CA2395295A1 - Nucleic acids, proteins and antibodies - Google Patents

Abstract

The present invention relates to novel digestive system related polynucleotides and the polypeptides encoded by these polynucleotides herein collectively known as "digestive system antigens", and the use of such digestive system antigens for detecting disorders of the digestive system, particularly the presence of cancer and cancer metastases. More specifically, isolated digestive system associated nucleic acid molecules are provided encoding novel digestive system associated polypeptides. Novel digestive system polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human digestive system associated polynucleotides and/or polypeptides. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the digestive system, including cancer, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention . The present invention further relates to methods and/or compositions for inhibiting the production and function of the polypeptides of the present invention.

Description

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Nucleic Acids, Proteins, and Antibodies [001] This application refers to a "Sequence Listing" that is provided only on electronic media in computer readable form pursuant to Administrative W structions Section 801(a)(i). The Sequence Listing forms a part of this description pursuant to Rule 5.2 and Administrative Instructions Sections 801 to 806, and is hereby incorporated in its entirety.

[002] The Sequence Listing is provided as an electronic file (PC002PCT
seqList.txt, 9,710,493 bytes in size, created on January 12, 2001) on four identical compact discs (CD-R), labeled "COPY l," "COPY 2," "COPY 3," and "CRF." The Sequence Listing complies with Annex C of the Administrative Instructions, and may be viewed, fox example, on an IBM-PC machine running the MS-Windows operating system by using the V viewer software, version 2000 (see World Wide Web URL:
http:llwww.fileviewer.com).
Field of the Invention [003] The present invention relates to novel digestive system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "digestive system amtigens," and antibodies that immux~ospecifically bind these polypeptides, and the use of such digestive system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing - disorders of the digestive system, including, but not limited to, the presence of cancer and cancer metastases. More specifically, isolated digestive system nucleic acid molecules are provided encoding novel digestive system polypeptides. Novel digestive system polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human digestive system polynucleotides, polypeptides, and/or antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the digestive system, including cancer, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting or promoting the production and/or function of the polypeptides of the invention.
Backg~ouhd of the Itwehtion [004] The Human Digestive System is a collection of specialized organs and body tissues that prepare food for use by hundreds of millions of body cells. Food when eaten cannot reach cells because it cannot pass through~the.intestinal walls to the bloodstream and, if it could would not be in a useful chemical state. The gut modifies food physically and chemically and disposes of unusable waste. Physical and chemical modification (digestion) depends on exocrine and endocrine secretions and controlled movement of food through the digestive tract.

[005] The three fundamental processes of the Digestive System are: Secretion (e.g., delivery of enzymes, mucus, ions and the like into the lumen, and hormones into blood), Absorption (e.g., transport of water, ions and nutrients from the lumen, across the epithelium and into blood), and Motility (e.g., contractions of smooth muscle in the wall of the tube that crush, mix and propel its contents). Control of digestive function is achieved through a combination of electrical and hormonal messages which originate either within the digestive system's own nervous and endocrine systems, as well as from the central nervous sytem and from endocrine organs such as the adrenal gland.

[006] The digestive system is composed of the digestive or alimentary tube and accessory digestive organs; which include the Mouth (e.g., tongue, taste buds, soft palate pharynx, salivary glands, teeth), Esophagus, Stomach, Liver, Gallbladder, Pancreas, Small Intestine (e.g., duodenum, jejunum, and ileum), and Large Intestine .
(e.g., caecum). ' _ _ [007] Common digestive.system disorders including infections; inflammations, ulcers and cancers of the the digestive or alimentary tube and above listed accessory digestive organs are described in more detail below.
Disorders of the Esophagus [008] Disorders of the Esophagus include dysphagia (e.g., difficulty in swallowing) and odynophagia (e.g., difficulty in swallowing accompanied by pain).
Dysphagia may be prominent in cases of degenerative disease of the.central nervous system, especially of the ganglia at the base of the brain. Congenital disorders of the esophagus are most often seen in infancy, primarily as a failure to develop normal passageways.
The lower end of the esophagus is subject to various developmental anomalies that shorten the organ so that the stomach is pulled up into the thoracic cavity. Anomalies of the diaphragm may contribute to a similiar outcome. Inflammatory disorders of the esophagus result from a variety of causes; for example, ingestion of noxious materials (e.g., corrosive esophagitis), lodgment of foreign bodies, or a complex of events associated with reflux of gastric contents from the stomach into the lower esophagus (e.g., peptic esophagitis).

[009] Disorders of the motility of the esophagus tend to be either precipitated or aggravated at times of nervous stress. A disorder commonly due to obesity is gastric reflux. Persisting reflux of gastric contents with acid and digesting enzymes leads to chemical inflammation of the lining of the esophagus and ultimately to (peptic) ulceration. If inadequately treated, the process leads to submucosal fibrosis and stricturing, and, besides the symptoms of heartburn and regurgitation, the patient experiences pain on eating and swallowing.

[010] Pouches in the walls of the structures in the digestive system that occur wherever weak spots exist between adjacent muscle layers are called diverticula. In the upper esophagus, these may occur in the area where the striated constrictor muscles of the pharynx merge with the smooth muscle of the esophagus just below the larynx.
Small diverticula just above the diaphragm sometimes are found after the introduction of surgical instruments into the esophagus. A serious injury to the esophagus is spontaneous rupture. It can occur in patients who have been vomiting or retching and in debilitated elderly persons with chronic lung disease. A rupture of this type confined _..

to the rnucosa only at the junction of the linings of the esophagus and stomach is called a Mallory-Weiss lesion.

[011] Benign tumors of the esophagus originate in the submucosal tissues and principally are leiomyomas (tumors composed of smooth muscle tissue) or lipomas (tumors composed of adipose, or fat, tissues). Malignant tumors are either epidermal cancers, made up of unorganized aggregates of cells, or adenocarcinomas, in which there are gland-like formations. Cancers arising from squamous tissues are found at all levels of the organ, whereas adenocarcinomas are more common at the lower end where a number of glands of gastric origin are normally present. The prognosis is poor because diagnosis is difficult and the tumor has usually been growing for one or two years before symptoms are apparent.
Disorders of the stomach [012] Any disorder that affects the power of coordination of the stomach muscles is capable of producing symptoms ranging from those that are mildly unpleasant (e.g., anorexia and nausea) to others that are life-threatening. The intrinsic muscles of the stomach are innervated by branches of the vagus nerves, which travel along the esophagus from their point of emergence in the brain stem. Severing these nerves or altering their function by the use of anticholinergic medication may produce temporary or more prolonged change in the ability of the stomach to empty itself.
Gastric retention may result from the degeneration of the nerves to the stomach that can result from diabetes mellitus. Obstruction due to scarring in the area of the gastric outlet, or . to tumors encroaching on the lumen, causes the stomach to fill up with its own secretions as well as with partially digested food. In these circumstances, vomiting leads to dehydration and to electrolyte losses, which threaten life if not corrected.

[013] Disorders of the stomach include, ulcerative diseases; which involve mucosal breakdown either confined'to the superficial layers of the mucosa (e.g., an erosion) or extending through the intrinsic layer of muscle of the mucosa into the tissues below (e.g., an ulcer): The circumstances that contribute to mucosal injury and ulcer formation include physical and chemical trauma that result from hot fluids and food, aspirin and other drugs, irritating spices, and pickling fluids. In addition, genetic factors are involved in the development of ulcers. The complications of peptic ulcers are hemorrhage, perforation, and obstruction of the outlet of the stomach (pyloric stenosis) by scarring of the duodenal bulb or of the pyloric channel. A
diffuse inflammation of the stomach lining, gastritis, is usually an acute process caused by contaminated food, alcohol abuse, or by bacterial- or viral-induced inflammation of the gastrointestinal tract (gastroenteritis). The other form of gastritis is gastric atrophy, in which the thickness of the mucosa is diminished. Diffuse gastric atrophy leads to partial loss of the glands and secreting cells throughout the stomach and may be associated with iron-deficiency anemia.
[014] Malignant tumors of the stomach are common and are probably a result of both genetic and environmental factors. Gastric cancer affects men more often than women and accounts for about 20 percent of all deaths from cancers of the gastrointestinal tract in the United States. Other malignant tumors that involve~the stomach are tumors ordinarily made up of lymphoid and connective tissue. Benign tumors, especially leiomyomas, are common and may, when large, cause massive hemorrhage.
Polyps.of the stomach are not common except in the presence of gastric atrophy.
Disorders of the Duodenum and Small Intestine [015] Primary cancer of the duodenum is an infrequent disease, however, benign tumors of the duodenum particularly polyps and carcinoids, are more frequent.
Cancers of the common bile duct or of the pancreas are important causes of death. A
common disorder of the small intestine, distension, is caused by lack of coordination ~of the inner circular and outer .longitudinal muscular layers of the intestinal wall which usually results in an accumulation of excess contents in the lumen. The most common cause of disturbed motility in the small intestine is food that contains an unsuitable additive, organism, or component. One of the most serious problems in small intestine are motor disturbances which arise from an~ intestinal obstruction that results from an actual encroachment on the bowel by an adhesive band or from an internal block produced by a tumor or gallstone. In addition, as profound an obstruction results when a portion of the intestine undergoes partial necrosis, or death, from failure of its blood supply.

[016] The extremely common disorder known as the irritable bowel syndrome is probably due to a disturbance of the motility. of the whole intestinal tract.
The symptoms vary from watery diarrhea to constipation and the passage of stools with difficulty. When the colon is involved, an excess of mucus is often observed in the stools. Occasionally the irritable bowel syndrome may be due to an allergy to a particular foodstuff. The syndrome may develop following an infection such as bacillary dysentery, after which the small intestine remains irritable for many months.

[017] A further disorder, malabsorption occurs when the small intestine is unable to transport properly broken down products of digestive materials from the lumen of the intestine into the lymphatics or mesenteric veins, where they are distributed to the rest of the body. Defects in transport occur either because the absorptive cells of the intestine lack certain enzymes, whether by birth defect or ~ by acquired disease, or because they are hindered in their work by other disease processes that infiltrate the tissues, disturb motility, permit bacteria to overpopulate the bowel, or block the pathways over which transport normally proceeds. A malabsorption disorder of unknown cause, tropical sprue, is associated with partial atrophy of the mucosa of the small intestine.

[018] Several disorders of the small intestine are congentital. For example, Meckel's diverticulum is a corrimon congenital malformation that occurs when the duct leading from the navel to the small intestine in the fetus fails to atrophy and close.
'Another congenital problem in the small intestine is the presence of multiple diverticula, or outpouchings of mucosa and serosa. A third congenital malformation is a failure of complete rotation of the small and ~ large intestine, which is a normal step in the development of the fetus. This can result in abnormal intestinal attachments with a subsequent risk of obstruction when the intestine twists around the attachments.

[019] Disorders of the small intestine also include bacterial and parasitic infections.
Traveler's diarrhea (e.g., diarrhea which is watery, accompanied by cramps, and lasts a few days) is most often caused by toxin-generating Escherichia coli, and less often by other organisms. Such diarrhea generally disappears spontaneously with abstention from food accompanied by drinking of nonalcoholic fluids. Species of Salmonella that cause typhoid and paratyphoid remain endemic in some contries and, together with Shigella, are occasional causes of epidemics in institutions. Cholera, caused by Vibrio cholerae, is endemic to Southeast Asia and periodically becomes pandemic. In equatorial countries, parasitism is endemic, with Roundworms, tapeworms, amoebae, ___ ___ 6 _ hookworms, strongyloides, threadworms, and blood flukes (schistosomiasis) being the main types of parasites. Roundworms, or Ascariasis lumbricoides interfere with the absorption of fat and protein in the intestine, which causes diarrhea.
Hookworm, or Ancylostoma duodenale, infection deplete the body of nutrients, and a major effect is severe chronic iron-deficiency anemia. Threadworms, or Enterobius vermicularis, live mainly in the cecum and cause anal itching. Common tapeworms are Taenia saginata, found in beef, and T. solium, found in pork. Larvae of Echinococcus granulosus, Diphyllobothrium species, and some dwarf tapeworms also cause disease:
Tapeworms found in beef and pork only give rise to symptoms if their number and size cause intestinal obstruction. Diphyllobothrium latum, a fish tapeworm, may cause a severe anemia similar to pernicious anemia, because it consumes most of the vitamin in the diet of the host. ' [020] Appendicitis is an inflammation of the vermiform appendix that may be caused by infection or partial or total obstruction. Chronic inflammations of the small intestine include tuberculosis and regional enteritis (Crohn's disease). Celiac disease causes damage to the mucosa of the small intestine, though it is not clear whether it is caused by an immune reaction, or an inability to break down a toxic protein, gluten, to smaller peptide fractions. Studies of the immune function of those with celiac disease suggest that at least a major part of the process is a delayed hypersensitivity reaction and that the morphological changes are correlated with the presence of circulating antibodies to gluten. The mucosal reaction results in progressive atrophy, with dwarfing, if not complete' disappearance, of the microvilli and villi that line the intestinal tract.
Disorders of the Large Intestine [021] A wide variety of diseases and disorders occur in the large intestine.
Imperfect fetal development may result in an anus that has no opening, a defect that requires major plastic surgery to correct. Abnormal rotation of the colon is fairly frequent and ' occasionally leads to disorders. Unusually long mesenteries (the supporting tissues of the large intestine) may permit recurrent twisting, cutting off the blood supply to the involved loop. Brain disease, metabolic failure, or drugs can dull the normal signals that give rise to the urge to defecate. Poor abdominal musculature or a poor pelvic floor makes it difficult to mobilize effective pressures to bring about defecation.
._ ~

[022] A disease that is analogous to achalasia of the esophagus is an idiopathic condition called aganglionic megacolon, or Hirschsprung's disease. It is characterized by the absence of ganglion cells and normal nerve fibres from the distal (or lower) portion of the large intestine, which results in reduced neuromuscular transmission and .
ceased peristalsis. The entire colon slowly becomes more and more distended and thick-walled. A related disorder, acquired megacolon, is commonly caused by a combination of faulty toilet training and emotional disorders during childhood, in which the child withholds defecation. This starts a cycle of the administration of increasing amounts of laxatives with, ultimately, damage to the intrinsic innervation in the intestinal wall. A huge, dilated rectum full of feces develops over the years and act as an obstruction, leading to voluminus dilatation of the whole colon in some cases.
The same phenomenon is occasionally encountered in those with schizophrenia and severe depression.

[023] Abscesses in the perianal area are common complicating features of many diseases and disorders of the large intestine. Fungal and bacterial infections are also common causes of large intestine disorders. Fungal infections of the moist and poorly cleansed area around the anus permit the maceration of tissue and the invasion by , bacteria from the skin and colon. The colon may become inflammed and ulcerate because of invasion by pathogenic, or disease-causing, bacteria or parasites, or viral infection. For example, Shigella species may attack the mucous membrane of the colon and produce an intense but .rather superficial hemorrhage; Salmonella species may damage the lymph follicles of the colon, but do not produce a generalized inflammation of the colon; cytomegalic virus can cause a severe colitis producing ulcerations; Lymphopathia vene~eum can cause a more generalized and superficial colitis; and Entamoeba histolytica lodge in the cecum and ascending colon, undermine the mucosal coat, and may create large ulcerations that bleed impressively.

[024] The .most common form of chronic colitis, ulcerative colitis, is idiopathic. It varies from a mild inflammation of the mucosa of the rectum, giving rise to excessive mucus and some spotting of blood in the stools, to a severe, sudden, intense illness, _ with destruction of a large part of the colonic mucosa, considerable blood loss, toxemia and, less commonly, perforation. The most common variety affects only the rectum and sigmoid colon and is characterized by diarrhea and the passage of mucus.

Apart from the greater tendency' for fistulas to form and for the wall of the intestine to thicken until the channel is obstructed, Crohn's disease is distinguishable from ulcerative colitis by microscopic findings. In Crohn's disease, the maximum damage occurs beneath the mucosa, and lymphoid conglomerations, known as granulomata, are formed in the submucosa. Crohn's disease attacks the perianal tissues more often than does ulcerative colitis. Although these two diseases are not common, they are disabling.

