala Val Phe Gln Phe Ile Glu Lys Asp Leu Ile Leu Leu Gly Ala Thr Ala Val Glu Asp Arg Leu Gln Asp Lys Val Arg Glu Thr Ile Glu Ala Leu Arg Met Ala Gly Ile Lys Val Trp Val Leu Thr Gly Asp Lys His Glu Thr Ala Val Ser Va1 Ser Leu Ser Cys Gly His Phe His Arg Thr Met Asn Ile Leu Glu Leu Ile Asn Gln Lys Ser Asp Ser Glu Cys Ala Glu Gln Leu Arg Gln Leu Ala Arg Arg Ile Thr Glu Asp His Val I1e Gln His Gly Leu Val Val Asp Gly Thr Ser Leu Ser Leu Ala Leu Arg Glu His Glu Lys Leu Phe Met Glu Val Cys Arg Asn Cys Ser Ala Val Leu Cys Cys Arg Met Ala Pro Leu Gln Lys A1a Lys Val Ile Arg Leu Ile Lys Ile Ser Pro Glu Lys Pro Ile Thr Leu Ala Val Gly Asp Gly A1a Asn Asp Val Ser Met Ile Gln Glu Ala His Val Gly Ile Gly Ile Met Gly Lys Glu Gly Arg Gln Ala Ala Arg Asn Ser Asp Tyr Ala Ile Ala Arg Phe Lys Phe Leu Ser Lys Leu Leu Phe Val His Gly His Phe Tyr Tyr Ile Arg Ile Ala Thr Leu Val Gln Tyr Phe Phe Tyr Lys Asn Val Cys Phe Ile Thr Pro Gln Phe Leu Tyr Gln Phe Tyr Cys Leu Phe Ser Gln Gln Thr Leu Tyr Asp Ser Val Tyr Leu Thr Leu Tyr Asn Ile Cys Phe Thr Ser Leu Pro Ile Leu Ile Tyr Ser Leu Leu Glu Gln His Va1 Asp 860 . 865 870 Pro His Val Leu Gln Asn Lys Pro Thr Leu Tyr Arg Asp Ile Ser Lys Asn Arg Leu Leu Ser Tle Lys Thr Phe Leu Tyr Trp Thr I1e Leu Gly Phe Ser His Ala Phe Ile Phe Phe Phe Gly Ser Tyr Leu Leu Ile Gly Lys Asp Thr Ser Leu Leu G1y Asn Gly Gln Met Phe Gly Asn Trp Thr Phe Gly Thr Leu Val Phe Thr Val Met Val Ile Thr Val Thr Val Lys Met Ala Leu Glu Thr His Phe Trp Thr Trp Ile Asn His Leu Val Thr Trp Gly Ser Ile Ile Phe Tyr Phe Val Phe Ser Leu Phe Tyr Gly Gly Ile Leu Trp Pro Phe Leu Gly Ser Gln Asn Met Tyr Phe Val Phe Ile Gln Leu Leu Ser Ser Gly Ser Ala Trp Phe Ala Ile Ile Leu Met Val Val Thr Cys Leu Phe Leu Asp Ile Ile Lys Lys Val Phe Asp Arg His Leu His Pro Thr Ser Thr Glu Lys A1a Gln Leu Thr Glu Thr Asn Ala Gly Ile Lys Cys Leu Asp Ser Met Cys Cys Phe Pro Glu Gly Glu Ala Ala Cys Ala Ser Val Gly Arg Met Leu Glu Arg Val Ile Gly Arg Cys Ser Pro Thr His Ile Ser Arg Cys Glu Ile Ser Leu Ser Ser Leu Cys Cys Arg <210> 21 <211> 707 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477720CD1 <400> 21 Met Ala Leu G1n Met Phe Va1 Thr Tyr Ser Pro Trp Asn Cys Leu Leu Leu Leu Val Ala Leu Glu Cys Ser Glu Ala Ser Ser Asp Leu Asn Glu Ser Ala Asn Ser Thr Ala Gln Tyr Ala Ser Asn Ala Trp Phe Ala Ala Ala Ser Ser Glu Pro Glu Glu Gly Ile Ser Va1 Phe Glu Leu Asp Tyr Asp Tyr Val Gln Ile Pro Tyr Glu Val Thr Leu Trp Ile Leu Leu Ala Ser Leu Ala Lys I1e Gly Phe His Leu Tyr His Arg Leu Pro Gly Leu Met Pro Glu Ser Cys Leu Leu Ile Leu Val Gly Ala Leu Val Gly Gly Ile Ile Phe Gly Thr Asp His Lys Ser Pro Pro Val Met Asp Ser Ser Ile Tyr Phe Leu Tyr Leu Leu Pro Pro Ile Val Leu Glu Gly Gly Tyr Phe Met Pro Thr Arg Pro Phe Phe Glu Asn Ile Gly Ser Ile Leu Trp Trp Ala Val Leu Gly Ala Leu Ile Asn Ala Leu Gly Ile Gly Leu Ser Leu Tyr Leu Ile Cys Gln Val Lys Ala Phe Gly Leu Gly Asp Val Asn Leu Leu Gln Asn Leu Leu Phe Gly Ser Leu Ile Ser Ala Val Asp Pro Val Ala Val Leu Ala Val Phe Glu Glu Ala Arg Val Asn Glu Gln Leu Tyr Met Met Ile Phe Gly Glu Ala Leu Leu Asn Asp Gly Ile Thr Val Val Leu Tyr Asn Met Leu Ile Ala Phe Thr Lys Met His Lys Phe Glu Asp Ile Glu Thr Val Asp Ile Leu Ala Gly Cys Ala Arg Phe Ile Val Val Gly Leu Gly Gly Val Leu Phe Gly Ile Val Phe Gly Phe Ile Ser Ala Phe Ile Thr Arg Phe Thr Gln Asn Ile Ser Ala Ile Glu Pro Leu Ile Val Phe Met Phe Ser Tyr Leu Ser Tyr Leu Ala Ala Glu Thr Leu Tyr Leu Ser Gly Ile Leu Ala Ile Thr Ala Cys Ala Val Thr Met Lys Lys Tyr Val Glu Glu Asn Val Ser Gln Thr Ser Tyr Thr Thr Ile Lys Tyr Phe Met Lys Met Leu Ser Ser Val Ser Glu Thr Leu Ile Phe Ile Phe Met Gly Val Ser Thr Val Gly Lys Asn His Glu Trp Asn Trp Ala Phe Ile Cys Phe Thr Leu Ala Phe Cys Gln Ile Trp Arg Ala Ile Ser Val Phe Ala Leu Phe Tyr Ile Ser Asn Gln Phe Arg Thr Phe Pro Phe Ser Ile Lys Asp Gln Cys Ile Ile Phe Tyr Ser Gly Val Arg G1y Ala Gly Ser Phe Ser Leu Ala Phe Leu Leu Pro Leu Ser Leu Phe Pro Arg Lys Lys Met Phe Val Thr Ala Thr Leu Val Val Ile Tyr Phe Thr Val Phe Ile Gln Gly Ile Thr Val Gly Pro Leu Val Arg Tyr Leu Asp Val Lys Lys Thr Asn Lys Lys Glu Ser Ile Asn Glu Glu Leu His Ile Arg Leu Met Asp His Leu Lys Ala G1y Ile Glu Asp Val Cys Gly His Trp Ser His Tyr Gln Val Arg Asp Lys Phe Lys Lys Phe Asp His Arg Tyr Leu Arg Lys Ile Leu Ile Arg Lys Asn Leu Pro Lys Ser Ser Ile Val Ser Leu Tyr Lys Lys Leu Glu Met Lys Gln Ala Ile Glu Met Val Glu Thr Gly Ile Leu Ser Ser Thr Ala Phe Ser Ile Pro His Gln Ala Gln Arg Ile Gln Gly Ile Lys Arg Leu Ser Pro Glu Asp Val Glu Ser Ile Arg Asp Ile Leu Thr Ser Asn Met Tyr Gln Val Arg Gln Arg Thr Leu Ser Tyr Asn Lys Tyr Asn Leu Lys Pro Gln Thr Ser Glu Lys Gln Ala Lys Glu Ile Leu Ile Arg Arg Gln Asn Thr Leu Arg Glu Ser Met Arg Lys Gly His Ser Leu Pro Trp Gly Lys Pro Ala Gly Thr Lys Asn Ile Arg Tyr Leu Ser Tyr Pro Tyr Gly Asn Pro Gln Ser Ala Gly Arg Asp Thr Arg Ala Ala Gly Phe Ser Gly Lys Leu Pro Thr Trp Leu Leu Cys Cys Phe Ser Va1 Glu Ser Gly Gly Lys Tyr Leu Gly Val Trp Ala Lys Arg Gln His <210> 22 <211> 729 <212> PRT
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 7477852CD1 <400> 22 Met Gly Gly Phe Leu Pro Lys Ala Glu Gly pro Gly Ser Gln Leu Gln Lys Leu Leu Pro Ser Phe Leu Val Arg Glu Gln Asp Trp Asp Gln His Leu Asp Lys Leu His Met Leu Gln Gln Lys Arg Ile Leu Glu Ser Pro Leu Leu Arg Ala Ser Lys Glu Asn Asp Leu Ser Val Leu Arg Gln Leu Leu Leu Asp Cys Thr Cys Asp Val Arg Gln Arg Gly Ala Leu Gly Glu Thr Ala Leu His Ile Ala Ala Leu Tyr Asp Asn Leu Glu Ala Ala Leu Val Leu Met Glu Ala Ala Pro Glu Leu Val Phe Glu Pro Thr Thr Cys Glu Ala Phe A1a Gly Gln Thr Ala Leu His Tle Ala Va1 Val Asn Gln Asn Val Asn Leu Val Arg Ala Leu Leu Thr Arg Arg Ala Ser Val Ser Ala Arg Ala Thr Gly Thr Ala Phe Arg Arg Ser Pro Arg Asn Leu Ile Tyr Phe Gly Glu His Pro Leu Ser Phe Al.a Ala Cys Val Asn Ser G1u Glu Ile Val Arg Leu Leu Ile Glu His Gly Ala Asp I1e Arg Ala G1n Asp Ser Leu Gly Asn Thr Va1 Leu His Ile Leu Ile Leu Gln Pro Asn Lys Thr Phe Ala Cys Gln Met Tyr Asn Leu Leu Leu Ser Tyr Asp Gly His Gly Asp His Leu Gln Pro Leu Asp Leu Val Pro Asn His Gln Gly Leu Thr Pro Phe Lys Leu Ala Gly Val Glu Gly Asn Thr Val Met 245 . 250 255 Phe Gln His Leu Met Gln Lys Arg Arg His Ile Gln Trp Thr Tyr Gly Pro Leu Thr Ser Ile Leu Tyr Asp Leu Thr Glu Ile Asp Ser Trp Gly Glu Glu Leu Ser Phe Leu Glu Leu Val Val Ser Ser Asp Lys Arg Glu Ala Arg Gln Ile Leu Glu Gln Thr Pro Va1 Lys Glu Leu Val Ser Phe Lys Trp Asn Lys Tyr Gly Arg Pro Tyr Phe Cys Ile Leu Ala Ala Leu Tyr Leu Leu Tyr Met Ile Cys Phe Thr Thr Cys Cys Val Tyr Arg Pro Leu Lys Phe Arg Gly Gly Asn Arg Thr His Ser Arg Asp Ile Thr Ile Leu Gln Gln Lys Leu Leu Gln Glu Ala Tyr Glu Thr Arg Glu Asp Ile Ile Arg Leu Val Gly Glu Leu Val Ser I1e Val Gly Ala Val Ile Ile Leu Leu Leu Glu Ile Pro Asp Ile Phe Arg Val Gly Ala Ser Arg Tyr Phe Gly Lys Thr Ile Leu Gly G1y Pro Phe His Val Ile Met Ile Thr Tyr Ala Ser Leu Val Leu Val Thr Met Val Met Arg Leu Thr Asn Thr Asn G1y Glu Val Val Pro Met Ser Phe Ala Leu Val Leu Gly Trp Cys Ser Val 455 4&0 465 Met Tyr Phe Thr Arg Gly Phe Gln Met Leu Gly Pro Phe Thr Ile Met Ile G1n Lys Met Ile Phe Gly Asp Leu Met Arg Phe Cys Trp Leu Met Ala Val Val Ile Leu Gly Phe Ala Ser Ala Phe Tyr Tle Ile Phe Gln Thr Glu Asp Pro Thr Ser Leu Gly Gln Phe Tyr Asp Tyr Pro Met Ala Leu Phe Thr Thr Phe Glu Leu Phe Leu Thr Val Ile Asp Ala Pro Ala Asn Tyr Asp Val Asp Leu Pro Phe Met Phe Ser Ile Va1 Asn Phe Ala Phe Ala Ile Ile Ala Thr Leu Leu Met Leu Asn Leu Phe Ile Ala Met Met Gly Asp Thr His Trp Arg Val Ala Gln Glu Arg Asp Glu Leu Trp Arg Ala Gln Val Val Ala Thr Thr Val Met Leu Glu Arg Lys Leu Pro Arg Cys Leu Trp Pro Arg Ser Gly Ile Cys Gly Cys Glu Phe Gly Leu Gly Asp Arg Trp Phe Leu Arg Val Glu Asn His Asn Asp Gln Asn Pro Leu Arg Val Leu Arg Tyr Val Glu Val Phe Lys Asn Ser Asp Lys Glu Asp Asp Gln Glu His Pro Ser Glu Lys Gln Pro Ser Gly Ala Glu Ser Gly Thr Leu Ala Arg Ala Ser Leu Ala Leu Pro Thr Ser Ser Leu Ser Arg Thr Ala Ser Gln Ser Ser Ser His Arg Gly Trp Glu Ile Leu Arg Gln Asn Thr Leu Gly His Leu Asn Leu Gly Leu Asn Leu Ser Glu Gly Asp Gly Glu Glu Val Tyr His Phe <210> 23 <211> 492 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 1471717CD1 <400> 23 Met Ala Thr Lys Pro Thr Glu Pro Val Thr Ile Leu Ser Leu Arg Lys Leu Ser Leu Gly Thr Ala Glu Pro Gln Val Lys Glu Pro Lys Thr Phe Thr Val Glu Asp Ala Val Glu Thr I1e Gly Phe Gly Arg Phe His Ile Ala Leu Phe Leu Tle Met Gly Ser Thr Gly Val Val Glu Ala Met Glu Ile Met Leu Ile Ala Val Val Ser Pro Val Ile Arg Cys Glu Trp Gln Leu Glu Asn Trp Gln Val Ala Leu Val Thr Thr Met Val Phe Phe Gly Tyr Met Val Phe Ser Ile Leu Phe Gly Leu Leu Ala Asp Arg Tyr Gly Arg Trp Lys I1e Leu Leu Ile Ser Phe Leu Trp Gly Ala Tyr Phe Ser Leu Leu Thr Ser Phe Ala Pro Ser Tyr Ile Trp Phe Val Phe Leu Arg Thr Met Val Gly Cys Gly Val Ser Gly His Ser Gln Gly Leu Ile Ile Lys Thr Glu Phe Leu Pro Thr Lys Tyr Arg Gly Tyr Met Leu Pro Leu Ser Gln Val Phe Trp Leu A1a Gly Ser Leu Leu Ile Ile Gly Leu Ala Ser Val Ile Ile Pro Thr Tle Gly Trp Arg Trp Leu Ile Arg Val Ala Ser I1e Pro Gly Ile Ile Leu Ile Va1 Ala Phe Lys Phe Ile Pro Glu Ser Ala Arg Phe Asn Val Ser Thr Gly Asn Thr Arg Ala Ala Leu Ala Thr Leu Glu Arg Val Ala Lys Met Asn Arg Ser Val Met Pro G1u Gly Lys Leu Val Glu Pro Val Leu G1u Lys Arg Gly Arg Phe A1a Asp Leu Leu Asp Ala Lys Tyr Leu Arg Thr Thr Leu Gln Ile Trp Val Ile Trp Leu Gly Ile Ser Phe Ala Tyr Tyr Gly Val Ile Leu Ala Ser Ala Glu Leu Leu Glu Arg Asp Leu Val Cys Gly Ser Lys Ser Asp Ser Ala Val Val Val Thr Gly Gly Asp Ser Gly Glu Ser Gln Ser Pro Cys Tyr Cys His Met Phe Ala Pro Ser Asp Tyr Arg Thr Met Ile Ile Ser Thr Ile Gly Glu Ile Ala Leu Asn Pro Leu Asn Ile Leu Gly Ile Asn Phe Leu Gly Arg Arg Leu Ser Leu Ser Ile Thr Met Gly Cys Thr Ala Leu Phe Cys Leu Leu Leu Asn Ile Cys Thr Ser Ser Ala Gly Leu Ile Gly Phe Leu Phe Met Leu Arg Ala Leu Val Ala Ala Asn Phe Asn Thr Val Tyr Ile Tyr Thr Ala Glu Val Tyr Pro Thr Thr Met Arg Ala Leu Gly Met Gly Thr Ser Gly Ser Leu Cys Arg Ile Gly Ala Met Val Ala Pro Phe Ile Ser G1n Val Leu Met Ser Ala Ser Ile Leu Gly Ala Leu Cys Leu Phe Ser Ser Val Cys Val Val Cys A1a I1e Ser Ala Phe Thr Leu Pro Ile Glu Thr Lys Gly Arg Ala Leu Gln Gln Ile Lys <210> 24 <211> 1494 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3874406CD1 <400> 24 Met Asn Met Lys Gln Lys Ser Val Tyr Gln Gln Thr Lys Ala Leu Leu Cys Lys Asn Phe Leu Lys Lys Trp Arg Met Lys Arg G1u Ser Leu Leu Glu Trp Gly Leu Ser Ile Leu Leu Gly Leu Cys Ile Ala Leu Phe Ser Ser Ser Met Arg Asn Val Gln Phe Pro Gly Met Ala Pro Gln Asn Leu G1y Arg Val Asp Lys Phe Asn Ser Ser Ser Leu Met Val Va1 Tyr Thr Pro Ile Ser Asn Leu Thr Gln Gln Tle Met Asn Lys Thr Ala Leu Ala Pro Leu Leu Lys Gly Thr Ser Val Ile GIy Ala Pro Asn Lys Thr His Met Asp Glu I1e Leu Leu Glu Asn Leu Pro Tyr Ala Met Gly Ile Ile Phe Asn Glu Thr Phe Ser Tyr Lys Leu Ile Phe Phe Gln Gly Tyr Asn Ser Pro Leu Trp Lys Glu Asp Phe Ser Ala His Cys Trp Asp Gly Tyr Gly Glu Phe Ser Cys Thr Leu Thr Lys Tyr Trp Asn Arg Gly Phe Va1 Ala Leu Gln Thr Ala Ile Asn Thr Ala Ile Ile Glu Val Ala Leu Val Phe Leu Met Ser Val Leu Leu Lys Lys Ala Val Leu Thr Asn Leu Val Val Phe Leu Leu Thr Leu Phe Trp Gly Cys Leu Gly Phe Thr Va1 Phe Tyr Glu Gln Leu Pro Ser Ser Leu Glu Trp Ile Leu Asn Ile Cys Ser Pro Phe Ala Phe Thr Thr Gly Met Ile Gln Ile Ile Lys Leu Asp Tyr Asn Leu Asn Gly Val Ile Phe Pro Asp Pro Ser Gly Asp Ser Tyr Thr Met I1e Ala Thr Phe Ser Met Leu Leu Leu Asp Gly Leu Ile Tyr Leu Leu Leu Ala Leu Tyr Phe Asp Lys Ile Leu Pro Tyr Gly Asp Glu Arg His Tyr Ser Pro Leu Phe Phe Leu Asn Ser Ser Ser Cys Phe Gln His Gln Arg Thr Asn Ala Lys Val Ile G1u Lys Glu Ile Asp Ala Glu His Pro Ser,Asp Asp Tyr Phe Glu Pro Val Ala Pro Glu Phe Gln Gly Lys G1u Ala IIe Arg Ile Arg Asn Val Lys Lys Glu Tyr Lys Gly Lys Ser Gly Lys Va1 Glu Ala Leu Lys Gly Leu Leu Phe Asp Ile Tyr Glu Gly Gln Ile Thr Ala Ile Leu Gly His Ser Gly Ala Gly Lys Ser Ser Leu Leu Asn Ile Leu Asn Gly Leu Ser Val Pro Thr Glu Gly Ser Val Thr Ile Tyr Asn Lys Asn Leu Ser Glu Met Gln Asp Leu Glu G1u Ile Arg Lys Ile Thr Gly Val Cys Pro Gln Phe Asn Val Gln Phe Asp Ile Leu Thr Val Lys Glu Asn Leu Ser Leu Phe Ala Lys Ile Lys Gly Ile His Leu Lys G1u Val Glu Gln Glu Val Gln Arg Ile Leu Leu Glu Leu Asp Met Gln Asn Ile Gln Asp Asn Leu Ala Lys His Leu Ser Glu Gly Gln Lys Arg Lys Leu Thr Phe Gly Ile Thr Ile Leu Gly Asp Pro Gln Ile Leu Leu Leu Asp Glu Pro Thr Thr Gly Leu Asp Pro Phe Ser Arg Asp Gln Val Trp Ser Leu Leu Arg Glu Arg Arg Ala Asp His Val Ile Leu Phe Ser Thr Gln Ser Met Asp Glu Ala Asp Ile Leu Ala Asp Arg Lys Val Ile Met Ser Asn Gly Arg Leu Lys Cys Ala Gly Ser Ser Ile Phe Leu Lys Arg Arg Trp Gly Leu Gly Tyr His Leu Ser Leu His Arg Asn G1u Ile Cys Asn Pro Glu Gln I1e 39!87 Thr Ser Phe Ile Thr His His Ile Pro Asp Ala Lys Leu Lys Thr Glu Asn Lys Glu Lys Leu Val Tyr Thr Leu Pro Leu Glu Arg Thr Asn Thr Phe Pro Asp Leu Phe Ser Asp Leu Asp Lys Cys Ser Asp G1n Gly Val Thr Gly Tyr Asp Ile Ser Met Ser Thr Leu Asn Glu Val Phe Met Lys Leu Glu Gly Gln Ser Thr Ile Glu Gln Asp Phe Glu Gln Val Glu Met Ile Arg Asp Ser Glu Ser Leu Asn Glu Met Glu Leu Ala His Ser Ser Phe Ser Glu Met Gln Thr Ala Val Ser Asp Met Gly Leu Trp Arg Met G1n Val Phe Ala Met Ala Arg Leu Arg Phe Leu Lys Leu Lys Arg Gln Thr Lys Va1 Leu Leu Thr Leu Leu Leu Va1 Phe Gly Ile Ala Ile Phe Pro Leu Ile Val Glu Asn Ile Ile Tyr Ala Met Leu Asn Glu Lys Ile Asp Trp Glu Phe Lys Asn Glu Leu Tyr Phe Leu Ser Pro Gly Gln Leu Pro Gln Glu Pro Arg Thr Ser Leu Leu Ile Ile Asn Asn Thr Glu Ser Asn Ile Glu Asp Phe Ile Lys Ser Leu Lys His Gln Asn Ile Leu Leu Glu Val Asp Asp Phe Glu Asn Arg Asn Gly Thr Asp Gly Leu Ser Tyr Asn G1y Ala Ile Ile Val Ser Gly Lys Gln Lys Asp Tyr Arg Phe Ser Val Val Cys Asn Thr Lys Arg Leu His Cys Phe Pro Ile Leu Met 845 ' 850 855 Asn Ile Ile Ser Asn Gly Leu Leu Gln Met Phe Asn His Thr Gln His Ile Arg Ile Glu Ser Ser Pro Phe Pro Leu Ser His Ile Gly Leu Trp Thr Gly Leu Pro Asp Gly Ser Phe Phe Leu Phe Leu Val Leu Cys Ser Ile Ser Pro Tyr Ile Thr Met Gly Ser Ile Ser Asp Tyr Lys Lys Asn Ala Lys Ser Gln Leu Trp Ile Ser Gly Leu Tyr Thr Ser Ala Tyr Trp Cys Gly Gln Ala Leu Val Asp Val Ser Phe Phe Ile Leu Ile Leu Leu Leu Met Tyr Leu Ile Phe Tyr I1e Glu Asn Met Gln Tyr Leu Leu Ile Thr Ser Gln Ile Val Phe Ala Leu Val Ile Val Thr Pro Gly Tyr Ala Ala Ser Leu Val Phe Phe Ile Tyr Met Ile Ser Phe Ile Phe Arg Lys Arg Arg Lys Asn Ser Gly Leu Trp Ser Phe Tyr Phe Phe Phe Ala Ser Thr Ile Met Phe Ser Ile Thr Leu Tle Asn His Phe Asp Leu Ser Tle Leu Ile Thr Thr Met Val Leu Val Pro Ser Tyr Thr Leu Leu Gly Phe Lys Thr Phe Leu Glu Val Arg Asp Gln Glu His Tyr Arg Glu Phe Pro Glu Ala Asn Phe Glu Leu Ser Ala Thr Asp Phe Leu Val Cys Phe Ile Pro Tyr Phe Gln Thr Leu Leu Phe Val Phe Val Leu Arg Cys Met Glu Leu Lys Cys Gly Lys Lys Arg Met Arg Lys Asp Pro Val Phe Arg Ile Ser Pro Gln Ser Arg Asp Ala Lys Pro Asn Pro G1u Glu Pro Ile Asp Glu Asp G1u Asp Ile Gln Thr Glu Arg Ile Arg Thr Val Thr Ala Leu Thr Thr Ser Ile Leu Asp Glu Lys Pro Val Ile Ile Ala Ser Cys Leu His Lys Glu Tyr Ala Gly Gln Lys Lys Ser Cys Phe Ser Lys Arg Lys Lys Lys Ile Ala Ala Arg Asn Ile Ser Phe Cys Val G1n Glu Gly Glu Ile Leu Gly Leu Leu Gly Pro Ser Gly Ala G1y Lys Ser Ser Ser Ile Arg Met Ile Ser Gly Ile Thr Lys Pro Thr Ala G1y Glu Val Glu Leu Lys Gly Cys Ser Ser Val Leu Gly His Leu Gly Tyr Cys Pro Gln Glu Asn Val Leu Trp Pro Met Leu Thr Leu Arg Glu His Leu Glu Val Tyr Ala Ala Val Lys Gly Leu Arg Glu Ala Asp Ala Arg Leu Ala Ile Ala Arg Leu Val Ser Ala Phe Lys Leu His Glu G1n Leu Asn Val Pro Val Gln Lys Leu Thr Ala Gly Ile Thr Arg Lys Leu Cys Phe Val Leu Ser Leu Leu Gly Asn Ser Pro Val Leu Leu Leu Asp G1u Pro Ser Thr Gly Ile Asp Pro Thr Gly Gln Gln Gln Met Trp Gln Ala Ile Gln Ala Val Val Lys Asn Thr Glu Arg Gly Val Leu Leu Thr Thr His Asn Leu Ala Glu Ala Glu Ala Leu Cys Asp Arg Val Ala Ile Met Val Ser Gly Arg Leu Arg Cys Ile Gly Ser Ile Gln His Leu Lys Asn Lys Leu Gly Lys Asp Tyr Ile Leu Glu Leu Lys Val Lys G1u Thr Ser Gln Val Thr Leu Val His Thr Glu I1e Leu Lys Leu Phe Pro Gln Ala Ala Gly Gln Gln Arg Tyr Ser Ser Leu Leu Thr Tyr Lys Leu Pro Val Ala Asp Val Tyr Pro Leu Ser Gln Thr Phe His Lys Leu G1u Ala Val Lys His Asn Phe Asn Leu G1u Glu Tyr Ser Leu Ser Gln Cys Thr Leu Glu Lys Val Phe Leu G1u Leu Ser Lys Glu Gln 1460 1465 ~ 1470 Glu Val Gly Asn Phe Asp Glu Glu Ile Asp Thr Thr Met Arg Trp Lys Leu Leu Pro His Ser Asp Glu Pro <210> 25 <211> 774 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4599654CD1 <400> 25 Met Glu Ala Glu Gln Arg Pro Ala Ala Gly Ala Ser Glu Gly Ala Thr Pro Gly Leu Glu Ala Val Pro Pro Val Ala Pro Pro Pro Ala Thr Ala Ala Ser Gly Pro Ile Pro Lys Ser Gly Pro Glu Pro Lys Arg Arg His Leu Gly Thr Leu Leu Gln Pro Thr Val Asn Lys Phe Ser Leu Arg Val Phe Gly Ser His Lys Ala Val Glu Ile Glu Gln Glu Arg Val Lys Ser Ala Gly Ala Trp Ile Ile His Pro Tyr Ser Asp Phe Arg Phe Tyr Trp Asp Leu Ile Met Leu Leu Leu Met Val Gly Asn Leu Ile Val Leu Pro Val Gly Ile Thr Phe Phe Lys Glu Glu Asn Ser Pro Pro Trp Ile Val Phe Asn Val Leu Ser Asp Thr Phe Phe Leu Leu Asp Leu Val Leu Asn Phe Arg Thr Gly Ile Val Val Glu Glu Gly A1a Glu Ile Leu Leu Ala Pro Arg Ala