AU2019222816B2

AU2019222816B2 - A method of diagnosing neoplasms - II

Info

Publication number: AU2019222816B2
Application number: AU2019222816A
Authority: AU
Inventors: Robert Dunne; Lawrence C Lapointe; Trevor John Lockett; Peter Laurence Molloy; William J Wilson; Graeme P Young
Original assignee: Commonwealth Scientific and Industrial Research Organization CSIRO; Clinical Genomics Pty Ltd
Current assignee: Commonwealth Scientific and Industrial Research Organization CSIRO; Clinical Genomics Pty Ltd
Priority date: 2007-10-23
Filing date: 2019-08-27
Publication date: 2021-05-27
Anticipated expiration: 2028-10-23
Also published as: AU2015202210A1; AU2018200017A1; AU2018200017B2; AU2019222816A1; AU2015202210B2

Abstract

The present invention relates generally to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The DNA or the expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the DNA or the RNA or protein expression profile of one or more nucleic acid molecule markers.

Description

A METHOD OF DIAGNOSING NEOPLASMS - II

This is a divisional of Australian Patent Application No. 2018200017 which is a divisional of Australian Patent Application No. 2015202210 which is a divisional of No. 2008316313, which is the Australian National phase of PCT/AU2008/001565, which claims priority from United States Patent Application No. 60/982,115, filed 23 October 2007. The contents of each application listed in this paragraph are fully incorporated by reference herein.

FIELD OF THE INVENTION The present invention relates generally to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset, predisposition to the onset and/or progression of a neoplasm. More particularly, the present invention is directed to nucleic acid molecules in respect of which changes to the DNA or to the RNA or protein expression profiles are indicative of the onset and/or progression of a large intestine neoplasm, such as an adenoma or an adenocarcinoma. The DNA or the expression profiles of the present invention are useful in a range of applications including, but not limited to, those relating to the diagnosis and/or monitoring of colorectal neoplasms, such as colorectal adenocarcinomas. Accordingly, in a related aspect the present invention is directed to a method of screening a subject for the onset, predisposition to the onset and/or progression of a neoplasm by screening for modulation in the DNA or the RNA or protein expression profile of one or more nucleic acid molecule markers.

BACKGROUND OF THE INVENTION Bibliographic details of the publications referred to by author in this specification are collected alphabetically at the end of the description.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Adenomas are benign tumours, or neoplasms, of epithelial origin which are derived from glandular tissue or exhibit clearly defined glandular structures. Some adenomas show recognisable tissue elements, such as fibrous tissue (fibroadenomas) and epithelial structure, while others, such as bronchial adenomas, produce active compounds that might give rise to clinical syndromes.

Adenomas may progress to become an invasive neoplasm and are then termed adenocarcinomas. Accordingly, adenocarcinomas are defined as malignant epithelial tumours arising from glandular structures, which are constituent parts of many organs of the body. The term adenocarcinoma is also applied to tumours showing a glandular growth pattern. These tumours may be sub-classified according to the substances that they produce, for example mucus secreting and serous adenocarcinomas, or to the microscopic arrangement of their cells into patterns, for example papillary and follicular adenocarcinomas. These carcinomas may be solid or cystic (cystadenocarcinomas). Each organ may produce tumours showing a variety of histological types, for example the ovary may produce both mucinous and cystadenocarcinoma.

Adenomas in different organs behave differently. In general, the overall chance of carcinoma being present within an adenoma (i.e. a focus of cancer having developed within a benign lesion) is approximately 5%. However, this is related to size of an adenoma. For instance, in the large bowel (colon and rectum specifically) occurrence of a cancer within an adenoma is rare in adenomas of less than 1 centimetre. Such a development is estimated at 40 to 50% in adenomas which are greater than 4 centimetres and show certain histopathological change such as villous change, or high grade dysplasia. Adenomas with higher degrees of dysplasia have a higher incidence of carcinoma. In any given colorectal adenoma, the predictors of the presence of cancer now or the future occurrence of cancer in the organ include size (especially greater than 9mm) degree of change from tubular to villous morphology, presence of high grade dysplasia and the morphological change described as "serrated adenoma". In any given individual, the additional features of increasing age, familial occurrence of colorectal adenoma or cancer, male gender or multiplicity of adenomas, predict a future increased risk for cancer in the organ - so-called risk factors for cancer. Except for the presence of adenomas and its size, none of these is objectively defined and all those other than number and size are subject to observer error and to confusion as to precise definition of the feature in question. Because such factors can be difficult to assess and define, their value as predictors of current or future risk for cancer is imprecise.

Once a sporadic adenoma has developed, the chance of a new adenoma occurring is approximately 30% within 26 months.

Colorectal adenomas represent a class of adenomas which are exhibiting an increasing incidence, particularly in more affluent countries. The causes of adenoma, and of progression to adenocarcinoma, are still the subject of intensive research. To date it has been speculated that in addition to genetic predisposition, environmental factors (such as diet) play a role in the development of this condition. Most studies indicate that the relevant environmental factors relate to high dietary fat, low fibre, low vegetable intake, smoking, obesity, physical inactivity and high refined carbohydrates.

Colonic adenomas are localised areas of dysplastic epithelium which initially involve just one or several crypts and may not protrude from the surface, but with increased growth in size, usually resulting from an imbalance in proliferation and/or apoptosis, they may protrude. Adenomas can be classified in several ways. One is by their gross appearance and the major descriptors include degrees of protrusion: flat sessile (i.e. protruding but without a distinct stalk) or pedunculated (i.e. having a stalk). Other gross descriptors include actual size in the largest dimension and actual number in the colon/rectum. While small adenomas (less than say 5 or 10 millimetres) exhibit a smooth tan surface, pedunculated and especially larger adenomas tend to have a cobblestone or lobulated red-brown surface. Larger sessile adenomas may exhibit a more delicate villous surface. Another set of descriptors include the histopathological classification; the prime descriptors of clinical value include degree of dysplasia (low or high), whether or not a focus of invasive cancer is present, degree of change from tubular gland formation to villous gland formation (hence classification is tubular, villous or tubulovillous), presence of admixed hyperplastic change and of so-called "serrated" adenomas and its subgroups. Adenomas can be situated at any site in the colon and/or rectum although they tend to be more common in the rectum and distal colon. All of these descriptors, with the exception of number and size, are relatively subjective and subject to interobserver disagreement.

The various descriptive features of adenomas are of value not just to ascertain the neoplastic status of any given adenomas when detected, but also to predict a person's future risk of developing colorectal adenomas or cancer. Those features of an adenoma or number of adenomas in an individual that point to an increased future risk for cancer or recurrence of new adenomas include: size of the largest adenoma (especially 10mm or larger), degree of villous change (especially at least 25% such change and particularly 100% such change), high grade dysplasia, number (3 or more of any size or histological status) or presence of serrated adenoma features. None except size or number is objective and all are relatively subjective and subject to interobserver disagreement. These predictors of risk for future neoplasia (hence "risk") are vital in practice because they are used to determine the rate and need for and frequency of future colonoscopic surveillance. More accurate risk classification might thus reduce workload of colonoscopy, make it more cost-effective and reduce the risk of complications from unnecessary procedures.

Adenomas are generally asymptomatic, therefore rendering difficult their diagnosis and treatment at a stage prior to when they might develop invasive characteristics and so became cancer. It is technically impossible to predict the presence or absence of carcinoma based on the gross appearance of adenomas, although larger adenomas are more likely to show a region of malignant change than are smaller adenomas. Sessile adenomas exhibit a higher incidence of malignancy than pedunculated adenomas of the same size. Some adenomas result in blood loss which might be observed or detectable in the stools; while sometimes visible by eye, it is often, when it occurs, microscopic or "occult". Larger adenomas tend to bleed more than smaller adenomas. However, since blood in the stool, whether overt or occult, can also be indicative of non-adenomatous conditions, the accurate diagnosis of adenoma is rendered difficult without the application of highly invasive procedures such as colonoscopy combined with tissue acquisition by either removal (i.e. polypectomy) or biopsy and subsequent histopathological analysis.

Accordingly, there is an on-going need to elucidate the causes of adenoma and to develop more informative diagnostic protocols or aids to diagnosis that enable one to direct colonoscopy at people more likely to have adenomas. These adenomas may be high risk, advanced or neither of these, in particular protocols which will enable the rapid, routine and accurate diagnosis of adenoma. Furthermore, it can be difficult after colonoscopy to be certain that all adenomas have been removed, especially in a person who has had multiple adenomas. An accurate screening test may minimise the need to undertake an early second colonoscopy to ensure that the colon has been cleared of neoplasms. Accordingly, the identification of molecular markers for adenomas would provide means for understanding the cause of adenomas and cancer, improving diagnosis of adenomas including development of useful screening tests, elucidating the histological stage of an adenoma, characterising a patient's future risk for colorectal neoplasia on the basis of the molecular state of an adenoma and facilitating treatment of adenomas.

To date, research has focused on the identification of gene mutations which lead to the development of colorectal neoplasms. In work leading up to the present invention, however, it has been determined that changes in the DNA or the RNA or protein expression profiles of genes which are also expressed in healthy individuals are indicative of the development of neoplasms of the large intestine, such as adenomas and adenocarcinomas. It has been further determined that in relation to neoplasms of the large intestine, diagnosis can be made based on screening for one or more of a panel of these differentially expressed genes. In a related aspect, it has still further been determined that to the extent that neoplastic tissue has been identified either by the method of the invention or by some other method, the present invention provides still further means of characterising that tissue as an adenoma or a cancer. In yet another aspect, it has been determined that a proportion of these genes are characterised by gene expression which occurs in the context of non-neoplastic tissue but not in the context of neoplastic tissue, thereby facilitating the development of qualitative analyses which do not require a relative analysis to be performed against a non-neoplastic or normal control reference level. Accordingly, the inventors have identified a panel of genes which facilitate the diagnosis of adenocarcinoma and adenoma development and/or the monitoring of conditions characterised by the development of these types of neoplasms.

SUMMARY OF THE INVENTION

Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

As used herein, the term "derived from" shall be taken to indicate that a particular integer or group of integers has originated from the species specified, but has not necessarily been obtained directly from the specified source. Further, as used herein the singular forms of "a", "and" and "the" include plural referents unless the context clearly dictates otherwise.

Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

The subject specification contains amino acid and nucleotide sequence information prepared using the programme Patentln Version 3.4, presented herein after the bibliography. Each amino acid and nucleotide sequence is identified in the sequence listing by the numeric indicator <210> followed by the sequence identifier (eg. <210>1, <210>2, etc). The length, type of sequence (amino acid, DNA, etc.) and source organism for each sequence is indicated by information provided in the numeric indicator fields <211>m <212> and <213>, respectively. Amino acid and nucleotide sequences referred to in the specification are identified by the indicator SEQ ID NO: followed by the sequence identifier (eg. SEQ ID NO:1, SEQ ID NO: 2, etc). The sequence identifier referred to in the specification correlates to the information provided in numeric indicator field <400> in the sequence listing, which is followed by the sequence identifier (eg. <400>1, <400>2, etc). That is SEQ ID NO: 1 as detailed in the specification correlates to the sequence indicated as <400>1 in the sequence listing.

One aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 210133_at 227235_at 200621_at 210139_s_at 227265at 200795_at 210298_x_at 227404_s_at 200799_at 210299_s_at 227529_s_at

200845sat 210302sat 227561at 200859_x_at 210495_x_at 227623_at 200897_s_at .210517_s_at 227662_at 200974_at 210764_s_at 227705_at 200986_at 210809_s_at 227727_at 201041sat 210946at 227826sat 201058_s_at 210982_s_at 227827_at 201061_s_at 211161_s_at 228202_at 201069_at 211548_s_at 228504_at 201105_at 211596_s_at 228507_at 201137sat 211643xat 228640at 201141_at 211644_x_at 228706_s_at 201150_s_at 211645_x_at 228707_at 201289_at 211671_s_at 228750_at 201300_s_at 211696_x_at 228766_at 201324at 211719xat 228846at 201348_at 211798_x_at 228854_at 201426_s_at 211813_x_at 228885_at 201427_s_at 211848_s_at 229530_at 201438_at 211889_x_at 229839_at 201496xat 211896sat 230087at 201497_x_at 211959_at 230264_s_at 201539_s_at 211964_at 230788_at 201540_at 211985_s_at 230830_at 201616_s_at 211990_at 231120_x_at 201617_x at 211991_s at 231579_s at 201645_at 212077_at 231773_at 201667_at 212091_s_at 234764_x_at 201739_at 212097_at 234987_at 201743_at 212136_at 236300_at 201744sat 212158at 236313_at 201842_s_at 212185_x_at 242317_at 201852_x_at 212192_at 200884_at 201858_s_at 212195_at 201495_x_at 201859_at 212230_at 202266_at 201865xat 212233at 202350sat 201893_x_at 212265_at 202731_at 201920_at 212288_at 202741_at

201957_at 212386_at 202742_s_at 202007_at 212387_at 202768_at 202037_s_at 212397_at 202838_at 202069_s_at 212414_s_at 203058_s_at 202133_at 212419_at 203060_s_at 202222_s_at 212464_s_at 203240at 202242_at 212667_at 203296_s_at 202274_at 212671_s_at 203343_at 202283_at 212713_at 203474_at 202291_s_at 212730_at 203638_s_at 202388at 212764at 203963at 202555_s_at 212859_x_at 204018_x_at 202620_s_at 212956_at 204034_at 202686_s_at 213068_at 204036_at 202746_at 213071_at 204130_at 202760sat 213428sat 204388sat 202766_s_at 213509_x_at 204389_at 202888_s_at 213624_at 204508_s_at 202920_at 213746_s_at 204532_x_at 202953_at 213891_s_at 204607_at 202957at 214027xat 204673at 202992_at 214038_at 204818_at 202994_s_at 214091_s_at 204895_x_at 202995_s_at 214142_at 204897_at 203000_at 214414_x_at 205112_at 203001sat 214505sat 205259at 203066_at 214677_x_at 205403_at 203131_at 214696_at 205480_s_at 203305_at 214752_x_at 205554_s_at 203382_s_at 214768_x_at 205593_s_at 203477at 214777at 205892sat 203645_s_at 215049_x_at 205929_at 203680_at 215076_s_at 206000_at 203729_at 215118_s_at 206094_x_at 203748_x_at 215176_x_at 206262_at 203766_s_at 215193_x_at 206377at 203881_s_at 215382_x_at 206385_s_at 203908_at 215388_s_at 206664_at

203913_s_at 215657_at 207126xat 203914_x_at 216207_x_at 207245_at 203951_at 216401_x_at 207390_s_at 203980_at 216442_x_at 207392_x_at 204069_at 216474_x_at 207432_at 204083sat 216576xat 207761sat 204122_at 216834_at 208596_s_at 204135_at 216984_x_at 208920_at 204326_x_at 217148_x_at 209114_at 204438_at 217179_x_at 209374_s_at 204457sat 217235xat 209458_x_at 204570_at 217258_x_at 209791_at 204688_at 217378_x_at 210107_at 204697_s_at 217480_x_at 210524_x_at 204719_at 217546_at 210735_s_at 204745xat 217757at 211372sat 204834_at 217762_s_at 211538_s_at 204894_s_at 217764_s_at 211549_s_at 204931_at 217767_at 211637_x_at 204938_s_at 217897_at 211699_x_at 204939sat 217967sat 211745xat 204940_at 218087_s_at 212224_at 204955_at 218162_at 212592_at 205097_at 218224_at 212741_at 205200_at 218312_s_at 212814_at 205267at 218353at 213317at 205382_s_at 218418_s_at 213451_x_at 205412_at 218468_s_at 213629_x_at 205433_at 218469_at 213921_at 205464_at 218559_s_at 213953_at 205547sat 218756sat 214164xat 205683_x_at 219014_at 214433_s_at 205935_at 219087_at 214598_at 205950_s_at 219508_at 214916_x_at 206134_at 219607_s_at 215125_s_at 206143at 219669at 215299_x_at 206149_at 219799_s_at 215867_xat 206198_s_at 220026_at 216336_x_at

206199_at 220037_s_at 216491x-at 206208_at 220376_at 216510_x_at 206209_s_at 220834_at 217022_s_at 206422_at 221541_at 217109_at 206461_x_at 221667_s_at 217110_s_at 206561_s_at 221747_at 217165xat 206576_s_at 221748_s_at 217232_x_at 206637_at 222043_at 217414x_at 206641_at 222162_s_at 218541_s_at 206710_s_at 222453_at 218546_at 206784_at 222513_s_at 219059sat 207003_at 222717_at 219543_at 207080_s_at 222722_at 219796_s_at 207134_x_at 223121_s_at 219948_x_at 207266_x_at 223122_s_at 220075_s_at 207502_at 223235_s_at 220266sat 207961_x_at 223343_at 220468_at 207977_s_at 223395_at 220645_at 207980_s_at 223551_at 220812_s_at 208131_s_at 223623_at 221004_s_at 208370_s_at 223952_x_at 221305sat 208383_s_at 224009_x_at 221584_s_at 208399_s_at 224352_s_at 221841_s_at 208450_at 224412_s_at 221896_s_at 208581_x_at 224480_s_at 223484_at 208747_s_at 224560_at 223597at 208763_s_at 224663_s_at 223754_at 208788_at 224694_at 224342_x_at 208789_at 224823_at 224989_at 208791_at 224836_at 224990_at 208792_s_at 224840_at 225458at 208894_at 224959_at 225728_at 209047_at 224963_at 226147_s_at 209074_s_at 224964_s_at 226302_at 209101_at 225207_at 226594_at 209116_x_at 225242_s_at 226654at 209138_x_at 225269_s_at 226811_at 209147_s_at 225275_at 227052_at

209156_s_at 225353_s_at 227522at 209167_at 225381_at 227682_at 209170_s_at 225442_at 227725_at 209191_at 225575_at 227735_s_at 209209_s_at 225602_at 227736_at 209210_s_at 225604_s_at 228133sat 209283_at 225626_at 228195_at 209301_at 225688_s_at 228232_s_at 209312_x_at 225710_at 228241_at 209335_at 225720_at 228469_at 209357at 225721at 228961at 209373_at 225782_at 229070_at 209436_at 225894_at 229254_at 209457_at 225895_at 229659_s_at 209496_at 226001_at 229831_at 209498_at 226051_at 230595at 209612_s_at 226084_at 231925_at 209613_s_at 226103_at 231975_s_at 209621_s_at 226303_at 233565_s_at 209651_at 226304_at 235146_at 209656_s_at 226333_at 235766_x_at 209667_at 226430_at 235849_at 209668_x_at 226492_at 238143_at 209687_at 226682_at 238750_at 209735_at 226694_at 238751_at 209763_at 226818_at 239272at 209868_s_at 226834_at 241994_at 209948_at 226841_at 242447_at 210084_x_at 227006_at 242601_at 227099_s_at 227061_at 243278_at; and/or

(ii) CLCA4 SGK MTIX ZG16 CFL2 AOC3 CA2 ClS PPAP2A CA1 SELENBPl ZSCAN18 MS4A12 MT1E IVD AQP8 ADAMTS1 SFRP1 SLC4A4 ITM2A COL4A2

CEACAM7 POU2AFI GPM6B TAGLN FAM55D EPB41L3 GUCAlB C6orf2O4 MAOA GCG AKAP12 DMD ADHIB TUBB6 MSRB3 UGT2B 17 LGALS2 PLOD2 ADAMDEC1 KIAA0828 G9orfl 9 MT1M MGC14376 MIER3 AKR1B1O PPPIR14A XDH ENI MUC4 CLDN23 MGP PKIB SGCE CXCL12 PIGR FOXF2 PDK4 ASPN AGR3 CA4 A2M IGLJ3 PYY L0C25845 QKI IGHAl LGALS1 L0C399959 TPM2 BCHE ANKRD25 C6orflO5 ST6GALNAC1 CRISPLD2 HPGD GJA1 ANK2 ADHIC SCNN1B L0C283666 CLCA1 FABP4 CRYAB FABP1 F13AI ACATI ENAM CD36 IGL@ CFD SPARCL1 PBLD GUCA2B ZCWPW2 CCL8 FBLN1 TNC LIFR L0C63928 MT1A HLA-DRB1 ABCA8 L0C652745 UGP2 POSTN MALL IGKVlD-13 DCN GNG2 APIS2 ITLNI DNASE1L3 EMP3 COL6A2 EGRI MMP28 FCGBP CMBL UGT2A3 SLC26A2 GCNT3 RGS5 PGM5 SERPING1 PTGIS DMN MEIS1 DUSP5 GPNMB EDN3 MFAP4 IGFBP5 MSN UGTIA6

CLEC3B MT1G PRKAR2B L0C253012 TPSAB I HHLA2 DPT GPX3 L0C652128 PCK1 CDKN2B C3 CNN1 FOSB ATP2B4 HSD17B2 HSPA1A HBA1 PLAC8 CYBRD1 TCF21 TMEM47 PTGER4 PPID OGN MAGI PPAP2B CALDI BEST2 SPON1 ACTG2 HLA-DQA1 PHLDB2 MGC4172 PRIMAl RARRES2 MAB21L2 MT1F ETHEI RPL24 MAFB MMP2 ABCG2 FAM107A SRI CCDC80 PRKACB CNTN3 UGT1A1 SELM RGS2 MRC1 TYROBP COL6A1 HSD1 1B2 TNS1 FBN1 ANPEP MYHI1 MXD1 MATN2 ITM2C PLCE1 PRNP CES2 KCNMB1 AB13BP MS4A4A CALM1 HLA-C PDGFRA HLA-DPB1 NDE1 CA12 SMOC2 SRPX FKBP5 L0C285382 WWTR1 HSPB8 CLIC5 HMGCS2 TPSB2 APOE L0C646627 FGL2 SERPINFI KRT20 ClQB PPPlR12B KLF4 ANGPTL1 HSPB6 FHL1 MEPlA FNBP1 ARL14 GUCY1A3 C4orf34 LUM UGDH SORBS2 SORBS1I DUSPI GPA33 METTL7A C2orf4O GALNAC4S-6ST FAM129A PLN CFHR1 SCARA5 UGT2B 15 MGC13057

SI PDLIM3 ClOorf56 ACTA2 TP53INP2 SULTIAl CD177 ATP8B1 TTRAP ClOorf99 ANK3 CCL28 COL15AI CTGF IDH3A NR3C2 MUCDHL EDG2 DHRS9 SDPR UGT1A8 LMOD1 COLL4Al RAB27A EFEMPI DSCR1 ANTXR1 GREMI CITED2 EMPi IL1R2 MT1H CSRP1 L0C387763 NEXN PLEKHII~ TIMP3 MUC2 L0C572558 MYLK NIDL FOXP2 CLDN8 HBB HSPA2 RDX GCNT2 ATP1A2 TSPAN7 C2Oorfl 18 TNXB TNFRSF1 7 SLC20AI FUCAl SYNP02 CD14 MRGPRF vim KCTD12 HIGD1A SMPDL3A RBMSI MFSD4 P2RY14 PTRF AXL CHGA TSPAN1 AQP1 ClI5orf48 UGT1A9 MAPIB CO3AI 'COX7A1 PALLD CYR61 MUC12 MPEG1 TRPM6 PDCD4 KLHL5 OSTheta CAVI TCEAL7 IGLV1-44 FAM46C FILIP1L VSIG2 LRIG1 IQGAP2 IGUM HLA-DPA1 PRDX6 LRRC19 ClIorfll15 RAB31 CD 163 HBA2 L0C966 10 CEACAMI EDIL3 FGFR2 TIMP2 DES PAPSS2 ENTPD5 MT2A XLKD1 DDR2 KCNMA1 SMTh CHRDL1 GAS1 C8orf4

SRGN TBC1D9 SDCBP2 PDE9A C7 CCL11 PMP22 P2RY1 ELOVL5 FLNA NR3C1 FOXF1 STMN2 STOM RELLI MYL9 CKB PNMA1 SEMA6D CLU LOC339562 PADI2 SLC26A3 PALM2-AKAP2 SEPPI SDC2 PAGI TGFB1I1 SST HCLS1 SFRP2 HLA-DRA RGS1 UGT1A3 TSC22D3 FXYD6 MS4A7 IL6ST OLFML3 ALDH1A1 C1QC COL6A3

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

Another aspect of the present invention provides a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 220026_at; and/or

(ii) CLCA4

in a biological sample from said individual wherein a lower level of expression of the gene or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

In yet another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 214142_at; and/or

(ii) ZG16

In still another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 209301at 205950_s_at; and/or

(ii) CA2 CAl

In still yet another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 220834_at; and/or

(ii) MS4A12

In yet still another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 206784_at; and/or

(ii) AQP8

In a further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: 203908_at, 206198_sat, 205547_sat, 207003_at, 206422_at, 209613_sat, 207245_at; and/or

(ii) SLC4A4, CEACAM7, TAGLN, GUCAlB, GCG, ADHIB, UGT2B17,

In another further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

the gene, genes or transcripts detected by Affymetrix probeset IDs: 203908_at, 206198_s-at, 205547_s-at, 207003at, 206422at, 209613_s_at, 207245_at; and/or

(ii) SLC4A4, CEACAM7, TAGLN, GUCAlB, GCG, ADH1B, UGT2B17,

In still another further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 225207_at 211548_s_at 205382_s_at 206208_at 206262_at 207502_at 207080_s_at 210107_at 202995_s_at 215118_s_at 205892_s_at 206149_at 204083sat 212592at 204719at 229070_at; and/or

(ii) PDK4 HPGD CFD CA4 ADHIC GUCA2B PYY CLCA1 FBLN1 IGHA1 FABPl LOC63928 TPM2 ENAM ABCA8 C6orfl05

In yet still yet another further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 210809_s_at 201617_x_at 202133_at 201893xat 202274at 204607at 223597_at 218756_s_at 238143_at 209156_s_at 210302_s_at 213953_at 203240_at 228885_at 220266_s_at 224963_at 209735_at 210299_s_at 226303at 228504at 220468at 212730_at 225242_s_at 201744_s_at 201141_at 215125_s_at 218087_s_at 211959_at 204438_at 207761_s_at 205200_at 204130_at 217967_s_at 242601at 202888sat 229839at 213068_at 202350_s_at 206664_at 208383_s_at 201300_s_at 200974_at

203951_at 223395_at 219669_at 204818_at 214768_x_at 227736_at 219014_at 228133_s_at 203477_at 209656_s at 204955_at 205259_at 222722_at; and/or

(ii) POSTN OGN WWTR1 DCN CALDI HMGCS2 ITLN1 ACTG2 LOC646627 COL6A2 MGC4172 KRT20 FCGBP MAB21L2 KLF4 SLC26A2 RPL24 FHL1 PGM5 ABCG2 ARL14 DMN CCDC80 LUM GPNMB UGT1A1 SORBS1 IGFBP5 MRC1 METTL7A CLEC3B HSDllB2 FAM129A LOC253012 ANPEP SCARA5 DPT MATN2 SI PCK1 PRNP ACTA2 CNN1 ABI3BP CD177 HSD17B2 HLA-C COorf99 PLAC8 NDE1 COL15A1 TMEM47 SRPX NR3C2

In a related aspect the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 208788_at 215382_x_at 200665_s_at 208789_at 215388_s_at 200799_at 208894_at 216442xat 200845_s_at 209047_at 216474_x_at

200859xat 209101at 216834at 200897_s_at 209138_x_at 217480_x_at 200974_at 209147_s_at 217757_at 200986_at 209156_s_at 217762_s_at 201041_s_at 209191_at 217764_s_at 201061_s_at 209209_s_at 217767at 201069_at 209210_s_at 217897_at 201105_at 209312_x_at 218162_at 201137_s_at 209335_at 218224_at 201141_at 209436_at 218312_s_at 201150_s_at 209457_at 218353at 201289_at 209496_at 218418_s_at 201300_s_at 209621_s_at 218468_s_at 201426_s_at 209651_at 218469_at 201438_at 209656_s_at 218559_s_at 201616_s_at 209868_s_at 219087at 201617_x_at 210084_x_at 219607_s_at 201645_at 210133_at 221541_at 201667_at 210139_s_at 222043_at 201743_at 210495_x_at 222453_at 201744_s_at 210517_s_at 222513sat 201842_s_at 210764_s_at 223121_s_at 201852_x_at 210809_s_at 223122_s_at 201858_s_at 210982_s_at 223235_s_at 201859_at 211161_s_at 223343_at 201865_x_at 211596_s_at 224560at 201893_x_at 211671_s_at 224694_at 201920_at 211719_x_at 224840_at 202007_at 211813_x_at 224964_s_at 202069_s_at 211896_s_at 225242_s_at 202133_at 211959_at 225269sat 202283_at 211964_at 225353_s_at 202291_s_at 211985_s_at 225381_at 202403_s_at 211990_at 225442_at 202620_s_at 211991_s_at 225602_at 202686_s_at 212077_at 225604sat 202760_s_at 212091_s_at 225626_at 202766_s_at 212136_at 225688_s at

202953at 212158at 225710at 202957_at 212185_x_at 22600 1_at 202994_s_at 212195_at 226051_at 202995_s_at 212230_at 226084_at 203066_at 212233_at 226103_at 203131_at 212265_at 226430_at 203305_at 212386_at 226682_at 203382_s_at 212387_at 226694_at 203477_at 212397_at 226818_at 203645_s_at 212414_s_at 226834_at 203680_at 212419_at 226841_at 203729_at 212464_s_at 227061_at 203748_x_at 212667_at 227099_s_at 204069_at 212671_s_at 227235_at 204122_at 212713_at 227404_s_at 204135_at 212764_at 227529_s at 204438_at 212956_at 227561_at 204457_s_at 213428_s_at 227623_at 204570_at 213509_x_at 227705_at 204688_at 213746_s_at 227727_at 205412at 213891sat 228507_at 205683_x_at 214038_at 228750_at 205935_at 214677_x_at 228846_at 207134_x_at 214752_x_at 229530_at 207266_x_at 215049_x_at 230264_s_at 208131_s-at 215076sat 231579sat 208370_s_at 215193_x_at 234987_at;and/or 208747_s_at

(ii) A2M FBN1 PALLD ACATI FILIPIL PALM2-AKAP2 ACTA2 FKBP5 PDGFRA AKAP12 FLNA PDLIM3 ANKRD25 FN1 PHLDB2 ANTXR1 FOXF1 PLEKHCl AP1S2 FXYD6 PLOD2 APOE GALNAC4S-6ST PMP22 AQP1 GAS1 PNMA1

ASPN GJAl POSTN ATP2B4 GNG2 PPAP2A AXL GPNMB PPAP2B ClOorf56 GREMI PRDX6 C1QB GUCY1A3 PRKAR2B C1QC HCLS1 PRNP cis HLA-DPA1 PTGIS C2Oorfl 18 HLA-DPB1 PTRF C3 HLA-DQA1 QKI C9orfl 9 HLA-DRA RAB31 CALDI HLA-DRB1 RARRES2 CALM HSPA1A RBMS1 CCDC80 IDH3A RDX CCL11 IGFBP5 RELLI CCL8 IGL@ RGS1 CD14 IGLJ3 RGS5 CD163 IL6ST SDC2 CES2 KLHL5 SELM CFHR1 LGALS1 SEPT6 CLU L0C283666 SERPINF1 COL14A1 L0C339562 SERPING1 COL15A1 L0C387763 SFRP2 COL1A2 L0C399959 SGCE COL3A1 LRIG1 SLC20AI COL4A2 LUM SMOC2 COL6A1 MAFB SORBS1 COL6A2 MAPIB SPARC COL6A3 MEISi SPONI COX7A1 MFAP4 SRGN CRISPLD2 MGP STOM CTGF MMP2 TBC1D9 CYBRD1 MPEG1 TCEAL7 CYR61 MRC1 TGFB1I1 DCN MRGPRF TIMP2 DDR2 MS4A4A TIMP3 DSCR1 MS4A7 TMEM47 DUSPI MSN TNC DUSP5 MT2A TPSAB1

EFEMP1 MXD1 TPSB2 EGRI NEXN TUBB6 ELOVL5 NIDI TYROBP EMP3 NR3C1 VIM F13A1 OLFML3 WWTR1 FBLN1 PAGI ZSCAN18

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In another aspect of the present invention there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

() the gene or genes detected by Affymetrix probeset IDs: 200884at 208596sat 220812sat 201495_x_at 208920_at 221004_s_at 202266_at 209114_at 221305_s_at 202350_s_at 209374_s_at 221584_s_at 202731_at 209458_x_at 221841_s_at 202741_at 209791_at 221896_s at 202742_s_at 210107_at 223484_at 202768_at 210524_x_at 223597_at 202838_at 210735_s_at 223754_at 203058_s_at 211372_s_at 224342_x_at 203060_s at 211538_s at 224989_at 203240_at 211549_s_at 224990_at 203296_s_at 211637_x_at 225458_at 203343_at 211699_x_at 225728_at 203474_at 211745_x_at 226147_s_at 203638sat 212224at 226302at 203963_at 212592_at 226594_at 204018_x_at 212741_at 226654_at 204034_at 212814_at 226811_at 204036_at 213317_at 227052_at 204130at 213451_x-at 227522at 204388_s_at 213629_x_at 227682_at

204389at 213921at 227725_at 204508_s_at 213953_at 227735_s_at 204532_x_at 214164_x_at 227736_at 204607_at 214433_s_at 228133_s_at 204673_at 214598_at 228195_at 204818at 214916xat 228232sat 204895_x_at 215125_s_at 228241_at 204897_at 215299_x_at 228469_ at 205112_at 215867_x_at 228961_at 205259_at 216336_x_at 229070_at 205403at 216491_x at 229254at 205480_s_at 216510_x_at 229659_s_at 205554_s_at 217022_s_at 229831_at 205593_s_at 217109_at 230595_at 205892_s_at 217110_s_at 231925_at 205929_at 217165_x at 231975_s at 206000_at 217232_x_at 233565_s_at 206094_x_at 217414_x_at 235146_at 206262_at 218541_s_at 235766_x_at 206377_at 218546_at 235849_ at 206385sat 219059sat 238143at 206664_at 219543_at 238750_at 207126_x_at 219796_s_at 238751_at 207245_at 219948_x_at 239272_at 207390_s_at 220075_s_at 241994_at 207392__x at 220266sat 242447at 207432_at 220468_at 242601_at 207761_s_at 220645_at 243278_at;and/or

(ii) ADH1C HIGD1A NR3C2 AGR3 HMGCS2 P2RY1 ALDHlAl HPGD PADI2 ANK3 HSDllB2 PAPSS2 ARL14 HSD17B2 PBLD ATP1A2 HSPA2 PDCD4 ATP8B1 IGHA1 PDE9A BEST2 IGHM PIGR COorf99 IL1R2 PLCE1

C15orf48 IL8 PPID Clorfl15 IQGAP2 PRKACB C4orf34 ITLN1 PTGER4 C6orflO5 ITM2C RAB27A C8orf4 KCNMA1 SCARA5 CA12 KIAA0828 SDCBP2 CCL28 KLF4 SELENBP1 CKB KRT20 SI CLCA1 LOC253012 SMTN CLDN8 LOC25845 SORBS2 CLIC5 LOC285382 SRI CMBL LOC572558 SST CNTN3 LOC646627 ST6GALNACl DNASE1L3 LOC652128 SULTlA1 EDG2 LOC96610 TNXB ENAM MAOA TSPAN1 ENTPD5 MATN2 TTRAP ETHEl MEPlA UGDH FABP1 METTL7A UGP2 FAM46C MFSD4 UGT1A1 FAM55D MGC13057 UGT1A3 FCGBP MIER3 UGT1A6 FGFR2 MMP28 UGT1A8 FOSB MT1A UGTlA9 FOXF2 MTlF UGT2A3 FOXP2 MT1M UGT2B15 FUCA1 MUC12 UGT2B17 GPA33 MUC2 VSIG2 HBA1 MUC4 XDH HBA2 MUCDHL XLKD1 HBB MYH11 ZCWPW2 HHLA2 NDE1

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

In still another aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 202920_at 222717_at 231120_x_at 203881sat 224412sat 231773at 204719_at 225381_at 203296_s_at 204931_at 225575_at 206664_at 204940_at 227529_s_at 211549_s_at 205433_at 227623_at 214598_at 206637_at 227705_at 219948_x at 207080_s_at 227827_at 220812_s_at 207980_s_at 228504_at 221305_s_at 209170_s_at 228706_s_at 229831_at 209209_s_at 228766_at 231925_at 209613sat 228854at 235146at 220037_s_at 228885_at 238751_at 220376_at 230788_at 243278_at;and/or

(ii) ADHIB ANGPTL1 HHLA2 SORBS2 DMD SORBS2 PYY GCNT2 CLDN23 ABCA8 SDPR CNTN3 RPL24 PKIB PLEKHC1 SI CITED2 LRRC19 CLDN8 TCF21 LIFR P2RY14 P2RY1 ATPlA2 PLN ANK2 HPGD TRPM6 XLKD1 GPM6B CD36 LOC399959 UGTlA8 BCHE AKAP12 FOXP2 TCEAL7 UGT2A3

in a biological sample from said individual wherein a level of expression of the genes or transcripts of group (i) and/or group (ii) which is not substantially above background levels is indicative of a neoplastic cell or a cell predisposed to the onset of a neoplastic state.

In a further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 209209_s_at, 225381_at, 227529_s_at, 227623_at, 227705_at; and/or

(ii) AKAP12, LOC399959, PLEKHCl, TCEAL7,

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) which is not substantially above background levels is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In yet still another further aspect there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 203296_s at 219948xat 231925at 206664_at 220812_s_at 235146_at 211549_s_at 221305_s_at 238751_at 214598_at 229831_at 243278_at;and/or

(ii) ATP1A2 HHLA2 SORBS2 CLDN8 HPGD UGTlA8 CNTN3 P2RY1 UGT2A3 FOXP2 SI

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) which is not substantially above background levels is indicative of a cancer cell or a cell predisposed to the onset of a cancerous state.

In another further aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 204006_s_at 213428_s at 200665_s_at 204051_s_at 213524_s_at

200832_s_at 204122_at 213869xat 200974_at 204320_at 213905_x_at 200986_at 204475_at 214247_s_at 201058_s_at 204620_s_at 215049_x_at 201069_at 205479 s at 215076_s_at 201105_at 205547_s_at 215646sat 201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at 201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at 201163_s_at 208782_at 217764sat 201185_at 208788_at 218468_s_at 201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at 201426_s_at 209101_at 218638_s_at 201438_at 209156_s_at 219087at 201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at 201667_at 209396_sat 221730_at 201744_s_at 209596_at 221731_x_at 201792_at 209875_s_at 37892at 201842_s_at 209955_s_at 223122_s_at 201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at 201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724at 202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at 202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at 202311_s_at 211813_x_at 226237at 202403_s_at 211896_s_at 226311_at 202404_s_at 211959_at 226694_at 202450_s_at 211964_at 226777_at 202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s at 202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at

202917sat 212344_at 229218_at 202998_s_at 212353_at 229802_at 203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at 203382_s_at 212488_at 231879_at 203477at 212489_at 232458_at 203570_at 212667_at 233555_s_at 203645_s_at 213125_at 234994_at; and/or 203878_s_at

(ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPPI LOXL2 GOS2 MMP1 MYL9 SQLE SPARC DCN EFEMPI LUM CALD1 APOE GREMI FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINFI SFRP2 FSTL1 ISLR SULFI COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRA1 KIAA1913 COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPING1 CDH11 VIM TYROBP THBS2 TIMP2 ACTA2 COL15Al SCD COL3A1 COLllAl TIMP3 PLOD2 S100A8 AEBP1 MMPl FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1 COL6A1 LOC541471

GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1 COL4A1 CiS LOXL1 RAB31 DKK3 CD93

in said cell or cellular population wherein a lower level of expression of the genes of group (i) and/or group (ii) relative to a gastrointestinal cancer control level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In still another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:

200884_at 214234_s_at 226248_s at 203240_at 214235_at 226302_at 203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at 204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s_at 204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at 205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at 205927_s_at 221841_s at 235976_at 208063_s_at 221874_at 236894_at 208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at;and/or 213106_at

(ii) CLCA1 CTSE ATP8B1 FCGBP C6orflO5 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8A1 CYP3A5P2 L1TD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2

VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B IDI KIAA1324 FAM3D CYP3A5

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

In yet another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene or genes detected by Affymetrix probeset IDs: 202404_s_at, 212464_s_at, 210809_s_at, 225681_at;and/or

(ii) COLlA2, FN1, POSTN, CTHRC1

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to a gastrointestinal cancer control level is indicative of an adenoma cell or a cell predisposed to the onset of an adenoma state.

In yet still another aspect, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 209875_s_at 227140_at 204475_at; and/or

(ii) SPP1 MMP1

In still yet another aspect the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200665_s_at 226237_at 226930_at 201744_s_at 225664_at 204051_s at 218468_s_at 221730_at 210511_s_at 202859_x_at 207173_x_at 209156_s_at 211959_at 203083_at 224694_at 223122_s_at 203477_at 201141_at 212353at 37892at 213905xat 219087_at 202917_s_at 205547_s_at 201438_at; and/or

(ii) SPARC COL8A1 SFRP4 LUM COL12A1 INHBA GREM1 COL5A2 COL6A2 IL8 CDH11 ANTXR1 IGFBP5 THBS2 GPNMB SFRP2 COL15Al BGN SULF1 COL1lAl TAGLN ASPN S100A8 COL6A3 FNDC1

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal cancer control level is indicative of an adenoma or a cell predisposed to the onset of an adenoma state.

In yet another aspect the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 210107_at; and/or

(ii) CLCA1

in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or (ii) relative to a gastrointestinal adenoma control level is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 203240_at 219955_at 242601_at 204607_at 232481_s_at 227725at 223969_s_at 228232_s_at; and/or

(ii) FCGBP LITD1 LOC253012 HMGCS2 SLITRK6 ST6GALNAC1 RETNLB VSIG2

A further aspect of the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene or genes detected by Affymetrix probeset IDs: 235976_at 236894_at 237521;and/or

(ii) SLITRK6 LlTD1

in a biological sample from said individual wherein expression of the genes or transcripts of group (i) and/or (ii) at a level which is not substantially greater than background neoplastic tissue levels is indicative of a cancer or a cell predisposed to the onset of a cancerous state.

A related aspect of the present invention provides a molecular array, which array comprises a plurality of:

(i) nucleic acid molecules comprising a nucleotide sequence corresponding to any one or more of the neoplastic marker genes hereinbefore described or a sequence exhibiting at least 80% identity thereto or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or

(ii) nucleic acid molecules comprising a nucleotide sequence capable of hybridising to any one or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or

(iii) nucleic acid probes or oligonucleotides comprising a nucleotide sequence capable of hybridising to any one or more of the sequences of (i) under medium stringency conditions or a functional derivative, fragment, variant or homologue of said nucleic acid molecule; or

(iv) probes capable of binding to any one or more of the proteins encoded by the nucleic acid molecules of (i) or a derivative, fragment or, homologue thereof

wherein the level of expression of said marker genes of (i) or proteins of (iv) is indicative of the neoplastic state of a cell or cellular subpopulation derived from the large intestine.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 is a graphical representation of alcohol dehydrogenase IB (classI), beta polypeptide.

Figure 2 is a graphical representation of the methylation of MAMDC2 and GPM6B in normal and neoplastic tissues and cell lines. Panel A shows the methylation level of the MAMDC2 gene as assessed by methylation specific PCR, using amplification of the CAGE gene to normalise for input DNA levels. Each point represents an individual tissue sample or cell line. Samples included DNAs from 18 colorectal cancer tissues, 12 colorectal adenomas, 22 matched normal colorectal tissues, 6 other normal tissues and a cell line and 6 colon cancer cell lines. Panel B shows the relative level of methylation of the GPM6B gene assessed by a COBRA assay. Levels of methylation were scored between 0 (no restriction enzyme digestion) and 5 (complete restriction enzyme digestion). Each point represents a single tissue sample. Samples included 14 colorectal cancer tissues, 11 colorectal adenomas and 22 matched normal tissues.

Figure 3 is a schematic representation of predicted RNA variants derived from hCG_1815491. cDNA clones derived from map region 8579310 to 8562303 on human chromosome 16 were used to locate exon sequences. Arrows: Oligo nucleotide primer sets were designed to allow measurement of individual RNA variants by PCR. Primers covering splice junctions are shown as spanning intron sequences which is not included in the actual oligonucleotide primer sequence.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated, in part, on the elucidation of gene expression profiles which characterise large intestine cellular populations in terms of their neoplastic state and, more particularly, whether they are malignant or pre-malignant. This finding has now facilitated the development of routine means of screening for the onset or predisposition to the onset of a large intestine neoplasm or characterising cellular populations derived from the large intestine based on screening for downregulation of the expression of these molecules, relative to control expression patterns and levels. To this end, in addition to assessing expression levels of the subject genes relative to normal or non-neoplastic levels, it has been determined that a proportion of these genes are not expressed in the diseased state, thereby facilitating the development of a simple qualitative test based on requiring assessment only relative to test background levels.

In accordance with the present invention, it has been determined that the genes detailed above are modulated, in terms of differential changes to their levels of expression, depending on whether the cell expressing that gene is neoplastic or not. It should be understood that reference to a gene "expression product" or "expression of a gene" is a reference to either a transcription product (such as primary RNA or mRNA) or a translation product such as protein. In this regard, one can assess changes to the level of expression of a gene either by screening for changes to the level of expression product which is produced (i.e. RNA or protein), changes to the chromatin proteins with which the gene is associated, for example the presence of histone H3 methylated on lysine at amino acid position number 9 or 27 (repressive modifications) or changes to the DNA itself which acts to downregulate expression, such as changes to the methylation of the DNA. These genes and their gene expression products, whether they be RNA transcripts, changes to the DNA which act to downregulate expression or encoded proteins, are collectively referred to as "neoplastic markers".

Accordingly, one aspect of the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 210133_at 227235_at 200621_at 210139_s_at 227265_at 200795_at 210298_x_at 227404_s_at 200799_at 210299_s_at 227529_s at 200845_s_at 210302_s_at 227561_at

200859xat 210495xat 227623at 200897_s_at 210517_s_at 227662_at 200974_at 210764_s_at 227705_at 200986_at 210809_s_at 227727_at 201041_s_at 210946_at 227826_s_at 201058sat 210982sat 227827at 201061_s_at 211161_s_at 228202_at 201069_at 211548_s_at 228504_at 201105_at 211596_s_at 228507_at 201137_s_at 211643_x_at 228640_at 201141at 211644xat 228706sat 201150_s_at 211645_x_at 228707_at 201289_at 211671_s_at 228750_at 201300_s_at 211696_x_at 228766_at 201324_at 211719_x_at 228846_at 201348at 211798xat 228854at 201426_s_at 211813_x_at 228885_at 201427_s_at 211848_s_at 229530_at 201438_at 211889_x_at 229839_at 201496_x_at 211896_s_at 230087_at 201497xat 211959at 230264sat 201539_s_at 211964_at 230788_at 201540_at 211985_s_at 230830_at 201616_s_at 211990_at 231120_x_at 201617_x_at 211991_s_at 231579_s_at 201645at 212077at 231773at 201667_at 212091_s_at 234764_x_at 201739_at 212097_at 234987_at 201743_at 212136_at 236300_at 201744_s_at 212158_at 236313_at 201842sat 212185xat 242317at 201852_x_at 212192_at 200884_at 201858_s_at 212195_at 201495_x_at 201859_at 212230_at 202266_at 201865_x_at 212233_at 202350_s_at 201893_x_at 212265_at 202731_at 201920_at 212288_at 202741_at 201957_at 212386_at 202742_s at

202007at 212387_at 202768at 202037_s_at 212397_at 202838_at 202069_s_at 212414_s_at 203058_s_at 202133_at 212419_at 203060_s_at 202222_s_at 212464_s_at 203240_at 202242at 212667at 203296sat 202274_at 212671_s_at 203343_at 202283_at 212713_at 203474_at 202291_s_at 212730_at 203638_s_at 202388_at 212764_at 203963_at 202555sat 212859xat 204018xat 202620_s_at 212956_at 204034_at 202686_s_at 213068_at 204036_at 202746_at 213071_at 204130_at 202760_s_at 213428_s_at 204388_s_at 202766sat 213509xat 204389at 202888_s_at 213624_at 204508_s_at 202920_at 213746_s_at 204532_x_at 202953_at 213891_s_at 204607_at 202957_at 214027_x_at 204673_at 202992at 214038at 204818at 202994_s_at 214091_s_at 204895_x_at 202995_s_at 214142_at 204897_at 203000_at 214414_x_at 205112_at 203001_s_at 214505_s_at 205259_at 203066at 214677xat 205403at 203131_at 214696_at 205480_s_at 203305_at 214752_x_at 205554_s_at 203382_s_at 214768_x_at 205593_s_at 203477_at 214777_at 205892_s_at 203645sat 215049xat 205929at 203680_at 215076_s_at 206000_at 203729_at 215118_s_at 206094_x_at 203748_x_at 215176_x_at 206262_at 203766_s_at 215193_x_at 206377_at 203881_s_at 215382_x_at 206385sat 203908_at 215388_s_at 206664_at 203913_s_at 215657_at 207126_x_at

203914_x_at 216207_x_at 207245at 203951_at 216401_x_at 207390_s_at 203980_at 216442_x_at 207392_x_at 204069_at 216474_x_at 207432_at 204083_s_at 216576_x_at 207761_s_at 204122_at 216834_at 208596_s_at 204135_at 216984_x_at 208920_at 204326_x_at 217148_x_at 209114_at 204438_at 217179_x_at 209374_s_at 204457_s_at 217235_x_at 209458_x_at 204570at 217258xat 209791at 204688_at 217378_x_at 210107_at 204697_s_at 217480_x_at 210524_x_at 204719_at 217546_at 210735_s_at 204745_x_at 217757_at 211372_s_at 204834_at 217762_s_at 211538sat 204894_s_at 217764_s_at 211549_s_at 204931_at 217767_at 211637_x_at 204938_s_at 217897_at 211699_x_at 204939_s_at 217967_s_at 211745_x_at 204940_at 218087_s_at 212224at 204955_at 218162_at 212592_at 205097_at 218224_at 212741_at 205200_at 218312_s_at 212814_at 205267_at 218353_at 213317_at 205382sat 218418sat 213451x-at 205412_at 218468_s_at 213629_x_at 205433_at 218469_at 213921_at 205464_at 218559_s_at 213953_at 205547_s_at 218756_s_at 214164_x_at 205683_x_at 219014_at 214433sat 205935_at 219087_at 214598_at 205950_s_at 219508_at 214916_x_at 206134_at 219607_s at 215125_s at 206143_at 219669_at 215299_x at 206149_at 219799_s_at 215867xat 206198_s_at 220026_at 216336_x_at 206199_at 220037_s_at 216491_x at

206208_at 220376_at 216510xat 206209_s_at 220834_at 217022_s_at 206422_at 221541_at 217109_at 206461_x_at 221667_s_at 217110_s_at 206561_s_at 221747_at 217165_x_at 206576sat 221748sat 217232xat 206637_at 222043_at 217414_x_at 206641_at 222162_s_at 218541_s_at 206710_s_at 222453_at 218546_at 206784_at 222513_s_at 219059_s_at 207003at 222717at 219543at 207080_s_at 222722_at 219796_s_at 207134_x_at 223121_s_at 219948_x_at 207266_x_at 223122_s_at 220075_s_at 207502_at 223235_s_at 220266_s_at 207961xat 223343at 220468at 207977_s at 223395_at 220645_at 207980 s at 223551_at 220812_s at 208131_s_at 223623_at 221004_s_at 208370_s_at 223952_x_at 221305_s_at 208383sat 224009xat 221584sat 208399_s_at 224352_s_at 221841_s_at 208450_at 224412_s_at 221896_s_at 208581_x_at 224480_s_at 223484_at 208747_s_at 224560_at 223597_at 208763sat 224663sat 223754at 208788_at 224694_at 224342_x_at 208789_at 224823_at 224989_at 208791_at 224836_at 224990_at 208792_s_at 224840_at 225458_at 208894at 224959at 225728at 209047_at 224963_at 226147_s_at 209074_s_at 224964_s_at 226302_at 209101_at 225207_at 226594_at 209116_x_at 225242_s_at 226654_at 209138_x_at 225269_s_at 226811_at 209147_s_at 225275_at 227052_at 209156_s_at 225353_s_at 227522_at

209167_at 225381_at 227682_at 209170_s_at 225442_at 227725_at 209191_at 225575_at 227735_s_at 209209_s_at 225602_at 227736_at 209210_s_at 225604_s_at 228133_s_at 209283at 225626at 228195at 209301_at 225688_s_at 228232_s_at 209312_x_at 225710_at 228241_at 209335_at 225720_at 228469_at 209357_at 225721_at 228961_at 209373at 225782at 229070at 209436_at 225894_at 229254_at 209457_at 225895_at 229659_s_at 209496_at 226001_at 229831_at 209498_at 226051_at 230595_at 209612sat 226084at 231925at 209613_s_at 226103_at 231975_s_at 209621_s_at 226303_at 233565_s_at 209651_at 226304_at 235146_at 209656_s_at 226333_at 235766_x_at 209667at 226430at 235849at 209668_x_at 226492_at 238143_at 209687_at 226682_at 238750_at 209735_at 226694_at 238751_at 209763_at 226818_at 239272_at 209868sat 226834at 241994at 209948_at 226841_at 242447_at 210084_x_at 227006_at 242601_at 227099_s_at 227061_at 243278_at; and/or

(ii) CLCA4 SGK MTlX ZG16 CFL2 AOC3 CA2 ClS PPAP2A CAl SELENBP1 ZSCAN18 MS4A12 MT1E IVD AQP8 ADAMTS1 SFRP1 SLC4A4 ITM2A COL4A2 CEACAM7 POU2AF1 GPM6B

TAGLN FAM55D EPB4IL3 GUCAIB C6orf2O4 MAOA GCG AKAP12 DMD ADHIB TUBB6 MSRB3 UGT2B17 LGALS2 PLOD2 ADAMDEC1 KIAA0828 C9orfl 9 MT1M MGC14376 MIER3 AKR1B1O PPPIR14A XDH FN1 MUC4 CLDN23 MGP PKIB SGCE CXCL12 PIGR FOXF2 PDK4 ASPN AGR3 CA4 A2M IGLJ3 PYY L0C25845 QKI IGHAl LGALS1 L0C399959 TPM2 BCHE ANKRD25 C6orflO05 ST6GALNAC1 CRISPLD2 HPGD GJA1 ANK2 ADHIC SCNN1B L0C283666 CLCA1 FABP4 CRYAB FABP1 F13A1 ACATI ENAM CD36 IGL@ CFD SPARCL1 PBLD GUCA2B ZCWPW2 CCL8 FBLN1 TNC LIFR L0C63928 MTIA HLA-DRB1 ABCA8 L0C652745 UGP2 POSTN MALL IGKVID-13 DCN GNG2 AP1S2 ITLNI DNASEIL3 EMP3 COL6A2 EGRI MMP28 FCGBP CMBL UGT2A3 SLC26A2 GCNT3 RGS5 PGM5 SERPINGI PTGIS DMN MEIS1 DUSP5 GPNMB EDN3 MFAP4 IGFBP5 MSN UGT1A6 CLEC3B MT1G PRKAR2B

L0C253012 TPSAB1I HHLA2 DPT GPX3 L0C652128 PCK1 CDKN2B C3 CNN1 FOSB ATP2B4 HSD17B2 HSPAIA HBAl PLAC8 CYBRD1 TCF21 TMEM47 PTGER4 PPID OGN MAGI PPAP2B CALDI BEST2 SPONI ACTG2 HLA-DQA1 PHLDB2 MGC4172 PRIMAL RARRES2 MAB21L,2 MT1F ETHEl RPL24 MAFB MMP2 ABCG2 FAM107A SRI CCDC80 PRKACB CNTN3 UGTlA1 SELM RGS2 MRC1 TYROBP COL6A1 HSD11IB2 TNS1 FBN1 ANPEP MYHi1 MXD1 MATN2 ITM2C PLCE1 PRNP CES2 KCNMB1 AB13BP MS4A4A CALM HLA-C PDGFRA HLA-DPBI NDE1 CA12 SMOC2 SRPX FKBP5 L0C285382 WWTR1 HSPB8 CLIC5 HMGCS2 TPSB2 APOE L0C646627 FGL2 SERPINFi KRT20 C1QB PPPlR12B KLF4 ANGPTL1 HSPB6 FHLI MEPIA FNBP1 ARL14 GUCY1A3 C4orf34 LU2M UGDH SORBS2 SORBS1 DUSPI GPA33 METTL7A C2orf4O GALNAC4S-6ST FAM129A PLN CFHR1 SCARA5 UGT2B 15 MGC 13057 SI PDLIM3 ClOorf56

ACTA2 TP531NP2 SULTIAl CD177 ATP8B1 TTRAP ClOorf99 ANK3 CCL28 COL15A1 CTGF IDH3A NR3C2 MUCDHL EDG2 DHRS9 SDPR UGT1A8 LMOD1 COL14AI RAB27A EFEMPI DSCR1 ANTXR1 GREMi CITED2 EMPi IL1R2 MT1H CSRP1 L0C387763 NEXN PLEKIJC1 TIMP3 MUC2 L0C572558 MYLK NIDi FOXP2 CLDN8 HBB HSPA2 RDX GCNT2 ATP1A2 TSPAN7 C2Oorfl 18 TNXB TNFRSF17 SLC20AI FUCAl SYNP02 CD14 MRGPRF vim KCTD12 HIGD1A SMPDL3A RBMS1 MFSD4 P2RY14 PTRF AXL CHGA TSPAN1 AQP1 ClI5orf48 UGT1A9 MAPlB COL3A1 COX7A1 PALLD CYR61 MUC12 MPEG1 TRPM6 PDCD4 KLHL5 OSTheta CAV1 TCEAL7 IGLV1-44 FAM46C FILIPIL VSIG2 LRIG1 IQGAP2 IGHM HLA-DPA1 PRDX6 LRRC19 ClIorfl 15 RAB31 CD163 HBA2 L0C96610 CEACAM1 EDIL3 FGFR2 TIMP2 DES PAPSS2 ENTPD5 MT2A XLKDI DDR2 KCNMA1 SMTh CHRDL1 GASI C8orf4 SRGN TBClD9 SDCBP2

PDE9A C7 CCL11 PMP22 P2RY1 ELOVL5 FLNA NR3C1 FOXF1 STMN2 STOM RELL1 MYL9 CKB PNMA1 SEMA6D CLU LOC339562 PADI2 SLC26A3 PALM2-AKAP2 SEPP1 SDC2 PAG1 TGFBlI1 SST HCLS1 SFRP2 HLA-DRA RGS1 UGT1A3 TSC22D3 FXYD6 MS4A7 IL6ST OLFML3 ALDHlA1 C1QC COL6A3

In one embodiment, said expression is assessed by screening for DNA changes which impact on methylation, in particular hypermethylation. In another embodiment expression is assessed by the association of DNA with chromatin proteins carrying repressive modifications, for example, methylation of lysines 9 or 27 of the histone H3.