[025] Tumors of the colon are usually polyps or cancers. A peculiar form of polyp is the vinous adenoma, often a slowly growing, fernlike stnzcture that spreads along the surface of the colon for some distance. In the West, cancer of the colon is a more common tumor than is cancer of the stomach, and it occurs about equally in both sexes. Cancers compress the colonic lumen to produce obstruction, they attach to neighbouring structures to produce pain, and they perforate to give rise to peritonitis.
Cancers also may metastasize to distant organs before local symptoms appear.
[02b] Anorectal disorders related to defecation are more common in the Western world than elsewhere. These disorders usually take the form of fissures (cuts or cracks in the skin or mucous membrane) at the junction of the anal mucous membrane with the skin between the thighs. Anal fistulas sometimes occur as complications of serious bowel disease, as in tuberculosis or Crohn's disease of the bowel, or in certain parasitic diseases. A more general disorder is the enlargement of veins of the rectum and anus to form external or internal hemorrhoids. Hemorrhoids protrude, are associated with anal itching and pain, and bleed, especially when they come in contact with hard stools.
Disorders of the Liver [027] A variety of agents, including viruses, drugs, environmental pollutants, genetic disorders, and systemic diseases, can affect the liver. The resulting disorders usually affect one of the three functional components of the liver: the hepatocyte (liver cell) itself, the bile secretory (cholangiolar) apparatus, or the blood vascular system. Most acute liver diseases are self limited, and liver functioning returns to normal once the causes are removed or eliminated. In some cases, however, the acute disease process destroys massive areas of liver tissue in a short time, leading to extensive death 9 _ ~____ _. _. .

(necrosis) of hepatic cells and often to death of the patient. Hepatitis may result from viral infections or toxic damage from drugs or poisons. When acute hepatitis lasts for six months or more, a slow but progressive destruction of the surrounding liver cells and bile ducts occurs, a stage called chronic active hepatitis. If hepatocellular damage is severe enough to destroy entire acini (clusters of lobules), they are often replaced with fibrous scar tissue. Bile canaliculi and hepatocytes regenerate -in an irregular fashion adjacent to the scar tissue and result in a chronic condition called cirrhosis of the liver. Where inflammatory activity continues after the onset of cirrhosis, the disorderly regeneration of hepatocytes and cholangioles may lead to the development of hepatocellular or cholangiolar cancer.
[028] Although a number of viruses affect the liver, including the cytomegalovirus of infancy and childhood and the Epstein-Barr virus of infectious mononucleosis, there axe three distinctive transmissible viruses that are specifically known to cause acute damage to liver cells: hepatitis virus A (HAV), hepatitis virus B (HBV), and hepatitis virus non-A, non-B (NANB). The hepatitis A virus is transmitted almost exclusively by the fecal-oral route, and it thrives in areas where sanitation and food handling are poor and hand washing is infrequent. Hepatitis B virus is present throughout the world in asymptomatic human carriers who may or may not have ongoing liver disease and formerly, the disease was widely spread by the transfusion of whole blood or blood products. The hepatitis NANB virus has not been isolated, and currently is the major cause of posttransfusion hepatitis. The symptoms characteristic of the acute hepatitis caused by the HAV, HBV, and NANB viruses are essentially indistinguishable from one another.
[029] Acute hepatitis also may be caused by the overconsumption of alcohol ox other poisons, such as commercial solvents (e.g., carbon tetrachloride), acetaminophen, and certain fungi. Such agents are believed to cause hepatitis when the formation of their toxic intermediate metabolites in the liver cell (phase I reactions) is beyond the capacity of the hepatocyte to conjugate, or join them with another substance for detoxification (phase II reactions) and excretion. As long as the levels of these agents are small enough to permit complete phase I and phase II reactions, there is no damage to the liver cell. Acute canalicular (cholestatic) hepatitis is most commonly caused by certain drugs, such as chlorpromazine, that lead to idiosyncratic. reactions or, at times, __ _. -_ __ _. 1p by hepatitis viruses. Acute congestive Iiver disease usually results from the sudden engorgement of the liver by fluids after congestive heart failure.
[030] Chronic active hepatitis, the result of unresolved acute injury, is associated with ongoing liver damage. A milder form of chronic disease, called persistent hepatitis, does not appear to lead to progressive liver damage despite evidence of a continuing mild inflammation. These conditions may result from viral hepatitis, drug-induced hepatitis, autoimmune liver diseases (lupoid hepatitis), or congenital abnormalities. A prominent autoimmune Iiver disease is Wilson's disease, which is caused by abnormal deposits of large amounts of copper in the liver.
Granulomatous hepatitis, a condition in which localized areas of inflammation (granulomas) appear in any portion of the liver lobule, is a type of inflammatory disorder associated with many systemic diseases, including tuberculosis, sarcoidosis, schistosomiasis, and certain drug reactions. Granulomatous hepatitis rarely leads to serious interference with hepatic function, although it is often chronic.
[031] The end result of many forms of chronic liver injury is cirrhosis, or scarring of liver tissue in reponse to previous acinar necrosis and irregular regeneration of liver nodules and bile ducts. Among the congenital disorders producing cirrhosis are Wilson's disease, hemochromatosis (over-deposition of iron pigment), cystic fibrosis, biliary atresia (congenital absence of a part of the bile ducts), and alphal-antitrypsin def ciency, or the congenital absence of a proteolytic enzyme inhibitor that results in the accumulation of abnormal forms of carbohydrate in hepatocytes. In the Wesl, cirrhosis of the liver most commonly results from, chronic heavy intake of alcohol, while chronic viral hepatitis is probably , the leading cause of cirrhosis in underdeveloped countries. Primary biliary cirrhosis, a widespread, though uncommon, autoimmune inflammatory disease of bile ducts, is a disorder primarily affecting middle-aged and older women. Secondary biliary cirrhosis results from chronic obstruction or recurrent infection in the extrahepatic bile ducts caused by strictures, .
gallstones, or tumors. Infestation of the biliary tract with a liver fluke, Clonorchis sirae~sis, is a cause of secondary biliary cirrhosis in Asia. Cirrhosis occasionally is the result of chronic vascular congestion .of the liver in persons with prolonged heart failure and in those with chronic obstruction of the hepatic veins caused by benign blood clots or metastatic cancer.

[032] Hepatic encephalopathy refers to the changes in the brain that occur in patients with advanced acute or chronic liver disease. If liver cells are damaged, certain substances that are normally cleansed from the blood by the healthy liver are not removed. In the case of cirrhosis, blood from the portal system is not exposed to ' functioning hepatocytes because it is transported through blood vessels in the liver that do not run through regenerating nodules of hepatocytes; owing to the atypical growth inherent in the cirrhotic process. These products of cell metabolism are primarily . nitrogenous substances derived from protein, especially ammonia, or possibly certain straight-chain fatty acids. They pass to the brain where they damage functioning nervous tissue or subvert the actions of neurotransmitters, chemical messengers that carry impulses from one brain cell to another. In acute diseases, the brain exposed to those agents becomes swollen to the point where normal breathing may cease.
Chronic exposure can lead to destruction of neiwe cells with replacement by scar tissue (gliosis).
[033] ~ Portal hypertension, the increased pressure in the portal vein and its tributaries that is the result of impediments to venous flow into the liver, is brought about by the scarring characteristic of the cirrhotic process. The increased pressure causes feeders of the portal vein to distend markedly, producing varices, or dilations of the veins.
When varices are located in superficial tissues, they may rupture and bleed profusely.
Two such locations are the lower esophagus and the perianal region. The accumulation of fluid in the abdominal cavity, or ascites, is related to portal hypertension, significant reduction in serum albumin, and renal retention of sodium. When albumin levels in blood are lower than normal, there is a marked reduction in the force that holds plasma water within the blood vessels and normally resists the effects. of the intravascular pressure. The resulting increase in intravascular pressure, coupled with the increased .
internal pressure caused by the portal venous obstruction in the liver, leads to massive losses of plasma water into the abdominal cavity. The associated reduction of blood flow to the kidneys causes increased elaboration of the hormone aldosterone, which, in turn, causes the retention of sodium and water and a reduction in urinary output. In addition, because the movement of intestinal lymph into the liver is blocked by the cirrhotic process in the liver, the backflow of this fluid into the .
abdominal cavity is greatly increased. A progressive reduction in kidney function that often occurs in persons with advanced acute or chronic liver disease, hepatorenal syndrome, probably results from an inadequate perfusion of blood through the cortical (outer) portions of the kidneys, where most removal. of waste products occurs. With advanced hepatocytic dysfunction, a spasm of blood vessels in the renal cortex can occur, often with good blood flow to the rest of the kidney. This spasm results in progressive failure in kidney function and often leads to death.
[034] Although not uncommon, cancer originating in the liver, usually in hepatocytes and less frequently in cells of bile duct origin, is rare in the West and is almost always associated with active cirrhosis, particularly the form found in patients with chronic hepatitis. The survival rate from liver cancer is small. In certain underdeveloped countries, especially in tribal Africa, the incidence of this malignancy is high and is a major cause of death in the population. Most of these cases appear to stem from the prevalence of chronic viral hepatitis or the chronic presence of viruses in the blood (viremia) caused by hepatitis B. Long exposure to certain environmental poisons, such as vinyl chloride or carbon tetrachloride, has also been shown to lead to hepatic cancer. Cancers arising elsewhere in the body, particularly in abdominal organs, lungs, and lymphoid tissue, commonly lead to metastatic cancer in the liver and are by far the most frequent type of hepatic malignancy. Various benign types of tumors and cysts arise from certain components of the Liver, such as the hepatocytes (adenomas) or blood vessels (hemangiomas). While the cause of these lesions is not always clear, hepatic adenomas are associated with the prolonged use of female sex hormones (estrogens). Benign cysts in the Liver may occur as congenital defects or as the result of infections from infestation of the dog tapeworm (Echinococcus g~anulosus).
Abscesses on the liver result from the spread of infection from the biliary tract .or from other parts of the body, especially the appendix and the pelvic organs.
Specific liver abscesses also result from infections with the intestinal parasite Entamoeba histolytica.
Disorders of the Biliary Tract [035] Cholelithiasis, or the formation of gallstones in the gallbladder, is the most common disease of the biliary tract. There are three types of Gallstones:
stones containing primarily calcium bilirubinate (pigment stones); stones containing percent or more of cholesterol; and stones composed of variable mixtures of both bilirubin and cholesterol (mixed gallstones). Pigment stones are the result of an increased amount of bilirubin in the liver (due to hemolytic disease) and the consequent secretion into the biliary tract of increased amounts of the water-soluble conjugate, bilirubin diglucuronide, a pigment that is normally secreted in the urine. In the biliary tract, particularly in the gallbladder, some of this bilirubin diglucuronide is broken down by bacterial or mucosal enzymes into water-insoluble bilirubin, which then tends to form stones. Cholesterol and mixed cholesterol-bilirubinate stones occur when the proportion of cholesterol in bile exceeds the capacity of bile acids and lecithin to contain the total amount of cholesterol in micellar colloidal solution. When this critical micellar concentration is surpassed and the solution is saturated, crystalline particles of cholesterol are formed. The resulting gallstones contain large amounts of crystalline cholesterol and smaller quantities of calcium bi.lirubinate.
Postcholecystectomy syndrome comprises painful attacks, often resembling preoperative symptoms, that occasionally occur following the surgical removal of gallstones and the gallbladder. These attacks may be related to intermittent muscular spasms of the sphincter of Oddi or of the bile ducts.
[036] Cancer of the biliary tract is rare but may occur in almost any area, including the gallbladder, the hepatic ducts, the common bile duct, or the ampulla of Vater. In cancer of the bile duct,.congenital cysts and parasitic infections, such as liver flukes, seem to lead to increased rislcs. Persons with extensive chronic ulcerative colitis also show a greater than normal incidence of bile duct carcinoma.
[037] Jaundice, or yellowing of the skin, scleras, and mucous membranes, occurs whenever the level of bilirubin in the blood is significantly above normal.
This condition is evident in three different types of disorders including, .unconjugated, or hemolytic, jaundice; hepatocellular jaundice; and cholestatic, or obstructivejaundice.
Unconjugated jaundice results when the amount ~ of bilirubin produced from hemoglobin by the destruction of red blood cells or muscle tissue (myoglobin) overwhelms the normal capacity of the liver to transport it or when the ability .of the liver to conjugate normal amounts of bilirubin into bilirubin diglucuronide is significantly reduced by inadequate intracellular transport or enzyme systems.
Hepatocellular jaundice arises when liver cells are damaged so severely that their ability to transport bilirubin diglucuronide into the biliary system is reduced; allowing some of this yellow pigment to regurgitate into the bloodstream. Cholestatic jaundice, occurs when essentially normal liver cells are unable to transport bilirubin either through the hepatocytic-bile capillary membrane, because of damage in.that area, or through the biliary tract, because of anatomical obstructions (e.g., atresias, gallstones, cancer).
Disorders of the Pancreas [038] Inflammation of the pancreas, or pancreatitis, is probably the most common disease of this organ. The disorder may be confined to either singular or repeated acute episodes, or it may become a chronic disease. There are many factors associated with the onset of pancreatitis, including direct injury, certain drugs, viral infections, heredity, hyperlipidemia (increased levels of blood fats), and congenital derangements of the ductal system. Localized, severe abdominal and midback pain resulting from enzyme leakage, tissue damage, and nerve irritation is the most common symptom of acute pancreatitis. In severe cases, respiratory failure, shock, and even death may occur. Chronic pancreatitis rarely follows repeated acute attacks. It seems instead to be a separate disorder that results in mucus plugs and precipitation of calcium salts in the smaller pancreatic ducts. Cystic fibrosis is inherited, but it is not expressed unless both members of a pair of hemologous, or corresponding, chromosomes carry the trait. The major functional abnormality in persons with the disease appears to be the elaboration by mucous glands throughout the body of secretions containing greater than normal concentrations of protein and calcium. This imbalance leads to increased viscosity of . the secretions and precipitation of mucus and organic constituents in gland ducts. The resulting plugging process in the pancreas almost invariably causes destruction and scarring of the acinar tissue, usually without damaging the islets of Langerhans. A
similar process in the hepatic biliary system produces foci of fibrosis and bile duct proliferation, a singular form of cirrhosis.
[039] The discovery of new human digestive system associated polynucleotides, the polypeptides encoded by them, and antibodies that immunospecifically bind these polypeptides, satisfies a need in the art by providing new-compositions which are useful in the diagnosis, treatment, prevention and/or prognosis of disorders of the digestive system, including, but not limited to, dysphagia, odynophagia, congenital disorders of the esophagus, gastric reflux, diverticula, Mallory-Weiss lesions, leiomyomas of the esophagus, lipoma, anorexia, nausea, ulcerative disease, pyloric stenosis, gastroenteritis, gastritis, gastric atropy, gastric cancer, benign tumors of the duodenum (e.g., polyps and carcinoids), pancreatic cancer, cancer of the bile duct, distension, irritable bowel syndrome, malabsorption, congenital disorders of the small intestine (e.g., Meckel's diverticulum,_ multiple diverticula), bacterial and parasitic infection (e.g., traveler's diarrhea, typhoid, paratyphoid, cholera, roundworms, tapeworms, amoebae, hookworms, strongyloides, threadworms, and blood flukes), megacolon (e.g., Hirschsprung's disease, aganglionic megacolon, acquired megacol~n), colitis (e.g., due to bacterial, fungal, or parasitic infection, ulcerative colitis), tumors of the colon (e.g., polyps or cancers), anorectal disorders (e.g., anal fistulas, hemorrhoids, hepatitis (e.g., acute, chronic, persistent hepatitis, viral (for example, hepatitis caused by hepatitis virus A (HAV), hepatitis virus B (HBV), and hepatitis virus non-A, non-B (NANB) infection), congenital disorders of the liver (e.g., Wilson's disease, hemochromatosis, cystic fibrosis, biliary atresia, and alphal-antitrypsin deficiency), cirrhosis, portal hypertension, cholelithiasis, cancer of the biliary tract, jaundice (e.g., unconjugated, hemolytic, hepatocellular, cholestatic, or obstructive jaundice).
Summary of the Invention [040] The present invention relates to novel digestive system related polynucleotides, the polypeptides encoded by these polynucleotides herein collectively referred to as "digestive system antigens," and antibodies that immunospecifically bind these polypeptides, and the use of such digestive system polynucleotides, antigens, and antibodies for detecting, treating, preventing and/or prognosing disorders of the digestive system, including, but not limited to, the presence of cancer and cancer metastases. More specifically, isolated digestive system nucleic acid molecules are provided encoding novel digestive system polypeptides. Novel digestive system polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human digestive system polynucleotides, polypeptides, and/or antibodies. The _ _-__--___ invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to the digestive system, including cancer, and therapeutic methods for treating such disorders. The invention further relates to screening methods for identifying agonists and antagonists of - polynucleotides and polypeptides of the invention. The invention further relates to methods and/or compositions for inhibiting .or promoting the production and/or function of the polypeptides of the invention.
Detailed Description Tables -[041] Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ID:) and contig nucleotide sequence identifier (SEQ ID NO:X)) and fuxther summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA plasmid related to each digestive system associated contig sequence disclosed in Table 1A. The second column provides a unique contig identifier, "Contig ID:" for each of the contig sequences disclosed in Table 1A. The third column provides the sequence identifier, . "SEQ ID NO:X", for each of the contig polynucleotide. sequences disclosed in Table . 1A. The fourth column, "ORF (From-To)", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:X that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A as SEQ ID NO:Y (column 5). Column 6 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ ID NO:Y). Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4:181-186 (1988)); specifically, the Genetics Computer Group (GCG). implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wisc.). This method returns a measure of the probability that a given residue is found on the surface of the protein.
Regions where the antigenic index score is greater than 0:9 over at least 6 amino acids l~ _ _~___ ___ are indicated in Table 1A as "Predicted Epitopes." In particular embodiments, digestive system associated polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
Column 7, '.'Tissue Distribution" shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention. The first number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. Expression' of these polynucleotides was not observed in the other tissues and/or cell libraries tested. For those identifier codes in which the first two letters are riot "AR", the second number in column 7 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID NO:X) was identified in the tissue/cell source. Those tissue/cell source identifier codes in ' which the first two letters are "AR" designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell Iines.
Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]:" represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissues) which show a predominant expression pattern o.f the corresponding polynucleotide of the invention onto identify polynucleotides .__ _ 1$ .

which show predominant and/or specific tissue and/or cell expression. Column 8, "Cytologic Band," provides the chromosomal location of polynucleotides corresponding to SEQ ID NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore; MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2000. World Wide Web URL: http:/lwww.ncbi.nlm.nih.gov/omim/). If the putative chromosomal location of the Query overlapped with the chromosomal location of a Morbid Map entry, an OMIM identification number is provided in Table 1A, 'column 9 labeled "OMIM
Disease References)". A key to the OMIM reference ,identification numbers is provided in Table 5. ' [042] Table 1 B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z),~contig sequences (contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID
NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, "Clone ID NO:Z", for a~cDNA clone related to each contig sequence.
The second column provides the sequence identifier, "SEQ ID NO:X", for each contig sequence. The third column provides a unique contig identifier, "Contig ID:"
for each contig sequence. The fourth column, provides a BAC identifier "BAC ID NO:A"
for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six; and fragments and variants thereof).