Ile Arg Thr Arg Tyr Leu Arg Thr Trp Phe Leu Val Asp Leu Ile Ser Ser Ile Pro Val Asp Tyr Ile Phe Leu Val Val Glu Leu Glu Pro Arg Leu Asp Ala Glu Val Tyr Lys Thr A1a Arg Ala Leu Arg Ile Val Arg Phe Thr Lys Ile Leu Ser Leu Leu Arg Leu Leu Arg Leu Ser Arg Leu Ile Arg Tyr Ile His Gln Trp Glu Glu Ile Phe His Met Thr Tyr Asp Leu Ala Ser Ala Val Val Arg I1e Phe Asn Leu I1e Gly Met Met Leu Leu Leu Cys His Trp Asp Gly Cys Leu Gln Phe Leu Val Pro Met Leu Gln Asp Phe Pro Pro Asp Cys Trp Val Ser Tle Asn His Met Val Asn His Ser Trp Gly Arg Gln Tyr Ser His Ala Leu Phe Lys Ala Met Ser His Met Leu Cys Ile Gly Tyr Gly G1n Gln Ala Pro Val Gly Met Pro Asp Val Trp Leu Thr Met Leu Ser Met Ile Val Gly Ala Thr Cys Tyr Ala Met Phe Ile Gly His Ala Thr Ala Leu Ile Gln Ser Leu Asp Ser Ser Arg Arg Gln Tyr Gln Glu Lys Tyr Lys Gln Val Glu Gln Tyr Met Ser Phe His Lys Leu Pro Ala Asp Thr Arg Gln Arg Ile His Glu Tyr Tyr Glu His Arg Tyr Gln Gly Lys Met Phe Asp Glu Glu Ser Ile Leu Gly Glu Leu Ser Glu Pro Leu Arg Glu Glu Ile Ile Asn Phe Thr Cys Arg Gly Leu Val Ala His Met Pro Leu Phe Ala His Ala Asp Pro Ser Phe Val Thr Ala Va1 Leu Thr Lys Leu Arg Phe Glu Val Phe Gln Pro Gly Asp Leu Val Val Arg Glu Gly Ser Val Gly Arg Lys Met Tyr Phe Ile Gln His Gly Leu Leu Ser Val Leu Ala Arg Gly Ala Arg Asp Thr Arg Leu Thr Asp Gly Ser Tyr Phe Gly Glu Ile Cys Leu Leu Thr Arg Gly Arg Arg Thr Ala Ser Val Arg Ala Asp Thr Tyr Cys Arg Leu Tyr Ser Leu Ser Val Asp His Phe Asn Ala Val Leu Glu Glu Phe Pro Met Met Arg Arg Ala Phe Glu Thr Val Ala Met Asp Arg Leu Leu Arg I1e Gly Lys Lys Asn Ser Tle Leu Gln Arg Lys Arg Ser Glu Pro Ser Pro Gly Ser Ser Gly Gly Ile Met Glu Gln His Leu Val Gln His Asp Arg Asp Met Ala Arg Gly Va1 Arg Gly Arg Ala Pro Ser Thr Gly Ala Gln Leu Ser Gly Lys Pro Val Leu Trp Glu Pro Leu Val His Ala Pro Leu Gln Ala A1a Ala Val Thr Ser Asn Va1 Ala Ile Ala Leu Thr His Gln Arg Gly Pro Leu Pro Leu Ser Pro Asp Ser Pro Ala Thr Leu Leu Ala Arg Ser Ala Trp Arg Ser Ala Gly Ser Pro Ala Ser Pro Leu Val Pro Val Arg Ala Gly Pro Trp Ala Ser Thr Ser Arg Leu Pro Ala Pro Pro Ala Arg Thr Leu His Ala Ser Leu Ser Arg Ala Gly Arg Ser Gln Val Ser Leu Leu Gly Pro Pro Pro Gly Gly Gly Gly Arg Arg Leu Gly Pro Arg Gly Arg Pro Leu Ser Ala Ser G1n Pro Ser Leu Pro 710 7l5 720 Gln Arg Ala Thr Gly Asp Gly Ser Pro Gly Arg Lys Gly Ser Gly Ser Glu Arg Leu Pro Pro Ser Gly Leu Leu Ala Lys Pro Pro Arg Thr Ala Gln Pro Pro Arg Pro Pro Val Pro Glu Pro Ala Thr Pro Arg Gly Leu Gln Leu Ser Ala Asn Met <210> 26 <211> 614 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5047435CD1 <400> 26 Met A1a Glu Gly Glu Arg Gly Ala Asp Val Pro His Gly Leu Gly Ala Trp Leu Ala Asp Val Ala Leu Ala Ala Leu Arg Ala G1y Gly Gln Gly Arg Arg Asp Arg Gly Gly Gly Gly Pro Glu Ser Leu Ser Gly Gly Ser Gly Val Gly Asp Ser Gly Gly Gly Cys Ala Pro Gly Pro Ser Ala Pro Pro Ala Arg Arg Arg Val Pro Leu Ala Met Gly His Ser Pro Pro Val Leu Pro Leu Cys Ala Ser Val Ser Leu Leu Gly Gly Leu Thr Phe Gly Tyr Glu Leu Ala Val Ile Ser Gly Ala Leu Leu Pro Leu Gln Leu Asp Phe G1y Leu Ser Cys Leu Glu Gln 1l0 115 120 Glu Phe Leu Val Gly Ser Leu Leu Leu Gly Ala Leu Leu Ala Ser Leu Va1 Gly Gly Phe Leu Ile Asp Cys Tyr Gly Arg Lys Gln Ala Ile Leu Gly Ser Asn Leu Val Leu Leu Ala Gly Ser Leu Thr Leu Gly Leu Ala Gly Ser Leu Ala Trp Leu Val Leu Gly Arg Ala Val Val G1y Phe Ala Tle Ser Leu Ser Ser Met Ala Cys Cys Ile Tyr Val Ser Glu Leu Val Gly Pro Arg Gln Arg Gly Val Leu Val Ser Leu Tyr Glu Ala Gly Ile Thr Val G1y Ile Leu Leu Ser Tyr Ala Leu Asn Tyr Ala Leu Ala Gly Thr Pro Trp Gly Trp Arg His Met Phe Gly Trp Ala Thr Ala Pro Ala Val Leu Gln Ser Leu Ser Leu Leu Phe Leu Pro Ala Gly Thr Asp Glu Thr A1a Thr His Lys Asp Leu Ile Pro Leu Gln Gly Gly GIu Ala Pro Lys Leu Gly Pro Gly Arg Pro Arg Tyr Ser Phe Leu Asp Leu Phe Arg Ala Arg Asp Asn Met Arg Gly Arg Thr Thr Val Gly Leu Gly Leu Val Leu Phe Gln Gln Leu Thr Gly Gln Pro Asn Val Leu Cys Tyr Ala Ser Thr Ile Phe Ser Ser Val Gly Phe His Gly Gly Ser Ser Ala Val Leu Ala Ser Val Gly Leu Gly Ala Val Lys Val Ala Ala Thr Leu Thr Ala Met Gly Leu Val Asp Arg Ala Gly Arg Arg Ala Leu Leu Leu Ala Gly Cys Ala Leu Met Ala Leu Ser Val Ser Gly Ile Gly Leu Va1 Ser Phe AIa Val Pro Met Asp Ser Gly Pro Ser Cys Leu Ala Val Pro Asn Ala Thr Gly Gln Thr Gly Leu Pro Gly Asp Ser Gly Leu Leu Gln Asp Ser Ser Leu Pro Pro Ile Pro Arg Thr Asn Glu Asp Gln Arg Glu Pro Ile Leu Ser Thr Ala Lys Lys Thr Lys Pro His Pro Arg Ser Gly Asp Pro Ser Ala Pro Pro Arg Leu Ala Leu Ser Ser Ala Leu Pro Gly Pro Pro Leu Pro Ala Arg Gly His A1a Leu Leu Arg Trp Thr Ala Leu Leu Cys Leu Met Val Phe Val Ser Ala Phe Ser Phe Gly Phe Gly Pro Val Thr Trp Leu Val Leu Ser Glu Ile Tyr Pro Val Glu Ile Arg Gly Arg Ala Phe Ala Phe Cys Asn Ser Phe Asn Trp Ala A1a Asn Leu Phe Ile Ser Leu Ser Phe Leu Asp Leu Ile Gly Thr Ile Gly Leu Ser Trp Thr Phe Leu Leu Tyr Gly Leu Thr Ala Val Leu Gly Leu Gly Phe Ile Tyr Leu Phe Val Pro Glu Thr Lys Gly Gln Ser Leu Ala Glu Ile Asp Gln Gln Phe G1n Lys Arg Arg Phe Thr Leu Ser Phe Gly His Arg G1n Asn Ser Thr Gly Ile Pro Tyr Ser Arg Ile Glu Ile Ser Ala Ala Ser <210> 27 <211> 2180 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7475603CD1 <400> 27 Met Arg Phe Arg Lys Gly Gln Glu Leu Pro Ala Ala Ala Pro His Val Phe Ser Pro Thr Val Val Leu Thr Ser Leu Ser Arg Pro Leu Pro Ser Leu Thr Met Ala Phe Trp Thr Gln Leu Met Leu Leu Leu Trp Lys Asn Phe Met Tyr Arg Arg Arg Gln Pro Val Gln Leu Leu Val Glu Leu Leu Trp Pro Leu Phe Leu Phe Phe Ile Leu Val Ala Val Arg His Ser His Pro Pro Leu Glu His His Glu Cys His Phe Pro Asn Lys Pro Leu Pro Ser Ala Gly Thr Val Pro Trp Leu Gln Gly Leu Ile Cys Asn Val Asn Asn Thr Cys Phe Pro Gln Leu Thr Pro Gly Glu Glu Pro Gly Arg Leu Ser Asn Phe Asn Asp Ser Leu Val Ser Arg Leu Leu Ala Asp Ala Arg Thr Val Leu Gly Gly Ala Ser Ala His Arg Thr Leu Ala Gly Leu Gly Lys Leu Ile Ala Thr Leu Arg Ala Ala Arg Ser Thr Ala Gln Pro Gln Pro Thr Lys Gln Ser Pro Leu Glu Pro Pro Met Leu Asp Val Ala Glu Leu Leu Thr Ser Leu Leu Arg Thr G1u Ser Leu Gly Leu A1a Leu Gly Gln Ala 200 205 2l0 Gln Glu Pro Leu His Ser Leu Leu Glu Ala Ala Glu Asp Leu Ala G1n G1u Leu Leu Ala Leu Arg Ser Leu Val Glu Leu Arg A1a Leu Leu Gln Arg Pro Arg Gly Thr Ser Gly Pro Leu Glu Leu Leu Ser 245 250 . 255 Glu Ala Leu Cys Ser Val Arg Gly Pro Ser Ser Thr Val Gly Pro Ser Leu Asn Trp Tyr Glu Ala Ser Asp Leu Met Glu Leu Val Gly Gln Glu Pro-Glu Ser Ala Leu Pro Asp Ser Ser Leu Ser Pro Ala Cys Ser G1u Leu Ile Gly Ala Leu Asp Ser His Pro Leu Ser Arg Leu Leu Trp Arg Arg Leu Lys Pro Leu Ile Leu Gly Lys Leu Leu Phe Ala Pro Asp Thr Pro Phe Thr Arg Lys Leu Met Ala G1n Va1 Asn Arg Thr Phe Glu Glu Leu Thr Leu Leu Arg Asp Val Arg Glu Val Trp Glu Met Leu Gly Pro Arg Ile Phe Thr Phe Met Asn Asp Ser Ser Asn Val Ala Met Leu Gln Arg Leu Leu Gln Met Gln Asp Glu Gly Arg Arg Gln Pro Arg Pro G1y Gly Arg Asp His Met Glu Ala Leu Arg Ser Phe Leu Asp Pro Gly Ser Gly Gly Tyr Ser Trp Gln Asp Ala His A1a Asp Val Gly His Leu Val Gly Thr Leu Gly Arg Val Thr Glu Cys Leu Ser Leu Asp Lys Leu Glu Ala Ala Pro Ser Glu Ala Ala Leu Val Ser Arg Ala Leu Gln Leu Leu Ala Glu His Arg Phe Trp Ala Gly Val Val Phe Leu Gly Pro Glu Asp Ser Ser Asp Pro Thr Glu His Pro Thr Pro Asp Leu Gly Pro G1y His Val Arg Ile Lys I1e Arg Met Asp Ile Asp Val Val Thr Arg Thr Asn Lys I1e Arg Asp Arg Phe Trp Asp Pro Gly Pro Ala Ala Asp Pro Leu Thr Asp Leu Arg Tyr Val Trp G1y Gly Phe Val Tyr Leu Gln Asp Leu Val Glu Arg Ala Ala Val Arg Val Leu Ser Gly Ala Asn Pro Arg Ala Gly Leu Tyr Leu Gln Gln Met Pro Tyr Pro Cys Tyr Val Asp Asp Val Phe Leu Arg Val Leu Ser Arg Ser Leu Pro Leu Phe Leu Thr Leu Ala Trp Ile Tyr Ser Val Thr Leu Thr Val Lys Ala Val Val Arg Glu Lys Glu Thr Arg Leu Arg Asp Thr Met Arg A1a Met Gly Leu Ser Arg Ala Val Leu Trp Leu Gly Trp Phe Leu Ser Cys Leu Gly Pro Phe Leu Leu Ser Ala Ala Leu Leu Val Leu Va1 Leu Lys Leu Gly Asp Ile Leu Pro Tyr Ser His Pro Gly Val Val Phe Leu Phe Leu Ala Ala Phe Ala Val Ala Thr Val Thr Gln Ser Phe Leu Leu Ser Ala Phe Phe Ser Arg Ala Asn Leu Ala Ala Ala Cys Gly Gly Leu Ala Tyr Phe Ser Leu Tyr Leu Pro Tyr Val Leu Cys Val Ala Trp Arg Asp Arg Leu Pro Ala Gly Gly Arg Val Ala Ala Ser Leu Leu Ser Pro Val Ala Phe Gly Phe Gly Cys Glu Sex Leu Ala Leu Leu Glu Glu Gln G1y Glu Gly Ala Gln Trp His Asn Val Gly Thr Arg Pro Thr Ala Asp Val Phe Ser Leu Ala Gln Val Ser Gly Leu Leu Leu Leu Asp Ala Ala Leu Tyr Gly Leu Ala Thr Trp Tyr Leu Glu Ala Val Cys Pro Gly Gln Tyr Gly Ile Pro Glu Pro Trp Asn Phe Pro Phe Arg Arg Ser Tyr Trp Cys Gly Pro Arg Pro Pro Lys Ser Pro Ala Pro Cys Pro Thr Pro Leu Asp Pro Lys Val Leu Val Glu Glu Ala Pro Pro Gly Leu Ser Pro Gly Val Ser Val Arg Ser Leu Glu Lys Arg Phe Pro G1y Ser Pro Gln Pro Ala Leu Arg Gly Leu Ser Leu Asp Phe Tyr Gln Gly His Ile Thr Ala Phe Leu Gly His Asn Gly Ala Gly Lys Thr Thr Thr Leu Ser Ile Leu Ser Gly Leu Phe Pro Pro Ser Gly Gly Ser Ala Phe Ile Leu Gly His Asp Val Arg Ser Ser Met Ala Ala Ile Arg Pro His Leu Gly Val Cys Pro Gln Tyr Asn Val Leu Phe Asp Met Leu Thr Val Asp Glu His Val Trp Phe Tyr Gly Arg Leu Lys Gly Leu Ser Ala Ala Val Val Gly Pro Glu Gln Asp Arg Leu Leu Gln Asp Val Gly Leu Val Ser Lys Gln Ser Val Gln Thr Arg His Leu Ser Val Ser Glu Leu Val Gly Pro Arg Gln Arg Gly Val Leu Val Ser Gly Gly Met Gln Arg Lys Leu Ser Val Ala Ile Ala Phe Val Gly Gly Ser Gln Val Val Ile Leu Asp Glu Pro Thr Ala Gly Val Asp Pro Ala Ser Arg Arg Gly I1e Trp Glu Leu Leu Leu Lys Tyr Arg G1u Gly Arg Thr Leu Ile Leu Ser Thr His His Leu Asp Glu Ala Glu Leu Leu Gly Asp Arg Va1 Ala Val Val Ala Gly Gly Arg Leu Cys Cys Cys Gly Ser Pro Leu Phe Leu Arg Arg His Leu Gly Ser Gly Tyr Tyr Leu Thr Leu Val Lys Ala Arg Leu Pro Leu Thr Thr Asn Glu Lys Ala Asp Thr Asp Met Glu Gly Ser Val Asp Thr Arg Gln Glu Lys Lys Asn Gly Ser Gln Gly Ser Arg Val Gly Thr Pro Gln Leu Leu Ala Leu Val Gln His Trp Val Pro Gly Ala Arg Leu Val Glu Glu Leu Pro His Glu Leu Val Leu Val Leu Pro Tyr Thr Gly Ala His Asp Gly Ser Phe Ala Thr Leu Phe Arg Glu Leu Asp Thr Arg Leu Ala Glu Leu Arg Leu Thr Gly Tyr Gly Ile Ser Asp Thr Ser Leu Glu Glu Ile Phe Leu Lys Val Val G1u Glu Cys Ala Ala Asp Thr Asp Met Glu Asp Gly Ser Cys Gly Gln His Leu Cys Thr Gly Ile Ala G1y Leu Asp Val Thr Leu Arg Leu Lys Met Pro Pro Gln Glu Thr Ala Leu Glu Asn Gly Glu Pro Ala Gly Ser A1a Pro Glu Thr Asp Gln Gly Ser Gly Pro Asp Ala Val Gly Arg Val Gln Gly Trp Ala Leu Thr Arg Gln Gln Leu Gln Ala Leu Leu Leu Lys Arg Phe Leu Leu Ala Arg Arg Sex Arg Arg Gly Leu Phe Ala Gln Ile Val Leu Pro Ala Leu Phe Val G1y Leu Ala Leu Val Phe Ser Leu Ile Val Pro Pro Phe Gly His Tyr Pro Ala Leu Arg Leu Ser Pro Thr Met Tyr Gly Ala G1n Val Ser Phe Phe Ser Glu Asp Ala Pro Gly Asp Pro Gly Arg Ala Arg Leu Leu Glu Ala Leu Leu Gln Glu Ala Gly Leu Glu Glu Pro Pro Val Gln His Ser Ser His Arg Phe Ser Ala Pro Glu Val Pro Ala Glu Val Ala Lys Val Leu Ala Ser Gly Asn Trp Thr Pro Glu Ser Pro Ser Pro Ala Cys Gln Cys Ser Arg Pro Gly Ala Arg Arg Leu Leu Pro Asp Cys Pro Ala Ala Ala Gly Gly Pro Pro Pro Pro Gln Ala VaI Thr Gly Ser Gly Glu Val Val Gln Asn Gln Thr Gly Arg Asn Leu Ser Asp Phe Leu Va1 Lys Thr Tyr Pro Arg Leu Val Arg Gln Gly Leu Lys Thr Lys Lys Trp Val Asn Glu Val Arg Tyr Gly Gly Phe Ser Leu Gly Gly Arg Asp Pro Gly Leu Pro Ser Gly Gln Glu Leu Gly Arg Ser Val Glu Glu Leu Trp Ala Leu Leu Ser Pro Leu Pro Gly Gly Ala Leu Asp Arg Val Leu Lys Asn Leu Thr Ala Trp Ala His Ser Leu Asp Ala Gln Asp Ser Leu Lys Ile Trp Phe Asn Asn Lys Gly Trp His Ser Met Val Ala Phe Val Asn Arg Ala Ser Asn Ala Ile Leu Arg Ala His Leu Pro Pro Gly Pro Ala Arg His Ala His Ser I1e Thr Thr Leu Asn His Pro Leu Asn Leu Thr Lys Glu Gln Leu Ser Glu Ala Ala Leu Met Ala Ser Ser Val Asp Val Leu Val Ser Ile Cys Val Val Phe Ala Met Ser Phe Val Pro Ala Ser.Phe Thr Leu Val Leu Ile Glu Glu Arg Val Thr Arg Ala Lys His Leu Gln Leu Met Gly Gly Leu Ser Pro Thr Leu Tyr Trp Leu Gly Asn Phe Leu Trp Asp Met Cys Asn Tyr Leu Val Pro Ala Cys Ile Val Val Leu Ile Phe Leu Ala Phe Gln Gln Arg Ala Tyr Val Ala Pro Ala Asn Leu Pro Ala Leu Leu Leu Leu Leu Leu Leu Tyr Gly Trp Ser Ile Thr Pro Leu Met Tyr Pro Ala Ser Phe Phe Phe Ser Val Pro Ser Thr Ala Tyr Val Val Leu Thr Cys Ile Asn Leu Phe Ile Gly Ile Asn 1685 . 1690 1695 G1y Ser Met A1a Thr Phe Val Leu Glu Leu Phe Ser Asp Gln Lys Leu Gln Glu Val Ser Arg Ile Leu Lys Gln Val Phe Leu Ile Phe Pro His Phe Cys Leu Gly Arg Gly Leu Ile Asp Met Val Arg Asn Gln Ala Met Ala Asp Ala Phe Glu Arg Leu Gly Asp Arg Gln Phe Gln Ser Pro Leu Arg Trp Glu Val Val Gly Lys Asn Leu Leu Ala Met Val Ile Gln Gly Pro Leu Phe Leu Leu Phe Thr Leu Leu Leu Gln His Arg Ser Gln Leu Leu Pro Gln Pro Arg Val Arg Ser Leu Pro Leu Leu Gly Glu Glu Asp Glu Asp Val Ala Arg Glu Arg Glu Arg Val Val G1n Gly Ala Thr Gln Gly Asp Val Leu Val Leu Arg Asn Leu Thr Lys Val Tyr Arg Gly Gln Arg Met Pro Ala Val Asp Arg Leu Cys Leu Gly Ile Pro Pro Gly Glu Cys Phe G1y Leu Leu Gly Val Asn Gly Ala Gly Lys Thr Ser Thr Phe Arg Met Va1 Thr Gly Asp Thr Leu A1a Ser Arg Gly Glu Ala Val Leu Ala Gly His Ser Val Ala Arg Glu Pro Ser Ala Ala His Leu Ser Met Gly Tyr Cys Pro Gln Ser Asp Ala Ile Phe Glu Leu Leu Thr Gly Arg Glu His Leu G1u Leu Leu Ala Arg Leu Arg Gly Val Pro Glu Ala Gln Val Ala Gln Thr A1a Gly Ser Gly Leu Ala Arg Leu Gly Leu Ser Trp Tyr Ala Asp Arg Pro Ala Gly Thr Tyr Ser Gly Gly Asn Lys Arg Lys Leu Ala Thr Ala Leu Ala Leu Val Gly Asp Pro Ala Val Val Phe Leu Asp Glu Pro Thr Thr Gly Met Asp Pro Ser Ala Arg Arg Phe Leu Trp Asn Ser Leu Leu Ala Val Val Arg Glu Gly Arg Ser Val Met Leu Thr Ser His Ser Met Glu Glu Cys Glu Ala Leu Cys Ser Arg Leu Ala Ile Met Val Asn G1y Arg Phe Arg Cys Leu Gly Ser Pro Gln His Leu Lys Gly Arg Phe Ala Ala Gly His Thr Leu Thr Leu Arg Val Pro Ala Ala Arg Ser Gln Pro Ala Ala Ala Phe Val Ala Ala Glu Phe Pro Gly Ala Glu Leu Arg Glu Ala His G1y Gly Arg Leu Arg Phe Gln Leu Pro Pro Gly Gly Arg Cys Ala Leu Ala Arg Val Phe Gly Glu Leu Ala Val His G1y Ala Glu His Gly Val Glu Asp Phe Ser Va1 Ser Gln Thr Met Leu Glu Glu Val Phe Leu Tyr Phe Ser Lys Asp Gln Gly Lys Asp Glu Asp Thr G1u Glu Gln Lys Glu Ala Gly Val Gly Val Asp Pro Ala Pro Gly Leu 2150 2155 21&0 Gln His Pro Lys Arg Val Ser G1n Phe Leu Asp Asp Pro Ser Thr 21&5 2170 2175 Ala Glu Thr Val Leu <210> 28 <211> 1737 <212> PRT
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477845CD1 <400> 28 Met Leu Lys Arg Lys Gln Ser Ser Arg Va1 Glu Ala G1n Pro Val Thr Asp Phe Gly Pro Asp Glu Ser Leu Ser Asp Asn Ala Asp Ile Leu Trp Ile Asn Lys Pro~Trp Val His Ser Leu Leu Arg Ile Cys Ala Ile Ile Ser Val I1e Ser Val Cys Met Asn Thr Pro Met Thr Phe Glu His Tyr Pro Pro Leu Gln Tyr Val Thr Phe Thr Leu Asp Thr Leu Leu Met Phe Leu Tyr Thr Ala Glu Met Ile Ala Lys Met His Ile Arg Gly Ile Val Lys Gly Asp Ser Ser Tyr Val Lys Asp Arg Trp Cys Val Phe Asp Gly Phe Met Val Phe Cys Leu Trp Val Ser Leu Val Leu Gln Val Phe Glu Ile Ala Asp Ile Val Asp Gln Met Ser Pro Trp Gly Met Leu Arg Ile Pro Arg Pro Leu I1e Met Ile Arg Ala Phe Arg Ile Tyr Phe Arg Phe Glu Leu Pro Arg Thr Arg Ile Thr Asn Ile Leu Lys Arg Ser Gly Glu Gln I1e Trp Ser Val Ser Ile Phe Leu Leu Phe Phe Leu Leu Leu Tyr Gly Ile Leu Gly Val Gln Met Phe Gly Thr Phe Thr Tyr His Cys Val Val Asn Asp Thr Lys Pro Gly Asn Val Thr Trp Asn Ser Leu Ala Ile Pro Asp Thr His Cys Ser Pro Glu Leu Glu Glu Gly Tyr Gln Cys Pro Pro Gly Phe Lys Cys Met Asp Leu Glu Asp Leu Gly Leu Ser Arg Gln Glu Leu Gly Tyr Ser Gly Phe Asn Glu Ile Gly Thr Ser Ile Phe Thr Val Tyr Glu Ala Ala Ser Gln Glu Gly Trp Val Phe Leu Met Tyr Arg Ala Ile Asp Ser Phe Pro Arg Trp Arg Ser Tyr Phe Tyr Phe Ile Thr Leu Ile Phe Phe Leu Ala Trp Leu Val Lys Asn Val Phe Ile Ala Val Ile Ile Glu Thr Phe Ala Glu Ile Arg Val G1n Phe Gln G1n Met Trp Gly Ser Arg Ser Ser Thr Thr Ser Thr Ala Thr Thr Gln Met Phe His Glu Asp Ala Ala Gly Gly Trp Gln Leu Val Ala Val Asp Val Asn Lys Pro Gln Gly Arg Ala Pro Ala Cys Leu Gln Lys Met Met Arg Ser Ser Val Phe His Met Phe Ile Leu Ser Met Val Thr Val Asp Val Ile Val Ala Ala Ser Asn Tyr Tyr Lys Gly Glu Asn Phe Arg Arg Gln Tyr Asp Glu Phe Tyr Leu Ala Glu Val Ala Phe Thr Val Leu Phe Asp Leu Glu Ala Leu Leu Lys Tle Trp Cys Leu Gly Phe Thr Gly Tyr Ile Ser Ser Ser Leu His Lys Phe Glu Leu Leu Leu Val Ile Gly Thr Thr Leu His Val Tyr Pro Asp Leu Tyr His Ser Gln Phe Thr Tyr Phe Gln Val Leu Arg Val Val Arg Leu Ile Lys Ile Ser Pro Ala Leu Glu Asp Phe Val Tyr Lys Ile Phe Gly Pro Gly Lys Lys Leu Gly Ser Leu Val Val Phe Thr Ala Ser Leu Leu Ile Val Met Ser A1a Ile Ser Leu Gln Met Phe Cys Phe Val Glu Glu Leu Asp Arg Phe Thr Thr Phe Pro Arg Ala Phe Met Ser Met Phe Gln Ile Leu Thr Gln Glu Gly Trp Val Asp Val Met Asp Gln Thr Leu Asn Ala Val Gly His Met Trp Ala Pro Val Val Ala Ile Tyr Phe Ile Leu Tyr His Leu Phe Ala Thr Leu Ile Leu Leu Ser Leu Phe Val Ala Val Ile Leu Asp Asn Leu Glu Leu Asp Glu Asp Leu Lys Lys Leu Lys Gln Leu Lys G1n Ser Glu Ala Asn Ala Asp Thr Lys Glu Lys Leu Pro Leu Arg Leu Arg Ile Phe Glu Lys Phe Pro Asn Arg Pro Gln Met Val Lys Ile Ser Lys Leu Pro Ser Asp Phe Thr Val Pro Lys Ile Arg Glu Ser Phe Met Lys G1n Phe Ile Asp Arg G1n Gln Gln Asp Thr Cys Cys Leu Leu Arg Ser Leu Pro Thr Thr Ser Ser Ser Ser Cys Asp His Ser Lys Arg Ser Ala Ile Glu Asp Asn Lys Tyr Ile Asp G1n 5~/g~