Reference to "large intestine" should be understood as a reference to a cell derived from one of the six anatomical regions of the large intestine, which regions commence after the terminal region of the ileum, these being:

(i) the cecum; (ii) the ascending colon; (iii) the transverse colon; (iv) the descending colon; (v) the sigmoid colon; and (vi) the rectum.

Reference to "neoplasm" should be understood as a reference to a lesion, tumour or other encapsulated or unencapsulated mass or other form of growth which comprises neoplastic cells. A "neoplastic cell" should be understood as a reference to a cell exhibiting abnormal growth. The term "growth" should be understood in its broadest sense and includes reference to proliferation. In this regard, an example of abnormal cell growth is the uncontrolled proliferation of a cell. Another example is failed apoptosis in a cell, thus prolonging its usual life span. The neoplastic cell may be a benign cell or a malignant cell. In a preferred embodiment, the subject neoplasm is an adenoma or an adenocarcinoma. Without limiting the present invention to any one theory or mode of action, an adenoma is generally a benign tumour of epithelial origin which is either derived from epithelial tissue or exhibits clearly defined epithelial structures. These structures may take on a glandular appearance. It can comprise a malignant cell population within the adenoma, such as occurs with the progression of a benign adenoma to a malignant adenocarcinoma.

Preferably, said neoplastic cell is an adenoma or adenocarcinoma and even more preferably a colorectal adenoma or adenocarcinoma.

Each of the genes and transcripts detailed in sub-paragraphs (i) and (ii), above, would be well known to the person of skill in the art, as would their encoded proteins. The identification of the expression products of these genes and transcripts as markers of neoplasia occurred by virtue of differential expression analysis using Affymetrix HGUl33Aor HGUl33B gene chips. To this end, each gene chip is characterised by approximately 45,000 probe sets which detect the RNA transcribed from the genome. On average, approximately 11 probe pairs detect overlapping or consecutive regions of the RNA transcript. In general, the genes from which the RNA transcripts described herein are identifiable by the Affymetrix probesets are well known and characterised genes. However, to the extent that some of the probesets detect RNA transcripts which are not yet defined, these transcripts are indicated as "the gene, genes or transcripts detected by Affymetrix probe x". In some cases a number of genes may be detectable by a single probeset. It should be understood, however, that this is not intended as a limitation as to how the expression level of the subject gene or transcript can be detected. In the first instance, it would be understood that the subject gene transcript is also detectable by other probesets which would be present on the Affymetrix gene chip. The reference to a single probeset is merely included as an identifier of the gene transcript of interest. In terms of actually screening for the transcript, however, one may utilise a probe or probeset directed to any region of the transcript and not just to the 3- terminal 600bp transcript region to which the Affymetrix probes are often directed.

Reference to each of the genes and transcripts detailed above and their transcribed and translated expression products should therefore be understood as a reference to all forms of these molecules and to fragments or variants thereof. As would be appreciated by the person of skill in the art, some genes are known to exhibit allelic variation between individuals. Accordingly, the present invention should be understood to extend to such variants which, in terms of the present diagnostic applications, achieve the same outcome despite the fact that minor genetic variants between the actual nucleic acid sequences may exist between individuals or that within one individual there may exist 2 or more splice variants of the subject gene. The present invention should therefore be understood to extend to all forms of RNA (eg mRNA, primary RNA transcript, miRNA, etc), cDNA and peptide isoforms which arise from alternative splicing or any other mutation, polymorphic or allelic variation. It should also be understood to include reference to any subunit polypeptides such as precursor forms which may be generated, whether existing as a monomer, multimer, fusion protein or other complex.

To this end, in terms of the genes encompassed by the present invention, means for determining the existence of such variants, and characterising same, are described in Example 6. To the extent that the genes of the present invention are described by reference to an Affymetrix probeset, Table 6 provides details of the nucleic acid sequence to which each probe set is directed. Based on this information, the skilled person could, as a matter of routine procedure, identify the gene in respect of which that sequence forms part. A typical protocol for doing this is also outlined in Example 6.

It should be understood that the "individual" who is the subject of testing may be any human or non-human mammal. Examples of non-human mammals includes primates, livestock animals (e.g. horses, cattle, sheep, pigs, donkeys), laboratory test animals (e.g. mice, rats, rabbits, guinea pigs), companion animals (e.g. dogs, cats) and captive wild animals (e.g. deer, foxes). Preferably the mammal is a human.

The method of the present invention is predicated on the comparison of the level of the neoplastic markers of a biological sample with the control levels of these markers. The "control level" may be either a "normal level", which is the level of marker expressed by a corresponding large intestine cell or cellular population which is not neoplastic.

The normal (or "non-neoplastic") level may be determined using tissues derived from the same individual who is the subject of testing. However, it would be appreciated that this may be quite invasive for the individual concerned and it is therefore likely to be more convenient to analyse the test results relative to a standard result which reflects individual or collective results obtained from individuals other than the patient in issue. This latter form of analysis is in fact the preferred method of analysis since it enables the design of kits which require the collection and analysis of a single biological sample, being a test sample of interest. The standard results which provide the normal level may be calculated by any suitable means which would be well known to the person of skill in the art. For example, a population of normal tissues can be assessed in terms of the level of the neoplastic markers of the present invention, thereby providing a standard value or range of values against which all future test samples are analysed. It should also be understood that the normal level may be determined from the subjects of a specific cohort and for use with respect to test samples derived from that cohort. Accordingly, there may be determined a number of standard values or ranges which correspond to cohorts which differ in respect of characteristics such as age, gender, ethnicity or health status. Said "normal level" may be a discrete level or a range of levels. A decrease in the expression level of the subject genes relative to normal levels is indicative of the tissue being neoplastic.

Without limiting the present invention to any one theory or mode of action, although each of the genes or transcripts hereinbefore described is differentially expressed, either singly or in combination, as between neoplastic versus non-neoplastic cells of the large intestine, and is therefore diagnostic of the existence of a large intestine neoplasm, the expression of some of these genes was found to exhibit particularly significant levels of sensitivity, specificity and positive and negative predictive value. Accordingly, in a preferred embodiment one would screen for and assess the expression level of one or more of these genes. To this end, and without limiting the present invention to any one theory or mode of action, the following markers were determined to be expressed in neoplastic tissue at a level of 3-11 fold less than non-neoplastic tissue, when assessed by virtue of the method exemplified herein:

Fold Decrease Gene, genes or transcripts Gene detected by Affymetrix Probe No: 11 220026_at CLCA4 10 214142_at ZG16 209301_at CAl 9 205950sat CA2 8 220834_at MS4Al2 7 206784_at AQP8 203908_at SLC4A4 206198_s_at CEACAM7 205547_s_at TAGLN 6 207003_at GUCA1B 206422_at GCG 209613_s_at ADHI1B 207245_at UGT2B17 206134_at ADAMDECl 217546_at MTIM 5 206561_s_at AKRIB1O 211719x at FN1

Fold Decrease Gene, genes or transcripts Gene detected by Affymetrix Probe No: 202291_s_at MGP 209687at CXCL12 225207_at PDK4 206208_at CA4 207080_s_at PYY 215118_s_at IGHA1 204083_s_at TPM2 229070_at C6orflO5 211548_s_at HPGD

206262_at ADHIC 4 210107_at CLCAI 205892_s_at FABP1 212592_at. ENAM 205382_s_at CFD 207502_at GUCA2B 202995_s_at FBLN1 206149_at LOC63928 204719at ABCA8 210809_s_at POSTN 201893_x_at DCN 223597_at ITLNI 209156_s_at COL6A2 203240_at FCGBP 224963_at SLC26A2 226303_at PGM5 212730_at DMN

201141_at GPNMB 3 211959_at IGFBP5 205200_at CLEC3B 242601_at LOC253012 213068_at DPT 208383_s_at PCK1 203951_at CNN1 204818_at HSD17B2 219014_at PLAC8 209656_sat TMEM47

Fold Decrease Gene, genes or transcripts Gene detected by Affymetrix Probe No: 222722_at OGN 201617_x_at CALDI 202274_at ACTG2 218756_s_at MGC4172 210302_s_at MAB21L2 228885_at RPL24 209735_at ABCG2 228504_at CCDC80 225242_s_at UGT1A1 215125_s_at MRC1 204438_at HSD11B2 204130_at ANPEP 202888_s_at MATN2 202350_s_at PRNP 201300_s_at ABI3BP 223395_at HLA-C 214768_x_at NDE1 228133_s_at SRPX 204955_at WWTR1 202133_at HMGCS2 204607_at LOC646627 238143_at KRT20 213953_at KLF4 220266_s_at FHL1 210299_s_at ARL14 220468_at LUM 201744_s_at SORBS1 218087_s_at METTL7A 207761_s_at FAM129A 217967_s_at SCARA5 229839_at SI 206664_at ACTA2 200974_at CD177 219669_at COorf99 227736_at COL15A1 203477at NR3C2

Fold Decrease Gene, genes or transcripts Gene detected by Affymetrix Probe No: 205259_at

There is therefore more particularly provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) CLCA4

Preferably, said control level is a non-neoplastic level.

In another embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) ZG16

Preferably, said control level is a non-neoplastic level.

In yet another embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) CA2 CAI

Preferably, said control level is a non-neoplastic level.

In still yet another preferred embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) MS4A12

Preferably, said control level is a non-neoplastic level.

In yet still another preferred embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) AQP8

Preferably, said control level is a non-neoplastic level.

In a further embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) (i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 203908_at, 206198_sat, 205547_s_at, 207003_at, 206422_at, 209613_sat, 207245_at; and/or

(ii) SLC4A4, CEACAM7, TAGLN, GUCAIB, GCG, ADH1B, UGT2B17

Preferably, said control level is a non-neoplastic level.

In another further embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 206134_at, 217546_at, 206561_sat, 211719_x_at, 202291_sat, 209687_at; and/or

(ii) ADAMDEC1, MT1M, AKR1B10, FN1, MGP, CXCL12

Preferably, said control level is a non-neoplastic level.

In still another further embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 225207_at 211548_s_at 205382_s_at 206208_at 206262_at 207502_at 207080_s_at 210107_at 202995_s_at 215118_s_at 205892_s_at 206149_at

204083_s_at 212592_at 204719at 229070_at; and/or

(ii) PDK4 HPGD CFD CA4 ADH1C GUCA2B PYY CLCA1 FBLN1 IGHA1 FABP1 LOC63928 TPM2 ENAM ABCA8 C6orflO5

Preferably, said control level is a non-neoplastic level.

In yet still yet another further embodiment, there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 210809sat 201617xat 202133at 201893_x_at 202274_at 204607_at 223597_at 218756_s_at 238143_at 209156_s_at 210302_s_at 213953_at 203240_at 228885_at 220266_s_at 224963_at 209735_at 210299_s at 226303_at 228504_at 220468_at 212730_at 225242_s_at 201744_s_at 201141_at 215125_s_at 218087_s_at 211959_at 204438_at 207761_s_at 205200_at 204130_at 217967sat 242601_at 202888_s_at 229839_at 213068_at 202350_s_at 206664_at 208383_s_at 201300_s_at 200974_at 203951_at 223395_at 219669_at 204818_at 214768_x_at 227736at 219014_at 228133_s_at 203477_at 209656_s_at 204955_at 205259_at

222722_at; and/or

(ii) POSTN OGN WWTR1 DCN CALD HMGCS2 ITLN1 ACTG2 LOC646627 COL6A2 MGC4172 KRT20 FCGBP MAB21L2 KLF4 SLC26A2 RPL24 FHL1 PGM5 ABCG2 ARL14 DMN CCDC80 LUM GPNMB UGTlA1 SORBS1 IGFBP5 MRCl METTL7A CLEC3B HSDlB2 FAM129A LOC253012 ANPEP SCARA5 DPT MATN2 SI PCK1 PRNP ACTA2 CNN1 ABI3BP CD177 HSD17B2 HLA-C COorf99 PLAC8 NDEl COL15AI TMEM47 SRPX NR3C2

Preferably, said control level is a non-neoplastic level.

According to these aspects of the present invention, said large intestine tissue is preferably colorectal tissue.

In one embodiment, said expression is assessed by screening for DNA changes which impact on methylation, in particular hypermethylation. In another embodiment, expression is assessed by the association of DNA with chromatin proteins carrying repressive modifications, for example, methylation of lysines 9 or 27 of histone H3.

The detection method of the present invention can be performed on any suitable biological sample. To this end, reference to a "biological sample" should be understood as a reference to any sample of biological material derived from an animal such as, but not limited to, cellular material, biofluids (eg. blood), faeces, tissue specimens (such as biopsy specimens), surgical specimens or fluid which has been introduced into the body of an animal and subsequently removed (such as, for example, the solution retrieved from an enema wash). The biological sample which is tested according to the method of the present invention may be tested directly or may require some form of treatment prior to testing. For example, a biopsy or surgical sample may require homogenisation prior to testing or it may require sectioning for in situ testing of the qualitative expression levels of individual genes. Alternatively, a cell sample may require permeabilisation prior to testing. Further, to the extent that the biological sample is not in liquid form, (if such form is required for testing) it may require the addition of a reagent, such as a buffer, to mobilise the sample.

To the extent that the neoplastic marker gene expression product is present in a biological sample, the biological sample may be directly tested or else all or some of the nucleic acid material present in the biological sample may be isolated prior to testing. In yet another example, the sample may be partially purified or otherwise enriched prior to analysis. For example, to the extent that a biological sample comprises a very diverse cell population, it may be desirable to enrich for a sub-population of particular interest. It is within the scope of the present invention for the target cell population or molecules derived therefrom to be pretreated prior to testing, for example, inactivation of live virus or being run on a gel. It should also be understood that the biological sample may be freshly harvested or it may have been stored (for example by freezing) prior to testing or otherwise treated prior to testing (such as by undergoing culturing).

The choice of what type of sample is most suitable for testing in accordance with the method disclosed herein will be dependent on the nature of the situation. Preferably, said sample is a faecal (stool) sample, enema wash, surgical resection, tissue or blood specimen.

In a related aspect, it has been determined that certain of the markers hereinbefore defined are more indicative of adenoma development versus cancer development or vice versa. This is an extremely valuable finding since it enables one to more specifically characterise the likely nature of a neoplasm which is detected by virtue of the method of the present invention.

Accordingly, in a related aspect the present invention is directed to a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 208788_at 215382_ x_at 200665_s_at 208789_at 215388_s_at

200799_at 208894_at 216442xat 200845_s_at 209047_at 216474_x_at 200859_x_at 209101_at 216834_at 200897_s_at 209138_x_at 217480_x_at 200974_at 209147_s_at 217757_at 200986_at 209156_s_at 217762sat 201041_s_at 209191_at 217764_s_at 201061_s_at 209209_s_at 217767_at 201069_at 209210_s_at 217897_at 201105_at 209312_x_at 218162_at 201137_s_at 209335_at 218224at 201141_at 209436_at 218312_s_at 201150_s_at 209457_at 218353_at 201289_at 209496_at 218418_s_at 201300_s_at 209621_s_at 218468_s_at 201426sat 209651at 218469at 201438_at 209656_s_at 218559_s_at 201616_s_at 209868_s_at 219087_at 201617_x_at 210084_x_at 219607_s_at 201645_at 210133_at 221541_at 201667at 210139sat 222043at 201743_at 210495_x_at 222453_at 201744_s_at 210517_s_at 222513_s_at 201842_s_at 210764_s_at 223121_s_at 201852_x_at 210809_s_at 223122_s_at 201858_s_at 210982_s_at 223235sat 201859_at 211161_s_at 223343_at 201865_x_at 211596_s_at 224560_at 201893_x_at 211671_s_at 224694_at 201920_at 211719_x_at 224840_at 202007at 211813xat 224964sat 202069_s_at 211896_s_at 225242_s_at 202133_at 211959_at 225269_s_at 202283_at 211964_at 225353_s_at 202291_s_at 211985_s_at 225381_at 202403_s_at 211990_at 225442at 202620_s_at 211991_s_at 225602_at 202686_s_at 212077_at 225604_sat

202760_s_at 212091_s_at 225626_at 202766_s_at 212136_at 225688_s_at 202953_at 212158_at 225710_at 202957_at 212185_x_at 226001_at 202994_s_at 212195_at 226051_at 202995_s_at 212230_at 226084at 203066_at 212233_at 226103_at 203131_at 212265_at 226430_at 203305_at 212386_at 226682_at 203382_s_at 212387_at 226694_at 203477_at 212397_at 226818at 203645_s_at 212414_s_at 226834_at 203680_at 212419_at 226841_at 203729_at 212464_s_at 227061_at 203748_x_at 212667_at 227099_s_at 204069_at 212671_s_at 227235at 204122_at 212713_at 227404_s_at 204135_at 212764_at 227529_s_at 204438_at 212956_at 227561_at 204457_s_at 213428_s_at 227623_at 204570_at 213509_x at 227705at 204688_at 213746_s_at 227727_at 205412_at 213891_s_at 228507_at 205683_x_at 214038_at 228750_at 205935_at 214677_x_at 228846_at 207134_x_at 214752_x_at 229530at 207266_x_at 215049_x_at 230264_s_at 208131_s_at 215076_s_at 231579_s_at 208370_s_at 215193_x_at 234987_at;and/or 208747_s_at

(ii) A2M FBN1 PALLD ACATI FILIPIL PALM2-AKAP2 ACTA2 FKBP5 PDGFRA AKAP12 FLNA PDLIM3 ANKRD25 FN1 PHLDB2 ANTXR1 FOXF1 PLEKHC1 AP1S2 FXYD6 PLOD2

APOE GALNAC4S-6ST PMP22 AQP1 GASI PNMA1 ASPN GJAl POSTN ATP2B4 GNG2 PPAP2A AXL GPNMB PPAP2B ClOorf56 GREM1 PRDX6 C1QB GUCY1A3 PRKAR2B ClQC HCLS1 PRNP CiS HLA-DPA1 PTGIS C20orfl18 HLA-DPB1 PTRF C3 HLA-DQA1 QKI C9orfl9 HLA-DRA RAB31 CALDI HLA-DRB1 RARRES2 CALM HSPA1A RBMS1 CCDC80 IDH3A RDX CCL11 IGFBP5 RELLI CCL8 IGL@ RGS1 CD14 IGLJ3 RGS5 CD163 IL6ST SDC2 CES2 KLHL5 SELM CFHR1 LGALS1 SEPT6 CLU LOC283666 SERPINF1 COL14A1 LOC339562 SERPING1 COL15A1 LOC387763 SFRP2 COL1A2 LOC399959 SGCE COL3A1 LRIG1 SLC20A1 COL4A2 LUM SMOC2 COL6A1 MAFB SORBS1 COL6A2 MAP1B SPARC COL6A3 MEIS1 SPONI COX7A1 MFAP4 SRGN CRISPLD2 MGP STOM CTGF MMP2 TBC1D9 CYBRD1 MPEG1 TCEAL7 CYR61 MRCl TGFB1Il DCN MRGPRF TIMP2 DDR2 MS4A4A TIMP3 DSCR1 MS4A7 TMEM47

DUSP1 MSN TNC DUSP5 MT2A TPSAB1 EFEMP1 MXD1 TPSB2 EGRI NEXN TUBB6 ELOVL5 NIDI TYROBP EMP3 NR3Cl VIM F13A1 OLFML3 WWTR1 FBLN1 PAGI ZSCAN18

In another preferred embodiment of this aspect of the present invention there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene or genes detected by Affymetrix probeset IDs: 200884_at 208596_s_at 220812_s_at 201495_x_at 208920_at 221004sat 202266_at 209114_at 221305_s_at 202350_s_at 209374_s_at 221584_s_at 202731_at 209458_x_at 221841_s_at 202741_at 209791_at 221896_s_at 202742_s at 210107_at 223484_at 202768_at 210524_x_at 223597_at 202838_at 210735_s_at 223754_at 203058_s__at 211372_s_at 224342_x_at 203060_s_at 211538_s_at 224989_at 203240_at 211549_s_at 224990at 203296_s_at 211637_x_at 225458_at 203343_at 211699_x_at 225728_at 203474_at 211745_x_at 226147_s_at 203638_ s_at 212224_at 226302_at 203963_at 212592_at 226594at 204018_x_at 212741_at 226654_at 204034_at 212814_at 226811_at

204036_at 213317_at 227052_at 204130_at 213451_x_at 227522_at 204388_s_at 213629_x_at 227682_at 204389_at 213921_at 227725_at 204508_s_at 213953_at 227735_s_at 204532xat 214164xat 227736at 204607_at 214433_s_at 228133_s_at 204673_at 214598_at 228195_at 204818_at 214916_x_at 228232_s_at 204895_x_at 215125_s_at 228241_at 204897at 215299xat 228469at 205112_at 215867_x_at 228961_at 205259_at 216336_x_at 229070_at 205403_at 216491_x_at 229254_at 205480_s_at 216510_x_at 229659_s_at 205554sat 217022sat 229831at 205593_s_at 217109_at 230595_at 205892_s_at 217110_s_at 231925_at 205929_at 217165_x_at 231975_s_at 206000_at 217232_x_at 233565_s_at 206094xat 217414xat 235146at 206262_at 218541_s_at 235766_x_at 206377_at 218546_at 235849_at 206385_s_at 219059_s_at 238143_at 206664_at 219543_at 238750_at 207126xat 219796sat 238751_at 207245_at 219948_x_at 239272_at 207390_s_at 220075_s_at 241994_at 207392_x_at 220266_s_at 242447_at 207432_at 220468_at 242601_at 207761sat 220645at 243278_at; and/or

(ii) ADHIC HIGD1A NR3C2 AGR3 HMGCS2 P2RY1 ALDH1A1 HPGD PADI2 ANK3 HSD11B2 PAPSS2 ARL14 HSD17B2 PBLD ATP1A2 HSPA2 PDCD4

ATP8B1 IGHA1 PDE9A BEST2 IGHM PIGR C1Oorf99 IL1R2 PLCE1 C15orf48 IL8 PPID Clorfl15 IQGAP2 PRKACB C4orf34 ITLN1 PTGER4 C6orflO5 ITM2C RAB27A C8orf4 KCNMA1 SCARA5 CA12 KIAA0828 SDCBP2 CCL28 KLF4 SELENBP1 CKB KRT20 SI CLCA1 LOC253012 SMTN CLDN8 LOC25845 SORBS2 CLIC5 LOC285382 SRI CMBL LOC572558 SST CNTN3 LOC646627 ST6GALNAC1 DNASElL3 LOC652128 SULTlA1 EDG2 LOC96610 TNXB ENAM MAOA TSPAN1 ENTPD5 MATN2 TTRAP ETHEL MEPlA UGDH FABP1 METTL7A UGP2 FAM46C MFSD4 UGT1A1 FAM55D MGC13057 UGT1A3 FCGBP MIER3 UGT1A6 FGFR2 MMP28 UGTIA8 FOSB MT1A UGTlA9 FOXF2 MTIF UGT2A3 FOXP2 MT1M UGT2B15 FUCA1 MUCl2 UGT2B17 GPA33 MUC2 VSIG2 HBA1 MUC4 XDH HBA2 MUCDHL XLKD1 HBB MYH11 ZCWPW2 HHLA2 NDEI

According to these aspects, said control levels are preferably non-neoplastic levels and said large intestine tissue is colorectal tissue. Even more preferably, said biological sample is a stool sample or blood sample.

In a related aspect, it has been determined that a subpopulation of the markers of the present invention are not only expressed at levels lower than normal levels, their expression pattern is uniquely characterised by the fact that expression levels above that of background control levels are not detectable in neoplastic tissue. This determination has therefore enabled the development of qualitative screening systems which are simply designed to detect marker expression relative to a control background level. In accordance with this aspect of the present invention, said "control level" is therefore the "background level".

According to this aspect, there is therefore provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 202920_at 222717_at 231120_ x_at 203881_s_at 224412_s_at 231773_at 204719_at 225381_at 203296sat 204931_at 225575_at 206664_at 204940_at 227529_s_at 211549_s_at 205433_at 227623_at 214598_at 206637_at 227705_at 219948_x_at 207080_s at 227827_at 220812_s at 207980_s_at 228504_at 221305_s_at 209170_s_at 228706_s_at 229831_at 209209_s_at 228766_at 231925_at 209613_s_at 228854_at 235146_at 220037_s_at 228885_at 238751_at 220376_at 230788_at 243278_at; and/or

(ii) ADHIB ANGPTL1 HHLA2 SORBS2 DMD SORBS2 PYY GCNT2 CLDN23 ABCA8 SDPR CNTN3 RPL24 PKIB PLEKHC1 SI CITED2 LRRC19 CLDN8 TCF21 LIFR P2RYl4 P2RY1 ATP1A2 PLN ANK2 HPGD TRPM6 XLKD1 GPM6B CD36 LOC399959 UGT1A8 BCHE AKAP12 FOXP2 TCEAL7 UGT2A3

In a most preferred embodiment, said genes or transcripts are selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 209613_s_at, 227827_at, 204719_at, 228504_at, 228885_at, 206664_at, 207080_sat; and/or

(ii) ADHIB, SORBS2, PYY, ABCA8, RPL24, SI

Preferably, said neoplasm is an adenoma or an adenocarcinoma and said gastrointestinal tissue is colorectal tissue.

In yet another embodiment, it has been determined that a further subpopulation of these markers are more characteristic of adenoma development, while others are more characteristic of cancer development. Accordingly, there is provided a convenient means of qualitatively obtaining indicative information in relation to the characteristics of the subject neoplasm.

According to this embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:

209209_s_at, 225381_at, 227529_sat, 227623_at, 227705_at; and/or

(ii) AKAP12, LOC399959, PLEKHC1, TCEAL7

In yet still another preferred embodiment there is provided a method of screening for the onset or predisposition to the onset of a large intestine neoplasm in an individual, said method comprising screening the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 203296_s_at 219948_x_at 231925_at 206664_at 220812_s_at 235146_at 211549_s at 221305sat 238751at 214598_at 229831_at 243278_at;and/or

(ii) ATPlA2 HHLA2 SORBS2 CLDN8 HPGD UGTlA8 CNTN3 P2RY1 UGT2A3 FOXP2 SI

Preferably, said large intestine tissue is colorectal tissue.

More preferably, said biological sample is a stool sample or a blood sample.

As detailed hereinbefore, the present invention is designed to screen for a neoplastic cell or cellular population, which is located in the large intestine. Accordingly, reference to "cell or cellular population" should be understood as a reference to an individual cell or a group of cells. Said group of cells may be a diffuse population of cells, a cell suspension, an encapsulated population of cells or a population of cells which take the form of tissue.

Reference to "expression" should be understood as a reference to the transcription and/or translation of a nucleic acid molecule. In this regard, the present invention is exemplified with respect to screening for neoplastic marker expression products taking the form of RNA transcripts (eg primary RNA or mRNA). Reference to "RNA" should be understood to encompass reference to any form of RNA, such as primary RNA or mRNA. Without limiting the present invention in any way, the modulation of gene transcription leading to increased or decreased RNA synthesis will also correlate with the translation of some of these RNA transcripts (such as mRNA) to produce a protein product. Accordingly, the present invention also extends to detection methodology which is directed to screening for modulated levels or patterns of the neoplastic marker protein products as an indicator of the neoplastic state of a cell or cellular population. Although one method is to screen for mRNA transcripts and/or the corresponding protein product, it should be understood that the present invention is not limited in this regard and extends to screening for any other form of neoplastic marker expression product such as, for example, a primary RNA transcript.

In terms of screening for the downregulation of expression of a marker it would also be well known to the person of skill in the art that changes which are detectable at the DNA level are indicative of changes to gene expression activity and therefore changes to expression product levels. Such changes include but are not limited to, changes to DNA methylation. Accordingly, reference herein to "screening the level of expression" and comparison of these "levels of expression" to control "levels of expression" should be understood as a reference to assessing DNA factors which are related to transcription, such as gene/DNA methylation patterns.

It would also be known to a person skilled in the art that changes in the structure of chromatin are indicative of changes in gene expression. Silencing of gene expression is often associated with modification of chromatin proteins, methylation of lysines at either or both positions 9 and 27 of histone H3 being well studied examples, while active chromatin is marked by acetylation of lysine 9 of histone H3. Thus association of gene sequences with chromatin carrying repressive or active modifications can be used to make an assessment of the expression level of a gene.

It is well within the skill of the person of skill in the art to determine the most appropriate screening method for any given situation. To this end, the genes which are known to encode an expression product which is either secreted by the cell or membrane bound is detailed in the table below. It would be appreciated that screening for neoplastic markers which are secreted or membrane bound may provide particular advantages in terms of the design of a diagnostic screening product.

The gene or genes detected by Affymetrix probe Nos: 200600_at 205593_s_at 212185_x_at 224480_s_at 200845_s_at 205765_at 212192_at 224663_s_at 200859_x_at 205892_s_at 212224_at 224694_at 200884_at 205927_s_at 212230_at 224823_at 200897_s_at 205929_at 212233_at 224836_at 200974_at 205935_at 212265_at 224840_at 201041_s_at 205935_at 212288_at 224959_at 201058_s_at 205950_s_at 212386_at 224963_at 201061_s_at 206000_at 212387_at 224964_s_at 201069_at 206094_x_at 212397_at 224989_at 201105_at 206143_at 212414_s_at 224990_at 201137_s_at 206149_at 212419_at 225207_at 201300_s_at 206198_s_at 212671_s_at 225242_s_at 201324_at 206199_at 212730_at 225269_s_at 201426_s_at 206208_at 212741_at 225381_at 201539_s_at 206209_s_at 212764_at 225442_at 201540_at 206262_at 212814_at 225458_at 201616_s_at 206377_at 212859_x_at 225575_at 201617_x_at 206385_s_at 212956_at 225602_at 201667_at 206461_x_at 213106_at 225604_s_at 201739_at 206561_s_at 213317_at 225626_at 201743_at 206576_s_at 213509_x_at 225710_at 201865_x_at 206637_at 213629_x_at 225720_at 201920_at 206664_at 213746_s_at 225721_at 201957_at 206710_s_at 213891_s_at 225782_at 202007_at 206784_at 213953_at 225894_at 202069_s_at 207126_x_at 214027_x_at 225895_at 202133_at 207245_at 214234_s_at 226001_at 202242_at 207266_x_at 214235_at 226051_at 202266_at 207390_s_at 214414_x_at 226084_at 202274_at 207392_x_at 214433_s_at 226103_at 202388_at 207432_at 214505_s_at 226147_s_at 202555_s_at 207761_s_at 214598_at 226248_s_at 202620_s_at 207980_s_at 214677_x_at 226302_at

202686_s_at 208063_s_at 214696_at 226303_at 202731_at 208131_s_at 214752_x_at 226304_at 202741_at 208370_s_at 214768_x_at 226333_at 202742_s_at 208383_s_at 214777_at 226430_at 202746at 208450at 215049xat 226594at 202760_s_at 208581_x_at 215118_s_at 226654_at 202768_at 208596_s_at 215125_s_at 226682_at 202888_s_at 208763_s_at 215176_x_at 226694_at 202920_at 208788_at 215193_x_at 226811_at 202957_at 208789_at 215299_x_at 226818_at 202992_at 208920_at 215657_at 226834_at 202994_s_at 208937_s_at 216207_x_at 226841_at 202995_s_at 209047_at 216336_x_at 227006_at 203000_at 209074_s_at 216401_x_at 227052_at 203001_s_at 209114_at 216491_x_at 227061_at 203058_s_at 209116_x_at 216576_x_at 227099_s_at 203060_s_at 209138_x_at 216834_at 227235_at 203066_at 209147_s_at 216984_x_at 227404_s_at 203131_at 209156_s_at 217022_s_at 227522_at 203240_at 209167_at 217148_x_at 227529_s_at 203305_at 209170_s_at 217165_x_at 227561_at 203343_at 209191_at 217232_x_at 227623_at 203382_s_at 209209_s_at 217235_x_at 227662_at 203474_at 209210_s_at 217378_x_at 227682_at 203638_s_at 209283_at 217414_x_at 227705_at 203645_s_at 209301_at 217480_x_at 227719_at 203680_at 209312_x_at 217546_at 227725_at 203729_at 209357_at 217762_s_at 227727_at 203748_x_at 209373_at 217764_s_at 227735_s_at 203766_s_at 209374_s_at 217897_at 227736_at 203908_at 209457_at 217967_s_at 228202_at 203913_s_at 209458_x_at 218087_s_at 228232_s_at 203914_x_at 209498_at 218211_s_at 228469_at 203951_at 209612_s_at 218224_at 228504_at 203980_at 209613_s_at 218312_s_at 228507_at 204018_x_at 209621_s_at 218353_at 228640_at 204034_at 209651_at 218418_s_at 228766_at 204036_at 209656sat 218546_at 228846_at

204069_at 209667_at 218559_s_at 228854_at 204083_s at 209668_x at 219014_at 228961_at 204122_at 209868_s_at 219059_s_at 229070_at 204130_at 209948_at 219508_at 229254_at 204135_at 210107_at 219543_at 229530_at 204326_x_at 210139_s_at 219607_s_at 229659_s_at 204388_s_at 210298_x_at 219796_s_at 229831_at 204389_at 210299_s_at 219948_x_at 229839_at 204438_at 210302_s_at 219955_at 230087_at 204457_s_at 210517_s_at 220026_at 230264_s_at 204532_x_at 210524_x_at 220037_s_at 230595_at 204570_at 210524_x_at 220075_s_at 230788_at 204607_at 210946_at 220266_s_at 230830_at 204688_at 211372_s_at 220376_at 231120_x_at 204697_s_at 211538_s_at 220468_at 231832_at 204719_at 211548_s_at 220812_s_at 231925_at 204745_x_at 211549_s_at 220834_at 231975_s_at 204818_at 211596_s_at 221004_s_at 232176_at 204894_s_at 211637_x_at 221305_s_at 232481_s_at 204897_at 211643_x_at 221667_s_at 233565_s_at 204931_at 211645_x_at 221747_at 234987_at 204938_s_at 211671_s_at 221748_s_at 235146_at 204939_s_at 211696_x_at 221841_s_at 235766_x_at 204940_at 211699_x_at 221874_at 235849_at 204955_at 211745_x_at 221896_s_at 235976_at 205097_at 211798_x_at 222513_s_at 236300_at 205112_at 211848_s_at 222717_at 236313_at 205259_at 211889_x_at 223235_s_at 236894_at 205267_at 211964_at 223343_at 237521_x_at 205403_at 211985_s_at 223395_at 238750_at 205412_at 211990_at 223484_at 241994_at 205433_at 211991_s_at 223551_at 242317_at 205464_at 212077_at 223597_at 242447_at 205480_s_at 212097_at 223623_at 242601_at 205547_s_at 212136_at 224352_s_at 243278_at 205554_s_at 212158at 224412_s at

ABCA8 EGR1 LOC25845 PPID ABI3BP ELOVL5 LOC283666 PPP1R12B ACATI EMPI LOC285382 PPP1R14A ACTA2 EMP3 LOC339562 PRDX6 ACTG2 ENTPD5 LOC387763 PRIMAl ADHIB EPB41L3 LOC399959 PRKACB ADHIC ETHEl LOC572558 PRKAR2B AKAP12 F13A1 LOC63928 PRNP AKR1B1O FABP1 LOC652128 PTGER4 ALDH1A1 FABP4 LOC652745 PTGIS ANK2 FAM107A LRIG1 PTRF ANK3 FAM129A LRRC19 QKI ANKRD25 FAM46C MAB21L2 RAB27A ANPEP FBLN1 MAFB RAB31 ANTXR1 FCGBP MAGI RBMS1 AOC3 FGFR2 MALL RDX AP1S2 FHL1 MAOA RELL1 APOE FILIPIL MAPIB RGS1 AQP1 FKBP5 MEIS1 RGS2 AQP8 FLNA MEP1A RGS5 ARL14 FNBP1 METTL7A SCARA5 ATP2B4 FOSB MFSD4 SCNN1B ATP8Al FOXF1 MGC14376 SDC2 AXL FOXF2 MIER3 SDCBP2 BCHE FOXP2 MLPH SDPR BEST2 FXYD6 MMP2 SELENBP1 ClOorf56 GALNAC4S- MPEG1 SELM COorf99 6ST MPEG1 SGCE C15orf48 GASI MRCI SGK Clorfl15 GCNT2 MRGPRF SI C20orfl18 GCNT3 MS4A12 SLC20A1 C2orf4O GJA1 MS4A4A SLC26A2 C4orf34 GNG2 MS4A7 SLC26A3 C6orfl05 GPA33 MSN SLC4A4 C6orf2O4 GPM6B MSRB3 SLITRK6 C7 GUCYlA3 MTlA SMOC2 C9orfl9 HBAl MT1E SMTN CA1 HBA2 MT1F SORBS1

CA2 HBB MT1G SRI CA4 HCLS1 MT1H SRPX CALDI HHLA2 MT1M ST6GALNACl CALM HIGD1A MT1X STMN2 CAPN9 HLA-C MT2A STOM CAV1 HLA-DPA1 MUC12 SULTIA1 CCDC80 HLA-DPB1 MUCDHL SYNPO2 CCL28 HLA-DQA1 MXDL TAGLN CD14 HLA-DRB1 MYL9 TBCID9 CD163 HMGCS2 MYLK TCEAL7 CD36 HPGD NEXN TCF21 CDKN2B HSD11B2 NIDI TGFB1I1 CEACAMI HSD17B2 NR3C1 TMEM47 CEACAM7 HSPA2 NR3C2 TNSL CES2 HSPB6 OSTheta TP531NP2 CFL2 HSPB8 P2RY1 TPM2 CHGA IDI P2RY14 TRPM6 CITED2 IDH3A PAG1 TSC22D3 CKB IGHA1 PALLD TSPAN1 CLCA1 IGHM PALM2- TSPAN7 CLCA4 IGKV1D-13 AKAP2 TTRAP CLDN8 IGL@ PAPSS2 TUBB6 CLIC5 IGLJ3 PBLD TYROBP CMBL IL1R2 PCK1 UGDH CNN1 IQGAP2 PDCD4 UGP2 CNTN3 ITLN1 PDE9A UGTIA1 COL4A2 ITM2A PDGFRA UGTIA3 COL6A2 ITM2C PDK4 UGT1A6 COX7A1 KCNMA1 PDLIM3 UGT1A8 CRYAB KCNMB1 PGM5 UGT1A9 CTSE KCTD12 PIGR UGT2A3 CYP3A5 KIAA0828 PKIB UGT2B15 CYP3A5P2 KIAA1324 PLAC8 UGT2B17 DDR2 KLF4 PLCE1 VIM DES KLHL5 PLEKHC1 VSIG2 DMN KRT20 PLN WDR51B DNASE1L3 L1TD1 PLOD2 WWTR1 DSCR1 LGALS1 PMP22 XDH

DUSPI LGALS2 PNMA1 XLKD1 DUSP5 LIFR POU2AF1 ZSCAN18 EDG2 LMOD1 PPAP2A LOC253012 PPAP2B

Reference to "nucleic acid molecule" should be understood as a reference to both deoxyribonucleic acid molecules and ribonucleic acid molecules and fragments thereof. The present invention therefore extends to both directly screening for mRNA levels in a biological sample or screening for the complementary cDNA which has been reverse-transcribed from an mRNA population of interest. It is well within the skill of the person of skill in the art to design methodology directed to screening for either DNA or RNA. As detailed above, the method of the present invention also extends to screening for the protein product translated from the subject mRNA or the genomic DNA itself.

In one preferred embodiment, the level of gene expression is measured by reference to genes which encode a protein product and, more particularly, said level of expression is measured at the protein level. Accordingly, to the extent that the present invention is directed to screening for markers which are detailed in the preceding table, said screening is preferably directed to the encoded protein.

In another particularly preferred embodiment, said gene expression is assessed by analysing genomic DNA methylation. In another embodiment, expression is assessed by the association of DNA with chromatin proteins carrying repressive modifications, for example, methylation of lysines 9 or 27 of histone H3.

As detailed hereinbefore, it should be understood that although the present invention is exemplified with respect to the detection of expressed nucleic acid molecules (e.g. mRNA), it also encompasses methods of detection based on screening for the protein product of the subject genes. The present invention should also be understood to encompass methods of detection based on identifying both proteins and/or nucleic acid molecules in one or more biological samples. This may be of particular significance to the extent that some of the neoplastic markers of interest may correspond to genes or gene fragments which do not encode a protein product. Accordingly, to the extent that this occurs it would not be possible to test for a protein and the subject marker would have to be assessed on the basis of transcription expression profiles or changes to genomic DNA.

The term "protein" should be understood to encompass peptides, polypeptides and proteins (including protein fragments). The protein may be glycosylated or unglycosylated and/or may contain a range of other molecules fused, linked, bound or otherwise associated to the protein such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins. Reference herein to a "protein" includes a protein comprising a sequence of amino acids as well as a protein associated with other molecules such as amino acids, lipids, carbohydrates or other peptides, polypeptides or proteins.

The proteins encoded by the neoplastic markers of the present invention may be in multimeric form meaning that two or more molecules are associated together. Where the same protein molecules are associated together, the complex is a homomultimer. An example of a homomultimer is a homodimer. Where at least one marker protein is associated with at least one non-marker protein, then the complex is a heteromultimer such as a heterodimer.

Reference to a "fragment" should be understood as a reference to a portion of the subject nucleic acid molecule or protein. This is particularly relevant with respect to screening for modulated RNA levels in stool samples since the subject RNA is likely to have been degraded or otherwise fragmented due to the environment of the gut. One may therefore actually be detecting fragments of the subject RNA molecule, which fragments are identified by virtue of the use of a suitably specific probe.

Reference to the "onset" of a neoplasm, such as adenoma or adenocarcinoma, should be understood as a reference to one or more cells of that individual exhibiting dysplasia. In this regard, the adenoma or adenocarcinoma may be well developed in that a mass of dysplastic cells has developed. Alternatively, the adenoma or adenocarcinoma may be at a very early stage in that only relatively few abnormal cell divisions have occurred at the time of diagnosis. The present invention also extends to the assessment of an individual's predisposition to the development of a neoplasm, such as an adenoma or adenocarcinoma. Without limiting the present invention in any way, changed levels of the neoplastic markers may be indicative of that individual's predisposition to developing a neoplasia, such as the future development of an adenoma or adenocarcinoma or another adenoma or adenocarcinoma.

In yet another related aspect of the present invention, markers have been identified which enable the characterisation of neoplastic tissue of the large intestine in terms of whether it is an adenoma or a cancer. This development now provides a simple yet accurate means of characterising tissue using means other than the traditional methods which are currently utilised.

According to this aspect of the present invention, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200600_at 204006_s_at 213428_s_at 200665_s_at 204051_s_at 213524_s_at 200832_s_at 204122_at 213869xat 200974_at 204320_at 213905_x_at 200986_at 204475_at 214247_s_at 201058_s_at 204620sat 215049_x_at 201069_at 205479_s_at 215076_s_at 201105_at 205547_s_at 215646sat 201141_at 205828_at 216442_x_at 201147_s_at 207173_x_at 217430_x_at 201150_s_at 207191_s_at 217762_s_at 201162_at 208747_s_at 217763_s_at 201163_s_at 208782_at 217764_s_at 201185_at 208788_at 218468_s_at 201261_x_at 208850_s_at 218469_at 201289_at 208851_s_at 218559_s_at 201426_s_at 209101_at 218638_s_at 201438at 209156sat 219087at 201616_s_at 209218_at 221011_s_at 201645_at 209395_at 221729_at 201667_at 209396_s_at 221730_at 201744_s_at 209596_at 221731_x_at 201792_at 209875_s_at 37892at 201842_s_at 209955_s_at 223122_s_at 201852_x_at 210095_s_at 223235_s_at 201859_at 210495_x_at 224560_at 201893_x_at 210511_s_at 224694_at 202237_at 210764_s_at 224724_at 202238_s_at 210809_s_at 225664_at 202283_at 211161_s_at 225681_at 202291_s_at 211571_s_at 225710_at 202310_s_at 211719_x_at 225799_at 202311_s_at 211813_x_at 226237at 202403_s_at 211896_s_at 226311_at 202404_s_at 211959_at 226694 at

202450_s_at 211964_at 226777at 202620_s_at 211966_at 226930_at 202766_s_at 211980_at 227099_s_at 202859_x_at 211981_at 227140_at 202878_s_at 212077_at 227566_at 202917_s_at 212344_at 229218at 202998_s_at 212353_at 229802_at 203083_at 212354_at 231579_s_at 203325_s_at 212464_s_at 231766_s_at 203382_s_at 212488_at 231879_at 203477_at 212489_at 232458_at 203570_at 212667_at 233555_s_at 203645_s_at 213125_at 234994_at; and/or 203878_s_at

(ii) COL1A2 LGALS1 SRGN CTHRC1 ELOVL5 LBH FN1 MGP CTGF POSTN MMP2 TNC SPP1 LOXL2 GOS2 MMP1 MYL9 SQLE SPARC DCN EFEMPI LUM CALDI APOE GREM1 FBN1 MSN IL8 MMP3 IGFBP3 IGFBP5 IGFBP7 SERPINF1 SFRP2 FSTL1 ISLR SULF1 COL4A2 HNT ASPN VCAN COL5A1 COL6A3 SMOC2 OLFML2B COL8A1 HTRAl KIAA1913 COL12A1 CYR61 PALM2-AKAP2 COL5A2 FAP SERPINGI CDHl1 VIM TYROBP THBS2 TIMP2 ACTA2 COL15Al SCD COL3AI COLlAl TIMP3 PLOD2 S100A8 AEBP1 MMPll

FNDC1 GJA1 CD163 SFRP4 NNMT FCGR3B INHBA COL1A1 PLAU COL6A2 SULF2 MAFB ANTXR1 COL6A1 LOC541471 GPNMB SPON2 LOC387763 BGN CTSK CHI3L1 TAGLN MXRA5 THY1 COL4A1 CiS LOXL1 RAB31 DKK3 CD93

In another aspect there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs:

200884_at 214234_s at 226248_s at 203240_at 214235_at 226302_at 203963_at 214433_s_at 227676_at 204508_s_at 215125_s_at 227719_at 204607_at 215867_x_at 227725_at 204811_s_at 217109_at 228232_s at 204895_x_at 217110_s_at 229070_at 204897_at 218211_s_at 231832_at 205259_at 219543_at 232176_at 205765_at 219955_at 232481_s_at 205927_s_at 221841_s_at 235976at 208063_s_at 221874_at 236894_at 208937_s_at 223969_s_at 237521_x_at 210107_at 223970_at 242601_at; and/or 213106_at

(ii) CLCA1 CTSE ATP8B1

FCGBP C6orflO5 CACNA2D2 HMGCS2 CKB KLF4 RETNLB ATP8Al CYP3A5P2 LlTD1 MUC4 CAPN9 SLITRK6 UGT1A1 NR3C2 VSIG2 SELENBP1 PBLD LOC253012 PTGER4 CA12 ST6GALNAC1 MLPH WDR51B IDI KIAA1324 FAM3D CYP3A5

Preferably, said gastrointestinal tissue is colorectal tissue.