[043] Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, "Clone ID
NO:Z", corresponding to a cDNA disclosed in Table 1A. The second column provides the unique contig identifier, "Contig ID:" corresponding to contigs in Table 1A
and allowing for correlation with the information in Table 1A. The third column provides the sequence identifier; "SEQ ID NO:X", for the contig polynucleotide sequences.
The fourth column provides the analysis method by which the homology/identity disclosed in the row was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as "NR"), or a database of protein families (herein referred to as "PFAM") as further described below. The fifth column provides a description of PFAM/NR hits having significant matches tb a polypeptide of the invention.
Column six provides the accession number of the PFAM/NR hit disclosed in the fifth column.
Column seven, "Score/Percent Identity", provides a quality score or the percent identity, of the hit disclosed in column five. Columns 8 and 9, "NT From" and "NT
To" respectively, delineate the polynucleotides in "SEQ ID NO:X" that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth column. In specific embodiments, polypeptides of the invention comprise, or alternatively consist of~ an amino acid sequence encoded by the polynucleotides in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.
[044] Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to digestive system associated contig sequences disclosed in Table 1A. ' The second column provides the sequence identifier, "SEQ ID. NO:X", for contig polynucleotide sequences disclosed in Table 1A. The third column provides the unique contig identifier, "Contig ID", for contigs disclosed in Table 1A. The fourth column provides a unique integer 'a' where 'a' is any integer between 1 and .the final nucleotide minus 15 of SEQ ID NO:X, represented as "Range of a",.and the fifth column provides a unique integer 'b' where 'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X, represented as "Range of b", where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14. For each of the ,.
polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be substituted into the general formula of a-b, and used to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the polynucleotides of the invention (including polynucleotide fragments and variants as described herein and diagnostic and/or therapeutic uses based on these polynucleotides) are at least one, two, three, four, five, ten, or more of the polynucleotide sequences) having the accession numbers) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequences) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table --(including for example, the actual sequence contained in an identified BAC
clone).
[045] Table 4 provides a key to the tissue/cell source identifier code disclosed in Table 1A, column 7. Column 1 provides the key to the tissue/cell source identifier code disclosed in Table 1A, Column 7. Columns 2-5 provide a description. of the tissue or cell source. Codes corresponding to diseased tissues are indicated in column 6 with the word "disease". The use of the word "disease'.' in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ).
Furthermore, tissues and/or cells lacking the "disease" designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identifies the vector used to generate the library.
[046] Table 5 provides a key to the OMIMTM reference identification numbers disclosed in Table, 1A, column 9. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL:
http://www.ncbi.nlm.nih.gov/omimn. Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 8, as determined from the Morbid Map 21' database.
(047] Table, 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.
[048] Table 7 shows the cDNA libraries sequenced, tissue source description, vector information and ATCC designation numbers relating to these cDNA libraries.
[049] Table 8 provides a physical characterization of clones encompassed by the invention. The first column provides the unique clone identifier, "Clone ID
NO:Z", for certain cDNA clones of the invention, as described in Table 1A. The second column provides the size of the cDNA insert contained in the corresponding cDNA
clone.
Definitions [0S0] The following definitions are provided to facilitate understanding of certain terms used throughout this specification. _ ' [051] In the present invention, "isolated" refers to material removed from its original environment (e.g., the natural environment if it is naturally occurring), and thus is "
altered "by the hand of man" from its natural state. For example, an ~
isolated polynucleotide could be part of a vector or a composition of matter, or could be contained within a cell, and still be "isolated" ~ because that vector, composition of matter, or particular cell is not the original environment of the polynucleotide. The term "isolated" does not refer to genomic or cDNA libraries, whole cell total or mRNA
preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic .DNA preparations or other compositions where the ~ art demonstrates no distinguishing features of the polynucleotide sequences of the present invention. -[052] As used herein, a "polynucleotide" refers to a molecule having a nucleic acid sequence encoding SEQ ID NO:Y or a fragment or variant thereof, a nucleic acid sequence contained in SEQ ID NO:X (as described iri column 3 of Table 1A) or the complement thereof, a cDNA sequence contained in Clone ID NO:Z (as described in column 1 of Table 1A and contained within a library deposited with the ATCC);
a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as def ned in column 6. of Table 1 B or a fragment or variant thereof; or WO 01/55314. PCT/USO1/01324 a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B
or the complement thereof. For example, the polynucleotide can contain the nucleotide sequence of the full length cDNA sequence, including the 5' and 3' untranslated sequences, the coding region, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence. Moreover, as used herein, a "polypeptide" refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA).
[053] As used herein, a "digestive system antigen" refers collectively to any polynucleotide disclosed herein (e.g., a nucleic acid sequence contained in SEQ ID
NO:X or the complement therof, or cDNA sequence contained in Clone ID NO:Z, or a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B, or a nucleotide coding sequence in SEQ ID NO:B as defined in column 6 of Table 1B or the complement thereof and fragments or variants thereof as described herein) or any polypeptide disclosed herein (e.g., an amino acid sequence contained in SEQ ID NO:Y, an amino acid sequence encoded by SEQ ID NO:X, or the complement thereof, an amino acid sequence encoded by the cDNA sequence contained in Clone ID NO:Z, an amino acid sequence encoded. by SEQ ID NO:B, or the complement thereof, and fragments or variants thereof as described herein). These digestive system antigens have been determined to be predominantly expressed in digestive system tissues, including normal or diseased tissues (as shown in Table 1A column 7 and Table 4).
[054] In the present invention, "SEQ ID NO:X" was often generated by overlapping sequences contained in multiple clones (contig analysis). A representative clone containing all or most of the sequence fox SEQ ID NO:X is ,deposited at Human Genome Sciences, Inc. (HGS) in a catalogued and archived library. As shown, for example, in column 1 of Table 1A, each clone is identified by a cDNA Clone ID
(identifier generally referred to herein as Clone ID NO:Z). Each Clone ID is unique to an individual clone and the Clone ID is all the information needed to retrieve a given clone from the HGS library. Furthermore, certain clones disclosed in this application have been deposited with the ATCC on October 5, 2000, having the ATCC

designation numbers PTA 2574 and PTA 2575; and on January 5, 2001, having the depositor reference numbers TS-1, TS-2,' AC-1, and AC-2. In addition to the individual cDNA clone deposits,. most of the cDNA libraries from which the clones were derived were deposited at the American Type Culture Collection (hereinafter "ATCC"). ~ Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ID NO:Z to determine the library source by reference to Tables 6 and 7.
Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC
Deposit. Library names contain four characters, fox example, "HTWE." The name of a cDNA clone (Clone ID NO:Z) isolated from that library begins with the same four characters, for example "HTWEP07". As mentioned below, Table 1A correlates the Clone ID NO:Z names with SEQ ID' NO:X. Thus, starting with an SEQ ID NO:X, one can use Tables 1A, 6 and 7 to determine the corresponding Clone ID NO:Z, which library it came from and which ATCC deposit the library is contained in.
Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC ~is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC deposits were made pursuant to the terms of the . Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.
[055] In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at-least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50~kb, 15 kb, 10 kb, 7.5 kb, 5 lib, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further 'embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed 'herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest in the genome). In other embodiments, the polynucleotides of the invention 'do not contain the coding sequence of more than 1000, 500, 250, 100, 50, 25, 20, 15, 10, 5, 4, 3, 2, or 1 genomic flanking gene(s).
[056] A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, under stringent hybridization conditions, to sequences contained in SEQ ID NO:X, or the complement thereof (e.g., the complement of any 24.

one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated in columns 8 and 9 of Table 2 or the complement thereof, and/or cDNA sequences contained in Clone ID NO:Z (e.g., the complement of any one, two, three, .four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA clones deposited with the ATCC, described herein) and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof. "Stringent hybridization conditions" refers to an overnight incubation at 42 degree C in a solution comprising 50% formamide, 5x SSC (750 mM NaCI, 75 mM
trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10%
dextran sulfate, and 20 ~,g/ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65 degree C.
[057] Also contemplated are nucleic acid molecules that hybridize to the polynucleotides of the present invention at lower stringency hybridization conditions..
Changes in the stringency of hybridization and signal detection are primarily accomplished through the manipulation of formamide concentration (lower percentages of formamide result in lowered stringency), salt conditions, or temperature. For example, lower stringency conditions ~ include an overnight incubation at 37 degree C in a solution~comprising 6X SSPE (20X SSPE = 3M
NaCI;
0.2M NaH2P0~; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/ml salmon sperm blocking DNA; followed by washes at 50 degree C with 1XSSPE, 0.1%
SDS. In addition, to achieve even lower stringency, washes performed following stringent Hybridization can be done at higher salt concentrations (e.g. 5X
SSC).
[058] ' Note that variations in the above conditions may be accomplished through the inclusion and/or substitution of alternate blocking reagents used to suppress background in hybridization experiments. Typical blocking reagents include Denhardt's reagent, BLOTTO, heparin, denatured salmon sperm DNA, and commercially available proprietary formulations. The inclusion of specific blocking reagents may require: modification of the hybridization conditions described above, due to problems with compatibility.
[059] Of course, a polynucleotide which hybridizes only to polyA+ sequences (such as any 3' terminal polyA+ tract of a cDNA shown in the sequence listing), or to a complementary stretch of T (or U) residues, would not be included in the definition of _ 25 ..__ ' "polynucleotide," since such a polynucleotide would hybridize to any nucleic acid molecule containing a poly (A) stretch.or the complement thereof (e.g., practically any double-stranded cDNA clone generated using oligo dT as a primer).
[060] The polynucleotide of the present invention can be composed of. any polyribonucleotide or polydeoxribonucleotide, which may be unmodified RNA or DNA or modified RNA or DNA. For example, polynucleotides can be composed of single- and double-stranded DNA, DNA that is a mixture of single- and double-stranded regions, single- and double-stranded RNA, and RNA that is mixture of single- and double-stranded regions, hybrid molecules comprising DNA and RNA
that may be single-stranded or, more typically,. double-stranded or a mixture of single- and double-stranded regions. , In addition, the polynucleotide can be composed of triple-stranded regions comprising RNA or DNA or both RNA and DNA. A polynucleotide may also contain one or more modified bases or DNA or RNA backbones modified for stability or for other reasons. "Modified" bases include, for example, tritylated bases and unusual bases such as inosine. A variety of modifications can be made to DNA
and RNA; thus, "polynucleotide" embraces chemically, enzymatically, or metabolically modified forms.
[061] . The polypeptide of the present invention can be composed of .amino acids joined to each other by peptide bonds or modified peptide bonds, i.e., peptide isosteres, and may contain amino acids other than the 20 gene-encoded amino acids. The polypeptides may be modified by either natural processes, such as posttranslational processing, or by chemical modification techniques which are well known in the art.
Such modifications are well described in basic texts and in more detailed monographs, as well as in a voluminous research literature. Modifications can occur anywhere in a polypeptide, including the peptide backbone, the amino acid side-chains and the amino.
or carboxyl termini. It will be appreciated that the same type of modification may be present in the same or varying degrees at several sites in a given polypeptide. Also, a given polypeptide may contain many types of modifications. Polypeptides may be branched, for example, as a result of ubiquitination, and they may be cyclic, with or without branching. Cyclic, branched, and branched cyclic polypeptides may result from posttranslation natural processes or may be made by synthetic methods.
Modifications include acetylation, acylation, ADP-ribosylation, amidation, covalent __ . . _ 26 attachment of flavin, covalent attachment of a heme moiety, covalent attachment of a nucleotide or nucleotide derivative, covalent attachment of a lipid or lipid .derivative, covalent attachment of phosphotidylinositol, cross-linking, cyclization, disulfide bond formation, demethylation, formation of covalent cross-links, formation of cysteine, formation of pyroglutamate, formylation, gamma-carboxylation; glycosylation, GPI
anchor formation, hydroxylation, iodination, methylation, myristoylation, oxidation, pegylation, proteolytic processing, phosphorylation, prenylation, racemization, selenoylation, sulfation, transfer-RNA mediated addition of amino acids to proteins such as arginylation, and ubiquitination. (See, for instance, PROTEINS --STRUCTURE AND MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H.
Freeman and Company, New York (1993); POSTTRANSLATIONAL COVALENT
MODIFICATION OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs. 1-12 (1983); Seifter et al., Meth. Enzymol. 182:626-646 (I990); Rattan et al., Ann. N.Y. Acad. Sci. 663:48-62 (1992).) ' [062j "SEQ ID NO:X" refers to a polynucleotide sequence described, for example, in Tables 1A or 2, while "SEQ TD NO:Y" refers to a polypeptide sequence described in column S of Table 1A. SEQ ID NO:X is identified by an integer specified in column 3 of Table 1A. The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone ID NO:Z" refers to a _ cDNA clone described in column 1 of Table 1A.
[063] "A polypeptide having biological activity" refers to a polypeptide exhibiting activity similar to, but not necessarily identical to, an activity of a polypeptide of the present invention, including mature forms, as measured in a particular biological assay, with or without dose dependency. In the case where dose dependency does exist, it need not be identical to that of the polypeptide, but rather substantially similar to the dose-dependence in a given activity as compared to the polypeptide of the present invention (i.e., the candidate polypeptide will exhibit greater activity or not more than about 2S-fold less and, preferably, not more than about tenfold less activity, and .most preferably, not more than about three-fold less activity relative to the polypeptide of the present invention).
[064] Table 1A summarizes some of the digestive system associated polynucleotides encompassed by the invention (including contig sequences (SEQ ID NO:X) and clones (Clone ID NO:Z) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.
Polynucleotides and Polypentides v 0 0 0 0 0 0 ~ 00 O O Ov 01 ~ N V7 ~n tmn e4; M oo N N o0 00 00 0o N N

0o000 N
N
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~
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.

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' it W M ~ 000000 000od H 3.1 p ~ a1 ~
' nr ~ p O Q1d1d\ 0101l "'~ p 01 O O O O O O d ~

A O1 ,--1 O .-~
G~ ;~ O M __ Ho x x x x x xxo ~ .