Lys Leu Arg Lys Ser Val Phe Ser Ile Arg Ala Arg Asn Leu Leu Glu Lys Glu Thr Ala Val Thr Lys Ile Leu Arg Ala Cys Thr Arg Gln Arg Met Leu Ser Gly Ser Phe Glu Gly Gln Pro Ala Lys Glu Arg Ser Ile Leu Ser Val Gln His His Ile Arg Gln Glu Arg Arg Ser Leu Arg His Gly Sex Asn Ser Gln Arg Ile Ser Arg G1y Lys Ser Leu Glu Thr Leu Thr Gln Asp His Cys Asn Thr Val Ile Tyr Arg Asn Ala Gln Arg Glu Val Ser Glu Ile Lys Met Ile Gln Glu Lys Lys Glu Leu Ala Glu Met Leu Gln Gly Lys Cys Lys Lys Glu Leu Arg Glu Ser His Pro Tyr Phe Asp Lys Pro Leu Phe Ile Val Gly Arg Glu His Arg Phe Arg Asn Phe Cys Arg Val Val Val Arg Ala Arg Phe Asn Ala Ser Lys Thr Asp Pro Val Thr Gly Ala Val Lys Asn Thr Lys Tyr His Leu Leu Tyr Asp Leu Leu Gly Leu Val Thr Tyr Leu Asp Trp Val Met Ile Ile Val Thr Ser Asp Ser Cys Ile Ser Met Met Phe Glu Ser Pro Phe Arg Arg Val Met His Ala Pro Thr Leu Gln Ile Ala Glu Tyr Val Phe Va1 Ile Phe Met Ser Ile Glu Leu Asn Leu Lys Ile Met Ala Asp Gly Leu Phe Phe Thr Pro Thr Ala Val Ile Arg Asp Phe Gly Gly Val Met Asp Ile Phe Ile Tyr Leu Val Ser Leu Ile Phe Leu Cys Trp Met Pro Gln Asn Val Pro Ala G1u Ser Gly Ala Gln Leu Leu Met Val Leu Arg Cys Leu Arg Pro Leu Arg Ile Phe Lys Leu Val Pro Gln Met Arg Lys Val Val Arg Glu Leu Phe Ser Gly Phe Lys Glu I1e Phe Leu Va1 Ser Ile Leu Leu Leu Thr Leu Met Leu Val Phe A1a Ser Phe Gly Val G1n Leu Phe Ala Gly Lys Leu Ala Lys Cys Asn Asp Pro Asn Ile Ile Arg Arg Glu Asp Cys Asn Gly Ile Phe Arg Ile Asn Val Ser Val Ser Lys Asn Leu Asn Leu Lys Leu Arg Pro Gly Glu Lys Lys Pro Gly Phe Trp Val Pro Arg Val Trp Ala Asn Pro Arg Asn Phe Asn Phe Asp Asn Val Gly Asn Ala Met Leu Ala Leu Phe Glu Val Leu Ser Leu Lys Gly Trp Val Glu Val Arg Asp Val Ile Ile His Arg Val Gly Pro Ile His Gly Ile Tyr Ile His Val Phe Val Phe Leu Gly Cys Met Ile Gly Leu Thr Leu Phe Val Gly Val Val Ile Ala Asn Phe Asn Glu Asn Lys Gly Thr Ala Leu Leu Thr Va1 Asp Gln Arg Arg Trp Glu Asp Leu Lys Ser Arg Leu Lys Ile Ala Gln Pro Leu His Leu Pro Pro Arg Pro Asp Asn Asp Gly Phe Arg Ala Lys Met Tyr Asp Ile Thr Gln His Pro Phe Phe Lys Arg Thr Ile Ala Leu Leu Val Leu Ala Gln Ser Val Leu Leu Ser Val Lys Trp Asp Val Glu Asp Pro Val Thr Val Pro Leu Ala Thr Met Ser Val Val Phe Thr Phe Ile Phe Val Leu Glu Val Thr Met Lys Ile Ile Ala Met Ser Pro Ala Gly Phe Trp Gln Ser Arg Arg Asn Arg Tyr Asp Leu Leu Val Thr Ser Leu Gly Val Val Trp Val Val Leu His Phe Ala Leu Leu Asn Ala Tyr Thr Tyr Met Met Gly Ala Cys Val Ile Val Phe Arg Phe Phe Ser Ile Cys Gly Lys His Val Thr Leu Lys Met Leu Leu Leu Thr Val Val Val Ser Met Tyr Lys Ser Phe Phe Ile Ile Val Gly Met Phe Leu Leu Leu Leu Cys Tyr Ala Phe Ala Gly Val Val Leu Phe Gly Thr Val Lys Tyr Gly Glu Asn Ile Asn Arg His Ala Asn Phe Ser Ser Ala Gly Lys Ala Ile Thr Val Leu Phe Arg Ile Val Thr Gly Glu Asp Trp Asn Lys Ile Met His Asp Cys Met Val Gln Pro Pro Phe Cys Thr Pro Asp Glu Phe Thr Tyr Trp Ala Thr Asp Cys Gly Asn Tyr A1a Gly Ala Leu Met Tyr Phe Cys Ser Phe Tyr Val Ile Ile Ala Tyr Ile Met Leu Asn Leu Leu Val Ala Ile Ile Val Glu Asn Phe Ser Leu Ile Tyr Ser Thr Glu Glu Asp Gln Leu Leu Ser Tyr Asn Asp Leu Arg His Phe G1n Ile I1e Trp Asn Met Val Asp Asp Lys Arg Glu Val Phe Pro Thr Phe Arg Val Lys Phe Leu Leu Arg Leu Leu Arg Gly Arg Leu Glu Val Asp Leu Asp Lys Asp Lys Leu Leu Phe Lys His Met Cys Tyr Glu Met Glu Arg Leu His Asn Gly Gly Asp Val Thr Phe His Asp Val Leu Ser Met Leu Ser Tyr Arg Ser Val Asp Ile Arg Lys Ser Leu Gln Leu Glu Glu Leu Leu Ala Arg Glu Gln Leu Glu Tyr Thr Ile Glu G1u Glu Val Ala Lys Gln Thr Ile Arg Met Trp Leu Lys Lys Cys Leu Lys Arg Ile Arg A1a Lys Gln Gln Gln Ser Cys Ser I1e Ile His Ser Leu Arg Glu Ser Gln Gln Gln Glu Leu Ser Arg Phe Leu Asn Pro Pro Ser Ile Glu Thr Thr Gln Pro Ser Glu Asp Thr Asn Ala Asn Ser Gln Asp Asn Ser Met Gln Pro Glu Thr Ser Ser Gln Gln Gln Leu Leu Ser Pro Thr Leu Ser Asp Arg Gly Gly Ser Arg Gln Asp Ala Ala Asp Ala Gly Lys Pro Gln Arg Lys Phe Gly G1n Trp Arg Leu Pro Ser Ala Pro Lys Pro Ile Ser His Ser Val Ser Ser Val Asn Leu Arg Phe Gly Gly Arg Thr Thr Met Lys Ser Val Val Cys Lys Met Asn Pro Met Thr Asp Ala Ala Ser Cys Gly Sex Glu Val Lys Lys Trp Trp Thr Arg Gln Leu Thr Val Glu Ser Asp Glu Ser Gly Asp Asp Leu Leu Asp Ile <210> 29 <211> 547 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 168827CD1 <400> 29 Met A1a Phe Gln Asp Leu Leu Asp Gln Val Gly Gly Leu Gly Arg Phe Gln Ile Leu Gln Met VaI Phe Leu Ile Met Phe Asn Val Ile Val Tyr His Gln Thr Gln Leu Glu Asn Phe Ala Ala Phe Ile Leu Asp His Arg Cys Trp Val His Ile Leu Asp Asn Asp Thr Ile Pro Asp Asn Asp Pro Gly Thr Leu Ser Gln Asp Ala Leu Leu Arg Ile Ser Ile Pro Phe Asp Sex Asn Leu Arg Pro Glu Lys Cys Arg Arg Phe Val His Pro Gln Trp Lys Leu Ile His Leu Asn Gly Thr Phe Pro Asn Thr Ser Glu Pro Asp Thr Glu Pro Cys Val Asp Gly Trp Val Tyr Asp Gln Ser Ser Phe Pro Ser Thr Ile Val Thr Lys Trp Asp Leu Val Cys Glu Ser Gln Pro Leu Asn Ser Val Ala Lys Phe Leu Phe Met Ala Gly Met Met Val Gly Gly Asn Leu Tyr Gly His Leu Ser Asp Arg Phe Gly Arg Lys Phe Va1 Leu Arg Trp Ser Tyr Leu Gln Leu Ala Ile Val Gly Thr Cys Ala Ala Phe Ala Pro Thr Ile Leu Val Tyr Cys Ser Leu Arg Phe Leu Ala Gly Ala Ala Thr Phe Ser Ile Ile Val Asn Thr Val Leu Leu Ile Val Glu Trp Ile Thr His Gln Phe Cys Ala Met Ala Leu Thr Leu Thr Leu Cys Ala Ala Ser Ile Gly His Ile Thr Leu Gly Ser Leu Ala Phe Val Ile Arg Asp Gln Cys Ile Leu Gln Leu Val Met Ser Ala Pro Cys Phe Val Phe Phe Leu Phe Ser Arg Trp Leu Ala Glu Ser Ala Arg Trp Leu Ile Ile Asn Asn Lys Pro Glu Glu Gly Leu Lys Glu Leu Thr Lys Ala Ala His Arg Asn Gly Met Lys Asn Ala Glu Asp Ile Leu Thr Met Glu Val Leu Lys Ser Thr Met Lys Gln Glu Leu G1u Ala Ala Gln Lys Lys His Ser Leu Cys Glu Leu Leu Arg Ile Pro Asn Ile Cys Lys Arg Ile Cys Phe Leu Ser Phe Val Arg Phe Ala Ser Thr Ile Pro Phe Trp Gly Leu Thr Leu His Leu Gln His Leu Gly Asn Asn Va1 Phe Leu Leu Gln Thr Leu Phe Gly Ala Va1 Thr Leu Leu Ala Asn Cys Val Ala Pro Trp A1a Leu Asn His Met Ser Arg Arg Leu Ser Gln Met Leu Leu Met Phe Leu Leu Ala Thr Cys Leu Leu A1a Ile Ile Phe Val Pro Gln Glu Met Gln Thr Leu Arg Val Val Leu Ala Thr Leu Gly Val Gly Ala Ala Ser Leu Gly Ile Thr Cys Ser Thr Ala Gln Glu Asn Glu Leu Ile Pro Ser Ile Ile Arg Gly Arg Ala Thr Gly Ile Thr Gly Asn Phe Ala Asn Ile Gly Gly Ala Leu Ala Ser Leu Met Met Ile Leu Ser Ile Tyr Ser Arg Pro Leu Pro Trp Ile Ile Tyr Gly Val Phe Ala Ile Leu Ser Gly Leu Val Val Leu Leu Leu Pro Glu Thr Arg Asn Gln Pro Leu Leu Asp Ser Ile Gln Asp Val Glu Asn Glu Gly Val Asn Ser Leu Ala Ala Pro Gln Arg Ser Ser Val Leu <210> 30 <211> 547 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472734CD1 <400> 30 Met G1y Phe Asp Val Leu Leu Asp Gln Val Gly Gly Met Gly Arg Phe Gln I1e Cys Leu Ile Ala Phe Phe Cys Ile Thr Asn Ile Leu Leu Phe Pro Asn Ile Val Leu Glu Asn Phe Thr Ala Phe Thr Pro Ser His Arg Cys Trp Val Pro Leu Leu Asp Asn Asp Thr Val Ser Asp Asn Asp Thr Gly Thr Leu Ser Lys Asp Asp Leu Leu Arg Ile Ser Ile Pro Leu Asp Ser Asn Leu Arg Pro Gln Lys Cys Gln Arg Phe Ile His Pro Gln Trp Gln Leu Leu His Leu Asn Gly Thr Phe Pro Asn Thr Asn Glu Pro Asp Thr Glu Pro Cys Val Asp Gly Trp Va1 Tyr Asp Arg Ser Ser Phe Leu Ser Thr Ile Val Thr Glu Trp Asp Leu Val Cys Glu Ser G1n Ser Leu Lys Ser Met Val Gln Ser Leu Phe Met Ala Gly Ser Leu Leu Gly Gly Leu Ile Tyr Gly His Leu Ser Asp Arg Phe GIy Arg Lys Phe Val Leu Arg Trp Ser Tyr Leu Gln Leu Ala Ile Val Gly Thr Cys Ala Ala Phe A1a Pro Thr Ile Leu Val Tyr Cys Ser Leu Arg Phe Leu Ala Gly Ala Ala Thr Phe Ser Ile Ile Val Asn Thr Val Leu Leu Ile Val Glu Trp Ile Thr His Gln Phe Cys Ala Met Ala Leu Thr Leu Thr Leu Cys Ala Ala Ser Ile Gly His Ile Thr Leu Gly Ser Leu Ala Phe Val Ile Arg Asp Gln Cys Ile Leu G1n Leu Val Met Ser Ala Pro Cys Phe Val Phe Phe Leu Phe Ser Arg Trp Leu Ala Glu Ser Ala Arg Trp Leu Ile Ile Asn Asn Lys Pro Glu Glu Gly Leu Lys Glu Leu Arg Lys Ala Ala His Arg Asn Gly Met Lys Asn Ala Glu Asp Ile Leu Thr Met Glu Val Leu Lys Ser Thr Met Lys Gln Glu Leu Glu Ala Ala Gln Lys Lys His Ser Leu Cys Glu Leu Leu Arg Ile Pro Asn Ile Cys Lys Arg I1e Cys Phe Leu Ser Phe Val Arg Phe Ala Ser Thr Ile Pro Phe Trp Gly Leu Thr Leu His Leu Gln His Leu Gly Asn Asn Val Phe Leu Leu Gln Thr Leu Phe Gly Ala Val Thr Leu 380 385 ~ 390 Leu Ala Asn Cys Val Ala Pro Trp Ala Leu Asn His Met Ser Arg Arg Leu Ser Gln Met Leu Leu Met Phe Leu Leu Ala Thr Cys Leu Leu Ala Ile Ile Phe Val Pro Gln Glu Met Gln Thr Leu Arg Val Val Leu Ala Thr Leu Gly Val Gly Ala Ala Ser Leu Gly Ile Thr 440 445 ' 450 Cys Ser Thr Ala Gln Glu Asn Glu Leu Ile Pro Ser Ile I1e Arg Gly Arg Ala Thr Gly Ile Thr Gly Asn Phe Ala Asn Ile Gly Gly Ala Leu Ala Ser Leu Met Met Ile Leu Ser Ile Tyr Ser Arg Pro Leu Pro Trp Ile Ile Tyr Gly Val Phe Ala Ile Leu Ser Gly Leu Val Val Leu Leu Leu Pro Glu Thr Arg Asn Gln Pro Leu Leu Asp Ser Ile Gln Asp Val Glu Asn Glu Gly Val Asn Ser Leu Ala Ala Pro Gln Arg Ser Ser Val Leu <210> 31 <211> 988 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473473CD1 <400> 31 Met Pro Gly Gly Lys Arg Gly Leu Val Ala Pro Gln Asn Thr Phe Leu Glu Asn Ile Val Arg Arg Ser Ser Glu Ser Ser Phe Leu Leu Gly Asn Ala Gln Ile Val Asp Trp Pro Val Val Tyr Ser Asn Asp Gly Phe Cys Lys Leu Ser Gly Tyr His Arg Ala Asp Va1 Met Gln Lys Ser Ser Thr Cys Ser Phe Met Tyr Gly Glu Leu Thr Asp Lys Lys Thr Ile Glu Lys Val Arg Gln Thr Phe Asp Asn Tyr Glu Ser Asn Cys Phe Glu Val Leu Leu Tyr Lys Lys Asn Arg Thr Pro Val Trp Phe Tyr Met Gln Ile Ala Pro Ile Arg Asn Glu His Glu Lys Val Val Leu Phe Leu Cys Thr Phe Lys Asp Ile Thr Leu Phe Lys Gln Pro Ile Glu Asp Asp Ser Thr Lys Gly Trp Thr Lys Phe Ala Arg Leu Thr Arg Ala Leu Thr Asn Ser Arg Ser Val Leu Gln Gln Leu Thr Pro Met Asn Lys Thr Glu Val Val His Lys His Sex Arg Leu Ala Glu Val Leu Gln Leu Gly Ser Asp Ile Leu Pro Gln Tyr Lys Gln Glu Ala Pro Lys Thr Pro Pro His Ile Ile Leu His Tyr Cys Ala Phe Lys Thr Thr Trp Asp Trp Val Ile Leu Ile Leu Thr Phe Tyr Thr Ala Ile Met Val Pro Tyr Asn Val Ser Phe Lys Thr Lys Gln Asn Asn Ile Ala Trp Leu Val Leu Asp Ser Val Val Asp Val Ile Phe Leu Val Asp Ile Val Leu Asn Phe His Thr Thr Phe Val Gly Pro Gly Gly Glu Val Ile Ser Asp Pro Lys Leu Ile Arg Met Asn Tyr Leu Lys Thr Trp Phe Val Ile Asp Leu Leu Ser Cys Leu Pro Tyr Asp Ile Ile Asn Ala Phe Glu Asn Val Asp Glu Gly Ile Ser Ser Leu Phe Ser Ser Leu Lys Val Val Arg Leu Leu Arg Leu Gly Arg Val Ala Arg Lys Leu Asp His Tyr Leu Glu Tyr Gly Ala Ala Val Leu Val Leu Leu Val Cys Va1 Phe Gly Leu Val Ala His Trp Leu Ala Cys Ile Trp Tyr Ser I1e Gly Asp Tyr Glu Val Ile Asp Glu Val Thr Asn Thr Ile Gln Ile Asp Ser Trp Leu Tyr Gln Leu Ala Leu Ser Ile Gly Thr Pro Tyr Arg Tyr Asn Thr Ser Ala Gly Ile Trp Glu G1y Gly Pro Ser Lys Asp Ser Leu Tyr Val Ser Ser Leu Tyr Phe Thr Met Thr Ser Leu Thr Thr Ile Gly Phe Gly Asn Ile Ala Pro Thr Thr Asp Val Glu Lys Met Phe Ser Val Ala Met Met Met Val Gly Ala Leu Leu Tyr Ala Thr Ile Phe Gly Asn Val Thr Thr Ile Phe Gln Gln Met Tyr Ala Asn Thr Asn Arg Tyr His Glu Met Leu Asn Asn Val Arg Asp Phe Leu Lys Leu Tyr Gln Val Pro Lys Gly Leu Ser Glu Arg Val Met Asp Tyr Ile Val Ser Thr Trp Ser Met Ser Lys Gly Ile Asp Thr Glu Lys Val Leu Ser I1e Cys Pro Lys Asp Met Arg Ala Asp Ile Cys Val His Leu Asn Arg Lys Val Phe Asn Glu His Pro Ala Phe Arg Leu Ala Ser Asp Gly Cys Leu Arg Ala Leu Ala Val Glu Phe Gln Thr Ile His Cys Ala Pro Gly Asp Leu Ile Tyr His A1a Gly Glu Ser Val Asp Ala Leu Cys Phe Val Val Ser Gly Ser Leu Glu Va1 Ile Gln Asp Asp Glu Val Val A1a Ile Leu Gly Lys Gly Asp Val Phe Gly Asp Ile Phe Trp Lys Glu Thr Thr Leu A1a His Ala Cys Ala Asn Val 56!87 Arg Ala Leu Thr Tyr Cys Asp Leu His Ile Ile Lys Arg G1u Ala Leu Leu Lys Val Leu Asp Phe Tyr Thr Ala Phe Ala Asn Ser Phe Ser Arg Asn Leu Thr Leu Thr Cys Asn Leu Arg Lys Arg Ile Ile Phe Arg Lys Ile Ser Asp Val Lys Lys Glu Glu Glu Glu Arg Leu Arg Gln Lys Asn Glu Val Thr Leu Ser I1e Pro Val Asp His Pro Val Arg Lys Leu Phe Gln Lys Phe Lys Gln Gln Lys Glu Leu Arg Asn Gln Gly Ser Thr Gln G1y Asp Pro Glu Arg Asn Gln,Leu Gln Val Glu Ser Arg Ser Leu Gln Asn Gly Ala Ser Ile Thr Gly Thr Ser Val Val Thr Val Ser Gln Ile Thr Pro Ile Gln Thr Ser Leu Ala Tyr Val Lys Thr Ser Glu Ser Leu Lys Gln Asn Asn Arg Asp Ala Met Glu Leu Lys Pro Asn Gly Gly Ala Asp Gln Lys Cys Leu Lys Val Asn Ser Pro Ile Arg Met Lys Asn Gly Asn Gly Lys Gly Trp Leu Arg Leu Lys Asn Asn Met Gly Ala His Glu Glu Lys Lys Glu Asp Trp Asn Asn Val Thr Lys Ala Glu Ser Met Gly Leu Leu Ser Glu Asp Pro Lys Ser Ser Asp Ser Glu Asn Ser Va1 Thr Lys Asn Pro Leu Arg Lys Thr Asp Ser Cys Asp Ser Gly Tle Thr Lys Ser Asp Leu Arg Leu Asp Lys Ala Gly Glu Ala Arg Ser Pro Leu Glu His Ser Pro Ile Gln Ala Asp Ala Lys His Pro Phe Tyr Pro Ile Pro Glu Gln Ala Leu Gln Thr Thr Leu Gln Glu Val Lys His Glu Leu Lys Glu Asp Ile Gln Leu Leu Ser Cys Arg Met Thr Ala Leu G1u Lys Gln Val Ala Glu Ile Leu Lys Ile Leu Ser Glu Lys Ser Val Pro Gln Ala Ser Ser Pro Lys Ser Gln Met Pro Leu Gln Val Pro Pro Gln Ile Pro Cys Gln Asp Ile Phe Ser Val Ser Arg Pro Glu Ser Pro Glu Ser Asp Lys Asp Glu Ile His Phe <210> 32 <211> 533 <212> PRT
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477725CD1 <400> 32 Met Ala Phe Glu Glu Leu Leu Ser Gln Val Gly Gly Leu Gly Arg Phe Gln Met Leu His Leu Va1 Phe Ile Leu Pro Ser Leu Met Leu Leu Ile Pro His I1e Leu Leu Glu Asn Phe Ala Ala Ala Ile Pro Gly His Arg Cys Trp Val His Met Leu Asp Asn Asn Thr Gly Ser Gly Asn Glu Thr Gly Ile Leu Ser Glu Asp Ala Leu Leu Arg Ile Ser I1e Pro Leu Asp Ser Asn Leu Arg Pro Glu Lys Cys Arg Arg Phe Val His Pro Gln Trp Gln Leu Leu His Leu Asn Gly Thr Ile His Ser Thr Ser Glu Ala Asp Thr Glu Pro Cys Val Asp Gly Trp Val Tyr Asp Gln Ser Tyr Phe Pro Ser Thr Ile Val Thr Lys Trp Asp Leu Val Cys Asp Tyr Gln Ser Leu Lys Ser Val Val Gln Phe Leu Leu Leu Thr Gly Met Leu Val Gly Gly Ile Ile Gly Gly His Val Ser Asp Arg Phe Gly Arg Arg Phe Ile Leu Arg Trp Cys Leu Leu Gln Leu Ala Ile Thr Asp Thr Cys Ala Ala Phe Ala Pro Thr Phe Pro Val Tyr Cys Val Leu Arg Phe Leu Ala Gly Phe Ser Ser Met Ile Ile Ile Ser Asn Asn Ser Leu Pro Ile Thr Glu Trp I1e Arg Pro Asn Ser Lys Ala Leu Val Val Ile Leu Ser Ser Gly Ala Leu Ser Ile Gly Gln Ile Ile Leu Gly Gly Leu Ala Tyr Val Phe Arg Asp Trp Gln Thr Leu His Val Val Ala Ser Val Pro Phe Phe Val Phe Phe Leu Leu Ser Arg Trp Leu Val G1u Ser Ala Arg Trp Leu Ile Ile Thr Asn Lys Leu Asp Glu Gly Leu Lys Ala Leu Arg Lys Val Ala Arg Thr Asn Gly Ile Lys Asn Ala Glu Glu Thr Leu Asn Ile Glu Val Val Arg Ser Thr Met Gln G1u Glu Leu Asp Ala Ala Gln Thr Lys Thr Thr Val Cys Asp Leu Phe Arg Asn Pro Ser Met Arg Lys Arg Ile Cys I1e Leu Val Phe Leu Arg Phe Ala Asn Thr Ile Pro Phe Tyr Gly Thr Met Val Asn Leu Gln His Val Gly Ser Asn Ile Phe Leu Leu Gln Val Leu Tyr Gly Ala Val Ala Leu Tle Va1 Arg Cys Leu Ala Leu Leu Thr Leu Asn His Met Gly Arg Arg Ile Ser Gln Ile Leu Phe Met Phe Leu Val Gly Leu Ser Ile Leu Ala Asn Thr Phe Val Pro Lys Glu Met G1n Thr Leu Arg Va1 Ala Leu~AIa Cys Leu Gly Tle Gly Cys Ser Ala Ala Thr Phe Ser Ser Val Ala Val His Phe Ile Glu Leu Ile Pro Thr Val Leu Arg Ala Arg Ala Ser Gly .Ile Asp Leu Thr Ala Ser Arg Ile Gly Ala Ala Leu Ala Pro Leu Leu Met Thr Leu Thr Val Phe Phe Thr Thr Leu Pro Trp Ile Ile Tyr Gly Ile Phe Pro Ile Ile Gly Gly Leu Ile Val Phe Leu Leu Pro Glu Thr Lys Asn Leu Pro Leu Pro Asp Thr Ile Lys Asp Val Glu Asn Gln <210> 33 <211> 1775 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 3474673CB1 <400> 33 atttcaggaa atgtgagggg gctctgggcc ccttccctca gcgcctgcgg tcacccagca 60 gcttcctcct tctccctggc ctaggcctag caggtgggca ccccgcacac atttgaggcg 120 gggccagatg cccacagttc agagcctctt tttgtcccgg ggattggatc ccagggctgg 180 gtggggccag gctgtcccat tccccaacac tcctcctccc cggcgaaacc gggcaccagc 240 aggcgtttgc gagaggagat acgagctgga cgcctggccc ttccctccca ccgggtccta 300 gtccaccgct cccggcgccg gctccccgcc tctcccgcta tgtaccgacc gcgagcccgg 360 gcggctcccg agggcagggt ccggggctgc gcggtgccca gcaccgtgct cctgctgctc 420 gcctacctgg cttacctggc gctgggcacc ggcgtgttct ggacgctgga gggccgcgcg 480 gcgcaggact ccagccgcag cttccagcgc gacaagtggg agctgttgca gaacttcacg 540 tgtctggacc gcccggcgct ggactcgctg atccgggatg tcgtccaagc atacaaaaac 600 ggagccagcc tcctcagcaa caccaccagc atggggcgct gggagctcgt gggctccttc 660 ttcttttctg tgtccaccat caccaccatt ggctatggca acctgagccc caacacgatg 720 gctgcccgcc tcttctgcat cttctttgcc cttgtgggga tcccactcaa cctcgtggtg 780 ctcaaccgac tggggcatct catgcagcag ggagtaaacc actgggccag caggctgggg 840 ggcacctggc aggatcctga caaggcgcgg tggctggcgg gctctggcgc cctcctctcg 900 ggcctcctgc tcttcctgct gctgccaccg ctgctcttct cccacatgga gggctggagc 960 tacacagagg gcttctactt cgccttcatc accctcagca ccgtgggctt cggcgactac 1020 gtgattggaa tgaacccctc ccagaggtac ccactgtggt acaagaacat ggtgtccctg 1080 tggatcctct ttgggatggc atggctggcc ttgatcatca aactcatcct ctcccagctg 1140 gagacgccag ggagggtatg ttcctgctgc caccacagct ctaaggaaga cttcaagtcc 1200 caaagctgga gacagggacc tgaccgggag ccagagtccc actccccaca gcaaggatgc 1260 tatccagagg gacccatggg aatcatacag catctggaac cttctgctca cgctgcaggc 1320 tgtggcaagg acagctagtt atactccatt ctttggtcgt cgtcctcggt agcaagaccc 1380 ctgattttaa gctttgcaca tgtccaccca aactaaagac tacattttcc atccacccta 1440 gaggctgggt gcagctatat gattaattct gcccaatagg gtatacagag acatgtcctg 1500 ggtgacatgg gatgtgactt tcgggtgtcg gggcagcatg cccttctccc ccacttcctt 1560 actttagcgg gctgcaatgc cgccgatatg atggctggga gctctggcag ccatacggca 1620 ccatgaagta gcggcaatgt ttgagcggca caataagata ggaagagtct ggatctctga 1680 tgatcacaga gccatcctaa caaacggaat atcacccgac ctcctttatg tgagagagaa 1740 ataaacatct tatgtaaaat accaaaaaaa aaaaa 1775 <210> 34 <211> 1545 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4588877CB1 <400> 34 aatgagggcc ctgggggttg ggcccaggag tggggctgtg gtggtgagtg gacagggctg 60 ggctggaaat gtcccctgag tgccccctct cacctcaggc tatggcaacc tgagccccaa 120 cacgatggct gcccgcctct tctgcatctt ctttgccctt gtggggatcc cactcaacct 180 cgtggtgctc aaccgactgg ggcatctcat gcagcaggga gtaaaccact gggccagcag 240 gctggggggc acctggcagg tgagggggct gctggacggg gtggggatgg gtcacttcta 300 gaatgagggg ctgtggtggg aattggggtt actaatgaca agaggtggga gcaagtgtta 360 ctggtgaggt tgtgttggga ttgggggtca ctgctcagaa tagggtcctt agtgaaaaag 420 ggcattaatg gtggagatgg ggtgggactg ggcagacagg aaggacatga ggcacaggct 480 ccaggcaggg aacctggaga acacagacca ggtgaagagc ccccttctta ctggggacag 540 ctctggcctg cctccagctc cctcggctcc cacgcatggg gtgaaggcct caggaggcct 600 ggggacaata ttgcacccac aggatcctga caaggcgcgg tggctggegg gctctggcgc 660 cctcctctcg ggcctcctgc tcttcctgct gctgccaccg ctgctcttct cccacatgga 720 gggctggagc tacacagagg gcttctactt cgccttcatc accctcagca ccgtgggctt 780 cggcgactac gtgattggaa tgaacccctc ccagaggtac ccactgtggt acaagaacat 840 ggtgtccctg tggatcctct ttgggatggc atggctggcc ttgatcatca aactcatcct 900 ctcccagctg gagacgccag ggagggtatg ttcctgctgc caccacagct ctaaggaaga 960 cttcaagtcc caaagctgga gacagggacc tgaccgggag ccagagtccc actccccaca 1020 gcaaggatgc tatccagagg gacccatggg aatcatacag catctggaac cttctgctca 1080 cgctgcaggc tgtggcaagg acagctagtt atactccatt ctttggtcgt cgtcctcggt 1140 agcaagaccc ctgattttaa gctttgcaca tgtccaccca aactaaagac tacattttcc 1200 atccacccta gaggctgggt gcagctatat gattaattct gcccaatagg gtatacagag 1260 acatgtcctg ggtgacatgg gatgtgactt tcgggtgtcg gggcagcatg cccttctccc 1320 ccacttcctt actttagcgg gctgcaatgc cgccgatatg atggctggga gctctggcag 1380 ccatacggca ccatgaagta gcggcaatgt ttgagcggca caataagata ggaagagtct 1440 ggatctctga tgatcacaga gccatcctaa caaacggaat atcacccgac ctcctttatg 1500 tgagagagaa ataaacatct tatgtaaaat accaaaaaaa aaaaa 2545 <210> 35 <211> 1941 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472214CB1 <400> 35 atggcggaga aggcgctgga ggccgtgggc tgtggactag ggccgggggc tgtggccatg 60 gccgtgacgc tggaggacgg ggcggaaccc cctgtgctga ccacgcacct gaagaaggtg 120 gagaaccaca tcactgaagc ccagcgcttc tcccacctac ccaagcgctc agccgtggac 180 atcgagttcg tggagctgtc ctattccgtg cgggaggggc cctgctggcg caaaaggggt 240 tataagaccc ttctcaagtg cctctcaggt aaattctgcc gccgggagct gattggcatc 300 atgggcccct caggggctgg caagtctaca ttcatgaaca tcttggcagg atacagggag 360 tctggaatga aggggcagat cctggttaat ggaaggccac gggagctgag gaccttccgc 420 aagatgtcct gctacatcat gcaagatgac atgctgctgc cgcacctcac ggtgttggaa 480 gccatgatgg tgtctgctaa cctgaatctt actgagaatc ccgatgtgaa aaacgatctc 540 gtgacagaga tcctgacggc actgggcctg atgtcgtgct cccacacgag gacagccctg 600 ctctctggcg ggcagaggaa gcgtctggcc atcgccctgg agctggtcaa caacccgcct 660 gtcatgttct ttgatgagcc caccagtggt ctggatagcg cctcttgttt ccaagtggtg 720 tccctcatga agtccctggc acaggggggc cgtaccatca tctgcaccat ccaccagccc 780 agtgccaagc tctttgagat gtttgacaag ctctacatcc tgagccaggg tcagtgcatc 840 ttcaaaggcg tggtcaccaa cctgatcccc tatctaaagg gactcggctt gcattgcccc 900 acctaccaca acccggctga cttcgtcatc gaggtggcct ctggcgagta tggagacctg 960 aaccccatgt tgttcagggc tgtgcagaat gggctgtgcg ctatggctga gaagaagagc 1020 agccctgaga agaacgaggt ccctgcccca tgccctcctt gtcctccgga agtggatccc 1080 attgaaagcc acacctttgc caccagcacc ctcacacagt tctgcatcct cttcaagagg 1140 accttcctgt ccatcctcag ggacacggtg ctgacccacc tacggttcat gtcccacgtg 1200 gttattggcg tgctcatcgg cctcctctac ctgcatattg gcgacgatgc cagcaaggtc 1260 ttcaacaaca ccggctgcct cttcttctcc atgctgttcc tcatgttcgc cgccctcatg 1320 ccaactgtgc tcaccgtccc cttagagatg gcggtcttca tgagggagca cctcaactac 1380 tggtacagcc tcaaagcgta ttacctggcc aagaccatgg ctgacgtgcc ctttcaggtg 1440 gtgtgtccgg tggtctactg cagcattgtg tactggatga cgggccagcc cgctgagacc 1500 agccgcttcc tgctcttctc agccctggcc accgccaccg ccttggtggc ccaatctttg 1560 gggctgctga tcggagctgc ttccaactcc ctacaggtgg ccacttttgt gggcccagtt 1620 accgccatcc ctgtcctctt gttctccggc ttctttgtca gcttcaagac catccccact 1680 tacctgcaat ggagctccta tctctcctat gtcaggtatg gctttgaggg tgtgatcctg 1740 acgatctatg gcatggagcg aggagacctg acatgtttag aggaacgctg cccgttccgg 1800 gagccacaga gcatcctccg agcgctggat gtggaggatg ccaagctcta catggacttc 1860 ctggtcttgg gcatcttctt cctagccctg cggctgctgg cctaccttgt gctgcgttac 1920 cgggtcaagt cagagagata g 1941 <210> 36 <211> 4971 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473053CB1 <400> 36 caaagtagcg ggccgaggcc cgggggagcg gggccgcagc tgggggggcg ggagcccgtg 60 gggagccgag ccgagcgccc cccgccccag cccccggcat gggcagtacg gggccgccgg 120 ggcgggcgcc gagcgctgag cgctgagggt ctcccatggg attgctggga tcttgctggg 180 tgagatggca gtgtgtgcaa aaaagcgccc cccagaagaa gaaaggaggg cgcgggctaa 240 tgaccgagaa tacaatgaga aattccagta tgcgagtaac tgcatcaaga cctccaagta 300 caatattctc accttcctgc ctgtcaacct ctttgagcag ttccaggaag ttgccaacac 360 ttacttcctg ttcctcctca ttctgcagtt gatcccccag atctcttccc tgtcctggtt 420 caccaccatt gtgcctttgg ttcttgtcct caccatcaca gctgttaaag atgccactga 480 tgactatttc cgccacaaga gcgataacca ggtgaataac cgccagtctc aggtgctgat 540 caacggaatc ctccagcagg agcagtggat gaatgtctgt gttggtgata ttatcaagct 600 agaaaataac cagtttgtgg cggcggatct cctcctcctt tccagcagtg agccccatgg 660 gctgtgttac atagagacag cagaacttga tggcgagacc aacatgaaag tacgtcaggc 720 gattccagtc acctcagaat tgggagacat cagtaagctt gccaagtttg acggtgaagt 780 gatctgtgaa cctcccaaca acaaactgga caaattcagc ggaaccctct actggaagga 840 aaataagttc cctctgagca accagaacat gctgctgcgg ggctgtgtgc tgcgaaacac 900 cgagtggtgc ttcgggctgg tcatctttgc aggtcccgac actaagctga tgcaaaacag 960 cggcagaaca aagttcaaaa gaacgagtat cgatcgccta atgaataccc tggtgctctg 1020 gatttttgga ttcctggttt gcatgggggt gatcctggcc attggcaatg ccatctggga 1080 gcacgaggtg gggatgcgtt tccaggtcta cctgccgtgg gatgaggcag tggacagtgc 1140 cttcttctct ggcttcctct ccttctggtc ctacatcatc atcctcaaca ccgttgtgcc 1200 catttcactc tatgtcagtg tggaggtcat ccgtctgggc cacagctact tcatcaactg 1260 ggataagaag atgttctgca tgaagaagcg gacgcctgca gaagcccgca ccaccaccct 1320 aaacgaggag ctgggccagg tggagtacat cttctccgac aagacgggca ccctcaccca 1380 gaacatcatg gttttcaaca agtgctccat caatggccac agctatggtg atgtgtttga 1440 cgtcctggga cacaaagctg aattgggaga gaggcctgaa cctgttgact tctccttcaa 1500 tcctctggct gacaagaagt tcttattttg ggaccccagc ctgctggagg ctgtcaagat 1560 cggggacccc cacacgcatg agttcttccg cctcctttcc ctgtgtcata ctgtcatgtc 1620 agaagaaaag aacgaaggag agctgtacta caaagctcag tccccagatg agggggccct 1680 ggtcaccgca gccaggaact ttggttttgt tttccgctct cgcaccccca aaacaatcac 1740 cgtccatgag atgggcacag ccatcaccta ccagctgctg gccatcctgg acttcaacaa 1800 catccgcaag cggatgtcgg tcatagtgcg gaatccagag gggaagatcc gactctactg 1860 caaaggggct gacactatcc tactggacag actgcaccac tccactcaag agctgctcaa 1920 caccaccatg gaccacctta atgagtacgc aggggaaggg.ctgaggaccc tggtgctggc 1980 ctacaaggat ctggatgaag agtactatga ggagtgggct gagcgacgcc tccaggccag 2040 cctggcccag gacagccggg aggacaggct ggctagcatc tatgaggagg ttgagaacaa 2100 catgatgctg ctgggtgcaa cggccattga ggacaaactt cagcaagggg ttccagagac 2160 cattgccctc ctgacactgg ccaacatcaa gatttgggtg ctaaccggag acaagcaaga 2220 gacggctgtg aacatcggct attcctgcaa gatgctgacg gatgacatga ctgaggtttt 2280 catagtcact ggccatactg tcctggaggt gcgggaggag ctcaggaaag cccgggagaa 2340 gatgatggac tcatcccgct ctgtaggcaa cggcttcacc tatcaggaca agctttcttc 2400 ttccaagcta acttctgtcc tggaggccgt tgctggggag tacgccctgg tcataaatgg 2460 tcacagcctg gcccacgcac tggaggcaga catggagctg gagtttctgg agacagcgtg 2520 tgcctgcaaa gctgtcatct gctgccgggt gacccccttg cagaaggcac aggtggtaga 2580 actggtcaag aagtacaaga aggctgtgac gcttgccatt ggagacggag ccaatgatgt 2640 cagcatgatc aaaacggctc acattggtgt ggggatcagt gggcaggaag ggatccaggc 2700 tgtcttggcc tccgattact ccttctccca gttcaagttc ctgcagcgcc tcctgctggt 2760 gcatgggcgc tggtcctacc tgcgaatgtg caagtttctt tgctatttct tctacaaaaa 2820 ctttgctttc accatggtcc acttctggtt tggcttcttc tgtggcttct cagcccagac 2880 cgtctatgac cagtatttca tcaccctgta taacatcgtg tacacctccc tgccagtcct 2940 ggctatgggg gtctttgatc aggatgtccc cgagcagcgg agcatggagt accctaagct 3000 gtatgagccg ggccagctga accttctctt caacaagcgg gagttcttca tctgcatcgc 3060 ccagggcatc tacacctccg tgctcatgtt cttcattccc tatggggtgt ttgctgatgc 3120 cacccgggat gatggcactc agctggctga ctaccagtcc tttgcagtca ctgtggccac 3180 atccttggtc attgtggtta gcgtgcagat tgggctcgac acaggctact ggacggccat 3240 caaccacttc ttcatctggg gaagccttgc tgtttacttt gccatcctct ttgccatgca 3300 cagcaatggg ctcttcgaca tgtttcccaa ccagttccgg tttgtgggga atgcccagaa 3360 caccttggcc cagcccacgg tgtggctgac cattgtgctc accacagtcg tctgcatcat 3420 gcccgtggtt gccttccgat tcctcaggct caacctgaag ccggatctct ccgacacggt 3480 ccgctacaca cagctcgtga ggaagaagca gaaggcccag caccgctgca tgcggcgggt 3540 tggccgcact ggctcccggc gctccggcta tgccttctcc catcaggagg gcttcgggga 3600 gctcatcatg tctggcaaga acatgcggct gagctctctc gcgctctcca gcttcaccac 3660 ccgctccagc tccagctgga ttgagagcct gcgcaggaag aagagtgaca gtgccagtag 3720 ccccagtggc ggtgccgaca agcccctcaa gggctgaagg ccgaggatgg atgccctgtg 3780 ccagtgacca gagcacccag ggctggccag tcactgaggg aacagcgtct cggaactgct 3840 ggtcctcatt ccttgcttcc cgtccccccg gtagactctg tcctgctggt cccaccacac 3900 atggctggga catctgttcc cagctgtagg cccttccacc agctggggag ctagagggag 3960 caggcccaag ggcagagcag aggctgaggc acggggagcc agccccactc ggggaccaga 4020 agtggaacca aaaacaagaa aaaactgtga gagattgtgt ctgcccctgc cctgcctggg 4080 acccacaggg agactataat ctccttattt ttttactcct actccccaga ggggccctag 4140 tgcctctgtt cctgaattac ataagaatgt accatgccgg gaagccagag acctgcaggg 4200 gcctcggccc ctcacatcgt gtatgtctct ccttgatttg tgttgtgtcc agtttggttt 4260 tgtctttttt tatttggcaa gtggaggagg cttttatgtg acttttatgt tgtggttggt 4320 gtcttaactc tcctgggaaa aggaggctgg cacacactgg gatgccgcag cctggccggc 4380 tgtggggtgg tttgggagga tccatgtcgg ctctgcctgc agtgaccagt gctctgtggg 4440 gcagaggagc tgaccaggga gggaggtacc catgagcaga gggtagtggg agagtgtaaa 4500 ggagggtttg gtcctgtctg cttcctcacc ttgagagtaa agtgctgccc tctgccccca 4560 acacacacac atatcaattc ctggattcct tagtcctgct ggccttgggc tggagcctag 4620 gaaagtggcc cccaaatcct tagtgagcta aagctgggtc tgaaatttgg tcagtgggga 4680 ggggtagttt tcttttcttt tttctttttc tttttttctt tttttttttg agatggagtc 4740 tcactcttgt cacctaggca agagtgcaat ggcacaatct cagctcactg caacctccac 4800 ctcctgggtt caagcgattc tcctgcctcc ccggacccaa ccactggact taatctcact 4860 ttcttaaatt cttctattct cagacacggg tctagtacca ttccttcctc ttagccccag 4920 ggagcaaatt aaagaggtta cgagttaaaa tcctaaaaaa aaaaaaaaaa a 4971 <210> 37 <211> 1404 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473347CB1 <400> 37 atggtcctgg ctttccagtt agtctccttc acctacatct ggatcatatt gaaaccaaat 60 gtttgtgctg cttctaacat caagatgaca caccagcggt gctcctcttc aatgaaacaa 120 acctgcaaac aagaaactag aatgaagaaa gatgacagta ccaaagcgcg gcctcagaaa 180 tatgagcaac ttctccatat agaggacaac gatttcgcaa tgagacctgg atttggaggg 240 tctccagtgc cagtaggtat agatgtccat gttgaaagca ttgacagcat ttcagagact 300 aacatggact ttacaatgac tttttatctc aggcattact ggaaagacga gaggctctcc 360 tttcctagca cagcaaacaa aagcatgaca tttgatcata gattgaccag aaagatctgg 420 gtgcctgata tcttttttgt ccactctaaa agatccttca tccatgatac aactatggag 480 aatatcatgc tgcgcgtaca ccctgatgga aacgtcctcc taagtctcag gataacggtt 540 tcggccatgt gctttatgga tttcagcagg tttcctcttg acactcaaaa ttgttctctt 600 gaactggaaa gctatgccta caatgaggat gacctaatgc tatactggaa acacggaaac 660 aagtccttaa atactgaaga acatatgtcc ctttctcagt tcttcattga agacttcagt 720 gcatctagtg gattagcttt ctatagcagc acaggctggt acaataggct tttcatcatc 780 tctgtgctaa ggaggcatgt tttcttcttt gtgctgccaa cctattaccc agccatattg 840 atggtgatgc tttcatgggt ttcattttgg attgaccgaa gagctgttcc tgcaagagtt 900 tccctgggaa tcaccacagt gctgaccatg tccacaatca tcactgctgt gagcgcctcc 960 atgccccagg tgtcctacct caaggctgtg gatgtgtacc tgtgggtcag ctccctcttt 1020 gtgttcctgt cagtcattga gtatgcagct gtgaactacc tcaccacagt ggaagagcgg 1080 aaacaattca agaagacagg aaagatttct aggatgtaca atattgatgc agttcaagct 1140 atggcctttg atggttgtta ccatgacagc gagattgaca tggaccagac ttccctctct 1200 ctaaactcag aagacttcat gagaagaaaa tcgatatgca gccccagcac cgattcatct 1260 cggataaaga gaagaaaatc cctaggagga catgttggta gaatcattct ggaaaacaac 1320 catgtcattg acacctattc taggatttta ttccccattg tgtatatttt atttaatttg 1380 ttttactggg gtgtatatgt atga <220> 38 <211> 4048 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474240CB1 <400> 38 cttccatccc ccctcagcca ttccttactg ctctgggcaa ccgccaggtt aagcccattt 60 gcactgggaa attggcgctg tttgggagaa gagaaacaga tcgattgccc ttgtgactcc 120 ccgccccctt cccatcccca cccccaccgc tctctccctc tttccctccc ccgccacctc 180 ccctcacccc gcctccttcc cgttccccac ccccaaaccc tctcacccgc ggcagtccgg 240 tgcgaggccc cctccggaag gtgaggggaa tggattggac tccggtggag aaagcgggtg 300 tctagaagtg gtgctaatgg gaagagaatt ctggtttcaa aagaggatgc tctgccacaa 360 agagcggctc gcgcgctggc ctgggctcta gccgaggaga gatcccggga ggactccaga 420 gctccggggg agcgctcctc ggaagaccgg ggccaacatg cctgtgcgca gggggcatgt 480 ggcaccacaa aatacatttc tggggaccat cattcggaaa tttgaagggc aaaataaaaa 540 atttatcatt gcaaatgcca gagtgcagaa ctgtgccatc atttattgca acgatgggtt 600 ctgtgagatg actggtttct ccaggccaga tgtcatgcaa aagccatgca cctgcgactt 660 tctccatgga cccgagacca agaggcatga tattgcccaa attgcccagg cattgctggg 720 gtcagaagag aggaaagtgg aggtcaccta ctatcacaaa aatgggtcca cttttatttg 780 taacactcac ataattccag tgaaaaacca agagggcgtg gctatgatgt tcatcattaa 840 ttttgaatat gtgacggata atgaaaacgc tgccacccca gagagggtaa acccaatatt 900 accaatcaaa actgtaaacc ggaaattttt tgggttcaaa ttccctggtc tgagagttct 960 cacttacaga aagcagtcct taccacaaga agaccccgat gtggtggtca tcgattcatc 1020 taaacacagt gatgattcag tagccatgaa gcattttaag tctcctacaa aagaaagctg 1080 cagcccctct gaagcagatg acacaaaagc tttgatacag cccagcaaat gttctccctt 1140 ggtgaatata tccggacctc ttgaccattc ctctcccaaa aggcaatggg accgactcta 1200 ccctgacatg ctgcagtcaa gttcccagct gtcccattcc agatcaaggg aaagcttatg 1260 tagtatacgg agagcatctt cggtccatga tatagaagga ttcggcgtcc accccaagaa 1320 catatttaga gaccgacatg ccagcgaaga caatggtcgc aatgtcaaag ggccttttaa 1380 tcatatcaag tcaagcctcc tgggatccac atcagattca aacctcaaca aatacagcac 2440 cattaacaag attccacagc tcactctgaa tttttcagag gtcaaaactg agaaaaagaa 1500 ttcatcacct ccttcttcag ataaaaccat tattgcaccc aaggttaaag atcgaacaca 1560 caatgtgact gagaaagtga cccaggttct ctctttagga gcagatgtcc tacctgaata 1620 caaactgcag acaccacgca tcaacaagtt tacgatattg cactacagcc ctttcaaggc 1680 agtctgggac tggcttatcc tgctgttggt catatacact gctatattta ctccctactc 1740 tgcagccttc ctcctcaatg acagagaaga acagaaaaga cgagaatgtg gctattcttg 1800 tagccctttg aatgtggtag acttgattgt ggatattatg tttatcatag atattttaat 1860 aaacttcaga acaacatatg taaatcagaa tgaagaagtg gtaagtgatc ccgccaaaat 1920 agcaatacac tacttcaaag gctggttcct gattgacatg gttgcagcaa ttccttttga 1980 cttgctgatt tttggatcag gttctgatga gacaacaaca ttaattggtc ttttgaagac 2040 tgcccgactc ctccgtcttg tgcgcgtggc caggaaactg gatcgatatt cagaatatgg 2100 cgctgctgtt ctaatgctct taatgtgcat ctttgccctg attgctcact ggctggcttg 2160 catttggtat gcgattggga atgtagaaag gccttacctg actgacaaaa tcggatggtt 2220 ggattcctta ggacagcaaa ttgggaaacg ttacaatgac agtgactcaa gttctggacc 2280 atccattaaa gacaaatacg tcacagcact ttattttacc ttcagcagtt taaccagtgt 2340 aggattcggg aatgtgtctc ctaacacgaa ttcggagaaa atcttttcaa tttgtgtcat 2400 gttgattggc tcactaatgt atgcaagcat ttttgggaat gtatctgcaa ttatccaaag 2460 actatactcg ggaactgcca ggtaccacat gcagatgctg cgagtaaaag agttcattcg 2520 ctttcaccaa atccccaacc ctctgaggca acgtcttgaa gaatatttcc agcacgcatg 2580 gacttacacc aatggcattg acatgaacat ggtcctaaag ggtttcccag aatgcttaca 2640 agcagacatt tgtctacatc tcaaccagac attgctgcaa aactgcaaag cctttcgggg 2700 ggcaagtaaa ggttgcctta gagctttggc aatgaagttc aaaaccaccc atgcacctcc 2760 aggagacacc ctcgttcact gtggggatgt cctcactgca ctttatttct tatccagagg 2820 ctccattgaa attctcaaag atgacattgt ggtggctatt ctgggaaaaa atgatatatt 2880 tggagaaatg gttcatcttt atgccaaacc tggaaagtct aatgcagatg taagagccct 2940 cacatactgt gacttgcata agattcagcg agaagacttg ttagaggttt tggatatgta 3000 tcctgagttt tctgatcact ttctaacaaa cctagagttg actttcaacc taaggcatga 3060 gagcgcaaag gctgatctcc tacgatcaca atccatgaat gattcagaag gagacaactg 3120 taaactaaga agaaggaaat tgtcatttga aagtgaagga gagaaagaaa acagtacaaa 3180 tgatcctgaa gactctgcag ataccataag acattatcag agttccaaga gacactttga 3240 agagaaaaaa agcagatcct catctttcat ctcctccatt gatgatgaac aaaagccgct 3300 cttctcagga atagtagact cttctccagg aatagggaaa gcatctgggc tcgattttga 3360 agaaacagtg cccacctcag gaagaatgca catagataaa agaagtcact cttgcaaaga 3420 tatcactgac atgcgaagct gggaacgaga aaatgcacat ccccagcctg aagactccag 3480 tccatctgca cttcagcgag ctgcctgggg tatctctgaa accgaaagcg acctcaccta 3540 cggggaagtg gaacaaagat tagatctgct ccaggagcaa cttaacaggc ttgaatccca 3600 aatgaccact gacatccaga ccatcttaca gttgctgcag aaacaaacca ctgtggtccc 3660 cccagcctac agtatggtaa cagcaggatc agaatatcag agacccatca tccagctgat 3720 gagaaccagt caaccggaag catccatcaa aactgaccga agtttcagcc cttcctcaca 3780 atgtcctgaa tttctagacc ttgaaaaatc taaacttaaa tccaaagaat ccctttcaag 3840 tggggtgcat ctgaacacag cttcagaaga caacttgact tcacttttaa aacaagacag 3900 tgatctctct ttagagcttc acctgcggca aagaaaaact tacgttcatc caattaggca 3960 tccttctttg ccagattcat ccctaagcac tgtaggaatc gtgggtcttc ataggcatgt 4020 ttctgatcct ggtcttccag ggaaataa 4048 <210> 39 <211> 1539 <212> DNA
<213> Homo sapiens <220>