Reference to an "adenoma control level" or "cancer control level" should be understood as a reference to the level of said gene expression in a population of adenoma or cancer gastrointestinal cells, respectively. As discussed hereinbefore in relation to "normal levels", the subject level may be a discrete level or a range of levels. Accordingly, the definition of "adenoma control level" or "cancer control level" should be understood to have a corresponding definition to "normal level", albeit in the context of the expression of genes by a neoplastic population of large intestine cells.

In terms of this aspect of the present invention, the subject analysis is performed on a population of neoplastic cells. These cells may be derived in any manner, such as sloughed off neoplastic cells which have been collected via an enema wash or from a gastrointestinal sample, such as a stool sample. Alternatively, the subject cells may have been obtained via a biopsy or other surgical technique.

Without limiting this aspect of the invention in any way, several of the markers of this aspect of the present invention have been determined to be expressed at particularly significant levels below those of neoplastic cells. For example, decreased expression levels of 3 to 9 fold have been observed in respect of the following markers which are indicative of gastrointestinal adenomas, when assessed by the method herein exemplified.

Gene, genes or transcripts Fold Decrease detected by Affymetrix Gene Probe No: 9 202404sat COL1A2 8 225681_at CTHRC1 FN1 7 212464_s_at 210809_s_at POSTN 6 209875sat SPP1 221740_at 5 -MMP1 204475_at 200665_s_at SPARC 201744_s_at LUM 4 218468_s_at GREMI 202859_x_at IL8 211959.at IGFBP5 223122_s_at SFRP2 212353_at SULF1 219087_at ASPN 201438_at COL6A3 226237_at COL8A1 225664_at COL12A1 221730_at COL5A2 207173_x_at CDH11 203083_at THBS2 203477_at COL15A1 3 37892_at COL1lAI 202917_s_at S100A8 226930_at FNDC1 204051_s_at SFRP4 210511_s_at INHBA 209156_s_at COL6A2 224694_at ANTXR1 201141_at GPNMB 213905_x_at BGN 205547sat TAGLN

In another example, decreased expression levels of between 3 to 5 fold have been observed in respect of the following markers which are indicative of gastrointestinal cancers, when assessed by the method herein exemplified.

Gene, genes or transcripts Fold Decrease detected by Affymetrix Gene Probe No: 5 210107_at CLCA1 203240_at FCGBP 204607_at HMGCS2 223969_s_at RETNLB 219955_at L1TD1 3 232481_s_at SLITRK6 228232_s_at VSIG2 242601_at LOC253012 227725_at ST6GALNAC1

According to this embodiment, there is therefore provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene or genes detected by Affymetrix probeset IDs: 202404_s_at, 212464_sat, 210809_s_a, 225681_at;and/or

(ii) COLlA2, CTHRC1, FN1, POSTN

In another embodiment, there is provided a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 209875sat 227140at 204475_at; and/or

(ii) SPP1 MMP1

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 200665_s_at 226237_at 226930at 201744_s_at 225664_at 204051_s_at 218468_s_at 221730_at 210511_s_at 202859_x_at 207173_x_at 209156_s_at 211959_at 203083_at 224694_at 223122_s_at 203477_at 201141at 212353_at 37892_at 213905_x_at 219087_.at 202917_s_at 205547_s_at 201438_at; and/or

(ii) SPARC COL8A1 SFRP4 LUM COL12A1 INHBA GREMI COL5A2 COL6A2 IL8 CDHll ANTXR1 IGFBP5 THBS2 GPNMB SFRP2 COL15A1 BGN SULFI COLIlAl TAGLN ASPN S100A8 COL6A3 FNDCl

In yet another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) CLCA1

In still yet another preferred embodiment the present invention is directed to a method of characterising a cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(i) the gene, genes or transcripts detected by Affymetrix probeset IDs: 203240_at, 204607at, 223969_s_at, 219955at, 23248_s-at, 242601_at, 227725_at, 228232_s_at; and/or

(ii) FCGBP, HMGCS2, RETNLB, LlTD , SLITRK6, VSIG2, LOC253012, ST6GALNAC

Preferably, said gastrointestinal tissue is colorectal tissue.

Even more preferably, said biological sample is a tissue sample.

In still another related aspect it has been determined that a subset of the markers of this aspect of the present invention are useful as qualitative markers of neoplastic tissue characterisation in that these markers, if not detectable at levels substantially above background levels in neoplastic tissue are indicative of cancerous tissue.

According to this aspect, the present invention provides a method of characterising a neoplastic cell or cellular population, which cell or cellular population is derived from the large intestine of an individual, said method comprising assessing the level of expression of one or more genes or transcripts selected from:

(ii) SLITRK6 LITDI

Preferably, said gastrointestinal tissue is colorectal tissue.

Still more preferably, said biological sample is a tissue sample.

In a most preferred embodiment, the methods of the present invention are preferably directed to screening for proteins encoded by the markers of the present invention or changes to DNA methylation of genomic DNA. In another embodiment, expression is assessed by the association of DNA with chromatin proteins carrying repressive modifications, for example, methylation of lysines 9 or 27 of histone H3.

Although the preferred method is to detect the expression product or DNA changes of the neoplastic markers for the purpose of diagnosing neoplasia development or predisposition thereto, the detection of converse changes in the levels of said markers may be desired under certain circumstances, for example, to monitor the effectiveness of therapeutic or prophylactic treatment directed to modulating a neoplastic condition, such as adenoma or adenocarcinoma development. For example, where reduced expression of the subject markers indicates that an individual has developed a condition characterised by adenoma or adenocarcinoma development, for example, screening for an increase in the levels of these markers subsequently to the onset of a therapeutic regime may be utilised to indicate reversal or other form of improvement of the subject individual's condition.

The method of the present invention is therefore useful as a one off test or as an on-going monitor of those individuals thought to be at risk of neoplasia development or as a monitor of the effectiveness of therapeutic or prophylactic treatment regimes directed to inhibiting or otherwise slowing neoplasia development. In these situations, mapping the modulation of neoplastic marker expression levels in any one or more classes of biological samples is a valuable indicator of the status of an individual or the effectiveness of a therapeutic or prophylactic regime which is currently in use. Accordingly, the method of the present invention should be understood to extend to monitoring for increases or decreases in marker expression levels in an individual relative to their normal level (as hereinbefore defined), background control levels, cancer levels, adenoma levels or relative to one or more earlier marker expression levels determined from a biological sample of said individual.

Means of assessing the subject expressed neoplasm markers in a biological sample can be achieved by any suitable method, which would be well known to the person of skill in the art. To this end, it would be appreciated that to the extent that one is examining either a homogeneous cellular population (such as a tumour biopsy or a cellular population which has been enriched from a heterogeneous starting population) or a tissue section, one may utilise a wide range of techniques such as in situ hybridisation, assessment of expression profiles by microassays, immunoassays and the like (hereinafter described in more detail) to detect the absence of or downregulation of the level of expression of one or more markers of interest. However, to the extent that one is screening a heterogenous cellular population or a bodily fluid in which heterogeneous populations of cells are found, such as a blood sample, the absence of or reduction in level of expression of a particular marker may be undetectable due to the inherent expression of the marker by non-neoplastic cells which are present in the sample. That is, a decrease in the level of expression of a subgroup of cells may not be detectable. In this situation, a more appropriate mechanism of detecting a reduction in a neoplastic subpopulation of the expression levels of one or more markers of the present invention is via indirect means, such as the detection of epigenetic changes.

Without limiting the present invention to any one theory or mode of action, during development gene expression is regulated by processes that alter the availability of genes for expression in different cell lineages without any alteration in gene sequence, and these states can be inherited through a cell division - a process called epigenetic inheritance. Epigenetic inheritance is determined by a combination of DNA methylation (modification of cytosine to give 5-methyl cytosine, 5meC) and by modifications of the histone chromosomal proteins that package DNA. Thus methylation of DNA at CpG sites and modifications such as deacetylation of histone H3 on lysine 9, and methylation on lysine 9 or 27 are associated with inactive chromatin, while the converse state of a lack of DNA methylation, acetylation of lysine 9 of histone H3 is associated with open chromatin and active gene expression. In cancer, this epigenetic regulation of gene expression is frequently found to be disrupted (Esteller & Herman, 2000; Jones & Baylin, 2002). Genes such as tumour suppressor or metastasis suppressor genes are often found to be silenced by DNA methylation, while other genes may be hypomethylated and inappropriately expressed. Thus, among genes that show a decrease or loss of expression in cancer, this is often characterised by methylation of the promoter or regulatory region of the gene.

A variety of methods are available for detection of aberrantly methylated DNA of a specific gene, even in the presence of a large excess of normal DNA (Clark 2007). Thus, loss of expression of a gene which can be difficult to detect at the protein or RNA level except by immunohistochemistry can often be detected in tumour samples and in bodily fluids of cancer patients by the presence of hypermethylated DNA of the gene's promoter. Similarly DNA hypomethylation may be used for the detection of certain genes whose expression is elevated in cancer. Epigenetic alterations and chromatin changes in cancer are also evident in the altered association of modified histones with specific genes (Esteller, 2007); for example repressed genes are often found associated with histone H3 that is deacetylated and methylated on lysine 9. The use of antibodies targeted to altered histones allows for the isolation of DNA associated with particular chromatin states and its potential use in cancer diagnosis.

Other methods of detecting changes to gene expression levels, particularly where the subject biological sample is not contaminated with high numbers of non-neoplastic cells, include but are not limited to:

(i) In vivo detection.

Molecular Imaging may be used following administration of imaging probes or reagents capable of disclosing altered expression of the markers in the intestinal tissues.

Molecular imaging (Moore et al., BBA, 1402:239-249, 1988; Weissleder et al., Nature Medicine 6:351-355, 2000) is the in vivo imaging of molecular expression that correlates with the macro-features currently visualized using "classical" diagnostic imaging techniques such as X-Ray, computed tomography (CT), MRI, Positron Emission Tomography (PET) or endoscopy.

(ii) Detection of downregulation of RNA expression in the cells by Fluorescent In Situ Hybridization (FISH), or in extracts from the cells by technologies such as Quantitative Reverse Transcriptase Polymerase Chain Reaction (QRTPCR) or Flow cytometric qualification of competitive RT-PCR products (Wedemeyer et al., Clinical Chemistry 48:9 1398-1405, 2002).

(iii) Assessment of expression profiles of RNA, for example by array technologies (Alon et al., Proc. Natl. Acad. Sci. USA: 96, 6745-6750, June 1999).

A "microarray" is a linear or multi-dimensional array of preferably discrete regions, each having a defined area, formed on the surface of a solid support. The density of the discrete regions on a microarray is determined by the total numbers of target polynucleotides to be detected on the surface of a single solid phase support. As used herein, a DNA microarray is an array of oligonucleotide probes placed onto a chip or other surfaces used to amplify or clone target polynucleotides. Since the position of each particular group of probes in the array is known, the identities of the target polynucleotides can be determined based on their binding to a particular position in the microarray.

Recent developments in DNA microarray technology make it possible to conduct a large scale assay of a plurality of target nucleic acid molecules on a single solid phase support. U.S. Pat. No. 5,837,832 (Chee et al.) and related patent applications describe immobilizing an array of oligonucleotide probes for hybridization and detection of specific nucleic acid sequences in a sample. Target polynucleotides of interest isolated from a tissue of interest are hybridized to the DNA chip and the specific sequences detected based on the target polynucleotides' preference and degree of hybridization at discrete probe locations. One important use of arrays is in the analysis of differential gene expression, where the profile of expression of genes in different cells or tissues, often a tissue of interest and a control tissue, is compared and any differences in gene expression among the respective tissues are identified. Such information is useful for the identification of the types of genes expressed in a particular tissue type and diagnosis of conditions based on the expression profile.

In one example, RNA from the sample of interest is subjected to reverse transcription to obtain labelled cDNA. See U.S. Pat. No. 6,410,229 (Lockhart et al.) The cDNA is then hybridized to oligonucleotides or cDNAs of known sequence arrayed on a chip or other surface in a known order. In another example, the RNA is isolated from a biological sample and hybridised to a chip on which are anchored cDNA probes. The location of the oligonucleotide to which the labelled cDNA hybridizes provides sequence information on the cDNA, while the amount of labelled hybridized RNA or cDNA provides an estimate of the relative representation of the RNA or cDNA of interest. See Schena, et al. Science 270:467-470 (1995). For example, use of a cDNA microarray to analyze gene expression patterns in human cancer is described by DeRisi, et al. (Nature Genetics 14:457-460 (1996)).

In a preferred embodiment, nucleic acid probes corresponding to the subject nucleic acids are made. The nucleic acid probes attached to the biochip are designed to be substantially complementary to the nucleic acids of the biological sample such that specific hybridization of the target sequence and the probes of the present invention occurs. This complementarity need not be perfect, in that there may be any number of base pair mismatches that will interfere with hybridization between the target sequence and the single stranded nucleic acids of the present invention. It is expected that the overall homology of the genes at the nucleotide level probably will be about 40% or greater, probably about 60% or greater, and even more probably about 80% or greater; and in addition that there will be corresponding contiguous sequences of about 8-12 nucleotides or longer. However, if the number of mutations is so great that no hybridization can occur under even the least stringent of hybridization conditions, the sequence is not a complementary target sequence. Thus, by "substantially complementary" herein is meant that the probes are sufficiently complementary to the target sequences to hybridize under normal reaction conditions, particularly high stringency conditions.

A nucleic acid probe is generally single stranded but can be partly single and partly double stranded. The strandedness of the probe is dictated by the structure, composition, and properties of the target sequence. In general, the oligonucleotide probes range from about 6, 8, 10, 12, 15, 20, 30 to about 100 bases long, with from about 10 to about 80 bases being preferred, and from about 15 to about 40 bases being particularly preferred. That is, generally entire genes are rarely used as probes. In some embodiments, much longer nucleic acids can be used, up to hundreds of bases. The probes are sufficiently specific to hybridize to a complementary template sequence under conditions known by those of skill in the art. The number of mismatches between the probe's sequences and their complementary template (target) sequences to which they hybridize during hybridization generally do not exceed 15%, usually do not exceed 10% and preferably do not exceed 5%, as-determined by BLAST (default settings).

Oligonucleotide probes can include the naturally-occurring heterocyclic bases normally found in nucleic acids (uracil, cytosine, thymine, adenine and guanine), as well as modified bases and base analogues. Any modified base or base analogue compatible with hybridization of the probe to a target sequence is useful in the practice of the invention. The sugar or glycoside portion of the probe can comprise deoxyribose, ribose, and/or modified forms of these sugars, such as, for example, 2'-O-alkyl ribose. In a preferred embodiment, the sugar moiety is 2'-deoxyribose; however, any sugar moiety that is compatible with the ability of the probe to hybridize to a target sequence can be used.

In one embodiment, the nucleoside units of the probe are linked by a phosphodiester backbone, as is well known in the art. In additional embodiments, internucleotide linkages can include any linkage known to one of skill in the art that is compatible with specific hybridization of the probe including, but not limited to phosphorothioate, methylphosphonate, sulfamate (e.g., U.S. Pat. No. 5,470,967) and polyamide (i.e., peptide nucleic acids). Peptide nucleic acids are described in Nielsen et al. (1991) Science 254: 1497-1500, U.S. Pat. No. 5,714,331, and Nielsen (1999) Curr. Opin. Biotechnol. 10:71-75.

In certain embodiments, the probe can be a chimeric molecule; i.e., can comprise more than one type of base or sugar subunit, and/or the linkages can be of more than one type within the same primer. The probe can comprise a moiety to facilitate hybridization to its target sequence, as are known in the art, for example, intercalators and/or minor groove binders. Variations of the bases, sugars, and internucleoside backbone, as well as the presence of any pendant group on the probe, will be compatible with the ability of the probe to bind, in a sequence-specific fashion, with its target sequence. A large number of structural modifications, are possible within these bounds. Advantageously, the probes according to the present invention may have structural characteristics such that they allow the signal amplification, such structural characteristics being, for example, branched DNA probes as those described by Urdea et al. (Nucleic Acids Symp. Ser., 24:197-200 (1991)) or in the European Patent No. EP-0225,807. Moreover, synthetic methods for preparing the various heterocyclic bases, sugars, nucleosides and nucleotides that form the probe, and preparation of oligonucleotides of specific predetermined sequence, are well-developed and known in the art. A preferred method for oligonucleotide synthesis incorporates the teaching of U.S. Pat. No. 5,419,966.

Multiple probes may be designed for a particular target nucleic acid to account for polymorphism and/or secondary structure in the target nucleic acid, redundancy of data and the like. In some embodiments, where more than one probe per sequence is used, either overlapping probes or probes to different sections of a single target gene are used. That is, two, three, four or more probes, are used to build in a redundancy for a particular target. The probes can be overlapping (i.e. have some sequence in common), or are specific for distinct sequences of a gene. When multiple target polynucleotides are to be detected according to the present invention, each probe or probe group corresponding to a particular target polynucleotide is situated in a discrete area of the microarray.

Probes may be in solution, such as in wells or on the surface of a micro-array, or attached to a solid support. Examples of solid support materials that can be used include a plastic, a ceramic, a metal, a resin, a gel and a membrane. Useful types of solid supports include plates, beads, magnetic material, microbeads, hybridization chips, membranes, crystals, ceramics and self-assembling monolayers. One example comprises a two-dimensional or three-dimensional matrix, such as a gel or hybridization chip with multiple probe binding sites (Pevzner et al., J. Biomol. Struc. & Dyn. 9:399 410, 1991; Maskos and Southern, Nuc. Acids Res. 20:1679-84, 1992). Hybridization chips can be used to construct very large probe arrays that are subsequently hybridized with a target nucleic acid. Analysis of the hybridization pattern of the chip can assist in the identification of the target nucleotide sequence. Patterns can be manually or computer analyzed, but it is clear that positional sequencing by hybridization lends itself to computer analysis and automation. In another example, one may use an Affymetrix chip on a solid phase structural support in combination with a fluorescent bead based approach. In yet another example, one may utilise a cDNA microarray. In this regard, the oligonucleotides described by Lockkart et al (i.e. Affymetrix synthesis probes in situ on the solid phase) are particularly preferred, that is, photolithography.

As will be appreciated by those in the art, nucleic acids can be attached or immobilized to a solid support in a wide variety of ways. By "immobilized" herein is meant the association or binding between the nucleic acid probe and the solid support is sufficient to be stable under the conditions of binding, washing, analysis, and removal. The binding can be covalent or non-covalent. By "non-covalent binding" and grammatical equivalents herein is meant one or more of either electrostatic, hydrophilic, and hydrophobic interactions. Included in non-covalent binding is the covalent attachment of a molecule, such as streptavidin, to the support and the non-covalent binding of the biotinylated probe to the streptavidin. By "covalent binding" and grammatical equivalents herein is meant that the two moieties, the solid support and the probe, are attached by at least one bond, including sigma bonds, pi bonds and coordination bonds. Covalent bonds can be formed directly between the probe and the solid support or can be formed by a cross linker or by inclusion of a specific reactive group on either the solid support or the probe or both molecules. Immobilization may also involve a combination of covalent and non-covalent interactions.

Nucleic acid probes may be attached to the solid support by covalent binding such as by conjugation with a coupling agent or by covalent or non-covalent binding such as electrostatic interactions, hydrogen bonds or antibody-antigen coupling, or by combinations thereof. Typical coupling agents include biotin/avidin, biotin/streptavidin, Staphylococcus aureus protein A/IgG antibody Fe fragment, and streptavidin/protein A chimeras (T. Sano and C. R. Cantor, Bio/Technology 9:1378-81 (1991)), or derivatives or combinations of these agents. Nucleic acids may be attached to the solid support by a photocleavable bond, an electrostatic bond, a disulfide bond, a peptide bond, a diester bond or a combination of these sorts of bonds. The array may also be attached to the solid support by a selectively releasable bond such as 4,4'-dimethoxytrityl or its derivative. Derivatives which have been found to be useful include 3 or 4 [bis-(4 methoxyphenyl)]-methyl-benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)] methyl-benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)]-hydroxymethyl benzoic acid, N-succinimidyl-3 or 4 [bis-(4-methoxyphenyl)]-chloromethyl-benzoic acid, and salts of these acids.

In general, the probes are attached to the biochip in a wide variety of ways, as will be appreciated by those in the art. As described herein, the nucleic acids can either be synthesized first, with subsequent attachment to the biochip, or can be directly synthesized on the biochip.

The biochip comprises a suitable solid substrate. By "substrate" or "solid support" or other grammatical equivalents herein is meant any material that can be modified to contain discrete individual sites appropriate for the attachment or association of the nucleic acid probes and is amenable to at least one detection method. The solid phase support of the present invention can be of any solid materials and structures suitable for supporting nucleotide hybridization and synthesis. Preferably, the solid phase support comprises at least one substantially rigid surface on which the primers can be immobilized and the reverse transcriptase reaction performed. The substrates with which the polynucleotide microarray elements are stably associated and may be fabricated from a variety of materials, including plastics, ceramics, metals, acrylamide, cellulose, nitrocellulose, glass, polystyrene, polyethylene vinyl acetate, polypropylene, polymethacrylate, polyethylene, polyethylene oxide, polysilicates, polycarbonates, Teflon, fluorocarbons, nylon, silicon rubber, polyanhydrides, polyglycolic acid, polylactic acid, polyorthoesters, polypropylfumerate, collagen, glycosaminoglycans, and polyamino acids. Substrates may be two-dimensional or three-dimensional in form, such as gels, membranes, thin films, glasses, plates, cylinders, beads, magnetic beads, optical fibers, woven fibers, etc. A preferred form of array is a three-dimensional array. A preferred three-dimensional array is a collection of tagged beads. Each tagged bead has different primers attached to it. Tags are detectable by signalling means such as color (Luminex, Illumina) and electromagnetic field (Pharmaseq) and signals on tagged beads can even be remotely detected (e.g., using optical fibers). The size of the solid support can be any of the standard microarray sizes, useful for DNA microarray technology, and the size may be tailored to fit the particular machine being used to conduct a reaction of the invention. In general, the substrates allow optical detection and do not appreciably fluoresce.

In one embodiment, the surface of the biochip and the probe may be derivatized with chemical functional groups for subsequent attachment of the two. Thus, for example, the biochip is derivatized with a chemical functional group including, but not limited to, amino groups, carboxy groups, oxo groups and thiol groups, with amino groups being particularly preferred. Using these functional groups, the probes can be attached using functional groups on the probes. For example, nucleic acids containing amino groups can be attached to surfaces comprising amino groups, for example using linkers as are known in the art; for example, homo-or hetero-bifunctional linkers as are well known. In addition, in some cases, additional linkers, such as alkyl groups (including substituted and heteroalkyl groups) may be used.

In this embodiment, the oligonucleotides are synthesized as is known in the art, and then attached to the surface of the solid support. As will be appreciated by those skilled in the art, either the 5' or 3' terminus may be attached to the solid support, or attachment may be via an internal nucleoside. In an additional embodiment, the immobilization to the solid support may be very strong, yet non-covalent. For example, biotinylated oligonucleotides can be made, which bind to surfaces covalently coated with streptavidin, resulting in attachment.

The arrays may be produced according to any convenient methodology, such as preforming the polynucleotide microarray elements and then stably associating them with the surface. Alternatively, the oligonucleotides may be synthesized on the surface, as is known in the art. A number of different array configurations and methods for their production are known to those of skill in the art and disclosed in WO 95/25116 and WO 95/35505 (photolithographic techniques), U.S. Pat. No. 5,445,934 (in situ synthesis by photolithography), U.S. Pat. No. 5,384,261 (in situ synthesis by mechanically directed flow paths); and U.S. Pat. No. 5,700,637 (synthesis by spotting, printing or coupling); the disclosure of which are herein incorporated in their entirety by reference. Another method for coupling DNA to beads uses specific ligands attached to the end of the DNA to link to ligand-binding molecules attached to a bead. Possible ligand-binding partner pairs include biotin-avidin/streptavidin, or various antibody/antigen pairs such as digoxygenin-antidigoxygenin antibody (Smith et al., Science 258:1122-1126 (1992)). Covalent chemical attachment of DNA to the support can be accomplished by using standard coupling agents to link the 5'-phosphate on the DNA to coated microspheres through a phosphoamidate bond. Methods for immobilization of oligonucleotides to solid-state substrates are well established. See Pease et al., Proc. Natl. Acad. Sci. USA 91(11):5022-5026 (1994). A preferred method of attaching oligonucleotides to solid state substrates is described by Guo et al., Nucleic Acids Res. 22:5456-5465 (1994). Immobilization can be accomplished either by in situ DNA synthesis (Maskos and Southern, supra) or by covalent attachment of chemically synthesized oligonucleotides (Guo et al., supra) in combination with robotic arraying technologies.

In addition to the solid-phase technology represented by biochip arrays, gene expression can also be quantified using liquid-phase arrays. One such system is kinetic polymerase chain reaction (PCR). Kinetic PCR allows for the simultaneous amplification and quantification of specific nucleic acid sequences. The specificity is derived from synthetic oligonucleotide primers designed to preferentially adhere to single-stranded nucleic acid sequences bracketing the target site. This pair of oligonucleotide primers form specific, non-covalently bound complexes on each strand of the target sequence. These complexes facilitate in vitro transcription of double-stranded DNA in opposite orientations. Temperature cycling of the reaction mixture creates a continuous cycle of primer binding, transcription, and re-melting of the nucleic acid to individual strands. The result is an exponential increase of the target dsDNA product. This product can be quantified in real time either through the use of an intercalating dye or a sequence specific probe. SYBR(r) Green 1, is an example of an intercalating dye, that preferentially binds to dsDNA resulting in a concomitant increase in the fluorescent signal. Sequence specific probes, such as used with TaqMan technology, consist of a fluorochrome and a quenching molecule covalently bound to opposite ends of an oligonucleotide. The probe is designed to selectively bind the target DNA sequence between the two primers. When the DNA strands are synthesized during the PCR reaction, the fluorochrome is cleaved from the probe by the exonuclease activity of the polymerase resulting in signal dequenching. The probe signalling method can be more specific than the intercalating dye method, but in each case, signal strength is proportional to the dsDNA product produced. Each type of quantification method can be used in multi-well liquid phase arrays with each well representing primers and/or probes specific to nucleic acid sequences of interest. When used with messenger RNA preparations of tissues or cell lines, an array of probe/primer reactions can simultaneously quantify the expression of multiple gene products of interest. See Germer et al., Genome Res. 10:258-266 (2000); Heid et al., Genome Res. 6:986-994 (1996).

(iv) Measurement of altered neoplastic marker protein levels in cell extracts, for example by immunoassay.

Testing for proteinaceous neoplastic marker expression product in a biological sample can be performed by any one of a number of suitable methods which are well known to those skilled in the art. Examples of suitable methods include, but are not limited to, antibody screening of tissue sections, biopsy specimens or bodily fluid samples.

To the extent that antibody based methods of diagnosis are used, the presence of the marker protein may be determined in a number of ways such as by Western blotting, ELISA or flow cytometry procedures. These, of course, include both single-site and two-site or "sandwich" assays of the non-competitive types, as well as in the traditional competitive binding assays. These assays also include direct binding of a labelled antibody to a target.

Sandwich assays are a useful and commonly used assay. A number of variations of the sandwich assay technique exist, and all are intended to be encompassed by the present invention. Briefly, in a typical forward assay, an unlabelled antibody is immobilized on a solid substrate and the sample to be tested brought into contact with the bound molecule. After a suitable period of incubation, for a period of time sufficient to allow formation of an antibody-antigen complex, a second antibody specific to the antigen, labelled with a reporter molecule capable of producing a detectable signal is then added and incubated, allowing time sufficient for the formation of another complex of antibody-antigen-labelled antibody. Any unreacted material is washed away, and the presence of the antigen is determined by observation of a signal produced by the reporter molecule. The results may either be qualitative, by simple observation of the visible signal, or may be quantitated by comparing with a control sample. Variations on the forward assay include a simultaneous assay, in which both sample and labelled antibody are added simultaneously to the bound antibody. These techniques are well known to those skilled in the art, including any minor variations as will be readily apparent.

In the typical forward sandwich assay, a first antibody having specificity for the marker or antigenic parts thereof, is either covalently or passively bound to a solid surface. The solid surface is typically glass or a polymer, the most commonly used polymers being cellulose, polyacrylamide, nylon, polystyrene, polyvinyl chloride or polypropylene. The solid supports may be in the form of tubes, beads, discs of microplates, or any other surface suitable for conducting an immunoassay. The binding processes are well-known in the art and generally consist of cross-linking, covalently binding or physically adsorbing, the polymer-antibody complex is washed in preparation for the test sample. An aliquot of the sample to be tested is then added to the solid phase complex and incubated for a period of time sufficient (e.g. 2-40 minutes) and under suitable conditions (e.g. 25 0C) to allow binding of any subunit present in the antibody. Following the incubation period, the antibody subunit solid phase is washed and dried and incubated with a second antibody specific for a portion of the antigen. The second antibody is linked to a reporter molecule which is used to indicate the binding of the second antibody to the antigen.

An alternative method involves immobilizing the target molecules in the biological sample and then exposing the immobilized target to specific antibody which may or may not be labelled with a reporter molecule. Depending on the amount of target and the strength of the reporter molecule signal, a bound target may be detectable by direct labelling with the antibody. Alternatively, a second labelled antibody, specific to the first antibody is exposed to the target-first antibody complex to form a target-first antibody-second antibody tertiary complex. The complex is detected by the signal emitted by the reporter molecule.

By "reporter molecule" as used in the present specification, is meant a molecule which, by its chemical nature, provides an analytically identifiable signal which allows the detection of antigen-bound antibody. Detection may be either qualitative or quantitative. The most commonly used reporter molecules in this type of assay are either enzymes, fluorophores or radionuclide containing molecules (i.e. radioisotopes) and chemiluminescent molecules.

In the case of an enzyme immunoassay, an enzyme is conjugated to the second antibody, generally by means of glutaraldehyde or periodate. As will be readily recognized, however, a wide variety of different conjugation techniques exist, which are readily available to the skilled artisan. Commonly used enzymes include horseradish peroxidase, glucose oxidase, beta-galactosidase and alkaline phosphatase, amongst others. The substrates to be used with the specific enzymes are generally chosen for the production, upon hydrolysis by the corresponding enzyme, of a detectable color change. Examples of suitable enzymes include alkaline phosphatase and peroxidase. It is also possible to employ fluorogenic substrates, which yield a fluorescent product rather than the chromogenic substrates noted above. In all cases, the enzyme-labelled antibody is added to the first antibody hapten complex, allowed to bind, and then the excess reagent is washed away. A solution containing the appropriate substrate is then added to the complex of antibody-antigen-antibody. The substrate will react with the enzyme linked to the second antibody, giving a qualitative visual signal, which may be further quantitated, usually spectrophotometrically, to give an indication of the amount of antigen which was present in the sample. "Reporter molecule" also extends to use of cell agglutination or inhibition of agglutination such as red blood cells on latex beads, and the like.

Alternately, fluorescent compounds, such as fluorecein and rhodamine, may be chemically coupled to antibodies without altering their binding capacity. When activated by illumination with light of a particular wavelength, the fluorochrome labelled antibody adsorbs the light energy, inducing a state to excitability in the molecule, followed by emission of the light at a characteristic color visually detectable with a light microscope. As in the EIA, the fluorescent labelled antibody is allowed to bind to the first antibody-hapten complex. After washing off the unbound reagent, the remaining tertiary complex is then exposed to the light of the appropriate wavelength the fluorescence observed indicates the presence of the hapten of interest. Immunofluorescence and EIA techniques are both very well established in the art and are particularly preferred for the present method. However, other reporter molecules, such as radioisotope, chemiluminescent or bioluminescent molecules, may also be employed.

(v) Determining altered expression of protein neoplastic markers on the cell surface, for example by immunohistochemistry.

(vi) Determining altered protein expression based on any suitable functional test, enzymatic test or immunological test in addition to those detailed in points (iv) and (v) above.

A person of ordinary skill in the art could determine, as a matter of routine procedure, the appropriateness of applying a given method to a particular type of biological sample.

Without limiting the present invention in any way, and as detailed above, gene expression levels can be measured by a variety of methods known in the art. For example, gene transcription or translation products can be measured. Gene transcription products, i.e., RNA, can be measured, for example, by hybridization assays, run-off assays., Northern blots, or other methods known in the art.

Hybridization assays generally involve the use of oligonucleotide probes that hybridize to the single-stranded RNA transcription products. Thus, the oligonucleotide probes are complementary to the transcribed RNA expression product. Typically, a sequence-specific probe can be directed to hybridize to RNA or cDNA. A "nucleic acid probe", as used herein, can be a DNA probe or an RNA probe that hybridizes to a complementary sequence. One of skill in the art would know how to design such a probe such that sequence specific hybridization will occur. One of skill in the art will further know how to quantify the amount of sequence specific hybridization as a measure of the amount of gene expression for the gene was transcribed to produce the specific RNA.

The hybridization sample is maintained under conditions that are sufficient to allow specific hybridization of the nucleic acid probe to a specific gene expression product. "Specific hybridization", as used herein, indicates near exact hybridization (e.g., with few if any mismatches). Specific hybridization can be performed under high stringency conditions or moderate stringency conditions. In one embodiment, the hybridization conditions for specific hybridization are high stringency. For example, certain high stringency conditions can be used to distinguish perfectly complementary nucleic acids from those of less complementarity. "High stringency conditions", "moderate stringency conditions" and "low stringency conditions" for nucleic acid hybridizations are explained on pages 2.10.1-2.10.16 and pages 6.3.1-6.3.6 in Current Protocols in Molecular Biology (Ausubel, F. et al., "Current Protocols in Molecular Biology", John Wiley & Sons, (1998), the entire teachings of which are incorporated by reference herein). The exact conditions that determine the stringency of hybridization depend not only on ionic strength (e.g., 0.2.times.SSC, 0.1.times.SSC), temperature (e.g., room temperature, 42 0C., 68°C.) and the concentration of destabilizing agents such as formamide or denaturing agents such as SDS, but also on factors such as the length of the nucleic acid sequence, base composition, percent mismatch between hybridizing sequences and the frequency of occurrence of subsets of that sequence within other non identical sequences. Thus, equivalent conditions can be determined by varying one or more of these parameters while maintaining a similar degree of identity or similarity between the two nucleic acid molecules. Typically, conditions are used such that sequences at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95% or more identical to each other remain hybridized to one another. By varying hybridization conditions from a level of stringency at which no hybridization occurs to a level at which hybridization is first observed, conditions that will allow a given sequence to hybridize (e.g., selectively) with the most complementary sequences in the sample can be determined.

Exemplary conditions that describe the determination of wash conditions for moderate or low stringency conditions are described in Kraus, M. and Aaronson, S., 1991. Methods Enzymol., 200:546-556; and in, Ausubel et al., Current Protocols in Molecular Biology, John Wiley &

Sons, (1998). Washing is the step in which conditions are usually set so as to determine a minimum level of complementarity of the hybrids. Generally, starting from the lowest temperature at which only homologous hybridization occurs, each C. by which the final wash temperature is reduced (holding SSC concentration constant) allows an increase by 1% in the maximum mismatch percentage among the sequences that hybridize. Generally, doubling the concentration of SSC results in an increase in Tm of about 170 C. Using these guidelines, the wash temperature can be determined empirically for high, moderate or low stringency, depending on the level of mismatch sought. For example, a low stringency wash can comprise washing in a solution containing 0.2.times.SSC/0.1% SDS for 10 minutes at room temperature; a moderate stringency wash can comprise washing in a pre-warmed solution (42C) solution containing 0.2.times.SSC/0.1%SDS for 15 minutes at 42 0C.; and a high stringency wash can comprise washing in pre-warmed (68°C.) solution containing O.1.times.SSC/0.1% SDS for 15 minutes at 680 C. Furthermore, washes can be performed repeatedly or sequentially to obtain a desired result as known in the art. Equivalent conditions can be determined by varying one or more of the parameters given as an example, as known in the art, while maintaining a similar degree of complementarity between the target nucleic acid molecule and the primer or probe used (e.g., the sequence to be hybridized).

Preferably, said percent identity is at least 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%.

Low stringency includes and encompasses from at least about 1% v/v to at least about 15% v/v formamide and from at least about 1M to at least about 2M salt for hybridisation, and at least about 1M to at least about 2M salt for washing conditions. Alternative stringency conditions may be applied where necessary, such as medium stringency, which includes and encompasses from at least about 16% v/v at least about 30% v/v formamide and from at least about 0.5M to at least about 0.9M salt for hybridisation, and at least about 0.5M to at least about 0.9M salt for washing conditions, or high stringency, which includes and encompasses from at least about 31% v/v to at least about 50% v/v formamide and from at least about 0.01M to at least about 0.15M salt for hybridisation, and at least about 0.01M to at least about 0.15M salt for washing conditions. In general, washing is carried out at Tm = 69.3 + 0.41 (G + C) % [19]= 12°C. However, the Tm of a duplex DNA decreases by 1°C with every increase of 1% in the number of mismatched based pairs (Bonner et al (1973) J. Mol. Biol. 81:123).

Preferably, the subject probes are designed to bind to the nucleic acid or protein to which they are directed with a level of specificity which minimises the incidence of non-specific reactivity. However, it would be appreciated that it may not be possible to eliminate all potential cross-reactivity or non-specific reactivity, this being an inherent limitation of any probe based system.

In terms of the probes which are used to detect the subject proteins, they may take any suitable form including antibodies and aptamers.

A library or array of nucleic acid or protein probes provides rich and highly valuable information. Further, two or more arrays or profiles (information obtained from use of an array) of such sequences are useful tools for comparing a test set of results with a reference, such as another sample or stored calibrator. In using an array, individual probes typically are immobilized at separate locations and allowed to react for binding reactions. Primers associated with assembled sets of markers are useful for either preparing libraries of sequences or directly detecting markers from other biological samples.

A library (or array, when referring to physically separated nucleic acids corresponding to at least some sequences in a library) of gene markers exhibits highly desirable properties. These properties are associated with specific conditions, and may be characterized as regulatory profiles. A profile, as termed here refers to a set of members that provides diagnostic information of the tissue from which the markers were originally derived. A profile in many instances comprises a series of spots on an array made from deposited sequences.

A characteristic patient profile is generally prepared by use of an array. An array profile may be compared with one or more other array profiles or other reference profiles. The comparative results can provide rich information pertaining to disease states, developmental state, receptiveness to therapy and other information about the patient.

Another aspect of the present invention provides a diagnostic kit for assaying biological samples comprising an agent for detecting one or more neoplastic marker reagents useful for facilitating the detection by the agent in the first compartment. Further means may also be included, for example, to receive a biological sample. The agent may be any suitable detecting molecule.

The present invention is further described by the following non-limiting examples:

EXAMPLE1

Methods and Materials

Affymetrix GeneChip data Gene expression profiling data and accompanying clinical data was purchased from GeneLogic Inc (Gaithersburg, MD USA). For each tissue analysed, oligonucleotide microarray data for 44,928 probesets (Affymetrix HGU133A & HGU133B, combined), experimental and clinical descriptors, and digitally archived microscopy images of histological preparations were recieved. A quality control analysis was performed to remove arrays not meeting essential quality control measures as defined by the manufacturer.

Transcript expression levels were calculated by both Microarray Suite (MAS) 5.0 (Affymetrix) and the Robust Multichip Average (RMA) normalization techniques (Affymetrix. GeneChip expression data analysis fundamentals. Affymetrix, Santa Clara, CA USA, 2001; Hubbell et al. Bioinformatics, 18:1585-1592, 2002; Irizarry et al. Nucleic Acid Research, 31, 2003)MAS normalized data was used for performing standard quality control routines and the final data set was normalized with RMA for all subsequent analyses.

Univariatedifferentialexpression Differentially expressed gene transcripts were identified using a moderated t-test implemented in the limma library downloaded from the Bioconductor repository for R. (G. K. Smyth. StatisticalApplications in Genetics and Molecular Biology, 3(l):Article 3, 2004; G K Smyth. Bioinformatics and Computational Biology Solutions using R and Bioconductor. Springer, New York, 2005). Significance estimates (p-values) were corrected to adjust for multiple hypothesis testing using the Bonferonni correction.

Tissue specific expression patterns To construct a filter for hypothetically 'turned off gene expression the mean expression level for all 44,928 probesets across the full range of 454 tissues was first estimated. To estimate an expression on/off threshold, the 44,928 mean values were ranked and the expression value equivalent to the 30th percentile across the dataset calculated. This arbitrary threshold was chosen because it was theorized that the majority of transcripts (and presumably more than 30%) in a given specimen should be transcriptionally silenced. Thus this threshold represents a conservative upper bound for what is estimated as non-specific, or background, signal.

Gene symbol annotations To map Affymetrix probeset names to official gene symbols the annotation metadata available from Bioconductor was used. Hgul33plus2 library version 1.16.0, which was assembled using Entrez Gene data downloaded on 15 March 2007, was used.

Estimates ofperformance characteristics Diagnostic utility for each table of markers shown herein was estimated including: sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratio positive, likelihood ratio negative. These estimates were calculated in the same data used to discover the markers and will therefore potentially overestimate the performance characteristics in future tissue samples. To improve the generalisabilty of the estimates a modified jackknife resampling technique was used to calculate a less biased value for each characteristic.

Results A range of univariate statistical tests were applied on Affymetrix oligonucleotide microarray data to reveal human genes that could be used to discriminate colorectal neoplastic tissues from non-neoplastic tissues. There were further identified a number of gene transcripts that appear to be useful for differentiating colorectal adenomas from colorectal carcinoma. Also identified were a subset of these transcripts that may have particular diagnostic utility due to the protein products being either secreted or displayed on the cell surface of epithelial cells. Finally, there were identified a further subset of transcripts expressed specifically in neoplastic tissues and at low- or near-background levels in non-neoplastic tissues.

Genes differentially expressed in neoplastic tissues From a total GeneChip set of 44,928 probesets it was determined that over 11,000 probesets were differentially expressed by moderated t-test using the limma package in BioConductor (G. K. Smyth, 2004 supra) employing conservative (Bonferroni) multiple test correction. When this list was further filtered to include only those probesets demonstrating a 2-fold or greater mean expression change between the neoplastic and non-neoplastic tissues, 560 probesets were found to be expressed lower in neoplasias relative to normal tissues.

These 560 probesets were annotated using the most recent metadata and annotation packages available for the chips. The 560 underexpressed probesets were mapped to 434 gene symbols.

A-expression ProbeSet ID Gene Symbol Maps DOWN 560 434

Hypothetical markers specificfor colorectalneoplasia While differential gene expression patterns are useful for diagnostic purposes this project also seeks to identify diagnostic proteins shed into the lumen of the gut by neoplastic colorectal epithelia. To discover candidate proteins, the list of differentially expressed transcripts was filtered with a selection criteria aimed at identifying markers specifically turned off in colorectal neoplasia tissues. To identify 'off genes the filter criteria were designed to find genes with i) neoplastic expression levels below a theoretical on/off threshold and ii) normal signals at least 2-fold higher. The expression profile of an example transcript that is 'turned off' in neoplastic tissues is shown in Figure 1.

EXAMPLE2 PROBESETS ELEVATED IN NON-NEOPLASIA RELATIVE TO NEOPLASTIC TISSUES

Differential expression analysis was applied to identify down-regulated probesets in Affymetrix gene chip data measuring RNA concentration in 454 colorectal tissues including 161 adenocarcinoma specimens, 29 adenoma specimens, 42 colitis specimens and 222 non diseased tissues. Using conservative corrections for multiple hypothesis testing and a 2-fold absolute fold change cut-off it was determined that 560 probesets exhibit a decreased expression level in neoplastic tissues relative to non-neoplastic controls. 560 of these probesets have been mapped to 434 putative gene symbols based on transcript nucleotide sequence.

Validation/Hypothesistesting RNA expression levels of these candidates were measured in independently derived clinical specimens. 526 probesets were hybridised to RNA extracts from 68 clinical specimens comprising 19 adenomas, 19 adenocarcinomas, and 30 non-diseased controls using a custom designed 'Adenoma Gene Chip'. Thirty-four (34) probesets were not tested as they were not included on the custom design. It was confirmed that 459 of 526 of the target probesets (or directly related probesets with the same gene locus target) were likewise differentially expressed (P < 0.05) in these independently-derived tissues. The results of differential expression analysis of these 459 probesets is shown in Table 1.

The 372 of the 434 unique gene loci to which the 560 probesets are understood to hybridise were further tested. The remaining 62 gene symbols were not represented in the validation data. It was observed that 328 of 372 gene symbols were represented in the validation data by at least one differentially expressed probeset and many symbols included multiple probesets against regions across the putative locus. A complete list of probesets that bind to target loci is shown in Table 2.

Conclusion The candidate probesets and symbols shown in Tables 1 and 2. respectively, are differentially expressed lower in neoplastic colorectal tissues compared to non-neoplastic controls.

EXAMPLE3 PROBESETS DEMONSTRATING A NON-NEOPLASIA SPECIFIC PROFILE

During analysis of the discovery data, a novel expression profile was observed between neoplastic and non-neoplastic phenotypes. It was hypothesized that a subset of quantitatively differentially expressed probesets are furthermore qualitatively differentially expressed. Such probesets show no evidence of a gene expression activity in neoplastic tissues, i.e. these probesets appear to be expressed above background levels in non-neoplastic tissues only. This observation and the resulting hypothesis are based on two principles:

1. That the majority of human transcripts that are present on a genome-wide GeneChip (e.g. U133) will not likely be expressed in the colorectal mucosa; and

2. That microarray binding intensity for such'off probesets (to labeled cRNA) will reflect technical assay background, i.e. non-specific oligonucleotide binding.

To generate a list of non-neoplasia specific probesets the neoplastic intensity of differentially expressed probesets were compared with a hypothetical background signal threshold from across all probesets on the chip. We note that, by design, all probesets in the candidate pool from which the 'on' transcripts are chosen are at least two fold over-expressed in the non diseased tissues relative to diseased tissues. Combined, these criteria yield the subset of differentially expressed transcript species that are specifically expressed in non-neoplastic tissues.

This analysis demonstrated that 42 probesets corresponding to approximately 41 gene loci exhibit a non-neoplasia specific transcription expression profile.

Validation/Hypothesis Testing The custom gene chip design precludes testing the non-neoplasia-specific probesets using the same principles as used for discovery. In particular, the custom gene chip (by design) does not contain a large pool of probesets anticipated to hybridise to hypothetically 'off/'non transcribed' gene transcripts. This is because the custom gene chip design is heavily biased toward differentially expressed transcripts in colorectal neoplastic tissues.

The usual differential expression testing (limma) was therefore applied to these candidate probesets for specifically expressed in non-neoplastic tissues. Of the 37 (of 42) probesets on the custom gene chip, 33 probesets (or probesets which bind to the same locus) were differentially expressed between the 38 neoplastic tissues (adenoma & cancer) and non neoplastic controls. The results of these validation experiments is shown in Table 3.

It was further aimed to test all probesets which are known to hybridise to the gene loci to which the probesets claimed herein. Of the 41 putative gene loci targeted by the probesets, 33 were present in the validation data. All thirty-three (33) of these 33 (100%) gene symbols demonstrated at least one hybridising probeset which was differentially expressed in the neoplastic tissues. Results for these experiments, including all probesets that bind to each target locus in a differentially expressed manner are shown in Table 4.

EXAMPLE4

MATERIALS AND METHODS FOR EXAMPLES 2 AND 3

Gene expression profiling data measured in 454 colorectal tissue specimens including neoplastic, normal and non-neoplastic disease controls was purchased from GeneLogic Inc (Gaithersburg, MD USA). For each tissue specimen Affymetrix (Santa Clara, CA USA) oligonucleotide microarray data totalling 44,928 probesets (HGU133A & HGU133B, combined), experimental and clinical descriptors, and digitally archived microscopy images of histological preparations was received. Prior to applying discovery methods to these data, extensive quality control methods, including statistical exploration, review of clinical records for consistency and histopathology audit of a random sample of arrays was carried out. Microarrays that did not meet acceptable quality criteria were removed from the analysis.

Hypothesis testing Candidate transcription biomarkers were tested using a custom oligonucleotide microarray of 25-mer oligonucleotide probesets designed to hybridise to candidate RNA transcripts identified during discovery. Differential expression hypotheses were tested using RNA extracts derived from independently collected clinical samples comprising 30 normal colorectal tissues, 19 colorectal adenoma tissues, and 19 colorectal adenocarcinoma tissues. Each RNA extract was confirmed to meet strict quality control criteria.

Colorectaltissue specimens All tissues used for hypothesis testing were obtained from a tertiary referral hospital tissue bank in metropolitan Adelaide, Australia (Repatriation General Hospital and Flinders Medical Centre). Access to the tissue bank for this research was approved by the Research and Ethics Committee of the Repatriation General Hospital and the Ethics Committee of Flinders Medical Centre. Informed patient consent was received for each tissue studied.

Following surgical resection, specimens were placed in a sterile receptacle and collected from theatre. The time from operative resection to collection from theatre was variable but not more than 30 minutes. Samples, approximately 125mm3 (5x5x5mm) in size, were taken from the macroscopically normal tissue as far from pathology as possible, defined both by colonic region as well as by distance either proximal or distal to the pathology. Tissues were placed in cryovials, then immediately immersed in liquid nitrogen and stored at -150°C until processing.

RNA extraction RNA extractions were performed using Trizol(R)reagent (Invitrogen, Carlsbad, CA, USA) as per manufacturer's instructions. Each sample was homogenised in 3 0 0 pL of Trizol reagent using a modified Dremel drill and sterilised disposable pestles. Additional 200pL of Trizol reagent was added to the homogenate and samples were incubated at RT for 10 minutes. 100pL of chloroform was then added, samples were shaken vortexed for 15 seconds, and incubated at RT for 3 further minutes. The aqueous phase containing target RNA was obtained by centrifugation at 12,000 rpm for 15 min, 40C. RNA was then precipitated by incubating samples at RT for 10 min with 250pL of isopropanol. Purified RNA precipitate was collected by centrifugation at 12,000 rpm for 10 minutes, 40C and supernatants were discarded. Pellets were then washed with lmL 75% ethanol, followed by vortexing and centrifugation at 7,500g for 8 min, 40°C. Finally, pellets were air-dried for 5 min and resuspended in 80pL of RNase free water. To improve subsequent solubility samples were incubated at 55°C for 10 min. RNA was quantified by measuring the optical density at A260/280 nm. RNA quality was assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip processing To test hypotheses related to biomarker candidates for colorectal neoplasia RNA extracts were assayed using a custom GeneChip designed by us in collaboration with Affymertix (Santa Clara, CA USA). These custom GeneChips were processed using the standard Affymetrix protocol developed for the HU Gene ST 1.0 array described in (Affy:WTAssay).

Statisticalsoftware and data processing The R statistics environment R and BioConductor libraries (BioConductor, www.bioconductor.org) (BIOC) was used for most analyses. To map probeset IDs to gene symbol on the Custom GeneChip hgul33plus2 library version 2.2.0 was used which was assembled using Entrez Gene data downloaded on Apr 18 12:30:55 2008 (BIOC).

Hypothesis testing of differentially expressed biomarkers To assess differential expression between tissue classes the Student's t test for equal means between two samples or the robust variant provided by the limma library (Smyth)(limma) was used. To mitigate the impact of false discovery due to multiple hypothesis testing, a Bonferroni adjustment to P values in the discovery process (MHT:Bonf) was applied. For hypotheses testing the slightly less conservative multiple hypothesis testing correction of Benjamini & Hochberg, which aims to control the false discovery rate of solutions(MHT:BH), was applied.

Discovery of tissue-specific gene expression patterns Discovery methods using gene expression data often yield numerous candidates, many of which are not suitable for commercial products because they involve subtle gene expression differences that would be difficult to detect in laboratory practice. Pepe et al. note that the 'ideal' biomarker is detectable in tumor tissue but not detectable (at all) in non-tumour tissue (Pepe:biomarker:development.) To bias the discovery toward candidates that meet this criteria, an analysis method was developed that aims to enrich the candidates for biomarkers whose qualitative absence or presence measurement is diagnostic for the phenotype of interest. This method attempts to select candidates that show a prototypical 'turned-on'or'turned-off pattern relative to an estimate of the background/noise expression across the chip. It is theorized that such RNA transcripts are more likely to correlate with downstream translated proteins with diagnostic potential or to predict upstream genomic changes (e.g. methylation status) that could be used diagnostically. This focus on qualitative rather than quantitative outcomes may simplify the product development process for such biomarkers.