N

O ~ ~

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O ~ ~ p ~ ~1 ~-i .'~"'~-, N V ~
1 ,-, ~;, N
rn ~aa o o ' ~' ~' 0 0 0~"" .o 0 M ~ O O
~ ' ' 00 ~n ' ' ~"' ~O N ~ d' ' N ~~N ~ N~

~x~c~a ~ act a N N N N N 'NN N
~

z ~, N ~O~n~ co01 N O N ~

M Q1 ~OV7O M \O~

N M d w v0t~o0 ~z bA O d- N ood- d-ooM

'.I;. ' ~ ~ OOM M 0 0 0 ~ M O ~Oo0 O O O

O A M ~O M 01O .--a~

O O O O O O

d' M N r.,.-m p ~ ~
n C7 ~ U W Co7 ~ _ Ga v~v~c~ v~~ v~ .

, N ~ ~ x x ~ x x ...

O O O O O O O ~ O O N --~ ~
O ~n ~O O V~ ~ O O O O ~ W n O ~O
~ co l~

N a1 r1- Ov O ~ ~ N ~O V'Wn N N oo N d-Ot~C3l~l~NM V~oo~O.~p00.-~.NN

~t~l~O.-~NMMd'~ V~OOOOO

.--i .-m-.i N N N N N N N N
~O ~O ~O ~O ~O

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a .~ o , ~

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cri . N N ,-;d'N N N
00 -~ O

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~O ~, Do co~ d:~O ~n .. d- ' O O ,-.~01 01~ O ~ co O

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C/~

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N

N ~ d' ~ op"
d-o H i ~ H .
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r +, o y 0 0 o +~

O
M

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O

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1H aH ~ v ~

~ ~P
-01 O ~ N M d' ~n 00 0000 000o co N N N N N N N

01 ~ ~n N O~

M , M ~ ~O d'M

i M

O, N y ~ t~
N d- ~ M

N -~ N

O1 O ~ N M dw n N N N N N N

' N 01 O d' M M 00 d' V>. Q1d' O N M

v1 lm n N ~ON l~

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V~ oo ~n d- N ~nO d'd- d- d' ~ ' O ~ ~O

00 O 01 d' ~ l0~ Q1d' O 01 01 M o0 N

~O l~ 00 00 00l~d10oO ~ ,-W O d' N Q\
.

~n t~ ~n o o a1o m t~ M v~ M ~n o0 00 .

N N O O O O ~OO ~O N . t~ ~n ~ 01 O

a1 ~ t~ v~ v~~ d1y O a1 ~n~ a1 lW O a, .--y-M l~00 M 0O ~ M "~ 00 ' M 01 V7M O M .-fp IS . d M d' O

~1 ~1~1~1U U

as as .

x x x x x x x x x N N N
x x x ~

a a~

~

-, ,-,,-~ ~ N
. . . (~

~ ~ o ~ '~

o, ~i o; ~i ~
, ~

O O O oo ~
-1 a1 N

_ -. .~ .-~ w, O M O "t~ O
d O O O' O O
~O d ,~ ~' t~

Ha Ha ~' H '~~
a ~ ~

O

p N

O.-O

~ .

~- ~O
~' d v ~n ~n C N N N N

00 ~n d~ ~ ~n i M

M

~O (~ 00 01 .

tn In V1 N N N N

O l~ ~O \p l~ \O O O

O ~n ~O O

l~ ~' t~ M

a1 ,--~ ~O N

~n t~ ~ a1 U' [065] The first column in Table 1A provides a unique "Clone ID NO:Z" for a cDNA
clone related to each contig sequence-disclosed in Table 1A. This clone ID
references the cDNA clone which contains at Ieast the 5' .most sequence of the assembled contig and at least a portion of SEQ ID NO:X was determined by directly sequencing the referenced clone. The reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods known in the art and/or as described elsewhere herein.
[066] The second column in Table 1A provides a unique "Contig ID"
identification for each contig sequence. The third column provides the "SEQ ID NO:X"
identifier for each of the digestive system associated contig polynucleotide sequences disclosed in Table 1A. The fourth column, "ORF (From-To)", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence "SEQ ID NO:X"
that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1A, column 5, as SEQ ID NO:Y. Where the nucleotide position number "To" is lower than the nucleotide position number "From", the preferred ORF
is the reverse complement of the referenced polynucleotide sequence.
[067] The fifth column in Table 1A provides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated in column 4.
In one embodiment, the invention provides an amino acid sequence comprising, or.
alternatively consisting of, a polypeptide encoded by the portion of SEQ ID
NO:X
delineated by "ORF (From-To)''. . Also provided are polynucleotides encoding such amino acid sequences and the complementary strand thereto.
[068] Column 6 in Table 1A lists residues comprising epitopes contained in the polypeptides encoded by the preferred ORF (SEQ ID NO:Y), as predicted using the algorithm of Jamesori and Wolf, (I988) Comp. Appl. Biosci.. 4:181-186. The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN (Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228 South Park Street Madison, WI). In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, f ve or more of the predicted epitopes as described in Table 1A., It will be appreciated that depending on WO 01/55314 . PCT/USO1/01324 the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
[069] Column 7 in Table 1A provides an expression profile and library code:
count for each of the contig sequences (SEQ ID NO:X) disclosed in Table 1A, which can routinely be combined with the information provided iii Table 4 and used to determine the normal or diseased tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention. The first number in column 7 (preceding the colon), represents the tissue/cell source identifier code corresponding to the code and description provided in Table 4. For those identifier codes in which the first two letters are not "AR", the second number in column 7 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source. Those tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR
and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines.
Probe synthesis was performed in the presence of 33P dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A local background signal subtraction was performed before the total ~ signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]:" represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissues) which show a predominant expression pattern of the corresponding polynucleotide of the invention or ~to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. The sequences disclosed herein have been determined to be predominantly expressed in digestive system tissues, including normal and diseased' digestive system tissues (See Table 1A, column 7 and Table 4). -(070] Column 8 in Table 1A provides a chromosomal map location for certain ---polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequences) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.
[071] A modified version of the computer program BLASTN (Altshul et al., J.
Mol.
Biol. 215:403-410 (1990), and Gish et al., Nat. Genet. 3:265-272 (1993)) was used to search the UniGene database for EST or cDNA sequences that contain exact or near-exact matches to. a polynucleotide sequence of the invention (the 'Query'). A
sequence from the UniGene database (the 'Subject') was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence. If all of the matches that met this . criteria were in the same UniGene cluster, and mapping' data was available for this cluster, it is indicated in Table 1A under the heading "Cytologic Band". Where a cluster had been further localized to a distinct cytologic band, that band is disclosed;
where no banding information was available, but the gene had been localized to a single chromosome, the chromosome is disclosed.
[001] Once a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was 'identified by comparison with a database of diseases which have been experimentally associated with genetic loci. The database used was the Morbid Map, derived from OMIMTM
(supra). If the putative chromosomal location of a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OMIM reference identification number was noted in column 9, Table 1A, labeled "OMIM Disease References)". Table 5 is a key to the OMIM reference identification 143 _ numbers (column 1), and provides a description of the associated disease in Column 2.

Clone ID SEQ CONTIG BAC ID: SEQ ID EXON
ID A

NO:Z NO:X ID: NO:B From-To . ~ 11678-11844 HALSC22 13 503082 AC013783 2534 ~ 1-325 HALSC22 13 503082 ~AC013783 2535 1-319 HALSC22 13 503082 AL354797 2541 ~ 1-490 ~

~

. ~ 166-273 HALSGOl 1S 500834 AC027052 2S4S 1-68 . ~ 2033-2385 _H_AT,SGO11S 500834 AC0270S2 2548 1-33S

79.46-8127 HCNAI~56 27 832249 AC023479 2564 1-256 HCNAI~56 27 ~ 832249 AL136231 2565 1-256 HCNAI~56 27 832249 AL136231 2567 1-258 HCNAK56 27 832249 AL136231 2568 ' 1-644 ~

HCNAL66 28 ~ 832247 AC011747 2569 1-755 .

266-'796 HCNAN69 29 655816 AC068589 2574 ' 1-318 HCNAN69 29 655816 AC009675 2575 . 1-318 HCNA020 30 832251 AC073219 2577 . -1-123 ~

HCNAR21 31 _948746 AC006595 2582 1-421 HCNAR21 31 _948746 AP002392 2583 _ . 1-187 _ HCNCN84 35 766990 AC074373 2590 1-270 --- ' 10648-11165 HCNCU02 39 918993 ~AL3-564602596 1-1488 HCNCY39 42 960373 AC004874 2601 l-291 HCNDD83 44. 832230 AC022537 2607 1-149 HCNDF20 45 669111 AL13$777 2614 1-264 HCNDH18 47 832215 AC007956 2617 ~ 1-283 HCNDI01 48 ~ 832213 AC068150 2619 1-902 HCNDI01 4_8 832213 AC068150 2620 l-577-_ HCNDK62 49 7_42883 AP000482 2621 _ HCND 50 52 7239'76 AC019047 2626 1-386 HCND 50 52 723976 AC019047 2627. 1-159 HCNSP37 'S5 655829 AL121874 2631 1-265 HCNUA84 58 . 522523 AC023767 2635 1-655 -HCQAK31 59, 915563 283819 2637 1-192 HCQCR67 60 974592 AC010997 2640 . 1-721 HCRMR08 64 ~ 958489 AC024554 2645 1-I06 HCRMR69 65 877118 AC005546. 2646 1-84 _ _ ~ . 687-742 - ~ 1271-1463 . ~ 7271-7363 HCRNF63 68 ' 916063 AC016501 2649 1-2271 , 6207-7370 HCRNH81 69 914840 AC009955 2654 ~ 1-604 _ 6207-7370 8204=9136 _ 9951-11649. , _ _ _ ~ 2969-3239 ' ~ ~ 4899-4998 766.1-8404 . 9249-9590 _ 12628-13109 _ 1318213470 . 18342-18428 - ~ 20007-20565 .

HCRNI04 70 849408 AC023257 2661 ~l-157 HCRQG35 80 954968 AC026676 2665 . 1-1626 ~

HCR G35 80 9549b8 AC026676 2666 1-797 a 7426-8007.

HDR'MA28 83 841936 AC023984 2672 1-345 ' HFL F55 90 719018 AC026070 2675 1-98'7 HFLQF55 90 ~ 719018 AL360008 2676 1-988 HFLSI23 93 509743 AC022022 2684 ' 1-599 , HFLSI23 93 509743 AC0.16197 2686 1-599 ~

HFLSI23 93 ~ 509743 C016197~ _ 1-115 ~ ~ 2687 ' ' 9489-9609 _ 20488-20746 ' 21568-21678 ' ~ 25794-25921 ~ 32736-33009 . _ 34554-34899 .

HFLSK11. 95 964908 AC007845 2691 1-1671 HFLSKll 95 964908 AC016026 2694 1-287 HFLSKll 95 964908 AC007845 2695 1-492 HFLSKll 95 964908 AC007845 2696 1-287 .

HFLSK31 96 535238 AC009397 2703 ' 1-315 HFLSK81 97 761133 AL031584 2705 . 1-141 HFLUF43 98 928026 AL365495 2707 ~ I-1200 HFLUG50~ 100 526181 AC026874 2711 1-341 .

HFLVE6'1 101 539872 AC006254 2713 1-99 . 4942-5113 ' 8496-8801 . 13712-14209 HFLVE85 102 531014 AL356112~ 2715 1-931 ' HFVHT75 114 573301 AC022504 27_29 1-486 HGBAH38 _1_18 50_3211 298946 2737 1-306 - ~HGBAI39 120 503055 AL157391 2743 1-615 HGBAI70 123 _707918 AC023888 2746 1-321 HGBAI~23 124 500801 AC068228 2749 1-184 HGBAM75 126 509546 AC.025183 2756 1-180 ' ~ 631-1406 . 1404-1583 HGBAM75 126 509546' AC025181 2761 1-409 HGBAN21 127 509538 AC011885 _2763 1-322' HGBAN21 127 509538 AC013434 2765. 1-98 HGBA008 128 854321 AC009022 2768 ' 1-472 ~

HGBAP09 129 509265 AC006323 2771 ~1-350 ' 1290-1697 _ _ - _ . 2905-3015 _.

6'113-6495 _ 20510-21239 ~

HGBA 37 1.31 500799 AC064833 2775 1-383 HGBAQ81 132 509533 AC021094 2.776 1-121 ~

HGBAQ81 132 509533 AL0353,67 2777 ~ ~ 1-630 _ ~._____~_~_ __ _ 156 .
a L( . ~ !
,i:,~~
, .
- . :.wi-, - ~.y.r 5262-5348-'~
v -8071-8196 '.

9179-9669 ' HGBA 81 132 509533 AL035367 2780 1-119 r - ~ 557-3437 3464-4398 ' HGBAU93 134 625250 AL158049 2783 - _ d HGBAU93 134 625250 AL139044 2784 ? 1-54 ' 237-430 HGBAU93 134 625250 AL158049 2785 1-1078 .

_ HGBAU93 134 625250 AL139044 2786 l-1078 HGBAZ13 135 971646 AL35489.2 2787 1-360 -HGBB062 137 509691 AC011894 2788 1-1040 ~~-HGBB062 137 509691 AC004-938 2789 r 1-1040 HGBB062 137 509691 ACOl 1894 2790 - ' 1-188 _ ~ HGBB062 137 509691 AC011894 2791 1-341 .

HGBB062 137 509691 AC004938 2793' 1-188 HGBCH13 139 508982 AC044825 2794 1-726 :

.

HGBDB21 142 753848 AL162497. 2797 ~ 1-356 -3 5 i 7-3 806 ~

.

' 9937-10357 _ 10997-11857 10786=11044 ' 17176-18144 21515-2187.0 . 26261-27318 .

_ 768-1182 6305-6501.

_. 1474-2022 HGBGI57 162. 573752 AL121753 2823 1-77 . 20064-20199 HGBGI57 162 57375.2 AL356652 2824 1-77 ' . 3692-4433 ~

_._ _ _ 1007-1386 4494-4928.

_ 5613-5727 .

_ 7678-7848 ' ' HGBHY06 171 937940 AC027113 2847 ~ 1-201 HGBID55 173 575197 AC024120 2848 1-239.

HISAC25 176. 678054 AC019281 2857 1-480 ~HISAI35 177 707172 AC022087 2861 I-668 HISAN47 180 710943 AP001542 2866 1-11'7 ' 6227-6281 . 6286-6870 .

_ 7420-7582 301'6-3432 HISBG13 186 657005 AC046158' 2874 1-433 HISBG13 186 657005 AC046158 2876 1'-363 ~

HISBH10 187 964359 AC024701 2878. 1-424 HISB064 189 745884 AC011612 _ 1-501 HISBU45 191 717604 ACQ07608 _ 1-631 ' 3165-4094 _ HISCH85 195 761973 AC015918 2890 _ ' ~ 1770-2055 ' 4128-4567 HISCN24 199 764837 AC027447 2898 ' 1-312 _ HISCV30 201 883892 AC027630 2907 . 1-1944 HISDT82 205 790966 AC012586 2912 ___ ~ ~ 1-703 HISDV63 20_7__ 788753 AC026707 2918 1-2217 HISDV63 207 788753 AC026707 2920 . 1-333 .

HISDV63 207. 788753 AC008954 2923 1-476 .

' -HISEN88 213 760209 .AC069030 2937 1-399 ' _ ~.

HLDBJ86 217 882365 AC026532 2943 ~ 1-426 HLD.BJ86 217 882365 AC026532 2944 1-864 HLDBR32 218 752494 AL136980 2946 _ 1-2747 , . 7256-8971 __._ __ _ ~ 13756-14277 . 34737-35155 398'95-40015 .

. ' 16093-16520 ~

.. 18310-18546 WO 01/55314 . PCT/USO1/01324 - ~ 20760-21783 . 41921-42617 ' 49336-49727 _ _ 51004-51119 _ _ 58364-58551 . 74471-74744 91270=91706 '. 97472-97589 w 99438-99506 __. .. 107818-. 109168 ~

. 110182 _ ~ 114249 11.6709-' 116960 HLDDL55 226 875000 AC02223-1 2954 ' 1-151 .

HLDDL55 226 87_5000 AP001451 2955 1-96 HLDDL55 226 875000 _AC009524_2956 1-151 ' .