<221> misc_feature <223> Incyte TD No: 7475338CB1 <400> 39 atggagaaca aagaggcggg aacccctcca cccattccat ccagggaggg gcggctccag 60 ccgacgctgt tgctggcgac actgagcgcg gcctttggct cagccttcca gtacggctac 120 aacctctctg tggtcaacac gccgcacaag gtgttcaagt cattttacaa cgaaacctac 180 tttgagcgac acgcaacatt catggacggg aagctcatgc tgcttctatg gtcttgcacc 240 gtctccatgt ttcctctggg cggcctgttg gggtcattgc tcgtgggcct gctggttgat 300 agctgcggca ggaaggggac cctgctgatc aacaacatct ttgccatcat ccccgccatc 360 ctgatgggag tcagcaaagt ggccaaggct tttgagctga tcgtcttttc ccgagtggtg 420 ctgggagtct gtgcaggtat ctcctacagc gcccttccca tgtacctggg agaactggcc 480 cccaagaacc tgagaggcat ggtgggaaca atgaccgagg ttttcgtcat cgttggagtc 540 ttcctagcac agatcttcag cctccaggcc atcttgggca acccggcagg ttggccggtg 600 cttctggcgc tcacaggggt gcccgccctg ctgcagctgc tgaccctgcc cttcttcccc 660 gaaagccccc gctactccct gattcagaaa ggagatgaag ccacagcgcg acaagctctg 720 aggaggctga gaggccacac ggacatggag gccgagctgg aggacatgcg tgcggaggcc 780 cgggccgagc gcgccgaggg ccacctgtct gtgctgcacc tctgtgccct gcggtccctg 840 cgctggcagc tcctctccat catcgtgctc atggccggcc agcagctgtc gggcatcaat 900 gcgatcaact actatgcgga caccatctac acatctgcgg gcgtggaggc cgctcactcc 960 caatatgtaa cggtgggctc tggcgtcgtc aacatagtga tgaccatcac ctcggctgtc 1020 cttgtggagc ggctgggacg gcggcacctc ctgctggccg gctacggcat ctgcggctct 1080 gcctgcctgg tgctgacggt ggtgctccta ttccagaaca gggtccccga gctgtcctac 2140 ctcggcatca tctgtgtctt tgcctacatc gcgggacatt ccattgggcc cagtcctgtc 1200 ccctcggtgg tgaggaccga gatcttcctg cagtcctccc ggcgggcagc tttcatggtg 1260 gacggggcag tgcactggct caccaacttc atcataggct tcctgttccc atccatccag 1320 gaggccatcg gtgcctacag tttcatcatc tttgccggaa tctgcctcct cactgcgatt 1380 tacatctacg tggttattcc ggagaccaag ggcaaaacat ttgtggagat aaaccgcatt 1440 tttgccaaga gaaacagggt gaagcttcca gaggagaaag aagaaaccat tgatgctggg 1500 cctcccacag cctctcctgc caaggaaact tccttttag 1539 <210> 40 <221> 3114 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7476747CB1 <400> 40 ccaagcagtg cctcacttct gccttgtcta gctgtactct ggaaaattaa gaaatttatg 60 agtgtagcac caagtatacc aatgggaagg atgggagtca gaagtcaagt gaactcagcc 120 cgcctctgtg tactttgcac ttttccattt cccttggtac caggcacttt catacttaat 180 ccatagtgga gctgtcacag tgagcaactc tgacaatgac agcttctacc ccagaggcga 240 ccccaaacat ggagctaaag gctccagctg caggaggtct taatgctggc cctgtccccc 300 cagctgccat gtccacgcag agacttcgga atgaagacta ccacgactac agctccacgg 360 acgtgagccc tgaggagagc ccgtcggaag gcctcaacaa cctctcctcc ccgggctcct 420 accagcgctt tggtcaaagc aatagcacaa catggttcca gaccttgatc cacctgttaa 480 aaggcaacat tggcacagga ctcctgggac tccctctggc ggtgaaaaat gcaggcatcg 540 tgatgggtcc catcagcctg ctgatcatag gcatcgtggc cgtgcactgc atgggtatcc 600 tggtgaaatg tgctcaccac ttctgccgca ggctgaataa atcctttgtg gattatggtg 660 atactgtgat gtatggacta gaatccagcc cctgctcctg gctccggaac cacgcacact 720 ggggaagacg tgttgtggac ttcttcctga ttgtcaccca gctgggattc tgctgtgtct 780 attttgtgtt tctggctgac aactttaaac aggtgataga agcggccaat gggaccacca 840 ataactgcca caacaatgag acggtgattc tgacgcctac catggactcg cgactctaca 900 tgctctcctt cctgcccttc ctggtgctgc tggttttcat caggaacctc cgagccctgt 960 ccatcttctc cctgttggcc aacatcacca tgctggtcag cttggtcatg atctaccagt 1020 tcattgttca gaggatccca gaccccagcc acctcccctt ggtggcccct tggaagacct 1080 accctctctt ctttggcaca gcgatttttt catttgaagg cattggaatg gttctgcccc 1140 tggaaaacaa aatgaaggat cctcggaagt tcccactcat cctgtacctg ggcatggtca 1200 tcgtcaccat cctctacatc agcctggggt gtctggggta cctgcaattt ggagctaata 1260 tccaaggcag cataaccctc aacctgccca actgctggtt gtaccagtca gttaagctgc 2320 tgtactccat cgggatcttt ttcacctacg cactccagtt ctacgtcccg gctgagatca 1380 tcatcccctt ctttgtgtcc cgagcgcccg agccctgtga gttagtggtg gacctgtttg 1440 tgcgcccagt gctggtctgc ctgacatcac tgtctggcag tgttgacaat ggctggtatg 1500 gcacggaagc cgatggcacc tcctgcggca gtgcaccatt ggtcttcgtc agttcctcct 1560 tcctggctca cccgtggctg agtttcagat gtgagagcca gtgggtgtcc tgtcacagag 1620 atacggtcgt cgtgtggggc ttcgccaggg gcatcttggc catcctcatc ccccgcctgg 1680 acctggtcat ctccctggtg ggctccgtga gcagcagcgc cctggccctc atcatcccac 1740 cgctcctgga ggtcaccacc ttctactcag agggcatgag ccccctcacc atctttaagg 1800 acgccctgat cagcatcctg ggcttcgtgg gctttgtggt ggggacctat gaggctctct 1860 atgagctgat ccagccaagc aatgctccca tcttcatcaa ttccacctgt gccttcatat 1920 agggatctgg gttcgtctct gcagctgcct acccctgccc catgtgtccc ccgttacctg 1980 tcctcagagc ctcaggtatg gtccaggctc tgaggaaagt cagggttgct gtgtgggaac 2040 ccctctgcct ggcacctgga taccctgggc caggtaacct gagggcagtg gagaggtggg 2100 gtggcagaca cgcagaagtg ctactagtga cagggctgcc atcgctcacc tgtacctatt 2160 tacacccaga actttccagc tccccctcat catgcctcct ccttcctacc tgcctcccct 2220 ctgctggtgc acctcgccca actcattctt actgcacagt tcactttatt taacaatttt 2280 catgtccccc acctcatgtt ttcacctttt ctgggccagg catagattaa gtaactggga 2340 acgccccctc tttataaagc tgggcttctt tctcatctct ctcccaaatg ttgtatctca 2400 gtattcttcc tattcgagtc tccagggggt ggctggacct acctggtcat ttgaaacagg 2460 cccccaagct ggagttttta atctggactc tctggcttgc tgtgacccct aaggcaatgc 2520 ttctcttccc tggattcctt agtgtgggtc acagtactgt gttcttagtt gctttagctc 2580 ttaaaacata cgaagtgttg cctaaactga aaatatttat cttttattta aaatcagatt 2640 tttgttttta gactgtctta gatctggggc tattacgaat cacttcttct tcagtaaact 2700 ttgactcaac ttctcctgct gaaaagaagc tcgctccaga tgtctgcatg ggtcctcggc 2760 actcttggct gaggactcaa aggttttaat caggatcgtc taaaaatgta cctcggtgag 2820 gaggcacaga ttttgcctcc tgttgaccag cctggtttca taccgaaaag acattgaagg 2880 actgcagaaa tgtatgggtg caccgggccg agggaagggt ggctgagtga gaggcgtata 2940 aaatggggct gtgtgcatgc aggcccatgt ttcagcctca gcccacgcca ggtgaaagga 3000 tcagcaatgc tctgttgcca tcgtgctggg acgacaccag ctctattgcc accgatgagt 3060 agctgaggtc agtgtgcaca gagtttgaaa ttaagttaat agactttaca gcag 3114 <210> 41 <211> 2877 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477898CB1 <400> 41 atgccggtcc gcaggggcca cgtcgctccc caaaacactt acctggacac catcatccgc 60 aagttcgagg gccaaagtcg gaagttcctg attgccaatg ctcagatgga gaactgcgcc 120 atcatttact gcaacgacgg cttctgcgaa ctcttcggct actcccgagt ggaggtgatg 180 cagcaaccct gcacctgcga cttcctcaca ggccccaaca caccaagcag cgccgtgtcc 240 cgcctagcgc aggccctgct gggggctgag gagtgcaagg tggacatcct ctactaccgc 300 aaggatgcct ccagcttccg ctgcctggta gatgtggtgc ccgtgaagaa cgaggacggg 360 gctgtcatca tgttcattct caacttcgag gacctggccc agctcctggc caagtgcagc 420 agccgcagct tgtcccagcg cctgttgtcc cagagcttcc tgggctccga gggctctcat 480 ggcaggccag gcggaccagg gccaggcaca ggcaggggca agtacaggac catcagccag 540 atcccacagt tcacgctcaa cttcgtggag ttcaacttgg agaagcaccg ctccagctcc 600 accacggaga ttgagatcat cgcgccccat aaggtggtgg agcggacaca gaacgtcact 660 gagaaggtca cccaggtcct gtccctgggc gcggatgtgc tgccggagta caagctgcag 720 gcgccgcgca tccaccgctg gaccatcctg cactacagcc ccttcaaggc cgtgtgggac 780 tggctcatcc tgctgctggt catctacacg gctgtcttca cgccctactc agccgccttc 840 ctgctcagcg atcaggacga atcacggcgt ggggcctgca gctatacctg cagtcccctc 900 actgtggtgg atctcatcgt ggacatcatg ttcgtcgtgg acatcgtcat caacttccgc 960 accacctatg tcaacaccaa tgatgaggtg gtcagccacc cccgccgcat cgccgtccac 1020 tacttcaagg gctggttcct cattgacatg gtggccgcca tccctttcga cctcctgatc 1080 ttccgcactg gctccgatga gaccacaacc ctgattgggc tattgaagac agcgcggctg 1140 ctgcggctgg tgcgcgtagc acggaagctg gaccgctact ctgagtatgg ggcggctgtg 1200 ctcttcttgc tcatgtgcac ctttccgctc atagcgcact ggctggcctg catctggtac 1260 gccatcggca atgtggagcg gccctaccta gaacacaaga tcggctggct ggacagcctg 1320 ggtgtgcagc ttggcaagcg ctacaacggc agcgacccag cctcgggccc ctcggtgcag 1380 gacaagtatg tcacagccct ctacttcacc ttcagcagcc tcaccagcgt gggcttcggc 1440 aatgtctcgc ccaacaccaa ctccgagaag gtcttctcca tctgcgtcat gctcatcggc 1500 tccctgatgt acgccagcat cttcgggaac gtgtccgcga tcatccagcg cctgtactcg 1560 ggcaccgcgc gctaccacac gcagatgctg cgtgtcaagg agttcatccg cttccaccag 1620 atceccaacc cactgcgcca gcgcctggag gagtatttcc agcacgcctg gtcctacacc 1680 aatggcattg acatgaacgc ggtgctgaag ggcttccccg agtgcctgca ggctgacatc 1740 tgcctgcacc tgcaccgcgc actgctgcag cactgcccag ctttcagcgg cgccggcaag 1800 ggctgcctgc gcgcgctagc cgtcaagttc aagaccaccc acgcgccgcc tggggacacg 1860 ctggtgcacc tcggcgacgt gctctccacc ctctacttca tctcccgagg ctccatcgag 1920 atcctgcgcg acgacgtggt cgtggccatc ctaggaaaga atgacatctt tggggaaccc 2980 gtcagcctcc atgcccagcc aggcaagtcc agtgcagacg tgcgggctct gacctactgc 2040 gacctgcaca agatccagcg ggcagatctg ctggaggtgc tggacatgta cccggccttt 2100 gcggagagct tctggagtaa gctggaggtc accttcaacc tgcgggacgt aaccgggggt 2160 ctccactcat ccccccgaca ggctcctggc agccaagacc accaaggttt ctttctcagt 2220 gacaaccagt cagatgcagc ccctcccctg agcatctcag atgcattctg gctctggcct 2280 gagctactgc aggaaatgcc cccaaagcac agcccccaaa gccctcagga agacccagat 2340 tgctggcctc tgaagctggg ctccaggcta gagcagctcc aggcccagat gaacaggctg 2400 gagtcccgcg tgtcctcaga cctcagccgc atcttgcagc tcctccagaa gcccatgccc 2460 cagggccacg ccagctacat tctggaagcc cctgcctcca atgacctggc cttggttcct 2520 atagcctcgg agacgacgag tccagggccc aggctgcccc agggctttct gcctcctgca 2580 cagaccccaa gctatggaga cttggatgac tgtagtccaa agcacaggaa ctcctccccc 2640 aggatgcctc acctggctgt ggcaatggac aaaactctgg caccatcctc agaacaggaa 2700 cagcctgagg ggctctggcc acccctagcc tcacctctac atcccctgga agtacaagga 2760 ctcatctgtg gtccctgctt ctcctccctc cctgaacacc ttggctctgt tcccaagcag 2820 ctggacttcc agagacatgg ctcagatcct ggatttgcag ggagttgggg ccactga 2877 <210> 42 <211> 2820 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472728CB1 <400> 42 atggggcatc aagggccatt tgaagaagga aatggtggac tgagagtgat agcgacctgg 60 aggaggaagg aggcttggag aagggactgt cttttaggag ccctgcccag tgtttcctgt 120 ggagggtggg gccatcgtgg aagacagacc tatggtaggg cttgtggggt gaaagaaaag 180 ccctttagtc ttttgggtcc tcaaatcaca gtttatgcag tttggcccca gtcagaggga 240 ccccaggaag gcagactcag ggtaaattct gcctgtcttc caccagagag gggactcacc 300 aacgcttgta caaaccatga agaactctct ttggactgtt tgctttttga gaatgttaac 360 accttgactc tggatttctg cctatgggaa aaaaccacaa tagtgccagg ggtgcttcca 420 tatgcaggat taactctgca gtcaaagttt ctgttgggca gagcattgtt agcaggggtc 480 catgtgatca cactgacacc tgagagagtg acacaccatg tacatggctg gtatatggag 540 gatggattta agggggacag gactgaaggc tgtcgcagtg attcagtggc cgttcccgca 600 gcagcaccgg tgtgccagcc caagagcgcc actaacgggc aacccccggc tccggctccg 660 actccaactc cgcgcctgtc catttcctcc cgagccacag tggtagccag gatggaaggc 720 acctcccaag ggggcttgca gaccgtcatg aagtggaaga cggtggttgc catctttgtg 780 gttgtggtgg tctaccttgt cactggcggt cttgtcttcc gggcattgga gcagcccttt 840 gagagcagcc agaagaatac catcgccttg gagaaggcgg aattcctgcg ggatcatgtc 900 tgtgtgagcc cccaggagct ggagacgttg atccagcatg ctcttgatgc tgacaatgcg 960 ggagtcagtc caataggaaa ctcttccaac aacagcagcc actgggacct cggcagtgcc 1020 tttttctttg ctggaactgt cattacgacc atgtatggga atattgctcc gagcactgaa 1080 ggaggcaaaa tcttttgtat tttatatgcc atctttggaa ttccactctt tggtttctta 1140 ttggctggaa ttggagacca acttggaacc atctttggga aaagcattgc aagagtggag 1200 aaggtctttc gaaaaaagca agtgagtcag accaagatcc gggtcatctc aaccatcctg 1260 ttcatcttgg ccggctgcat tgtgtttgtg acgatccctg ctgtcatctt taagtacatc 1320 gagggctgga cggccttgga gtccatttac tttgtggtgg tcactctgac cacggtgggc 1380 tttggtgatt ttgtggcagt ggttgttttc aggggaaacg ctggcatcaa ttatcgggag 1440 tggtataagc ccctagtgtg gttttggatc cttgttggcc ttgcctactt tgcagctgtc 1500 ctcagtatga tcggagattg gctacgggtt ctgtccaaaa agacaaaaga agaggtgggt 1560 gaaatcaagg cccatgcggc agagtggaag gccaatgtca cggctgagtt ccgggagaca 1620 cggcgaaggc tcagcgtgga gatccacgat aagctgcagc gggcagccac catccgcagc 1680 atggagcgcc ggcggctggg cctggaccag cgggcccact cactggacat gctgtccccc 2740 gagaagcgct ctgtctttgc tgccctggac accggccgct tcaaggcctc atcccaggag 1800 agcatcaaca accggcccaa caacctgcgc ctgaaggggc cggagcagct gaacaagcat 1860 gggcagggtg cgtccgagga caacatcatc aacaagttcg ggtccacctc cagactcacc 1920 aagaggaaaa acaaggacct caaaaagacc ttgcccgagg acgttcagaa aatctacaag 1980 accttccgga attactccct ggacgaggag aagaaagagg aggagacgga aaagatgtgt 2040 aactcagaca actccagcac agccatgctg acggactgta tccagcagca cgctgagttg 2100 gagaacggaa tgatacccac ggacaccaaa gaccgggagc cggagaacaa ctcattactt 2160 gaagacagaa actaaatgtg aaggacattg gtcttggact gagcgttgtg tgtgtgtgtg 2220 tgtgtgtgtt tttaatattc acactgagac atgtgcctta aacagacttt ttagtccaaa 2280 attacatagc attgaagaat atatttcact gtgccataaa caactgaaag cttgctctgc 2340 caaaaggaat cagagaacaa gaacttcatt tcagatagca aacgcaggac acaccaagag 2400 tgtccgtgca cgtagccggt tctggccgta catgttaagg gcatttcagt ggcagtgctg 2460 tacccctggg cagtgctacc tgggcacaca cgtagacaag ggcagctatt ccttagacca 2520 gcctcctgaa agaaacaggt gtgtcttttt agtggagtcg tagtaatatg tgcacacaca 2580 gaaggggacc tgattgggtg ggagctggtt atgtgtaact agcgttggag ttgacatttt 2640 ggcatgtgct ctgagcttga attttgatac caaccattca gtgcatcata cctagtcttt 2700 ctatgctcca aatgaatgtc tgtggggacc tgagagcacc tggaatttgt tggaagcaga 2760 tcagagcaca cgtacgaaaa ggtgcaattc cttttctcat gacaaaaggg aaaaaaataa 2820 <210> 43 <211> 1440 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474322CB1 <220>
<221> unsure <222> 757 <223> a, t, c, g, or other <400> 43 atgtacaatg agattctgat gctgggggcc aaactgcacc cgacgctgaa gctggaggag 60 ctcaccaaca agaagggaat gacgccgctg gctctggcag ctgggaccgg gaagatcggg 120 aatcgccacg acatgctctt ggtggagccg ctgaaccgac tcctgcagga caagtgggac 180 agattcgtca agcgcatctt ctacttcaac ttcctggtct actgcctgta catgatcatc 240 ttcaccatgg ctgcctacta caggcccgtg gatggcttgc ctccctttaa gatggaaaaa 300 actggagact atttccgagt tactggagag atcctgtctg tgttaggagg agtctacttc 360 tttttccgag ggattcagta tttcctgcag aggcggccgt cgatgaagac cctgtttgtg 420 gacagctaca gtgagatgct tttgtttctg cagtcactgt tcatgctggc caccgtggtg 480 ctgtacttca gccacctcaa ggagtatgtg gcttccatgg tattctccct ggccttgggc 540 tggaccaaca tgctctacta cacccgcggt ttccagcaga tgggcatcta tgccgtcatg &00 atagagaaga tgatcctgag agacctgtgc cgtttcatgt ttgtctacat cgtcttcttg 660 ttcgggtttt ccacagcggt ggtgacgctg attgaagacg ggaagaatga ctccctgccg 720 tctgagtcca cgtcgcacag gtggcggggg cctgctngca ggcccaatag ctcctacaac 780 agcctgtact ccacctgcct ggagctgttc aagttcacca tcggcatggg cgacctggag 840 ttcactgaga actatgactt caaggctgtc ttcatcatcc tgctgctggc ctatgtaatt 900 ctcacctaca tagttctcct cctcaacatg ctcattgctc tgatgggcga gactgtggag 960 aacgtctcca aggagagcga acgcatctgg cgcctgcaga gagccatcac catcctggac 1020 acggagaaga gcttccttaa gtgcatgagg aaggccttcc gctcaggcaa gctgctgcag 1080 gtggggtaca cacctgatgg caaggacgac taccggtggt gcttcgtgga cgaggtgaac 1140 tggaccacct ggaacaccaa cgtgggcatc atcaacgaag acccgggcaa ctgtgagggc 1200 gtcaagcgca ccctgagctt ctccctgcgg tcaagcagag tttcaggcag acactggaag 1260 aactttgccc tggtccccct tttaagagag gcaagtgctc gagataggca gtctgctcag 1320 cccgaggaag tttatctgcg acagttttca gggtctctga agccagagga cgctgaggtt 1380 ttcaagagtc ctgccgcttc cggggagaag tgaggacgtc acgcagacag cactgtcaac 1440 <210> 44 <211> 2394 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 5455&21CB1 <400> 44 atttcagaac acatctgaat tccttctctg tggcatatgc tttaggagag gagcagacag 60 ctcttagcta gggtcagatt tcaaattctc atctcttggt gccaatacca ccaccagatt 120 cttctttgaa gtcaactttt gagatcttca ctaagtacac gttggtgtct gaagattcac 180 acgagtgcct ctggtaatca ttttcttcag ggaatcacag tctctcctct cagcaaagca 240 tccactgtac tgaactttgc ttttggaaac atcttcttcc tgagacctcg ttgaaagaaa 300 ctctctggtg tcatactttc caatatggag gtgaagaact ttgcagtttg ggattatgtt 360 gtatttgcag ccctcttttt catttcctct ggaattgggg tgttctttgc cattaaggag 420 agaaaaaagg caacttcccg agagttcctg gttgggggaa ggcaaatgag ctttggccct 480 gtcggcttgt ctctgacagc cagcttcatg tcagctgtca cggtcctggg gaccccttct 540 gaagtctacc gctttggggc atccttccta gtcttcttca ttgcttacct atttgtcatc 600 ctcttaacat cagagctctt tctccctgtg ttctacagat ctggtatcac cagcacttat 660 gagtacttac aactacgatt caacaaacca gttcgctatg ctgccacagt catctacatt 720 gtacagacga ttctctacac aggagtggtg gtgtatgctc ctgccctggc actcaatcaa 780 gtgactgggt ttgatctctg gggctctgtg tttgcaacag gaattgtttg cacattctac 840 tgtaccctgg gaggattaaa agcagtggtg tggacagatg catttcagat ggttgtcatg 900 attgtgggct tcttaacggt tctcattcaa ggatcaactc atgctggggg attccacaat 960 gtattagagc aatcaacaaa tggatctcga ctacatatat ttgactttga tgtagatcct 1020 ctcaggcgac acactttttg gactatcaca gtgggaggaa cttttacttg gctcggaatc 1080 tatggggtca atcaatcaac tattcagcga tgcatctctt gcaaaacaga aaagcatgct 1140 aagcttgcct tgtattttaa cttgctgggt ctctggatca ttctggtgtg tgctgtcttc 1200 tctggcttaa tcatgtactc tcactttaaa gactgtgacc cttggacttc tggcatcatc 1260 tcagcaccag accagctgat gccgtacttt gtcatggaga tatttgccac aatgccagga 1320 ctgccaggac tttttgtggc ttgtgccttc agtggaactc tgagcaccgt ggcttccagc 1380 atcaatgcct tggcaacagt gacctttgag gattttgtca agagctgttt tcctcatctc 1440 tccgacaagc tgagcacctg gatcagtaaa ggcttatgtc tcttatttgg cgtgatgtgt 1500 acctctatgg ctgtggctgc atctgtcatg ggaggtgttg tgcaggcttc cctcagcatt 1560 cacggcatgt gtggaggacc aatgctgggc ttattctccc tgggaatcgt gttccctttt 1620 gtgaactgga agggtgcact aggaggtctt cttactggaa tcaccttgtc attttgggtg 1680 gccattgggg ccttcattta ccctgcacca gcctctaaga catggccttt gcctctatca 1740 acagaccaat gtatcaaatc aaatgtgaca gcaacagggc ctccagtact atccagcaga 1800 cctggaatag ctgatacctg gtactcgatc tcctaccttt actacagtgc actgggctgc 1860 ttaggatgca ttgttgctgg agtaatcatc agcctcataa caggtcgcca aagaggtgag 1920 gatattcaac cactgttaat tagaccagtt tgtaatttat tttgcttttg gtctaagaag 1980 tacaaaacac tatgctggtg tggagttcag catgacagtg ggacagagca ggaaaacctt 2040 gagaatggca gtgcccggaa acagggggct gaatctgtct tacagaacgg actcagaaga 2100 gaaagcctgg tacatgttcc aggctatgat cctaaggaca aaagctacaa caatatggca 2160 tttgagacta cccatttcta aggcaatacc tgtatgaatg cacacacaca cgtgcaatac 2220 acacacacac acacaaactc cacatacttc ttgcctactt gttagtagat atgtatagtt 2280 gccattgcta gaagacaggg atgtctggtg cctatttcta cttatttata actacatgca 2340 aaatgactgt ctctcgggat attctttgaa agactccaac tttcacagag aaaa 2394 <210> 45 <211> 2890 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477248CB1 <400> 45 gaatactaag ccagggcaga atgcttgtga agtagcaact aaagtggcag tgtttcttct 60 gaaattctca ggcagtcaga ctgtcttagg caaatcttga taaaatagcc cttatccagg 120 tttttatcta aggaatccca agaagactgg ggaatggaga gacagtcaag ggttatgtca 180 gaaaaggatg agtatcagtt tcaacatcag ggagcggtgg agctgcttgt cttcaatttt 240 ttgctcatcc ttaccatttt gacaatctgg ttatttaaaa atcatcgatt ccgcttcttg 300 catgaaactg gaggagcaat ggtgtatggc cttataatgg gactaatttt acgatatgct 360 acagcaccaa ctgatattga aagtggaact gtctatgact gtgtaaaact aactttcagt 420 ccatcaactc tgctggttaa tatcactgac caagtttatg aatataaata caaaagagaa 480 ataagtcagc acaacatcaa tcctcatcaa ggaaatgcta tacttgaaaa gatgacattt 540 gatccagaaa tcttcttcaa tgttttactg ccaccaatta tatttcatgc aggatatagt 600 ctaaagaaga gacacttttt tcaaaactta ggatctattt taacgtatgc cttcttggga 660 actgccatct cctgcatcgt catagggtta attatgtatg gttttgtgaa ggctatgata 720 catgctggcc agctgaaaaa tggagacttt catttcactg actgtttatt ttttggttca 780 ctgatgtctg ctacagatcc agtgacagtg ctggccattt tccatgaact gcacgtcgac 840 cctgacctgt acacactctt gtttggagag agtgtgttga atgatgcagt ggccatagtc 900 cttacatatt ctatatccat ttacagtccc aaggagaatc caaatgcatt tgatgccgca 960 gcattcttcc agtctgtggg gaatttcctg ggaatcttcg ctggctcatt tgcaatgggg 1020 tctgcgtatg ccatcatcac agcactgttg accaaattta ccaagctgtg tgagttcccg 1080 atgctggaaa ccggcctgtt tttcctgctt tcttggagtg ccttcctgtc tgccgaggct 1140 gccggcctaa cagggatagt tgctgttctc ttctgtggag tcacacaagc acattatacc 1200 tacaacaatc tgtcttcgga ttccaaaata agaactaaac agttgtttga atttatgaac 1260 tttttggcgg agaacgtcat cttctgttac atgggcctgg cactgttcac gttccagaat 1320 catatcttta atgctctttt tatacttgga gcctttctag caatttttgt tgccagagcc 1380 tgcaacatat atcccctctc cttcctcctg aatctaggcc gaaaacagaa gatcccctgg 1440 aactttcagc acatgatgat gttttcaggt ttgcgaggag cgatcgcatt tgccttagct 1500 attcggaaca cagaatctca gcccaaacaa atgatgttta ccactacgct gctcctcgtg 1560 ttcttcactg tctgggtatt tggaggagga acaaccccca tgttgacttg gcttcagatc 1620 agagttggcg tggacctgga tgaaaatctg aaggaggacc cctcctcaca acaccaggaa 1680 gcaaataact tggataaaaa catgacgaaa gcagagagtg ctcggctctt cagaatgtgg 1740 tatagctttg accacaagta tctgaaacca attttaaccc actctggtcc tccgctgact 1800 acaacattac ctgaatggtg tggtccgatt tccaggctgc ttaccagtcc tcaagcctat 1860 ggggaacagc taaaagagga tgatgtggaa tgcattgtaa accaggatga actagccata 1920 aattaccagg agcaagcctc ctcaccctgc agtcctcctg caaggctagg tctggaccag 1980 aaagcttcac cccagacgcc aggcaaggaa aacatttatg agggagacct cggccctggg 2040 aggctatgaa ctcaagcttg agcaaacttt gggtcaatcc cagttgaatt aattggcatg 2100 aagagtacag atgtaatcac aagtaatgca agactcactg aggaatacaa gccaagctga 2160 tgaggcagta caggggagag gctggaaaac atattaagag cataaattgg agagaatcaa 2220 agccttgtca catggatcct ctggtgcctg aagaaatgag attttattat ccctctctat 2280 tatgcaaatg aatttagttt tttgacagca gccattctga ttactggatt ggctggggtg 2340 gggatggagg tatcaggagt ctagctgctg gaggatggga cagctgtgct gggtcttcag 2400 ggcatttctg ctgcgaatgc ggctctccag gcccttcact tctattctgg attttattcc 2460 ctccattaag gagagtttaa aaataaaaga aagcttctga gagtaaacat tttgctccta 2520 agctgaaggg aatgcccagc tatttagtaa gtgataagtt tcttattttg aggacttgac 2580 tcccatttgc tctcagtgac cccagggcag agcccagaga agtgttccgt acccactgct 2640 gatggtttcc cagagcccac actgagttga agaacctatt gttcttcttg gcatccttct 2700 tatgctactt ctcccatcgc tcaaaggggt tgcctatggc tgggtgtgcc ctgccctaaa 2760 tgcagcacca ctttcaagca gcttctagct atagctttcc accaggtatt tttaatccca 2820 tttcacctcc tcccccagca attcaccagt caggagtgat ttttactgta aagatggttg 2880 cttagtaaaa 2890 <210> 46 <211> 3926 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 2944004CB1 <400> 46 ctggaccttt aatccactgt aggtatggac agggaagaaa ggaagaccat caatcagggt 60 caagaagatg aaatggagat ttatggttac aatttgagtc gctggaagct tgccatagtt 120 tctttaggag tgatttgctc tggtggggtt tctcctcctc ctctctattg gatgcctgag 180 tggcgggtga aagcgacctg tgtcagagct gcaattaaag actgtgaagt agtgctgctg 240 aggactactg atgaattcaa aatgtggttt tgtgcaaaaa ttcgcgttct ttctttggaa 300 acttacccag tttcaagtcc aaaatctatg tctaataagc tttcaaatgg ccatgcagtt 360 tgtttaattg agaatcccac tgaagaaaat aggcacagga tcagtaaata ttcacagact 420 gaatcacaac agattcgtta tttcacccac catagtgtaa aatatttctg gaatgatacc 480 attcacaatt ttgatttctt aaagggactg gatgaaggtg tttcttgtac gtcaatttat 540 gaaaagcata gtgcaggact gacaaagggg atgcatgcct acagaaaact gctttatgga 600 gtaaatgaaa ttgctgtaaa agtgccttct gtttttaagc ttctaattaa agaggttctc 660 aacccatttt acattttcca gctgttcagt gttatactgt ggagcactga tgaatactat 720 tactatgctc tagctattgt ggttatgtcc atagtatcaa tcgtaagctc actatattcc 780 attagaaagc aatatgttat gttgcatgac atggtggcaa ctcatagtac cgtaagagtt 840 tcagtttgta gagtaaatga agaaatagaa gaaatctttt ctaccgacct tgtgccagga 900 gatgtcatgg tcattccatt aaatgggaca ataatgcctt gtgatgctgt gcttattaat 960 ggtacctgca ttgtaaacga aagcatgtta acaggagaaa gtgttccagt gacaaagact 1020 aatttgccaa atccttcagt ggatgtgaaa ggaataggag atgaattata taatccagaa 1080 acacataaac gacatacttt gttttgtggg acaactgtta ttcagactcg tttctacact 1140 ggagaactcg tcaaagccat agttgttaga acaggattta gtacttccaa aggacagctt 1200 gttcgttcca tattgtatcc caaaccaact gattttaaac tctacagaga tgcctacttg 1260 tttctactat gtcttgtggc agttgctggc attgggttta tctacactat tattaatagc 1320 attttaaatg aggtacaagt tggggtcata attatcgagt ctcttgatat tatcacaatt 1380 actgtgcccc ctgcacttcc tgctgcaatg actgctggta ttgtgtatgc tcagagaaga 1440 ctgaaaaaaa tcggtatttt ctgtatcagt cctcaaagaa taaatatttg tggacagctc 1500 aatcttgttt gctttgacaa gactggaact ctaactgaag atggtttaga tctttggggg 1560 attcaacgag tggaaaatgc acgatttctt tcaccagaag aaaatgtgtg caatgagatg 1620 ttggtaaaat cccagtttgt tgcttgtatg gctacttgtc attcacttac aaaaattgaa 1680 ggagtgctct ctggtgatcc acttgatctg aaaatgtttg aggctattgg atggattctg 1740 gaagaagcaa ctgaagaaga aacagcactt cataatcgaa ttatgcccac agtggttcgt 1800 69!87 cctcccaaac aactgcttcc tgaatctacc cctgcaggaa accaagaaat ggagctgttt 1860 gaacttccag ctacttatga gataggaatt gttcgccagt tcccattttc ttctgctttg 1920 caacgtatga gtgtggttgc cagggtgctg ggggatagga aaatggacgc ctacatgaaa 1980 ggagcgcccg aggccattgc cggtctctgt aaacctgaaa cagttcctgt cgattttcaa 2040 aacgttttgg aagacttcac taaacagggc ttccgtgtga ttgctcttgc acacagaaaa 2100 ttggagtcaa aactgacatg gcataaagta cagaatatta gcagagatgc aattgagaac 2160 aacatggatt ttatgggatt aattataatg cagaacaaat taaagcaaaa aacccctgca 2220 gtacttgaag atttgcataa agccaacatt cgcaccgtca tggtcacagg tgacagtatg 2280 ttgactgctg tctctgtggc cagagattgt ggaatgattc tacctcagga taaagtgatt 2340 attgctgaag cattacctcc aaaggatggg aaagttgcca aaataaattg gcattatgca 2400 gactccctca cgcagtgcag tcatccatca gcaattgacc cagaggctat tccggttaaa 2460 ttggtccatg atagcttaga ggatcttcaa atgactcgtt atcattttgc aatgaatgga 2520 aaatcattct cagtgatact ggagcatttt caagaccttg ttcctaagtt gatgttgcat 2580 ggcaccgtgt ttgcccgtat ggcacctgat cagaagacac agttgataga agcattgcaa 2640 aatgttgatt attttgttgg gatgtgtggt gatggcgcaa atgattgtgg tgctttgaag 2700 agggcacacg gaggcatttc cttatcggag ctcgaagctt cagtggcatc tccctttacc 2760 tctaagactc ctagtatttc ctgtgtgcca aaccttatca gggaaggccg tgctgcttta 2820 ataacttcct tctgtgtgtt taaattcatg gcattgtaca gcattatcca gtacttcagt 2880 gttactctgc tgtattctat cttaagtaac ctaggagact tccagtttct cttcattgat 2940 ctggcaatca ttttggtagt ggtatttaca atgagtttaa atcctgcctg gaaagaactt 3000 gtggcacaaa gaccaccttc gggtcttata tctggggccc ttctcttctc cgttttgtct 3060 cagattatca tctgcattgg atttcaatct ttgggttttt tttgggtcaa acagcaacct 3120 tggtatgaag tgtggcatcc aaaatcagat gcttgtaata caacaggaag cgggttttgg 3180 aattcttcac acgtagacaa tgaaaccgaa cttgatgaac ataatataca aaattatgaa 3240 aataccacag tgttttttat ttccagtttt cagtacctca tagtggcaat tgccttttca 3300 aaaggaaaac ccttcaggca accttgctac aaaaattatt tttttgtttt ttctgtgatt 3360 tttttatata tttttatatt attcatcatg ttgtatccag ttgcctctgt tgaccaggtt 3420 cttcagatag tgtgtgtacc atatcagtgg cgtgtaacta tgctcatcat tgttcttgtc 3480 aatgcctttg tgtctatcac agtggagaac ttcttccttg acatggtcct ttggaaagtt 3540 gtgttcaacc gagacaaaca aggagagtat cggttcagca ccacacagcc accgcaggag 3600 tcagtggatc ggtggggaaa atgctgctta ccctgggccc tgggctgtag aaagaagaca 3660 ccaaaggcaa agtacatgta tctggcgcag gagctcttgg ttgatccaga atggccacca 3720 aaacctcaga caaccacaga agctaaagct ttagttaagg agaatggatc atgtcaaatc 3780 atcaccataa catagcagtg aatcagtctc agtggtattg ctgatagcag tattcaggaa 3840 tatgtgattt taggagtttc tgatcctgtg tgtcagaatg gcactagttc agtttatgtc 3900 ccttctgata tagtagctta tttgac 3926 <220> 47 <211> 2135 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Tncyte ID No: 3046849CB1 <400> 47 cgctcaggcc cctctttcga atgctccacg ccctcctgcg atctagaacg attcagggca 60 ggatcctgct cctgaccatc tgcgctgccg gcattggtgg gacttttcag tttggctata 120 acctctctat catcaatgcc ccgaccttgc acattcagga attcaccaat gagacatggc 180 aggcgcgtac tggagagcca ctgcccgatc acctagtcct gcttatgtgg tccctcatcg 240 tgtctctgta tcccctggga ggcctctttg gagcactgct tgcaggtccc ttggccatca 300 cgctgggaag gaagaagtcc ctcctggtga ataacatctt tgtggtgtca gcagcaatcc 360 tgtttggatt cagccgcaaa gcaggctcct ttgagatgat catgctggga agactgctcg 420 tgggagtcaa tgcaggtgtg agcatgaaca tccagcccat gtacctgggg gagagcgccc 480 ctaaggagct ccgaggagct gtggccatga gctcagccat ctttacggct ctggggatcg 540 tgatgggaca ggtggtcgga ctcagggagc tcctaggtgg ccctcaggcc tggcccctgc 600 tgctggccag ctgcctggtg cccggggcgc tccagctcgc ctccctgcct ctgctccctg 660 aaagcccgcg ctacctcctc attgactgtg gagacaccga ggcctgcctg gcagcactac 720 ggcagctacg gggctccggg gacttggcag gggagctgga ggagctggag gaggagcgcg 780 ctgcctgcca gggctgccgt gcccggcgcc catgggagct gttccagcat cgggccctga 840 ggagacaggt gacaagcctc gtggttctgg gcagtgccat ggagctctgc gggaatgact 900 cggtgtacgc ctacgcctcc tccgtgttcc ggaaggcagg agtgccggaa gcgaagatcc 960 agtacgcgat catcgggact gggagctgcg agctgctcac ggcggttgtt agttgtgtgg 1020 taatcgagag ggtgggtcgg cgcgtgctgc tcatcggtgg gtacagcctg atgacctgct 1080 gggggagcat cttcactgtg gccctgtgcc tgcagagctc cttcccctgg acactctacc 1140 tggccatggc ctgcatcttt gccttcatcc