The method is based on the assumption that the pool of extracted RNA species in any given tissue (e.g. colorectal mucosae) will specifically bind to a relatively small subset of the full set of probesets on a GeneChip designed to measure the whole genome. On this assumption, it is estimated that most probesets on a full human gene chip will not exhibit specific, high intensity signals.

This observation is utilised to approximate the background or'non-specific binding' across the chip by choosing a theoretical level equal to the value of e.g. lowest 25% quantile of the ranked mean values. This quantile can be arbitrarily set to some level below which there is made a reasonable assumption that the signals do not represent above-background RNA binding. Finally, this background estimate is used as a threshold to estimate the 'OFF' probesets in an experiment for, say, the non-neoplastic tissue specimens.

Conversely, it is further hypothesized that probesets which are 1) expressed above this theoretical threshold level and 2) at differentially higher levels in the tumour specimens may be a tumour specific candidate biomarker. It is noted that in this case the concept of'fold change' thresholds can also be conveniently applied to further emphasize the concept of absolute expression increases in a putatively 'ON' probeset.

Given the assumption of low background binding for a sizeable fraction of the measured probesets, this method was only used in the large GeneLogic data and discovery. To construct a filter for hypothetically 'turned on'biomarker in the GeneLogic discovery data, the mean expression level for all 44,928 probesets across the full range of 454 tissues was estimated. The 44,928 mean values were then ranked and the expression value equivalent to the 25th percentile across the dataset calculated. This arbitrary threshold was chosen because the majority of transcripts (and presumably more than 25%) in a given specimen should exhibit low concentration which effectively transcriptional silence. Thus this threshold represents a conservative upper bound for what is estimated is non-specific, or background, expression.

EXAMPLE5 DNA METHYLATION DATA

Assays were developed for detection of methylation in the promoter regions the eight down regulated genes in Table 5. Methods for bisulphite treatment of DNA and assays for determination of DNA methylation levels, including MSP and COBRA, are described in Clark et al.. (2006).

Five MSP assays used the primer pairs shown in TABLE 7. A control PCR for unbiased amplification of the CAGE gene was used to determine the quantity of input DNA to provide a reference for quantification of the level of methylation of each gene. For PCRs, 25 yL reactions in Biorad iQ SyBr Green Super Mix contained 5ng of bisulphite-treated DNAs (1 ng for cell line assays and 6 ng for clinical specimens) and 200nM of forward and reverse primers. PCR cycling conditions were:

95.0°C for 2 min Followed by 50 cycles of: 95.0°C/15sec Temp°C/30sec 72.0°C/30sec

Where "Temp" is the re-annealing temperature optimised for each gene as shown in Table yy.

For the DF gene, 3 preliminary cycles were done using a 95.0°C melting temperature, followed by 50 cycles with a lower, 84.0°C melting temperature (to reduce nonspecific amplification).

A standard curve was generated using DNA methylated with M.SssI methylase (100% methylated) and DNA that had been in vitro amplified using Phi29 DNA polymerase (0% methylation).

COBRA assays were developed for three genes as shown in TABLE 8. PCRs were setup as above with cycling conditions:

95. 0 °C for 2 min Followed by 50 cycles of: 95.0°C/15sec Temp°C/30sec 72.0°C/30sec

After PCR, 10 yL of PCR product was digested with the appropriate enzyme (TABLE 8), digestion products analysed by gel electrophoresis and methylation levels determined semiquantitatively.

The methylation state of the eight genes was determined in four colorectal cancer cell lines, Caco2, HCT116, HT29 and SW480 as well as normal blood DNA and the normal lung fibroblast cell line, MRC5. The level of methylation in summarised in Table 5. The promoter regions of all eight genes show strong methylation in 2 or 3 of the four colorectal cancer cell lines tested. All showed a lack or low level of methylation in DNA from normal blood DNA and the fibroblast cell line MRC5, except for methylation of DF in MRC5.

For two of these genes, MAMDC2 and GPM6B analysis has been extended to a set of 12 adenoma, 18 cancer and 22 matched normal tissue samples (Figure 2, A and B).

For MAMDC2 quantitative analysis demonstrated that 2 of 12 adenomas and 6 of 18 cancer samples showed elevated methylation compared with the highest level observed in normal tissue samples. Methylation levels of the GPM6B gene were determined by semiquantitative COBRA assays, scored on a scale of 0 to 5 based on visual inspection of restriction digestions. A clear trend toward increasing promoter methylation in progression from normal to adenoma to cancer was evident (Figure 2, panel B).

These data demonstrate for a number of examples of the down-regulated genes that such downregulation in colorectal cancer cell lines and primary neoplasia tissue may be associated with DNA methylation and that assays of DNA methylation can be used to discriminate cancer and normal tissue.

EXAMPLE6

Determine Gene Identity of a Nucleic Acid Sequence of Interest which is Define by an Affymetrix Probeset

BLAST the sequence of interest using online available Basic Local Alignment Search Tools

[BLAST]. e.g. NCBI/BLAST (http://blast.ncbi.nlm.nih.gov/Blast.cgi) (a) Select "Human" in BLAST ASSEMBLED GENOMES on the web page http://blast.nebi.nlm.nih.gov/Blast.cgi (b) Leave the default settings, i.e.: • Database: Genome (all assemblies) • Program: megaBLAST: compare highly related nucleotide sequences • Optional parameters: Expect: 0.01, Filter: default, Descriptions: 100, Alignments: 100 (c) Copy/Paste Sequence into the "BLAST" window (d) Click "Begin Search" (e) Click "View Report"

Assessment ofthe Open BLAST Search Results Multiple significant sequence alignments may be identified when "blasting" the sequence.

Identify gene nomenclature of the identified sequence match (a) Click the link to one of the identified hits (b) The new page will schematically depict the position of the hit on one chromosome. It will be apparent which gene is hit. (c) Retrieve the "hit" sequence clicking on the link (d) Do a search for the gene in the provided "search" window. This provides the gene nucleotide coordinates for the gene.

Determinepromiscuity of Sequence (a) Open the NCBI/BLAST tool, (http://blast.ncbi.nlm.nih.gov/Blast.cgi) (b) Click on "nucleotide Blast" under "basic BLAST" (c) Copy/paste the sequence of interest into the "Query Sequence" window (d) Click "Blast".

Assessment ofthe nBLAST Search Results ofthe Sequence (a) The nBLAST exercise with the Sequence may result in multiple Blast hits of which some accession entry numbers are listed in "Description". (b) These hits should be reviewed.

Determine location of the Sequence in the Gene The Ensembl database is an online database, which produces and maintains automatic annotation selected eukaryotic genomes (www.ensembl.orq/index.html)

Identify location of the Sequence in the Gene (a) Set "Search" to Homo Sapiens, Type "the gene name" in the provided Search Field Ensemble.org/index.html) (b) Click "Go" (c) Click the "vega proteincoding Gene: OTTHUMGOOOOOO144184" link to get an annotation report (d) Click on "Gene DAS Report" to retrieve information regarding Alternative splice site database: Type "the gene name" in search field • Click on "the gene entry" • Scroll down to "evidences" • Review alternative splice sites • Click "Confirmed intron/exons" to get a list of coordinates for the exons & introns.

Alternative splicing and/or transcription

The AceView Database provides curated and non-redundant sequence representation of all public mRNA sequences. The database is available through NCBI: http://www.ncbi.nlm.nih.gov/IEB/Research/Acembly/

Furtherinvestigation ofthe Gene mRNA transcripts (a) Type "the gene name" into the provided "search" field (b) Click "Go" (c) The following information is available from the resulting entry in AceView: • The number of cDNA clones from which the gene is constructed (ie originated from experimental work involving isolation of mRNA) • The mRNAs predicted to be produced by the gene • The existence of non-overlapping alternative exons and validated alternative polyadenylation sites • The existence of truncations • The possibility of regulated alternate expression • Introns recorded as participating in alternatively splicing of the gene (d) Classic splice site motives

Application ofMethod to LOC643911/hCG_1815491

Materials and Methods

ExtractionofRNA

RNA extractions were performed using Trizol(R) reagent (Invitrogen, Carlsbad, CA, USA) as per manufacturer's instructions. Each sample was homogenised in 300pL of Trizol reagent using a modified dremel drill and sterilised disposable pestles. Additional 200pL of Trizol reagent was added to the homogenate and samples were incubated at RT for 10 minutes. 100pL of chloroform was then added, samples were shaken vortexed for 15 seconds, and incubated at RT for 3 further minutes. The aqueous phase containg target RNA was obtained by centrifugation at 12,000 rpm for 15 min, 40- C. RNA was then precipitated by incubating samples at RT for 10 min with 250pL of isopropanol. Purified RNA precipitate was collected by centrifugation at 12,000 rpm for 10 minutes, 40o C and supernatants were discarded. Pellets were then washed withlmL 75% ethanol, followed by vortexing and centrifugation at 7,500g for 8 min, 400 C . Finally, pellets were air-dried for 5 min and resuspended in 80pL of RNase free water. To improve subsequent solubility samples were incubated at 55o C for 10 min. RNA was quantified by measuring the optical density at A260/280 nm. RNA quality was assessed by electrophoresis on a 1.2% agarose formaldehyde gel.

Gene Chip processing

RNA samples to analyze on Human Exon 1.0 ST GeneChips were processed using the Affymetrix WT target labeling and control kit (part# 900652) following the protocol described in (Affymetrix 2007 P/N 701880 Rev.4). Briefly: First cycle cDNA was synthesized from 100ng ribosomal reduced RNA using random hexamer primers tagged with T7 promoter sequence and SuperScript II (Invitrogen, Carlsbad CA), this was followed by DNA Polymerase I synthesis of the second strand cDNA. Anti-sense cRNA was then synthesized using T7 polymerase. Second cycle sense cDNA was then synthesised using SuperScript II, dNTP+ dUTP, and random hexamers to produce sense strand cDNA incorporating uracil. This single stranded uracil containing cDNA was then fragmented using a combination of uracil DNA glycosylase (UDG) and apurinic/ apyrimidinic endonuclease1 (APE 1). Finally the DNA was biotin labelled using terminal deoxynucleotidyl transferase (TdT) and the Affymetrix proprietary DNA Labeling reagent. Hybridization to the arrays was carried out at 45°C for 16 18hours.

Washing and staining of the hybridized GeneChips was carried out using the Affymetrix Fluidics Station 450 and scanned with the Affymetrix Scanner 3000 following recommended protocols.

SYBR green based QuantitativeReal Time-PCR

Quantitative real time polymerase chain reaction was performed on RNA isolated from clinical samples for the amplification and detection of the various hCG_1815491 transcripts.

Firstly cDNA was synthesized from 2ug of total RNA using the Applied Biosystems High Capacity Reverse transcription Kit (P/N 4368814). After synthesis the reaction was diluted 1:2 with water to obtain a final volume of 40ul and lul of this diluted cDNA used in subsequent PCR reactions.

PCR was performed in a 25ul volume using 12.5ul Promega 2x PCR master mix (P/N M7502), 1.5ul 5uM forward primer, 1.5ul 5uM reverse primer, 7.875ul water, 0.625ul of a 1:3000 dilution of 10,000x stock of SYBR green 1 pure dye (Invitrogen P/N S7567), and lul of cDNA.

Cycling conditions for amplification were 950 for 2minutes xl cycle, 95° for 15 seconds and 60° for 1 minute x40 cycles. The amplification reactions were performed in a Corbett Research

Rotor-Gene RG3000 or a Roche LightCycler480 real-time PCR machine. When the Roche LightCycler480 real-time PCR machine was used for amplification the reaction volume was reduced to lOul and performed in a 384 well plate but the relative ratios between all the components remained the same. Final results were calculated using the AACt method with the expression levels of the various hCG_1815491 transcripts being calculated relative to the expression level of the endogenous house keeping gene HPRT.

End-pointPCR

End point PCR was performed on RNA isolated from clinical samples for the various hCG_1815491 transcripts. Conditions were identical to those described for the SYBR green assay above but with the SYBR green dye being replaced with water. The amplification reactions were performed in a MJ Research PTC-200 thermal cycler. 2.5pl of the amplified products were analysed on 2% agarose E-gel (Invitrogen) along with a 100-base pair DNA Ladder Marker.

Results

The nucleotide structure and expression levels of transcripts related to hCG_1815491 was analysed based on the identification of diagnostic utility of Affymetrix probesets 238021_s_at and 238022_at from the gene chip analysis.

The gene hCG_1815491 is currently represented in NCBI as a single RefSeq sequence, XM_93911. The RefSeq sequence of hCG_1815491 is based on 89 GenBank accessions from 83 cDNA clones. Prior to March 2006, these clones were predicted to represent two overlapping genes, LOC388279 and LOC650242 (the latter also known as LOC643911). In March 2006, the human genome database was filtered against clone rearrangements, co aligned with the genome and clustered in a minimal non-redundant way. As a result, LOC388272 and LOC650242 were merged into one gene named hCG_1815491 (earlier references to hCG_1815491 are: LOC388279, LOC643911, LOC650242, XM_944116, AF275804, XM_373688).

It has been determined that the Ref Sequence, which is defined by the genomic coordinates 8579310 to 8562303 on human chromosome 16 as defined by the NCBI contig reference NT_010498.15 I Hsl6_10655, NCBI 36 March 2006 genome encompasses hCG_1815491. The 10 predicted RNA variants derived from this gene have been aligned with the genomic nucleotide sequence residing in the map region 8579310 to 8562303. This alignment analysis revealed the existence of at least 6 exons of which several are alternatively spliced. The identified exons are in contrast to the just 4 exons specified in the NCBI hCG_1815491 RefSeq XM_93911. Two additional putative exons were also identified in the Ref Sequence by examination of included probesets on Affymetrix Genechip HuGene Exon 1.0 that target nucleotide sequences embedded in the Ref Sequence. The identified and expanded exon-intron structure of hCG_1815491 have been used to design specific oligonucleotide primers, which allowed measurement of the expression of RNA variants generated from the Ref Sequence by using PCR-based methodology (Figure 4)

TABLES

The probeset designations include both HG-133plus2 probeset IDs and Human Gene 1.OST array probe ids. The latter can be conveniently mapped to Transcript Cluster ID using the Human Gene 1.OST probe tab file provided by Affymetrix (http://www.affymetrix.com/Auth/analysis/downloads/na22/wtgene/HuGene-I 0-st vi.probe.tab.zip). Using publicly available software such as NetAffx (provided by Affymetrix), the Transcript Cluster ID may be further mapped to gene symbol, chromosomal location, etc.

Table 1

Probesets demonstrated to be expressed higher in non-neoplastic tissues relative to neoplastic controls. TargetPS: Affymetrix HG-Ul33plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id - multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of non-neoplasia vs. neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 2

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting RNA concentration differences between non-neoplastic tissues and neoplastic controls. Symbol: gene symbol; ValidPSDOWN: Affymetrix probeset IDs demonstrating statistically significant overexpression in non-neoplastic RNA extracts relative to neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of non neoplasia vs. neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 3

Probesets which demonstrate a qualitatively (in addition to quantitative) elevated profile in non-neoplastic tissues relative to neoplastic controls. TargetPS: Affymetrix HG-U33plus2 probeset id; Symbol: putative gene symbol corresponding to target probeset id - multiple symbol names indicate the possibility of probeset hybridisation to multiple gene targets; Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of non neoplasia vs. neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Table 4

Evidence of multiple probesets which correspond to gene symbols claimed herein exhibiting qualitative changes in RNA concentration in non-neoplastic tissues compared to neoplastic tissues. Symbol: gene symbol; ValidPSDOWN: Affymetrix probeset IDs demonstrating statistically significant overexpression in neoplastic RNA extracts relative to non-neoplastic controls. Signif. FDR: Adjusted p-value for mean difference testing between RNA extracted from neoplasia and non-neoplastic tissues. Adjustment is made using Benjamini & Hochberg correction for multiple hypothesis testing (Benjamini and Hochberg, 1995); D.value50: Diagnostic effectiveness parameter estimate corresponding to the area of a receiver operator characteristic ROC. This parameter provides a convenient estimate of diagnostic utility and is described in (Saunders, 2006); FC: fold change between mean expression level of non neoplasia vs. neoplasia; Sens-Spec: Estimate of diagnostic performance corresponding to the ROC curve point demonstrating equal sensitivity and specificity; CI (95): 95% confidence interval of sensitivity and specificity estimates.

Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

TABLE 1

TargetPS Symbol Signif. FDR D.va15 FC Sens- CI (95) Spec 230788_at SPTLC3:GCNT2 2.16E-27 3.9512 13.36 97.6 94.2-99.2 207502at GUCA2B 7.04E-25 3.6279 51.78 96.5 92.3-98.6 207003_at GUCAIB 7.32E-25 3.565 10.7 96.3 92-98.5 206208_at CA4 1.73E-24 3.6263 10.41 96.5 92.4-98.6 206209_s at CA4 1.73E-24 3.6265 10.41 96.5 92.3-98.6 203908_at LOC727995:SLC4A4:LOC730 2.23E-23 3.6298 3.58 96.5 92.4-98.6 895 206784_at AQP8 2.98E-22 3.3284 10.82 95.2 90.3-97.9 205950_s at CAI 3.15E-22 3.368 38.27 95.4 90.6-98 209735_at ABCG2 1.09E-21 3.2584 31.53 94.8 89.7-97.7 230830_at OSTbeta 6.23E-21 3.1861 7.15 94.4 89.2-97.5 223754_at MGC13057 6.94E-21 3.2036 3.18 94.5 89.3-97.5 228195_at MGC13057 6.94E-21 3.2023 3.18 94.5 89.4-97.5 228706sat CLDN23 4.27E-20 3.0757 3.47 93.8 88.2-97.1 228707at CLDN23 4.27E-20 3.072 3.47 93.8 88.3-97.1 223551_at PKIB 5.94E-20 3.1219 3.28 94.1 88.6-97.3 231120_x_at PKIB 5.94E-20 3.1226 3.28 94.1 88.6-97.3 226492_at SEMA6D 6.07E-20 3.0898 4.27 93.9 88.4-97.2 220026_at CLCA4 1.25E-19 3.1909 16.3 94.5 89.2-97.5 224836 at TP53INP2 1.45E-19 3.0248 3.78 93.5 87.9-96.9 220834_at MS4A12 2.13E-19 3.29 7.15 95 90-97.8 224412s_ at TRPM6 2.25E-19 3.01 7.5 93.4 87.7-96.8 220037_s_at XLKD1 3.60E-19 2.9412 7.44 92.9 87.1-96.6 219059_s_at XLKD1 3.60E-19 2.942 7.44 92.9 87-96.6 209612_s_at ADH1B:ADH1A 4.70E-19 3.0183 4.67 93.4 87.7-96.9 209613_s_at ADHIB:ADH1A 4.70E-19 3.0147 4.67 93.4 87.7-96.9 200845_s at LOC389249:PRDX6 5.56E-19 2.8412 2.76 92.2 86.1-96.1 209301_at CA2 5.87E-19 2.9662 9.22 93.1 87.3-96.7 208399_s_at EDN3 6.42E-19 2.9342 11.21 92.9 87-96.5 228961_at MIER3 9.14E-19 2.9183 3.91 92.8 86.9-96.5 231975_s_at MIER3 9.14E-19 2.9172 3.91 92.8 86.8-96.4 204719_at ABCA8 1.26E-18 2.9172 6.82 92.8 86.8-96.5 207761s at METTL7A 1.35E-18 3.1247 1.93 94.1 88.6-97.3 207977_s_at DPT 1.53E-18 2.8967 9.07 92.6 86.6-96.4 213068_at DPT 1.53E-18 2.8973 9.07 92.6 86.7-96.4 213071_at DPT 1.53E-18 2.8962 9.07 92.6 86.7-96.4 218756_s_at MRMI:MGC4172 1.74E-18 2.9041 3.74 92.7 86.6-96.4 212288_at FNBP1:Clorf85:CCT3 1.76E-18 3.0475 2.04 93.6 88-97 204036_at EDG2 2.44E-18 2.8853 3.19 92.5 86.4-96.3 202037_s at SFRP1 2.77E-18 2.8647 15.53 92.4 86.3-96.2 206143_at SLC26A3 4.18E-18 2.9202 21.4 92.8 86.9-96.5 215657at SLC26A3 4.18E-18 2.9226 21.4 92.8 86.9-96.5 231773_at ANGPTL1 1.42E-17 2.7938 4.64 91.9 85.6-95.9 205480 s at UGP2 1.64E-17 2.7911 2.41 91.9 85.6-95.9

204955_at SRPX 1.79E-17 2.7753 3.91 91.7 85.5-95.8 222722_at OGN 2.25E-17 2.7048 13.67 91.2 84.8-95.4 202555_s at MYLK 2.33E-17 2.773 3.99 91.7 85.4-95.8 224823_at MYLK 2.33E-17 2.7727 3.99 91.7 85.4-95.8 225575_at LIFR 2.45E-17 2.7823 6.36 91.8 85.5-95.8 214142_at LOC653808:ZG16 2.51E-17 2.8119 8.14 92 85.8-95.9 206710 _s _at EPB41L3 2.62E-17 2.8298 2.51 92.1 85.9-96.1 205464_at SCNN1B 3.20E-17 2.7209 16.15 91.3 84.9-95.5 220812_s at HHLA2 3.47E-17 2.6717 10.02 90.9 84.4-95.3 203913_s at HPGD 3.65E-17 2.8441 3.21 92.2 86.1-96.1 203914_x_at HPGD 3.65E-17 2.8456 3.21 92.3 86.1-96.1 211548_s_at HPGD 3.65E-17 2.8446 3.21 92.3 86.1-96.1 211549_s_at HPGD 3.65E-17 2.8466 3.21 92.3 86.1-96.1 206198_s_at CEACAM7 3.96E-17 2.7882 10.4 91.8 85.5-95.9 206199 at CEACAM7 3.96E-17 2.7855 10.4 91.8 85.6-95.8 211848_s at CEACAM7 3.96E-17 2.7882 10.4 91.8 85.6-95.8 226430_at SMAD5:RELL1 4.10E-17 2.6968 2.5 91.1 84.6-95.4 202992_at C7 4.40E-17 2.7163 6.67 91.3 84.9-95.5 205112_at PLCE1 6.91E-17 2.7542 2.43 91.6 85.2-95.7 229839_at SCARA5 1.25E-16 2.6897 2.86 91.1 84.6-95.3 235849_at SCARA5 1.25E-16 2.6918 2.86 91.1 84.5-95.3 209763_at CHRDL1 1.49E-16 2.6093 13.88 90.4 83.7-94.9 205259_at NR3C2 2.08E-16 2.5812 3.19 90.2 83.4-94.7 202242_at TSPAN7 2.13E-16 2.6519 3.68 90.8 84.1-95.1 203000_at STMN2 2.25E-16 2.6115 6.13 90.4 83.7-94.9 203001_s_at STMN2 2.25E-16 2.6141 6.13 90.4 83.7-94.9 209074_s at FAM107A 2.52E-16 2.6171 2.92 90.5 83.8-94.9 202920 at ANK2 2.59E-16 2.6499 6.76 90.7 84.1-95.1 213317_at CLIC5 3.68E-16 2.696 2.37 91.1 84.6-95.4 204697_s_at CHGA 5.54E-16 2.6087 7.21 90.4 83.7-94.9 212814_at KIAA0828 5.58E-16 2.5495 4.09 89.9 83-94.5 225275_at EDIL3 6.21E-16 2.6252 2.96 90.5 83.9-95 208370_s_at DSCR1 6.21E-16 2.6146 2.14 90.4 83.7-94.9 209147_s_at PPAP2A 6.43E-16 2.5961 2.4 90.3 83.6-94.8 210946at PPAP2A 6.43E-16 2.5967 2.4 90.3 83.5-94.8 202731_at PDCD4 8.67E-16 2.4558 2.6 89 82-94 219799 s at DHRS9:GORASP2 1.09E-15 2.7368 1.51 91.4 85.1-95.6 223952_x_at DHRS9:GORASP2 1.09E-15 2.7334 1.51 91.4 85-95.6 224009_x at DHRS9:GORASP2 1.09E-15 2.7359 1.51 91.4 85.1-95.6 236313_at CDKN2B 1.34E-15 2.5442 10.09 89.8 83-94.5 231925_at P2RY1 1.41E-15 2.5354 3.6 89.8 82.9-94.4 238143_at LOC646627 1.58E-15 1.9142 5.02 83.1 74.8-89.4 224480_s at LPAAT-THETA 2.06E-15 2.3867 2.63 88.4 81.1-93.5 212230_at PPAP2B 2.44E-15 2.5821 1.81 90.2 83.4-94.7 207080_s_at PYY 3.50E-15 2.4811 11.71 89.3 82.3-94.1 205200_at CLEC3B 4.65E-15 2.4426 4.46 88.9 81.8-93.8 228133 s at NDE1 4.84E-15 2.514 1.99 89.6 82.7-94.3 214038_at CCL8 5.75E-15 2.4504 7.51 89 81.9-93.9 219014 at PLAC8 5.76E-15 2.4248 3.87 88.7 81.6-93.7

219796 s at MUCDHL 5.81E-15 2.4346 3.06 88.8 81.6-93.8 220075_s_at MUCDHL 5.81E-15 2.4354 3.06 88.8 81.7-93.8 215299_x_at SULTlA1:SULT1A2 7.17E-15 2.4231 3.37 88.7 81.5-93.7 233565sat SDCBP2 9.28E-15 2.4871 2.37 89.3 82.3-94.1 228885_at RPL24:LOC731365 1.23E-14 2.5555 1.63 89.9 83.1-94.6 209687_at CXCL12 1.54E-14 2.4322 3.79 88.8 81.7-93.8 218546_at Clorfl15 1.95E-14 2.4106 2.95 88.6 81.4-93.6 205097at SLC26A2 2.08E-14 2.4219 7.83 88.7 81.5-93.7 224959at SLC26A2 2.08E-14 2.4229 7.83 88.7 81.6-93.7 224963at SLC26A2 2.08E-14 2.4205 7.83 88.7 81.5-93.7 204069 at MEISI 2.49E-14 2.3759 5.44 88.3 81-93.4 223121_s_at SFRP2 3.05E-14 2.3937 7.39 88.4 81.2-93.5 223122_s_at SFRP2 3.05E-14 2.3967 7.39 88.5 81.2-93.5 209191 at TUBB3:MC1R:TUBB6 3.55E-14 2.3684 5.9 88.2 80.9-93.3 201348_at GPX3 5.68E-14 2.36 2.57 88.1 80.8-93.2 214091_s at GPX3 5.68E-14 2.3613 2.57 88.1 80.7-93.3 228766_at CD36 6.27E-14 2.4671 1.65 89.1 82.1-94 221896_s_at HIGD1A 6.29E-14 2.3985 2.09 88.5 81.3-93.5 201865_x_at NR3C1 7.65E-14 2.3539 2.51 88 80.6-93.2 211671_s at NR3C1 7.65E-14 2.3517 2.51 88 80.7-93.2 206149at LOC63928 8.09E-14 2.3513 3.2 88 80.7-93.2 228846_at MXD1 8.35E-14 2.4074 2.11 88.6 81.4-93.6 225602 at C9orfl9 1.74E-13 2.3619 1.95 88.1 80.9-93.3 225604_s_at C9orfl9 1.74E-13 2.3646 1.95 88.1 80.8-93.3 201893_x_at DCN 2.05E-13 2.311 5.62 87.6 80.2-92.9 209335_at DCN 2.05E-13 2.3115 5.62 87.6 80.3-92.9 211813_x at DCN 2.05E-13 2.3145 5.62 87.6 80.2-92.9 211896_s at DCN 2.05E-13 2.3124 5.62 87.6 80.2-92.9 204818_at HSD17B2 2.32E-13 2.196 4.76 86.4 78.7-92 204931_at TCF21 2.51E-13 2.306 2.34 87.6 80.1-92.9 204438_at MRC1 2.72E-13 2.3105 2.6 87.6 80.2-92.9 206262at ADH1A:ADH1C 2.94E-13 2.3719 3.1 88.2 80.9-93.3 205433_at BCHE 3.18E-13 2.2514 6.21 87 79.5-92.5 225242sat CCDC80 3.60E-13 2.2316 3.67 86.8 79.2-92.3 207980 s at CITED2 5.29E-13 2.2709 1.64 87.2 79.7-92.6 209357_at CITED2 5.29E-13 2.2704 1.64 87.2 79.7-92.6 208383_s_at PCK1 5.74E-13 2.3242 3.6 87.7 80.4-93 206385_s_at ANK3:LOC729184:LOC7311 7.46E-13 2.2305 2.45 86.8 79.2-92.2 86 203305_at F13A1 8.82E-13 2.1821 4.74 86.2 78.6-91.8 206134_at ADAMDEC1 9.04E-13 2.2607 3.19 87.1 79.5-92.5 215118 s at AHNAK:IGHG1 9.41E-13 2.3277 1.73 87.8 80.3-93 217022_s at AHNAK:IGHG1 9.41E-13 2.3254 1.73 87.8 80.4-93 223395_at ABI3BP 9.47E-13 2.2207 3.62 86.7 79-92.2 225626_at PAGI 1.11E-12 2.2136 2.68 86.6 78.9-92.1 213953_at KRT20 1.26E-12 2.0964 5.49 85.3 77.4-91.1 226594_at ENTPD5 1.43E-12 2.1687 3.01 86.1 78.4-91.8 209373_at MALL 2.10E-12 2.1597 3.96 86 78.3-91.7 212713 at MFAP4 2.96E-12 2.1797 2.51 86.2 78.5-91.9

208920_at SRI 3.03E-12 2.0982 2.43 85.3 77.4-91.1 201739_at SGK 3.12E-12 2.1221 4.08 85.6 77.8-91.3 214696_at MGC14376 3.39E-12 2.1045 2.58 85.4 77.5-91.2 204034_at ETHEl 3.46E-12 2.2127 1.75 86.6 79-92.1 209667_at CES2 3.51E-12 2.102 2.87 85.3 77.4-91.2 209668_x_at CES2 3.51E-12 2.0978 2.87 85.3 77.4-91.1 213509 _x_at CES2 3.51E-12 2.097 2.87 85.3 77.4-91.1 202291_s_at MGP:Cl2orf46 3.63E-12 2.1448 4.68 85.8 78-91.5 209167_at GPM6B 4.04E-12 2.1568 3.59 86 78.2-91.6 209170 s at GPM6B 4.04E-12 2.1581 3.59 86 78.2-91.6 225720at SYNPO2 5.07E-12 2.1053 6.43 85.4 77.5-91.2 225721_at SYNPO2 5.07E-12 2.1069 6.43 85.4 77.5-91.2 225894_at SYNPO2 5.07E-12 2.1043 6.43 85.4 77.5-91.2 225895_at SYNPO2 5.07E-12 2.1069 6.43 85.4 77.5-91.2 227662 at SYNPO2 5.07E-12 2.1043 6.43 85.4 77.5-91.2 206422 at GCG 5.58E-12 2.1185 12.56 85.5 77.7-91.3 205593_s at PDE9A 6.56E-12 2.1443 3.91 85.8 78-91.5 220376_at LRRC19 6.75E-12 2.076 4.51 85 77.1-91 204130_at HSD11B2 6.97E-12 2.0896 2.53 85.2 77.3-91.1 224964s at GNG2 7.25E-12 2.1405 1.91 85.8 78-91.5 219508_at GCNT3 8.39E-12 2.0843 3.94 85.1 77.2-91 211645 x at No Symbol 9.19E-12 2.1536 1.61 85.9 78.2-91.6 212233_at No Symbol 9.19E-12 2.1541 1.61 85.9 78.1-91.6 212764_at No Symbol 9.19E-12 2.1541 1.61 85.9 78.1-91.6 214777_at No Symbol 9.19E-12 2.1543 1.61 85.9 78.2-91.6 217235_xat No Symbol 9.19E-12 2.155 .1.61 85.9 78.2-91.6 225710_at No Symbol 9.19E-12 2.1539 1.61 85.9 78.1-91.6 226333_at No Symbol 9.19E-12 2.1529 1.61 85.9 78.1-91.6 226834_at No Symbol 9.19E-12 2.154 1.61 85.9 78.1-91.6 227061_at No Symbol 9.19E-12 2.152 1.61 85.9 78.1-91.6 228504_at No Symbol 9.19E-12 2.1533 1.61 85.9 78.1-91.6 228507_at No Symbol 9.19E-12 2.1538 1.61 85.9 78.2-91.6 228640_at No Symbol 9.19E-12 2.1532 1.61 85.9 78.2-91.6 228854_at No Symbol 9.19E-12 2.1532 1.61 85.9 78.2-91.7 236300_at No Symbol 9.19E-12 2.1532 1.61 85.9 78.2-91.6 242317_at No Symbol 9.19E-12 2.1529 1.61 85.9 78.1-91.6 210524_x at No Symbol 9.19E-12 2.1554 1.61 85.9 78.2-91.7 224989_at No Symbol 9.19E-12 2.1526 1.61 85.9 78.2-91.6 227052_at No Symbol 9.19E-12 2.151 1.61 85.9 78.1-91.6 227682_at No Symbol 9.19E-12 2.1549 1.61 85.9 78.2-91.6 235146at No Symbol 9.19E-12 2.1527 1.61 85.9 78.2-91.7 207126_x_at UGT1A1O:UGT1A7:UGT1A8: 9.98E-12 2.0677 4.56 84.9 77-90.9 UGT1A1:UGTIA9:UGTlA6: UGT1A5:UGT1A3:UGT1A4 206094_x_at UGT1A1O:UGT1A7:UGT1A8: 1.01E-11 2.0693 4.56 85 77-90.8 UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGTIA4 208596_s_at UGTlA10:UGTIA7:UGTIA8: L.O1E-11 2.0662 4.56 84.9 76.9-90.8 UGT1A1:UGTIA9:UGTIA6: UGT1A5:UGT1A3:UGT1A4

221305_sat UGT1A1O:UGT1A7:UGT1A8: 1.03E-11 2.0663 4.56 84.9 77-90.9 UGTIAI:UGT1A9:UGTIA6: UGT1A5:UGT1A3:UGTIA4 204532_x_at UGTIA1O:UGTlA7:UGT1A8: 1.18E-11 2.0678 4.56 84.9 77-90.9 UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGTIA4 215125_s_at UGT1A1O:UGT1A7:UGTIA8: 1.18E-11 2.0682 4.56 84.9 77-90.9 UGT1A1:UGT1A9:UGT1A6: UGT1A5:UGT1A3:UGT1A4 209791_at PADI2 1.46E-11 2.0258 3.98 84.4 76.4-90.5 219669 at CD177 1.49E-11 2.0618 5.77 84.9 76.9-90.8 201539_s_at FHL1 1.63E-11 2.0448 3.25 84.7 76.7-90.7 201540at FHL1 1.63E-11 2.0466 3.25 84.7 76.7-90.7 210298_x_at FHL1 1.63E-11 2.0438 3.25 84.7 76.7-90.6 210299_s at FHL1 1.63E-11 2.0458 3.25 84.7 76.6-90.6 214505 s at FHL1 1.63E-11 2.0459 3.25 84.7 76.7-90.6 206576_s at CEACAMI 2.66E-11 2.0448 2.85 84.7 76.7-90.7 209498_at CEACAMI 2.66E-11 2.0446 2.85 84.7 76.7-90.7 211889_x at CEACAMI 2.66E-11 2.0471 2.85 84.7 76.7-90.7 202994_s_at FBLN1 2.82E-11 2.0183 3.55 84.4 76.3-90.4 202995_s_at FBLN1 2.82E-11 2.0191 3.55 84.4 76.3-90.4 201427_s at SEPPI 2.83E-11 2.034 4.15 84.5 76.5-90.6 212956_at TBC1D9 3.89E-11 2.1428 1.54 85.8 78-91.5 203963_at CA12 4.32E-11 2.0024 2.65 84.2 76.1-90.2 204508 s at CA12 4.32E-11 2.0029 2.65 84.2 76.2-90.3 210735_s_at CA12 4.32E-11 2.0016 2.65 84.2 76.1-90.2 214164_x at CA12 4.32E-11 2.0016 2.65 84.2 76.1-90.3 215867_x_at CA12 4.32E-11 2.0027 2.65 84.2 76.1-90.3 203881_s at DMD 5.01E-11 2.0159 4.74 84.3 76.2-90.4 213624_at SMPDL3A 5.84E-11 1.9409 3.14 83.4 75.2-89.6 226304_at HSPB6 6.16E-11 1.9486 6.88 83.5 75.4-89.8 206561_s_at LOC441282:AKR1B1O:LOC3 7.91E-11 1.9478 5.17 83.5 75.3-89.7 40888 203343at UGDH 8.72E-11 1.9619 2.4 83.7 75.6-89.9 205892_s at FABP1 9.02E-11 1.9694 6.54 83.8 75.6-89.9 206637at P2RY14 1.31E-10 1.9821 2 83.9 75.8-90.1 202266_at TTRAP 1.59E-10 1.9147 2.2 83.1 74.9-89.4 206000_at LOC642840:MEP1A:LOC389 2.07E-10 1.9873 3.17 84 75.9-90.1 747:LOC644777 201496_x_at MYHIl 2.15E-10 1.8577 5.35 82.4 74-88.8 201497_x at MYHI1 2.15E-10 1.8599 5.35 82.4 74.1-88.8 207961_x at MYH1l 2.15E-10 1.859 5.35 82.4 74.1-88.9 201495 x at MYHI1 2.15E-10 1.8585 5.35 82.4 74-88.8 204388_s_at MAOA 2.49E-10 2.0297 2.18 84.5 76.4-90.5 204389_at MAOA 2.49E-10 2.0256 2.18 84.4 76.5-90.5 212741_at MAOA 2.49E-10 2.0267 2.18 84.5 76.5-90.5 214598_at CLDN8 2.92E-10 1.862 12.96 82.4 74.2-88.9 202838_at FUCAl 4.24E-10 1.8831 2.03 82.7 74.4-89.1 217897_at MB:FXYD6 6.39E-10 1.8109 2.92 81.7 73.3-88.3 220468_at ARL14 7.01E-10 1.8242 3.06 81.9 73.5-88.4 201920 at SLC20A1 7.65E-10 1.7849 4.04 81.4 72.9-88.1

210302 s at MAB21L2 1.05E-09 1.7744 5.2 81.3 72.8-87.9 209114_at TSPAN1 1.16E-09 1.7896 2.16 81.5 73-88.1 220266_s_at KLF4 1.19E-09 1.8515 2.27 82.3 73.8-88.7 221841_s_at KLF4 1.19E-09 1.8493 2.27 82.2 73.9-88.8 209283_at CRYAB 1.47E-09 1.7693 3.91 81.2 72.7-87.8 223484_at C15orf48 1.54E-09 1.8189 3.07 81.8 73.4-88.4 205412_at ACATI 1.70E-09 1.8575 1.77 82.3 73.9-88.8 202888_s_at ANPEP 2.04E-09 1.7673 8.18 81.2 72.6-87.8 225458 at EXOC3 2.25E-09 1.7957 3.17 81.5 73.1-88.1 204834_at FGL2 2.64E-09 1.8245 2.07 81.9 73.4-88.5 227265_at FGL2 2.64E-09 1.8246 2.07 81.9 73.6-88.4 228469_at PPID 3.34E-09 1.8032 1.73 81.6 73.2-88.3 221004_s at ITM2C 3.87E-09 1.7063 2.22 80.3 71.8-87.1 213921_at SST 4.16E-09 1.7652 6.14 81.1 72.6-87.8 230087_at PRIMA1 4.74E-09 1.7085 2.75 80.4 71.8-87.2 201842_s at EFEMPI 5.80E-09 1.8196 1.69 81.9 73.4-88.4 222162_s at ADAMTS1 6.42E-09 1.7467 2.37 80.9 72.3-87.6 210517_s at AKAP12 7.41E-09 1.7454 2.83 80.9 72.3-87.6 227529_s_at AKAP12 7.41E-09 1.7437 2.83 80.8 72.3-87.6 228750_at COL14A1 7.60E-09 1.7813 1.67 81.3 72.9-88 219948x_at LOC642329:UGT2A3 8.64E-09 1.7422 4.89 80.8 72.2-87.5 208131 s at PTGIS 9.15E-09 1.7212 3.98 80.5 71.9-87.3 207432_at BTN2A2:BEST2 9.19E-09 1.7179 3.63 80.5 71.9-87.3 219607 s at MS4A4A:LOC643680 9.59E-09 1.8197 1.55 81.9 73.4-88.4 204688_at SGCE 1.02E-08 1.7438 2.03 80.8 72.3-87.6 207134 x at TPSB2 1.24E-08 1.3713 1.87 75.4 66.3-82.9 209156sat COL6A2 1.30E-08 1.68 2.08 80 71.3-86.8 202741_at PRKACB 1.30E-08 1.7217 2.18 80.5 71.9-87.3 202742 s at PRKACB 1.30E-08 1.721 2.18 80.5 71.9-87.3 200795_at SPARCL1 1.33E-08 1.6379 2.85 79.4 70.7-86.3 219543_at PBLD 1.38E-08 1.6981 2.74 80.2 71.6-87.1 225207_at PDK4 1.45E-08 1.705 3.02 80.3 71.7-87.2 202222_s at SPEG:LOC729871:DES 1.47E-08 1.7229 6.66 80.6 72-87.3 214027 x at SPEG:LOC729871:DES 1.47E-08 1.7254 6.66 80.6 72-87.4 239272 at MMP28 1.80E-08 1.6622 2.47 79.7 71-86.6 222453_at THEM4:CYBRD1 1.84E-08 1.6934 2.7 80.1 71.6-87 212195_at MAGEA4:IL6ST 1.87E-08 1.764 1.58 81.1 72.6-87.8 203980_at FABP4 2.01E-08 1.6762 5.55 79.9 71.3-86.8 211985_s at CALMI - 2.12E-08 1.6839 1.72 80 71.4-86.9 221747_at TNS1:AKAP9 2.21E-08 1.7434 2.01 80.8 72.2-87.5 221748s at TNS1:AKAP9 2.21E-08 1.7409 2.01 80.8 72.3-87.5 201324_at EMPI 2.59E-08 1.7149 1.95 80.4 71.9-87.3 212397_at LOC643244:RDX 3.06E-08 1.7431 1.9 80.8 72.3-87.6 205382 s at CFD 3.06E-08 1.6462 2.81 79.5 70.8-86.4 201141 at GPNMB 3.11E-08 1.6928 1.99 80.1 71.5-87 205683_x at TPSAB1,TPSAB1 3.52E-08 1.7075 1.93 80.3 71.8-87.1 210084 x at TPSAB1,TPSAB1 3.52E-08 1.7045 1.93 80.3 71.8-87.1 215382_x at TPSAB1,TPSAB1 3.52E-08 1.7091 1.93 80.4 71.7-87.2 216474 x at TPSAB1,TPSAB1 3.52E-08 1.7069 1.93 80.3 71.7-87.2

227006_at PPP1R14A 3.54E-08 1.619 2.51 79.1 70.3-86.1 242601_at LOC253012 3.59E-08 1.6517 4.46 79.6 70.8-86.5 212730_at DMN 4.36E-08 1.6046 4.05 78.9 70.2-86 226818_at MPEG1 4.58E-08 1.6466 1.86 79.5 70.8-86.5 226841 at MPEG1 4.58E-08 1.6484 1.86 79.5 70.8-86.5 203474_at IQGAP2 5.06E-08 1.6275 2.51 79.2 70.6-86.2 203766_s_at LMOD1 5.55E-08 1.58 2.97 78.5 69.8-85.6 214916_x_at LOC652128:IGHG1:IGHM:IG 5.75E-08 1.6352 3.1 79.3 70.6-86.3 HV4-31:LOC647189:IGHV1 69:IGHA1:IL8:EXOC7:SIX6:I GHD:IGH@:IGHG3:Cl2orf32 :ZCWPW2:IF16:IGHG4:IGHA 2:IGHG2:RAC1 226303_at PGM5 5.87E-08 1.6215 5.87 79.1 70.4-86.2 225442_at DDR2 5.89E-08 1.562 2.61 78.3 69.4-85.4 227561_at DDR2 5.89E-08 1.5604 2.61 78.2 69.4-85.5 202760_s_at AKAP2:PALM2:PALM2- 6.28E-08 1.6137 2.17 79 70.3-86.1 AKAP2 226694_at AKAP2:PALM2:PALM2- 6.28E-08 1.6143 2.17 79 70.2-86.1 AKAP2 204894_s_at AOC3 6.43E-08 1.556 2.92 78.2 69.4-85.4 203058_s_at PAPSS2 6.43E-08 1.6171 1.97 79.1 70.4-86.1 203060_s_at PAPSS2 6.43E-08 1.6159 1.97 79 70.4-86.1 208763_s_at TSC22D3 7.22E-08 1.6098 2.76 79 70.2-86 222717at SDPR 9.62E-08 1.5998 2.21 78.8 70.1-85.9 203680at PRKAR2B 1.05E-07 1.6759 2.1 79.9 71.2-86.8 201041_s_at DUSPI 1.06E-07 1.5295 2.44 77.8 68.9-85 209374_s_at LOC652128:IGHG1:IGHM:IG 1.12E-07 1.6333 3.1 79.3 70.6-86.3 HV4-31:LOC647189:IGHV1 69:IGHA1:IL8:EXOC7:SIX6:I GHD:IGH@:IGHG3:C12orf32 :ZCWPW2:IF16:IGHG4:IGHA 2:IGHG2:RAC1 216491_x_at LOC652128:IGHG1:IGHM:IG 1.12E-07 1.6335 3.1 79.3 70.5-86.3 HV4-31:LOC647189:IGHV1 69:IGHA1:IL8:EXOC7:SIX6:I GHD:IGH@:IGHG3:Cl2orf32 :ZCWPW2:IF16:IGHG4:IGHA 2:IGHG2:RAC1 229831_at CNTN3 1.20E-07 1.6157 3.93 79 70.2-86.1 235766xat RAB27A 1.22E-07 1.5984 1.79 78.8 70.1-85.9 229070at C6orflO5 1.38E-07 1.6049 2.13 78.9 70.1-86 226654 at MUC12 1.53E-07 1.4559 4.89 76.7 67.7-84.1 202686_s_at AXL 1.59E-07 1.5758 1.71 78.5 69.7-85.6 205403_at IL1R2 1.73E-07 1.5237 2.54 77.7 68.8-84.9 211372_s at IL1R2 1.73E-07 1.5229 2.54 77.7 68.7-85 205929at GPA33 1.86E-07 1.7056 1.61 80.3 71.7-87.2 202069_s at IDH3A 2.08E-07 1.5696 1.75 78.4 69.5-85.5 202350_s at MATN2 2.11E-07 1.506 2.23 77.4 68.4-84.7 212859 x at NUTF2:MT1E:MT1M 2.14E-07 1.6442 2.41 79.4 70.8-86.4 217546_at NUTF2:MT1E:MT1M 2.14E-07 1.645 2.41 79.5 70.7-86.5 216336_x at NUTF2:MT1E:MT1M 2.14E-07 1.645 2.41 79.5 70.8-86.4

221667_s_at HSPB8 2.61E-07 1.514 3.85 77.5 68.6-84.8 217757_at A2M 2.72E-07 1.598 1.64 78.8 70.1-85.9 216510_x_at LOC652128:IGHG1:IGHM:IG 2.80E-07 1.6346 3.1 79.3 70.6-86.4 HV4-31:LOC647189:IGHV1 69:IGHA1:IL8:EXOC7:SIX6:I GHD:IGH@:IGHG3:Cl2orf32 :ZCWPW2:IFI6:IGHG4:IGHA 2:IGHG2:RAC1 223343_at NYD-SP21:MS4A7 2.92E-07 1.5396 2.27 77.9 69.1-85.1 202620_s at PLOD2 3.06E-07 1.5551 2.33 78.2 69.3-85.4 207245at UGT2B17 3.75E-07 1.4796 4.88 77 68.1-84.5 210139_s at PMP22 3.97E-07 1.5183 2.23 77.6 68.7-84.9 204938_s_at PLN 4.14E-07 1.5454 2.01 78 69.1-85.2 204939_s_at PLN 4.14E-07 1.5425 2.01 78 69.1-85.2 204940_at PLN 4.14E-07 1.5436 2.01 78 69.1-85.2 203951 at CNN1 4.77E-07 1.4324 4.56 76.3 67.3-83.8 202746_at ITM2A 5.27E-07 1.4988 2.77 77.3 68.4-84.6 221584_s at KCNMA1 6.86E-07 1.4959 2.37 77.3 68.4-84.6 241994_at XDH 8.13E-07 1.4709 2.03 76.9 67.9-84.3 209621 s at PDLIM3 8.20E-07 1.4805 2.38 77 68-84.4 204326 x at LOC645652:MT1X 9.84E-07 1.4427 4.35 76.5 67.4-83.9 208581 x at LOC645652:MT1X 9.84E-07 1.4397 4.35 76.4 67.5-83.9 201616 s at CALDI 1.02E-06 1.4583 3.29 76.7 67.8-84.1 201617_x at CALDI 1.02E-06 1.4617 3.29 76.8 67.7-84.1 212077_at CALDI 1.02E-06 1.4581 3.29 76.7 67.8-84.1 225782_at MSRB3 1.20E-06 1.4747 2.24 77 68-84.3 209436 at SPONI 1.46E-06 1.4849 1.88 77.1 68.1-84.4 223623_at C2orf4O 1.69E-06 1.416 2.97 76.1 67-83.5 218087_s at SORBS1:KIAA0894 2.18E-06 1.4259 2.54 76.2 67.3-83.7 222513 s at SORBS1:KIAA0894 2.18E-06 1.4263 2.54 76.2 67.2-83.7 224990_at C4orf34 2.55E-06 1.3853 1.95 75.6 66.5-83.1 203131 at FIP1L1:PDGFRA 2.94E-06 1.4845 1.37 77.1 68.2-84.5 203638_s_ at FGFR2 3.55E-06 1.5287 1.31 77.8 68.9-85 201957_at PPP1R12B:LOC731632 4.26E-06 1.3611 2.21 75.2 66.2-82.8 217967_s_at FAM129A 4.59E-06 1.4131 1.8 76 67-83.5 210809_s at POSTN 4.94E-06 1.3954 2.25 75.7 66.7-83.2 226302_at ATP8B1 5.73E-06 1.313 1.67 74.4 65.3-82.1 238750 at CCL28 6.01E-06 1.4932 1.53 77.2 68.3-84.6 226103_at NEXN 6.83E-06 1.3666 2.23 75.3 66.2-82.8 209101_at CTGF 6.96E-06 1.4774 1.3 77 68.1-84.4 229254_at MFSD4 7.19E-06 1.3235 2.12 74.6 65.4-82.3 219087 at ASPN 7.45E-06 1.3249 2.74 74.6 65.5-82.3 209457_at DUSP5 8.60E-06 1.3336 1.91 74.8 65.7-82.4 221541 at CRISPLD2 9.24E-06 1.3664 1.64 75.3 66.2-82.9 206377_at FOXF2 9.50E-06 1.3032 2.08 74.3 65.1-82 207392_x_at UGT2B11:LOC728160:UGT2 9.73E-06 1.3478 5.72 75 65.8-82.6 B15,UGT2B1 l:LOC728160:U GT2B15 202274_at ACTG2 1.07E-05 1.4015 1.82 75.8 66.8-83.4 227522_at CMBL 1.09E-05 1.3588 1.58 75.2 66-82.8