~

HLDOR73 233 683262 AC025902 2967 _. _ 1-199 ~

' 224-338 ~ 856-2249 HLDOU12 234 857106 AC074203 2972 ' 1-109 HLDOU12 234 857106 ~AC074203 2974 1-204 _ 4992-5110 HLDOU12 234 857106 AC007707~ 2975 1-204 1.440-1511 ' 3414-3645 HLD C62 239 923559 AL359893 2981 ' 1-544 HLDQC62. 239 923559 AL359893 2982 1-387 ' ~ 4249-4748 w '7115-8799 HLDRD54 243 727954 AC008807 2986 ' 1-1113 ~HLDRD54 243 727954 AC008807 2988 1-849 HLDRI94 246 784582 AL158839 299.2 1-102 HLDRI94 246 784582 AL354872 2994. 1-573 ' ~ 24108-24166 _ H~LDR 82 248 837031 AC012313 3002 1-S13 , 187 HLIBI3S 250 870387 AC016127 3005 _ HLIBI3S 2S0 870387 .AC023989 3007 . 1-919 ~

HLIB003 2S2 923519 AL139113 3013 ' 1-106 WO01/55314 ,~-- ,;,~~ ;. t.~ .,~;~~.",.3,PCT/USO1/01324,~",.,=."" ~.
HL AN64 261 966910 AC010192 _3017 1-606 HL AN64 261 966910 AC_O10 3018 1-1020 HLQAZ69 262 960046 _ 3019 1-216 HLQAZ69 262 960046 .AL356581 3020 - 1-184 HLQAZ69 262 960046 AL137798 3022 1-216 , HL AZ69 262 960046 AL137798 3025 ~ 1-114 1974-5541 . ' ~

HLQBF72 263 608371. AC004893 3028 .l-41 4568-4632 , - 10401-10.479 ' ' 11027-11398 _ 12127-12683 ' 13818-13849 19602-19720, '171 _ HLQBI2I 265 52_9342 AL021879 3029 1-50 ~

HL BX23 268 676205 AC068301 3030. 1-377 HL BX23 268 6'76205 AC068301 3032 1-552 HLQDB55 271 731601 AL1~60004 3036 1-519 . 6610-7334 ' HL, DP11 274 966775 AL121601 3045 1-469 -..

HLQDY10 276 856755 AC02~5343 3050 -293 .

HL ED11 277 966015 AC005072 3058 l-269 -. 8396-8663 . 9800-10439 HL ES58 279 856725 AC003034. 3061 1-431 .656-1001 ' ' 3475-3937 HL GK74 283 856736 AC026532 3066 ' 1-376 ~

HLQGN56 284 .842004, AC069033~ 3069 1-55 , ..

'2354-2457 HNJBN94 294 948996 AL121756 3083 . 1-76 . 7752-7812 . 8649-8936 _. 175 _ 12857-12903 HNJBN94 294 948996 AL121756 3084 ~ 1-676 ~

~ ~

. 4230-4383 .6054=6117 HNJEC12 299 969099 AL355362 3088 ' 1-1120 HNJEC12 _299 969099 AL023582 3089 1-1119 _ HNKDV89~ 307 963354 AC008401 3098 1-686 .

HNKDV89 307 963354 AC008865 3100 1-76' HPASD70 310 522675 AF207953.3104 1-272 HPKAA65 311 753931 AC008733 3107 1-75 _ _ HPK.AA65 311 753931 AC017110 3108 1-75 HPKA.A.65 311 753931 'AC0087333109 1-194 HPI~AAA65 311 753931 AC017110 3110 1-194 ' 2770-2963 HROAL51 313 526487 AC013655 3114 1-23.8 HROAL51 313 526487 AC015681 3115 .1-238 HROAV94 .316 963714 AC026073.3123 1-311 --.

177 -' __.

_ 2087-2266 .

HROBF77 319 677615 AL161891 3127 _ _ _ 5809-5876 . 8585-8949 6035-6343 .

15075-15567.
.

11.41-1425 ' 9352-9691 HROB~ 03 321 867044 AC007783 3137 1-1312 HROB 03 321 867044 AC022007 3141 , ' 1-223 ~

HROBX40 323 835594 AC008963 3145 . 1-72 - . 11698-12149 21404-21'475 ' .

.

.

HROCE61 324 741263 AC008821 3154 _ 1-553 ~

. HRODC11 325 966298 AC026347 3157 1-702 HRODCl 325 966298 AC069242 3158 1-702 l HRODC11 325 966298 AC011859 3160 1-39.1 HRODH54 327 922899 AL049610 3164 1-204.

HROEA83 332 710615 AC011148 3167 ' 1-389 HROEA83 332 710615 AC012125 3168 ~ . 1-389 HROEA83' 332_ 710615 AC012586 3169 I-389 HROEB10 333. 963706 AC002540 3172 1-693 .

3330-3.932 HSICP51 338 531307 AC003656 3176' 1-119 ~

HSICR32 339 507173 AP001403 3180 l-449 .

_.. ...._ 4616-5205 . _ ' 5493-5609 ' . 10078-10523 - , 12594-12687 HSICV78 343 712629 AC008542 319,4 1-1412 ~

_ 7289-7442 ' 10747-11178 _ ___ - 182 ' 17434-17481 2175-2634.

.' . 1736-2548 =5024-6752 HSICX21 344 531267 AC024101 3203 . 1-447 ~

HSIDA42 346 531264 AC011381 _3208 1-289 . 605-1008 . 7879-9508 _ ___ _ _ _ 11641-11736 ' . 17199-17268 3410-410.3 ' 5402-5510 ' 7011-7826 .

.___ _ 184 HSIDP49 353 531064 AC069294 3218 ' 1-1297 _ 9044-9545 . 12036-13559 ' 17551-17904 ~

HSIDV75 359 531265 AC023891 3229 ' 1-321 ~

185 ._ __ 5555-5679 HSIDV82 360 531297 AL36017~ 3232 1-289 ' 7359-7483 ' 186 _ ._,._ ~ 208-351 HSIE062 .368 531249 AC026272 3242 1-483 HSIE062 368 531249 AC005575 3243. 1-483 HSIE062 368 531249 AC011379 3244 ' 1-150 ~

HSIFa06 369 866573 AC067882 3247 1-340 HSIFN66 3_77 _742966 AC055884 3249 1-737 ~

HSIFW89 382. 771820 AC001234 3261 1-308 HSIFW94 383 765203 AC005084 3263 , 1-316 . .

. 25686-25849 . 34044-34139 - ~ ' 2853-3069 ' 9534-9.788 13585-1'3694 ' ~ 2414-25.30 .

_ .. __._ 472-1744 . _ HSIGD07 390. 952508 AC073230 32$2 1-574 HSIGF11 392 866552 AC012169 .3283 1-420 _ HSIGJ45 396 718728 AC073061 3285 1-358 HSIGJ45 396. 718728 AC073061 3288 1-1110 HSIGJ45. 396 718728 AL162260 3289 1-343 HSIGJ45 396 718728 AL162260 3292 ~ 1-1.110 HSIGL56 397 906942 ~AC023099 3293 , - I-36I

HSIGL56 3,97 906942 AC022264 3294 1-361 HSIGL56 397 9069.42 AC023099 3298 ~ 1-101 HSIGL56 397 906942 AC002042 3301. 1-361 HSIGL,94 398 769754 AC024952 3302 1-126 '2845-2947 ~

. 13786-13869 _ _ 21556-21640 _ _ _ 22127-22645 '' HSOAW33 404 702709 AC020988. 3317 1-415 _ . 191 HSOBF65 _407 747484 AC074186 3320 1-395 _ HSOBL59 410 738858 AL358333 3326 ' 1-300 HSOBL59 410 738858 AL358333 3328 ~ 1-188 .

HSOB 14 413 719796 AC069506 3333' 1-585 HSOBQ82 414 779093 AC022366 3336 1-1004' . 4155-4983 HSOD056 417 835876 AC009480 3348 ~ 1-3959 HSPAF44 4_22 761986 AC027522 3354 I-II7 HSPAK46 423 968901 AC026283 3358 ' 1-96 .

__. . 2929-3301 _ _ 519-633 ' 5381-5485 ' 1842=2080 _ 7897-8098 _ 5910-6019 194 , _ __ 1443-2331 HTNTD72 433 870030 AC011597 3379 '1-171 HTNTD72 433. 870030 AC067726 3380 1-171 HTPAFOl 436 961063 AC012459 3385 ' 1-157 HTPAG78 437 773936 AL138689 3386 1-393.

HTPBQ47 439 922777 AC020913~ 3390 1-425 -_ 1074-1240 ' ~ 2370-2873 163'0-1763 ' 7522-7653 HTPBQ47 439 922777 AC010646 3395. 1-147 HTPCN85 443 529760 AC040988 3400 ' -208 HTPCR51' 445 526406 AC023393 3403 1-263 HTPCR51 445 526406 AC0.73879 3404 1-263 HTPDI16_ 454 83b553 AL353658 3413 1-458 _ _ 1821-1956 HTPDJ94 456 669158 AC022315 3421 ~- 1-293 HTPDK32 4_57 699457 AC008749 3424 1-112 HTPEH20 466 573667 AL1173S6 3428 . 1-605 ' r 2640-2835 .

$

_ 2286-2655 -~

' 285-428 -,_____.HTPFJ95 470 933120 ACOlS748 344p 1-460 197' HTPFM04 472 926728 AC005013 344_1 ~ 1-524 ' HTPFM04 472 926728 AC034183.3445 1-459 _ 6898-7029 ,8341-8822 18911-20377' HTPFW04 476 926537 AC010687 3451 1-843.

' 1885-2418 . 3832-4539 HTPFZ03 4,81 922755 AL352978 3464 1-317 _ HTPFZ03 481 922755 AL359402 3465 1-310 ' HTPGF79 484' 974301 AC027164 3473 1-556 ~HTPGK10 486 963169 AC011382 3474 1-485 738=1845 HTPGW12 489 969522 AC011571 3487 .1-400 HTPGW 12 489 969522 AL I2 i 3489 I-444 HTPCrWl2 489 969522 AL121944 3490 1-400 _ 10334-10512 . 3973-4151 HTPHD53 490 869795 AL137802 3497 . 1-117 HTPHE36. 491 869814 AC008955 3499 1-600 ~

HTPHE36 491 869814 AC008452 3501 ~ I-600 HTPHE36 491 869814 AC008906 3502 ~ 1-600 2071-2197 .

4835-.5125 HTPHV17. 498 926455 AL359095 3514 1-487 . 8096-8208 , 10499-10599 . 11298-11645 _ 16318-16421 2.0115-20644 24169.-24295 _ _ 25772-25881 _ 3718-3872 ' .

HUFAG~81 503 966223 AC013693 3521 1-518 ' ' ' 17530-17844 ' 19678-20070 202 _ HLJFAN64. 506 678677 AP002027 3528 1-281 998-1679 _.

HUFBU14 511 868993 AP000436 3537 ~ 1-290 ~

HUFBU14 511 868993 AP000814 3539 ' 1-150 HUFGH78 516 6597.22 AL035413 3542 1-260 I O

7998-83.66 _ 19042-19175 34.722-35083 386'13-38736 . 44600-45100 ' ~HWGAC19 S34 668126 AL161932 3565 1-102 HWGAC19 534 668126 AC006101. 3566 1-193 ~

HWGQD52 537 726390 AC.074091 3567 1-1376 WO 01/55314 . PCT/USO1/01324 HWLAL74 539 7&1974 AL161795 3570 1-148 HWLCV54 544 929742 AL139054 3575 1-686.

HWLD022 545 83872_1 ACO61989 3576 1-1555 HWLD022 54S _ AF207953 3577 1-1556 WLED58. _546 830_33 ACO22097 35 1-500 _ _ _ ACO09229 _ 1-500 HWLEF86 _ _ AL355336 3582 1-158 547 _ HWLEK39 552 918545 AL358177 3593 _ HWLEN20 554 963418 AL355388 3595 ~ 1-634 HWLEN20 5S4' 963418 AL355388 3599 1-114 _ 2227-2464 . ~ 10817-11045 _ l I80-1555 ' HWLEP95 556 751199 AC023287 3606 I-250 , ' 1060-1374 ' ~ 6204-6681 _ ~ 8287-9016 HWLEQ36 557 966250 ACO11405 3609 1-18,8 ~ ~

HWLER88 559 915168 AC026593 3611 1-324, ' ~

HWLFB08 560 849136 AL133243 3615 ~ 1-607 ~

HWLFF40 _ 830287 AC012114 3620 1-314 ~

HWLFF40 563 830287 AC005751 3625 _ 1-224 HWLFF62 564 915155 ACp73957 3627 I-449 HWLF070 _568 756_554 AC005595 36_31 1-421 _ HWLF092 570. 791052 AC021212 3636 1-565 HWLFP37 571 708985 AC022022 3637 ' 1-59 HWLFP37 571 708985 AC016197 3638 . 1-59 HWLFP37 571 708985 AC022022 3640 . 1-599 HWLFP37 571 708985 AC016197 3641 . ~ 1-216 HWLFP37 571 708985 AC016197 3642. 1-599 HWLF 48 573 721154 AC025264 3644 ~-421 4790-5.180 6022-6108.

1276-'1426 ' 16183-16277 _ 2_402_3-26112 HWLF 48 573 721154 AC0116Ol 3648 1-534 HWLFSOl 574 915531 ACOlI075 3650 I-473 HWLFSO1 574 915531 AC010082 3653 ' 1-190 ' ~ 245-410 HWLFS86 575 830246 AC009986 3654__ 1-1426 _ HWLFV61 576 922924 AC010732 _ 1-366 HWLFV61 576 922924 AC010732 3659. 1-114 HWLGP10 579 883139 AC021094 36'61 1-2212 .209 HWLGP10 579 8$3139 AC021094 3663 1-119 .

HWLGT12 582 966044 AC005103 _3670 1-940 HWLGX56 585 830329 AC026367 3683 ~ 1-624 HWLGX56 585, 830329 AC048339 3688 1-86 .

HWLH001 588 915158. AC010442 3692 ~ 1-I14 84' WO 01/55314 _ PCT/USO1/01324 HWLIL65 596 74.7440 AL139150 3707 1-454 HWLI073 598 761965 AC021972 3709 . 1-629 '1339-1830 HWLJB04 602 926066. AC010472 3716 1-243 HWLJE89 604 928258. AC022485 3718 1-591 HWLJL14~ 606 832205 AC067812~ 3721 1-486 ' HWLJL14. 606 832205 AC020549 3725 ~ 1-489 ~ 2250-3207 . , 10534-10971 -HWLJZ30 613 925870 AC006483 3733 . 1-311 5009-6576 ..._ .
-HWLKL17 616 928720 AL117341 3738. 1-486 HWLKV91 619 830214 AL121574 '3742 ~ 1-6 HWLKV91 619 830214 AL121574 3743 _ ~

HWLLH25 625 933479 AC024243 3750 l-533 11415=11561 . 2933-3032 HWLMA84 630 929421 AF067844 3760 ~ 1-169 2704-3'023 HWLPGOS 633 930991 AP000813 3765 1-1220.

4452=5671 .

_ HWLUB86 635 966462 AC022384 3771 _ _ __ 1-514 HWLV006 637' 933592 AC004460 3775 1-1009 HWMFG10 64'8 963406 AL355134 3786 1-592 HWMF 90 _651 928646 AL138996. 3796__ 1-376 HWMHG26 655' 957665 AC022728 3800 1-646 3806=4126 ~

HWMIR03 661 922302 AL354820 3819' 1-432 HWMI~I01 664 913841 AC009097 3828 1-1453 HWMI~I01 664 913841 AC009097 3829 1-190 HWMMA12 667 969173 AL359706 3832' 1-106 --- HWMMY66 '670 966367 AL161931 3840 1-107 ' .2407-3485 _ ~ ~ 13029-13568 ' 16350-16527 ' 18198-18335 __ 2809-3259 5365-5973 .

HWNFZ48 679 933522 AC007227 3860 ~ 1-490 , -HWNDU11 685 96538.2 AC073532 3865 . 1-1075 ~

' 4385-4566 __ ~ - . 11518-11855 ' 16177-16549 ' 20305-20887 35487-35810.

w 218 .

HWNAL06 689 933591 AC022133 3877 ' 1-520 HWMBY62 692 937234 AP001562 3883 ~ 1-1678 HWMBY62 692 937234 AC011123 3884 l-381 HWMBY62 692 937234 _ 3f886 1-240 HWMAE12 694 969692 AC004601 3889 ' 1-321 .

HWLVfJ33 696 972979 AC016757 3891 1-606 HWLW33 696 972979 AC016757 3892 . 1-79 _ 3756-3966 HWLVK02 697 922696 AC026691 3893 v 1-1784 ~ ' HWLUY15~ 698 874966 AC021094 3894 1-460 HWLUY15 698 874966 AC020664 3895 ~ 1-460 HWLUY15 698 874966 AC021094 3896 ~ 1-650 WO 01/55314. PCT/USO1/01324 HWLQS70 699 933799 AL161797. 3900 1-427 ~

S

, 61-772' HWLOL02 702 918320 AC068942 3910 ~ 1-647 HWLOL02 702. 918320 AC012309 3915 1-91 220 , _ HWLNC88 704 875790 AC074274 '3917 1-510 HWLMIl6 706 918726 AC067952 3918 1-2563 HWLMI16 706 918726 AC025IQ8 3920 _ I-90 . , 813-916 ' .