tcagctttgg cattggccct gccggagtga 1200 cggggatcct ggccacagag ctgtttgacc agatggccag gcctgctgcc tgcatggtct 1260 gcggggcgct catgtggatc atgctcatcc tggtcggcct gggatttccc tttatcatgg 1320 aggccttgtc ccacttcctc tatgtccctt tccttggtgt ctgtgtctgt ggggccatct 1380 acactggcct gttccttcct gagaccaaag gcaagacctt ccaagagatc tccaaggaat 1440 tacacagact caacttcccc aggcgggccc agggccccac gtggaggagc ctggaggtta 1500 tccagtcaac agaactctag tcccaaaggg gtggccagag ccaaagccag ctactgtcct 1560 gtcctctgct tcctgccagg gccctggtcc tcactccctc ctgcattcct catttaagga 1620 gtgtttattg agcacccttt gtgtgcagac atggctccag gtgcttagca atcaatggtg 1680 agcgtggtat tccaggctaa aggtaattaa ctgacagaaa atcagtaaca acataattac 1740 aggctggttg tggcagctca tgactgtaat cccagcactt tgggaggcca aggtgggagg 1800 atcaattgag gccagagttt gaaaccagcc taggtaacat agtgagaccc cctatctcta 1860 caaaaaattt taaacattag ctgggcatgg tggtatgtgc taacagctct agctactcag 1920 gaggctgagg cagcaggatc acttgagtcc caagagttca aggtagcagt aagctaacaa 1980 ttcacaccac tgcatgccca gactggggtg acagagggag acttcatctc tttaaaaaca 2040 taataataat aattacggac tccggaaatg cgttgacaac gaaacatacc ggtggccccg 2100 tgaggtggtg atcccgtatc ccagccttgg gaagc 2135 <210> 48 <211> 2637 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4538363CB1 <400> 48 atgggctgga gatgccactg tccgcttggt ttaatgatca atgagctccc tgccaggaaa 60 ccctttctga cctggtttgc ccctcagtcc ctcgggctca tacctagtgc ctgcggcagg 120 acagccatgg ccgccaactc caccagcgac ctccacactc ccgggacgca gctgagcgtg 180 gctgacatca tcgtcatcac tgtgtatttt gctctgaacg tggccgtggg catatggtcc 240 tcttgtcggg ccagtaggaa cacggtgaat ggctacttcc tggcaggccg ggacatgacg 300 tggtggccga ttggagcctc cctcttcgcc agcagcgagg gctctggcct cttcattgga 360 ctggcgggct caggcgcggc aggaggtctg gccgtggcag gcttcgagtg gaatgccacg 420 tacgtgctgc tggcactggc atgggtgttc gtgcccatct acatctcctc agagatcgtc 480 accttacctg agtacattca gaagcgctac gggggccagc ggatccgcat gtacctgtct 540 gtcctgtccc tgctactgtc tgtcttcacc aagatatcgc tggacctgta cgcgggggct 600 ctgtttgtgc acatctgcct gggctggaac ttctacctct ccaccatcct cacgctcggc 660 atcacagccc tgtacaccat cgcagggggc ctggctgctg taatctacac ggacgccctg 720 cagacgctca tcatggtggt gggggctgtc atcctgacaa tcaaagcttt tgaccagatc 780 ggtggttacg ggcagctgga ggcagcctac gcccaggcca ttccctccag gaccattgcc 840 aacaccacct gccacctgcc acgtacagac gccatgcaca tgtttcgaga cccccacaca 900 ggggacctgc cgtggaccgg gatgaccttt ggcctgacca tcatggccac ctggtactgg 960 tgcaccgacc aggtcatcgt gcagcgatca ctgtcagccc gggacctgaa ccatgccaag 1020 gcgggctcca tcctggccag ctacctcaag atgctcccca tgggcctgat catcatgccg 1080 ggcatgatca gccgcgcatt gttcccagat gatgtgggct gcgtggtgcc gtccgagtgc 1140 ctgcgggcct gcggggccga ggtcggctgc tccaacatcg cctaccccaa gctggtcatg 1200 gaactgatgc ccatcggtct gcgggggctg atgatcgcag tgatgctggc ggcgctcatg 1260 tcgtcgctga cctccatctt caacagcagc agcaccctct tcactatgga catctggagg 1320 cggctgcgtc cccgctccgg cgagcgggag ctcctgctgg tgggacggct ggtcatagtg 1380 gcactcatcg gcgtgagtgt ggcctggatc cccgtcctgc aggactccaa cagcgggcaa 1440 ctcttcatct acatgcagtc agtgaccagc tccctggccc caccagtgac tgcagtcttt 1500 gtcctgggcg tcttctggcg acgtgccaac gagcaggggg ccttctgggg cctgatagca 1560 gggctggtgg tgggggccac gaggctggtc ctggaattcc tgaacccagc cccaccgtgc 1620 ggagagccag acacgcggcc agccgtcctg gggagcatcc actacctgca cttcgctgtc 1680 gccctctttg cactcagtgg tgctgttgtg gtggctggaa gcctgctgac cccaccccca 1740 cagagtgtcc agattgagaa ccttacctgg tggaccctgg ctcaggatgt gcccttggga 1800 actaaagcag gtgatggcca aacaccccag aaacacgcct tctgggcccg tgtctgtggc 1860 ttcaatgcca tcctcctcat gtgtgtcaac atattctttt atgcctactt cgcctgaaca 1920 ctgccatcct ggacagaaag gcaggagctc tgagtcctca ggtccaccca tttccctcat 1980 ggggatcccg aggccccaag aggggcagat tcccctcaca gctgcacagc agctcggtgc 2040 ccaagaactg gccaagccag caaagcggga gcctgaaaac attagggggg aaactgggac 2100 gaaacataag tgtgactttt tccaaacaac agcacccaaa gcaagtcaag catttggaac 2160 gcgacaaact tagattttcc tgaccgggcc caccacaccc caacctcctc acctcccaaa 2220 ctaccaacac agctcatcac catactcaca ccacccacag cggcccgccc ccactccaat 2280 cagaaaggca cccccccact ctcaagacgc gacggcgcaa tcgactgcaa ctccataacg 2340 atgccaaaac gacacaagcc aggacacggc actgtataca gcacgagggt gatctgcaac 2400 gttgtggccg aatgcagaaa atacactggg tgctggcgta aggaagatcc gcgagtaaac 2460 aacggtcttg taaacttact gcatccacca aggtacactt ccagaacgag accagacaac 2520 tacactccac acaacctgca gccacaccct atttctgcta tcataaagag cccccgcacc 2580 acataataat gccggcagac tcagtgcgcg aaacccttgt gctggacttc accacgg 2637 <210> 49 <211> 3783 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 6427460CB1 <400> 49 gcactagtac cccggagccc atgggcgcgc cgagccgggc gcgggggcgc tgaacggcgg 60 agcgggagcg gccggaggag ccatggactg cagcctcgtg cggacgctcg tgcacagata 120 ctgtgcagga gaagagaatt gggtggacag caggaccatc tacgtgggac acagggagcc 180 acctccgggc gcagaggcct acatcccaca gagataccca gacaacagga tcgtctcgtc 240 caagtacaca ttttggaact ttatacccaa gaatttattt gaacaattca gaagagtagc 300 caacttttat ttccttatca tatttctggt gcagttgatt attgatacac ccacaagtcc 360 agtgacaagc ggacttccac tcttctttgt cattactgtg acggctatca aacagggtta 420 tgaagactgg cttcgacata aagcagacaa tgccatgaac eagtgtcctg ttcatttcat 480 tcagcacggc aagctcgttc ggaaacaaag tcgaaagctg cgagttgggg acattgtcat 540 ggttaaggag gacgagacct ttccctgcga cttgatcttc ctttccagca accggggaga 600 tgggacgtgc cacgtcacca ccgccagctt ggatggagaa tccagccata aaacgcatta 660 cgcggtccag gacaccaaag gcttccacac agaggaggat atcggcggac ttcacgccac 720 catcgagtgt gagcagcccc agcccgacct ctacaagttc gtgggtcgca tcaacgttta 780 cagtgacctg aatgaccccg tggtgaggcc cttaggatcg gaaaacctgc tgcttagagg 840 agctacactg aagaacactg agaaaatctt tggtgtggct atttacacgg gaatggaaac 900 caagatggca ttaaattatc aatcaaaatc tcagaagcga tctgccgtgg aaaaatcgat 960 gaatgcgttc ctcattgtgt atctctgcat tctgatcagc aaagccctga taaacactgt 1020 gctgaaatac gtgtggcaga gtgagccctt tcgggatgag ccgtggtata atcagaaaac 1080 ggagtcggaa aggcagagga atctgttcct caaggcattc acggacttcc tggccttcat 1140 ggtcctcttt aactacatca tccctgtgtc catgtacgtc acggtcgaga tgcagaagtt 1200 cctcggctct tacttcatca cctgggacga agacatgttt gacgaggaga ctggcgaggg 1260 gcctctggtg aacacgtcgg acctcaatga agagctggga caggtggagt acatcttcac 1320 agacaagacc ggcaccctca cggaaaacaa catggagttc aaggagtgct gcatcgaagg 1380 ccatgtctac gtgccccacg tcatctgcaa cgggcaggtc ctcccagagt cgtcaggaat 1440 cgacatgatt gactcgtccc ccagcgtcaa cgggagggag cgcgaggagc tgtttttccg 1500 ggccctctgt ctctgccaca ccgtccaggt gaaagacgat gacagcgtag acggccccag '1560 gaaatcgccg gacgggggga aatcctgtgt gtacatctca tcctcgcccg acgaggtggc 1620 gctggtcgaa ggtgtccaga gacttggctt tacctaccta aggctgaagg acaattacat 1680 ggagatatta aacagggaga accacatcga aaggtttgaa ttgctggaaa ttttgagttt 1740 tgactcagtc agaaggagaa tgagtgtaat tgtaaaatct gctacaggag aaatttatct 1800 gttttgcaaa ggagcagatt cttcgatatt cccccgagtg atagaaggca aagttgacca 1860 gatccgagcc agagtggagc gtaacgcagt ggaggggctc cgaactttgt gtgttgctta 1920 taaaaggctg atccaagaag aatatgaagg catttgtaag ctgctgcagg ctgccaaagt 1980 ggcccttcaa gatcgagaga aaaagttagc agaagcctat gagcaaatag agaaagatct 2040 tactctgctt ggtgctacag ctgttgagga ccggctgcag gagaaagctg cagacaccat 2100 cgaggccctg cagaaggccg ggatcaaagt ctgggttctc acgggagaca agatggagac 2160 ggccgcggcc acgtgctacg cctgcaagct cttccgcagg aacacgcagc tgctggagct 2220 gaccaccaag aggatcgagg agcagagcct gcacgacgtc ctgttcgagc tgagcaagac 2280 ggtcctgcgc cacagcggga gcctgaccag agacaacctc tccggacttt cagcagatat 2340 gcaggactac ggtttaatta tcgacggagc tgcactgtct ctgataatga agcctcgaga 2400 agacgggagt tccggcaact acagggagct cttcctggaa atctgccgga gctgcagcgc 2460 ggtgctctgc tgccgcatgg cgcccttgca gaaggctcag attgttaaat taatcaaatt 2520 ttcaaaagag cacccaatca cgttagcaat tggcgatggt gcaaatgatg tcagcatgat 2580 tctggaagcg cacgtgggca taggtgtcat cggcaaggaa ggccgccagg ctgccaggaa 2640 cagcgactat gcaatcccaa agtttaagca tttgaagaag atgctgcttg ttcacgggca 2700 tttttattac attaggatct ctgagctcgt gcagtacttc ttctataaga acgtctgctt 2760 catcttccct cagtttttat accagttctt ctgtgggttt tcacaacaga ctttgtacga 2820 caccgcgtat ctgaccctct acaacatcag cttcacctcc ctccccatcc tcctgtacag 2880 cctcatggag cagcatgttg gcattgacgt gctcaagaga gacccgaccc tgtacaggga 2940 cgtcgccaag aatgccctgc tgcgctggcg cgtgttcatc tactggacgc tcctgggact 3000 gtttgacgca ctggtgttct tctttggtgc ttatttcgtg tttgaaaata caactgtgac 3060 aagcaacggg cagatatttg gaaactggac gtttggaacg ctggtattca ccgtgatggt 3120 gttcacagtt acactaaagc ttgcattgga cacacactac tggacttgga tcaaccattt 3180 tgtcatctgg gggtcgctgc tgttctacgt tgtcttttca cttctctggg gaggagtgat 3240 ctggccgttc ctcaactacc agaggatgta ctacgtgttc atccagatgc tgtccagcgg 3300 gcccgcctgg ctggccatcg tgctgctggt gaccatcagc ctccttcccg acgtcctcaa 3360 gaaagtcctg tgccggcagc tgtggccaac agcaacagag agagtccagc agaatgggtg 3420 cgcacagcct cgggaccgcg actcagaatt cacccctctt gcctctctgc agagcccagg 3480 ctaccagagc acctgtccct cggccgcctg gtacagctcc cactctcagc aggtgacact 3540 cgcggcctgg aaggagaagg tgtccacgga gcccccaccc atcctcggcg gttcccatca 3600 ccactgcagt tccatcccaa gtcacagctg ccctaggtcc cgtgtgggaa tgctcgtgtg 3660 atggatggtc ctaagcctgt ggagactgtg cacgtgcctc ttcctggccc ccagcaggca 3720 aggagggggg tcacaggcct tgccctcgaa catggcaccc tggccgcctg gacccagcac 3780 tgt 3783 <210> 50 <211> 2105 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7474127CB1 <400> 50 ccagcgccca gggaagcggc tcaaccacct gaatccggaa aacgccaaca agtagtttct 60 cgtcggagaa gggcggctca cctgggcgcc aagactcagt cccgctgccc agagaacctc 120 gtccactcgg aaaccaaagc agaaccactt ttctctcggt ctcgttaagt catgtctgag 180 tcacagagat gggcaagatc gagaacaacg agagggtgat cctcaatgtc gggggcaccc 240 ggcacgaaac ctaccgcagc accctcaaga ccctgcctgg aacacgcctg gcccttcttg 300 cctcctccga gcccccaggc gactgcttga ccacggcggg cgacaagctg cagccgtcgc 360 cgcctccact gtcgccgccg ccgagagcgc ccccgctgtc ccccgggcca ggcggctgct 420 tcgagggcgg cgcgggcaac tgcagttccc gcggcggcag ggccagcgac catcccggtg 480 gcggccgcga gttcttcttc gaccggcacc cgggcgtctt cgcctatgtg ctcaattact 540 accgcaccgg caagctgcac tgccccgcag acgtgtgcgg gccgctcttc gaggaggagc 600 tggccttctg gggcatcgac gagaccgacg tggagccctg ctgctggatg acctaccggc 660 agcaccgcga cgccgaggag gcgctggaca tcttcgagac ccccgacctc attggcggcg 720 accccggcga cgacgaggac ctggcggcca agaggctggg catcgaggac gcggcggggc 780 tcgggggccc cgacggcaaa tctggccgct ggaggaggct gcagccccgc atgtgggccc 840 tcttcgaaga cccctactcg tccagagccg ccaggtttat tgcttttgct tctttattct 900 tcatcctggt ttcaattaca actttttgcc tggaaacaca tgaagctttc aatattgtta 960 aaaacaagac agaaccagtc atcaatggca caagtgttgt tctacaatat gaaattgaaa 1020 cagatcctgc cttgacgtat gtagaaggag tgtgtgtggt gtggtttact tttgaatttt 1080 tagtccgtat tgttttttca cccaataaac ttgaattcat caaaaatctc ttgaatatca 1140 ttgactttgt ggccatccta cctttctact tagaggtggg actcagtggg ctgtcatcca 1200 aagctgctaa agatgtgctt ggcttcctca gggtggtaag gtttgtgagg atcctgagaa 1260 ttttcaagct cacccgccat tttgtaggtc tgagggtgct tggacatact cttcgagcta 1320 gtactaatga atttttgctg ctgataattt tcctggctct aggagttttg atatttgcta 1380 ccatgatcta ctatgccgag agagtgggag ctcaacctaa cgacccttca gctagtgagc 1440 acacacagtt caaaaacatt cccattgggt tctggtgggc tgtagtgacc atgactaccc 1500 tgggttatgg ggatatgtac ccccaaacat ggtcaggcat gctggtggga gccctgtgtg 1560 ctctggctgg agtgctgaca atagccatgc cagtgcctgt cattgtcaat aattttggaa 1620 tgtactactc cttggcaatg gcaaagcaga aacttccaag gaaaagaaag aagcacatcc 1680 ctcctgctcc tcaggcaagc tcacctactt tttgcaagac agaattaaat atggcctgca 1740 atagtacaca gagtgacaca tgtctgggca aagacaatcg acttctggaa cataacagat 1800 cagtgttatc aggtgacgac agtacaggaa gtgagccgcc actatcaccc ccagaaaggc 1860 tccccatcag acgctctagt accagagaca aaaacagaag aggggaaaca tgtttcctac 1920 tgacgacagg tgattacacg tgtgcttctg atggagggat caggaaaggt tatgaaaaat 1980 cccgaagctt aaacaacata gcgggcttgg caggcaatgc tctgaggctc tctccagtaa 2040 catcacccta caactctcct tgtcctctga ggcgctctcg atctcccatc ccatctatct 2100 tgtaa 2105 <210> 51 <211> 2069 <212> DNA
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 7476949CB1 <400> 51 atgagcaagg acctggcagc aatggggcct ggagcttcag gggacggggt caggactgag 60 acagctccac acatagcact ggactccaga gttggtctgc acgcctacga catcagcgtg 120 gtggtcatct actttgtctt cgtcattgct gtggggatct ggtcgtccat ccgtgcaagt 180 cgagggacca ttggcggcta tttcctggcc gggaggtcca tgagctggtg gccaattgga 240 gcatctctga tgtccagcaa tgtgggcagt ggcttgttca tcggcctggc tgggacaggg 300 gctgccggag gccttgccgt aggtggcttc gagtggaacg caacctggct gctcctggcc 360 cttggctggg tcttcgtccc tgtgtacatc gcagcaggtg tggtcacaat gccgcagtat 420 ctgaagaagc gatttggggg ccagaggatc caggtgtaca tgtctgtcct gtctctcatc 480 ctctacatct tcaccaagat ctcgactgac atcttctctg gagccctctt catccagatg 540 gcattgggct ggaacctgta cctctccaca gggatcctgc tggtggtgac tgccgtctac 600 accattgcag gtggcctcat ggccgtgatc tacacagatg ctctgcagac ggtgatcatg 660 gtagggggag ccctggtcct catgtttctg ggctttcagg acgtgggctg gtacccaggc 720 ctggagcagc ggtacaggca ggccatccct aatgtcacag tccccaacac cacctgtcac 780 ctcccacggc ccgatgcttt ccacattctt cgggaccctg tgagcgggga catcccttgg 840 ccaggtctca ttttcgggct cacagtgctg gccacctggt gttggtgcac agaccaggtc 900 attgtgcagc ggtctctctc ggccaagagt ctgtctcatg ccaagggagg ctccgtgctg 960 gggggctacc tgaagatcct ccccatgttc ttcatcgtca tgcctggcat gatcagccgg 1020 gccctgttcc cagacgaggt gggctgcgtg gaccctgatg tctgccaaag aatctgtggg 1080 gcccgagtgg gatgttccaa cattgcctac cctaagttgg tcatggccct catgcctgtt 1140 ggtctgcggg ggctgatgat tgccgtgatc atggccgctc tcatgagctc actcacctcc 1200 atcttcaaca gcagcagcac cctgttcacc attgatgtgt ggcagcgctt ccgcaggaag 1260 tcaacagagc aggagctgat ggtggtgggc agagtgtttg tggtgttcct ggttgtcatc 1320 agcatcctct ggatccccat catccaaagc tccaacagtg ggcagctctt cgactacatc 1380 caggctgtca ccagttacct ggccccaccc atcaccgctc tcttcctgct ggccatcttc 1440 tgcaagaggg tcacagagcc cggagctttc tggggcctcg tgtttggcct gggagtgggg 1500 cttctgcgta tgatcctgga gttctcatac ccagcgccag cctgtgggga ggtggaccgg 1560 aggccagcag tgctgaagga cttccactac ctgtactttg caatcctcct ctgcgggctc 1620 actgccatcg tcattgtcat tgtcagcctc tgtacaactc ccatccctga ggaacagctc 1680 acacgcctca catggtggac tcggaactgc cccctctctg agctggagaa ggaggcccac 1740 gagagcacac cggagatatc cgagaggcca gccggggagt gccctgcagg aggtggagcg 1800 gcagagaact cgagcctggg ccaggagcag cctgaagccc caagcaggtc ctggggaaag 1860 ttgctctgga gctggttctg tgggctctct ggaacaccgg agcaggccct gagcccagca 1920 gagaaggctg cgctagaaca gaagctgaca agcattgagg aggagccact ctggagacat 1980 gtctgcaaca tcaatgctgt ccttttgctg gccatcaaca tcttcctctg gggctatttt 2040 gcgtgattca aacctggctt cactgtaga 2069 <210> 52 <211> 4245 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477249CB1 <400> 52 gcggcggcag gctcagctgc gccgggcggg ggcggcgctg gggccgcgcc tgtaggactc 60 ggggccgacg ccgcgggatg gggacgcggc gcggggagtg aggcagtggc ggcggcggcg 120 gtaagcggaa cttcggcccg aggggctcgc ccgctcccgc ctctgtcttg tcggcctcca 180 cctgcagccc cgcggccccc gcgccccgcg ggacccggac ggcgacgacg ggggaatgtg 240 gcgctggatc cggcagcagc tgggttttga cccaccacat cagagtgaca caagaaccat 300 ctacgtagcc aacaggtttc ctcagaatgg cctttacaca cctcagaaat ttatagataa 360 caggatcatt tcatctaagt acactgtgtg gaattttgtt ccaaaaaatt tatttgaaca 420 gttcagaaga gtggcaaact tttattttct tattatattt ttggttcagc ttatgattga 480 tacacctacc agtccagtta ccagtggact tccattattc tttgtgataa cagtaactgc 540 cataaagcag ggatatgaag attggttacg gcataactca gataatgaag taaatggagc 600 tcctgtttat gttgttcgaa gtggtggcct tgtaaaaact agatcaaaaa acattcgggt 660 gggtgatatt gttcgaatag ccaaagatga aatttttcct gcagacttgg tgcttctgtc 720 ctcagatcga ctggatggtt cctgtcacgt tacaactgct agtttggacg gagaaactaa 780 cctgaagaca catgtggcag ttccagaaac agcattatta caaacagttg ccaatttgga 840 cactctagta gctgtaatag aatgccagca accagaagca gacttataca gattcatggg 900 acgaatgatc ataacccaac aaatggaaga aattgtaaga cctctggggc cggagagtct 960 cctgcttcgt ggagccagat taaaaaacac aaaagaaatt tttggtgttg cggtatacac 1020 tggaatggaa actaagatgg cattaaatta caagagcaaa tcacagaaac gatctgcagt 1080 agaaaagtca atgaatacat ttttgataat ttatctagta attcttatat ctgaagctgt 1140 catcagcact atcttgaagt atacatggca agctgaagaa aaatgggatg aaccttggta 1200 taaccaaaaa acagaacatc aaagaaatag cagtaaggta gagtacgtgt ttacagataa 1260 aactggtaca ctgacagaaa atgagatgca gtttcgggaa tgttcaatta atggcatgaa 1320 ataccaagaa attaatggta gacttgtacc cgaaggacca acaccagact cttcagaagg 1380 aaacttatct tatcttagta gtttatccca tcttaacaac ttatcccatc ttacaaccag 1440 ttcctctttc agaaccagtc ctgaaaatga aactgaacta attaaagaac atgatctctt 1500 ctttaaagca gtcagtctct gtcacactgt acagattagc aatgttcaaa ctgactgcac 1560 tggtgatggt ccctggcaat ccaacctggc accatcgcag ttggagtact atgcatcttc 1620 accagatgaa aaggctctag tagaagctgc tgcaaggatt ggtattgtgt ttattggcaa 1680 ttctgaagaa actatggagg ttaaaactct tggaaaactg gaacggtaca aactgcttca 1740 tattctggaa tttgattcag atcgtaggag aatgagtgta attgttcagg caccttcagg 1800 tgagaagtta ttatttgcta aaggagctga gtcatcaatt ctccctaaat gtataggtgg 1860 agaaatagaa aaaaccagaa ttcatgtaga tgaatttgct ttgaaagggc taagaactct 1920 gtgtatagca tatagaaaat ttacatcaaa agagtatgag gaaatagata aacgcatatt 1980 tgaagccagg actgccttgc agcagcggga agagaaattg gcagctgttt tccagttcat 2040 agagaaagac ctgatattac ttggagccac agcagtagaa gacagactac aagataaagt 2100 tcgagaaact attgaagcat tgagaatggc tggtatcaaa gtatgggtac ttactgggga 2160 taaacatgaa acagctgtta gtgtgagttt atcatgtggc cattttcata gaaccatgaa 2220 catccttgaa cttataaacc agaaatcaga cagcgagtgt gctgaacaat tgaggcagct 2280 tgccagaaga attacagagg atcatgtgat tcagcatggg ctggtagtgg atgggaccag 2340 cctatctctt gcactcaggg agcatgaaaa actatttatg gaagtttgca gaaattgttc 2400 agctgtatta tgctgtcgta tggctccact gcagaaagca aaagtaataa gactaataaa 2460 aatatcacct gagaaaccta taacattggc tgttggtgat ggtgctaatg acgtaagcat 2520 gatacaagaa gcccatgttg gcataggaat catgggtaaa gaaggaagac aggctgcaag 2580 aaacagtgac tatgcaatag ccagatttaa gttcctctcc aaattgcttt ttgttcatgg 2640 tcatttttat tatattagaa tagctaccct tgtacagtat tttttttata agaatgtgtg 2700 ctttatcaca ccccagtttt tatatcagtt ctactgtttg ttttctcagc aaacattgta 2760 tgacagcgtg tacctgactt tatacaatat ttgttttact tccctaccta ttctgatata 2820 tagtcttttg gaacagcatg tagaccctca tgtgttacaa aataagccca ccctttatcg 2880 agacattagt aaaaaccgcc tcttaagtat taaaacattt ctttattgga ccatcctggg 2940 cttcagtcat gcctttattt tcttttttgg atcctattta ctaataggga aagatacatc 3000 tctgcttgga aatggccaga tgtttggaaa ctggacattt ggcactttgg tcttcacagt 3060 catggttatt acagtcacag taaagatggc tctggaaact catttttgga cttggatcaa 3120 ccatctcgtt acctggggat ctattatatt ttattttgta ttttccttgt tttatggagg 3180 gattctctgg ccatttttgg gctcccagaa tatgtatttt gtgtttattc agctcctgtc 3240 aagtggttct gcttggtttg ccataatcct catggttgtt acatgtctat ttcttgatat 3300 cataaagaag gtctttgacc gacacctcca ccctacaagt actgaaaagg cacagcttac 3360 tgaaacaaat gcaggtatca agtgcttgga ctccatgtgc tgtttcccgg aaggagaagc 3420 agcgtgtgca tctgttggaa gaatgctgga acgagttata ggaagatgta gtccaaccca 3480 catcagcagg tgtgaaatct ctctaagtag cctttgctgc agatgagtat cctatctgga 3540 acaggatgaa cctgccgctc tagataccta ataaatcagc agctggtttt accaactgaa 3600 gcaggaagtc tgctatttat tagcactctt tggtggtaga tttcactttg tggctttggg 3660 gtaagggctt tttcactcac aaaggaagag aaagcacctt tgaagagact tcatctaatg 3720 aacaaaaaat tttgtttcat aatctttcta aaatgtgctc agtaggagtg tgtttatggt 3780 actcttttat ggtttgtata actttctttt ttaaattata catatactat ttccttttta 3840 tttttttaaa atttttttgc tttttgtctt tacaaaataa tctcaacata acagtgaagt 3900 caaaggcttt ccttttctta ctctgtatgt atattttcca gttggttatt tgaggctttg 3960 aggtatttat aaacacaaaa ggctgtattt ctgctcccct acctcttctt atgtctgtaa 4020 tgaagttttg aaatgagtca tgatttttaa gtttcttttg cttggtattt attgcctaat 4080 taaaagtgta tgagttagaa caggcttttt aaattatgga gtaaaagaat cttagcattt 4140 ttgtcccctc ctaaatctgt ttcttgaatg agatttatca ccatgcctgc tgttgtgcac 4200 cataacgaaa aaaaacacct tttggtaaac accatttaaa attca 4245 <210> 53 <211> 2124 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477720CB1 <400> 53 atggctctgc agatgttcgt gacttacagt ccttggaatt gtttgctact gctagtggct 60 cttgagtgtt ctgaagcatc ttctgatttg aatgaatctg caaattccac tgctcagtat 120 gcatctaacg cttggtttgc tgctgccagc tcagagccag aggaagggat atctgttttt 180 gaactggatt atgactatgt gcaaattcct tatgaggtca ctctctggat acttctagca 240 tcccttgcaa aaataggctt ccacctctac cacaggctgc caggcctcat gccagaaagc 300 tgcctcctca tcctggtggg ggcgctggtg ggcggcatca tcttcggcac cgaccacaaa 360 tcgcctccgg tcatggactc cagcatctac ttcctgtatc tcctgccacc catcgttctg 420 gagggcggct acttcatgcc cacccggccc ttctttgaga acatcggctc catcctgtgg 480 tgggcagtat tgggggccct gatcaacgcc ttgggcattg gcctctccct ctacctcatc 540 tgccaggtga aggcctttgg cctgggcgac gtcaacctgc tgcagaacct gctgttcggc 600 agcctgatct ccgccgtgga cccagtggcc gtgctagccg tgtttgagga agcgcgcgtg 660 aacgagcagc tctacatgat gatctttggg gaggccctgc tcaatgatgg cattactgtg 720 gtcttataca atatgttaat tgcctttaca aagatgcata aatttgaaga catagaaact 780 gtcgacattt tggctggatg tgcccgattc atcgttgtgg ggcttggagg ggtattgttt 840 ggcatcgttt ttggatttat ttctgcattt atcacacgtt tcactcagaa tatctctgca 900 attgagccac tcatcgtctt catgttcagc tatttgtctt acttagctgc tgaaaccctc 960 tatctctccg gcatcctggc aatcacagcc tgcgcagtaa caatgaaaaa gtacgtggaa 1020 gaaaacgtgt cccagacatc atacacgacc atcaagtact tcatgaagat gctgagcagc 1080 gtcagcgaga ccttgatctt catcttcatg ggtgtgtcca ctgtgggcaa gaatcacgag 1140 tggaactggg ccttcatctg cttcaccctg gccttctgcc aaatctggag agccatcagc 1200 gtatttgctc tcttctatat cagtaaccag tttcggactt tccccttctc catcaaggac 1260 cagtgcatca ttttctacag tggtgttcga ggagctggaa gtttttcact tgcatttttg 1320 cttcctctgt ctctttttcc taggaagaaa atgtttgtca ctgctactct agtagttata 1380 tactttactg tatttattca gggaatcaca gttggccctc tggtcaggta cctggatgtt 1440 aaaaaaacca ataaaaaaga atccatcaat gaagagcttc atattcgtct gatggatcac 1500 ttaaaggctg gaatcgaaga tgtgtgtggg cactggagtc actaccaagt gagagacaag 1560 tttaagaagt ttgatcatag atacttacgg aaaatcctca tcagaaagaa cctacccaaa 1620 tcaagcattg tttctttgta caagaagctg gaaatgaagc aagccatcga gatggtggag 1680 actgggatac tgagctctac agctttctcc ataccccatc aggcccagag gatacaagga 7.740 atcaaaagac tttcccctga agatgtggag tccataaggg acattctgac atccaacatg 1800 taccaagttc ggcaaaggac cctgtcctac aacaaataca acctcaaacc ccaaacaagt 1860 gagaagcagg ctaaagagat tctgatccgc cgccagaaca ccttaaggga gagcatgagg 1920 aaaggtcaca gcctgccctg gggaaagccg gctggcacca agaatatccg ctacctctcc 1980 tacccctacg ggaatcctca gtctgcagga agagacacaa gggctgctgg gttctcaggt 2040 aagctgccca cctggctgct ctgctgcttt tctgtagagt caggtggtaa atatctgggg 2100 gtgtgggcca agaggcaaca ttaa 2124 <210> 54 <211> 2195 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477852CB1 <400> 54 atggggggtt ttctacctaa ggcagaaggg cccgggagcc aactccagaa acttctgccc 60 tcctttctgg tcagagaaca agactgggac cagcacctgg acaagcttca tatgctgcag 120 cagaagagga ttctagagtc tccactgctt cgagcatcca aggaaaatga cctgtctgtt 180 cttaggcaac ttctactgga ctgcacctgt gacgttcgac aaagaggagc cctgggggag 240 acggcgctgc acatagcagc cctctatgac aacttggagg cggccttggt gctgatggag 300 gctgccccag agctggtctt tgagcccacc acatgtgagg cttttgcagg tcagactgca 360 ctgcacatcg ctgttgtgaa ccagaatgtg aacctggtgc gtgccctgct cacccgcagg 420 gccagtgtct ctgccagagc cacaggcact gccttccgcc gtagtccccg caacctcatc 480 tactttggtg agcacccttt gtcctttgct gcctgtgtga acagcgagga gatcgtgcgg 540 ctgctcattg agcatggagc tgacatcagg gcccaggact ccctgggtaa cacagtatta 600 cacatcctca tcctccagcc caacaaaacc tttgcctgcc agatgtacaa cctgctgctg 660 tcctacgatg gacatgggga ccacctgcag cccctggacc ttgtgcccaa tcaccagggt 720 ctcaccccct tcaagctggc tggagtggag ggtaacactg tgatgttcca gcacctgatg 780 cagaagcgga ggcacatcca gtggacgtat ggacccctga cctccattct ctacgacctc 840 acagagatcg actcctgggg agaggagctg tccttcctgg agcttgtggt ctcctctgat 900 aaacgagagg ctcgccaaat tctggaacag accccagtga aggagctggt gagcttcaag 960 tggaacaagt atggccggcc gtacttctgc atcctggctg ccttgtacct gctctacatg 1020 atctgcttta ccacgtgctg cgtctaccgc ccccttaagt ttcgtggtgg caaccgcact 1080 cattctcgag acatcaccat cctccagcaa aaactactac aggaggccta tgagacacgt 1140 gaagatatca tcaggctggt gggggagctg gtgagcatcg ttggggctgt gatcatcctg 1200 ctcctagaga ttccagacat cttcagggtt ggtgcctctc gctattttgg aaagacgatt 1260 cttggggggc cattccatgt catcatgatc acctatgcct ccctggtgct ggtgaccatg 1320 gtgatgcggc tcaccaacac caatggggag gtggtgccca tgtcctttgc cctggtgctg 1380 ggctggtgca gtgtcatgta tttcactcga ggattccaga tgctgggtcc cttcaccatc 1440 atgatccaga agatgatttt tggagaccta atgcgtttct gctggctgat ggctgtggtc 1500 atcttgggat ttgcctccgc gttctatatc attttccaga cagaggaccc aaccagtctg 1560 gggcaattct atgactaccc catggcactg ttcaccacct ttgagctttt tctcactgtt 1620 attgatgcac ctgccaacta cgacgtggac ttgcccttca tgttcagcat tgtcaacttc 1680 gccttcgcca tcattgccac actgctcatg ctcaacttgt tcatcgccat gatgggcgac 1740 acccactgga gggtggccca ggagagggat gagctctgga gggcccaggt cgtggccacc 1800 acagtgatgc tggagcggaa gctgcctcgc tgcctgtggc ctcgctccgg gatctgtggg 1860 tgcgaattcg ggctggggga ccgctggttc ctgcgggttg agaaccacaa tgatcagaat 1920 cctctgcgag tgcttcgcta tgtggaagtg ttcaagaact cagacaagga ggatgaccag 1980 gagcatccat ctgagaaaca gccctctggg gctgagagtg ggactctagc cagagcctct 2040 ttggctcttc caacttcctc cctgtcccgg accgcgtccc agagcagcag tcaccgaggc 2100 tgggagatcc ttcgtcaaaa caccctgggg cacttgaatc ttggactgaa ccttagtgag 2160 ggggatggag aggaggtcta ccatttttga ttaac 2195 <210> 55 <211> 2055 <212> DNA
<213> Homo sapiens <220>
<221> misc_feature <223> Incyte ID No: 1471717CB1 <400> 55 cggctctggg ccctcagcct ggctcatgca caactgtctg aagtgctctg gactatggtg 60 atgaacagcg gccttcagac gcgaggctgg ggaggaatcg tcggggtttt tattattttt 120 gccgtatttg ctgtcctgac agtagccatc cttctgatca tggagggcct ctctgctttc 180 ctgcacgccc tgcgactgca ctgggaagct gtttggggaa cttgagctat ttagaagatg 240 gcaaccaagc caacagagcc tgtcacgatc ctcagccttc ggaaattgag cctggggacc 300 gcagagccac aggttaaaga gccaaagacg ttcaccgtgg aagatgcagt ggagactatc 360 ggcttcgggc gtttccacat tgccctcttt ctgatcatgg gcagtactgg ggtggttgag 420 gccatggaga tcatgttgat agctgttgtg tctcctgtca tccgctgtga atggcaactg 480 gagaattggc aggtggcatt agtaaccacg atggtgtttt ttggctacat ggttttcagt 540 atcctctttg gcctcctggc tgacagatat ggccgctgga agattctgct catctcgttc 600 ctgtggggag cctatttctc cttgctgacc tcgtttgctc cttcgtacat ctggtttgtc 660 ttcctgcgga cgatggtggg ctgtggtgtg tccggccact cgcaagggtt aatcataaag 720 actgaatttt tgcccacgaa ataccgaggc tatatgttac ccttgtctca ggtgttctgg 780 cttgcgggct ccctgctcat cattggcttg gcctctgtga tcatccccac catcgggtgg 840 cgctggctca ttcgcgtcgc ctccatcccg ggcatcatcc tcatcgtggc cttcaagttt 900 attcctgaat ctgcccggtt caatgtctcc actgggaaca ctcgggctgc cctggccact 960 ctggagcgcg ttgccaagat gaaccgctcg gtcatgccgg aggggaagct ggtggagccc 1020 gtcctggaaa aaagaggaag atttgcagac ctattggatg ctaaatattt acggaccaca 1080 ttacagatct gggtcatatg gcttggaatc tcttttgcct actatggggt tatcctggcc 1140 agtgctgagc tgctggagcg ggacttggtc tgtggttcaa agtcagactc tgcggtggtg 1200 gtgactgggg gggactcagg ggagagccag agcccctgct actgccacat gtttgcaccc 1260 tctgactatc ggaccatgat catcagcacc atcggtgaaa ttgctttgaa tcctttaaat 1320 atactgggca tcaatttcct gggaagacgg ctgagccttt ctattaccat gggatgcacg 1380 gctttattct gccttctcct caacatttgc acttcaagtg ccggcctgat tggcttcctc 1440 ttcatgctga gggctctggt agctgcaaac ttcaacaccg tctacattta cacagctgag 1500 gtctacccca ccacgatgcg cgctttgggg atgggaacca gcggctccct gtgtcgcatt 1560 ggtgcaatgg tggcgccatt tatatcccag gttcttatga gtgcatcaat actgggggcc 1620 ctgtgtctct tctcatctgt ctgtgttgta tgcgccattt ctgcattcac tctccccatc 1680 gaaaccaaag gacgggccct ccagcaaatt aaatgaagac ctgcaaagct atgtctacca 1740 gatgagaaaa atgaattcta tcttcagaac tgcggtgcat ttttttaaaa cttggtttta 1800 cttctgtatg ctactcggta attagtaaag tgattttttt ttaaaaggca tatatgggaa 1860 tggggtaggt aactgtatat tgatctcttc cttgaggaac aatatataaa gtacttttat 1920 aaaatataat ttaagctttc aaaggggtgt gagagggaga tggtgggggg gaagatggct 1980 tttcttcgtt gaaatcaagt ctgtaaacct ttatatgaat aaatactaaa ttttaaactt 2040 acaaaaaaaa aaaaa 2055 <210> 56 <211> 4727 <212> DNA
<213> Homo sapiens <220>