212192_at KCTD12 1.44E-05 1.3659 1.36 75.3 66.2-82.8 227727_at MRGPRF 1.52E-05 1.2965 2.99 74.2 65-82 234987at C20orfl18 1.75E-05 1.4278 1.3 76.2 67.3-83.7 209656s_at TMEM47 1.86E-05 1.2983 2.02 74.2 65.1-82 212265 at QKI 1.93E-05 1.3443 1.31 74.9 65.9-82.6 228232_s_at VSIG2 2.01E-05 1.2957 2.05 74.1 65-81.9 200799_at HSPA1A,HSPA1A 2.16E-05 1.272 2.41 73.8 64.6-81.6 218312_s_at ZNF447 3.05E-05 1.107 1.39 71 61.6-79.1 230264s at AP1S2 3.39E-05 1.2546 1.92 73.5 64.3-81.4 224840_at FKBP5 3.41E-05 1.2371 1.71 73.2 63.9-81.1 209948at KCNMB1 3.74E-05 1.2181 2.66 72.9 63.6-80.8 201426_s_at VIM 4.15E-05 1.2221 1.86 72.9 63.7-80.8 227826_s_at SORBS2 4.23E-05 1.3017 2.1 74.2 65.1-82 227827_at SORBS2 4.23E-05 1.3015 2.1 74.2 65.1-82 225728 at SORBS2 4.23E-05 1.3015 2.1 74.2 65.1-82 238751at SORBS2 4.23E-05 1.3019 2.1 74.2 65.1-82 228202_at C6orf2O4 4.90E-05 1.2062 2.07 72.7 63.5-80.6 220645_at FAM55D 5.67E-05 1.1786 3.48 72.2 63-80.2 224560 at TIMP2 6.40E-05 1.2304 1.82 73.1 63.9-80.9 231579 s at TIMP2 6.40E-05 1.2286 1.82 73 63.8-81 208788_at ELOVL5. 8.15E-05 1.1804 2.05 72.2 63-80.2 200974at ACTA2 1.OOE-04 1.2299 1.81 73.1 63.8-81 202388at RGS2 0.0001 1.1604 1.94 71.9 62.7-80 206461_x_at MT1A:MT1H:LOC645745:LO 0.0001 1.189 4.55 72.4 63.2-80.4 C727730 208747_s_at C1S:PRB1:PRB2,C1S:PRB2:P 0.0001 1.2884 1.61 74 64.9-81.9 RB1 208791 at CLU 0.0001 1.2303 1.42 73.1 63.9-80.9 208792sat CLU 0.0001 1.2302 1.42 73.1 63.9-81 212185_x_at NUTF2:LOC441019:MT2A:M 0.0001 1.1894 1.89 72.4 63.1-80.3 T1M,NUTF2:LOC441019:MT 2A:MT1M 222043_at CLU 0.0001 1.2306 1.42 73.1 63.9-81 227099s at LOC387763 0.0001 1.1963 1.36 72.5 63.2-80.5 202766_s at FBN1 0.0002 1.1359 1.93 71.5 62.2-79.6 204745x_at NUTF2:MT1G 0.0002 1.0888 2.66 70.7 61.3-78.9 218418_s_at ANKRD25 0.0002 1.1139 1.56 71.1 61.9-79.3 201058_s_at MYL9 0.0003 1.131 2.18 71.4 62.1-79.5 205547_s_at TAGLN 0.0003 1.0914 2.12 70.7 61.4-78.9 205935at FOXFI 0.0004 1.1743 1.28 72.1 62.9-80.1 208450 at LGALS2 0.0004 1.0845 3.07 70.6 61.4-78.8 203748 x at RBMS1 0.0005 1.1435 1.55 71.6 62.3-79.7 207266_x_at RBMS1 0.0005 1.1428 1.55 71.6 62.4-79.7 209868 s at RBMS1 0.0005 1.1437 1.55 71.6 62.3-79.7 225269 s at RBMS1 0.0005 1.1446 1.55 71.6 62.3-79.6 212158at SDC2 0.0006 1.0977 1.39 70.8 61.6-79.1 209209 s at PLEKHC1 0.0007 1.0309 1.82 69.7 60.3-77.9 209210 s at PLEKHC1 0.0007 1.0325 1.82 69.7 60.3-78 205554 s at ACTB:DNASE1L3 0.0007 1.0979 1.5 70.8 61.4-78.9 202283 at SERPINFI 0.0009 1.0003 1.47 69.2 59.8-77.5

209496_at RARRES2:LOC648925 0.0009 1.0318 1.6 69.7 60.3-77.9 224352 s at CFL2 0.0009 1.0586 1.75 70.2 60.8-78.4 224663sat CFL2 0.0009 1.0575 1.75 70.2 60.8-78.4 214433_s at SELENBP1 0.0009 1.0574 1.7 70.1 60.8-78.3 212592_at ENAM 0.0011 1.0024 2.58 69.2 59.8-77.5 213629_x_at MT1F 0.0012 0.9664 2.2 68.6 59.2-76.9 217165_x_at MTIF 0.0012 0.9649 2.2 68.5 59.2-76.9 203645_s_at CD163 0.0013 1.0231 1.9 69.6 60-77.9 215049 x at CD163 0.0013 1.0215 1.9 69.5 60.1-77.8 206641 at TNFRSF17 0.0015 1.0206 2.08 69.5 60.1-77.8 227235_at GUCYlA3 0.0015 1.0116 2.69 69.4 59.8-77.6 229530_at GUCY1A3 0.0015 1.0115 2.69 69.3 60-77.6 212097_at CAVI 0.0016 1.0199 1.58 69.5 60.1-77.7 200884_at CKB 0.0019 0.9758 2.27 68.7 59.2-77 202133_at WWTR1 0.002 0.9917 1.48 69 59.5-77.4 204607_at HMGCS2 0.0022 0.8777 2.67 67 57.5-75.5 218559_s_at MAFB 0.0034 0.9595 1.66 68.4 59-76.8 201061_s_at STOM 0.0035 1.0165 1.21 69.4 60-77.7 201743_at CD14 0.0035 0.9627 1.58 68.5 59.1-76.9 204895_x_at MUC4:TAF5L:LOC650855:L 0.0039 1.0448 1.2 69.9 60.6-78.2 OC645744 217109_at MUC4:TAF5L:LOC650855:L 0.0039 1.0458 1.2 69.9 60.6-78.1 OC645744 217110_s_at MUC4:TAF5L:LOC650855:L 0.0039 1.0453 1.2 69.9 60.5-78.2 OC645744 203382_s at APOE 0.0044 0.9388 1.56 68.1 58.7-76.5 206664_at SI 0.0054 0.9293 2.79 67.9 58.4-76.3 242447.at LOC285382 0.0058 0.7401 1.26 64.4 54.9-73.2 209312_x_at HLA-DRB1:HLA- 0.0063 1.0636 1.51 70.3 60.9-78.5 DRB6:LOC731247:LOC73041 5:HLA-DRB4:HLA DRB5:HLA DRB3:LOC651845 215193_x_at HLA-DRB1:HLA- 0.0063 1.0646 1.51 70.3 60.9-78.5 DRB6:LOC731247:LOC73041 5:HLA-DRB4:HLA DRB5:HLA DRB3:LOC651845 224694_at ANTXR1 0.0071 0.9531 1.29 68.3 58.8-76.7 226811_at FAM46C 0.0085 0.9163 1.38 67.7 58.1-76.1 201150_s_at TIMP3 0.0091 0.9049 1.81 67.5 57.9-76 226682 at LOC283666 0.0099 0.7784 1.22 65.1 55.7-73.8 218468_s at GREM1 0.0106 0.8585 3.03 66.6 57.2-75.2 218469_at GREMI 0.0106 0.8579 3.03 66.6 57.1-75.2 203240_at FCGBP:LOC651441:LOC652 0.0121 0.7868 1.99 65.3 55.8-73.9 599 211538_s at HSPA2 0.0123 0.8916 1.43 67.2 57.7-75.7 212091_s at COL6A1 0.0126 0.848 1.45 66.4 56.9-74.9 213428_s at COL6A1 0.0126 0.8474 1.45 66.4 56.9-74.9 226051_at SELM 0.0133 0.8606 1.32 66.7 57.1-75.1 200859_x at FLNA:WTAP 0.0157 0.7975 1.59 65.5 55.9-74

213746 s_at FLNA:WTAP 0.0157 0.7959 1.59 65.5 56-74.2 214752_x at FLNA:WTAP 0.0157 0.798 1.59 65.5 56-74.1 204570_at COX7A1 0.0161 0.8622 1.32 66.7 57.2-75.2 203729_at EMP3 0.0164 0.8043 1.41 65.6 56.1-74.3 223597 at ITLN1 0.021 0.7148 2.54 64 54.4-72.7 227735_s_at Cl0orf99 0.0218 0.7254 1.76 64.2 54.6-72.9 227736_at ClOorf99 0.0218 0.7259 1.76 64.2 54.6-72.9 200621at CSRP1 0.023 0.7246 1.39 64.1 54.6-72.9 204897_at PTGER4:LOC730002:LOC73 0.0237 0.8114 1.41 65.8 56.2-74.4 0882 204083s at PPIL5:TPM2 0.026 0.7531 1.53 64.7 55.2-73.4 211643_x_at HLA-C:HLA- 0.0268 0.9237 1.24 67.8 58.3-76.3 B:LOC730410:LOC652614:L OC732037 211644_x_at HLA-C:HLA- 0.0268 0.9229 1.24 67.8 58.3-76.2 B:LOC730410:LOC652614:L OC732037 214768_x_at HLA-C:HLA- 0.0268 0.9245 1.24 67.8 58.3-76.3 B:LOC730410:LOC652614:L OC732037 226147 s at PIGR 0.0278 0.7282 1.59 64.2 54.6-73 229659 s at PIGR 0.0278 0.7253 1.59 64.2 54.7-72.9 201300 s at PRNP 0.0288 0.7985 1.24 65.5 56-74.1 210133_at CCL11 0.0361 0.8534 1.32 66.5 57-75.1 225353 s at C1QC 0.0391 0.7457 1.36 64.5 55-73.2 201289_at CYR61 0.0425 0.7849 1.47 65.3 55.8-73.9 210764s at CYR61 0.0425 0.7836 1.47 65.2 55.6-73.9 200986_at SERPINGI 0.0503 0.7672 1.44 64.9 55.4-73.6 204122at TYROBP:ZNF160 0.053 0.8181 1.17 65.9 56.4-74.5 201667_at GJA1 0.0561 0.784 1.76 65.2 55.7-73.9 208789_at PTRF 0.0624 0.736 1.5 64.4 54.8-73.1 210107_at CLCA1 0.0681 0.7868 1.61 65.3 55.7-73.9 200665_s at SPARC 0.0684 0.6714 1.45 63.1 53.6-72.1 212667_at SPARC 0.0684 0.6732 1.45 63.2 53.6-71.9 211964at COL4A2 0.0738 0.7064 1.32 63.8 54.2-72.6 201858_s at PRG1 0.0972 0.5559 1.25 60.9 51.3-69.9 201859at PRG1 0.0972 0.5563 1.25 61 51.4-69.9 228241_at BCMP11 0.102 0.4028 1.28 58 48.4-67.1 217762_s_at RAB31 0.1041 0.8135 1.14 65.8 56.3-74.4 217764 s at RAB31 0.1041 0.8132 1.14 65.8 56.2-74.5 202007_at NIDI 0.105 0.7425 1.33 64.5 55-73.1 210495 x at FN1 0.1121 0.5756 1.73 61.3 51.8-70.2 211719_x at FN1 0.1121 0.5767 1.73 61.3 51.8-70.2 212464 s at FN1 0.1121 0.5765 1.73 61.3 51.6-70.3 216442 x at FN1 0.1121 0.5745 1.73 61.3 51.7-70.3 200600_at MSN 0.1499 0.7232 1.15 64.1 54.6-72.9 209138_x_at IGL@:LOC651536:LOC73106 0.1551 0.681 1.26 63.3 53.8-72.2 2:CPVL:IGLV2-14:IGLV4 3:IGLV3-25:IGLV3 21:IL8:RPL14 216984_xat IGL@:LOC651536:LOC73106 0.1551 0.6808 1.26 63.3 53.8-72.2

2:CPVL:IGLV2-14:IGLV4 3:IGLV3-25:IGLV3 21:IL8:RPL14 217148_x_at IGL@:LOC651536:LOC73106 0.1551 0.6808 1.26 63.3 53.9-72.1 2:CPVL:IGLV2-14:IGLV4 3:IGLV3-25:IGLV3 21:IL8:RPL14 201069_at MMP2 0.1755 0.6214 1.24 62.2 52.6-71 202403 s at COL1A2:LOC728628 0.1891 0.6508 1.9 62.8 53.2-71.5 202768 at FOSB 0.2076 0.6392 2.17 62.5 52.9-71.5 209116xat HBB 0.2357 0.6432 1.28 62.6 52.9-71.4 211696xat HBB 0.2357 0.6436 1.28 62.6 53.1-71.4 217232 x at HBB 0.2357 0.6444 1.28 62.6 53.1-71.5 205267_at POU2AF1 0.2389 0.6573 1.18 62.9 53.3-71.7 201852_x at COL3A1 0.2551 0.5524 1.35 60.9 51.3-69.8 211161_s at COL3A1 0.2551 0.5509 1.35 60.9 51.3-69.9 215076_s at COL3A1 0.2551 0.5513 1.35 60.9 51.3-69.8 217378 x at LOC391427 0.2627 0.2759 1.15 55.5 45.9-64.8 223235_s_at SMOC2 0.2701 0.656 1.34 62.9 53.2-71.7 204673at MUC5AC:LOC652741:MUC2 0.2802 0.8531 1.22 66.5 57-75.1 212414_s at Sep-06 0.3109 0.5714 1.21 61.2 51.7-70.2 201744s at LUM 0.3157 0.5425 1.54 60.7 51-69.7 202953_at C1QB 0.3668 0.4998 1.24 59.9 50.3-68.9 209651 at TGFB1Il 0.4093 0.4932 1.35 59.7 50.2-68.8 212224_at ALDH1A1 0.4232 0.3525 1.4 57 47.4-66.2 211596sat LRIG1 0.4614 0.5988 1.26 61.8 52.2-70.7 218541_s at C8orf4 0.475 0.4838 1.44 59.6 50-68.5 208894_at HLA-DRA:HLA-DQA1,HLA- 0.4823 0.3234 1.29 56.4 46.8-65.6 DRA:HLA-DQA1,HLA DRA:HLA-DQA1 210982_s_at HLA-DRA:HLA-DQAI,HLA- 0.4823 0.3228 1.29 56.4 46.8-65.6 DRA:HLA-DQA1,HLA DRA:HLA-DQA1 227404 s at EGRI 0.4851 0.5387 1.38 60.6 51-69.6 216401_x_at LOC652745 0.4864 0.1728 1.09 53.4 43.9-62.8 216207_x at IGKV1D-13 0.5177 0.16 1.1 53.2 43.6-62.6 203477_at COL15AI 0.6601 0.5385 1.22 60.6 51.1-69.7 211959_at IGFBP5 0.7663 0.3526 1.25 57 47.4-66.2 201105_at LGALS1 0.8555 0.4634 1.16 59.2 49.6-68.2 201438 at COL6A3 0.8739 0.4434 1.2 58.8 49.2-67.8 212671_s_at HLA-DQA1:HLA- 0.8836 0.5398 1.28 60.6 51.1-69.7 DQA2,HLA DQA1:LOC731682:HLA DQA2 227725_at ST6GALNAC1 0.9452 0.2599 1.15 55.2 45.6-64.5 211990_at HLA-DPA1,HLA-DPA1 0.9664 0.417 1.39 58.3 48.7-67.4 211991_s_at HLA-DPA1,HLA-DPA1 0.9664 0.4166 1.39 58.3 48.7-67.4 217179_x at IGLV1-44 0.9777 0.2852 1.07 55.7 46.1-65 234764_x at IGLV1-44 0.9777 0.2847 1.07 55.7 46.1-64.9 224342_x at IGLV1-44 0.9777 0.2848 1.07 55.7 46.1-65 215176 x at NTN2L:IGKC:IGKVI- 0.9858 0.4167 1.43 58.3 48.6-67.3

5:GJB6:HLA-C 216576_x_at NTN2L:IGKC:IGKV1- 0.9858 0.4171 1.43 58.3 48.6-67.4 5:GJB6:HLA-C 201645 at TNC 0.9905 0.3687 1.09 57.3 47.7-66.6 214414 x at HBA1:HBA2,HBA1:HBA2 0.9979 0.4707 1.21 59.3 49.7-68.3 204018 x_ at HBA1:HBA2,HBA1:HBA2 0.9979 0.4711 1.21 59.3 49.7-68.3 209458_x_at HBA1:HBA2,HBA1:HBA2 0.9979 0.4727 1.21 59.3 49.7-68.4 211699_x_at HBA1:HBA2,HBA1:HBA2 0.9979 0.4697 1.21 59.3 49.7-68.3 211745_x at HBA1:HBA2,HBA1:HBA2 0.9979 0.4708 1.21 59.3 49.8-68.3 217414_x at HBA1:HBA2,HBA1:HBA2 0.9979 0.469 1.21 59.3 49.7-68.4

TABLE2 Gene ValidPSDOWN Signif. FDI D.val5 FC Sen CI (95) Symbol s Spe c GCNT2 935239-HuGenest:225205-HuGenest:1026280- 2.16E-27 3.9513 13.36 97.6 94.2-99.2 HuGenest:668101-HuGenest:1099985 HuGenest:698568-HuGenest:134540 HuGenest:697147-HuGenest:250092 HuGenest:611927-HuGenest:972833 HuGenest:168891-HuGenest:990860 HuGenest:109287-HuGenest:322116 HuGenest:231019-HuGenest:211020_at:959570 HuGenest:858764-HuGene_st:215593_at:820195 HuGenest:239606_at:41059-HuGenest:669940 HuGenest:215595_x_at:230788_at GUCA2B 276512-HuGenest:1006871-HuGenest:948364- 7.04E-25 3.6268 51.78 96.5 92.4-98.6 HuGenest:46575-HuGenest:207502_at:436788 HuGenest:485636-HuGenest:60132 HuGenest:608718-HuGenest:779511 HuGenest:132431-HuGenest:974232 HuGenest:425596-HuGenest:308287 HuGenest:800088-HuGene st:827119 HuGene st:233789-HuGene st:623623-HuGene st GUCAIB 207003_at 7.32E-25 3.5625 10.7 96.3 91.9-98.5 CA4 636392-HuGenest:206209_s_at:365396- 1.73E-24 3.6291 10.41 96.5 92.4-98.7 HuGenest:978203-HuGenest:987169 HuGenest:638557-HuGenest:206208_at:1033858 HuGenest:597808-HuGenest:756864 HuGenest:326439-HuGenest:356096 HuGenest:478435-HuGenest:31642 HuGenest:682778-HuGenest:1006162 HuGenest:673533-HuGenest:491473 HuGenest:822299-HuGenest:871453 HuGenest:209666-HuGene st:465368 HuGene st:354896-HuGene st SLC4A4 810103-HuGenest:634869- 2.23E-23 3.6301 3.58 96.5 92.4-98.6 HuGenest:210739_x_at:211494_s_at:268096 HuGenest:70822-HuGenest:940785 HuGenest:484105 HuGenest:210738_s_at:203908_at:99375 HuGenest:238833-HuGene-st:149464-

HuGenest:874564-HuGenest:161948 HuGenest:501640-HuGenest:65687 HuGenest:886057-HuGenest:495376 HuGenest:247215-HuGenest:847550 HuGenest:190252-HuGenest:244077 HuGene st:477911-HuGenest:904959 HuGenest:218417-HuGenest:1554027_a_at AQP8 486167-HuGene_st:126752-HuGenest:93102- 2.98E-22 3.3311 10.82 95.2 90.3-97.9 HuGenest:1090469-HuGenest:980308 HuGenest:107169-HuGenest:829020 HuGenest:1053234-HuGenest:954102 HuGenest:40331-HuGene_st:206784_at:990703 HuGenest:459706-HuGenest:863327 HuGenest:965233-HuGenest:459009 HuGenest:180228-HuGenest:944315 HuGenest:814773-HuGenest:810460 HuGenest:228837-HuGenest CA1 632246-HuGenest:205950_s_at:382371- 3.15E-22 3.3666 38.27 95.4 90.6-98 HuGenest:1004598-HuGenest:405837 HuGenest:551543-HuGenest:242482 HuGenest:267733-HuGenest:1074039 HuGenest:107073-HuGenest:485365 HuGenest:254908-HuGenest:257502 HuGenest:333301-HuGenest:180359 HuGenest:696950-HuGenest:588557 HuGenest:381399-HuGene st:495540 HuGene st:384192-HuGene st:205949 at ABCG2 236197-HuGenest:10623-HuGenest:1005470- 1.09E-21 3.2599 31.53 94.8 89.8-97.7 HuGenest:140860-HuGenest:492719 HuGenest:417387-HuGenest:113831 HuGenest:507347-HuGenest:944251 HuGenest:175319-HuGenest:784920 HuGenest:709551-HuGenest:136344 HuGenest:689536-HuGenest:209735_at:167748 HuGenest:759590-HuGenest:805222 HuGenest:945575-HuGenest:294363 HuGenest:958524-HuGenest:402982 HuGenest:301335-HuGenest OSTheta 552746-HuGenest:57742-HuGene_st:461622- 6.23E-21 3.188 7.15 94.5 89.2 HuGenest:965982-HuGenest:413709- 97.5 HuGenest:230830_at:232719-HuGenest:165400 HuGenest:203597-HuGenest:1025456 HuGenest:625341-HuGenest:881755 HuGenest:490180-HuGenest:113547 HuGenest:605512-HuGenest:179662 HuGenest:280309-HuGenest:647118-HuGenest MGC13057 926449-HuGenest:317301-HuGenest:834797- 6.94E-21 3.2029 3.18 94.5 89.3 HuGenest:173388-HuGenest:127937- 97.5 HuGenest:182395-HuGenest:800172 HuGenest:1041848-HuGenest:93911 HuGenest:810617-HuGenest:1035428 HuGenest:644866-HuGenest:343402 HuGenest:223754_at:228195_at:509933-HuGenest

CLDN23 403960-HuGenest:25144-HuGenest:947653- 4.27E-20 3.0777 3.47 93.8 88.2 HuGenest:228704_s_at:228706_s_at:320375- 97.1 HuGenest:441629-HuGenest:367414 HuGenest:855269-HuGenest:228707_at:788659 HuGenest:698816-HuGenest:95789 HuGenest:270197-HuGenest:472976 HuGene st:280539-HuGenest:1056334 HuGenest:516288-HuGenest:579963-HuGenest PKIB 866170-HuGenest:1055812-HuGenest:264946- 5.94E-20 3.1232 3.28 94.1 88.7 HuGenest:684057-HuGenest:124791- 97.3 HuGenest:134561-HuGenest:1026756 HuGenest:468593-HuGenest:1045852 HuGenest:939917-HuGenest:110205 HuGenest:660721-HuGene st:905229 HuGene st:223551_at:610426-HuGenest SEMA6D 855766-HuGenest:233882_s_at:543564- 6.07E-20 3.092 4.27 93.9 88.4 HuGenest:277987-HuGenest:1075165- 97.2 HuGenest:220574_at:732853-HuGene_st:410940 HuGenest:384488-HuGenest:1041056 HuGenest:233801_s_at:535378-HuGenest:477671 HuGenest:626423-HuGenest:101599 HuGenest:714098-HuGenest:301505 HuGenest:53682-HuGenest:177281 HuGenest:596415 HuGenest:244746_at:226492_at:699792 HuGene.st:73748-HuGenest:692437-HuGenest CLCA4 220026_at:1000955-HuGenest:215807- 1.25E-19 3.1922 16.3 94.5 89.2 HuGenest:108406-HuGenest:538359- 97.5 HuGenest:366726-HuGenest:727431 HuGenest:240891-HuGenest:485685 HuGenest:205213-HuGenest:476179 HuGenest:283676-HuGenest:933390 HuGenest:601908-HuGenest:844633 HuGenest:846667-HuGenest:99723 HuGenest:376041-HuGenest:71188 HuGene st:261183-HuGenest:498330 HuGenest:500064-HuGenest:785031-HuGenest TP53INP2 224836_at:294906-HuGenest:857693- 1.45E-19 3.0229 3.78 93.5 87.8 HuGenest:852970-HuGenest:594178- 96.9 HuGenest:868173-HuGenest:353925 HuGenest:212485-HuGenest:804363 HuGenest:778869-HuGenest:427072 HuGenest:451529-HuGenest:808765 HuGenest:205314-HuGenest:415164 HuGenest:1048358-HuGene_ st MS4AI2 220834_at:582400-HuGene_st:354845- 2.13E-19 3.2962 7.15 95 90-97.8 HuGenest:341876-HuGenest:769180 HuGenest:740541-HuGenest:436753 HuGenest:570027-HuGenest:26519 HuGenest:956581-HuGenest:335315 HuGenest:206721-HuGenest:589444 HuGenest:16629-HuGenest:113533 HuGenest:201614-HuGenest:774878 HuGenest:786494-HuGenest:493550 HuGenest:403871-HuGene-st:192686 HuGene st:846528-HuGene st:249799-HuGene st |

TRPM6 767074-HuGenest:695352-HuGenest:411125- 2.25E-19 3.0106 7.5 93.4 87.7 HuGenest:221102_s_at:234864_sat:240389_at:3582 96.8 29-HuGenest:755964-HuGenest:840301 HuGenest:959234-HuGene-st:782639 HuGenest:833079-HuGene-st:1066034 HuGenest:678013-HuGenest:249083 HuGenest:143934-HuGenest:159130 HuGenest:486486-HuGenest:185057 HuGenest:878793-HuGene st:133981 HuGene st:224412 s at:202194-HuGene st XLKD1 520080-HuGene_st:1091117-HuGenest:943125- 3.60E-19 2.94 7.44 92.9 87.1 HuGenest:444068-HuGenest:648558- 96.6 HuGenest:346991-HuGenest:1006205 HuGenest:373107-HuGenest:682535 HuGenest:1083245-HuGenest:863143 HuGenest:820120-HuGenest:1044561 HuGenest:220037_s_at:541228-HuGenest:220256 HuGenest:289122-HuGenest:219059_s at:246683 HuGene st:775976-HuGenest:207399 HuGenest:1052557-HuGenest:92121-HuGenest ADHIB 1078343-HuGenest:512808-HuGenest:614446- 4.70E-19 3.0172 4.67 93.4 87.7 HuGenest:910188-HuGenest:422504- 96.9 HuGenest:731361-HuGenest:209612_sat:258079 HuGenest:568239-HuGenest:879930 HuGenest:420417-HuGenest:1025048 HuGenest:908335-HuGenest:654633 HuGenest:947292-HuGenest:1087125 HuGenest:1004870-HuGene st:209613_s_at:579636 HuGenest:681018-HuGenest:822774-HuGenest PRDX6 353187-HuGenest:520885-HuGenest:919334- 5.56E-19 2.8414 2.76 92.2 86.1 HuGenest:646105-HuGenest:390352- 96.1 HuGenest:200844_s_at:855125 HuGenest:200845_sat:54231-HuGenest:612931 HuGenest:837652-HuGenest:538086 HuGenest:796167-HuGenest:208992 HuGenest:39945-HuGenest:489353 HuGenest:963499-HuGenest:376244 HuGenest:297536-HuGenest:495777 HuGenest:1005253-HuGenest:833460-HuGenest CA2 762141-HuGenest:111686-HuGenest:512916- 5.87E-19 2.9625 9.22 93.1 87.2 HuGenest:9132-HuGenest:995083- 96.7 HuGene_st:209301_at:578483-HuGenest:583428 HuGenest:961832-HuGenest:11748 HuGenest:1056641-HuGenest:545067 HuGenest:952781-HuGenest:689246 HuGenest:246103-HuGenest:803284 HuGenest:828842-HuGene st:694989 HuGene st:808226-HuGene st:199030-HuGene st EDN3 314103-HuGenest:217154_s_at:820613- 6.42E-19 2.937 11.21 92.9 87-96.5 HuGenest:1050996-HuGenest:348157 HuGenest:338856-HuGenest:594687 HuGenest:38595-HuGenest:270770 HuGenest:817067-HuGenest:766407 HuGenest:256284-HuGenest:208399_sat:200417 HuGenest:496738-HuGene-st:590141 HuGene st:137170-HuGene st:499250-

HuGenest:478524-HuGenest:720694 HuGenest:543565-HuGenest

MIER3 884917-HuGenest:740856-HuGenest:107094- 9.14E-19 2.9162 3.91 92.8 86.8 HuGenest:408774-HuGenest:461523- 96.5 HuGenest:153511-HuGenest:207042 HuGenest:737492-HuGenest:43443 HuGenest:614740-HuGenest:1559652_at:783045 HuGenest:887606-HuGenest:996253 HuGenest:1041635-HuGenest:142612 HuGenest:1553336_a_at:220555-HuGenest:975347 HuGenest:470750-HuGenest:1554450_s_at:804524 HuGenest:265536-HuGenest:774142 HuGenest:231975_s_at:34726 HuGene-st:1554449_at:228961_at ABCA8 57305-HuGenest:111752-HuGenest:61357- 1.26E-18 2.9165 6.82 92.8 86.8 HuGenest:123451-HuGenest:740746- 96.5 HuGenest:512280-HuGenest:389185 HuGenest:427721-HuGenest:346028 HuGenest:224566-HuGenest:149653 HuGenest:680699-HuGenest:76772 HuGenest:742091-HuGenest:423333 HuGenest:559944-HuGenest:341399 HuGenest:1565780_at:863400-HuGenest:921748 HuGenest:623719-HuGenest:204719_at:123143 HuGenest:1077391-HuGenest METTL7A 278779-HuGenest:481332-HuGenest:787584- 1.35E-18 3.1231 1.93 94.1 88.6 HuGenest:989793-HuGenest:278513- 97.3 HuGenest:424901-HuGenest:551005 HuGenest:921169-HuGenest:125176 HuGenest:277465-HuGenest:560742 HuGenest:207761_s_at:367459-HuGenest:224782 HuGenest:660194-HuGenest:266654 HuGenest:1086300-HuGenest:134633 HuGenest:211424_x_at:273973-HuGenest:947408 HuGenest:209703_x_at:617184-HuGene-st:864197 HuGenest:10061-HuGenest DPT 876245-HuGenest:1036210-HuGenest:214758- 1.53E-18 2.8977 9.07 92.6 86.7 HuGenest:1005554-HuGenest:178625- 96.4 HuGenest:701967-HuGenest:35076 HuGenest:33432-HuGenest:897771 HuGenest:304494-HuGenest:445757 HuGenest:491297-HuGenest:646408 HuGenest:842542-HuGenest:87795 HuGenest:213068_at:207977_s_at:553389 HuGenest:477075-HuGenest:213071_at:1046282 HuGene st MGC4172 339712-HuGenest:1089815-HuGenest:265870- 1.74E-18 2.9044 3.74 92.7 86.7 HuGenest:895908-HuGenest:226292- 96.4 HuGenest:322910-HuGenest:575887 HuGenest:416485-HuGenest:1055581 HuGenest:1088692-HuGenest:442194 HuGenest:218756_s_at:775684-HuGenest:773137 HuGene st:373028-HuGene st:512667-

HuGene st:164027-HuGene st:541185 HuGenest:593729-HuGenest:506796-HuGenest

FNBP1 728822-HuGenest:845505-HuGenest:1054016- 1.76E-18 3.0483 2.04 93.6 88-97 HuGenest:383098-HuGenest:230389_at:31865 HuGenest:981305-HuGenest:213940_s_at:755179 HuGenest:839717 HuGenest:230086_at:239453_at:985213 HuGenest:125814-HuGenest:451336 HuGenest:22306-HuGenest:540957 HuGenest:277486-HuGenest:314000 HuGenest:212288_at:662225-HuGenest:524650 HuGenest:605840-HuGenest:180978 HuGenest:604436-HuGenest EDG2 816816-HuGenest:309471-HuGenest:77020- 2.44E-18 2.8838 3.19 92.5 86.5 HuGenest:289373-HuGenest:10014- 96.3 HuGenest:981213-HuGenest:204038_s_at:1035537 HuGenest:75833-HuGenest:781880 HuGenest:494373-HuGenest:745317 HuGenest:497715-HuGenest:693528 HuGenest:806817-HuGenest:812294 HuGenest:204036_at:241773_at:176887 HuGenest:441141-HuGenest:189399 HuGenest:723788-HuGene_st:204037_at:485543 HuGenest:1014086-HuGenest:232716_at SFRP1 722739-HuGenest:1095144-HuGenest:1039611- 2.77E-18 2.8631 15.53 92.4 86.3 HuGenest:836419-HuGenest:34446- 96.2 HuGenest:50826-HuGenest:483033 HuGenest:202036_s_at:988375-HuGenest:774922 HuGenest:228413_s_at:665988-HuGenest:302344 HuGenest:202035_s_at:412438-HuGenest:995086 HuGenest:202037_s_at:181713-HuGenest:527962 HuGenest:880207-HuGenest:100260-HuGene_ st SLC26A3 206143_at:172542-HuGenest:768419- 4.18E-18 2.9214 21.4 92.8 86.8 HuGenest:820082-HuGenest:263997- 96.5 HuGenest:681117-HuGenest:581666 HuGenest:180553-HuGenest:356894 HuGenest:240715-HuGenest:718555 HuGenest:517735-HuGenest:339388 HuGenest:989337-HuGenest:1511 HuGenest:228629-HuGenest:354149 HuGenest:603695-HuGenest:791438 HuGenest:154730-HuGenest:905529 HuGenest:248690-HuGenest:431441 HuGenest:215657_at ANGPTL1 572942-HuGenest:891312-HuGene-st:953040- 1.42E-17 2.7929 4.64 91.9 85.6 HuGenest:232844-HuGenest:145730- 95.9 HuGenest:142205-HuGenest:227771 HuGenest:80584-HuGenest:982090 HuGenest:999640-HuGenest:672931 HuGenest:148578-HuGenest:224339_s_at:1046706 HuGenest:239183_at:155600-HuGenest:284674 HuGenest:231773_at:818064-HuGene_st:978991 HuGene st:728775-HuGene st

UGP2 795967-HuGenest:561220-HuGenest:754258- 1.64E-17 2.7904 2.41 91.9 85.6 HuGene-st:846757-HuGenest:868436- 95.9 HuGenest:321605-HuGenest:299097 HuGenest:7536-HuGenest:216268 HuGenest:925542-HuGenest:967807 HuGenest:205480_s_at:639621-HuGenest:177627 HuGenest:894271-HuGenest:617530 HuGenest:231698_at:971369-HuGenest:132663 HuGenest:215198-HuGenest:647604 HuGenest:537579-HuGene st:232180_at:1056881 HuGene st SRPX 195599-HuGenest:541428-HuGenest:143706- 1.79E-17 2.7749 3.91 91.7 85.5 HuGenest:728558-HuGenest:190938- 95.8 HuGenest:455214-HuGenest:522280 HuGenest:966576-HuGenest:650551 HuGenest:810331-HuGenest:396246 HuGenest:133110-HuGenest:232310 HuGenest:475511-HuGene st:225561 HuGenest:351281-HuGenest:204955_at OGN 955964-HuGenest:775073-HuGenest:678354- 2.25E-17 2.7078 13.67 91.2 84.7 HuGenest:238500-HuGenest:1019070- 95.4 HuGenest:614445-HuGenest:23784 HuGenest:658925-HuGenest:757128 HuGenest:632689-HuGenest:989474 HuGenest:233177-HuGenest:650498 HuGenest:950000-HuGenest:751146 HuGenest:67232-HuGenest:997991 HuGene_st:218730_s_at:222722_at:821488 HuGene st MYLK 527465-HuGenest:617817-HuGenest:716971- 2.33E-17 2.7729 3.99 91.7 85.4 HuGenest:942711-HuGenest:230460_at:161532- 95.8 HuGenest:767103-HuGenest:1041083 HuGenest:202167-HuGenest:738247 HuGenest:505966-HuGenest:62701 HuGenest:776564-HuGenest:679137 HuGenest:551306 HuGenest:202555_s_at:224823_at:986313 HuGenest:324943-HuGenest:218172 HuGenest:351524-HuGenest:1568770_at:280094 HuGene st:1017324-HuGene st:1563466 at LIFR 275506-HuGenest:323055-HuGenest:444251- 2.45E-17 2.7826 6.36 91.8 85.6 HuGenest:1056178-HuGenest:398104- 95.8 HuGenest:917434-HuGenest:1044918 HuGenest:167500-HuGenest:423760 HuGenest:837336-HuGenest:321505 HuGenest:918321-HuGenest:252278 HuGenest:884504-HuGenest:124845 HuGenest:499777-HuGenest:969722 HuGenest:709439-HuGenest:611505 HuGenest:227771_at:287217 HuGenest:205876_at:225571_at:229185_at:233367_a t:1093011-HuGenest

ZG16 287680-HuGenest:1704-HuGenest:61566- 2.51E-17 2.8097 8.14 92 85.8-96 HuGenest:964936-HuGenest:9737 HuGenest:620497-HuGenest:785765 HuGenest:214142_at:323025-HuGenest:1093257 HuGenest:398415-HuGenest:942991 HuGenest:871899-HuGenest:548837 HuGenest:605328-HuGenest:231918 HuGenest:461816-HuGenest:604283 HuGenest:971003-HuGenest:750108 HuGene st:927723-HuGenest:782940 HuGenest:98669-HuGenest EPB41L3 275431-HuGenest:540074-HuGenest:731277- 2.62E-17 2.8312 2.51 92.2 86-96.1 HuGenest:211776_s_at:218157-HuGenest:328922 HuGene_st:384314-HuGenest:272486 HuGenest:196590-HuGenest:294230 HuGenest:206710_s_at:747631-HuGenest:52743 HuGenest:1089957-HuGenest:423337 HuGenest:915755-HuGenest:623682 HuGenest:130815-HuGenest:497574 HuGene st:212681_at:77106-HuGenest:874781 HuGenest SCNN1B 773390-HuGenest:467376-HuGenest:411583- 3.20E-17 2.7219 16.15 91.3 84.9 HuGenest:433511-HuGenest:142579- 95.5 HuGenest:99655-HuGenest:278054 HuGene_st:371417-HuGenest:99189 HuGenest:491965-HuGenest:490957 HuGenest:916581-HuGenest:285916 HuGenest:359156-HuGenest:977951 HuGenest:291765-HuGenest:767266 HuGene st:206091-HuGenest:348267 HuGenest:205464_at:838576-HuGene-st HHLA2 371335-HuGenest:978721-HuGenest:1065567- 3.47E-17 2.6741 10.02 90.9 84.4 HuGenest:282548-HuGenest:240410- 95.2 HuGenest:170899-HuGenest:947848 HuGenest:438234-HuGenest:220812_s_at:927495 HuGenest:351364-HuGenest:234673_at:993142 HuGenest:1009637-HuGenest:335000 HuGenest:285313-HuGenest:533646 HuGenest:234624_at:458597-HuGenest:104838 HuGenest:26687-HuGenest:258409 HuGene st:493304-HuGenest:378019 HuGenest:576796-HuGenest HPGD 291863-HuGene_st:375608-HuGenest:793406- 3.65E-17 2.8433 3.21 92.2 86.1 HuGenest:436293-HuGenest:75568- 96.1 HuGenest:211549_s_at:684728-HuGenest:674596 HuGenest:527856-HuGenest:329920 HuGenest:748432-HuGenest:259392 HuGenest:769902-HuGenest:620673 HuGenest:450707-HuGene_st:203913_s_at:304752 HuGenest:447604-HuGenest:170968 HuGenest:852359-HuGenest:836377 HuGenest:242733_at:243846-HuGenest:136281 HuGenest:203914_x_at:211548_s_at:288252 HuGenest

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CHRDL1 335657-HuGenest:1058673-HuGenest:166016- 1.49E-16 2.6092 13.88 90.4 83.7 HuGenest:825273-HuGenest:35456- 94.9 HuGenest:91115-HuGenest:303433 HuGenest:209044-HuGenest:1081642 HuGenest:135625-HuGenest:284037 HuGenest:452295-HuGenest:313790 HuGenest:912814-HuGenest:712513 HuGenest:1078238-HuGenest:721877 HuGenest:209763_at:657006-HuGenest NR3C2 748063-HuGenest:177629-HuGene_st:964944- 2.08E-16 2.5811 3.19 90.2 83.3 HuGenest:346404-HuGenest:120283- 94.7 HuGenest:646104-HuGenest:731385 HuGenest:493776-HuGenest:440054 HuGenest:286582-HuGenest:1097927 HuGenest:804888-HuGenest:234142_at:49341 HuGenest:370558-HuGenest:22007 HuGenest:981978-HuGenest:100953 HuGenest:239673_at:149241-HuGenest:940356 HuGenest:628366 HuGene st:205259 at:1564236 at:328672-HuGene st TSPAN7 703402-HuGenest:745610-HuGenest:1018812- 2.13E-16 2.651 3.68 90.7 84.2 HuGenest:742943-HuGenest:168712- 95.1 HuGenest:234246_at:902239-HuGenest:285968 HuGenest:883914-HuGenest:113610 HuGenest:236336-HuGenest:511310 HuGenest:40850-HuGenest:346422 HuGenest:189042-HuGenest:745521 HuGenest:996022-HuGenest:202242_at:195303 HuGenest:70610-HuGene-st:31995 HuGene st:234245_at STMN2 459270-HuGenest:611227-HuGenest:295241- 2.25E-16 2.6147 6.13 90.4 83.8 HuGenest:935618-HuGenest:161827- 94.9 HuGenest:17520-HuGenest:337557 HuGenest:16478-HuGenest:1015231 HuGenest:790658-HuGenest:892767 HuGenest:343589-HuGenest:1047491 HuGenest:454759-HuGenest:9820 HuGenest:203001_s_at:472072 HuGene_st:203000_at:691598-HuGenest:1064573 HuGenest:811444-HuGenest:485134-HuGenest FAM107A 315531-HuGenest:294482-HuGenest:764207- 2.52E-16 2.6168 2.92 90.5 83.8 HuGenest:809908-HuGenest:209074_s_at:341591- 94.9 HuGenest:948705-HuGenest:207547_s_at:415418 HuGenest:215297-HuGenest:332641-HuGenest ANK2 314086-HuGenest:282874-HuGenest:382431- 2.59E-16 2.6501 6.76 90.7 84.1 HuGenest:229308-HuGenest:779600- 95.1 HuGenest:297624-HuGenest:385943 HuGenest:730140-HuGene_st:442277 HuGenest:699309-HuGenest:182816 HuGenest:202921_s_at:799860-HuGenest:868462 HuGenest:634421-HuGenest:571536 HuGenest:1050903-HuGene st:649509 HuGene st:239935-HuGene st:202920 at

CLIC5 217628_at:219866_at:116794-HuGenest:114619- 3.68E-16 2.6963 2.37 91.1 84.6 HuGenest:895974-HuGenest:749788- 95.4 HuGenest:485909-HuGenest:326032 HuGenest:1083118-HuGenest:213317_at:507492 HuGenest:480370-HuGenest:160114 HuGenest:637800-HuGenest:33914 HuGenest:1044626-HuGenest:243917_at:664038 HuGenest:867787-HuGenest:261656 HuGenest:399156-HuGenest:558641-HuGenest CHGA 152790-HuGenest:354161-HuGenest:365802- 5.54E-16 2.6097 7.21 90.4 83.6 HuGenest:813261-HuGenest:40004- 94.9 HuGenest:504502-HuGenest:624128 HuGenest:719186-HuGenest:916335 HuGenest:921714-HuGenest:489360 HuGenest:849455-HuGenest:231475 HuGenest:294992-HuGenest:204697_s-at:659997 HuGene st:521835-HuGenest:659283 HuGenest:890388-HuGenest:786316-HuGenest KIAA0828 613787-HuGenest:478932-HuGenest:67325- 5.58E-16 2.5514 4.09 89.9 83-94.5 HuGenest:668897-HuGenest:160683 HuGenest:1031978-HuGenest:1018444 HuGenest:237998-HuGenest:892138 HuGenest:262221-HuGenest:864937 HuGenest:917541-HuGenest:593865 HuGenest:55857-HuGenest:215672_s at:509888 HuGenest:302988-HuGenest:668914 HuGenest:507489-HuGenest:212814_at EDIL3 436107-HuGenest:1558643_s_at:214345_at:668780- 6.21E-16 2.6259 2.96 90.5 83.8-95 HuGenest:545521-HuGenest:641822 HuGenest:207379_at:411378-HuGenest:485618 HuGenest:576523-HuGenest:843058 HuGenest:910789-HuGenest:165720 HuGenest:79965-HuGenest:533665 HuGenest:237605-HuGenest:593615 HuGenest:396108-HuGenest:701416 HuGenest:325630-HuGenest:912197 HuGenest:224797-HuGenest:724765 HuGenest:167229 HuGenest:233668_at:225275at:16759 HuGene_st:233875_at DSCR1 535011-HuGenest:789105- 6.21E-16 2.6122 2.14 90.4 83.7 HuGenest:215253_s_at:838760-HuGenest:617570- 94.9 HuGenest:419279-HuGenest:1015938 HuGenest:208370_s_at:131478-HuGenest:228884 HuGenest:685397-HuGenest:68677 HuGenest:215254_at:656173-HuGenest:971107 HuGenest:1039926-HuGenest:206974 HuGenest:232227-HuGenest:546248 HuGenest:175597-HuGenest:1558181_at PPAP2A 282276-HuGenest:1062765-HuGenest:952258- 6.43E-16 2.596 2.4 90.3 83.6 HuGenest:214647-HuGenest:153982- 94.8 HuGenest:678140-HuGenest:209147_s_at:1083041 HuGenest:459000-HuGenest:505597 HuGenest:1035745-HuGenest:576550 HuGenest:243715_at:180473-HuGenest:527974 HuGene st:821572-HuGene st:260389-

HuGenest:1042377-HuGenest:138155 HuGenest:210946_at:243442_x_at

PDCD4 681770-HuGenest:1029160-HuGenest:594740- 8.67E-16 2.4578 2.6 89 82-93.9 HuGenest:247013-HuGenest:845755 HuGenest:813933-HuGenest:367555 HuGenest:456148-HuGenest:295280 HuGenest:144200-HuGenest:620666 HuGenest:212593_s_at:590149-HuGenest:87471 HuGenest:189624-HuGenest:202730_s_at:44562 HuGene-st:641673-HuGenest:577621 HuGene st:102842-HuGenest:202731_at:776615 HuGenest:615983-HuGenest:212594_at:1557166_at DHRS9 413956-HuGenest:371161- 1.09E-15 2.7371 1.51 91.4 85.1 HuGenest:224009_x_at:61832-HuGenest:874913- 95.6 HuGenest:321055-HuGene_st:223952_x_at:916038 HuGenest:313731-HuGenest:629747 HuGenest:836048-HuGenest:369374 HuGenest:157673-HuGenest:194386 HuGenest:1089433-HuGenest:352973 HuGenest:637905-HuGenest:1010893 HuGenest:219799_s_at:361862-HuGenest:800910 HuGenest:1012296-HuGenest CDKN2B 252481-HuGenest:1000015-HuGenest:172198- 1.34E-15 2.5433 10.09 89.8 82.9 HuGenest:967979-HuGenest:675431- 94.5 HuGenest:605224-HuGenest:277126 HuGenest:846115-HuGenest:452433 HuGenest:332731-HuGenest:563208 HuGenest:527577-HuGenest:207530_s_at:891201 HuGenest:512260-HuGene st:236313_at:26244 HuGene st:61586-HuGene st P2RY1 628249-HuGenest:113454-HuGenest:627857- 1.41E-15 2.5341 3.6 89.7 82.8 HuGenest:461281-HuGenest:207455_at:259065- 94.4 HuGenest:797734-HuGenest:135788 HuGenest:42916-HuGenest:315405 HuGenest:340050-HuGenest:173225 HuGenest:919818-HuGenest:591228 HuGenest:899117-HuGenest:785070 HuGenest:286200-HuGenest:231925_at LOC64662 238143_at 1.58E-15 1.9131 5.02 83.1 74.9-89.4 7 PPAP2B 484735-HuGenest:860271-HuGenest:501067- 2.44E-15 2.5819 1.81 90.2 83.4 HuGenest:180731-HuGenest:919245- 94.7 HuGenest:209355_s_at:322730-HuGenest:830995 HuGenest:212226_s_at:353268-HuGenest:989778 HuGenest:279549-HuGenest:583834 HuGenest:1035367-HuGenest:155537 HuGenest:782552-HuGenest:867734 HuGenest:267847-HuGenest:212230_at:619833 HuGenest:232324_x_at PYY 656845-HuGenest:816022-HuGenest:633572- 3.50E-15 2.4793 11.71 89.2 82.2-94 HuGenest:20355-HuGenest:240779 HuGenest:638358-HuGenest:879780 HuGene st:207080 s at:211253 x at:368591-

HuGenest

CLEC3B 794375-HuGenest:894763-HuGenest:152328- 4.65E-15 2.4437 4.46 88.9 81.7 HuGenest:669650-HuGenest:1090081- 93.8 HuGenest:251162-HuGenest:264101 HuGenest:367416-HuGenest:984078 HuGenest:512272-HuGenest:166348 HuGenest:181414-HuGenest:995862 HuGenest:603678-HuGenest:205200_at:56968 HuGenest:542483-HuGenest NDE1 228133_s_at:218414_s_at:555730-HuGenest:620739- 4.84E-15 2.5125 1.99 89.5 82.6 HuGene st:111363-HuGene st 94.3 CCL8 402294-HuGenest:1098932-HuGenest:930533- 5.75E-15 2.4512 7.51 89 81.9 HuGenest:524795-HuGenest:574692- 93.9 HuGenest:314202-HuGenest:719831 HuGenest:410906-HuGenest:643479 HuGenest:911966-HuGenest:31200 HuGenest:547634-HuGenest:39456 HuGenest:527508-HuGene-st:1057270 HuGenest:1062460-HuGene-st:214038_at PLAC8 219014_at:739479-HuGenest:354260- 5.76E-15 2.4228 3.87 88.7 81.5 HuGenest:994047-HuGenest:456534- 93.7 HuGenest:236727_at:330382-HuGenest:118286 HuGene_st:940467-HuGenest:493579 HuGenest:37786-HuGenest:776403 HuGenest:295172-HuGenest:271859 HuGenest:438305-HuGenest:770531 HuGenest:982881-HuGenest:543535 HuGenest:554805-HuGenest:667817 HuGenest:519806-HuGenest:1065533 HuGenest:345940-HuGenest MUCDHL 690807-HuGenest:11068-HuGenest:955242- 5.81E-15 2.4358 3.06 88.8 81.7 HuGenest:969280-HuGenest:220075_s_at:625411- 93.8 HuGenest:789310-HuGenest:444568 HuGenest:589749-HuGenest:265998 HuGenest:275576-HuGenest:219796_s_at:625643 HuGenest:452184-HuGenest:692224 HuGenest:1009431-HuGenest:311533 HuGenest:289109-HuGene st:101091 HuGenest:220074_at:307121-HuGenest SULTIA1 322199-HuGenest:1021081-HuGenest:372215- 7.17E-15 2.422 3.37 88.7 81.6 HuGenest:689177-HuGenest:215299_x_at:369102- 93.7 HuGenest:203615_x_at:761577-HuGenest:744847 HuGenest:691837-HuGenest:2491 HuGenest:742631-HuGene st:1037597 HuGene st:805936-HuGenest SDCBP2 233565_s_at:263537-HuGenest:901885- 9.28E-15 2.4869 2.37 89.3 82.3 HuGenest:421400-HuGenest:835589- 94.1 HuGenest:70935-HuGenest:462061 HuGenest:702702-HuGenest:719818 HuGenest:766065-HuGenest:612065 HuGenest:825595-HuGenest:1004265 HuGenest:206488-HuGenest:867231 HuGenest:858503-HuGene-st:29674 HuGene-st:26237-HuGene st:351356-

HuGenest:52388-HuGenest:192518-HuGenest

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HuGenest:442879-HuGenest:211870 HuGenest:638998-HuGenest:448080 HuGenest:948845-HuGene_st:313770-HuGene_st

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HuGenest:760559-HuGenest:446223 HuGenest:205427-HuGenest:983813 HuGenest:435034-HuGenest:250747-HuGenest IGL@ 173623-HuGene-st:408026-HuGene-st:38807- 2.50E-07 1.6337 3.1 79.3 70.7 HuGene st 86.3 HSPB8 688528-HuGenest:311091-HuGenest:415722- 2.61E-07 1.5121 3.85 77.5 68.7 HuGenest:56376-HuGenest:79205- 84.8 HuGenest:499751-HuGenest:214231 HuGenest:225808-HuGenest:174359 HuGenest:1083550-HuGene-st:221667_s_at:662744 HuGene st:346589-HuGene st A2M 897456-HuGenest:217757_at:164005- 2.72E-07 1.5968 1.64 78.8 69.9 HuGenest:848096-HuGenest:244657- 85.9 HuGenest:317437-HuGenest:330214 HuGenest:814658-HuGenest:1100520 HuGenest:451567-HuGenest:559737 HuGenest:600508-HuGenest:730036 HuGenest:385395-HuGenest:833129 HuGenest:101038-HuGenest:195639 HuGenest:371583-HuGenest:808161 HuGene st:893977-HuGenest:1558450_at:167145 HuGenest:660806-HuGenest MS4A7 803709-HuGenest:372940-HuGene_st:558657- 2.92E-07 1.5398 2.27 77.9 69.1 HuGenest:758990-HuGenest:279234- 85.2 HuGenest:716878-HuGenest:228770 HuGenest:77553-HuGenest:212226 HuGenest:148024-HuGenest:727350 HuGenest:223344_s_at:223343_at:224358_s_at:9320 03-HuGenest:584291-HuGenest:16857 HuGenest:751363-HuGenest:120594 HuGenest:66810-HuGenest:473741-HuGenest PLOD2 366970-HuGenest:202619_s_at:557917- 3.06E-07 1.5569 2.33 78.2 69.3 HuGenest:371377-HuGenest:606385- 85.4 HuGenest:54079-HuGenest:976248 HuGenest:572307-HuGenest:716158 HuGenest:754684-HuGenest:255595 HuGenest:17343-HuGenest:124945 HuGenest:770320-HuGenest:704827 HuGenest:202620_s_at:309852-HuGenest:509273 HuGenest:703772-HuGenest:1082989 HuGenest:550147-HuGenest:740582 HuGenest:6711-HuGene st UGT2B17 357315-HuGenest:493733-HuGene_st:353886- 3.75E-07 1.4818 4.88 77.1 68.2 HuGenest:207245_at:59042-HuGenest:1025125- 84.5 HuGene st PMP22 1086412-HuGenest:139615-HuGenest:864327- 3.97E-07 1.5173 2.23 77.6 68.8 HuGenest:1565637_at:493430-HuGenest:640953- 84.9 HuGenest:309874-HuGenest:1072798 HuGenest:761816-HuGenest:136620 HuGenest:441104-HuGenest:97712 HuGenest:800086-HuGenest:352501 HuGenest:363233-HuGenest:210139_s_at:48107 HuGenest:338800-HuGene st:532682 HuGene st:988715-HuGene st:853970-HuGene st