HWLKJ03 712 922371 AL080276 3924 ' 1-608 HWLJKOl 718 914089 AL353812 3928 1-1171 HWLJKO1 718 914089 AL353812 3929 ' 1-542 _ . 460-1278 - _ 1273-1517 12226=13392 ' 18962-I9I28 ' ~ 19792-20077 . 22573-23150 9903-10133.

.

19792-200'77 . 24074-24172 ' 27891-28841 HWLHU03 723 922931 AC005071 3939 . 1-3015 -. 3498-7063 WO 01/55314 . PCT/USO1/01324 7 25.
v HWLHH62 _ _ AC006479 3943 1-488 25 _ HWLGA04 _ 925682 AC024339 3944 1-574 HWLFY06 30 934635 AC02221l 3952 1-658 HWLFY06 _ 934635 AC022211 3953 1-348 HWLFY06 _ 934635 AC022211 3954 1-341 ~ _ ~

~

HWLFM69 733 754644 AC009556 39SS ~ ~ 1-973 ~

HWLFM69 733 754644 AL359314 3956 1-9'73 v HWLFM69 733 754644 AC009556 3958 I-657 _ 1089-1708 ' _1094-1713 HWLF1VI69 733 754644 AL161625 3963 . 1-657 , . 951-2100 ~

HWLEI57 742 734267 AL139329 3969___ 1-471 ~HWLEI57 742 734267 AL139329 3970 1-439 HWLB006 751 934630 AC016002 3974. 1-828 HWLB006 751 934630 AC022322 3975 ~ 1-828 _ 320-826 WO 01/55314 . PCT/USO1/01324 HWLAC70 758 775771 AL159140 3989 ~ 1-1022 HWLAC29 759 690263 AC026468 3992 ~ 1-849 ' 870_-1.491 HWLAB74 760 765196 AL357774 3995 ~ 1-376 ' ~ 997-1340 HWCAGlI 762 966623 AC009068 3999 1-142 ' HWCAG11 762 966623 AC018695 4000 1-129.

~

HVATY05 7.64 928713 AJ239320 4002 1-655 .

HVAPI01 766 913930 AC044796 '4005 1-772 HVAETOl 767 913958 AL133243 4010 1-428 - ~ 5357-6137 .

_ __ 17708-19731 _ 3402-4059 6661=6945 _ 7544-7614 HUFDOll 775 966407 AC069236 4016 1-317 HUFDH29 777 689979 AC020623 4019 . 1-1278 ~

HUFDH29 777 689979 AC020623 4023 . 1-354 HCJFDH29 777 689979 AC069245 4024 ' 1-354 _ 227 HUFA077 785 772133 AC004016 4037 ~ 1-276 _ 2479-2639 8242=8371 .HTPFF81 793 869862 AC009397 4046 1-415 HTPFF81 793 869862 AC008770 4047' 1-415 22~

_ 2856-3569 ~

HTPCR30 801' 574757 AC022214 4057 ~ 1-109 HTPBD55 806 754147 AC020988. 4060 1-318 HTPBD55 806 754147 AC020988 406.1 1-320 ~

HTP_ AP93 808 791415 AL133215 4062 1-181 . ~ 5346-5426 5763-62.43 HTNTA60 813 84.0258 AC012485 4067 1-323 HSPBD58 817 735472 AC03.90564072 1-785 HSPBD58 8.17 735472 AC039056 4073 1-3024 HSPBC71 818 7598$6 AC026229 4082 1-824 .

HSPAY58 819 964178 AL035249 _ 1-590 ' _ ' HSODZ52 823 825096 AC021937 4094 ' 1-452 .

16388=16950 HSOBP04 834 871340 ACO'10217 4104 1-593 HSOBP04 834 871340 AC010237 4105 .l-589 ' _ 1254-1882 HSOBP04 834 87134_0 AC012369 4113 1-932 HSOBN03 836 923315 AC009I94 4118 ~ 1-747 .

_ 1196-1509 HSOBK7S 838 766940 AC017064 4122 ~ I-936 ~

~

HSOBH84 840 782118 AP001394 4128 ~ 1-166 _ HSOBE61 842 908598 AC026487 4131 1-1439 . ~ 1878-2474 . 7767-8526 _ 1539-1808 ' 11721-11928 - ' HSOBE03 843 923322 AF235095 4135 1-583 ~

~

HSOAV11 847 967590 AL138762 4141 ' 1-245 ' HSOAM07 850 953954 AL160278 4154 ~ 1-453 ' HSOAG31 852 698357 .AC040174 4156 1-314 HSOAF76 853 877300 AL161430 4162 _ 1-493 IiSOAF76 853 877300 AC025797 4163 1-493 ~ 5535-5692 . 388-867 HSIGJ94 857 793624 AL161626 4168 ~ 1-2564 HSIGJ94 857 793624 AL138757 4170 ~ 1-295 ' HSIGG42 859 713339 ACOb8=82f14174 ~ 1-683 . ~

' HSIGG42 859 713339 AC008592 4176 ' 1-435 ' HSIGG42 859 713339 AC021124 4179 ' 1-435 HSIGG42 859 713339 AC008924 4181 1-435 , HSIGG42 859 7133.39 AC008821 4182 1-275 HSIGF42. 860 866561 AL138684 4185 1-1102 HSIGA25 862 677668 AL355973 4188 . 1-1819 '_ 961-1365 HSIGA25 862. 677668 AC000382 4190 1-916 -HSIGA25 862 67766.8 AC000382 4194 1-643 .

._ . . _235 ~

HSIFD30 871 691636 AP0015S7 4200 l-2538 ~

HSIFD30 871 691636 AP001557 4206 ' 1-434 HSIED64 872 747012 AC068289. 4208 1-349 10184-10314.

15527-.15936 WO 01/55314 . PCT/USO1/01324 H_SICU58 885 507172 AL356273 4221 1-166 HSIBB22 889 518673 AP001808 4225 ~ 1-122 HSIAD11 895 964915 AP002014 4230' 1-1836 HSIAB63 _896 745637 AL049709 4235 1-556 _ .

~

HSGBBOl 898 916772 AL079303 4241 1-452 HSGAA1~2 899 971541 AC073655 4242 1-863 ' 237 _- ..

S

HRTAN72 903 766328 AC031984 .4249 1-367 ~

HRTAN70 904 524889 AC024592 4254 ~ 1-279 HRTAN70 904 524889. A.C021165 4255 1-84 .--_..

HRTAD37 908 708782 AC013533 4260 _ HRTAD37 908 708782 AC010158 4265 1-29.8 ,HRTAD37 908 708782 AC010162 4268 1-297 .

. ~ 4491-4724 _ 24926-25440 33345=33436 -~ - 34515-34638 .

HRODX43 91.2 949765 AL137247 4277 1-296 ~

' ~ 1761-3704 HRODX43 912 9497_65 AL137247 4279 1-329 . , , ~ 1421-1864 ' 2858-3322' .__ , . 239 WO 01/55314 . PCT/USO1/01324 .

HROCB26 918 812019 AC068213 4289 ' 1-28 4406-4676 _ 6.871-7189 HROCB26 918 812019 AC015714 4290 1-28 .

_ 743-1285 _ _ 2199-2424 .

. 3694-3785 HROBR02 925 918985 AC017100 4304 _ 1-153 , . 3 90-651 HROBR02 925 918985 AP002474 4305 1-324' ~

HROBH25 927 677574 AL356309 4310 ' 1-225 ' HROBH25 927 677574 ~AC006443 4311 1-408 HROBG67 .928 751230 ALI38768 4314 l-464 HROBF19 929 668.013 AL121918 4317 1-414 HROBD79 93.0 774558 AL138898 4319 1-904 ~

~

HNSMD08 949 958337. AC019152 4334 1-357 HNSMD08 949 958337 ~AC007722 4335 1-99 HNSMD08 949. 958337 AC007722 4336 1-357 ~

HNKCM03 952 922136 AC016546 4338 .1-797 ' 3454-3 811 ' ~ 6316-6456 ~~ 15256-15417 - ~ 2133-4197 HNKA008 954 955691 AC036236 4342 I~193 HM~A008 954 955691 AL031003 4343 ~ 1-191 HNKA008 954 955691 AL031.003 4344 1-1526 HNALB10 960 968198 AC006328 4359 ~ 1-1133 HMZMD49 964 722624 AC012137 4362. 1-547 HMZAE53 965 86'8116 AL161652 4367 1-432 HMZAE53 965 868116 AL1.61652 4368 1-195 -- , 590-879 _ ~ 2974-3146 HMZAC09 966 625_188 AL354988 4371 1-744 HL HD03 971 856624 AC037452 4377 ' 1-827 HL GU11 973 965781 AL359963 4384. 1-341 HL GUll~ 973 965781 AC013568 4385 1-107 HL GUll 973 965781 AC013568 4386 1-341 HL GP25 974 893692 AC009119 4388 . 1-679 HL GA01 976 915066 AC069137 4393 1-750' ' . ' -HLQFQ08 978 961154 AC007114 4400 ~ 1-85 ' ~ ~ 23.14-2475 .

HLQEW11 980 966019 AC026407 4401 ~ 1-2070 - ~ ' 6150-6586 _ 9527-9700 HL EN07 982 856733 AC004621 4406 ' 1-260 HLQED04 984 969543 AC003034 4410 1'-1463 ~

_4494-4613 - ~ 6748-6856 ' 8243-9122 HL ED04 984 969543 AC003034 4411 1-431 , HL DVOl 986 916190 AC007281 4414 ~ 1-542 HL DVOl 986 -916190 AC007281 4415 1-387 ' ' HLQDVO1 986 916190 AC007281_ 4416 1-467 HL DR89 989 972425 AL359960 4417 _ HL DR89 989 972425 AL137145 4418 1~-795 _ . 1286-1382 HL. DR47 990 720145 AC025038 4426 1-479 8380-$506 11285-11405' . 14933-15793 1.9573-19930 ~. 20884-21063 ' 21218-21447 HL DM03 995 923862 AL365320. 4432 1-309 . 157-226 6234'-8655 HLQDF69 998 754302 AC009431 4439 1-2185 ._ . ,_ ~

HL DF69 998 754302 AC022900 4442 1.-1438 HL D$32 1000 707639 AL136961 4445 1-633 ~

~

HL CY79. 1005 774827 AC015918 4450 1-87 HLQCS58 1006 7.35841 AL022395 4453 1-466 . 3482-3822 ' 4489-4835 . 10629-10809 ' 31154-32844 HLQCS58 1006 735841 AL022395 4454 ~1-1835 ' HLQCH67 1012 751481 AC006977 4460 ' 1-506 HL BF91 1015 790408 AC026871 4466 ~ 1-4834 HLQAX31 1017 693626 AC002452 4467 ~ 1-675 HT,QAN75 1020 880815 AL390764 4468 1-101 . . . 4326-9299 _ ~ ' 1169-1310 --- ' ' 1401-1702 . 3371-3412 _ ~ 7294-7448 __- _.._ 11667-15866 . _.__ - ' ~ 1420-1543 . 4197-4968 _ 4999-5305 .

531'4-5454 135,78-13969 ' 15761-15953.

' ' 17275-19638 HLQAN75 1020 880815 AL136105 4471 ~ 1-32 - ' 4999-5305 _ _ . - 248 , ~

HL AN75 1020 880815 AL136105 4476 l-302 . . 1967-2228 _ 4653-4882 .HLICJ60 1028 739746 AC018630 4482 1-961 HLIBK17 1030 662438 AL15884.24488 ~ 1-453 ' _.. ~ 249 ' .. :_ HLIBBS4 1031 782180 AC009131 449.1 1-45 2205-2600' --- - ~ ~ - 5245-5372 ' - 8571-8685 HLDQH68 1036. 835571 AC002352 4508 1-379 ' 690-1196 HLDPE31 1039 697969 AC069069 4510 l-376 r ' 4952-5252 ' 6370-6479 ' HLDOS76 1042 770016 AL121926. 4518 1-.203 _-_ ___ 1830-1953 ..

5066-5270 ' - 7029-71'16 .

' .. ~ 5429-5833 HLDNR75 1048 767294 AP001~124 4523 1-223 ' . 996-1562 1770-2368 ' ' 3015-3123 _ 3499-6406 w ~ . 7526-8527 ___ HLDNR75 _1048 767294 AC010929 4524 1-1002 ~

~ ~

... _._ _--_ .

.

HLDNR54 1049 729853 AC002401 4527 __ . 1 ' ' 4817-5164 ' 7910-8192 HLDDY07 ' 1052 952751 AC019053 4531 1-139 " ,8443-8540 6681=7208 . v 11013-11074 ' 13826-13910 13989-140,92 ' 7986-8045 -' ~ 9541-10017 -. 10911-10983 HLDCW15 1054 705466. AC069227 4537 ' 1-438 .

' 2338-2448 ' ~

HLDCU74 1055 765307. AC010552 4541 1-124 - . 2620-2970 ' 3402-3481 _ _ _ _ ~ 2122-2214 _ _ _ 2235-2633 HLDCE01 1056 916444 AL3'60154 4548 1-372 HLDBW64 1057 746545 AC067872 4550 . 1-747 HLDBW64 1057 746545 AC022958 4551' 1-480 HLDBV65 1058 764915 AC008926 4553 ~ 1-1055 . 2677-2777 ~

. . 2677-2777 ' 2883-3082 HLDBV65 1058 764915 AC025179~ 4556 - 1-225 HLDBT71 1059 760347. AL031666 4559 1-508 2968-3.075 . 5480-5630 255 -. .

-HLDBE09 1064 625554 AC023309 4578 ' 1-193 -' . 2626-2925 HLDBE09 1064 625554 AL162741 4586 ,-1-102 . ~ 1880-2378 ' 4664-4815 '5427-5512 HLDBD,09 1065 625551 AC005390 4588 1-393 , ' 372-628 ' HLDBB08 1069 959385 AC022221 4600 ' 1-339 HLDBB08 1069 959385 _AC007897 4601 1-339 HLDAV38 1071 709140 AC037451 4609 ~ ' 1-89 _ ~

HLDAV38 1071 709140 AC068152 4617 . ~ 1-104 ' HLDAV38 1071 709140 AC009660 '4621 1-477 HLDAV38 1071 709140. AC068884 4627 1-122 HLDAV38 1071 709140 AC024659 4636 ~ 1-109 ~

HLDAV38 1071 709140 AL031622 4639 ~ 1-221 HLDAV38 1071 709140 ~AC015884 4642 1-131 HLDAV38 1071 709140 AC023232 4643 l-105 HLDAV~13 1072 657191 AC021312 4644 1-472 ._ 257 ~

HLDAV13 1072 ~ 657191 AC011405 4647 1-534 HLDAVOl 1073 916462 ACOI1004 4649 ' I-289 HLDAVOl 1073 916462 ACOlI004 4650 1-190 HLDARl2 1074 970634 AC068978 4652 1-486 ~

HISDL84 1085 782286 ACOlI813 4660 I-871 HISDL84 1085 782286 C011813 4661 - 1-409.
~ A

HISDFOS 1086 958417 AL049713~ 4662 1-83 ' . 2032-2121 .

HISCH73 1090 7.64281 AC002540 4667 1-439 ~ 72'8-1560 HISBW78 1095 840252 AC016561 4673 l-1606 ' 3301-3671 7245=8097 258 ....-_ . _ WO 01/55314 - . PCT/USO1/01324 532'7-5646 . ~ ' 16403-16556 ' 1913'7-20261 HISBV60 1096 740184 AP000585 4676 ~ 1-705 ' . , . 6494-7198 ' 9455-9608 HISBV54 1097 729356 AC010330 4684 ~ 1-582 ' .

. 563.3-5826 ~

HISBV54 1097 729356 AC010330 4690 ~ 1-826 HISBV54 1097 729356 ACO1.0330 4691 1-749 HISBU75 1098 767166 AC012306 4694 ~ 1-1500 .

HISBS95 1099 795748 AL121973 4697 ~ 1-944 HISBM13 11.00 656325 AL049776 4699 1-1379 .' 5150-5289 . 12782-13225 HISBM08 1101 _959051 AC016335 4701 1-465 ~

_ ' . ~ 3322-4126 ~. 5392-5795 _ 5835-6023 _ _ ' 260 .

.