<221> misc_feature <223> Incyte ID No: 3874406CB1 <400> 56 aagagctgct ggagtaggca cccatttaaa gaaaaaatga agaagcagca ataaagaagt 60 tgtaatcgtt acctagacaa acagagaact ggttttgaca gtgtttctag agtgcttttt 120 attattttcc tgacagttgt gttccaccat gattactttc tccttcagcg aataggctaa 180 atgaatatga aacagaaaag cgtgtatcag caaaccaaag cacttctgtg caagaatttt 240 cttaagaaat ggaggatgaa aagagagagc ttattggaat ggggcctctc aatacttcta 300 ggactgtgta ttgctctgtt ttccagttcc atgagaaatg tccagtttcc tggaatggct 360 cctcagaatc tgggaagggt agataaattt aatagctctt ctttaatggt tgtgtataca 420 ccaatatcta atttaaccca gcagataatg aataaaacag cacttgctcc tcttttgaaa 480 ggaacaagtg tcattggggc accaaataaa acacacatgg acgaaatact tctggaaaat 540 ttaccatatg ctatgggaat catctttaat gaaactttct cttataagtt aatatttttc 600 cagggatata acagtccact ttggaaagaa gatttctcag ctcattgctg ggatggatat 660 ggtgagtttt catgtacatt gaccaaatac tggaatagag gatttgtggc tttacaaaca 720 gctattaata ctgccattat agaagtagct ttggtgttcc tgatgagtgt gctgttaaag 780 aaagctgtcc tcaccaattt ggttgtgttt ctccttaccc tcttttgggg atgtctggga 840 ttcactgtat tttatgaaca acttccttca tctctggagt ggattttgaa tatttgtagc 900 ccttttgcct ttactactgg aatgattcag attatcaaac tggattataa cttgaatggt 960 gtaatttttc ctgacccttc aggagactca tatacaatga tagcaacttt ttctatgttg 1020 cttttggatg gtctcatcta cttgctattg gcattatact ttgacaaaat tttaccctat 1080 ggagatgagc gccattattc tcctttattt ttcttgaatt catcatcttg tttccaacac 1140 caaaggacta atgctaaggt tattgagaaa gaaatcgatg ctgagcatcc ctctgatgat 2200 tattttgaac cagtagctcc tgaattccaa ggaaaagaag ccatcagaat cagaaatgtt 1260 aagaaggaat ataaaggaaa atctggaaaa gtggaagcat tgaaaggctt gctctttgac 1320 atatatgaag gtcaaatcac ggcaatcctg ggtcacagtg gagctggcaa atcttcactg 1380 ctaaatattc ttaatggatt gtctgttcca acagaaggat cagttaccat ctataataaa 1440 aatctctctg aaatgcaaga cttggaggaa atcagaaaga taactggcgt ctgtcctcaa 1500 ttcaatgttc aatttgacat actcaccgtg aaggaaaacc tcagcctgtt tgctaaaata 1560 aaagggattc atctaaagga agtggaacaa gaggtacaac gaatattatt ggaattggac 1620 atgcaaaaca ttcaagataa ccttgctaaa catttaagtg aaggacagaa aagaaagctg 1680 acttttggga ttaccatttt aggagatcct caaattttgc tcttagatga accaactact 1740 ggattggatc ccttttccag agatcaagtg tggagcctcc tgagagagcg tagagcagat 1800 catgtgatcc ttttcagtac ccagtccatg gatgaggctg acatcctggc tgatagaaaa 1860 gtgatcatgt ccaatgggag actgaagtgt gcaggttctt ctatcttttt gaaaagaagg 1920 tggggtcttg gatatcacct aagtttacat aggaatgaaa tatgtaaccc agaacaaata 1980 acatccttca ttactcatca catccccgat gctaaattaa aaacagaaaa caaagaaaag 2040 cttgtatata ctttgccact ggaaaggaca aatacatttc cagatctttt cagtgatctg 2100 gataagtgtt ctgaccaggg agtgacaggt tatgacattt ccatgtcaac tctaaatgaa 2160 gtctttatga aactggaagg acagtcaact atcgaacaag atttcgaaca agtggagatg 2220 ataagagact cagaaagcct caatgaaatg gagctggctc actcttcctt ctctgaaatg 2280 cagacagctg tgagtgacat gggcctctgg agaatgcaag tctttgccat ggcacggctc 2340 cgtttcttaa agttaaaacg tcaaactaaa gtgttattga ccctattatt ggtatttgga 2400 atcgcaatat tccctttgat tgttgaaaat ataatatatg ctatgttaaa tgaaaagatc 2460 gattgggaat ttaaaaacga attgtatttt ctctctcctg gacaacttcc ccaggaaccc 2520 cgtaccagcc tgttgatcat caataacaca gaatcaaata ttgaagattt tataaaatca 2580 ctgaagcatc aaaatatact tttggaagta gatgactttg aaaacagaaa tggtactgat 2640 ggcctctcat acaatggagc tatcatagtt tctggtaaac aaaaggatta tagattttca 2700 gttgtgtgta ataccaagag attgcactgt tttccaattc ttatgaatat tatcagcaat 2760 gggctacttc aaatgtttaa tcacacacaa catattcgaa ttgagtcaag cccatttcct 2820 cttagccaca taggactctg gactgggttg ccggatggtt cctttttctt atttttggtt 2880 ctatgtagca tttctcctta tatcaccatg ggcagcatca gtgattacaa gaaaaatgct 2940 aagtcccagc tatggatttc aggcctctac acttctgctt actggtgtgg gcaggcacta 3000 gtggacgtca gcttcttcat tttaattctc cttttaatgt atttaatttt ctacatagaa 3060 aacatgcagt accttcttat tacaagccaa attgtgtttg ctttggttat agttactcct 3120 ggttatgcag cttctcttgt cttcttcata tatatgatat catttatttt tcgcaaaagg 3180 agaaaaaaca gtggcctttg gtcattttac ttcttttttg cctccaccat catgttttcc 3240 atcactttaa tcaatcattt tgacctaagt atattgatta ccaccatggt attggttcct 3300 tcatatacct tgcttggatt taaaactttt ttggaagtga gagaccagga gcactacaga 3360 gaatttccag aggcaaattt tgaattgagt gccactgatt ttctagtctg cttcataccc 3420 tactttcaga ctttgctatt cgtttttgtt ctaagatgca tggaactaaa atgtggaaag 3480 aaaagaatgc gaaaagatcc tgttttcaga atttcccccc aaagtagaga tgctaagcca 3540 aatccagaag aacccataga tgaagatgaa gatattcaaa cagaaagaat aagaacagtc 3600 actgctctga ccacttcaat cttagatgag aaacctgtta taattgccag ctgtctacac 3660 aaagaatatg caggccagaa gaaaagttgc ttttcaaaga ggaagaagaa aatagcagca 3720 agaaatatct ctttctgtgt tcaagaaggt gagattttgg gattgctagg acccagtggt 3780 gctggaaaaa gttcatctat tagaatgata tctgggatca caaagccaac tgctggagag 3840 gtggaactga aaggctgcag ttcagttttg ggccacctgg ggtactgccc tcaagagaac 3900 gtgctgtggc ccatgctgac gttgagggaa cacctggagg tgtatgctgc cgtcaagggg 3960 ctcagggaag cggacgcgag gctcgccatc gcaagattag tgagtgcttt caaactgcat 4020 gagcagctga atgttcctgt gcagaaatta acagcaggaa tcacgagaaa gttgtgtttt 4080 gtgctgagcc tcctgggaaa ctcacctgtc ttgctcctgg atgaaccatc tacgggcata 4140 gaccccacag ggcagcagca aatgtggcag gcaatccagg cagtcgttaa aaacacagag 4200 agaggtgtcc tcctgaccac ccataacctg gctgaggcgg aagccttgtg tgaccgtgtg 4260 gccatcatgg tgtctggaag gcttagatgc attggctcca tccaacacct gaaaaacaaa 4320 cttggcaagg attacattct agagctaaaa gtgaaggaaa cgtctcaagt gactttggtc 4380 cacactgaga ttctgaagct tttcccacag gctgcagggc agcaaaggta ttcctctttg 4440 ttaacctata agctgcccgt ggcagacgtt taccctctat cacagacctt tcacaaatta 4500 gaagcagtga agcataactt taacctggaa gaatacagcc tttctcagtg cacactggag 4560 aaggtattct tagagctttc taaagaacag gaagtaggaa attttgatga agaaattgat 4620 acaacaatga gatggaaact cctccctcat tcagatgaac cttaaaacct caaacctagt 4680 aattttcttg cttgatctcc tataaactta tgttttatgt aataatt 4727 <210> 57 <211> 3852 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 4599654CB1 <400> 57 cgccggcgat tccgagccta cgacgcctcc gctagagccc gcggggctgc gccgactcct 60 gctctggagg ggttgcgggt acctgatggc cacagagggc tctaggaggc cgagcgtgta 120 agcggggtgg gcgccatgga ggcagagcag cggccggcgg cgggggccag cgaaggggcg 180 acccctggac tggaggcggt gcctcccgtt gctcccccgc ctgcgaccgc ggcctcaggt 240 ccgatcccca aatctgggcc tgagcctaag aggaggcacc ttgggacgct gctccagcct 300 acggtcaaca agttctccct tcgggtgttc ggcagccaca aagcagtgga aatcgagcag 360 gagcgggtga agtcagcggg ggcctggatc atccacccct acagcgactt ccggttttac 420 tgggacctga tcatgctgct gctgatggtg gggaacctca tcgtcctgcc tgtgggcatc 480 accttcttca aggaggagaa ctccccgcct tggatcgtct tcaacgtatt gtctgatact 540 ttcttcctac tggatctggt gctcaacttc cgaacgggca tcgtggtgga ggagggtgct 600 gagatcctgc tggcaccgcg ggccatccgc acgcgctacc tgcgcacctg gttcctggtt 660 gacctcatct cttctatccc tgtggattac atcttcctag tggtggagct ggagccacgg 720 ttggacgctg aggtctacaa aacggcacgg gccctacgca tcgttcgctt caccaagatc 780 ctaagcctgc tgaggctgct ccgcctctcc cgcctcatcc gctacataca ccagtgggag 840 gagatcttcc acatgaccta tgacctggcc agtgctgtgg ttcgcatctt caacctcatt 900 gggatgatgc tgctgctatg tcactgggat ggctgtctgc agttcctggt gcccatgctg 960 caggacttcc ctcccgactg ctgggtctcc atcaaccaca tggtgaacca ctcgtggggc 1020 cgccagtatt cccatgccct gttcaaggcc atgagccaca tgctgtgcat tggctatggg 1080 cagcaggcac ctgtaggcat gcccgacgtc tggctcacca tgctcagcat gatcgtaggt 1140 gccacatgct acgccatgtt catcggccat gccacggcac tcatccagtc cctggactct 1200 tcccggcgtc agtaccagga gaagtacaag caggtggagc agtacatgtc cttccacaag 1260 ctgccagcag acacgcggca gcgcatccac gagtactatg agcaccgcta ccagggcaag 1320 atgttcgatg aggaaagcat cctgggcgag ctgagcgagc cgcttcgcga ggagatcatt 1380 aacttcacct gtcggggcct ggtggcccac atgccgctgt ttgcccatgc cgaccccagc 1440 ttcgtcactg cagttctcac caagctgcgc tttgaggtct tccagccggg ggatctcgtg 1500 gtgcgtgagg gctccgtggg gaggaagatg tacttcatcc agcatgggct gctcagtgtg 1560 ctggcccgcg gcgcccggga cacacgcctc accgatggat cctactttgg ggagatctgc 1620 ctgctaacta ggggccggcg cacagccagt gttcgggctg acacctactg ccgcctttac 1680 tcactcagcg tggaccattt caatgctgtg cttgaggagt tccccatgat gcgccgggcc 1740 tttgagactg tggccatgga tcggctgctc cgcatcggca agaagaattc catactgcag 1800 cggaagcgct ccgagccaag tccaggcagc agtggtggca tcatggagca gcatttggtg 1860 caacatgaca gagacatggc tcggggtgtt cggggtcggg ccccgagcac aggagctcag 1920 cttagtggaa agccagtact gtgggagcca ctggtacatg cgccccttca ggcagctgct 1980 gtgacctcca atgtggccat tgccctgact catcagcggg gccctctgcc cctctcccct 2040 gactctccag ccaccctcct tgctcgctct gcttggcgct cagcaggctc tccagcttcc 2100 ccgctggtgc ccgtccgagc tggcccatgg gcatccacct cccgcctgcc cgccccacct 2160 gcccgaaccc tgcacgccag cctatcccgg gcagggcgct cccaggtctc cctgctgggt 2220 ccccctccag gaggaggtgg acggcggcta ggacctcggg gccgcccact ctcagcctcc 2280 caaccctctc tgcctcagcg ggcaacaggc gatggctctc ctgggcgtaa gggatcagga 2340 agtgagcggc tgcctccctc agggctcctg gccaaacctc caaggacagc ccagcccccc 2400 aggccaccag tgcctgagcc agccacaccc cggggtctcc agctttctgc caacatgtaa 2460 aacctttgag tacatccagc cttagttctt ggggtgcagt agtatgtacc caagggcaga 2520 tgcctcttgg ggaaggccat ggggacctga aacattgccc catggaaatg tcgaccctgt 2580 gcggacattc cgcatactgc catgaagacg gtctctgtgt cctcagctca agaatcctgt 2640 agcttgtccc atcataatcc attcacccgt tcatcatgtg tactgagcag ctaccatgtt 2700 caaggtaata tgccaggcgc tgtatgtctc cactgccaag tagaagtga.c tcaaaaccct 2760 ctgacaagga tattcccttg gctatggtcc tgccaggtgc aggcccaggc ccatgacccc 2820 acctttacta agcacaagta cttgccactg ccatcactgc caagtaacta gatgtctctg 2880 tttccctgcc aatgatcctg caggttctgc ccggtctggt tatcttcctg tttcctgtag 2940 catagccagg cactgccagt cacctgtgcc cccattgctg tcagcagatg tcttgggtcc 3000 tgagtgtggg tatccacttt tacccgctca ctgccacctg tggacactct gtgtctaccc 3060 tctgagtggg aacatacttc taagttccct gcagtctctg tcctgtggta gaccatcttt 3120 ttgtaaactg cgagcttcct cttccctgta ccctctgccc cagtcgtgac cccctaaaag 3180 ttaaggggta gttggcacct ccttattaat atgccagcct agatcccccc cggtggaggg 3240 gcaaatggct gaatccttgt gtgatatttt tttcttcgct tgtttattta ttcatttatt 3300 taattgtatt tattcattta ctaactttat gtgttaccaa ttaattttgt ttacccattc 3360 ctttatccat ccctcccctc cttttcaggt aaggagacag gaggagtagg aggaggcagg 3420 gcctctccat gccagcctct gtggtccttg cccaaaccca tcagcgcaat acttgaacct 3480 tctcccaggt aggggcagga ggagccacat gagagaggga gaaggaccgc gtttaccttt 3540 agagttttgt tttgtttttt ccttctgagt ttgctgttgg tgcaggaata agggaaaggc 3600 ccaaggtatc caagcctggg gaagggcagg ccagccagca cctctgcctt ctcagggaca 3660 agagtagtcc tttaccaccc tcactctgcc tgtcccctct cctactctac agcattaaag 3720 actgtgggac caggacccta agtctccttt ccttctgggt ggggagttct aggggttctt 3780 ggtgtgtggg agaagtttta taattgcttc caaacagctg ggtttaaata taaaatagac 3840 acactcaaaa as 3852 <210> 58 <211> 1917 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 5047435CB1 <400> 58 atggcagaag gtgaaagggg agcagacgtg ccacatggcc tcggggcctg gctggccgac 60 gtggcgttgg cggcgctgcg cgcgggaggg cagggcagga gggacagagg cgggggcggg 120 ccggaaagtt tgtccggcgg cagcggcgtt ggggactccg gcgggggatg cgcgcccggc 180 ccctcagcgc ccccagcacg ccgccgagtc ccgctcgcca tgggccactc cccacctgtc 240 ctgcctttgt gtgcctctgt gtctttgctg ggtggcctga cctttggtta tgaactggca 300 gtcatatcag gtgccctgct gccactgcag cttgactttg ggctaagctg cttggagcag 360 gagttcctgg tgggcagcct gctcctgggg gctctcctcg cctccctggt tggtggcttc 420 ctcattgact gctatggcag gaagcaagcc atcctcggga gcaacttggt gctgctggca 480 ggcagcctga ccctgggcct ggctggttcc ctggcctggc tggtcctggg ccgcgctgtg 540 gttggcttcg ccatttccct ctcctccatg gcttgctgta tctacgtgtc agagctggtg 600 gggccacggc agcggggagt gctggtgtcc ctctatgagg caggcatcac cgtgggcatc 660 ctgctctcct atgccctcaa ctatgcactg gctggtaccc cctggggatg gaggcacatg 720 ttcggctggg ccactgcacc tgctgtcctg caatccctca gcctcctctt cctccctgct 780 ggtacagatg agactgcaac acacaaggac ctcatcccac tccagggagg tgaggccccc 840 aagctgggcc cggggaggcc acggtactcc tttctggacc tcttcagggc acgcgataac 900 atgcgaggcc ggaccacagt gggcctgggg ctggtgctct tccagcaact aacagggcag 960 cccaacgtgc tgtgctatgc ctccaccatc ttcagctccg ttggtttcca tgggggatcc 1020 tcagccgtgc tggcctctgt ggggcttggc gcagtgaagg tggcagctac cctgaccgcc 1080 atggggctgg tggaccgtgc aggccgcagg gctctgttgc tagctggctg tgccctcatg 1140 gccctgtccg tcagtggcat aggcctcgtc agctttgccg tgcccatgga ctcaggccca 1200 agctgtctgg ctgtgcccaa tgccaccggg cagacaggcc tccctggaga ctctggcctg 1260 ctgcaggact cctctctacc tcccattcca aggaccaatg aggaccaaag ggagccaatc 1320 ttgtccactg ctaagaaaac caagccccat cccagatctg gagacccctc agcccctcct 1380 cggctggccc tgagctctgc cctccctggg ccccctctgc ccgctcgggg gcatgcactg 1440 ctgcgctgga ccgcactgct gtgcctgatg gtctttgtca gtgccttctc ctttgggttt 1500 gggccagtga cctggcttgt cctcagcgag atctaccctg tggagatacg aggaagagcc 1560 ttcgccttct gcaacagctt caactgggcg gccaacctct tcatcagcct ctccttcctc 1620 gatctcattg gcaccatcgg cttgtcctgg accttcctgc tctacggact gaccgctgtc 1680 ctcggcctgg gcttcatcta tttatttgtt cctgaaacaa aaggccagtc gttggcagag 1740 atagaccagc agttccagaa gagacggttc accctgagct ttggccacag gcagaactcc 1800 actggcatcc cgtacagccg catcgagatc tctgcggcct cctgaggaat ccgtctgcct 1860 ggaaattctg gaactgtggc tttggcagac catctccagc atcctgcttc ctaggcc 1917 <210> 59 <211> 6791 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7475603CB1 <400> 59 cgcgctccct gcctgctgct gggcggaggg aaggcggcaa gagctgcgga gcccctggaa 60 gagcttccag gaaccctgcg ctgtgggata aaggaatgag gttcagaaag gggcaggagt 120 tgcccgcagc cgcaccgcac gtcttcagcc cgaccgttgt cctgacctct ctgtcccgtc 180 ccctgcccag tctcaccatg gccttctgga cacagctgat gctgctgctc tggaagaatt 240 tcatgtatcg ccggagacag ccggtccagc tcctggtcga attgctgtgg cctctcttcc 300 tcttcttcat cctggtggct gttcgccact cccacccgcc cctggagcac catgaatgcc'360 acttcccaaa caagccactg ccatcggcgg gcaccgtgcc ctggctccag ggtctcatct 420 gtaatgtgaa caacacctgc tttccgcagc tgacaccggg cgaggagccc gggcgcctga 480 gcaacttcaa cgactccctg gtctcccggc tgctagccga tgcccgcact gtgctgggag 540 gggccagtgc ccacaggacg ctggctggcc tagggaagct gatcgccacg ctgagggctg 600 cacgcagcac ggcccagcct caaccaacca agcagtctcc actggaacca cccatgctgg 660 atgtcgcgga gctgctgacg tcactgctgc gcacggaatc cctggggttg gcactgggcc 720 aagcccagga gcccttgcac agcttgttgg aggccgctga ggacctggcc caggagctcc 780 tggcgctgcg cagcctggtg gagcttcggg cactgctgca gagaccccga gggaccagcg 840 gccccctgga gttgctgtca gaggccctct gcagtgtcag gggacctagc agcacagtgg 900 gcccctccct caactggtac gaggctagtg acctgatgga gctggtgggg caggagccag 960 aatccgccct gccagacagc agcctgagcc ccgcctgctc ggagctgatt ggagccctgg 1020 acagccaccc gctgtcccgc ctgctctgga gacgcctgaa gcctctgatc ctcgggaagc 1080 tactctttgc accagataca ccttttaccc ggaagctcat ggcecaggtg aaccggacct 1140 tcgaggagct caccctgctg agggatgtcc gggaggtgtg ggagatgctg ggaccccgga 1200 tcttcacctt catgaacgac agttccaatg tggccatgct gcagcggctc ctgcagatgc 1260 aggatgaagg aagaaggcag cccagacctg gaggccggga ccacatggag gccctgcgat 1320 cctttctgga ccctgggagc ggtggctaca gctggcagga cgcacacgct gatgtggggc 1380 acctggtggg cacgctgggc cgagtgacgg agtgcctgtc cttggacaag ctggaggcgg 1440 caccctcaga ggcagccctg gtgtcgcggg ccctgcaact gctcgcggaa catcgattct 1500 gggccggcgt cgtcttcttg ggacctgagg actcttcaga ccccacagag cacccaaccc 1560 cagacctggg ccccggccac gtgcgcatca aaatccgcat ggacattgac gtggtcacga 1620 ggaccaataa gatcagggac aggttttggg accctggccc agccgcggac cccctgaccg 1680 acctgcgcta cgtgtggggc ggcttcgtgt acctgcaaga cctggtggag cgtgcagccg 1740 tccgcgtgct cagcggcgcc aacccccggg ccggcctcta cctgcagcag atgccctatc 1800 cgtgctatgt ggacgacgtg ttcctgcgtg tgctgagccg gtcgctgccg ctcttcctga 1860 cgctggcctg gatctactcc gtgacactga cagtgaaggc cgtggtgcgg gagaaggaga 1920 cgcggctgcg ggacaccatg cgcgccatgg ggctcagccg cgcggtgctc tggctaggct 1980 ggttcctcag ctgcctcggg cccttcctgc tcagcgccgc gctgctggtt ctggtgctca 2040 agctggggga catcctcccc tacagccacc cgggcgtggt cttcctgttc ttggcagcct 2100 tcgcggtggc cacggtgacc cagagcttcc tgctcagcgc cttcttctcc cgcgccaacc 2160 tggctgcggc ctgcggcggc ctggcctact tctccctcta cctgccctac gtgctgtgtg 2220 tggcttggcg ggaccggctg cccgcgggtg gccgcgtggc cgcgagcctg ctgtcgcccg 2280 tggccttcgg cttcggctgc gagagcctgg ctctgctgga ggagcagggc gagggcgcgc 2340 agtggcacaa cgtgggcacc cggcctacgg cagacgtctt cagcctggcc caggtctctg 2400 gccttctgct gctggacgcg gcgctctacg gcctcgccac ctggtacctg gaagctgtgt 2460 gcccaggcca gtacgggatc cctgaaccat ggaattttcc ttttcggagg agctactggt 2520 gcggacctcg gccccccaag agtccagccc cttgccccac cccgctggac ccaaaggtgc 2580 tggtagaaga ggcaccgccc ggcctgagtc ctggcgtctc cgttcgcagc ctggagaagc 2640 gctttcctgg aagcccgcag ccagccctgc gggggctcag cctggacttc taccagggcc 2700 acatcaccgc cttcctgggc cacaacgggg ccggcaagac caccaccctg tccatcttga 2760 gtggcctctt cccacccagt ggtggctctg ccttcatcct gggccacgac gtccgctcca 2820 gcatggccgc catccggccc cacctgggcg tctgtcctca gtacaacgtg ctgtttgaca 2880 tgctgaccgt ggacgagcac gtctggttct atgggcggct gaagggtctg agtgccgctg 2940 tagtgggccc cgagcaggac cgtctgctgc aggatgtggg gctggtctcc aagcagagtg 3000 tgcagactcg ccacctctct ggtgggatgc aacggaagct gtccgtggcc attgcctttg 3060 tgggcggctc ccaagttgtt atcctggacg agcctacggc tggcgtggat cctgcttccc 3120 gccgcggtat ttgggagctg ctgctcaaat accgagaagg tcgcacgctg atcctctcca 3180 cccaccacct ggatgaggca gagctgctgg gagaccgtgt ggccgtggtg gcaggtggcc 3240 gcttgtgctg ctgtggatcc ccactcttcc tgcgccgtca cctgggctcc ggctactacc 3300 tgacgctggt gaaggcccgc ctgcccctga ccaccaatga gaaggctgac actgacatgg 3360 agggcagtgt ggacaccagg caggaaaaga agaatggcag ccagggcagc agagtcggca 3420 ctcctcagct gctggccctg gtacagcact gggtgcccgg ggcacggctg gtggaggagc 3480 tgccacacga gctggtgctg gtgctgccct acacgggtgc ccatgacggc agcttcgcca 3540 cactcttccg agagctagac acgcggctgg cggagctgag gctcactggc tacgggatct 3600 ccgacaccag cctcgaggag atcttcctga aggtggtgga ggagtgtgct gcggacacag 3660 atatggagga tggcagctgc gggcagcacc tatgcacagg cattgctggc ctagacgtaa 3720 ccctacggct caagatgccg ccacaggaga cagcgctgga gaacggggaa ccagctgggt 3780 cagccccaga gactgaccag ggctctgggc cagacgccgt gggccgggta cagggctggg 3840 cactgacccg ccagcagctc caggccctgc ttctcaagcg ctttctgctt gcccgccgca 3900 gccgccgcgg cctgttcgcc cagatcgtgc tgcctgccct ctttgtgggc ctggccctcg 3960 tgttcagcct catcgtgcct cctttcgggc actacccggc tctgcggctc agtcccacca 4020 tgtacggtgc tcaggtgtcc ttcttcagtg aggacgcccc aggggaccct ggacgtgccc 4080 ggctgctcga ggcgctgctg caggaggcag gactggagga gcccccagtg cagcatagct 4140 cccacaggtt ctcggcacca gaagttcctg ctgaagtggc caaggtcttg gccagtggca 4200 actggacccc agagtctcca tccccagcct gccagtgtag ccggcccggt gcccggcgcc 4260 tgctgcccga ctgcccggct gcagctggtg gtccccctcc gccccaggca gtgaccggct 4320 ctggggaagt ggttcagaac cagacaggcc ggaacctgtc tgacttcctg gtcaagacct 4380 acccgcgcct ggtgcgccag ggcctgaaga ctaagaagtg ggtgaatgag gtcagatacg 4440 gaggcttctc gctggggggc cgagacccag gcctgccctc gggccaagag ttgggccgct 4500 cagtggagga gttgtgggcg ctgctgagtc ccctgcctgg cggggccctc gaccgtgtcc 4560 tgaaaaacct cacagcctgg gctcacagcc tggatgctca ggacagtctc aagatctggt 4620 tcaacaacaa aggctggcac tccatggtgg cctttgtcaa ccgagccagc aacgcaatcc 4680 tccgtgctca cctgccccca ggcccggccc gccacgccca cagcatcacc acactcaacc 4740 accccttgaa cctcaccaag gagcagctgt ctgaggctgc actgatggcc tcctcggtgg 4800 acgtcctcgt ctccatctgt gtggtctttg ccatgtcctt tgtcccggcc agcttcactc 4860 ttgtcctcat tgaggagcga gtcacccgag ccaagcacct gcagctcatg gggggcctgt 4920 cccccaccct ctactggctt ggcaactttc tctgggacat gtgtaactac ttggtgccag 4980 catgcatcgt ggtgctcatc tttctggcct tccagcagag ggcatatgtg gcccctgcca 5040 acctgcctgc tctcctgctg ttgctactac tgtatggctg gtcgatcaca ccgctcatgt 5100 acccagcctc cttcttcttc tccgtgccca gcacagccta tgtggtgctc acctgcataa 5160 acctctttat tggcatcaat ggaagcatgg ccacctttgt gcttgagctc ttctctgatc 5220 agaagctgca ggaggtgagc cggatcttga aacaggtctt ccttatcttc ccccacttct 5280 gcttgggccg ggggctcatt gacatggtgc ggaaccaggc catggctgat gcctttgagc 5340 gcttgggaga caggcagttc cagtcacccc tgcgctggga ggtggtcggc aagaacctct 5400 tggccatggt gatacagggg cccctcttcc ttctcttcac actactgctg cagcaccgaa 5460 gccaactcct gccacagccc agggtgaggt ctctgccact cctgggagag gaggacgagg 5520 atgtagcccg tgaacgggag cgggtggtcc aaggagccac ccagggggat gtgttggtgc 5580 tgaggaactt gaccaaggta taccgtgggc agaggatgcc agctgttgac cgcttgtgcc 5640 tggggattcc ccctggtgag tgttttgggc tgctgggtgt gaatggagca gggaagacgt 5700 ccacgtttcg catggtgacg ggggacacat tggccagcag gggcgaggct gtgctggcag 5760 gccacagcgt ggcccgggaa cccagtgctg cgcacctcag catgggatac tgccctcaat 5820 ccgatgccat ctttgagctg ctgacgggcc gcgagcacct ggagctgctt gcgcgcctgc 5880 gcggtgtccc ggaggcccag gttgcccaga ccgctggctc gggcctggcg cgtctgggac 5940 tctcatggta cgcagaccgg cctgcaggca cctacagcgg agggaacaaa cgcaagctgg 6000 cgacggccct ggcgctggtt ggggacccag ccgtggtgtt tctggacgag ccgaccacag 6060 gcatggaccc cagcgcgcgg cgcttccttt ggaacagcct tttggccgtg gtgcgggagg 6120 gccgttcagt gatgctcacc tcccatagca tggaggagtg tgaagcgctc tgctcgcgcc 6180 tagccatcat ggtgaatggg cggttccgct gcctgggcag cccgcaacat ctcaagggca 6240 gattcgcggc gggtcacaca ctgaccctgc gggtgcccgc cgcaaggtcc cagccggcag 6300 cggccttcgt ggcggccgag ttccctgggg cggagctgcg cgaggcacat ggaggccgcc 6360 tgcgcttcca gctgccgccg ggagggcgct gcgccctggc gcgcgtcttt ggagagctgg 6420 cggtgcacgg cgcagagcac ggcgtggagg acttttccgt gagccagacg atgctggagg 6480 aggtattctt gtacttctcc aaggaccagg ggaaggacga ggacaccgaa gagcagaagg 6540 aggcaggagt gggagtggac cccgcgccag gcctgcagca ccccaaacgc gtcagccagt 6600 tcctcgatga ccctagcact gccgagactg tgctctgagc ctccctcccc tgcggggccg 6660 cggggaggcc ctgggaatgg caagggcaag gtagagtgcc taggagccct ggactcaggc 6720 tggcagaggg gctggtgccc tggagaaaat aaagagaagg ctggagagaa gccgtggtgg 6780 tgaaaaaaaa a 6791 <210> 60 <211> 5214 <212> DNA