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MTIX 788358-HuGenest:20578-HuGenest:92311- 9.84E-07 1.4411 4.35 76.4 67.5 HuGenest:501820-HuGenest:208581_x_at:73687- 83.9 HuGenest:905260-HuGenest:1087816 HuGenest:204326_x_at:96216-HuGenest:764373 HuGenest:103649-HuGene st:40373 HuGene st:198342-HuGenest CALDI 796040-HuGenest:839187-HuGenest:412659- 1.02E-06 1.4584 3.29 76.7 67.7 HuGenest:1023569-HuGenest:450656- 84.1 HuGenest:212077_at:201616_s_at:816439 HuGenest:165931-HuGene_st:201617_x_at:576686 HuGenest:1094139-HuGenest:201615_x_at:519079 HuGenest:558226-HuGenest:755661 HuGenest:243084_at:318906-HuGenest:688034 HuGenest:215199_at MSRB3 483115-HuGenest:439736-HuGenest:1096860- 1.20E-06 1.4754 2.24 77 68-84.4 HuGenest:644381-HuGenest:225790_at:306630 HuGenest:1073255-HuGenest:121556 HuGenest:126154-HuGenest:72517 HuGenest:480208-HuGenest:331986 HuGenest:294511-HuGenest:204701 HuGenest:1554127_s_at:42731-HuGene_st:675396 HuGenest:174560-HuGenest:1566481_at SPONI 209437_s_at:209436_at:892181-HuGenest:960315- 1.46E-06 1.4862 1.88 77.1 68.2 HuGenest:377887-HuGenest:253667- 84.5 HuGenest:48054-HuGenest:1008441 HuGene_st:979120-HuGenest:213994_s_at:811254 HuGenest:928583-HuGenest:405680 HuGenest:963535-HuGenest:836638 HuGenest:1033364-HuGenest:965345 HuGenest:936102-HuGenest:555640 HuGenest:22053-HuGenest:234367 HuGenest:224488_s_at:327210-HuGenest:481375 HuGene-st:213993_at:1013182-HuGenest C2orf4O 1011921-HuGenest:304065-HuGenest:441303- 1.69E-06 1.4159 2.97 76.1 67-83.6 HuGenest:1001854-HuGenest:999754 HuGenest:893886-HuGene st:951843 HuGene st:375926-HuGene st SORBS1 1041567-HuGenest:83451-HuGenest:29118- 2.18E-06 1.4269 2.54 76.2 67.2 HuGenest:222513_s_at:617821-HuGenest:56685- 83.7 HuGenest:280855-HuGenest:67922 HuGenest:1028489-HuGenest:611267 HuGenest:931477-HuGenest:66752 HuGenest:618734-HuGenest:624287 HuGenest:211819_s_at:581936 HuGenest:218087_s_at:1039879-HuGene-st:45815 HuGenest:186556-HuGenest:628496 HuGenest:242736_at C4orf34 576095-HuGenest:1061109-HuGenest:698934- 2.55E-06 1.3851 1.95 75.6 66.5 HuGenest:634224-HuGenest:854845- 83.1 HuGenest:18233-HuGenest:275684 HuGenest:784949-HuGenest:346086 HuGenest:91468-HuGenest:936558 HuGenest:163564-HuGenest:614699 HuGenest:428090-HuGenest:340671 HuGenest:90795-HuGenest:823553 HuGene st:431110-HuGene st:719502-

HuGenest:850208-HuGenest:224990_at:542653 HuGene-st PDGFRA 782752-HuGenest:789846-HuGenest:116091- 2.94E-06 1.4819 1.37 77.1 68.1 HuGenest:860506-HuGenest:537532- 84.4 HuGenest:112478-HuGenest:97681 HuGenest:514113-HuGenest:561375 HuGenest:115277-HuGenest:240764 HuGenest:578952-HuGenest:723105 HuGenest:230638-HuGene_st:544163 HuGenest:50957-HuGenest:468599 HuGenest:328136-HuGene st:346391 HuGene st:203131 at:853019-HuGene st FGFR2 476373-HuGenest:92078-HuGenest:969020- 3.55E-06 1.527 1.31 77.7 68.9-85 HuGenest:1022426-HuGenest:203639_s_at:24514 HuGenest:614945-HuGenest:211398_at:1097953 HuGenest:117962-HuGenest:777874 HuGenest:829764-HuGenest:868500 HuGenest:211401_s_at:403546-HuGenest:850416 HuGenest:208234_x_at:537762-HuGene_st:132866 HuGenest:426700-HuGene st:208228_s_at:831045 HuGene st:203638 s at:240913 at:230842 at PPPIR12B 23543-HuGenest:654289-HuGenest:947526- 4.26E-06 1.3592 2.21 75.2 66.1 HuGenest:714709-HuGenest:544138- 82.8 HuGenest:1557553_at:227411 HuGenest:201958_s_at:1559911_at:74838 HuGenest:201957_at:233700_at:67323 HuGenest:767707-HuGenest:224270_at:50561 HuGenest:233359-HuGenest:565179 HuGene st:317428-HuGenest:442074 HuGenest:591561-HuGenest FAM129A 148319-HuGenest:19042-HuGenest:1075897- 4.59E-06 1.4144 1.8 76 67-83.5 HuGenest:4911O-HuGenest:245230 HuGenest:154650-HuGenest:203917 HuGenest:503184-HuGenest:373453 HuGenest:432126-HuGenest:786874 HuGenest:648379-HuGenest:1033222 HuGenest:217966_s_at:574775 HuGenest:217967_s_at:156986-HuGenest:9160 HuGenest:212626-HuGenest:935377 HuGenest:921695-HuGenest:1053262-HuGenest POSTN 210809_s_at:297712- 4.94E-06 1.3944 2.25 75.7 66.7 HuGenest:1555778_a_at:608435-HuGenest:743877- 83.3 HuGenest:753556-HuGenest:388659 HuGenest:954838-HuGenest:724846 HuGenest:588010-HuGenest:713459 HuGenest:713707-HuGenest:106590 HuGenest:538299-HuGenest:649547 HuGenest:13993-HuGenest:417058 HuGenest:636479-HuGenest:228481_at:874100 |HuGene st:776445-HuGene st:779754-HuGene st

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HuGenest:471274-HuGene-st:1086281 HuGene st:740018-HuGene st:233829 at TMEM47 20487-HuGenest:587019-HuGenest:458329- 1.86E-05 1.301 2.02 74.2 65.1-82 HuGenest:944333-HuGenest:292459 HuGenest:436914-HuGenest:632184 HuGenest:209655_s_at:885991-HuGenest:33524 HuGenest:528167-HuGenest:555631 HuGenest:595266-HuGenest:503408 HuGenest:296998-HuGenest:672458 HuGenest:64704-HuGenest:285813 HuGene st:865055-HuGene st:734911-HuGene st QKI 214543_x_at:212262_at:696914-HuGene_st:363144- 1.93E-05 1.3452 1.31 74.9 65.8 HuGenest:820387-HuGenest:646624- 82.6 HuGenest:979853-HuGenest:658669 HuGenest:748520-HuGenest:656477 HuGenest:296134 HuGene_st:1555154_a_at:212636_at:234492_at:46289 4-HuGene st:1055543-HuGene st VSIG2 985113-HuGenest:555767-HuGenest:391438- 2.01E-05 1.2959 2.05 74.1 65.1 HuGenest:1093892-HuGenest:675062- 81.9 HuGenest:788466-HuGenest:826720 HuGenest:997596-HuGenest:1069591 HuGenest:228232_s_at:223925-HuGenest:637781 HuGenest:265221-HuGenest:652010 HuGenest:265186-HuGenest:343187 HuGenest:1095607-HuGenest HSPA1A 979726-HuGenest:1069731-HuGenest:50191- 2.16E-05 1.2699 2.41 73.7 64.6 HuGenest:799087-HuGenest:200799_at:539596- 81.5 HuGenest:150764-HuGenest:200800_s_at:492579 HuGenest APIS2 230413_s_at:230264_s_at:99873-HuGenest:57979- 3.39E-05 1.2572 1.92 73.5 64.3 HuGenest:985324-HuGene st:203300_x_at:84828- 81.3 HuGene st:910415-HuGene st FKBP5 204560_at:224856_at:246403-HuGenest:513199- 3.41E-05 1.2369 1.71 73.2 64-81 HuGenest:69253-HuGenest:642461 HuGenest:467598-HuGenest:1038165 HuGenest:512075-HuGenest:224840_at:797941 HuGenest:633285-HuGenest:511644 HuGenest:469540-HuGenest:209829 HuGenest:800516-HuGenest:247764 HuGenest:468711-HuGenest:112353 HuGene st:746630-HuGenest:337035 HuGenest:1014328-HuGenest:292916-HuGenest KCNMB1 17348-HuGenest:414025-HuGenest:792493- 3.74E-05 1.2189 2.66 72.9 63.7 HuGenest:131717-HuGenest:569127- 80.8 HuGenest:17962-HuGenest:504462 HuGene-st:758432-HuGenest:209948_at:772102 HuGenest:518039-HuGenest VIM 564251-HuGenest:201426_s_at:234475- 4.15E-05 1.2225 1.86 72.9 63.7 HuGenest:319318-HuGenest:339807- 80.9 HuGenest:527110-HuGenest:994975 HuGenest:837477-HuGenest:302722 HuGenest:516025-HuGenest:1079757 HuGenest:398387-HuGenest:155888 HuGenest:139661-HuGenest:192324 HuGene st:1093618-HuGene st:364983-

HuGene st:436158-HuGene st:410777 HuGene-st:1555938_xat SORBS2 238751 at:805920-HuGene st 4.23E-05 1.3007 2.1 74.2 65.1-82 C6orf2O4 486932-HuGenest:573436-HuGene st:400510- 4.90E-05 1.2042 2.07 72.6 63.5 HuGenest:228202_at:123307-HuGenest:181714- 80.6 HuGenest:206020-HuGenest:949623 HuGenest:814579-HuGenest:515524 HuGenest:514175-HuGenest FAM55D 633727-HuGenest:966568-HuGenest:625133- 5.67E-05 1.1792 3.48 72.2 62.9 HuGenest:858568-HuGenest:220645_at:201856- 80.2 HuGenest:1013940-HuGenest:316604 HuGenest:450702-HuGenest:1028406 HuGenest:1090862-HuGenest:741930 HuGenest:981211-HuGenest:970069 HuGenest:259706-HuGenest:291282 HuGenest:56493-HuGenest:888970 HuGene_st:821065-HuGenest:53354 HuGenest:752570-HuGenest:539086 HuGenest:204142-HuGenest TIMP2 1087828-HuGenest:231579_s_at:436546- 6.40E-05 1.2298 1.82 73.1 63.8 HuGenest:799495-HuGenest:563754- 80.9 HuGenest:914626-HuGenest:526357 HuGenest:203167_at:760416-HuGenest:651774 HuGenest:965142-HuGenest:224540 HuGenest:690107-HuGene_st:224560_at:319958 HuGenest:437652-HuGenest:43390 HuGenest:727465-HuGenest:310783 HuGenest:750028-HuGenest:957648 HuGenest:106688-HuGenest:289430 HuGenest:740790-HuGenest ELOVL5 NA 8.15E-05 1.1814 2.05 72.3 63-80.3 ACTA2 215787_at:743686-HuGenest:200974_at:1070983- 1.OOE-04 1.2318 1.81 73.1 63.9 HuGenest:120087-HuGenest:980364- 80.9 HuGenest:529704-HuGenest:855050 HuGenest:530590-HuGenest:692252 HuGenest:404109-HuGenest:630797 HuGenest:670805-HuGenest:293590 HuGenest:757648-HuGenest:445454 HuGenest:479447-HuGenest:548186 HuGenest:237159-HuGenest:90357 HuGenest:313690-HuGenest:183075 HuGenest:785232-HuGenest CiS 208747_s_at:233042_at:620011- 0.0001 1.2896 1.61 74 64.8 HuGenest:1555229_a_at:245571-HuGenest:426716- 81.9 HuGenest:866948-HuGenest:705447 HuGenest:947234-HuGenest:682561 HuGenest:332123-HuGenest LOC38776 1062323-HuGenest 0.0001 1.1943 1.36 72.5 63.2 3 80.5 CLU 222043 at:939366-HuGene st:832450- 0.0001 1.2285 1.42 73 63.8-81 HuGenest:208792_s_at:125360-HuGenest:216446 HuGenest:208791_at:1054768-HuGenest:1034873 HuGenest:1056536-HuGenest:787017 HuGenest:1060096-HuGenest:591687 HuGenest:1014914-HuGenest:213483 HuGene st:459630-HuGene st:1036064- | | ,

HuGenest:972503-HuGenest:492827 HuGenest:485686-HuGenest

MT1H 197989-HuGenest:589780-HuGenest:800631- 0.0001 1.1885 4.55 72.4 63.1 HuGenest:854292-HuGenest:644419- 80.4 HuGenest:851562-HuGenest:590830 HuGenest:727551-HuGenest:51225 HuGenest:206461_x_at:1099945-HuGenest:334778 HuGenest:6545-HuGenest:451479 HuGene-st:621584-HuGenest:885933 HuGenest:73199-HuGenest:882631-HuGenest RGS2 331021-HuGenest:202388_at:895469- 0.0001 1.1617 1.94 71.9 62.6 HuGenest:962521-HuGenest:843420- 79.9 HuGenest:767847-HuGenest:1022759 HuGenest:507303-HuGenest:121934 HuGenest:1094262-HuGenest:1067241 HuGenest:111860-HuGenest:661918-HuGene_ st FBN1 192231-HuGenest:794561-HuGenest:1094040- 0.0002 1.1368 1.93 71.5 62.2 HuGenest:427611-HuGenest:394963- 79.6 HuGenest:828273-HuGenest:202765_s_at:162818 HuGenest:169932-HuGenest:192029 HuGene-st:288955-HuGenest:600623 HuGenest:941525-HuGene st:971683 HuGenest:82155-HuGenest:359130 HuGene st:404656-HuGenest:921008 HuGenest:999573-HuGenest:112593-HuGenest ANKRD25 808074-HuGenest:932564-HuGenest:143731- 0.0002 1.1162 1.56 71.2 61.9 HuGenest:292383-HuGenest:393569- 79.3 HuGenest:201770-HuGenest:973796 HuGenest:824703-HuGenest:109143 HuGenest:132685-HuGenest:698165 HuGenest:218418_sat MT1G 226585-HuGenest:495514-HuGenest:159768- 0.0002 1.0893 2.66 70.7 61.3 HuGenest:186270-HuGenest:855342- 78.8 HuGenest:449379-HuGenest:1100995 HuGenest:617733-HuGenest:914660 HuGenest:884883-HuGenest:903179 HuGenest:311881-HuGenest:977536 HuGenest:210472_at:1061010-HuGenest:415267 HuGenest:1048754-HuGenest:1011704 HuGenest:59546-HuGenest:917923 HuGenest:204745_x_at MYL9 201058_s_at:543240-HuGenest:923797- 0.0003 1.1288 2.18 71.4 62-79.4 HuGenest:173220-HuGenest:874422 HuGenest:925187-HuGenest:979054 HuGenest:676360-HuGenest:117460 HuGenest:1092848-HuGenest:608837 HuGenest:404703-HuGenest:50995 HuGene st:206106-HuGene st:995028-HuGene st

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CFL2 545956-HuGenest:833414-HuGenest:214239- 0.0009 1.0592 1.75 70.2 60.8 HuGenest:192253-HuGenest:224663_s at:694174- 78.4 HuGenest:233496_s_at:992798-HuGene-st:328584 HuGenest:950857-HuGenest:612593 HuGenest:95686-HuGenest:177218 HuGenest:451953-HuGene st:800232 HuGenest:575557-HuGenest:794701-HuGenest RBMS1 375424-HuGenest:87825-HuGenest:1046943- 0.0009 1.1417 1.55 71.6 62.3 HuGenest:209868_s_at:207266_x-at:225269_s_at:23 79.7 8185_at SELENBPI 914892-HuGenest:582091-HuGenest:643114- 0.0009 1.0563 1.7 70.1 60.7 HuGenest:532506-HuGenest:823159- 78.4 HuGenest:171447-HuGenest:189960 HuGenest:75763-HuGenest:834358 HuGenest:245623 HuGenest:214433_s_at:233267_at:564186 HuGenest:637748-HuGenest:200643 HuGenest:781415-HuGenest:208204 HuGenest:730504-HuGenest:1008117 HuGenest:801694-HuGenest:433986 HuGenest:183676-HuGenest:634656 HuGenest:1087258-HuGenest ENAM 212592_at 0.0011 1.0044 2.58 69.2 59.9 77.5 MT1F 987574-HuGenest:213629_x_at:171840- 0.0012 0.9654 2.2 68.5 59.1 HuGenest:217165_x_at:867979-HuGenest:354284- 76.9 HuGenest:424055-HuGenest:998184 HuGenest:616693-HuGenest:459005 HuGenest:221141-HuGenest:338518 HuGenest:951452-HuGenest:915306 HuGenest:506126-HuGenest:845635 HuGenest:1048483-HuGenest:1094672 HuGenest:576368-HuGenest:414800-HuGenest CD163 620892-HuGenest:215049_x_at:32161- 0.0013 1.0234 1.9 69.6 60.2 HuGenest:867013-HuGenest:899841- 77.9 HuGenest:662901-HuGenest:97726 HuGenest:180883-HuGenest:706228 HuGenest:849505-HuGenest:217692 HuGenest:566183-HuGenest:154492 HuGenest:737668-HuGenest:203645_s_at:948100 HuGenest:900552-HuGenest:288236-HuGenest GUCY1A3 560981-HuGenest:1088572-HuGenest:692186- 0.0015 1.0136 2.69 69.4 60-77.7 HuGenest:648114-HuGenest:783434 HuGenest:221942_s_at:1026405-HuGenest:256104 HuGenest:965063-HuGenest:889044 HuGenest:752296-HuGenest:239580_at:185668 HuGenest:120195-HuGene-st:324658 HuGene st:229530 at TNFRSF17 1062688-HuGenest:38682-HuGenest:558270- 0.0015 1.0199 2.08 69.5 60.1 HuGenest:631025-HuGenest:24518- 77.7 HuGenest:240754-HuGenest:193693 HuGenest:255074-HuGenest:493368 HuGenest:191710-HuGenest:610232 HuGenest:544680-HuGene st:205576 HuGenest:738267-HuGene st:746498-HuGenest

CAVI 793412-HuGenest:1007317- 0.0016 1.0215 1.58 69.5 60.1 HuGenest:212097_at:203065_s_at:812832- 77.8 HuGenest:505037-HuGenest:819580 HuGenest:348883-HuGenest:659416 HuGenest:698493-HuGenest:861877 HuGenest:518081-HuGenest:35773-HuGenest CKB 718720-HuGenest:769422-HuGenest:581051- 0.0019 0.9741 2.27 68.7 59.2-77 HuGenest:549987-HuGenest:24890 HuGenest:1041238-HuGenest:16603 HuGenest:480007-HuGene_st:435665 HuGenest:25470-HuGenest:40899 HuGene_st:896708-HuGenest:373774 HuGenest:963331-HuGenest:23457 HuGenest:766369-HuGene-st:200884_at:405417 HuGene st:888623-HuGene st:396007-HuGene st WWTR1 202132_at:249804-HuGenest:735408- 0.002 0.9904 1.48 69 59.6 HuGenest:925151-HuGenest:213564- 77.3 HuGenest:561456-HuGenest:125734 HuGenest:367743-HuGenest:153369 HuGenest:628871-HuGenest:942493 HuGenest:949013-HuGenest:202134sat:426662 HuGenest:586249-HuGenest:228629_s_at:506281 HuGenest HMGCS2 729816-HuGenest:658722-HuGenest:253113- 0.0022 0.8767 2.67 66.9 57.5 HuGenest:900260-HuGenest:253100- 75.5 HuGenest:283650-HuGenest:624250 HuGenest:439478-HuGenest:407398 HuGenest:171889-HuGenest:397691 HuGenest:448587-HuGenest:593619 HuGenest:371076-HuGenest:228587 HuGenest:888308-HuGenest:538023 HuGenest:204607_at:43162-HuGenest:865416 HuGenest:619083-HuGene st:789982 HuGene st:616916-HuGene st MAFB 876871-HuGenest:600037-HuGene_st:177002- 0.0034 0.9563 1.66 68.4 59-76.8 HuGene st:3125-HuGenest:1057503 HuGenest:274807-HuGenest STOM 201060_x_at:669723-HuGenest:1099166- 0.0035 1.0176 1.21 69.5 60.1 HuGenest:201061_s_at:22513-HuGenest:430393- 77.7 HuGenest:486266-HuGenest:47888-HuGene_ st CD14 327635-HuGenest:201743_at:822666- 0.0035 0.9646 1.58 68.5 59-76.9 HuGenest:999890-HuGenest:753790 HuGenest:1080129-HuGenest:532035 HuGenest:1087885-HuGenest:528527 HuGenest:851691-HuGene st:905038 HuGene st:437599-HuGenest:31858-HuGenest MUC4 1061780-HuGenest:43545- 0.0039 1.0448 1.2 69.9 60.5 HuGenest:217110_s_at:47402-HuGenest:1042572- 78.2 HuGenest:548777-HuGenest:612341 HuGenest:711231-HuGenest:217109_at:278229 HuGenest:536580-HuGenest:235055_x_at:743233 HuGenest:223515-HuGenest:204895_x_at:670488 HuGenest:106413-HuGenest:35359 HuGenest:344313-HuGenest:284609 HuGene st:882714-HuGenest:512794-HuGenest

APOE 520118-HuGene st:886930-HuGene st:771679- 0.0044 0.9406 1.56 68.1 58.7 HuGenest:944600-HuGenest:169546- 76.6 HuGenest:483757-HuGenest:16650 HuGenest:511913-HuGenest:1099818 HuGenest:33219-HuGenest:663513-HuGenest SI 9605-HuGenest:514814-HuGenest:809314- 0.0054 0.9299 2.79 67.9 58.5 HuGenest:576613-HuGenest:45502- 76.4 HuGenest:369676-HuGene_st:438636 HuGenest:267204-HuGenest:326716 HuGenest:897825-HuGenest:377666 HuGenest:519273-HuGenest:325741 HuGenest:245381-HuGenest:108368 HuGenest:464198-HuGenest:679193 HuGene st:168180-HuGenest LOC28538 242447_at 0.0058 0.7422 1.26 64.5 55-73.2 2 HLA- 971813-HuGenest 0.0063 1.0668 1.51 70.3 60.9-78.6 DRB1 ANTXR1 241549_at:232956_at 0.0071 0.9507 1.29 68.3 58.8-76.7 FAM46C 197110-HuGenest:220306_at:110466- 0.0085 0.9172 1.38 67.7 58.2-76.1 HuGenest:988119-HuGenest:1098424 HuGenest:560529-HuGenest:387944 HuGenest:38645-HuGene st:221689 HuGene st:322082-HuGene st TIMP3 767021-HuGene_st:201150_s_at:201148_s_at:228752- 0.0091 0.9064 1.81 67.5 58-76 HuGenest:241221-HuGenest:201147_s_at:125730 HuGene _st LOC28366 235567_at:236266_at:1562682at:240951_at 0.0099 0.7796 1.22 65.2 55.6-73.8 6 1 GREMI 569365-HuGenest:407017- 0.0106 0.8579 3.03 66.6 57-75.1 HuGenest:218468_s_at:292333-HuGenest:330742 HuGenest:546941-HuGenest:556201 HuGenest:484435-HuGenest:326978 HuGenest:144073-HuGenest:411208 HuGenest:1081939-HuGene-st:345681 HuGenest:2445-HuGenest:864620-HuGenest FCGBP 22847-HuGenest:203240_at:338164- 0.0121 0.7889 1.99 65.3 55.7-74 HuGenest:516715-HuGenest:88809 HuGenest:948682-HuGenest:311904 HuGenest:997435-HuGenest:841000 HuGenest:508230-HuGenest:226428 HuGenest:634071-HuGenest:948120 HuGenest:1079875-HuGenest:71797 HuGenest:781083-HuGenest:426005 HuGenest:27264-HuGenest:16108 HuGenest:63672-HuGenest:1085208 HuGenest:708701-HuGenest HSPA2 831351-HuGenest:270747-HuGenest:720913- 0.0123 0.8908 1.43 67.2 57.7 HuGene st:660812-HuGenest:939000- 75.7 HuGenest:920196-HuGenest COL6A1 138366-HuGenest:528191-HuGenest:884210- 0.0126 0.8452 1.45 66.4 56.9-75 HuGenest:57954-HuGenest:737256 HuGenest:858575 HuGenest:212937_s_at:214200_s_at:190064 HuGene st:216904 at SELM NA 0.0133 0.8596 1.32 66.6 57.2-75.2

FLNA 296693-HuGenest:685285-HuGenest:704065- 0.0157 0.7967 1.59 65.5 55.9 HuGenest:445061-HuGenest:11735- 74.1 HuGenest:1066792 HuGenest:214752_x_at:213746_s_at:871038 HuGenest:396236-HuGenest:200859_x_at:786282 HuGenest:136680-HuGenest:50466 HuGenest:955232-HuGenest:588605 HuGenest:40025-HuGenest:1002306 HuGenest:833338-HuGenest:86435 HuGenest:172457-HuGenest COX7A1 386303-HuGene-st:354428-HuGenest 0.0161 0.8613 1.32 66.7 57.2 75.3 EMP3 736604-HuGenest:155271-HuGene-st:584704- 0.0164 0.8053 1.41 65.6 56.1 HuGenest 74.2 ITLN1 389198-HuGenest:496499-HuGene_st:48547- 0.021 0.7137 2.54 63.9 54.4 HuGenest:552029-HuGenest:126777- 72.7 HuGenest:223597_at:281671-HuGenest:45052 HuGenest:573120-HuGenest:137624 HuGenest:948945-HuGenest:527196 HuGenest:358648-HuGenest:45640 HuGenest:512550-HuGenest:839317 HuGene st:634036-HuGenest:101083 HuGenest:857541-HuGenest:404069-HuGene st ClOorf99 227735_s-at:563767-HuGenest:963471- 0.0218 0.724 1.76 64.1 54.7 HuGenest:965947-HuGenest:1081062- 72.9 HuGenest:354432-HuGenest:602661 HuGenest:227736_at:1009594-HuGenest:969063 HuGenest:77052-HuGenest:483367 HuGenest:50662-HuGenest:738457 HuGenest:69019-HuGenest:215415 HuGenest:1003926-HuGenest:676577 HuGenest:676855-HuGenest:225297 HuGenest:560897-HuGenest:886384 HuGene st:303754-HuGene st CSRP1 453033-HuGenest:673637-HuGenest:607761- 0.023 0.7234 1.39 64.1 54.6 HuGenest:582630-HuGenest:654799- 72.9 HuGenest:258474-HuGenest:200621_at:1028504 HuGenest:802909-HuGenest:339914 HuGenest:533385-HuGenest:256461 HuGenest:1043113-HuGenest:72101 HuGenest:105671-HuGenest:339691 HuGenest:108781-HuGenest:133369 HuGenest:614016-HuGenest:629648 HuGenest:81550-HuGenest PTGER4 450915-HuGenest:1067155-HuGenest:812085- 0.0237 0.8101 1.41 65.7 56.2 HuGenest:1943-HuGenest:109314- 74.4 HuGenest:204897_at:252442-HuGenest:800125 HuGenest:965220-HuGenest:446764 HuGenest:204896_s_at:23686-HuGenest:548266 HuGenest:392964-HuGenest:986807 HuGenest:619166-HuGenest TPM2 828216-HuGenest:373854-HuGenest:981165- 0.026 0.7539 1.53 64.7 55.2 HuGenest:191586-HuGenest:445912- 73.4 HuGenest:446500-HuGenest:922931 HuGenest:336603-HuGene st:272114 HuGene st:375166-HuGene st:8388-

HuGenest:204083_s_at:544548-HuGenest:945443 HuGenest:628440-HuGenest:763118 HuGenest:538951-HuGenest

PIGR 748831-HuGenest:226147_s_at:166398- 0.0278 0.7282 1.59 64.2 54.7-73 HuGenest:593192-HuGenest:204213_at:557727 HuGenest:229659_s_at:242106-HuGenest:146237 HuGenest:883137-HuGenest:691362 HuGenest:201991-HuGenest:1045753 HuGenest:589879-HuGenest:1017162 HuGenest:325979-HuGenest:105903 HuGenest:1063932-HuGenest:207526 HuGenest:566905-HuGenest HLA-C 754900-HuGene-st 0.0279 0.9253 1.24 67.8 58.3 76.2 PRNP 178399-HuGene_st:201300_s_at:386578- 0.0288 0.798 1.24 65.5 56-74.2 HuGenest:783439-HuGenest CCL11 495934-HuGenest 0.0361 0.8547 1.32 66.5 57.1-75 C1QC 137801-HuGenest:851445-HuGenest 0.0391 0.7457 1.36 64.5 54.9-73.3 CYR61 736150-HuGene-st:385534-HuGenest:48239- 0.0425 0.7875 1.47 65.3 55.7-73.9 HuGenest:242630-HuGenest SERPINGI NA 0.0503 0.7659 1.44 64.9 55.4-73.6 TYROBP NA 0.053 0.8176 1.17 65.9 56.3-74.5 GJA1 NA 0.0561 0.7839 1.76 65.2 55.6-73.9 PTRF NA 0.0624 0.7354 1.5 64.3 54.8-73.1 CLCA1 NA 0.0681 0.7855 1.61 65.3 55.8-74 SPARC NA 0.0684 0.6702 1.45 63.1 53.5-71.9 COL4A2 NA 0.0738 0.7081 1.32 63.8 54.3-72.5 RAB31 NA 0.1041 0.8159 1.14 65.8 56.3-74.4 NIDI NA 0.105 0.7428 1.33 64.5 54.9-73.2 FN1 NA 0.1121 0.5769 1.73 61.3 51.7-70.2 MSN NA 0.1499 0.7215 1.15 64.1 54.6-72.9 MMP2 NA 0.1755 0.6219 1.24 62.2 52.5-71.2 COL1A2 NA 0.1891 0.65 1.9 62.7 53.2-71.6 FOSB NA 0.2076 0.6389 2.17 62.5 52.9-71.4 HBB NA 0.2357 0.6434 1.28 62.6 53-71.5 POU2AF1 NA 0.2389 0.6564 1.18 62.9 53.3-71.7 COL3A1 NA 0.2551 0.5538 1.35 60.9 51.3-69.9 SMOC2 NA 0.2701 0.6533 1.34 62.8 53.2-71.7 MUC2 NA 0.2802 0.8523 1.22 66.5 57-75 Sep-06 NA 0.3109 0.5713 1.21 61.2 51.7-70.2 LUM NA 0.3157 0.5442 1.54 60.7 51.1-69.7 C1QB NA 0.3668 0.5005 1.24 59.9 50.4-69 TGFB1I1 NA 0.4093 0.4951 1.35 59.8 50.1-68.8 ALDH1A1 NA 0.4232 0.354 1.4 57 47.4-66.2 LRIG1 NA 0.4614 0.5998 1.26 61.8 52.2-70.7 C8orf4 NA 0.475 0.483 1.44 59.5 49.9-68.5 EGRI NA 0.4851 0.5374 1.38 60.6 51-69.6 LOC65274 NA 0.4864 0.1722 1.09 53.4 43.8-62.8

IGKV1D- NA 0.5177 0.1597 1.1 53.2 43.7-62.5

13 COL15A1 NA 0.6601 0.54 1.22 60.6 51-69.6 IGFBP5 NA 0.7663 0.3504 1.25 57 47.4-66.3 LGALS1 NA 0.8555 0.4626 1.16 59.1 49.5-68.3 COL6A3 NA 0.8739 0.4412 1.2 58.7 49.1-67.9 HLA- NA 0.9084 0.5417 1.28 60.7 51.1-69.6 DQA1 HLA-DRA NA 0.9084 0.5391 1.28 60.6 51-69.6 ST6GALN NA 0.9452 0.2594 1.15 55.2 45.6-64.5 AC1 HLA-DPA1 NA 0.9664 0.4166 1.39 58.3 48.7-67.4 IGLV1-44 NA 0.9777 0.2865 1.07 55.7 46.1-64.9 TNC NA 0.9905 0.3682 1.09 57.3 47.7-66.5 HBA1 NA 0.9979 0.47 1.21 59.3 49.6-68.4 HBA2 NA 0.9979 0.4705 1.21 59.3 49.6-68.3

TABLE3

TargetPS Symbol Signif. FDR D.val5 FC Sens- CI (95) Spec 230788_at SPTLC3:GCNT2 2.1587E-27 3.9562 13.36 97.6 94.2-99.2 228706_s at CLDN23 4.2694E-20 3.0727 3.47 93.8 88.3-97.1 231120_x_at PKIB 5.9397E-20 3.1191 3.28 94.1 88.6-97.3 224412_s at TRPM6 2.2514E-19 3.0115 7.5 93.4 87.7-96.8 220037 s at XLKD1 3.5991E-19 2.9405 7.44 92.9 87-96.5 209613_s at ADH1B:ADHIA 4.6957E-19 3.0158 4.67 93.4 87.7-96.9 204719_at ABCA8 1.2559E-18 2.9171 6.82 92.8 86.8-96.5 231773_at ANGPTL1 1.4172E-17 2.7946 4.64 91.9 85.6-95.9 225575 at LIFR 2.4532E-17 2.7797 6.36 91.8 85.5-95.8 220812_s at HHLA2 3.4739E-17 2.6718 10.02 90.9 84.4-95.2 211549_sat HPGD 3.6502E-17 2.8451 3.21 92.3 86.1-96.1 202920 at ANK2 2.5934E-16 2.6488 6.76 90.7 84.2-95.1 231925_at P2RY1 1.4091E-15 2.5329 3.6 89.7 82.8-94.4 207080_s at PYY 3.5022E-15 2.4783 11.71 89.2 82.2-94 228885_at RPL24:LOC731365 1.2312E-14 2.5575 1.63 90 83.1-94.6 228766_at CD36 6.2677E-14 2.4687 1.65 89.1 82.1-94 204931_at TCF21 2.5147E-13 2.3036 2.34 87.5 80.1-92.8 205433_at BCHE 3.1756E-13 2.2538 6.21 87 79.5-92.5 207980_s at CITED2 5.2905E-13 2.2709 1.64 87.2 79.7-92.6 209170_s at GPM6B 4.0429E-12 2.1588 3.59 86 78.1-91.6 220376_at LRRC19 6.7548E-12 2.0763 4.51 85 77.1-90.9 228504_at No Symbol 9.1926E-12 2.152 1.61 85.9 78.2-91.6 228854_at No Symbol 9.1926E-12 2.1538 1.61 85.9 78.2-91.6 235146_at No Symbol 9.1926E-12 2.1537 1.61 85.9 78.2-91.6 221305_s at UGT1A1O:UGT1A7:UGT1A8:UGT1 1.0319E-11 2.0677 4.56 84.9 77.1-90.9 A1:UGT1A9:UGT1A6:UGT1A5:UG TlA3:UGT1A4 03881_s _at DMD 5.0063E-11 2.0137 4.74 84.3 76.3-90.4 206637_at P2RY14 1.3104E-10 1.9836 2 83.9 75.8-90.1

214598_at CLDN8 2.9225E-10 1.8624 12.96 82.4 74.1-88.9 227529 s at AKAP12 7.4077E-09 1.7434 2.83 80.8 72.3-87.5 219948 x at LOC642329:UGT2A3 8.638E-09 1.741 4.89 80.8 72.3-87.6 222717_at SDPR 9.6207E-08 1.5993 2.21 78.8 70.1-85.9 229831_at CNTN3 1.1953E-07 1.6145 3.93 79 70.3-86.1 204940_at PLN 4.1416E-07 1.5439 2.01 78 69.2-85.2 227827 at SORBS2 4.2323E-05 1.3016 2.1 74.2 65.1-81.9 238751at SORBS2 4.2323E-05 1.3015 2.1 74.2 65.1-82 209209_s at PLEKHC1 0.0007 1.0304 1.82 69.7 60.3-78 206664at SI 0.0054 0.9301 2.79 67.9 58.4-76.3

TABLE4 Gene ValidPSDOWN Signif. D.val FC Sens- CI Symbol FDR 5 Spec (95) ANK2 314086-HuGenest:282874-HuGenest:382431- 2.59E-16 2.6515 6.76 90.884.1-95.1 HuGenest:229308-HuGenest:779600-HuGene_st:297624 HuGenest:385943-HuGenest:730140-HuGenest:442277 HuGenest:699309-HuGenest:182816 HuGenest:202921_s_at:799860-HuGenest:868462 HuGenest:634421-HuGenest:571536-HuGenest:1050903 HuGenest:649509-HuGenest:239935-HuGenest:202920_at DMD 945600-HuGenest:12596-HuGenest:434657- 5.01E-11 2.0162 4.74 84.376.3-90.4 HuGenest:676962-HuGenest:1020969-HuGenest:170680 HuGenest:855670-HuGenest:909848-HuGenest:134644 HuGenest:887814-HuGenest:649184-HuGenest:110990 HuGenest:914217-HuGenest:961622-HuGenest:514011 HuGenest:842792-HuGenest:445483 HuGenest:208086_s_at:987362-HuGenest:997308 HuGenest ABCA8 57305-HuGenest:111752-HuGenest:61357- 1.26E-18 2.9182 6.82 92.886.8-96.5 HuGenest:123451-HuGenest:740746-HuGenest:512280 HuGenest:389185-HuGenest:427721-HuGenest:346028 HuGenest:224566-HuGenest:149653-HuGenest:680699 HuGenest:76772-HuGenest:742091-HuGenest:423333 HuGenest:559944-HuGenest:341399 HuGenest:1565780_at:863400-HuGenest:921748 HuGenest:623719-HuGenest:204719_at:123143 HuGene st:1077391-HuGenest TCF21 804657-HuGenest:106365-HuGenest:710514- 2.51E-13 2.3037 2.34 87.5 80.1-92.9 HuGenest:299556-HuGenest:608149-HuGenest:242233 HuGenest:655881-HuGenest:356773-HuGenest:788445 HuGenest:709897-HuGenest:605488-HuGenest:652466 HuGenest:204931_at:830709-HuGenest:273418 HuGenest:1004754-HuGenest:990861-HuGenest:238739 HuGenest:836241-HuGenest:110045 HuGenest:229529_at:1001969-HuGenest PLN 204938_s_at:418214-HuGene_st:769837-HuGenest:603329- 4.14E-07 1.5399 2.01 77.969.2-85.2 HuGenest:1048096-HuGenest:944510-HuGenest:430402 HuGenest:86633-HuGenest:795093-HuGenest:377757 HuGenest:770145-HuGenest:920628-HuGene_st:594048 HuGenest:800583-HuGenest:204939_s_at:556723 HuGene_st:818339-HuGene_st:175524-HuGenest:498924 HuGenest:204940_at

BCHE 228090-HuGenest:752051-HuGenest:800167- 3.18E-13 2.2544 6.21 8779.4-92.5 HuGenest:221362-HuGenest:155900-HuGenest:717363 HuGenest:536584-HuGene_st:146780-HuGenest:302487 HuGenest:508472-HuGene st:516293-HuGene st:968992 HuGene st:666625-HuGene st:923158-HuGene st P2RY14 528057-HuGenest:780310-HuGenest:235178- 1.31E-10 1.9805 2 83.975.9-90 HuGenest:352954-HuGenest:699489-HuGenest:38001 HuGenest:637791-HuGenest:25606-HuGenest:40647 HuGenest:896487-HuGenest:672149-HuGene_st:863820 HuGenest:352427-HuGenest:632821-HuGene st:116148 HuGenest:561792-HuGenest:840910-HuGenest:296420 HuGenest:974643-HuGene-st:206637_at PYY 656845-HuGenest:816022-HuGenest:633572- 3.50E-15 2.4828 11.71 89.382.2-94 HuGenest:20355-HuGenest:240779-HuGenest:638358 HuGenest:879780 HuGene st:207080 s at:211253 x at:368591-HuGene st CITED2 125201-HuGenest:410723-HuGenest:463405- 5.29E-13 2.269 1.64 87.279.7-92.6 HuGenest:401168-HuGenest:1012057-HuGenest:235057 HuGenest:361772-HuGenest:207980_s_at:1091907 HuGenest:985355-HuGenest:175990 HuGenest:227287_at:48433-HuGenest:209357_at:477746 HuGenest:243264-HuGenest:904401-HuGenest:328536 HuGenest:1095110-HuGenest:89784-HuGenest:206734 HuGene st:927615-HuGene st GPM6B 599862-HuGenest:754598-HuGenest:503642- 4.04E-12 2.1547 3.59 85.978.2-91.7 HuGenest:224935-HuGenest:754449-HuGenest:577489 HuGenest:1073242-HuGenest:560873-HuGenest:1003662 HuGenest:430217-HuGenest:903323-HuGenest:231962 HuGene_st:244945-HuGenest:562460-HuGenest:583561 HuGenest:209168_at PLEKH 831786-HuGenest:88016-HuGenest:1087035- 7.OOE-04 1.0307 1.82 69.760.4-78 Cl HuGenest:530331-HuGenest:209209_s_at:184398 HuGenest:904923-HuGenest:193550-HuGenest:468805 HuGenest:104495-HuGenest:604317-HuGenest:501652 HuGenest:118096-HuGenest:321532-HuGenest:675257 HuGenest:79496-HuGene st:590867-HuGenest:147248 HuGenest:627402-HuGene__st:377514-HuGenest ADHIB 1078343-HuGenest:512808-HuGenest:614446- 4.70E-19 3.0174 4.67 93.487.7-96.9 HuGenest:910188-HuGenest:422504-HuGenest:731361 HuGenest:209612_s_at:258079-HuGenest:568239 HuGenest:879930-HuGenest:420417-HuGenest:1025048 HuGenest:908335-HuGenest:654633-HuGenest:947292 HuGenest:1087125-HuGenest:1004870 HuGenest:209613_s_at:579636-HuGenest:681018 HuGenest:822774-HuGenest XLKD1 520080-HuGene_st:1091117-HuGenest:943125- 3.60E-19 2.9461 7.44 9387.1-96.6 HuGenest:444068-HuGenest:648558-HuGenest:346991 HuGenest:1006205-HuGenest:373107-HuGenest:682535 HuGenest:1083245-HuGenest:863143-HuGenest:820120 HuGenest:1044561-HuGenest:220037_s_at:541228 HuGenest:220256-HuGenest:289122 HuGenest:219059_s_at:246683-HuGenest:775976 HuGenest:207399-HuGene-st:1052557-HuGenest:92121 HuGenest

LRRC19 177641-HuGenest:1070020-HuGenest:1055140- 6.75E-12 2.0779 4.51 85.177.1-91 HuGenest:525999-HuGenest:937256-HuGenest:620791 HuGenest:891251-HuGene_st:707559-HuGenest:892056 HuGenest:764919-HuGenest:382143-HuGene_st:52584 HuGenest:920414-HuGenest:1028155-HuGenest:755055 HuGenest:678651-HuGene_st:1080156-HuGenest:530282 HuGenest:523877-HuGenest:335198-HuGenest:787709 HuGene-st:153175-HuGenest:220376_at SDPR 878908-HuGenest:781527-HuGenest:331976- 9.62E-08 1.6036 2.21 78.970-85.9 HuGenest:238150-HuGenest:306039-HuGenest:535903 HuGenest:302361-HuGenest:1005813-HuGenest:71118 HuGenest:992629-HuGenest:218711_s_at:293110 HuGenest:779040-HuGene-st:222717_at:970479 HuGene st:581654-HuGene st TRPM6 767074-HuGene_st:695352-HuGenest:411125- 2.25E-19 3.0111 7.5 93.487.7-96.8 HuGenest:221102_s_at:234864_s_at:240389_at:358229 HuGenest:755964-HuGenest:840301-HuGenest:959234 HuGenest:782639-HuGenest:833079-HuGenest:1066034 HuGenest:678013-HuGenest:249083-HuGenest:143934 HuGenest:159130-HuGenest:486486-HuGene-st:185057 HuGenest:878793-HuGene_st:133981 HuGenest:224412_s_at:202194-HuGenest LIFR 275506-HuGenest:323055-HuGenest:444251- 2.45E-17 2.7814 6.36 91.885.5-95.8 HuGenest:1056178-HuGenest:398104-HuGenest:917434 HuGenest:1044918-HuGenest:167500-HuGenest:423760 HuGenest:837336-HuGene_st:321505-HuGenest:918321 HuGenest:252278-HuGenest:884504-HuGenest:124845 HuGenest:499777-HuGenest:969722-HuGenest:709439 HuGenest:611505-HuGenest:227771_at:287217 HuGenest:205876_at:225571at:229185_at:233367_at:10930 11 -HuGene-st AKAP12 212419-HuGenest:231067_s_at:379659- 7.41E-09 1.7456 2.83 80.972.4-87.6 HuGenest:1010338-HuGenest:1075094-HuGenest:42401 HuGenest:522584-HuGenest:480972-HuGenest:948623 HuGenest:701945-HuGenest:276784-HuGenest:64858 HuGenest:210517_s_at:874382-HuGenest:909976 HuGenest:182037-HuGene-st:417182-HuGenest:722881 HuGene st CLDN23 403960-HuGene_st:25144-HuGene_st:947653- 4.27E-20 3.0748 3.47 93.888.2-97.1 HuGenest:228704_s_at:228706_s_at:320375 HuGenest:441629-HuGenest:367414-HuGenest:855269 HuGenest:228707_at:788659-HuGenest:698816 HuGenest:95789-HuGenest:270197-HuGenest:472976 HuGenest:280539-HuGene_st:1056334-HuGenest:516288 HuGenest:579963-HuGene_ st CD36 392196-HuGenest:274514-HuGenest:477005- 6.27E-14 2.4696 1.65 89.282.1-94 HuGenest:691585-HuGenest:872909-HuGenest:543050 HuGenest:603343-HuGene_st:514557-HuGene_st:296850 HuGenest:945913-HuGenest:495755 HuGenest:206488_s_at:1035854-HuGenest:887301 HuGenest:836370-HuGenest:209555_s_at:939919 HuGenest:507440-HuGene_st:151788-HuGenest:146280 HuGenest:360545-HuGenest:1051486 HuGene st:228766_at:512885-HuGenest RPL24 1559655_at:1559656 a at:228885 at 1.23E-14 2.5568 1.63 89.983.1-94.6

GCNT2 935239-HuGenest:225205-HuGene-st:1026280- 2.16E-27 3.9536 13.36 97.694.1-99.2 HuGenest:668101-HuGenest:1099985-HuGenest:698568 HuGenest:134540-HuGenest:697147-HuGenest:250092 HuGenest:611927-HuGenest:972833-HuGenest:168891 HuGenest:990860-HuGenest:109287-HuGenest:322116 HuGenest:231019-HuGenest:211020_at:959570 HuGenest:858764-HuGenest:215593_at:820195 HuGenest:239606_at:41059-HuGenest:669940 HuGenest:215595_x_at:230788_at PKIB 866170-HuGenest:1055812-HuGenest:264946- 5.94E-20 3.1204 3.28 94.188.6-97.3 HuGenest:684057-HuGenest:124791-HuGenest:134561 HuGenest:1026756-HuGenest:468593-HuGenest:1045852 HuGenest:939917-HuGenest:110205-HuGenest:660721 HuGenest:905229-HuGenest:223551_at:610426-HuGenest ANGPT 572942-HuGenest:891312-HuGenest:953040- 1.42E-17 2.7964 4.64 91.985.6-95.9 Li HuGenest:232844-HuGenest:145730-HuGenest:142205 HuGenest:227771-HuGenest:80584-HuGenest:982090 HuGenest:999640-HuGenest:672931-HuGenest:148578 HuGenest:224339_s_at:1046706 HuGenest:239183_at:155600-HuGenest:284674 HuGenest:231773_at:818064-HuGenest:978991 HuGene-st:728775-HuGenest SI 9605-HuGenest:514814-HuGenest:809314- 5.40E-03 0.9299 2.79 67.958.4-76.4 HuGenest:576613-HuGenest:45502-HuGenest:369676 HuGenest:438636-HuGenest:267204-HuGenest:326716 HuGenest:897825-HuGenest:377666-HuGenest:519273 HuGenest:325741-HuGenest:245381-HuGenest:108368 HuGenest:464198-HuGene-st:679193-HuGenest:168180 HuGene st HPGD 291863-HuGenest:375608-HuGenest:793406- 3.65E-17 2.8462 3.21 92.386.2-96.1 HuGenest:436293-HuGenest:75568 HuGenest:211549_s_at:684728-HuGenest:674596 HuGenest:527856-HuGenest:329920-HuGenest:748432 HuGenest:259392-HuGenest:769902-HuGenest:620673 HuGenest:450707-HuGenest:203913_s_at:304752 HuGenest:447604-HuGene_st:170968-HuGenest:852359 HuGenest:836377-HuGenest:242733_at:243846 HuGenest:136281 HuGenest:203914_x_at:211548_s_at:288252-HuGene_ st CLDN8 1018006-HuGenest:190634-HuGenest:590280- 2.92E-10 1.8639 12.96 82.474.1-88.9 HuGenest:186468-HuGenest:954438-HuGenest:428391 HuGene_st:480543-HuGenest:944337-HuGenest:179725 HuGenest:508584-HuGenest:1009114-HuGenest:948216 HuGenest:658285-HuGenest:1022600-HuGenest:737498 HuGenest:470015-HuGenest:103315-HuGene-st:699348 HuGenest:89877-HuGenest:56937-HuGenest:862663 HuGenest:504945-HuGenest:214598_at UGT2A3 149647-HuGenest:860083-HuGenest:922544- 8.64E-09 1.7422 4.89 80.872.3-87.5 HuGenest:244206-HuGenest:503323-HuGenest:353576 HuGenest:603619-HuGenest:787458-HuGenest:219796 HuGenest:333564-HuGene_st:257402-HuGene_st:366699 HuGenest:461685-HuGenest:891681-HuGenest:644952 HuGenest:621618-HuGenest:737617-HuGene-st:88682 HuGenest:529761-HuGenest:895203-HuGenest:658594 HuGenest:455115-HuGenest ,__

HHLA2 371335-HuGenest:978721-HuGenest:1065567- 3.47E-17 2.6743 10.02 90.984.3-95.2 HuGenest:282548-HuGenest:240410-HuGenest:170899 HuGenest:947848-HuGenest:438234 HuGenest:220812_s_at:927495-HuGenest:351364 HuGenest:234673_at:993142-HuGene_st:1009637 HuGenest:335000-HuGenest:285313-HuGenest:533646 HuGenest:234624_at:458597-HuGenest:104838 HuGenest:26687-HuGenest:258409-HuGene_st:493304 HuGenest:378019-HuGenest:576796-HuGenest UGTIA8 116025-HuGenest:6488-HuGenest:881135- 1.32E-11 2.0703 4.56 8577.1-90.9 HuGenest:230953_at:221304_at:221305_s_at:511516 HuGene_st:594963-HuGenest:396121-HuGenest:123777 HuGenest:1016481-HuGene_st:204532_x_at:683377 HuGenest:1055169-HuGenest:1035103 HuGenest:1088102-HuGenest:207126_x_at:42874 HuGenest:215125_s_at:206094_x_at:208596_s_at:97211 HuGenest:1009861-HuGenest:603368 HuGenest:232654_s-at:625897-HuGenest:998604 HuGenest CNTN3 267567-HuGenest:782053-HuGenest:550157- 1.20E-07 1.6155 3.93 7970.3-86.1 HuGenest:541394-HuGenest:989173-HuGenest:15899 HuGenest:78622-HuGenest:339738-HuGenest:585282 HuGene._st:661814-HuGenest:360715-HuGenest:695033 HuGenest:483058-HuGenest:555394-HuGene st:315011 HuGenest:905374-HuGenest:1067212-HuGenest:557263 HuGenest:233502_at:811729-HuGenest:87414-HuGenest P2RY1 628249-HuGenest:113454-HuGenest:627857- 1.41E-15 2.5326 3.6 89.782.8-94.4 HuGenest:461281-HuGenest:207455_at:259065 HuGenest:797734-HuGenest:135788-HuGene_st:42916 HuGenest:315405-HuGenest:340050-HuGene st:173225 HuGenest:919818-HuGenest:591228-HuGene-st:899117 HuGenest:785070-HuGenest:286200-HuGenest:231925_at SORBS2 238751 at:805920-HuGene st 4.23E-05 1.3026 2.1 74.365.1-82