HISBE17 ll04 662758 AF230666 4708 -378 ~

' 25250-25347 ' ~ 28196-28402 ' 39881-40753 ' 43721-44114 __ 261 I-IISA 1113 973368 AC006480 4715 ~ 1-327 95 ' HISA049. 1114 722310 AC021704 4718 1-173 HISAL91 _ 790044 AL049597 4720 1-523 .

HISAB77 1121 772155 AC007009 4730 ~ 1-2.55 HISAB77 _ 772155 AC007009 4731 1-614 ~

HISAB28 1,125 686621 AC011609 4739 1-74 16'12-3 ~

~

.. , 263 HHNACO1 1128 913646 _AC021051 4758 1-722 ~

HHNACOl 1128 913646 AC016951 4759 1-723 HHNACOl 1128 913646 AC021051 4760 1-121 HHNACOl 1128 913646 AC016951 4761 1-93 ~

HGBID78 _1132 772814 AC019232 4770 1-818 __ HGBID78 1132 772814 AC025171 4772' 1-370 ' 938-1149 HGBID78 1132 772814 AC019232 4776 ~1-605 HGBHW 16 1133 662148 AL359634 4779' 1-927 HGBHM39 1136 705606 AP000104 4786 ~ 1-504 ~

HGBHM39 1136 705606 AP000180 4791 ~ 1-182 ~

HGBHE82 1140 780030 AC027045 4796. 1-1506 . 2938-3309 HGBGZ03 1145 924788 AC015686 4808 _ 945-1'531 HGBGP21 1146 671194 AC012513 4809 . 1-629 -_ 734-1972 HGBGP21 1146 671194 AC008123 4813 . 1-889 . 321-500 . 4296-4362 __.. __ ._. _ __ ' 6011-6085 ' HGBGL83 1148 638178 AC018785 4822. 1-88 . . ~ 376-582 ___ . 4902-5078 _ __ _ _ _ . _ ' . 266 . 27586-27755 3.0278-30761 _. 931-1038 ' .

. 1611-2347 ~

. 610-793 3 974=4246 . 7639-7729 . 1811-2343 WO 01/55314 . . PCT/USO1/01324 . 5106-5546 ' 12328-12461 ' ~ 2300-5776 ~ ' 2600-3298 _ HGBDG11 1159 964929 AC007938 4849 1-906 HGBCU53 1160 871948 AL,160231 4850 " 1-1745 .

HGBBP65 1162 753956 AC023766 4859 . 1-414 HGBBP65 1162 753956 AC023766 4860 ~ 1-256 ~

1513=1793 . 1667-1942 ' 2555-3264 __ . 4005-4122 _ 4241-4323 _ 269 HGAMC08 1168 958490 AC008174 4870 ' 1-463 .

_ __ _ 880,1-8916 HFVID08 1173 959739 AL354956 4880 ~ 1-87 WO 01/55314 . PCT/USO1/01324 .

.

. ~ 1462-1753 1.4983-15107 . 21908-22077 ' 27695-27842 __ _ 30155-30270 __ ' 30726-30785 . 32789-32924 ' ' 38373-38508 ' - 42232-42658 51280-51.449 ~HFVHX74 1176 854533 AP001130 4893 - 1-1'58 ~

__ HFVHROS 1178 932181 AC009557 4_898 1-644 HFVGM12 1181 971182 AL358773 4901 ' 1-2493 ~

HFLQJ68 1187 _753216 AC023761 4910 1-399 ' .5547-5780 w 2500-2950 .

5'485-5585 ' ~ 5616-5892 273. _ , HDDAF49 1193 _911314 AC068243 ~ 4919 1-474 HCYBL79 11'99 888275 AC018593 4930 1-154 HCYBL79 1199 888275 AL354666 4932 1~-455 __HCYBL79 1199 888275 AL358813 4946 1-579 HCYBL79 1199 888275 AC018593 4947 . 1-246 HCYBL79 1199 888275 AC024468 4948 1-478.

HCYBL79 1199 888275 AL354666 4949 ~ 1-376 HCYBL79 1199' 888275 AC024468 4950 1-835 . ' , 2616-2733 ' 4199-6427 HCRP 40 1201 881408 AC055713 4965 1'-247 HCRP 40 1201 881408 AC0557.13 4967 1-105 .. 323-415 ' 2360-2851 HCRNR03 1204 922819' AL138695 4972 1-43 ' -HCRNR03 1204 922819 AL139185 4974 1-618' HCRMX10 1206 963663 AC009093 4976. 1-372 HCRM~10 1206 963663 AC007615 4978 1-372 ' ' 6084-6248 _ 12918-13928 ' HC DA13 1209 908299 AC013608' 4982 1-1010 HCQCQ76 121'0 953491 AC010622 4989 l.-1315 ~

_ . ~ 14159-14747 WO 01/55314 . PCT/USO1/01324 HCNSR78 1212 _773818 AL357078 4996 1-551 HCNSE03 1214 925492 AC026347 5004 ~ 1-1101 _ _ 7946-8131 ' 8252-8642 HCNDV41 1216 862324 AC024315 ~ 5011 1-268 .

HCNCX2-7 12_21 682479 AC023214 5024 1-345 HCNCT'03 1222 923344 AL139155 5025 1-471 ~

___ _ 278 ~

_... _. _ _ . 6224-6585 .

' ~ 398-598 ' - , 811-1547 ' 1568-2200 HCNAA41 1234 791545 AC022674 50_53 1'-225 _ HCIA.C12 1237 970750 AL137856 5057 1-300 HASMC23 1238 675527 AC007879 5062 ' 1-678 WO 01/55314 . PCT/USO1/01324 15157-15759w 15796-16141.

HA NB68 1240 752573. AC031978 5068 1-525 HAQMK53 1242 727708 AL133216 5073. 1-306 ~

HA MK53~ 1242 727708 AL133216 5079 1-750 HA MK53 1242 727708 AF198096 5083 ' 1-373 ~

6925=7555 ' 10992-11330 HALSD51 1245 500852 AC005678 5092 . 1-781 ~

HALS_D34 1246 509765 AC025648 5096 1-353 ~

.

HAL,SC37 1248 705894 AL359175 5101 1-303 H2LAM15 1258 767606 AC005971 5109 _ 27.14-3008 . - 22325-22853 ' 26253-27613 , 5620-5781 WO 01/55314 . PCT/USO1/01324 ' 19219-19549 ~

_ 1542-1883 [073] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone ID NO:Z), contig sequences '_.. _____~ ____.~8~

(contig identifier (Contig ID:) contig nucleotide sequence identifiers (SEQ ID
NO:X)), and genomic sequences (SEQ ID NO:B). The' first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence.
The second column provides the sequence identifier, "SEQ ID NO:X", for each contig sequence. The third column provides a unique contig identifier, "Contig ID:"
for each contig sequence. The fourth column, provides a BAC identifier "BAC ID NO:A"
for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC
clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ ID NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide.sequences delineated in column six, and fragments and variants thereof).

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0o d~ t~d' [074] Table 2 further characterizes certain encoded polypeptides of the invention, by providing the results of comparisons to protein and protein family databases.
The first column provides a unique clone identifier, "Clone ID NO:", corresponding to a cDNA
clone disclosed in Table 1A. The second column provides the unique contig indenti~er, "Contig ID:" which allows correlation with the information in Table 1A.
The third column provides the sequence identifier, "SEQ ID NO:X", for the contig ,polynucleotide sequences. The fourth column provides the analysis method by which the homology/identity disclosed in the row was determined. The fifth column provides a description of PFam/NR hits having significant matches identified by each analysis. Column six provides the accession number of the PFam/NR hit disclosed in the fifth column. Column seven, "Score/Percent Identity", provides a quality score or the percent identity, of the hit disclosed in column five. Comparisons were made between polypeptides encoded by polynucleotides of the invention and a non-. redundant protein database (herein referred to as "NR"), or a database of protein families (herein referred to as "PFam"), as described below.
[075] The NR database, which comprises the NBRF PIR database, the NCBI
GenPept database, and the SIB SwissProt and TrEMBL databases, was made non-redundant using the computer program nrdb2 (Warren Gish, Washington University in Saint Louis). Each of the polynucleotides shown in Table 1A, column 3 (e.g., SEQ ID
NO:X or the 'Query' sequence) was used to search against the NR database. The computer program BLASTX was used to compare a 6-frame translation of the Query sequence to the NR database (for information about the BLASTX algorithm please see Altshul et al., J. Mol. Biol. 215:403-410 (1990), and Gish et al., Nat. Genet.
3:266-272 (1993)). A description of the sequence that is most similar to the Query sequence (the highest scoring 'Subject') is shown in column five of Table 2 and the database accession number for that sequence is provided in column six. The highest scoring 'Subject' is reported in Table 2 if (a) the estimated probability that the match occurred by chance alone is less than 1.0e-07, and (b) the match was not to a known repetitive element. BLASTX returns alignments of short polypeptide segments of the Query and Subject sequences which share a high degree of similarity; these segments are known as High-Scoring Segment Pairs or HSPs. Table 2 reports the degree of similarity between the Query and the Subject for each HSP as a percent identity in Column 7.

The percent identity is determined by dividing the number of exact matches between the two aligned sequences in the HSP, dividing by the number of Query amino acids in the HSP and multiplying by 100. The polynucleotides of SEQ ID NO:X which encode the polypeptide sequence that generates an HSP are delineated by columns 8 and 9 of Table 2.
[076] The PFam database, PFam version.5.2, (Sonnhammer et al., Nucl. Acids Res., 26:320-322, (1998)) consists of a series of multiple sequence alignments; one alignment for each protein family. Each multiple sequence alignment is converted into a probability model called a Hidden Markov Model, or HMM, that represents the position-specific, variation among the sequences that make up the multiple sequence alignment (see, e.g., R. Durbin et al., Biological sequence analysis:
probabilistic models ofproteins and nucleic acids, Cambridge University Press, 1998 for the theory of HMMs). The program HMMER version 1.8 (Sean Eddy, Washington University in Saint Louis) was used to compare the predicted protein sequence for each Query sequence (SEQ ID NO:Y in Table. 1A) to each of the HMMs derived from PFam version 5.2. A HMM derived from PFam version 5.2 was said to be a significant match to a polypeptide of the invention if the score returned by HMMER 1.8 was greater than 0.8 times the HMMER 1.8 score obtained with the most distantly related known member of that protein family. The description. of the PFam family which shares a significant match with.a polypeptide of the invention is listed in column 5 of Table 2, and the database accession number of the PFam hit is provided in column 6.
Column 7 provides the score returned by HMMER version 1.8 for the alignment.
Columns 8 and 9 delineate the polynucleotides of SEQ ID NO:X which encode the polypeptide sequence which shows a significant match to a PFam protein family.
[077] As mentioned, columns 8 and 9 in Table 2, "NT From" and "NT To", delineate the polynucleotides of "SEQ ID NO:X" that encode a polypeptide having a significant match to the PFam/NR database as disclosed in the fifth column of Table 2. In one embodiment, the invention provides a protein comprising, or alternatively consisting of, a polypeptide encoded,by the polynucleotides of SEQ ID NO:X delineated in columns 8 and 9 of Table 2. Also provided are polynucleotides encoding such proteins, and the complementary strand thereto..

[078] The nucleotide sequence SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently accurate and otherwise suitable for a variety of uses well known in the art and described further below. For instance, the nucleotide sequences of SEQ ID
NO:X
are useful for designing nucleic acid hybridization probes that will detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA contained in Clone ID. NO:Z.
These probes will also hybridize to nucleic acid molecules in biological samples, thereby enabling immediate applications in chromosome mapping, linkage analysis, , tissue identification and/or typing, and a variety of forensic and diagnostic methods of the invention. Similarly, polypeptides identified from SEQ ID NO:Y may be used to generate antibodies which bind specifically to these polypeptides, or fragments thereof, and/or to the polypeptides encoded by, the cDNA clones identified in, for example, Table 1A.
[079] Nevertheless, DNA sequences generated by sequencing reactions can contain sequencing errors. The errors exist as misidentified nucleotides, or as insertions or deletions of nucleotides in the generated DNA sequence. The erroneously inserted or deleted nucleotides cause frame shifts in the reading frames of the predicted amino acid sequence. In these cases, the predicted amino acid sequence diverges from the actual amino acid sequence, even though the generated DNA sequence may be greater than 99.9% identical to the actual DNA sequence (for example, one base insertion or deletion in an open reading frame of over 1000 bases).
[080] ~ Accordingly, for those applications requiring precision in the nucleotide sequence or the amino acid sequence, the present invention provides not only the generated nucleotide sequence identified as SEQ ID NO:X, and a predicted translated amino acid sequence identified as SEQ ID NO:Y, but also a sample of plasmid DNA
containing cDNA Clone ID NO:Z (deposited with the ATCC on October 5, 2000, and receiving ATCC designation numbers PTA 2574 and PTA 2575; deposited with the ATCC on January 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-1, a.nd AC-2; and/or as set forth, for example, in Table 1A, 6 and 7). The nucleotide sequence of each deposited clone can readily be determined by sequencing the deposited clone in accordance with known methods. Further, techniques known in the art can be used to verify the nucleotide' sequences of SEQ ID NO:X..

[081] The predicted amino acid sequence can then be verified from such deposits.
Moreover, the amino acid sequence of the protein encoded by a particular clone can also be directly determined by peptide sequencing or by expressing the protein in a suitable host cell,containing the deposited human cDNA, collecting the protein, and determining its sequence.
RACE Protocol For Recovery of Full-Length Genes [082] Partial cDNA clones can be made full-length by utilizing the rapid amplification of cDNA ends (RACE) procedure described in Frohman, M.A., et al., Proc. Nat'l.
Acad.
Sci. USA, 85:8998-9002 (1988). A cDNA clone missing either the 5' or 3' end can be reconstructed to include the absent base pairs extending to the translational start or, stop colon, respectively. In some cases, cDNAs are missing the start colon of .translation. The following briefly describes a modification of this original 5' RACE
procedure. Poly A+ or total RNA is reverse transcribed with Superscript II
(Gibco/BRL) and an antisense or complementary primer specific to the cDNA
sequence. The primer is removed from the reaction with a Microcon Concentrator (Amicon). The first-strand cDNA is then tailed with dATP and terminal deoxynucleotide transferase (Gibco/BRL). Thus, an anchor sequence. is produced which is needed for PCR amplification. The second strand is synthesized from the dA-tail in PCR buffer, Taq DNA polymerase (Perkin-Elmer Cetus), an oligo-dT
primer containing three adjacent restriction sites (XhoI, SaII and ClaI) at the 5' end and a primer containing just these restriction sites. This double-stranded cDNA is PCR
amplified for 40 cycles with the same primers as well as a nested cDNA-specific antisense primer. The PCR products are size-separated on an ethidium bromide-agarose gel and the region of gel containing cDNA products the predicted size of missing protein-coding DNA is removed. cDNA is purified from the agarose with the Magic PCR Prep kit (Promega), restriction digested with XhoI or SaIL, and ligated to a plasmid such as pBluescript SKII (Stratagene) at XhoI and EcoRV sites. This DNA is transformed into bacteria and. the plasmid clones sequenced to identify the correct protein-coding inserts. Correct 5' ends are confirmed by comparing this sequence with the putatively identified homologue and overlap with_the partial cDNA clone.
Similar methods known in the art and/or commercial kits are used to amplify and recover 3' ends.
[083] Several quality-controlled kits are commercially available for purchase.
Similar reagents and methods to those above are supplied in kit form from Gibco/BRL
for both 5' and 3' RACE for recovery of full length genes. A second kit is available from Clontech which is a modification of a related technique, SLIC (single-stranded ligation to single-stranded cDNA), developed by Dumas et al., Nucleic Acids Res., 19:5227-32, (1991). . The major differences in procedure are that the RNA is alkaline hydrolyzed after reverse transcription and RNA ligase is used to join a restriction site-containing anchor primer to the first-strand cDNA. This obviates the necessity for the dA-tailing reaction which results in a polyT stretch that is difficult to sequence past.
[084] An alternative to generating 5' or 3' cDNA from RNA is to use cDNA~
library double-stranded DNA. An asymmetric PCR-amplified antisense cDNA strand is synthesized with an antisense cDNA-specific primer-and a plasmid-anchored primer.
These primers are removed and a symmetric PCR reaction is performed with a nested cDNA-specific antisense primer and the plasmid-anchored primer.
RNA Ligase Protocol For Generating The S' or 3' End Sequences To Obtain Full Length Genes [085] Once a gene of interest is identified, several methods are available for the identification of the 5' or 3' portions of the gene which may not be present im the original cDNA plasmid. These methods include, but are not limited to, filter probing, clone enrichment using specific probes and protocols similar and identical to 5'F and 3' RACE. While the full length gene may be present in the library and can be identified by probing, a useful method for generating the 5' or 3' end is to use the existing sequence information from the original cDNA to generate the missing information. A.
method similar to 5' RACE is available for generating the missing 5' end of a desired full-length gene. (This method was published by Fromont-Racine et al., Nucleic Acids Res., 21(7):1683-1684 (1993)). Briefly, a specific RNA oligonucleotide is ligated to the 5' ends of a population of RNA presumably containing full-length gene RNA
transcript. A primer set containing a primer specific to the ligated RNA
oligonucleotide and a primer specific to a known sequence of the gene of interest, is used to PCR amplify the 5' portion of the desired full length gene which may then be sequenced and used to generate the full length gene. This method starts with total RNA isolated from the desired source, poly A RNA may be used but is not a prerequisite for this procedure. The RNA preparation may then be treated with phosphatase if necessary to eliminate 5' phosphate groups on degraded or damaged RNA which may interfere with the later RNA ligase step. The phosphatase, if used, is then inactivated and the RNA is treated with tobacco acid pyrophosphatase in order to remove the cap structure present at the 5' ends of messenger RNAs. This reaction leaves a 5' phosphate group at the 5' end of the cap cleaved RNA which can then be ligated to an RNA oligonucleotide using T4 RNA ligase. This modified RNA
preparation can then be used as a template for first strand cDNA synthesis using a gene specific oligonucleotide. The first strand synthesis reaction can then be used as a template for PCR amplification of the desired 5' end using a primer specific to the ligated RNA oligonucleotide and a primer specific to the known.sequence of the digestive system antigen of interest. The resultant product is then sequenced and analyzed to confirm that the 5' end sequence belongs to the relevant digestive system antigen.
[086] The present invention also relates to vectors or plasmids, which include such .
DNA sequences, as well as the use of the DNA sequences. The material deposited with the ATCC (deposited with the ATCC on October 5, 2000, and receiving ATCC
designation numbers PTA 2574.and PTA 2575; deposited with the ATCC on January 5,. 2001, having the depositor reference numbers TS-l, TS-2, AC-1, and AC-2;
and/or as set forth, for example, in Table 1A, 6 and 7) is a mixture of cDNA clones derived from a variety of human tissue and cloned in either a plasmid vector or a phage vector, as shown, for example, in Table 7. These deposits are referred to as "the deposits" ' herein. The tissues from which some of the clones were derived are listed in Table 7, and the vector in which the corresponding cDNA is contained is also indicated in Table 7. The deposited material includes cDNA clones corresponding to SEQ ID
NO:X described, for example, in Table 1A (Clone ID NO:Z). A clone which is isolatable from the ATCC Deposits by use of a sequence listed as SEQ ID NO:X, may include the entire coding region of a human gene or in other cases such clone may include a substantial portion of the coding region of a human gene.
Furthermore, __ _ . ~ 322 _._. __ .