<213> Homo sapiens <220>
<221> misc feature <223> Incyte ID No: 7477845CB1 <400> 60 atgctcaaaa ggaagcagag ttccagggtg gaagcccagc cagtcactga ctttggtcct 60 gatgagtctc tgtcggataa tgctgacatc ctctggatta acaaaccatg ggttcactct 120 ttgctgcgca tctgtgccat catcagcgtc atttctgttt gtatgaatac gccaatgacc 180 ttcgagcact atcctccact tcagtatgtg accttcactt tggatacatt attgatgttt 240 ctctacacgg cagagatgat agcaaaaatg cacatccggg gcattgtcaa gggggatagt 300 tcctatgtga aagatcgctg gtgtgttttt gatggattta tggtcttttg cctttgggtt 360 tctttggtgc tacaggtgtt tgaaattgct gatatagttg atcagatgtc accttggggc 420 atgttgcgga ttccacggcc actgattatg atccgagcat tccggattta tttccgattt 480 gaactgccaa ggaccagaat tacaaatatt ttaaagcgat cgggagaaca aatatggagt 540 gtttccattt ttctactttt ctttctactt ctttatggaa ttttaggagt tcagatgttt 600 ggaacattta cttatcactg tgttgtaaat gacacaaagc cagggaatgt aacctggaat 660 agtttagcta ttccagacac acactgctca ccagagctag aagaaggcta ccagtgccca 720 cctggattta aatgcatgga ccttgaagat ctgggactta gcaggcaaga gctgggctac 780 agtggcttta atgagatagg aactagtata ttcaccgtct atgaggccgc ctcacaggaa 840 ggctgggtgt tcctcatgta cagagcaatt gacagctttc cccgttggcg ttcctacttc 900 tatttcatca ctctcatttt cttcctcgcc tggcttgtga agaacgtgtt tattgctgtt 960 atcattgaaa catttgcaga aatcagagta cagtttcaac aaatgtgggg atcgagaagc 1020 agcactacct caacagccac cacccagatg tttcatgaag atgctgctgg aggttggcag 1080 ctggtagctg tggatgtcaa caagccccag ggacgcgccc cagcctgcct ccagaaaatg 1140 atgcggtcat ccgttttcca catgttcatc ctgagcatgg tgaccgtgga cgtgatcgtg 1200 gcggctagca actactacaa aggagaaaac ttcaggaggc agtacgacga gttctacctg 1260 gcggaggtgg cttttacagt actttttgat ttggaagcac ttctgaagat atggtgtttg 1320 ggatttactg gatatattag ctcatctctc cacaaattcg aactactact cgtaattgga 1'380 actactcttc atgtataccc agatctttat cattcacaat tcacgtactt tcaggtactc 1440 cgagtagttc ggctgattaa gatttcacct gcattagaag actttgtgta caagatattt 1500 ggtcctggaa aaaagcttgg gagtttggtt gtatttactg ccagcctctt gattgttatg 1560 tcagcaatta gtttgcagat gttctgcttt gtcgaagaac tggacagatt tactacgttt 1620 ccgagggcat ttatgtccat gttccagatc ctcacccagg aaggatgggt ggacgtaatg 1680 gaccaaactc taaatgctgt gggacatatg tgggcacccg tggttgccat ctatttcatt 1740 ctctatcatc tttttgccac tctgatcctc ctgagtttgt ttgttgctgt tattttggac 1800 aacttagaac ttgatgaaga cctaaagaag cttaaacaat taaagcaaag tgaagcaaat 1860 gcggacacca aagaaaagct ccctttacgc ctgcgaatct ttgaaaaatt tccaaacaga 1920 cctcaaatgg tgaaaatctc aaagcttcct tcagatttta cagttcctaa aatcagggag 1980 agttttatga agcagtttat tgaccgccag caacaggaca catgttgcct tctgagaagc 2040 ctcccgacca cctcttcctc ctcctgcgac cactccaaac gctcagcaat tgaggacaac 2100 aaatacatcg accaaaaact tcgcaagtct gttttcagca tcagggcaag gaaccttctg 2160 gaaaaggaga ccgcagtcac taaaatctta agggcttgca cccgacagcg catgctgagc 2220 ggatcatttg aggggcagcc cgcaaaggag aggtcaatcc tcagcgtgca gcatcatatc 2280 cgccaagagc gcaggtcact aagacatgga tcaaacagcc agaggatcag caggggaaaa 2340 tctcttgaaa ctttgactca agatcattgc aatacagtga tatatagaaa tgctcaaaga 2400 gaagtcagtg aaataaagat gattcaggaa aaaaaggagc tagcagagat gcttcaagga 2460 aagtgcaaaa aggaactcag agagagccac ccatacttcg ataagccact gttcattgtc 2520 gggcgagaac acaggttcag aaacttttgc cgggtggtgg tccgagcacg cttcaacgcg 2580 tctaaaacag accctgtcac aggagctgtg aaaaatacaa agtaccatct tctttatgat 2640 ttgctgggat tggtcactta cctggactgg gtcatgatca tcgtaacctc tgactcttgc 2700 atttccatga tgtttgagtc cccgtttcga agagtcatgc atgcacctac tttgcagatt 2760 gctgagtatg tgtttgtgat attcatgagc attgagctta atctgaagat tatggcagat 2820 ggcttatttt tcactccaac tgctgtcatc agggacttcg gtggagtaat ggacatattt 2880 atatatcttg tgagcttgat atttctttgt tggatgcctc aaaatgtacc tgctgaatcg 2940 ggagctcagc ttctaatggt ccttcggtgc ctgagacctc tgcgcatatt caaactggtg 3000 ccccagatga ggaaagttgt tcgagaactt ttcagcggct tcaaggaaat ttttttggtc 3060 tccattcttt tgctgacatt aatgctcgtt tttgcaagct ttggagttca gctttttgct 3120 ggaaaactgg ccaagtgcaa tgatcccaac attattagaa gggaagattg caatggcata 3180 ttcagaatta atgtcagtgt gtcaaagaac ttaaatttaa aattgaggcc tggagagaaa 3240 aaacctggat tttgggtgcc ccgtgtttgg gcgaatcctc ggaactttaa tttcgacaat 3300 gtgggaaacg ctatgctggc gttgtttgaa gttctctcct tgaaaggctg ggtggaagtg 3360 agagatgtta ttattcatcg tgtggggccg atccatggaa tctatattca tgtttttgta 3420 ttcctgggtt gcatgattgg actgaccctt tttgttggag tagttattgc taatttcaat 3480 gaaaacaagg ggacggcttt gctgaccgtc gatcagagaa gatgggaaga cctgaagagc 3540 cgactgaaga tcgcacagcc tcttcatctt ccgcctcgcc cggataatga tggttttaga 3600 gctaaaatgt atgacataac ccagcatcca ttttttaaga ggacaatcgc attactcgtc 3660 ctggcccagt cggtgttgct ctctgtcaag tgggacgtcg aggacccggt gaccgtacct 3720 ttggcaacaa tgtcagttgt tttcaccttc atctttgttc tggaggtaac catgaagatc 3780 atagcaatgt cgcctgctgg cttctggcaa agcagaagaa accgatacga tctcctggtg 3840 acgtcgcttg gcgttgtatg ggtggtgctt cactttgccc tcctgaatgc atatacttac 3900 atgatgggcg cttgtgtgat tgtatttagg tttttctcca tctgtggaaa acatgtaacg 3960 ctaaagatgc tcctcttgac agtggtcgtc agcatgtaca agagcttctt tatcatagta 4020 ggcatgtttc tcttgctgct gtgttacgct tttgctggag ttgttttatt tggtactgtg 4080 aaatatgggg agaatattaa caggcatgca aatttttctt cggctggaaa agctattacc 4140 gtactgttcc gaattgtcac aggtgaagac tggaacaaga ttatgcatga ctgtatggta 4200 cagcctccgt tttgtactcc agatgaattt acatactggg caacagactg tggaaattat 4260 gctggggcac ttatgtattt ctgttcattt tatgtcatca ttgcctacat catgctaaat 4320 ctgcttgtag ccataattgt ggagaatttc tccttgattt attccactga ggaggaccag 4380 cttttaagtt acaatgatct tcgccacttt caaataatat ggaacatggt ggatgataaa 4440 agagaggtat tccccacgtt ccgcgtcaag ttcctgctgc ggctactgcg tgggaggctg 4500 gaggtggacc tggacaagga caagctcctg tttaagcaca tgtgctacga aatggagagg 4560 ctccacaatg gcggcgacgt caccttccat gatgtcctga gcatgctttc ataccggtcc 4620 gtggacatcc ggaagagctt gcagctggag gaactcctgg cgagggagca gctggagtac 4680 accatagagg aggaggtggc caagcagacc atccgcatgt ggctcaagaa gtgcctgaag 4740 cgcatcagag ctaaacagca gcagtcgtgc agtatcatcc acagcctgag agagagtcag 4800 cagcaagagc tgagccggtt tctgaacccg cccagcatcg agaccaccca gcccagtgag 4860 gacacgaatg ccaacagtca ggacaacagc atgcaacctg agacaagcag ccagcagcag 4920 ctcctgagcc ccacgctgtc ggatcgagga ggaagtcggc aagatgcagc cgacgcaggg 4980 aaaccccaga ggaaatttgg gcagtggcgt ctgccctcag ccccaaaacc aataagccat 5040 tcagtgtcct cagtcaactt acggtttgga ggaaggacaa ccatgaaatc tgtcgtgtgc 5100 aaaatgaacc ccatgactga cgcggcttcc tgcggttctg aagttaagaa gtggtggacc 5160 cggcagctga ctgtggagag cgacgaaagt ggggatgacc ttctggatat ttag 5214 <210> 61 <211> 1818 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 168827CB1 <400> 61 ggaaattgct tccgtgaccc tgctgcagat gggagagagg gcccattaag aagagagtgg 60 ggtcaggatc aacacacaca cttagtgtga tttaaggaaa ggaaatattt tctctttgaa 120 cttatctgga tacagtcatt ttgtctcctc ttggggatca cttgtccagc ctcaatggcc 180 tttcaggacc tcctagatca agttggaggc ctggggagat tccagatcct tcagatggtt 240 ttccttataa tgttcaacgt catagtatac catcaaactc agctggagaa cttcgcagca 300 ttcatacttg atcatcgctg ctgggttcat atactggaca atgacactat ccctgacaat 360 gaccctggga ccctcagcca ggatgccctc ctgagaatct ccatcccatt cgactcaaat 420 ctgaggccag agaagtgtcg tcgctttgtc catccccagt ggaagctcat tcatctgaat 480 gggaccttcc ccaacacgag tgagccagat acagagccct gtgtggatgg ctgggtatat 540 gaccaaagct ccttcccttc caccattgtg actaagtggg atctggtatg cgaatctcaa 600 ccactgaatt cagtagctaa atttctattc atggctggaa tgatggtggg aggcaaccta 660 tatggccatt tgtcagacag gtttgggaga aagttcgtgc tcagatggtc ttacctccag 720 ctcgccattg taggcacctg tgcggccttt gctcccacca tcctcgtata ctgctccctg 780 cgcttcttgg ctggggctgc tacatttagc atcattgtaa atactgtttt gttaattgta 840 gagtggataa ctcaccaatt ctgtgccatg gcattgacat tgacactttg tgctgctagt 900 attggacata taaccctggg aagcctggct tttgtcattc gagaccagtg catcctccag 960 ttggtgatgt ctgcaccatg ctttgtcttc tttctgttct caaggtggct ggcagagtct 1020 gctcggtggc tcattatcaa caacaaacca gaagagggct taaaggaact tacaaaagct 1080 gcacacagga atggaatgaa gaatgctgaa gacatcctaa ccatggaggt tttgaaatcc 1140 accatgaagc aagaactgga ggcagcacag aaaaagcatt ctctttgtga attgctccgc 1200 atacccaaca tatgtaaaag aatctgtttc ctgtcctttg tgagatttgc aagtaccatc 1260 cctttttggg gccttacttt gcacctccag catctgggaa acaatgtttt cctgttgcag 1320 actctctttg gtgcagtcac cctcctggcc aattgtgttg caccttgggc actgaatcac 1380 atgagccgtc gactaagcca gatgcttctc atgttcctac tggcaacctg ccttctggcc 1440 atcatatttg tgcctcaaga aatgcagacc ctgcgtgtgg ttttggcaac cctgggtgtg 1500 ggagctgctt ctcttggcat tacctgttct actgcccaag aaaatgaact aattccttcc 1560 ataatcaggg gaagagctac tggaatcact ggaaactttg ctaatattgg gggagccctg 1620 gcttccctca tgatgatcct aagcatatat tctcgacccc tgccctggat catctatgga 1680 gtctttgcca tcctctctgg ccttgttgtc ctcctccttc ctgaaaccag gaaccagcct 1740 cttcttgaca gcatccagga tgtggaaaat gagggagtaa atagcctagc tgcccctcag 1800 aggagctctg tgctatag 1818 <210> 62 <211> 2245 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7472734CB1 <400> 62 cccttggaac agtaggatgt tggtgatgca aaagtcaatg tttaaactca acattccact 60 ttcctttaac taagaatagt ttttattaac ttttagtaaa actcagtcct agtccaaaaa 120 aagccctgct ctctgatctt tgtacaagaa catcataaag caattcactt tggattttct 180 aatatcccat ttctgagaag aatggcagac tattgaacag gtgtatttta ggtcacgtgg 240 ggactgcatc cacctgaaaa tccaccgttg acttatcagg aaactcagag atcaggatct 300 ttcacagagt agtcttttaa gaagattcag ttgteaacag ctagcagtct ctttgccaaa 360 taattatatc tgtgacttct gaaactattt ggctgcctaa agttaaagga cttggggaaa 420 gtccctccac tgctcttctg cagtagtgtc acaccactca gtgcagggcc caccaagaag 480 aaagcagtgt caggatccac atggcactat ggtaactttg tgaaagggga cattttctcc 540 ctctgaactt ctcttcataa agtcattgtg cttcctcttg gggatcaoct gttcagtctc 600 aatgggcttt gatgtgctcc tggatcaagt gggtggcatg gggagattcc agatttgtct 660 gatagctttc ttttgcatca ccaacatcct actgttccct aatattgtgt tggagaactt 720 cactgcattc acccctagtc atcgctgctg ggtccccctc ctggacaatg acactgtgtc 780 tgacaatgat accgggaccc tcagcaagga tgacctcctg agaatctcca tcccactgga 840 ctcaaacctg aggccacaga agtgtcagcg ctttatccat ccccagtggc agctccttca 900 cctgaacggg accttcccca acacaaatga gccagacacg gagccctgtg tggatggctg 960 ggtgtacgac agaagctctt tcctctccac catcgtgact gagtgggacc tggtatgtga 1020 atctcagtca ctaaaatcaa tggttcaatc cctatttatg gctgggtcac ttctgggagg 1080 tctaatatat ggccatcttt cagacaggtt tgggagaaag ttcgtgctca gatggtctta 1140 cctccagctc gccattgtag gcacctgtgc ggcctttgct cccaccatcc tcgtatactg 1200 ctccctgcgc ttcttggctg gggctgctac atttagcatc attgtaaata ctgttttgtt 1260 aattgtagag tggataactc accaattctg tgccatggca ttgacattga cactttgtgc 1320 tgctagtatt ggacatataa ccctgggaag cctggctttt gtcattcgag accagtgcat 1380 cctccagttg gtgatgtctg caccatgctt tgtcttcttt ctgttctcaa ggtggctggc 1440 agagtctgct cggtggctca ttatcaacaa caaaccagaa gagggcttaa aggaacttag 1500 aaaagctgca cacaggaatg gaatgaagaa tgctgaagac atcctaacca tggaggtttt 1560 gaaatccacc atgaagcaag aactggaggc agcacagaaa aagcattctc tttgtgaatt 1620 gctccgcata cccaacatat gtaaaagaat ctgtttcctg tcctttgtga gatttgcaag 1680 taccatccct ttttggggcc ttactttgca cctccagcat ctgggaaaca atgttttcct 1740 gttgcagact ctctttggtg cagtcaccct cctggccaat tgtgttgcac cttgggcact 1800 gaatcacatg agccgtcgac taagccagat gcttctcatg ttcctactgg caacctgcct 1860 tctggccatc atatttgtgc ctcaagaaat gcagaccctg cgtgtggttt tggcaaccct 1920 gggtgtggga gctgcttctc ttggcattac ctgttctact gcccaagaaa atgaactaat 1980 tccttccata atcaggggaa gagctactgg aatcactgga aactttgcta atattggggg 2040 agccctggct tccctcatga tgatcctaag catatattct cgacccctgc cctggatcat 2100 ctatggagtc tttgccatcc tctctggcct tgttgtcctc ctccttcctg aaaccaggaa 2160 ccagcctctt cttgacagca tccaggatgt ggaaaatgag ggagtaaata gcctagctgc 2220 ccctcagagg agctctgtgc tatag 2245 <210> 63 <211> 3196 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7473473CB1 <400> 63 gcggcggccg ggggagcgct actaccatga actgcctggt cctcctcccc agagctgctc 60 atccgggtcg ggctggagac acagtcaggg gaccccgtcg ccgccgccgc gccccctctt 120 ctttcggctc aatcttctct tccacctttt cctcctcttc ctccaccttc tttgcctgca 180 tccccccctc ccccgccgcg gatcctggcc gctgctctcc agacccagga tgccgggggg 240 caagagaggg ctggtggcac cgcagaacac atttttggag aacatcgtca ggcgctccag 300 tgaatcaagt ttcttactgg gaaatgccca gattgtggat tggcctgtag tttatagtaa 360 tgacggtttt tgtaaactct ctggatatca tcgagctgac gtcatgcaga aaagcagcac 420 ttgcagtttt atgtatgggg aattgactga caagaagacc attgagaaag tcaggcaaac 480 ttttgacaac tacgaatcaa actgctttga agttcttctg tacaagaaaa acagaacccc 540 tgtttggttt tatatgcaaa ttgcaccaat aagaaatgaa catgaaaagg tggtcttgtt 600 cctgtgtact ttcaaggata ttacgttgtt caaacagcca atagaggatg attcaacaaa 660 aggttggacg aaatttgccc gattgacacg ggctttgaca aatagccgaa gtgttttgca 720 gcagctcacg ccaatgaata aaacagaggt ggtccataaa cattcaagac tagctgaagt 780 tcttcagctg ggatcagata tccttcctca gtataaacaa gaagcgccaa agacgccacc 840 acacattatt ttacattatt gtgcttttaa aactacttgg gattgggtga ttttaattct 900 taccttctac accgccatta tggttcctta taatgtttcc ttcaaaacaa agcagaacaa 960 catagcctgg ctggtactgg atagtgtggt ggacgttatt tttctggttg acatcgtttt 1020 aaattttcac acgactttcg tggggcccgg tggagaggtc atttctgacc ctaagctcat 1080 aaggatgaac tatctgaaaa cttggtttgt gatcgatctg ctgtcttgtt taccttatga 1140 catcatcaat gcctttgaaa atgtggatga gggaatcagc agtctcttca gttctttaaa 1200 agtggtgcgt ctcttacgac tgggccgtgt ggctaggaaa ctggaccatt acctagaata 1260 tggagcagca gtcctcgtgc tcctggtgtg tgtgtttgga ctggtggccc actggctggc 1320 ctgcatatgg tatagcatcg gagactacga ggtcattgat gaagtcacta acaccatcca 1380 aatagacagt tggctctacc agctggcttt gagcattggg actccatatc gctacaatac 1440 cagtgctggg atatgggaag gaggacccag caaggattca ttgtacgtgt cctctctcta 1500 ctttaccatg acaagcctta caaccatagg atttggaaac atagctccta ccacagatgt 1560 ggagaagatg ttttcggtgg ctatgatgat ggttggcgct cttctttatg caactatttt 1620 tggaaatgtt acaacaattt tccagcaaat gtatgccaac accaaccgat accatgagat 1680 gctgaataat gtacgggact tcctaaaact ctatcaggtc ccaaaaggcc ttagtgagcg 1740 agtcatggat tatattgtct caacatggtc catgtcaaaa ggcattgata cagaaaaggt 1800 cctctccatc tgtcccaagg acatgagagc tgatatctgt gttcatctaa accggaaggt 1860 ttttaatgaa catcctgctt ttcgattggc cagcgatggg tgtctgcgcg ccttggcggt 1920 agagttccaa accattcact gtgctcccgg ggacctcatt taccatgctg gagaaagtgt 1980 ggatgccctc tgctttgtgg tgtcaggatc cttggaagtc atccaggatg atgaggtggt 2040 ggctatttta gggaagggtg atgtatttgg agacatcttc tggaaggaaa ccacccttgc 2100 ccatgcatgt gcgaacgtcc gggcactgac gtactgtgac ctacacatca tcaagcggga 2160 agccttgctc aaagtcctgg acttttatac agcttttgca aactccttct caaggaatct 2220 cactcttact tgcaatctga ggaaacggat catctttcgt aagatcagtg atgtgaagaa 2280 agaggaggag gagcgcctcc ggcagaagaa tgaggtgacc ctcagcattc ccgtggacca 2340 cccagtcaga aagctcttcc agaagttcaa gcagcagaag gagctgcgga atcagggctc~2400 aacacagggt gaccctgaga ggaaccaact ccaggtagag agccgctcct tacagaatgg 2460 agcctccatc accggaacca gcgtggtgac tgtgtcacag attactccca ttcagacgtc 2520 tctggcctat gtgaaaacca gtgaatccct taagcagaac aaccgtgatg ccatggaact 2580 caagcccaac ggcggtgctg accaaaaatg tctcaaagtc aacagcccaa taagaatgaa 2640 gaatggaaat ggaaaagggt ggctgcgact caagaataat atgggagccc atgaggagaa 2700 aaaggaagac tggaataatg tcactaaagc tgagtcaatg gggctattgt ctgaggaccc 2760 caagagcagt gattcagaga acagtgtgac caaaaaccca ctaagaaaaa cagattcttg 2820 tgacagtgga attacaaaaa gtgaccttcg tttggataag gctggggagg cccgaagtcc 2880 gctagagcac agtcccatcc aggctgatgc caagcacccc ttttatccca tccccgagca 2940 ggccttacag accacactgc aggaagtcaa acacgaactc aaagaggaca tccagctgct 3000 cagctgcaga atgactgccc tagaaaagca ggtggcagaa attttaaaaa tactgtcgga 3060 aaaaagcgta ccccaggcct catctcccaa atcccaaatg ccactccaag taccccccca 3120 gataccatgt caggatattt ttagtgtctc aaggcctgaa tcacctgaat ctgacaaaga 3180 tgaaatccac ttttaa 3196 <210> 64 <211> 1602 <212> DNA
<213> Homo Sapiens <220>
<221> misc_feature <223> Incyte ID No: 7477725CB1 <400> 64 atggcctttg aggagctctt gagtcaagtt ggaggccttg ggagatttca gatgcttcat 60 ctggttttta ttcttccctc tctcatgtta ttaatccctc atatactgct agagaacttt 120 gctgcagcca ttcctggtca tcgttgctgg gtccacatgc tggacaataa tactggatct 180 ggtaatgaaa ctggaatcct cagtgaagat gccctcttga gaatctctat cccactagac 240 tcaaatctga ggccagagaa gtgtcgtcgc tttgtccatc cccagtggca gcttcttcac 300 ctgaatggga ctatccacag cacaagtgag gcagacacag aaccctgtgt ggatggctgg 360 gtatatgatc aaagctactt cccttcgacc attgtgacta agtgggacct ggtatgtgat 420 tatcagtcac tgaaatcagt ggttcaattc ctacttctga ctggaatgct ggtgggaggc 480 atcataggtg gccatgtctc agacaggttt gggcgaagat ttattctcag atggtgtttg 540 ctccagcttg ccattactga cacctgcgct gccttcgctc ccaccttccc tgtttactgt 600 gtactacgct tcttggcagg tttttcttcc atgatcatta tatcaaataa ttctttgccc 660 attactgagt ggataaggcc caactctaaa gccctggtag taatattgtc atctggtgcc 720 cttagtattg gacagataat cctgggaggc ttggcttatg tcttccgaga ctggcaaacc 780 ctgcacgtgg tggcgtctgt acctttcttt gtcttctttc ttctttcaag gtggctggtg 840 gaatctgctc ggtggttgat aatcaccaat aaactagatg agggcttaaa ggcacttaga 900 aaagttgcac gcacaaatgg aataaagaat gctgaagaaa ccctgaacat agaggttgta 960 agatccacca tgcaggagga gctggatgca gcacagacca aaactactgt gtgtgacttg 1020 ttccgcaacc ccagtatgcg taaaaggatc tgtatcctgg tatttttgag atttgcaaac 1080 acaatacctt tttatggtac catggtcaat cttcagcatg tggggagcaa cattttcctg 1140 ttgcaggtac tttatggagc tgtcgctctc atagttcgat gtcttgctct tttgacacta 1200 aatcatatgg gccgtcgaat aagccagata ttgttcatgt tcctggtggg cctttccatt 1260 ttggccaaca cgtttgtgcc caaagaaatg cagaccctgc gtgtggcttt ggcatgtctg 1320 ggaatcggct gttctgctgc tactttttcc agtgttgctg ttcacttcat tgaactcatc 1380 cccactgttc tcagggcaag agcttcagga atagatttaa cggctagtag gattggagca 1440 gcactggctc ccctcttgat gaccttaacg gtatttttta ccactttgcc atggatcatt 1500 tatggaatct tccccatcat tggtggcctt attgtcttcc tcctaccaga aaccaagaat 1560 ctgcctttgc ctgacaccat caaggatgtg gaaaatcagt ga 1602