TABLE 5

Gene Normal MRC5 CaCo2 HCT116 HT29 SW480 Blood CXCL12 Unmeth low unmeth meth meth unmeth DF Low meth meth meth unmeth meth MAMDC2 Unmeth unmeth meth unmeth unmeth meth CA4 unmeth unmeth meth meth meth unmeth MT1M low low low meth low meth P2RY14 unmeth Low Meth Meth Unmeth Meth GPM6B Low Low Low Meth Meth Meth ADAMDEC1 low Unmeth Meth Meth unmeth meth

TABLE6

Probe Set ID Target Sequence tagtcttggggcaggatgattttggcctcattactttaccacccccacacctggaaagcatatactatattacaaaatgacattttgccaaaattattaatataagaag 1 200600 ctttcagtattagtgatgtcatctgtcactataggtcatacaatccatcttaaagtactgttatttgtttttattatactgtttgtcttctccccagggttcagtccctcaaggg 1t at gccatcctgtcccaccatgcagtgccccctagcttagagcctccctcaattccccctggccaccaccccccactctgtgcctgaccttgaggagtcttgtgtgcattg ctgtgaattagctcacttggtgatatgtcctatattggctaaatgaaacctggaattgtggggcaatctattaatagctgccttaaagtcagtaacttacccttaggga ggctgggggaaaaggttagatttgtattcaggggttttttgtgtactttttgggtttttaaaaaattgtttttggaggggtttatgctcaatccatgt gatagcctcccactaggactgggaggagaataacccaggtettaaggaccccaaagtcaggatgttgtttgatcttctcaaacatctagttccctgcttgatgggag gatcctaatgaaatacctgaaacatatattggcatttatcaatggctcaaatcttcatttatctctggccttaaccctggctcctgaggctgcggccagcagagccca 2 200621 ggccagggctctgttcttgccacacctgcttgatcctcagatgtggagggaggtaggcactgcctcagtcttcatccaaacacctttccctttgccctgagacctcag at aatcttccctttaacccaagaccctgcctcttccactccacccttctccagggacccttagatcacatcactccacccctgccaggccccaggttaggaatagtggt gggaggaaggggaaagggctgggcctcaccgctcccagcaactgaaaggacaacactatctggagccacccactgaaagggctgcaggcatgggtgta c gttggttcaaacttgggagcacggactgtcagtetctgggaagtggtcagcgcatcctgcagggcttctcctcctctgtcttttggagaaccagggctcttctcagg 3 200665 ggctctagggactgccaggctgtttcagccaggaaggccaaaatcaagagtgagatgtagaaagttgtaaaatagaaaaagtggagttggtgaatcggttgttc _s_at tttcctcacatttggatgattgtcataaggtttttagcatgttcctccttttcttcaccctcccctttgttcttctattaatcaagagaaacttcaaagttaatgggatggtcggat ctcacaggctgagaactcgttcacctccaagcatttcatgaaaaagctgcttcttattaatcatacaaactctcaccatgatgtg aacactgcataacccgtttctttgaggagtgtgaccccaacaaggataagcacatcaccctgaaggagtggggccactgctttggaattaaagaagaggacat 4 200795 agatgaaaatctcttgttttgaacgaagatttaaagaactcaactttccagcatcctcctctgttctaaccacttcagaaatatatgcagctgtgatacttgtagatttat at atttagcaaaatgttagcatgtatgacaagacaatgagagtaattgcttgacaacaacctatgcaccaggtatttaacattaactttggaaacaaaaatgtacaatt _a aagtaaagtcaacatatgcaaaatactgtacattgtgaacagaagtttaattcatagtaatttcactctctgcattgacttatgagataattaatgattaaactattaatg ataaaaataatgcatttgtattgttcataatatcatgtgcacttcaagaaaatggaatgctactcttttgtggtttac ggccgacaagaagaaggtgetggacaagtgtcaagaggtcatctcgtggetggacgccaacaccttggccgagaaggacgagtttgagcacaagaggaag 200799 gagctggagcaggtgtgtaaccccatcatcagcggactgtaccagggtgccggtggtcccgggcctgggggcttcggggctcagggtcccaagggagggtct 5t at gggtcaggccccaccattgaggaggtagattaggggccttccaagattgetgtttttgttttggagettcaagactttgcatttcctagtatttctgtttgtcagttetcaatt tcctgtgtttgcaatgttgaaattttttggtgaagtactgaacttgctttttttccggttctacatgcagagatgaatttatactgccatcttacgactatttcttctttttaataca cttaactcaggccatttttt tcctgtcacccattttgaagagtggcagaacttgaagttcaacttcctctgtaaatatccaagtataaagcccaggaacttctagaataacccagatgcgctttaatttt 6 200845 ttttaatatgttttgatcacagaacttctagaataacccagatgctctttcatattcttttaatacatcttgatcacagctgggggaaaaaaagctttttaattctgtaccttcc 6 a sat tagtagataagtgaagagcagggaaagagacctttaaatattttgetataaaaaaatttgtgataagtttctatcaaaatggggagattgcagaaaaggettccett ggctcccaaggaggtgtagcaggtgtgagcaatattagtgccatgtgcctttcacacagggtttgcatttatcagtctgttttccgatgatgtgtacatgaaagagtac accatgtgaagagaagagagaatgattgaaaatgtttagtatagaactcttcttgcagtgggttgctattttctagatttta gtttgtagactctctgaccaaggccacctgtgccccccagcatggggccccgggtcctgggcctgctgacgccagcaaggtggtggccaagggcctggggctg agcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtgggggttcatggcccaaggaccccct 7 200859 gcgaggagatcctggtgaagcacgtgggcagccggctctacagcgtgtcctacctgctcaaggacaagggggagtacacactggtggtcaaatgggggcac _x-at gagcacatcccaggcagcccctaccgcgttgtggtgccctgagtctggggcccgtgccagccggcagcccccaagcctgccccgctacccaagcagccccg ccctcttcccctcaaccccggcccaggccgccctggccgcccgcctgtcactgcagctgcccctgccctgtgccgtgctgcgctcacctgcctccccagccagcc gctgacctctcggctttcacttgggcagagggagccatttggtggcgctgct cctcacccagattgaaactctcttcaagtctaaggactatgagttcatgtggaaccctcacctgggctacatcctcacctgcccatccaacctgggcaccgggctg 200884 cgggcaggtgtcgatatcaagetgcccaacctgggcaagcatgagaagttctoggaggtgcttaagcggctgcgacttcagaagcgaggcacaggcggtgtg 8 gacacggctgcggtgggcggggtcttcgacgtctccaacgctgaccgcctgggcttctcagaggtggagctggtgcagatggtggtggacggagtgaagatgtt - catcgagatggaacagcggctggagcagggccaggccatcgacgacctcatgcctgcccagaaatgaagcccggcccacacccgacaccagccctgctg cttcctaacttattgcctgcagtgcccaccatgcacccctog atgttgccgtctggcgagcccttagccttgctgtaagg aagg cttccg tcacccttgg tag agtttat ctctcttagctcagttactcaattcatacgtagtatttttaaaataattttatatctgtgtaccaccccatatatttcatattactgtttcacatgtacagctttctacttctttgtaa 9 200897 gaacaccaaccaaccaaggtttaagtgataataggettgagcaccgggtggcagatgttctatgcagtgtggttcaagttctttgaccgcacttatatgcattgeta -s-at atatggaatttaagataccatacacagtctctcatggacctatctctattgtagaattatgacttatgtcttacttggcaaatttttctgaatgtgacctttttttgctgatttgct gggtttgggattaactagcattattttgccacctt aagagttacgagttgcctgatgggcaagtgatcaccatcggaaatgaacgtttccgctgcccagagaccctgttccagccatccttcatcgggatggagtctgctg 200974 gcatccatgaaaccacctacaacagcatcatgaagtgtgatattgacatcaggaaggacctctatgctaacaatgtcciatcagggggcaccactatgtaccctg 10 gcattgccgaccgaatgcagaaggagatcacggccctagcacccagcaccatgaagatcaagatcattgcccctccggagcgcaaatactctgtctggateg at gtggctccatcctggcctctctgtccaccttccagcagatgtggatcagcaaacaggaatacgatgaagccgggccttccattgtccaccgcaaatgcttctaaaa cactttcctgctctctctgtctctagcacacaactgtgaatgtcctgtggaattatgccttcagttcttttccaaatcattcctagccaaagctctgactcgt 11 200986 gacgaccagccaggatatgctctcaatcatggagaaattggaattcttcgatttttcttatgaccttaacctgtgtgggctgacagaggacccagatcttcaggtttct 11 gcgatgcagcaccagacagtgctggaactgacagagactggggtggaggcggctgcagcctccgccatctctgtggcccgcaccctgctggtctttgaagtgc at agcagcccttcctcttcgtgctctgggaccagcagcacaagttccctgtcttcatggggcgagtatatgaccccagggcctgagacctgcaggatcaggttaggg cgagcgetacctctccagcctcagctctcagttgcagccctgctgctgcctgcctggacttgcccctgccacctcctgcctcaggtgtccgctatccaccaaaaggg ctcctgagggtctgggcaagggacctgcttctattagcccttctccatggccctgccatgctctccaaaccacttttgcagctttctc gcaataactctgggaggggctcgagagggctggtccttatttatttaacttcacccgagttcctctgggtttctaagcagttatggtgatgacttagcgtcaagacattt 12 201041 gctgaactcagcacattcgggaccaatatatagtgggtacatcaagtccatctgacaaaatggggcagaagagaaaggactcagtgtgtgatccggtttctttttg _s_at ctcgcccctgttttgtagaatctcttcatgcttgacatacctaccagtattattcccgacgacacatatacatatgagaatataccttatttattttgtgtaggtgtctgcct tcacaaatgtcattgtctactcctagaa gcatcctcaaacatggcgccaaggataaacacgactaggccatccccagccccctgacacccagcccccgccagtcacccctccccgcacacacccgtcca 13 201058 taccagctccctgcccatgaccctogctcagggatccccctttgagggttagggtcccagttcccagtggaagaaacaggccaggagagtgcgtgccgagctg 13 a aggcagatgttcccacagtgaccccagagccctgggctatagtctctgacccctccaaggaaagaccaccttctggggacatgggctggagggcaggaccta _at gaggcaccaagggaaccgcattccggggctgttccccgaggaggaagggaagcctctgtgtgccccccaggaggaagaggccctgagtcctgggatcaga caccccttcacgtgtatcccacacaaatgcaagctcaccaaggtccc tatagctctctttagctcaaccactctgtccatccagccaatggatgtccttccctgtacccaattcaagcttatttagggaagccttgaaactaccatgtatctggctct 14 201061 agctgagttattgaggattgagccagtgcaacgttaaactcagtgcacttacatttgatttaaatgatggttttatctgttgtgtgaagtggttcacccttgaggaccagg _s-at agcctccatatcctgactgaaaaccttttctgagacttagagtaacagtacttttggttccttgagttctcctgtctccagatacctaaatgaccttgacttttctgccttgtg aattcgtagtccaatcagctgaaattaaatcacttgggagggacgcatagaaggagctctaggaacacagtgccagtgcagaagtttctccaggtggcc ctcagagccacccctaaagagatcctttgatattttcaacgcagccctgctttgggctgccctggtgctgccacacttcaggetcttctcctttcacaaccttctgtggct 201069 cacagaacccttggagccaatggagactgtctcaagagggcactggtggcccgacagcctggcacagggcagtgggacagggcatggccaggtggccact 15 ccagacccctggettttcactgctggetgccttagaacetttcttacattagcagtttgetttgtatgcactttgtttttttctttgggtettgttttttftttccacttagaaattgcatt at tcctgacagaaggactcaggttgtctgaagtcactgcacagtgcatctcagcccacatagtgatggttcccctgttcactctacttagcatgtccctaccgagtctctt ctccactggatggaggaaaaccaagccgtggctcccgctcagccctccctgcccctcccttcaaccattccccatgggaaat ctcctggactcaatcatggcttgtggtctggtcgccagcaacctgaatctcaaacctggagagtgccttcgagtgcgaggcgaggtggctcctgacgctaagagc 16 201105 ttcgtgetgaacctgggcaaagacagcaacaacctgtgcctgcacttcaaccetegettcaacgcccacggegacgccaacaccategtgtgcaacagcaag _at gacggcggggcctgggggaccgagcagcgggaggctgtctttcccttccagcctggaagtgttgcagaggtgtgcatcacctcgaccaggccaacctgaccg tcaagctgccagatggatacgaattcaagttccccaaccgcctcaacctggaggccatcaactacatggcagctgacggtgacttcaa ggcagcattcaagtccgatggttcctgaatggacaggaggaaacagctggggtcgtgtccaccaacctgatccgtaatggagactggaccatccagatcctggt 17 201137 gatgctggaaatgaccccccagcagggagacgtctacatctgccaagtggagcacaccagcctggatagttccgtcaccgtggagtggaaggcacagtetga a 17 sat ttctgcccagagtaagacattgacgggagetgggggettegtgotggggetcatcatctgtggagtgggactcttcatgcacaggaggagcaagaaagttcaac gaggatctgcataaacagggttcctgacctcaccgaaaagactaatgtgcctagaacaagcatttgctgtgtttgttaacacctggttccaggacagaccctcag cttcccaagaggatactgctgccaagaagttgctctgaagtcagttctatcgttctgctcttgattcaaa agaggcgggatactttcagctttccatgtaactgtatgcataaagccaatgtagtccagtttctaagatcatgttccaagctaactgaatcccacttcaatacacactc 201141 atgaactcctgatggaacaataacaggcccaagcctgtggtatgatgtgcacacttgctagactcagaaaaaatactactctcataaatgggtgggagtattttggt 18 1 gacaacctactttgcttggctgagtgaaggaatgatattcatatattcatttattccatggacatttagttagtgctttttatataccaggcatgatgctgagtgacactctt gtgtatatttccaaatttttgtatagtcgtgcacatatttgaaatcatatattaagactttccaaagatgaggtccctggtttttcatggcaacttgatcagtaaggatttca cctctgtttgtaacta gacttttggaatagccctgtctagggcaaactgtggcccccaggagacactacccttccatgccccagacctctgtcttgcatgtgacaattgacaatctggacta 201150 ccccaagatggcacccaagtgtttggcttctggctacctaaggttaacatgtcactagagtatttttatgagagacaaacattataaaaatctgatggcaaaagcaa 19 a aacaaaatggaaagtaggggaggtggatgtgacaacaacttccaaattggetetttggaggegagaggaaggggagaacttggagaatagtttttgotttgggg sat gtagaggcttcttagattctcccagcatccgcctttccctttagccagttgctgtcctgaaacccagaagtgatggagagaaaccaacaagagatctcgaaccct gtctagaaggaatgtatttgttgctaaattcgtagcactgtttacagttttcctccatgttatttatg

201289 gccacgattggagaatactttgcttcatagtattggagcacatgttactgcttcattttggagcttgtggagttgatgactttctgttttctgtttgtaaattatttgctaagcat at attttctctaggettttccttttggggttctacagtcgtaaaagagataataagattagttggacagtttaaagcttttattcgtctttgacaaaagtaaatgggagggc - attccatcccttcctgaagggggacactccatgagtgtctgtgagaggcagctatctgcactctaaactgc ttaggtcaagttcatagtttctgtaattggcttttgaatcaaagaatagggagacaatctaaaaaatatcttaggttggagatgacagaaatatgattgatttgaagtg 21 201300 gaaaaagaaattctgttaatgttaattaaagtaaaattattccctgaattgtttgatattgtcacctagcagatatgtattacttttctgcaatgttattattggcttgcactttg 21 a sat tgagtatctatgtaaaaatatatatgtatataaaatatatattgcataggacagacttaggagttttgttagagcagttaacatctgaagtgtctaatgcattaacttttgt aaggtactgaatacttaatatgtgggaaacccttttgcgtggtccttaggcttacaatgtgcactgaatcgtttcatgtaagaatccaaagtggacaccattaacaggt ctttgaaatatgcatgtactttatattttctatattgtaacttgcatgttcttgtttgtta 201324 caccaaattacctaggctgaggttagagagattggccagcaaaaactgtgggaagatgaactttgtcattatgatttcattatcacatgattatagaaggetgtctta 22 gtgcaaaaaacatacttacatttcagacatatccaaagggaatactcacattttgttaagaagttgaactatgactggagtaaaccatgtattcccttatcttttactttttt - tctgtgacatttatgtctcatgtaatttgcattactctggtggattgttctagtactgtattgggcttcttcgttaat 23 201348 accagotctaggtccaattgttctgctctaactgatacctcaaccttggggccagcatctcccactgcctccaaatattagtaactatgactgacgtccccagaagttt 23 ctgggtctaccacactccccaaccccccactcctacttcctgaagggccctcccaaggetacatccccaccccacagttctccctgagagagatcaacctccctg - agatcaaccaaggcagatgtgacagcaagggccacggaccccatggcaggggtggcgtctcatga tgtggatgtttccaagcctgacctcacggctgccctgcgtgacgtacgtcagcaatatgaaagtgtggetgccaagaacctgcaggaggcagaagaatggtaca 24 201426 aatccnagtttgctgacctctctgaggctgccaaccggnacnatgacgccctgcgccaggcnaagcaggagtccnctgagtaccggagacaggtgcagtccc _s_at tcacctgtgaagtggatgcccttaaaggaaccaatgagtccctggaacgccagatgcgtgaaatggaagagaactttgccgttgaagctgctaactaccaaga cactattggccgcctgcaggatgagattcagaatatgaaggaggaaatggctcgtcaccttcgtgaataccaagacctgctcaatgttaagatggcccttgacatt gagattgccacct gatccagaaatacttaacacgtgaatattttgctaaaaaagcatatataactattttaaatatccatttatcttttgtatatctaagactcatcctgattttactatcacacat 201427 gaataaaggcctttgtatetttctttctctaatgttgtatcatactcttctaaaacttgagtggctgtettaaaagatataaggggaaagataatattgtetgtetetatattgc _s_at ttagtaagtatttccatagtcaatgatggtttaataggtaaaccaaaccctataaacctgacctcctttatggttaatactataagcaagaatgcagtacagaattgg atacagtacggatttgtccaaat ctccagcagttctctogaatactttgaatgttgtgtaacagttagccactgctggtgtttatgtgaacattcctatcaatccaaattccctctggagtttcatgttatgcctgtt

26 201438 gcaggcaaatgtaaagtctagaaaataatgcaaatgtcacggctactctatatacttttgcttggttcattttttttccctttagttaagcatgactttagatgggaagcct 26 gtgtatcgtggagaaacaagagaccaactttttcattccctgcccccaatttcccagactagatttcaagctaattttctttftctgaagcctctaacaaatgatetagttc _a agaaggaagcaaaatcccttaatctatgtgcaccgttgggaccaatgccttaattaaagaatttaaaaaagttgtaatagagaatattttggcattcctctcaatgtt gtgtgtt caagtgcagcgatggggagcgggcccgggcggagctcaatgacaaagtccacaagctgcagaatgaagttgagagcgtcacagggatgcttaacgaggc

27 201495 cgaggggaaggccattaagctggccaaggacgtggcgtccctcagttcccagctccaggacacccaggagctgcttcaagaagaaacccggcagaagotc xat x~t aacgtgtctacgaagctgcgccagctggaggaggagcggaacagcctgcaagaccagctggacgaggagatggaggccaagcagaacctggagcgcca catctccactctcaacatccagctctccgactcgaagaagaagctgcaggactttgccagcaccgtggaagotctggaagaggggaagaagaggttccagaa ggagatcgagaacctcacccag tcaagtccaagttcaagtccaccatcgcggcgctggaggccaagattgcacagctggaggagcaggtcgagcaggaggccagagagaaacaggcggcca ccaagtcgctgaagcagaaagacaagaagctgaaggaaatcttgctgcaggtggaggacgagcgcaagatggccgagcagtacaaggagcaggcaga 28 201496 gaaaggcaatgccagggtcaagcagctcaagaggcagctggaggaggcagaggaggagtcccagcgcatcaacgccaaccgcaggaagctgcagcgg _x-at gagnnggatgaggccacggagagcaacgaggccatgggccgcgaggtgaacgcactcaagagcaagtcagagggccccccccacaggaaacttcgc agtgatgcaccaggcgaggaaacgagacctctttcgttccttctagaaggtctggaggacgtagagttattgaaaatgcagatggttctgaggaggaaacggac actcgagacgcagacttcaatggaaccaaggccagtgaataagcaacttctacagtttgcaccacgg tgagccaggaagaacgctccagcccaggacttcgaggctgcaatgagctataattgcatcattgcactccagcctgggcaacagagaccctgtctcaaccacc accaccaccaccacccctactacccctgtattcaaggtaaaaattgaagtttgtatgatgtaagagatgagaaaaacccaacaggaaacacagacacatcctc 29 201497 cagttctatcaatggattgtgcagacactgagtttttagaaaaacatatccacggtaaccggtecctggcaattetgtttacatgaaatggggagaaagtcaccgaa _x-at atgggtgccgccggcccccactcccaattcattccctaacctgcaaacctttccaacttctcacgtcaggcctttgagaattctttccccctctcctggtttccacacctc agacacgcacagttcaccaagtgccttctgtagtcacatgaattgaaaaggagacgctgctcccacggaggggagcaggaatgctgcactgtttacaccctga ctgtgcttaaaa 201539 tgaagtgcaacaaggccatcacatctggaggaatcacttaccaggatcagccctggcatgccgattgctttgtgtgtgttacctgetctaagaagctggetgggca s at gcgtttcaccgctgtggaggaccagtattactgcgtggattgctacaagaactttgtggccaagaagtgtgctggatgcaagaaccccatcactgg cagggctgtcatcaacatggatatgacatttcacaacagtgactagttgaatcccttgtaacgtagtagttgtctgctctttgtccatgtgttaatgaggactgcaaagt 31 201540 cccttctgttgtgattcccaggacttcctcaagaggaaatctggatttccacctaccgcttacctgaaatgcaggatcacctacttactgtattctacattattatatgac _at atagtataatgagacaatatcaaaagtaaacatgtaatgacaatacatactaacattcttgtaggagtggttagagaagctgatgcctcatttctacattctgtcatta gctattatcatctaacgtttcagtg cttgagaccaggagacgtatccagcaagcggaacctctgggaaaagcaatctgtggataaggtcacttcccccactaaggtttgagacagttccagaaagaac 32 201616 ccaagctcaagacgcaggacgagctcagttgtagagggctaattcgctctgttttgtatttatgttgatttactaaattgggttcattatcttttatttttcaatatcccagtaa a 32 sat acccatgtatattatcactatatttaataatcacagtctagagatgttcatggtaaaagtactgcctttgcacaggagcctgtttctaaagaaacccatgctgtgaaata gagactttctactgatcatcataactctgtatctgagcagtgataccaaccacatctgaagtcaacagaagatccaagtttaaaattgcctgcggaatgtgtgcagt atctagaaa tgttgtttctgcactttataataaagcatggaagaaattatcttagtaggcaattgtaacactttttgaaagtaacccatttcagatttgaaatactgcaataatggttgtctt 33 201617 taaaaaaaaaaagaatgtactgttaaggtattactttttttcatgctgatgattcatatctaaattacattattatgttagctgacagtggtactgattttttaggttggttgtttt a 33 xat gtggatttctttagtagtgatagtagcctgaaccacattttagataactcaattatgtatgtatgtgcatacacatatacaaacacactaatggtagaatgcttttttatgtg ctagactattatatagtagtatgtcattgtaactagccaatatcacagcttttgaaaaattaaaaaatcatcatcactataatatttcatatttgccaacagaaacatg gcagataggtatcaatatgttttcaatgcctgatgacctat ttttaccaaagcatcaatacaaccagcccaaccatcggtccacacctgggcatttggtgagaatcaaagctgaccatggatccctggggccaacggcaacagc 34 201645 atgggcctcacctcctctgtgatttctttctttgcaccaaagacatcagtctccaacatgtttctgttttgttgtttgattcagcaaaaatctcccagtgacaacatcgcaat 34 _at agttttttacttctcttaggtggetctgggatgg gag aggggtaggatgtacaggggtagtttgttttag aaccagccg tattttacatg aagctgtataattaattgtcatt atttgttagcaaagattaaatgtgtcattggaagccatccctttttttacatttcatacaacagaaaccagaaaagcaatactgtttccattttaaggatatgattaatat tattaatataataatgatgatgatgatgatgaaaactaaggattttcaagagatctttctttccaaaacatttctggacagtacctgattgt gagtggactattaaatgtgcctaaatgaattttgcagtaactggtattcttgggtttcctacttaatacacagtaattcagaacttgtattctattatgagtttagcagtctttt 201667 ggagtgaccagcaactttgatgtttgcactaagattttatttggaatgcaagagaggttgaaagaggattcagtagtacacatacaactaatttatttgaactatatgtt -at gaagacatctaccagtttctccaaatgccttttttaaaactcatcacagaagattggtgaaaatgctgagtatgacacttttcttcttgcatgcatgtcagctacataaa cagttttgtacaatgaaaattactaatttgtttgacattccatgttaaactacggtcatgttcagcttcattgcatgtaatgtagacctagtccatcaga tgctgtgtgaaccgtcgtgtgagtgtggtatgcctgatcacagatggattttgttataagcatcaatgtgacacttgcaggacactacaacgtgggacattgtttgtttct 36 201739 tccatatttggaagataaatttatgtgtagacttttttgtaagatacggttaataactaaaatttattgaaatggtcttgcaatgactcgtattcagatgcctaaagaaagc 36 attgetgetacaaatatttctattttagaaagggtttttatggaccaatgccccagttgtcagtcagagcogttggtgtttttcattgtttaaaatgtcacctgtaaaatggg at cattattatgtttttttttttgcattcctgataattgtatgtattgtataaagaacgtctgtacattgggttataacactagtatatttaaacttacaggcttatttgtaatgtaaac Icaccatttaatgtactgtaattaacatggttataatacgtacaatccttccctcatcccatcacacaactttttttg ccatccagaatctagcgctgcgcaacacaggaatggagacgcccacaggcgtgtgcgccgcactggcggcggcaggtgtgcagccccacagcctagacct cagccacaactcgctgcgcgccaccgtaaaccctagcgctccgagatgcatgtggtccagcgccctgaactccctcaatctgtcgttcgctgggetggaacagg 37 201743 tgcctaaaggactgccagccaagctcagagtgotcgatctcagctgcaacagactgaacagggcgccgcagcctgacgagctgcccgaggtggataacctg -at acactggacgggaatccettcctggtccctggaactgccctcccccacgagggctcaatgaactccggcgtggtcccagcctgtgcacgttcgaccctgtcggtg ggggtgtcgggaaccctggtgctgctccaaggggcccggggetttgcctaagatccaagacagaataatgaatggactcaaactgccttggcttcaggggagtc ccgtcaggacgttgaggacttttcgaccaattcaacc

38 201744 caaatgatgtgcaaaaccttttactggttgcatggaaatcagccaagtttataatccttaaatcttaatgttcctcaaagcttggattaaatacatatggatgttactctct sa tgcaccaaattatcttgatacattcaaatttgtctggtaaaaaaataggtggtagatattgaggccaagaatattgcaaaatacatgaagcttcatgcacttaaagaa _sat gtatttttagaataagaatttgcatactacctagtgaaacttttctagaatattttcactctaagtcatgtatgttctct tcagcagtatagggaccttccgcacaagctctgtgttaagattgacaataatagtggggccattttcattttagtctttctaagagtcaaccacaggcatttaagtcag 39 201842 ccaaagaatattgttaccttaaagcactatttatttatagatatatctagtgcatctacatctctatactgtacactcacccataattcaaacaattacaccatggtataa a 39 sat agtgggcatttaatatgtaaagattcaaagtttgtetttattactatatgtaaattagacattaatccactaaactggtettcttcaagagagctaagtatacactatctggt gaaactggattctttcctataaaagtgggaccaagcaatgatgatcttctgtggtgctaaggaaacttactagagctccactaacagtctcataaggaggcagcc atcataaccattga gtgccaatcctttgaatgttccacggaaacactggtggacagattctagtgctgagaagaaacacgtttggtttggagagtccatggatggtggttttcagtttagcta 201852 cggcaatcctgaacttcctgaagatgtccttgatgtgcagctggcattccttcgacttctctccagccgagcttcccagaacatcacatatcactgcaaaaatagcat a 40 xat tgcatacatggatcaggccagtggaaatgtaaagaaggccctgaagetgatggggtcaaatgaaggtgaattcaaggetgaaggaaatagcaaattcaceta cacagtctggaggatggttgcacgaaacacactggggaatggagcaaaacagtctttgaatatcgaacacgcaaggctgtgagactacctattgtagatattgc accctatgacattggtggtcctgatcaagaatttggtgtggacgttggccct cctggttctggaatcctcagttcaaggttatcctacgcagagagccaggtaccaatgggtgcgctgcaatccagacagtaattctgcaaactgccttgaagaaaa 41 201858 aggaccaatgttcgaactacttccaggtgaatccaacaagatcccccgtctgaggactgacctttccaaagacgagaatccaggacttgaatcgtatcttccca _s-at ctttctgaggactactctggatcaggcttcggctccggctccggctctggatcaggatctgggagtggcttcctaacggaaatggaacaggattaccaactagtag acgaaagtgatgctttccatgacaaccttaggtctcttgacaggaatctgccctcagac tatgctttaatgctgttatctatcttattgttcttgaaaatacctgcattttttggtatcatgttcaaccaacatcattatgaaattaattagattcccatggccataaaatggctt 42 201859 taaagaatatatatatatttttaaagtagcttgagaagcaaattggcaggtaatatttcatacctaaattaagactctgacttggattgtgaattataatgatatgcccctt 42at - ttcttataaaaacaaaaaaaaaataatgaaacacagtgaatttgtagagtgggggtatttgacatattttacagggtggagtgtactatatactattacctttgaatgtg tttgcagagctagtggatgtgtttgtctacaagtatgattgctgttacataacaccccaaattaactcccaaattaaaacacagttgtgctgtcaatacctcatactgctt tacctttttttcctggatatctgtgtatttc gttgagtcgtcatcacttttcagtgatgggagagtagatggtgaaatttattagttaatatatcccagaaattagaaaccttaatatgtggacgtaatctccacagtcaa agaaggatggcacctaaaccaccagtgcccaaagtctgtgtgatgaactttctcttcatactttttttcacagttggctggatgaaattttctagactttctgttggtgtatc 43 201865 ccccccctgtatagttaggatagcatttttgatttatgcatggaaacctgaaaaaaagtttacaagtgtatatcagaaaagggaagttgtgccttttatagctattactgt _x-at ctggttttaacaatttcctttatatttagtgaactacgcttgctcattttttcttacataattttttattcaagttattgtacagctgtttaagatgggcagctagttcgtagctttccc aaataaactctaaacattaatcaatcatctgtgtgaaaatgggttggtgcttctaacctgatggcacttagctatcagaagaccacaaaaattgactcaaatctcca glattcttg tctcctacatccgcattgctgataccaatatcaccagcattcctcaaggtcttcctccttcccttacggaattacatcttgatggcaacaaaatcagcagagttgatgc 44 201893 agctagcctgaaaggactgaataatttggctaagttgggattgagtttcaacagcatctctgctgttgacaatggctctctggccaacacgcctcatctgagggagc x a ttcacttggacaacaacaagcttaccagagtacctggtgggctggcagagcataagtacatccaggttgtctaccttcataacaacaatatctctgtagttggatca xat agtgactctgcccacctggacacaacaccaaaaaggcttcttattcgggtgtgagtctttcagcaacccggtccagtactgggagatacagccatccaccttca gatgtgtctacgtgcgctctgccattcaactcggaaactataagtaattctcaagaaagccctcattttataacctgg gtatcaggcttcaattccattatgttttaatgttgtctctgaagatgacttgtgattttttfttctttttftaaaccatgaagagccgtttgacagagcatgctctgcgttgttggtt 201920 tcaccagcttctgccctcacatgcacagggatttaacaacaaaaatataactacaacttcccttgtagtctcttatataagtagagtccttggtactctgccctcctgtc 45 at agtagtggcaggatctattggcatattegggagettettagagggatgaggttetttgaacacagtgaaaatttaaattagtaacttttttgcaagcagtttattgactgtt attgctaagaagaagtaagaaagaaaaagcctgttggcaatcttggttatttctttaagatttctggcagtgtgggatggatgaatgaagtggaatgtgaactttggg caagttaaatgggacagcctccatgttcatttgtctacctcttaactga gttgtgcctaccactggetggcacaccagggcaatgatttccctgcagaaggaaggaaagaatgtttcacccttgcatccttcttggagaagctacagcctgtgct 46 201957 cagttgagtggttcacactcagactttggctttatggttttccttcctccttgtctttgccctgaccttgatcaacaggggtgaaaagaaccaccctgaggtttccatgcct 46 ctcccatttagtggtagcattttgtgtetttactccaccettcaccctagttccaccaaggttcacacaccagatgtaactgtttticagetgagttgtatggattaaettca at gtccactgtaaatacacctgggatggggtggggttggggttgttagggagaagcagccagacttgctttgtgaactgaatgtatttttatgcaattttgagtggcctttc aaccctaaga tatcagtagctcgtgttatcttttatcaactgcttcccagngtcctaaaacaatagaaattttggattgaaaagttcagcataaggagtttgagtcagtaaaggatggg ataaaggagtcgagatgattcaatgaaaagtatcacaaaaaagagattgatcaacaagagaaataaaaaagcccaagaggaagtggtaggggaaggaat 47 202007 ttaagaacagcaataagtaaaactcttaagtaactccaaaaagaaaatggtacattttgccaaagaccacttatacttgagaacatggaagaatttgcctgatact _at ctctttggggaaaagagtctctcctcttttcctcaaaccccagtacactcagcctctctgccccaccttctcctgactttgtcctcacttgcttctgcagtacattggaacct gaattgaaagaaagtcttcttgaataattggagtttgtettgagaggcaaatatagccccaagaatcacaagattcgaggaccatgtaggtettttacgtagccca

148 202037 Is at laatccataaattagtctcactt tgtat tatcgtt catat aaaccctctatatca taacacttggetettggtacctgtgggttagcatcaagttetccccagggtagaattcaatcagagetccagtttgcatttggatgtgtaaattacagtaatcccatttcc caaacctaaaatctgtttttctcatcagactctgagtaactggttgctgtgtcataacttcatagatgcaggaggctcaggtgatctgtttgaggagagcaccctaggc agcctgcagggaataacatactggccgttctgacctgttgccagcagatacacaggacatggatgaaattcccgtttcctctagtttcttcctgtagtactcctctttta ______gatcc cagtcactctaaatggacaccacatgaacctctgtttagaatacctacgtatgtatgcattggtttgcttgtttcttgacagtacatttttagatctggccttttcttaacaaa 49 202069 atctgtgcaaaagatgcaggtggatgtccctaggtctgtttcaaagaactttttccaagtgottgttttatttattaagtgtctacctggtaaatgttttttttgtaaactctga 49 a gtggactgtatcatttgetattaaaccattttacacttaagttaaaatagttttetcagetgtaaataacaggatacagaattaacaagagaaaatgtetaacttttt s~t aagaaaaaccttattttcttcggttttgaaaaacataatggaaataaaacaggatattgacataatagcacaaaatgacactcttctaaaactaaatgggcacaa gagaattttcctggga gtcaaaacctaattgcaattctgttaaatctaagtaatttttagacagtgtttcaccgtattatttaggatgtgaaatgccatttctttcactgattacaccatatacaggaa 202133 acaggtaaaacagtgaaaactttattgtgctggttgatgccaacttggttgaaaagctctctgcagaagaagtgatctagactgacagaagtgttgctaattacaag 50 at ttgtgttctcatgacgtaattagaaagtaacttctcaaagtacaactttatgaaaaaaataagetgttaaaaaaaggaaatcgtaggttaatttaattgggaaaatgg gcaattgacagagaccatttcctaacacatatatgtgctagtactttaactttttaaaattttacttctacgttttgtaatataaaaatttctattttaagtttagaatgttatac gtaccgaaagtatgcagccaaatcgatcagatcaaaccattttacctggagtt 51 202222 agetgtgagcettggetgttggcagtgagtgagcctggetcttgtgctggatggagcccaggcgggagcggtggccctgtccctcccacctctgtgacctgaggcc s at tacgctttggctctggagatagccccagagcagggtgttgggatactgcagggccaggactgagcccc ctgttagctcctcactgtggtaaatgccacacacctttaagtagataagcagacgatagttatctgttcttttgacttaatctcatttggtttgattttccctctactaaggcttt 52 202242 cctaccttcttcaggctgcctaagacatgtaagcgaaacacttcaataattgtccatgaggagaaaaaaagcattgtcatgcatgaaggaaactgaacttgaggt 52at - ggcctccttgcttgttacatacctgggtatgtgtaggcagtttagtgcatetttgcctctcagttgaaacctgtataaccetgttacaaagetgtgttgttgettcttgtgaag gccatgatattttgttttttccccaattaattgctattgtgttattttactaacttctctctgtattttttcttgcattgacattatagacattgaggacctcatccaaacaatttaaa aatgagtgtgaagggggaacaagtcaaaatatttttaaaagatcttcaaaaataatgcctctgtctagcatgccaac tgtcagagttttcaacggtgcttatagctgccagctggattccaaacaggtaccccattgtctctgagctaatgtttatatttttccattcaggcaccgaaatagttaatat 53 202266 ttaaaataagtcttcaaaagaaaacataagagattattgagttcttgggactggatcctttatttcataagttcagatcatcttaaatgaaaatgccatgattatctgcag 53 ttaagtagatgacagctattctacatcagacttgattttgtcagctaattacataattggtaagetataattgaaacettatggettaaaattocttaactectttttgattca _a tgtttgtagtcatgttgtcaacagaggcaaagttaagcttgatgatggttaaaatcggtttgatagcaccatgggacattttctaacaaaaataaatgcatgaagag acatagccttttagttttgct aagagctatgagctgccagatgggcaggttatcaccattggcaatgagcgcttccgctgccctgagaccctcttccagccttcctttattggcatggagtccgctgg 54 202274 aattcatgagacaacctacaattccatcatgaagtgtgacattgacatccgtaaggacttatatgccaacaatgtcctctctgggggcaccaccatgtaccctggc 54at attgetgacaggatgcagaaggagatcacagccetggcccccagcaccatgaagatcaagattattgetcccccagagcggaagtactcagtetggatcggg - ggctctatcctggcctctctctccaccttccagcagatgtggatcagcaagcctgagtatgatgaggcagggccctccattgtccacaggaagtgcttctaaagtca gaacaggttctccaaggatcccc caactgcccttgaccggaagcatgagtatcatcttcttcctgcccctgaaagtgacccagaatttgaccttgatagaggagagcctcacctccgagttcattcatga catagaccgagaactgaagaccgtgcaggcggtcctcactgtccccaagctgaagctgagttacgaaggcgaagtcaccaagtccctgcaggagatgaagc 202283 tgcaatecttgtttgattcaccagactttagcaagatcacaggcaaacccatcaagotgactcaggtggaacaccgggetggetttgagtggaacgaggatggg _at gcgggaaccacccccagcccagggctgcagcctgcccacctcaccttcccgctggactatcaccttaaccagcctttcatettcgtactgagggacacagacac aggggcccttctcttcattggcaagattctggaccccaggggcccctaatatcccagtttaatattccaataccctagaagaaaacccgagggacagcagattcc acag ctgacctgcaggacgaaaccatgaagagcctgatccttcttgccatcctggccgccttagcggtagtaactttgtgttatgaatcacatgaaagcatggaatcttatg 202291 aacttaatcccttcattaacaggagaaatgcaaataccttcatatcccctcagcagagatggagagctaaagtccaagagaggatccgagaacgctctaagcct a 56 sat gtccacgagotcaatagggaagcctgtgatgactacagactttgegaacgctacgccatggtttatggatacaatgetgcctataatcgctacttcaggaagegcc gaggggccaaatgagactgagggaagaaaaaaaatctctttttttctggaggctggcacctgattttgtatccccctgtagcagcattactgaaatacataggcttat atacaatgcttctttcct gaagccctggaaaatcgcctgagatacagatgaagattagaaatcgcgacacatttgtagtcattgtatcacggattacaatgaacgcagtgcagagccccaa 202350 agctcaggctattgttaaatcaataatgttgtgaagtaaaacaatcagtactgagaaacctggtttgccacagaacaaagacaagaagtatacactaacttgtata 57 sata aatttatetaggaaaaaaatcttcagaattctaagatgaatttaccaggtgagaatgaataagctatgcaaggtattttgtaatatactgtggacacaaettgottctg cctcatcctgccttagtgtgcaatctcattgactatacgataaagtttgcacagtctacttctgtagaacactggccataggaaatgctgtttttttgtactggactttacc ttgatatatgt gctggtatcagaacagcttccctcactgtgtacagaacgcaagaagggaataggtggtctgaacgtggtgtctcactctgaaaagcaggaatgtaagatgatga 58 202388 aagagacaatgtaatactgttggtccaaaagcatttaaaatcaatagatctgggattatgtggccttaggtagctggttgtacatctttccctaaatcgatccatgttac 58 cacatagtagttttagtttaggattcagtaacagtgaagtgtttactatgtgcaagggtattgaagttcttatgaccacagatcatcagtactgttgictcatgtaatgeta at aaactgaaatggtccgtgtttgcattgttaaaaatgatgtgtgaaatagaatgagtgctatggtgttgaaaactgcagtgtccgttatgagtgccaaaaatctgtcttg aaggcagctacactt aacctgaaaacatcccagccaagaactggtataggagctccaaggacaagaaacacgtctggetaggagaaactatcaatgctggcagccagtttgaatata 59 202403 atgtagaaggagtgacttccaaggaaatggctacccaacttgccttcatgcgcctgctggccaactatgcctctcagaacatcacctaccactgcaagaacagc 59 a attgcatacatggatgaggagactggcaacctgaaaaaggetgtcattctacagggetetaatgatgttgaacttgttgotgagggcaacagcaggttcacttaca _at ctgttcttgtagatggctgctctaaaaagacaaatgaatggggaaagacaatcattgaatacaaaacaaataagccatcacgcctgcccttccttgatattgcacc I_ I tttggacatcggtggtgctgaccaggaattctttgtggacattggcccagtctgtt 202555 gagccattggaagactgtcctctatggcaatgatctcagggetcagtggcaggaaatectcaacagggtcaccaaccagccogotcaatgcagaaaaactag _ s at aatctgaagatgtgtcccaagctttcctgaggctgttgctgaggaaaagcctcatgtaaaaccctatttctctaagaccattcgcgatttagaagttgtggagggaa gtgctgctagatttg actgcaag attgaagg atacccagaccccgaggttg tctggttcaaagatg accagtcaatcagg gagtcccg ccacttccag atag act acgatgaggacgggaactgctctttaattattagtgatgtttgcggggatgacgatgccaagtacacctgcaaggctgtcaacagtcttggagaagccacctgca c ttatcaagtgtcaagatcagcaagtgtccttaagtcaaataggtttttttgttggtggttgtgcttgctttcctttttagaaagttctagaaaataggaaaacgaaaaatt

61 61a 202620 tcattgagatgagtagtgcatttaattatttaaaaaactttttaagtacttgaatttatatcaggaaaacaaagttgttgagccttgcttcttccgttttgccctttgtctcg ctccttattctttfttggggggagggttatttgttttatettcctggcataatttccattttattcttetgagtgtetatgttaacttccctetatcccgettataaaaaaattetcc at aacaaaaatacgttgacttgatgttttatcacttctctaagtaaggttgaaatatccttattgtagctactgtttaatgtaaaggttaaacttgaaaagaaattcttaat cacggtgccaaaattcattttctaacaccatgtgtt agattctaacggtctgttctgtttcaaggcactctagattccattggtccaagattccggatcctaagcatctaagttataagactctcacactcagttgtgactaactag 62 202686 acaccaaagttctaataatttctaatgttggacacctttaggttctttgctnnattctgcctctctaggaccatggttaagagtccaagaatccacatttctaaaatcttat a 62 sat agttctaggcactgtagttctaagactcaaatgttctaagtttctaagattaaaggtccacaggtetagactattaggtgcaatttcaaggttctaaccctatactgta gattcttggggtgcccctctccttcttagctatcattgcttcctcctccccaactgtgggggtgtgcccccttcaagcctgtgcaatgcattagggatgcctcctttccgc aggggatggacgatctcccacctttcgggccatgttgcccccgtgagccaatccctcaccttctgagtacagagtgtggactctggtgcctcca ggctctggaggtgggcagcaatctgtcaatcaccttgttaaagagattgatatgctgctgaaagaatatttactctctggagacatatctgaagctgaacattgcctta 63 63 202731 aggaactggaagtacctcattttcaccatgagcttgtatatgaagctattataatggttttagagtcaactggagaaagtacattaagatgattttggatttattaaagt ccctttggaagtcttctaccattactgtagaccaaatgaaaagaggttatgagagaatttacaatgaaattccggacattaatctggatgtcccacattcatactctgt at gctggagcggtttgtagaagaatgtttcaggctggaataatttggaaacaactcagagatctttgtccttcaaggggcagaaagcgttttgtaagcgaaggagat ggaggtcgtcttaaaccagagagctactgaatataagaactctgcagtcttagatgttat gtaagattcctcctaactttcacagtcgatgacaagattgtttttatctgatattttgaagggtatattgctttgaagtaagtctcaataaggcaatatattttagggcatc 64 202741 tttcttcttatctctgacagtgttcttaaaattatttgaatatcataagagccttggtgtctgtcctaattcctttctcactcaccgatgctgaatacccagttgaatcaaactgt 64 caacetaccaaaaacgatattgtggettatgggtattgetgtetcattcttggtatattcttgtgttaactgcccattggcctgaaaatactcattgtaagcctgaaaaaa _a aaaatetttcccactgttttttctgcttgttgtaagaatcaaatgaaataatgtatgtgaaagcaccttgtaaactgtaacctatcaatgtaaaatgttaaggtgtgttgttat ttcattaattacttctttgtttagaatggaatttcctatgcactactgtagc tacacttttttttgccaactgacttaacaacattgctgtcaggtggaaatttcaagcacttttgcacatttagttcagtgtttgttgagaatccatggettaacccacttgtttt 202742 getatttttttctttgctttaatttccccatctgatttatetctgegtttcagtgacetacettaaaacaacacacgagaagagttaaactgggttcattttaatgatcaattt -s-at acctgcatataaaatttatttttaatcaagctgatcttaatgtatataatcattctatttgctttattatcggtgcaggtaggtcattaacaccacttctttcatctgtaccaca ccctgtaactttgaagacataaaaaaaacctgtctgagatgttctttctaccaatctatatgtctttcggttatcaagtgtttctgcatggtaatgtc aaactactaaccactgcaagctcttgtcaaattagtttaattggcattgcttgtttfttgaaactgaaattacntgagtttcatttttctttgaatttatagggtttagatttctg

66 66 202746 aaagcagcatgaatatatcacctaacatcctgacaataaattccatccgttgtttttgtttgtttgttttttcttttcctttaagtaagctctttattcatcttatggtgcagcaa ttttaaaatttgaaatattttaaattgtttttgaacttttgtgtaaaatatatcagatetcaacattgttggtttcttttgtttttcattttgtacaacttettgaatttagaaattacat at ctttgcagttctgtaggtgctctgtaattaacctgacttatatgtgaacaattttcatgagacagtcatttttaactaatgcagtgattctttctcactactatctgtattgtgga atgcacaaaattgtgtaggtgctgaatgctgtaaggagtttaggttgtatgaattctacaaccctataata gagatactatttttgctgagcaaccagtgtgtttcaggatgatacaaagaaaaatatagaatagaaataagtgcaggcttggaatcagctacaaatcctaaagat 67 202760 ggggtgtgtgtggatgtgtgtgtgtgtgtgtgtacaccattgtgtgtttgtaaaatgtgtatgttcatgagtaagggtgtgtgtgtgtgtgtattaaaattccagagtgaccg a 67 sat tggcacttgggtgtacaggtaattcctccagagctgtttgctggcttcaggagtggagtgagaatttcttttttatgaaaagggatataaaggcaccgagctgatgca gtatttgtaatataagtgacctaacaaggtatttgcatgagtcacaattacaaagttttgagcggttttgtaatttgacattaggaaagtctcctatttattctcatacttta cattcatgcttagtatactatagaggatgccagctttaatcttctg gctttcaattgatggactactctattttttgcaaatttgtaaactttgcttctccaaatacaagtactaggttgtccatttatggtacctatttggtgctagtaaattttcaaacta 68 202766 gatttataaatgcactgtaatatgtacacaacttagaaaccaaattacaagtattcagttccaatacttcattaatttcaatcaaccaaagttagttcagtagcttatctc 68 saa agttatgagtataatacattacatgtaaattaagtgtgtgtatactgtaategtgctatttttatcattgaaacatttataaactagaataataatgcccttaatgtgagggt tgtaatggtgcttattaagaccaaagacttgttaaatgtatacaccaagtggtaatgaaatttcgtgactggcccacacgtgcatagaggtctgggaggaccagg aaacagcctcagtggccagaggatcaccagtgcatccttcatcacagcatgtgcaatatgccaagattaccctcggtcattcctgtcaacaaggg gcgtgagtgtgtgagcgcttctgcagcctcggcctaggtcacgttggccctcaaagcgagccgttgaattggaaactgcttctagaaactctggctcagcctgtctc 69 202768 gggctgacccttctgatcgtctcggcccctctgattgttcccgatggtctctctccctctgtcttttctcctccgcctgtgtccatctgaccgttttcacttgtctcctttctgac 69 at tgiccetgccaatgetccagetgtcgtetgactctgggttcgttggggacatgagatttatttttgtgagtgagactgagggatogtagatttttacaatetgtatetttga caatctgggtgcgagtgtgagagtgtgagcagggcttgctcctgccaaccacaattcaatgaatccccgacccccctaccccatgctgtacttgtggttctctttttgt attttgcatctgaccccggggggctgggacagattggcaatgggccgtccc agaaagaggcgctgctcactgtttcctgcttcagtttttctcttatagtaccatcactataatcaacgaacttctcttctccacccagagatggettttccaacacatttta 202838 attaaaggaactgagtacattaccctgatgtctaaatggaccaaagatctgagatccattgtgattatatctgtatcaggtcagcagaagaaggaactgagcagtt 70 at gaactctgagttcatcaattetaatatttggaaattatetacaatggaatettccctctgttetctgataacctacttgottactcaatgcetttaagccaagicaccetgttg cctatgggaggaggtggaaggatttggcaagctcaaccacatgctattagttagcatcagttgtcaccaacagtctttctgcaaagggcaggagagctttggggg aaaggaaaaggcttaccaggctgctatggtcaactcttcagaa -agccctggagaagacgaaagccaacatcaagtgggtgaaggagaacaaggaggtggtgctccagtggttcacagaaaacagcaaatagtccccagccctt 71 202888 gaagtcacccggccccgatgcaaggtgcccacatgtgtccatcccagcggctggtgcagggcctccattcctggagcccgaggcaccagtgtcctcccctcaa 1 at_at ggacaaagtctccagcccacgttctctctgcctgtgagccagtctagttcctgatgacccaggetgcctgagcacctcccagcccctgcccctcatgccaaccccg ccctaggcctggcatggcacctgtcgcccagtgccctggggctgatctcagggaagcccagctccagggccagatgagcagaagctctcgatggacaatgaa I I cggccttgctgggggccgccctgtaccctctttcacctttccctaaagaccctaaatctgaggaatcaacagggcagcagatctgtatatttttttc attatctggtctttcctgttgtgcaaaaatgactcattgctccgaatgtcaaaaacaaatgcgacaaacaatggcacttcatcatttaaagtaatgttgccaagagaa