although the sequence listing may in some instances list only a portion of the DNA
sequence in a clone included in the ATCC Deposits, it is well within the ability of one skilled in the art to sequence the DNA included in a clone contained in the.
ATCC
Deposits by use of a sequence (or portion thereof) described in, for example Tables 1A
or 2 by procedures hereinafter further described, and others apparent to those skilled in the art.
[087j Also provided in Table 7 is the name of the vector which contains the cDNA
clone. Each vector is routinely used in the art. The following additional information is provided for convenience.
[088] Vectors Lambda Zap (U.S. Patent Nos. 5,128,256 and 5,286,636), Uni-Zap XR
(U.S. Patent Nos. 5,128,256 and 5,2$6,636), Zap Express (U.S. Patent Nos.
5;128,256 and 5,286,636), pBluescript (pBS) (Short, J. M. et al., Nucleic Acids Res.
16:7583-7600 (1988); Alting-Mees, M. A. and Short, J. M:, Nucleic Acids Res. 17: 9494 (1989)) and pBK (Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are commercially available from Stratagene Cloning Systems, Inc., 11011 N. Torrey Pines Road, La Jolla, CA, 92037. pBS contains an ampicillin resistance gene and pBK contains a neomycin resistance gene. Phagemid pBS may be excised from the Lambda Zap and Uni-Zap XR vectors, and phagemid pBK may be excised from the Zap Express vector.
Both phagemids may be transformed into E. toll strain XL-1 Blue, also available from Stratagene.
[089] Vectors pSportl, pCMVSport 1.0, pCMVSport 2.0 and pCMVSport 3.0, were obtained from'Life Technologies, Inc., P: O. Box 6009, Gaithersburg, MD 20897.
All Sport vectors contain an ampicillin resistance gene and may be transformed into E.
toll strain DHlOB, also available from Life Technologies'. See, for instance, Gruber, C. E., et al., Focus 15:59- (1993). Vector lafmid BA (Bento . Soares, Columbia University, New York, NY) contains an ampicillin resistance gene and can be transformed into E. toll strain XL-f Blue. Vector pCR~2.1, which is available from Invitrogen, 1600 Faraday Avenue, Carlsbad, CA 92008, contains an ampicillin resistance gene and may be transformed into E. toll strain DH10B, available from Life Technologies.' See, for instance, Clark, J. M., Nuc. Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology'9: (1991).
323 ' [090] The present invention also relates to the genes corresponding to SEQ ID
NO:X, SEQ ID NO:Y, and/or the deposited clone (Clone ID NO:Z). The corresponding gene can be isolated in accordance with known methods using the sequence information disclosed herein. Such methods include preparing probes or primers from the disclosed sequence and identifying or amplifying the corresponding gene from appropriate sources of genomic material.
[091] Also provided in the present invention are allelic variants, orthologs, and/or species homologs. Procedures known in the art can be used to obtain full-length genes, allelic variants, splice variants, full-length coding portions, orthologs, and/or species homologs of digestive systenri associated genes corresponding to SEQ ID NO:X
or the complement thereof, polypeptides encoded by SEQ ID NO:X or the complement thereof, and/or the cDNA contained in Clone ID NO:Z, using information from the sequences disclosed herein or the clones deposited with the ATCC. For example, allelic variants and/or species homologs may be isolated and identified by making suitable probes or primers from the sequences provided herein and screening a suitable nucleic acid source for allelic variants and/or the desired homologue.
[092] ~ The polypeptides. of the invention can be prepared in any suitable manner.
Such polypeptides include isolated naturally occurring polypeptides, recombinantly produced polypeptides, synthetically produced polypeptides, or polypeptides produced by a combination of these methods. Means for preparing such polypeptides are well understood in the art. .
[093j The polypeptides. may be in the form of the secreted protein, including the mature form, or may be a part of a larger protein, such as a fusion protein (see below).
It is often advantageous to include an additional amino acid sequence which ~
contains secretory or leader sequences, pro-sequences, sequences which aid in purification, such as multiple histidine residues, or an additional sequence for stability during recombinant production.
[094]~ The polypeptides of the present invention are preferably provided in an isolated form, and preferably. are substantially purified. A recombinantly produced version of a~ polypeptide, including the secreted polypeptide, can be substantially purified using techniques described herein or otherwise known in the art, such as, for example, by the one-step method described in Smith and Johnson, Gene 67:31-40 (1988).

Polypeptides of the invention also can be purified from natural, synthetic or recombinant sources using techniques described herein or otherwise known in the art, such as, for example, antibodies of the invention raised against the digestive system polypeptides of the present invention in methods which are well known in the art.
[095] The present invention provides a polynucleotide comprising, or alternatively consisting of, the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA
sequence contained in Glone ID NO:Z. The present invention also provides a polypeptide comprising, or alternatively, consisting of, the polypeptide sequence of SEQ
ID NO:Y, a polypeptide encoded by SEQ ID NO:X or a complement thereof, a polypeptide encoded by the cDNA contained in Clone ID NO:Z, and/or the polypeptide sequence encoded by a nucleotide sequence in SEQ ID NO:B as defined in column 6 of Table 1B. Polynucleotides encoding a polypeptide comprising, or alternatively consisting of the polypeptide sequence of SEQ ID NO:Y, a polypeptide encoded by SEQ ID NO:X, a polypeptide encoded by the cDNA contained in Clone ID NO:Z and/or~a polypeptide sequence encoded by a nucleotide sequence~in SEQ ID NO:B as defined in column of Table 1B are also encompassed by the invention. The present invention further encompasses a polynucleotide comprising, or alternatively consisting of, the complement of the nucleic acid sequence of SEQ ID NO:X, a nucleic acid sequence encoding a polypeptide encoded by the complement of the nucleic acid sequence of SEQ ID NO:X, and/or the cDNA contained in Clone ID NO:Z.
[096] Moreover, representative examples of. polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strands) of the sequences delineated in Table 1B
column 6,'or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1.B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B
(see Table 1B, column 5). In additional embodiments, the above-described polyriucleotides of the invention comprise, or alternatively consist of, sequences delineated.in Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In ' additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC
clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.
[097] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist. of, one, two, three, four, five, six, seven, eight;
nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), or any combination thereof.
Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, 'one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strands) of the sequences delineated in column 6 of Table which correspond to the same Clone ID NO:Z (see Table 1B, column 1), or, any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and -have a nucleic acid sequence which is different from that of the BAC
fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B
which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that published for the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1) and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these- polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.
[098] Further, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2), or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strands) of the sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID
NO:X (see Table 1B, column 2), or any combination thereof. In further embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid sequence which is different from that of the BAC fragment having. the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively, consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ.ID NO:X (see Table 1B, column 2) and have a nucleic acid .
sequence which is different from that published for the BAC clone identified as~BAC
ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in column 6 of Table 1B which correspond to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) and have a nucleic acid sequence which 'is different from that contained in the BAC clone identified as BAC ID
NO:A
(See Table 1B, column 4). Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides and polypeptides are also encompassed by the invention.

[099] Moreover, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row ~of Table 1B column 6, or any combination thereof. Additional, representative examples of polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strands) of the sequences delineated in the same row of Table 1B' column 6, or any combination thereof. .In preferred embodiments, the polynucleotides of the invention comprise; or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the complementary strands) of the sequences delineated in the same row of Table 1B
column 6, wherein sequentially delineated sequences in the table (i.e.
corresponding to those exons located closest to each other) are directly contiguous in a 5' to 3' orientation. In further embodiments, above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that of the BAC fragment having the sequence disclosed in SEQ ID NO:B (see Table 1B, column 5). In additional embodiments; the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that published for the BAC clone, identified as BAC ID NO:A (see Table 1B, column 4). In additional embodiments, the above-described polynucleotides of the invention comprise, or alternatively consist of, sequences delineated in the same row of Table 1B, column 6, and have a nucleic acid sequence which is different from that contained in the BAC clone identified as BAC ID NO:A (see Table 1B, column 4).
Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
[0100] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1B, column 2) or fragments or variants thereof. Polypeptides encoded by these polynucleotides, other ..328 ~ _ polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
[0101] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or,more of the sequences delineated in column 6 of Table 1B which correspond to the same Clone ID NO:Z (see Table 1B, column 1), and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof.
In preferred embodiments, the delineated sequences) and polynucleotide sequence of SEQ ID NO:X correspond to the same Clone ID NO:Z. Polypeptides encoded by these polynucleotides, other, polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
[0102] In further specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, one, two, three, four, five, six, seven, eight, nine, ten, or more of the sequences delineated in the same row of column 6 of Table 1B, and the polynucleotide sequence of SEQ ID NO:X (e.g., as defined in Table 1A or 1B) or fragments or variants thereof. In preferred embodiments, the delineated sequences) and polynucleotide sequence of SEQ ID NO:X correspond to the same row of column 6 of Table 1B. Polypeptides encoded by these polynucleotides, other polynucleotides that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
[0103] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide.sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' polynucleotides of the sequence of SEQ ID NO:X are directly contiguous.
Nucleic acids which hybridize to the complement of these 20~contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids that encode these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.

[0104] In additional specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides_of one of the sequences delineated in column 6 of Table 1B and the 5' polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X are directly contiguous Nucleic acids which hybridize to the complement of these contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention.
Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
[0105] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of the sequence of SEQ ID NO:X and the 5' 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of Table 1B are directly contiguous.
Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also .encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
[0106] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of a fragment or variant of the sequence of SEQ ID NO:X and the 5' 10 polynucleotides of the sequence of one of the sequences delineated in column 6 of .
Table 1B are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybiidization~ conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides, are also encompassed by the invention. -[0107] In further' specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' polynucleotides of another sequence in column 6 are directly contiguous.
Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides andlor nucleic acids encoding these polypeptides,'and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by _, the invention. ' [0108] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides .of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of another sequence in column 6 corresponding to the same Clone ID
NO:Z (see Table 1B, column 1) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or.
nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
[0109] In specific embodiments, polynucleotides of the' invention comprise, or alternatively consist of, a polynucleotide sequence in which the 3' 10 polynucleotides of one sequence in column 6 corresponding to the same contig sequence identifer SEQ ID NO:X (see Table 1B, column 2) are directly contiguous. Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention.
Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
[0110] In specific embodiments, polynucleotides of the invention comprise, or alternatively consist of a polynucleotide sequence in which the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B and the 5' 10 polynucleotides of another sequence in column 6 corresponding to the same row are directly contiguous. In preferred embodiments, the 3' 10 polynucleotides of one of the sequences delineated in column 6 of Table 1B is directly contiguous with. the 5' 10 polynucleotides of the next sequential exon delineated in Table 1B, column 6.
Nucleic acids which hybridize to the complement of these 20 contiguous polynucleotides under stringent hybridization conditions or alternatively, under lower stringency conditions, are also encompassed by the invention. Polypeptides encoded by these -polynucleotides and/or nucleic acids, other polynucleotides and/or nucleic acids encoding these polypeptides, and antibodies that bind these polypeptides are also encompassed by the invention. Additionally, fragments and variants of the above-described polynucleotides, nucleic acids, and polypeptides are also encompassed by the invention.
[0111] Many polynucleotide sequences, such as EST sequences, are publicly available and accessible through sequence databases and may, have been publicly available prior to conception of the present invention. Preferably, such related polynucleotides are specifically excluded from the scope of the present invention.
Accordingly, for each contig sequence (SEQ ID NO:X) listed in the third column of ' Table 1A, preferably excluded are one or more polynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a is any integer between 1 and the final nucleotide minus 15 of SEQ ID NO:X, b is an integer of 15 to the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14. More specifically, preferably excluded are one or more po~lynucleotides comprising a nucleotide sequence described by the general formula of a-b, where a and b are integers as defined in columns 4 and 5, respectively, of Table 3. In specific embodiments, the polynucleotides of the invention do not consist of at least one, two, three, four, five, ten, or more of the specific polynucleotide sequences referenced by the Genbank Accession No. as disclosed in column 6 of Table 3(including for example, published sequence in connection with a particular BAC clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequences) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including-for example, the actual sequence contained in an identified BAC clone). In no way is this listing meant to encompass all of the sequences which may be excluded by the general formula, it is just a representative example. All references available through these accessions are hereby incorporated by reference in their entirety: .

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xxxxx x xx DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

~~ TTENANT LES PAGES 1 A 341 NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (24)

What Is Claimed Is:

1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence contained in Clone ID NO:Z, which is hybridizable to SEQ ID
NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide fragment of a polypeptide encoded by SEQ ID NO:X or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(f) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ TD
NO:X, having biological activity;
(g) a polynucleotide which is a variant of SEQ ID NO:X;
(h) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(i) a polynucleotide which encodes a species homologue of the SEQ ID NO:Y;
(j) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A residues or of only T residues.

2. The isolated nucleic acid molecule, of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a protein.

3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID
NO:Y or the polypeptide encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X.

4. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID NO:X or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID
NO:X.

5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.

7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.

8. A.method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.

9. A recombinant host cell produced by the method of claim 8.

10. The recombinant host cell of claim 9 comprising vector sequences.

11. An isolated polypeptide comprising an amino acid sequence at least 90%
identical to a sequence selected from the group consisting of:
(a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(b) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z, having biological activity;
(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(e) a full length protein of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(f) a variant of SEQ ID NO:Y;
(g) an allelic variant of SEQ ID NO:Y; or (h) a species homologue of the SEQ ID. NO:Y.

12. The isolated polypeptide of claim 11, wherein the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.

13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.

14. A recombinant host-cell that expresses the isolated polypeptide of claim 11.

15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.

16. The polypeptide produced by claim 15.

17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polynucleotide of claim 1.

18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.

19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.

20. A method fox identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.

21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.

22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;
(c) detecting an activity in a biological assay; and (d) identifying the protein in the supernatant having the activity.

23. The product produced by the method of claim 20.

24. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11.