Claims (108)

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:1-32, 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:1-32, c) a biologically active fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, and d) an immunogenic fragment of a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32.

2. An isolated polypeptide of claim 1 selected from the group consisting of SEQ ID NO:1-32.

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 selected from the group consisting of SEQ ID
NO:33-64.

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

11. An isolated polynucleotide selected from the group consisting of:

a) a polynucleotide comprising a polynucleotide sequence selected from the group consisting of SEQ ID N0:33-64, 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 N0:33-64, c) a polynucleotide complementary to a polynucleotide of a), d) a polynucleotide complementary to a polynucleotide of b), and e) an RNA equivalent of a)-d).

12. An isolated polynucleotide comprising at least 60 contiguous nucleotides of a polynucleotide of claim 11.

13. A method fox detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, 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.

14. A method of claim 13, wherein the probe comprises at least 60 contiguous nucleotides.

15. A method for detecting a target polynucleotide in a sample, said target polynucleotide having a sequence of a polynucleotide of claim 11, 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.

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

17. A composition of claim 16, wherein the polypeptide has an amino acid sequence selected from the group consisting of SEQ ID NO:1-32.

18. A method for treating a disease or condition associated with decreased expression of functional TRICH, comprising administering to a patient in need of such treatment the composition of claim 16.

19. A method for 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.

20. A composition comprising an agonist compound identified by a method of claim 19 and a pharmaceutically acceptable excipient.

21. A method for treating a disease or condition associated with decreased expression of functional TRICH, comprising administering to a patient in need of such treatment a composition of claim 20.

22. A method for 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.

23. A composition comprising an antagonist compound identified by a method of claim 22 and a pharmaceutically acceptable excipient.

24. A method for treating a disease or condition associated with overexpression of functional TRICH, comprising administering to a patient in need of such treatment a composition of claim 23.

25. A method of screening for a compound that specifically binds to the polypeptide of claim 1, said method comprising the steps of:

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.

26. A method of screening for a compound that modulates the activity of the polypeptide of claim 1, said 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.

27. A method for 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.

28. 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 of claim 11 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 11 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.

29. A diagnostic test for a condition or disease associated with the expression of TRICH in a biological sample comprising the steps of:

a) combining the biological sample with an antibody of claim 10, 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.

30. The antibody of claim 10, wherein the antibody is:

a) a chimeric antibody, b) a single chain antibody, c) a Fab fragment, d) a Flab' )2 fragment, or e) a humanized antibody.

31. A composition comprising an antibody of claim 10 and an acceptable excipient.

32. A method of diagnosing a condition or disease associated with the expression of TRICH
in a subject, comprising administering to said subject an effective amount of the composition of claim 31.

33. A composition of claim 31, wherein the antibody is labeled.

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

35. A method of preparing a polyclonal antibody with the specificity of the antibody of claim comprising:

a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, 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 binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32.

36. An antibody produced by a method of claim 35.

37. A composition comprising the antibody of claim 36 and a suitable carrier.

38. A method of making a monoclonal antibody with the specificity of the antibody of claim comprising:

a) immunizing an animal with a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32, 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 binds specifically to a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID
NO:1-32.

39. A monoclonal antibody produced by a method of claim 38.

40. A composition comprising the antibody of claim 39 and a suitable carrier.

41. The antibody of claim 10, wherein the antibody is produced by screening a Fab expression library.

42. The antibody of claim 10, wherein the antibody is produced by screening a recombinant immunoglobulin library.

43. A method for detecting a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32 in a sample, comprising the steps of:

a) incubating the antibody of claim 10 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 having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32 in the sample.

44. A method of purifying a polypeptide having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32 from a sample, the method comprising:

a) incubating the antibody of claim 20 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 having an amino acid sequence selected from the group consisting of SEQ ID NO:1-32.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

73. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:29.

74. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:30.

75. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:31.

76. A polypeptide of claim 1, comprising the amino acid sequence of SEQ ID
NO:32.

77. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:33.

78. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:34.

79. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:35.

80. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:36.

81. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:37.

82. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:38.

83. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:39.

84. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:40.

85. A polynucleotide of claim 1 l, comprising the polynucleotide sequence of SEQ ID
NO:41.

86. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:42.

87. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:43.

88. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:44.

89. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:45.

90. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:46.

91. A polynucleotide of claim 1 l, comprising the polynucleotide sequence of SEQ ID
NO:47.

92. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:48.

93. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:49.

94. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:50.

95. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:51.

96. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:52.

97. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:53.

98. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:54.

99. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:55.

100. A polynucleotide of claim 1 l, comprising the polynucleotide sequence of SEQ ID
NO:56.

101. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:57.

102. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:58.

103. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:59.

104. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:60.

105. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:61.

106. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:62.

107. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:63.

108. A polynucleotide of claim 11, comprising the polynucleotide sequence of SEQ ID
NO:64.