72 72 202920 aaaatttcctgggagggaggtttcccacaagccaaatctcctaagcctcaaatgctagcactttttggcagttggataggaaatgagacattctttggcagccaaa ataagagaggccgatggtgaaactttttgagacaccctatggccttcttgtcaaaaccttcactggagctcaagaaaagcatttctgttgtgttatttgcagtgcagat at gatgtctgtgtaacaacataatggttattcacctttttttgattttgatttgctgtgttatcaaaaacttgaatactgtgagaagaagtgaattttcagttgacgaatcagc atcttgttcccatggtgataac cttcgaccacgtgatcaccaacatgaacaacaattatgagccccgcagtggcaagttcacctgcaaggtgcccggtctctactacttcacctaccacgccagctc tcgagggaacctgtgcgtgaacctcatgcgtggccgggagcgtgcacagaaggtggtcaccttctgtgactatgcctacaacaccttccaggtcaccaccggtg 73 202953 gcatggtcctcaagctggagcagggggagaacgtcttcctgcaggccaccgacaagaactcactactgggcatggagggtgccaacagcatcttttccgggt _at cctgctctttccagatatggaggcctgacctgtgggctgcttcacatccaccccggctccccctgccagcaacgctcactctacccccaacaccaccccttgccca gccaatggacacagtagggcttggtgaatgtgctgagtgaatgagtaaataaactcttcaaggccaaggaacagtggtctaattcaactctgtgtcccagcact ggcacaccagaagtgccatgctcagaaa tgatgagctttcctttgatccggacgacgtaatcactgacattgagatggtggacgagggctggtggcggggacgttgccatggccactttggactcttccctgcaa 74 202957 attatgtcaagcttctggagtgactagagctcactgtctactgcaactgtgatttcccatgtccaaagtggctctgctccaccccctccctattcctgatgcaaatgtcta 7 t accagatgagtttctggacagacttccctctcctgcttcattaagggcttggggcagagacagcatggggaaggaggtccccttccccaagagtcctctctatcctg at gatgagctcatgaacatttctcttgtgttcctgactccttcccaatgaacacctctctgccaccccaagctctgctctcctcctctgtgagctctgggcttcccagtttgttt acccgggaaagtacgtctagattgtgtggtttgcctcattgtgctatttgcccactttccttccctgaagaaatatctgtgaaccttctttctgttcagtccta gctggaatacttactcttgtcgggagattgaaccactaaaatgttagagcagaattcattatgctgtggtcacaggggtgtcttgtctgagaacaaatacaattcagt 202992 cttctctttggggttttagtatgtgtcaaacataggactggaagtttgcccctgttcttttttcttttgaaagaacatcagttcatgcctgaggcatgagtgactgtgcatttga at gatagttttccctattctgtggatacagtcccagagttttcagggagtacacaggtagattagtttgaagcattgaccttttatttattccttatttctctttcatcaaaacaaa acagcagctgtgggaggagaaatgagagggcttaaatgaaatttaaaataagctatattatacaaatactatctctgtatgtctgaccctggtaaa aatgcgaaggctaagtgtcaccccctttctctgcctctggetgggccttgctaagggccaaggaaagaaagacattttttagggggcagccagtccaaatgccaa 76 202994 aagaagaccagttcttgccctgattgtatgaaattgacattttggcactttttttttttttnggccaatcagattttctatgttctaaggacatggetgetgtagaatagca _s_at cagacgtggatgataaattatccccagaagcagcatgacagaatgcctcggggagcacttggaagggaaattgcagttctgttgaaatagaggaaaatccctt ggtaaagacacagcctgttaggctcgtgtgggcctccagtatgttcaccaggggaa aacgatgtcacatgcgtgttcgaccccgtgcacaccatctcccacaccgtcatctcgctgcctaccttccgcgagttcacccgccctgaagagatcatcttcctccg 77 202995 ggccatcacgccaccgcatcctgccagccaggctaacatcatcttcgacatcacggaagggaacctgcgggactcttttgacatcatcaagcgttacatggacg 77 a at gcatgaccgtgggtgtcgtgcgccaggtgcggcccatcgtgggcccatttcatgccgtcctgaagctggagatgaactatgtggtcgggggcgtggtttcccacc gaaatggtcaacgtccgcatcttcgtctctgagtactggttctgagggctggtctgccgcacagccgcaggtgcacctccaggccaaatcattgctgccagtgac tgtggtctgtacttgtttataccctcag gacagacctgagaccaatctgggtagaagcaaaaagttgaacctttaaagtgctgaacacaaatccaaattcgaatggttcaagcagccgtgaaatcgctctt 78 78 203000 cataaagtgggcttaattctctagtttaagttcttttgatggaatgaattaattaatgtgtcaggtggcttatttgtggatgccatgattgatgatgttcattttaagctcttacc tatagtacaagtacatgatgotactgaatatttttccacttggaaactgtgagotggttgttgcattaaaacacacatacaaacaaaatcaaaaacactgeggacttt at cactcaagctggtctttcttccccagtgtaaggcaatcctgcctactaacaacaccaacaacaaaacactccatctgtgaanntgacgcagttaagggggctagg cagggcatttgtgccaactaagaatcaccagatacccaccataagtacctatcgcagttttgaagtc acctcgcaacatcaacatctatacttacgatgatatggaagtgaagcaaatcaacaaacgtgcctctggccaggcttttgagctgatcttgaagccaccatctcct 203001 atctcagaagccccacgaactttagettctccaaagaagaaagacctgtccctggaggagatccagaagaaactggaggctgcaggggaaagaagaaagt 79 aat ctcaggaggcccaggtgotgaaacaattggcagagaagagggaacacgagcgagaagtcettcagaaggetttggaggagaacaacaacttcagcaagat ggcggaggaaaagctgatcctgaaaatggaacaaattaaggaaaaccgtgaggctaatctagtgctattattgaacgtctgcaggaaaaggagaggcatgc tgcggaggtgcgcaggaacaaggaactccaggttgaactgtctggctgaagcaagggagggtctggcacgcc atggcctctgtgaataatgtaactccagttacacggtgactttaatagcatacagtgatttgatgaaaggacgtcaaacaatgtggcgatgtcgtggaaagttatctt 80 203058 a tcccgctctttgctgtggtcattgtgtcttgcagaaaggatggccctgatgcagcagcagcgccagctgtaataaaaaataattcacactatcagactagcaaggc actagaactggaaaagaccacagaaaacaaagaatccaaccetttcatettacaggtgaacaaactgtgatgatgcacatgtatgtgttttgtaagetgtgagca sat ccgtaacaaaatgtaaattgccattataggaaagtgctggtggcagtgaagaagcacccaggccacttgactcccagtctggtgccctgtctacaccagacaa cacaggagctgggtcagattcccctcagctgcttaacaaagttcctcgaacagaaagtgcttacaaagctgcctctcggatact agctgccttctcggatactgaaaggtcgagtttctgaactgcactgattttattgcagttgaaaaacccaaagctattccaaagatttcaagctgttctgagacatctt ctgatggctttacttcctgagaggcaatgtttttactttatgcataattcattgttgccaaggaataaagtgaagaaacagcacctttttaatatataggtctctctggaag 81 203060 agacctaaattagaaagagaaaactgtgacaattttcatattctcattcttaaaaaacactaatcttaactaacaaaagttcttttgagaataagttacacacaatgg _s-at ccacagcagtttgtctttaatagtatagtgcctatactcatgtaatcggttactcactactgcctttaaaaaaaaccagcatatttattgaaaacatgagacaggattat agtgccttaaccgatatattttgtgacttaaaaaatacatttaaaactgctcttctgctctagtaccatgcttagtgcaaatgattatttctatgtacaactgatgcttgttctt attt ttcagttgctaatgaggctcctccgctctggacacaacccttttatagattaatttctctgccaattaacttgtcattttcagtacatattttactattccacaccaaccataat 82 203066 tacaacaagggatttttcttatgcactcctatgcatgtgaataacatgtggtgtaattctgcttcttacagaagtattactgaaggtattatttccaatattatttggtttattat 82 gcggatcttttttatatatgcagtcccatcccttctgtgccactcaatgccatccagacatggtttttccctccaggggcctttctctccagagggcacttcggctgcctct at gcttcctctcattcgaggcccggctcttgctgacagaataggttccgttctgggcggtggttctcgagcctgccattcaaaaccaaagcaaattggagcatttctcac aacatggtattgaagttcctttttgttctcaaaagttgtgaccgtgttaaattgtactcccttagtcctgtaaggtatgttaagtgaatcgcagttacgctgtactttta 83 203131 agaaaatttgccaatetttoctactttctatttttatgatgacaatcaaagceggcetgagaaacactatttgtgactttttaaacgattagtgatgtcitaaaatgtggtet Iat gccaatctgtacaaaatggtcctattttgtgaagagggacataagataaaatgatgttatacatcaatatgtatatatgtatttctatatagacttggagaatactgcc aaaacatttatgacaagctgtatcactgccttcgtttatatttttttaactgtgataatccccacaggcacattaactgttgcacttttgaatgtccaaaatttatattttagaa ataataaaaagaaagatacttacatgttcccaaaacaatggtgtggtgaatgtgtgagaaaaactaacttgatagggtctaccaatacaaaatgtattacgaatg cccctgttcatgtt ccaggactacagaataccatcccctggtaccgtgtagttgccgaagtccagatctgccatggcaaaacggaggctgtgggccaggtccacatcttcttccaggat gggatggtgacgttgactccaaacaagggtgtgtgggtgaatggtctccgagtggatctcccagctgagaagttagcatctgtgtccgtgagtcgtacacctgatg 84 203240 gctccctgctagtccgccagaaggcaggggtccaggtgtggcttggagccaatgggaaggtggctgtgattgtcagcaatgaccatgctgggaaactgtgtggg _at gcctgtggaaactttgacggggaccagaccaatgattggcatgactcccaggagaagccagcgatggagaaatggagagcgcaggacttctccccatgttat ggctgatcagtcatccaccaggaacgaagatttcctgaagaagacctggtccctctggaggttgcggtggetgaaggatgcatcatgtgetcctaccctgctctac cgcttttctgggtcacagag aaagacaagcattgggtcagacccataaaccacctcccaaaggctgtcatttcattgcactggaattttgctttatcagaagcaaggaagtaagggagtcattgc 203296 cttgggcctgggaatctaagtgggagacaatattaatttggatccgattaattggagattactaactgtggacaaaagtttatetttgcacaatcaataaaaatggcat _s-at tttfttagtaaattaagagcataaacaatattgctagaggtggcatgtttagtctaccaaaaacaatacttttcaggcactttagaaatatccttttagaagcagcgagt gcatgggctaattatcatcaatctttatgtatttgttaaagaaacatctacaggatcttattggtgacctttgta gtccttcacatcaccattttgagacctcagcttggcactcaggtgctgaagggtaatatggactcagccttgcaaatagccagtgctagttctgacccaaccacaga 86 203305 ggatgctgacatcatttgtattatgttccaaggctactacagagaaggctgcctgctatgtatttgcaaggctgatttatggtcagaatttccctctgatatgtctagggtg 86att tgatttaggtcagtagactgtgatttagcaaaaaatgaacagtgataagtatactgggggcaaaatcagaatggaatgetetggtctatataaccacatttgag cctttgagactgttcctgagccttcagcactaacctatgagggtgagctggtcccctctatatatacatcatacttaacttactaagtaatctcacagcatttgccaagt ctcccaatatccaatt atgtgtcactgatttttagctcaaaatcatcactgttaatttccagtcaccccaaatatggttaaaagattttttttaatcatgaagagaaaattagtagcatttctttctc 87 203343 tccccattatttattggttttcctcactaatcttttttttttagtccaaaagccaaaaatatttatcttggtttacattttaatttccattcttaattgtaatttttttctttaaataagga -7at aaccaatataatctcatgtataaaaacttaaatatttacaagttacatatagcatcattctaaaataagaatttttttgtttctgtctgctttttcttatgtctcttgttgagtttt -atatttcagtggttattttgcttgtgttagatcattattaaaatatatccaatgtccctttgatacttgtgctctgctgagaatgtacagtttgcattaaacatcccaggtetca tccttcaggaattt gaagcgcctggcagtgtaccaggccggggcccgcgagggcgccgagcgcggcctcagcgccatccgcgagcgcctggggcccctggtggaacagggcc 88 203382 gcgtgcgggccgccactgtgggctccctggccggccagccgctacaggagcgggcccaggcctggggcgagcggctgcgcgcgcggatggaggagatgg s at gcagccggacccgcgaccgcctggacgaggtgaaggagcaggtggcggaggtgcgcgccaagctggaggagcaggcccagcagatacgcctgcaggc -- cgaggccttccaggcccgcctcaagagctggttcgagcccctggtggaagacatgcagcgccagtgggccgggctggtggagaaggtgcaggctgccgtgg gcaccagcgccgcccctgtgcccagcgacaatcactgaacgccgaagcc actgtgatataggtactctgatttaaaactttggacatcctgtgatctgttttaaagttggggggtgggaaatttagotgactagggacaaacatgtaaacctattttcct 89 203474 atgaaaaaagttttaaatgtcccactgaataacgtaattcttcatagtttttaatctatggataaatggaaacctaattatttgtaatgaattatttagacagttctaagc 89at cctgtettgggagttatcaatttaaagagaacttttgtgcaattcaaatgaagtttttataagtaattgaaaatgacaacacaataacacttetgtataaaagtatat - aatttatgtgatttattcctactaaatgaaagtgcactactgcctcatgtaaagactctgcacgcagagccttaagtgactaaggaacaacatagatagtgagcata gtccccacctccacccctcacaatttatttgaatactcaatgtgcctctcaa ttcagacagttatatcctccttttaaaccattgttgttgagtgtaagatgtccttcatgttttcttataaagtcagtgtttagaaatgttaccctttctaagttatatacagatca 203477 aatgettttctttcacgtacatccatcatttgcaactgetgttcgtacacagaaacaggactgetcaaatgatcctatttgtattttetgatgetatcagactctaatgtttttt _at tccctaaaatattattgccatcatgctttaggaattttatatttttacacaatcatattttagtatggtgtctgtttatgtaactctgacttgctggaaaagttgaaactccaaa taatctgaaactagaaaagaaatagcacataattactaccttccccttggcggctctcctcccccaacccccaccccacaattttatgacttcca caacgtctaactggacttcccaagataaatggtaccagcgtcctcttaaaagatgccttaatccattccttgaggacagaccttagttgaaatgatagcagaatgtg 91 203638 cttctctctggcagetggccttctgettctgagttgcacattaatcagattagcctgattctcttcagtgaattttgataatggettccagactctttgcgttggagacgcctg _s-at ttaggatcttcaagtcccatcatagaaaattgaaacacagagttgttctgctgatagttttggggatacgtccatctttttaagggattgctttcatctaattctggcagga cctcaccaaaagatccagcctcatacctacatcagacaaaatatcgccgttgttccttctgtactaaagtattgtgttttgctttggaaacacccactcact gccagacgctggggccatagtgagtgtgggcacaaggaagacgctgcagtgaattgcacagatatttcagtgcagaaaaccccacaaaaagccacaacag 92 203645 gtcgctcatcccgtcagtcatcctttattgcagtcgggatccttggggttgttctgttggccattttcgtcgcattattcttcttgactaaaaagcgaagacagagacagc 92s at ggettgcagtttcctcaagaggagagaacttagtccaccaaattcaataccgggagatgaattcttgcctgaatgcagatgatctggacctaatgaattcctcagg -- aggccattctgagccacactgaaaaggaaaatgggaatttataacccagtgagttcagcctttaagataccttgatgaagacctggactattgaatggagcaga I_ aattcacctctctcactgactattacagtgcattttatggagtctcttctcctaggattcc ttttcattgttcattgatatgctcagtatgctgccacataagatgaatttaattatattcaaccaaagcaatatactcttacatgatttctaggccccatgacccagtgtcta 93 203680 gagacattaattctaaccagttgtttgcttttaaatgagtgatttcattttgggaaacaggtttcaaatgaatatatatacatgggtaaaattactctgtgctagtgtagtett 93at - actagagaatgtttatggtcccacttgtatatgaaaatgtggttagaatgttaattggataatgtatatataagaagttaaagtatgtaaagtataacttcagccacatttt tagaacactgtttaacatttttgcaaaaccttcttgtaggaaaagagagtctctacatgaagatgacttgttttatatttcagattttattttaaaagccatgtctgttaaac aagaaaaaacacaaaagaactccagattcctggtcatcattctgtatcttactcactttttcaagtt atcctcattcttatactgcttttcgtggccactttggacaagtcctggtggactctccctgggaaagagtccctgaatctctggtacgactgcacgtggaacaacgaca 94 203729 ccaaaacatgggcctgcagtaatgtcagcgagaatggctggctgaaggcggtgcaggtcctcatggtgetctccctcattctctgctgtctctccttcatcctgttcat 94 gttccagctctacaccatgegacgaggaggtCtCttctatgccaccggcctetgccagotttgcaccagegtggcggtgtttactggegcettgatctatgccattcac _a gccgaggagatcctggagaagcacccgcgagggggcagcttcggatactgcttcgccctggcctgggtggccttccccctcgccctggtcagcggcatcatcta I I catccacctacggaagcgggagtgagcgccccgc caagtatcggggctctgctatcaaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatggagcaca ccatgtcactacagcccgcatcaatgatcagccctctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtcagctatg 203748 caaggagcctacttgccacagtatgcacatatgcagacgacagcggttoctgttgaggaggcaagtggtcaacagcaggtggetgtcgagacgtetaatgacc _x-at attctccatatacctttcaacctaataagtaactgtgagatgtacagaaaggtgttcttacatgaagaagggtgtgaaggctgaacaatcatggatttttctgatcaatt gtgctttaggaaattatgacagttgcacaggttcttgaaaacgttatttataatgaaatcaactaaaactatttttgctataagttctataaggtgcataaaacccttaa attcatctagtagctgttccccc caccttgggtctgtgtcacttgtaggtttctctgcctccaggttgcctcaacagcaggaggcacagcagtttcaccatctttgaggtgagggtggggtgccccagcta

96 96 203766 ggaagcaagatcgctgtgotaggtctgaccaaaaccagagggcagtctagtcctgggggtaaagccctcagatcccagggtacactcttctccattccctccac a ccacttgcctgtcaccccagtcacctaagcaatcactgggcccagaggagaggagacagacacacactggetectggacctaaagggtatgagetggagcta _at aggccagctagagcttccactgtcagccctcactgtcagccccactgcacccccctgtgcctgctgggcactgggcactagctagatgctttaggttgcttcagctg atccttcaactctgtgaggtg tatgtgacgctggaccttttctttacccaaggatttttaaaactcagatttaaaacaaggggttactttacatcctactaagaagtttaagtaagtaagtttcattctaaaa 97 203881 tcagaggtaaatagagtgcataaataattttgttttaatctttttgttttctttagacacattagctctggagtgagtctgtcataatatttgaacaaaaattgagagctttat 97 a tgetgcattttaagcataattaatttggacattatttcgtgttgtgttetttataaccaccgagtattaaactgtaaatcataatgtaactgaagcataaacatcacatgge s~t atgttttgtcattgttttcaggtactgagttcttacttgagtatcataatatattgtgttttaacaccaacactgtaacatttacgaattatttttttaaacttcagttttactgcatttt cacaacatatcagacttcaccaa tgtgtaatacgccaaccagtcaagttgtgttttggccagagatttagatatgtccaatttcctggctcatttcattgtgctctatgggtacgtataaaaagcaagaattctg 98 98 203908 tttcctaggcaaacattgcaactcagggctaaagtcatccagtgaaacttttagagccagaagtaactttgtcccagtcctacaatgtgaaaagagtgaatagttgc ctetttttagccattttcatggetggtacatattegtacgcattacttttcagaatcaatacgcactttcagatattettatttttattetettaagtetttattaaetttggagagag at aaatgatgcatctttatttaaatgaagtagatcaacatggtggaacaaaatgataaagaacagaaaacatttcaatatattactaataactttttccaatataaatc ctaaaattcctataacatagtatttacagttttatgaagctttctattgtgacttttatg aacactcacatacaagttcatactttaaaagaggaaagctacttaacaatgacaaatatttcacaataataatttttacttatataccatctttcaactgaacatttcagt 99 203913 tcttccaagagctcttagagtagtatattttgggggcagtcaaggaataaactacagtgtaaacatatcccagatgaaaactgctgtatggaaaaatgacagaaa 99a sat gtaactgattgacactgttgattcacagttcangcctcctatetgggaaagacatttcttoctctgetcactttaagaacttttaccgactccaaaaatetcaggaatta aactttaacagtacagcaataaagaatagttagtactccaaaaatattatatttaagatgctcaacaagaaaaaaatgcaaatgtaatatttttttcaaattacttctt tattgacttgtcca gatttccaaatcagtcgtttctcaaaaaaatatcgtataagtgactcatcctgtctgctaactccagacctcccagcttgaagccaaatctttccatgtgagattgatat 100 203914 ggattcctagaagtactggaatgttgtcatatcttgccctattttaattctgctatagaaaacaattgccttcacttttaaggagtaatttgaatattaataactctggtcta 100 t gatttcatataatgtattaaagacaaagtagtgaacatcaatgaacatetgatagagataaactgtaatcaggcataagettgtttgtatgttetggcagtgactaat _at cagtaaatgatgtcggtttgcccagtatcacttatcttctgtatttttcctctgtcgtgtaaatagtataaccttttcatttatggacaattttttggactagtagccttcaatata I cattctgctt acgcacacaactactacaattccgcctaggtccacaaggccttcactgttttccccccaagggaggctgctgctgctcttggctggagccagccagggccagcc 101 203951 gaccccctctccctgcatggcatcctccagcccctgtagaactcaacctctacagggttagagtttggagagagcagactggcggggggcccattggggggaa 11at - ggggaccetecgetctgtagtgetacagggtccaacatagaacagggtgtcccaacagcgcccaaaggacgcactgagcaacgetattccagetgtccccc cactccctcacaagtgggtacccccaggaccagaagctcccccagcaaagcccccagagcccaggctcggcctgcccccaccccattcccgcagtgggag caaactgcatgcccagagacccagcggacacacgcggtttggtttgcagcgactggcatac ccaaatttcatttcagccacttctgcaggatccctactgccaacctggaatggagacttttatctacttctctctctctgaagatgtcaaatcgtggtttagatcaaatata 102 102203963 tttcaagctataaaagcaggaggttatctgtgcagggggctggcatcatgtatttaggggcaagtaataatggaatgctactaagatactccatattcttccccgaat cacacagacagtttetgacaggcgcaactcctccattttcctccogcaggtgagaaccetgtggagatgagtcagtgccatgactgagaaggaaccgaccccta . at gttgagagcaccttgcagttccccgagaactttctgattcacagtctcattttgacagcatgaaatgtcctcttgaagcatagetttttaaatatctttttccttctactcctcc ctctgactctaagaattctctcttctggaatcgcttg gtgtgatgcttttgtaggtacctggaaacttgtctccagtgaaaactttgatgattatatgaaagaagtaggagtgggetttgccaccaggaaagtggetggcatggc 103 103203980 caaacctaacatgatcatcagtgtgaatggggatgtgatcaccattaaatctgaaagtacctttaaaaatactgagatttccttcatactgggccaggaatttgacga agtcactgcagatgacaggaaagtcaagagcaccataaccttagatgggggtgtcctggtacatgtgcagaaatgggatggaaaatcaaccaccataaaga at gaaaacgagaggatgataaactggtggtggaatgcgtcatgaaaggcgtcacttccacgagagtttatgagagagcataagccaagggacgttgacctggac tgaagttcgcattgaactctacaacattctgtgggatatattgttcaaaaagatattgttgttttccctgatttagcaagca ggtccccacagactcagagagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcga 104104204018 t gtatggtgcggaggccctggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggcca cggcaagaaggtggccgacgccctgaccaacgccgtggcgcacgtggacgacatgcccaacgogotgtoegccetgagcgacctgcacgcgcacaagett x~t cgggtggacccggtcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctgga caagtctgttctgtgagcaccgtgctgacctccaaataccgttaagctg gcccaggctgacttacacattgaggatggagactccatccgcttcgggcgcttcgcgttggagaccagggccagccctggccacaccccaggetgtgtcacctt 105 204034 cgtcctgaatgaccacagcatggccttcactggagatgccctgttgatccgtgggtgtgggcggacagacttccagcaaggctgtgccaagaccttgtaccactc 105 ggtccatg aaaagatettcacacttocagg ag actgtetg atctaccetgetcacg attaccatgggttcacagtgtecaccgtgg agg ag gag agg actctg aa at ccctcggctcaccctcagotgtgaggagtttgtcaaaatcatgggcaacctgaacttgcctaaacctcagcagatagactttgotgttccagccaacatgcgctgtg I_ I gggtgcagacacccactgcctgatctcacttctgtcagatgctcccatccactattaatgcactaggtgggaggagagggcggcaatgacactgcacct aattgccacatttcttatggcattaaaaattttacaaaaacataatttaatggctatattatattccattaatggatgcaactcangtttatttaaccattcccatngttgtt 106 204036 aactatttaggttgtttctaattcattattataaagttgcagaaatttggtgtacataaaactgtctccatataattgattattaggatatattcccatgaaggattcnttttttt 106at aaaaaaatgtgaaatntcatettgtacttacacctttcatgnaaagggatttoctgettttgtactgcatgggtggcagttgtgaggaaaagccagtcaaatgacetttt attacaaaagaaatgcagtggtcacttcagttgagagtgactttaatacaacaagatcaactagaagaattcaactgtctcaagaatcaaggtaccccaatatatct cgcaattccaaactttgtttgagggactcgttatccagctcttggtagccacacctgcaatgta aagccttacagttatcctgcaagggacaggaaggtctgatttgcaggattttagagcattaaaataactatcaggcagaagaatctttcttctcgcctaggatttcag 107 204069 ccatgcgcgcgctctctctctttctctctctttcctctctctccctctttctagcctggggcttgaatttgcatgtctaattcatttactcaccatatttgaattggcctgaacag 17 - at atgtaaatcgggaaggatgggaaaaactgcagtcatcaacaatgattaatcagctgttgcaggcagtgtcttaaggagactggtaggaggaggcatggaaacc aaaaggccgtgtgtttagaagcctaattgtcacatcaagcatcattgtccccatgcaacaaccaccaccttatacatcacttcctgttttaagcagctctaaaacata gactgaagattattttaatatgttgacttatttctgagcaaagcatcggtcatgtgtgtatttttcatagtcccacctggagcatttatg gaaggcggctgatgagagcgagagaggaatgaaggtcatcgaaaaccgggccatgaaggatgaggagaagatggaactgcaggagatgcagctgaag 108 204083 gaggccaagcacatcgctgaggattcagaccgcaaatatgaagaggtggccaggaagctggtgatcctggaaggagagtggagcgctggaggagagg 18 s at getgaggtggccgagagccgagccagacagetggaggaggaacttegaaccatggaccaggccctcaagtccctgatggcctcagaggaggagtattoca -- ccaaagaagataaatatgaagaggagatcaaactgttggaggagaagctgaaggaggctgagacccgagcagagtttgccgagaggtctgtggcaaagtt ggagaaaaccatcgatgac catggggggacttgaaccctgcagcaggctcctgctcctgcctctcctgctggctgtaagtggtctccgtcctgtccaggcccaggcccagagcgattgcagttgct 109 204122 ctacggtgagcccgggcgtgetggcagggatcgtgatgggagacctggtgetgacagtgetcattgccctggcegtgtacttcctgggccggetggtecctcggg _at ggcgaggggctgcggaggcagcgacccggaaacagcgtatcactgagaccgagtcgccttatcaggagotccagggtcagaggtcggatgtctacagcga cctcaacacacagaggccgtattacaaatgagcccgaatcatgacagtcagcaa tccccagcagtggctcggtgagccatgtgcacctatggcccagccactgcagcacaggaggctccgtgagccttggttcctccccgaaaacccccagcattac 110 204130 gatcccccaagtgtcctggaccctggcctaaagaatcccacccccacttcatgcccactgccgatgcccaatccaggcccggtgaggccaaggtttcccagtga 10 - at gcctetgegcctctccactgtttcatgagcccaaacaccctcctggcacaacgetctaccctgcagettggagaactccgetggatgggagictcatgcaagactt cactgcagcctttcacaggactctgcagatagtgcctctgcaaactaaggagtgactaggtgggttggggaccccctcaggattgtttctcggcaccagtgcctca gtgctgcaattgagggctaaatcccaagtgtctcttgactggctcaagaattagggcccca cagaccggcagtcatcatggcagtttcagcgttcaaacagcaatagctcaagtgtgataactactgaggataataaaatccacattcacttaggaagtccttacat 1 204135 gcaagctgtagccagcccttcagcaccactgcaggataaccgaactcaaggcttaattaacggggcactaaacaaaacaaccaataaagtcaccagcagta 111at ttactatcacaccaacagccacacctcttcctcgacaatcacaaattacagtaagtaatatatataactgaccacgctcaccctcatccagtccatactgatatttttg -tcaaggaactcaatccttttaatcatccctccatatcccccaagactgactgaactcgtactttgggaaggtttgtgcatgaactatacaagagtatctgaaactaac tgttgcctgcatagtcatatcgagtgtgcacttactgtatatctttcat gcgtgttttcctcttgatcgggaactcctgcttctccttgcctcgaaatggaccccaactgctcctgctcgcctgttggctcctgtgcctgtgccggctcctgcaaatgca 112 204326 aagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccctgtgggctgtgcnaagtgtgcccagggetgcatctgcaaagggacgtcagacaa _x at gtgcagctgotgtgcctgatgccaggacagctgtgctctcagatgtaaatagagcaacctatataaacctggattttttttttttttttttgtacaaccctgacccgtttgct acatctttttttctat 113 204388 ttccacatcagtaactgccctggggtttgtgctgtacaaatacaagctcctgccacggtcttgaagttctgttcttatgctctctgctcactggttttcaataccaccaaga s at ggaaaatattgacaagtttaaaggctgtgtcattgggccatgtttaagtgtactggatttaactacctttggcttaattccaatcattgttaaagtaaaaacaattcaaag - - aatcacctaattaatttcagtaagatcaagctccatcttatttgtcagtgtagatcaactcatgttaattgatagaataaagccttgtgatcact ctttgcgggcacagagactgccacaaagtggagcggetacatggaaggggcagttgaggctggagaacgagcagctagggaggtcttaaatggtctoggga 114 204389 aggtgaccgagaaagacatctgggtacaagaacctgaatcaaaggacgttccagoggtagaaatcacccacaccttctgggaaaggaacctgccctctgtttc _at tggcctgctgaagatcattggattttccacatcagtaactgccctggggtttgtgctgtacaaatacaagctcctgccacggtcttgaagttctgttcttatgctctctgct cactggttttcaataccaccaagaggaaaatattgacaagtttaaaggctgtgtcattgggccatgtttaagtgtactggattaactaccttg taattgcttgttttctagcctggcaagatattttcataaaagagggataacaatgctgattactaccttttaaaatatttagataaatgcacagcaccacagcaccaca 15 204438 tctaagcattagtgatgggtagctgatgtcagcttcatgtggattttaagcactctagaaacaatgaagcttcttggcatattttaaggagctcccaaaatgtgttacct 15 - at attaaattgtaactcagcaagtagaagaccatttgaaaagtcaggtacaaatttcctcaagtggcataaaaatgtagtcagttttctcttttaccagtttttatttccactc caattatttagaactttatttgtacatgtgcagaagaataaggcagctgagaatcttgtttcccccaagagagttttacaggctgagtgttgcaaatgtgttctttgtcctg I_ ttatatgtat gcactgccatgtatgaaagtctctttatgatgtttgtttttttgtcatttttgttctttacatcaagaaattttatgtttaaatatgcggagaatgtatattgcctctgctcctatcag 116 204457 ggttgctaaaccctggtacatcgtatataaaatgtattaaaactggggtttgttaccagttgctgtactttgtatatagaatttttataaattgtatgcttcagaaataatttat 16s at ttttaaaaagaaattaaaagtttaaactcacatccatattacaccttcccccctgaaatgtatagaatccatttgtcatcaggaatcaaaacccacagiccattgtga t agtgtgctatatttagaacagtcttaaaatgtacagtgtattttatagaattgaagttaacattcttattttcaagagaatttatggacgttgtagaaatgtacaaatgcattt ccaaactgccttaaacgttgtatt gggactgtctgtcaaaagactctgtatatctttgtggatgagttttgtgagagaacagagagaccattgtacctggcacaagggetettcatgaaaagggagactt 117 204508 actgggaggtgcaagacagtggcatttetcctctcctcttgetgetcagcacagccctggattgcagccccgaggetgagaccagacaaagcccgggaggcag -s at aaagatgctccaagaaccaacactatcaatgtctttgcaaatcctcacaggattcctgtgggtccagctttggaactgggaaacctttcttcggatccgcactcattc cactgatgccagctgcccctgaaggatgccagtactgtggtgtgtgagtctcagcagccgcccacacgctcctaactctgctgcatggcagatgcctaggtgga 18 204532 attaatcagccccagagtgctttaaaaaattctcttaaataaaaataatagactcgctagtcagtaaagatatttgaatatgtatcgtgccccctccggtgtctttgatc 118t aggatgacatgtgccatttttcagaggacgtgcagacaggetggcattctagattacttttcttactetgaaacatggcctgttgggagtgegggattcaaaggtggt xIat cccaccgctgcccctactgcaaatggcagttttaatcttatcttttggcttctgcagatggttgcaattgatccttaaccaataatggtcagtcctcatctctgtcctgcttc ataggtgccaccttgtgtgtttaaa ctacgcgtgtccttgggcggagaagggaggtgactccggcggaagaggacaaggcagaatgcaggcccttcgggtgtcccaggcgctgatccgctccttcag 119 204570 etccaccgcccggaaccgetttcagaaccgagtgcgcgagaaacagaagctettccaggaggacaatgacatcccgttgtacctgaagggcggcategttga _at caacatcctgtaccgagtgacaatgacgctgtgtctgggcggcactgtctacagcttgtactcccttggctgggcctccttccccaggaattaagaccaagaagcc tggggggcctgagagact tggtgacacaaacagccttttcccaggtacttggtacctggagcgagtggacgagcagcatcgccgaaagtatgcccggcgtcccgtctaaaggtgttctgcag 120 204607 atccatggaaagetcctgggaaacgtatgctagcagagettctccccgtgaatcatatttttaagatcccactettagetggtaaatgaatttgaatcgacatagtag _at ccccataagcatcagccctgtagagtgaggagccatctctagcgggcccttcattcctctccatgctgcaatcactgtcctgggcttatggtgcctatggactaggg gtcctttgtgaaagagcaagatggagcaatggagagaagacctcttcctgaatcactggactccagaaatgtgcatgcagatcagctgtgccttca ttgatgccagcatttgcatcccgggctccatcacattcatgcccaatggatgctgcaagacctgcacccctcgcaatgagaccagggtgccctgctccaccgtccc cgtcaccacggaggtttcgtacgccggctgcaccaagaccgtcctcatgaatcattgctccgggtcctgcgggacatttgtcatgtactcggccaaggcccaggc 121 204673 cctggaccacagctgctcctgctgcaaagaggagaaaaccagccagcgtgaggtggtcctgagctgccccaatggcggctcgctgacacacacctacaccc _at acatcg ag agctgccagtgccaggacaccgtctgcgggctccccaccggcacctcccgccgggcccggcgctcccctaggcatctgggg agcggg tg agcg gggtgggcacagcccccttcactgccctcgacagctttacctcccccggaccctctgagcctcctaagctcggcttcctctcttcagatatttattgtctgagtctttgttc agtccttg cttgcttatatcatgtgctgccgacgggaaggcgtggaaaagagaaacatgcaaacaccagacatccaactggtccatcacagtgctattcagaaatctaccaa 122 204688 ggagcttcgagacatgtccaagaatagagagatagcatggcccctgtcaacgcttcctgtgttccaccctgtgactggggaaatcatacctcctttacacacagac _at aactatgatagcacaaacatgccattgatgcaaacgcagcagaacttgccacatcagactcagattccccaacagcagactacaggtaaatggtatccctgaa aa actgaagcaatgaatttataatcagacaatatagcagttacatcacatttctttctcttccaataatgcatgagcttttctggcatatgt cctcccgggaggacagccttgaggcgggcctgcccctccaggtccgaggctaccccgaggagaagaaagaggaggagggcagcgcaaaccgcagacc agaggaccaggagctggagagcctgtcggccattgaagcagagctggagaaagtggcccaccagctgcaggcactacggcggggctgagacaccggctg 123 204697 gcagggctggccccagggcaccctgtggccctggctctgctgtccccttggcaggtcctggccagatggcccggacgctgcttccggtagggaggcagcctcc -s at agcctgcccaagcccaggccaccctatcgccccctacgcgccttgtctcctactcctgactcctacctgccctggaacatcctttgcagggcagccccacaacttt aaacattgacgattccttctctgaacacaggcagctttctagaagtttcccttcctccatcctatccactgggcacaactgcaataacttctgaccttttggtgaaagct gagaactcctgactgtaacatattctg gcaggccatactggttccattgttctgtataatactgaataaataaatttacttttacatgatcgtataagtttctagataagataaacaaattctgtttaaatttttttaataa 124 204719 aaatcttaaaacactttttctaacctagactgagaaattcatgtttacttttctaggtgtatgatactttgtaaagttgatactttcctaagaatttaacatgtcatatttttga 124 at aatagatttaagtgtgcttcttattgctaaaaatactaaatgtcatgggtcatagtatctgatatcaatatcgttgataacatatccacaggtaacaccatgatgtaggc ataaatggaaaacaaaaaccctactatttcaaatatattgtacttttttatttctgtaagccaactgtgtgccattttcactggacttaaatctagactttagtgatgtctac attgtaaatgatcttttgtggatatttgtcacttggtttcagaaagttcacaaatgtagcaacagctcacatgactgagt 125 204745 tcccttctcgctgggaactctagtctcgcctcgggttgcaatggaccccaactgctcctgtgccgctggtgtetcctgcacctgcgccagctcctgcaagtgcaaag agtgcaaatgcacctcctgcaagaagagctgotgetectgctgccctgtgggetgtgccaagtgtgcccaaggetgcatctgcaaaggggcatcggagaagtg 125 _x at cagctgctgcgcctgatgtcgggacagccctgctcccaagtacaaatagagtgacccgtaaaatctaggattttttgttttttgctacaatcttgacccct aaaggetggcatcttatggctcatcaaaggcggctgtgaccatgttctcatcagttatgagactggagctttccaagtggggaattaaagttgcttccatccaacctg 126 204818 gaggettcctaacaaatategcaggcaccagtgacaagtgggaaaagetggagaaggacattetggaccacctccccgetgaggtacaggaagactacggc _at caggactacatcttagcacagcggaatttcctcctattgatcaactcgttagccagcaaggacttctctccggtgctgcgggacatccagcatgctatcttggcgaa gagcccttttgcctattacacgccagggaaaggcgcttacttgtggatctgcctgctcactatttgcctattggca ggtgtcgaactatatgccttgtatgatcagttttatgtggetaatgagtttctcaaatatcgtttacacgttggtaactataatggcacagctggagatgcattacgtttca 127 127204834 acaaacattacaaccacgatctgaagttttcaccactccagataaagacaatgatcgatatccttctgggaactgtgggctgtactacagttcaggetggtggtttg atgcatgtetttctgcaaacttaaatggcaaatattatcaccaaaaatacagaggtgtccgtaatgggattttctggggtacctggcctggtgtaagtgaggcacacc at ctggtggctacaagtcctccttcaaagaggctaagatgatgatcagacccaagcactttaagccataaatcactctgttcattcctccaggtattcgttatctaatagg gcaattaattccttcagcacttt ccaggaggggctgtccaatcacattcaggcatgcgaatgagctgggccctgggtgaggtgggggtctggcctagtggggaggggcctggcctgggtggggca 128 128 204894 gggcctggcctggtccaggettgggetccattcccatcactgctgtccctcctgaggtctggattggggatggggacaaagaaatagcaagagatgagaaacaa sa t cagaaacttttttctctaaaggactggttaaatcaattctgatacagccttacaatacaatagtatgcagctaaaaaataattgtatgtctttatatactaatatgtaataa tcttcaggtgaaaaaggcaagccacagaaatgtgtatagcgcacttcccattgtgtttcagaaaggagtagaatataaacacataattgcttatgtatgcctattca gaataaatgggtaacactgattacttttgggaggggaaccagtaggttgaggacaggagagggaagggtcttaacacttacaccctttgtacattttg aggagcccaggaacgacgtggtcttccagccc 'atttccggggaagacgtgcgcgatgtgacagccctgaacgtgagcacgctgaaggcttacttcagatgcg 129 204895 atggctacaagggctacgacctggtctacagcccccagagcggcttcacctgcgtgtccccgtgcagtaggggctactgtgaccatggaggccagtgccagca 129 a cctgcccagtgggcccogetgcagotgtgtgtecttctccatetacacggcetggggegagcactgtgagcacctgagcatgaaactogacgegttctteggcate _at ttctttggggccctgggcggcctcttgctgctgggggtcgggacgttcgtggtcctgcgcttctggggttgctccggggccaggttctcctatttcctgaactcagctga ggccttgccttgaaggggcagctgtggcctaggctacctcaagactcacctcatccttaccgcacatttaaggcgccattgcttttgggagact agcagcttattgtttctctgaaagtgtgtgtagttttactttcctaaggaattaccaagaatatcctttaaaatttaaaaggatggcaagttgcatcagaaagctttattttg 130 204897 agatgtaaaaagattcccaaacgtggttacattagccattcatgtatgtcagaagtgcagaattggggcacttaatggtcaccttgtaacagttttgtgtaactcccag _at tgatgctgtacacatatttgaagggtctttctcaaagaaatattaagcatgttttgttgctcagtgtttttgtgaattgcttggttgtaattaaattctgagcctgatattgatat g

131 204931 gaccggctactggtcattgaagggtcgggacgccggaggcctcccggtttt agatcccactattaactttaftaacttctaccgtgaatgactctgcaagccttgctggtcca 132 204938 fcccacctaafcgctcgctcgttagaaatcaaccccccgttaaggccactgatc - - tgatcgcagttgccacatcagcftaaa 133 204939 tgcacatcttcgtacfgaagggtggacgcatgggcgaatfacacatgcattgca s at aaaccttactataacataaacagtaaattaacacatafttttcgtttatattattatacactatattcctacaataaagt

134 204940 agattggatttacaafacactcaatttttgactaactaafcgagttgagtttcatc

taccftcftactcacatggcgtgatttaagttag cccaacacagg cttcatgaattgagtgcactaccttt

-at acgcatttctagtgagcacaatggtacgaagtgacaagcagctgttaacccaggtgaaagtattagaggataagcct

at gcfgccccatgcacaagtgggacgacatgaatacggcaaccatgccggagacagaactgccgcttagggcac

_____ _______gcaagtggttcgacaagcgctgccgcgatcagctgccctacatctgccagttcgggatcgtgtagccggc

139 205259 ggtgtgacgttgtfacagtcgcctgggccagactgtgtaaacagcttcaatagtat -at gcgccgcaatttttccttfttcaatcctaattgttgaatctatacaagtaaattaga _____ taaaatgaagcaatttatatctftatgcaaaaacatatgtctgtcttgcaaagga _______cactaaaftag

140 205267 accgactacaagactagfaffattttgtggactagtgaggcggttacgttcacct -at aatacttcfggatgtacacgtaaccactattagaaatcgtgaatcttgatagc _____ttttctgggaaatacttttctgggaaatgacagttctttgacatattttctttgcccact

141 205382 ggtaccgccccttcgacgagaccgacaacgggcacaggctgtgcggctgca -sat gggggcgagcggcccacaaatcggatagctccctcttgtgctatacctcatc agaaggggag 142 205403 ggcccagaataaataggatcfgatcatatfgtcgccaaagttcctgftaaggtt - at ctaactatfcgccagaccgcagactccagttcggctggtgccctccgctctgttg ggaatatggatgcacagacggtgcaaacacagaactggaaaagcagatggtctgactgtgctatggcctcatcatcaagacttcaatcctatcccaa

143 205412 attgctcctgtatatgctgcatctatggftcfaaagatgtgggaftgaaaaaagaagataftgcaatgtgggaagtaaatgaagcctttagtctggttgtactagcaa

gagacaaccctatgtgaccagaa

_____ ctaaaaggatcttttttaaatgaattaaataftgaaacactgtacaccatagfttaca

I___ I____ ggtggtggagagatggaagggcatcaggtgtagggaccctgccaagtggcacctgatttactctag ttaatgtgccaaggagccgttttctgcctgtcaaaaccacatcagatctcttgctggtgatgtcaaacctctatagtcttaatgcaggatctctgacaatgagtgaaaa

146 205480 gcgggaattcctacagtgcccttggttaaattaggcagttcttttacgaaggttcaagattatctaagaagatttgaaagtataccagatatgcttgaattggatcacc 16 s at tcacagtttcaggagatgtgacatttggaaaaaatgtttcattaaagggaacggttatcatcattgcaaatcatggtgacagaattgatatcccacctggagcagtat a tagagaacaagatagtgtctggaaaccttcgcatcttggaccactgaaatgaaaaatactgtggacacttaaataatgggetagtttcttacaatgaaatgttctcta ggatttaggcactaaaaggtactttactatgttactgtaccctgc caagaatgatgggcactaccgtggagatcccaactggtttatgaagaaagcgcaggagcataagagggaattcacagagagccagctgcaggagggaaa gcatgtcattggccttcagatgggcagcaacagaggggcctcccaggccggcatgacaggctacggacgacctcggcagatcatcagttagagcggagagg 147 205547 getagccctgagcccggcgetcccccagctecttggetgcagccatccogettagcctgcctcacccacacccgtgtggtacettcagccctggccaagetttgag _s-at gctctgtcactgagcaatggtaactgcacctgggcagctcctccctgtgcccccagcctcagcccaacttcttacccgaaagcatcactgccttggcccctccctcc cggcggcccccatcacctctactgttcctccctgggctaagcaggggagaagcgggtgggggtagcctggatgtgggcgaagtccactgtcctccttggcgg caaaagcccatt tcaaagacttcgtgattatccccctgcacaccaccccagagacatccgttaaggagatcgatgagttggttgaggtctacacggacgtgaaacaccgctggaag 148 205554 gcggagaatttcattttcatgggtgacttcaatgccggctgcagctacgtccccaagaaggcctggaagaacatccgcttgaggactgaccccaggtttgtttggct 18 s at gatcggggaccaagaggacaccacggtgaagaagagcaccaactgtgcatatgacaggattgtgcttagaggacaagaaatcgtcagttctgttgttcccaag -- tcaaacagtgtttttgacttccagaaagcttacaagctgactgaagaggaggccctggatgtcagcgaccactttccagttgaatttaaactacagtcttcaagggc I cttcaccaacagcaaaaaatctgtcactctaaggaagaaaacaaagagcaaacgctcctagacccaagggtctcatcttattaaccatttcttgcctctaaata aacgaggagcacatgaccctgctgaagatgattttgataaaatgctgtgatatctctaacgaggtccgtccaatggaagtcgcagagccttgggtggactgtttatt agaggaatattttatgcagagcgaccgtgagaagtcagaaggccttcctgtggcaccgttcatggaccgagacaaagtgaccaaggccacagcccagattgg 149 205593 gttcatcaagtttgtectgatcccaatgtttgaaacagtgaccaagetettccccatggttgaggagatcatgetgcagccactttgggaatccogagategetacga s at ggagctgaagcggatagatgacgccatgaaagagttacagaagaagactgacagcttgacgtctggggccaccgagaagtccagagagagaagcagag atgtgaaaaacagtgaaggagactgtgcctgaggaaagcggggggcgtggctgcagttctggacgggctggccgagctgcgcgggatccttgtgcagggaa gagctgccctgggcacctggcaccacaagaccatgttttctaa tgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgtccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagg gcgactccggagggcccctggtgtgcaaggtgaatggcacctggetgcaggcgggcgtggtcagctggggcgagggctgtgcccagcccaaccggcctggc 150 205683 atetacacccgtgtcacctactacttggactggatccaccactatgtecccaaaaagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaacc _x-at cctgctgtccaaaacaccactgcttcctacccaggtggcgactgccccccacaccttccctgccccgtcctgagtgccccttcctgtcctaagccccctgctctcttct gagccccttcccctgtcctgaggacccttccctatcctgagcccccttccctgtcctaagcctgacgcctgcaccgggccctccagccctcccctgcccagataget ggtggtgggcgctaatcct 151 205892 gaagagggagctctattgccaccatgagtttctccggcaagtaccaactgcagagccaggaaaactttgaagccttcatgaaggcaatcggtetgccggaaga 1 s at getcatccagaaggggaaggatatcaagggggtgtcggaaategtgcagaatgggaagcacttcaagttcaccatcaccgetgggtccaaagtgatccaaaa - - cgaattcacggtggg ccttctctggtctccttgagatgatcgtagacacagggatgattcccacccaaacccacgtattcattcagtgagttaaacacgaattgatttaaagtgaacacaca 12 205929 caagggagcttgcttgcagatggtctgagttcttgtgtcctggtaattcctctccaggccagaataattggcatgtctcctcaacccacatggggttcctggttgttcctg 12at - catcccgatacctcagccctggccctgcccagcccatttgggetctggttttctggtggggetgtcctgetgccetccacagcctccttetgtttgtcgagcatttcttet actcttgagagctcaggcagcgttagggctgcttaggtetcatggaccagtggetggtctcacccaactgcagtttactattgctatcttttctggatgatcagaaaaat aattccataaatctattgtctacttgcgattttttaaaaaatgtatatttttatatatattgttaaatccttgcttcattcca tctcccaacctctactgtaaactttctggtccgagaacgagccgaacacagcgcgacgcagggactaggacggcccggtgaccgcgcggattcaggattgcg 153 205935 gggacgcagaaaggttaaggcacttttaaaaactatagcaaggctectgtttatttattctactttctttccctaataatcaaaacaccgcgtaggctcctccgtttatca 13 - at gtattaatggtgtaactttgttggcaatatttgccgtgtagaattttttttagatatccattgtaaatttgaaacaaagaccgatctgtgtaaaaacaaatttccatatgtttta tataaatatatatataatatgaaggactaccctcctttt gtattttggctgctagagtgcagcatttgtgacacgtatttgaaatttgaaatttccttctgcactgtat aaaaggaccatttgaggatgtttgcctttgtgtatttt gagccccattcacaaatttgacccctctactctccttccttcatccctggatttctggacctaccctggctctctgactcatcctcctctttatgagagtgtaacttggatc atctgtaaggagagcatcagtgtcagotcagagcagctggcacaattccgcagccttctatcaaatgttgaaggtgataacgctgtccccatgcagcacaacaa 154 205950 ccgcccaacccaacctctgaagggcagaacagtgagagettcattttgatgattctgagaagaaacttgtccttcctcaagaacacagccctgcttctgacataat -s-at ccagttaaaataataatttttaagaaataaatttatttcaatattagcaagacagcatgccttcaaatcaatctgtaaaactaagaaacttaaattttagttcttactgctt aattcaaataataattagtaagctagcaaatagtaatctgtaagcataagottatcttaaattcaagtttagtttg aggaattctttaaaattacaactaagtg atttg tat gtctatttttttc ggcagctttttatcagccttgctttggataggacctccaaggactaagcctccagccccatgtgtgacccttgtcatctctctgccccacataattatgttactttgctat 155 206000 gtgctcctaatgtatctagtgtgtcctgtgacaacactcatcacacttcattgtaaatcacttgttttattgactgtctttcctatagactgtaagctccatgagggcaggca 155 catgttgttctcattgaccgtgetggccccagtgcctagatgcatggetggcacattgttggcactcaacaatggttgaatgaataaaacaataaatgaatgaataa at ctaagatatagaaactctcatttatattgcagattgaatatatatgatgaaattcttatgttgaatatgttagaatcaaatactcatttttcattagatacagtagtgtcatca I ctcttttaagatcttgttaaagatttcaaataaaggtacttctggcgagccaggctgcacagcatttgctttcct 156 206094 tatttgaatatgtatcgtgccccctccggagtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggctggcattctagattacttttcttactctgaa 16 x at acatggcctgtttgggagtgegggattcaaaggtggteccacggetgcccctactgcaaatggcagttttaatettatettttggettetgcagatggttgcattgatectt - - aaccaataatggtcagtcctcatctctgtcctgacttcataggt 157 206134 etttctatattgttatcagtccaggaaacaggtaaacagatgtaattagagacattggetetttgtttaggcctaatetttttttacttttttttcttttttctttttttttaaagate -at atgaatttgtgacttagttctgccctttggagaacaaaagaaagcagtcttccatcaaatcaccttaaaatgcacggctaaactaticagagttaacactccagaatt gttaaattacaagtactatgctttaatgcttctttcatcttactagtatggcctataaaaaaaataataccacttgatgggtgaaggctttggcaatagaaagaagaata gaattcaggttttatgttattcctctgtgttcacttcgccttgctcttgaaagtgcagtatttttctacatcatgtcgagaatgattcaatgtaaatattttcattttatcatgtata tcctatacacacatctccttcatcatcatatatgaagttattttgagaagtctacattgctacattt taacaatccatgatgctgtttgcatattttgatgaagaaagattacagtacttcaaagtttaatcccagtcaggaaaaagatggaaaaattgattttaccataaatac

158 206143 aaatggaggattacgtaatcgggtatatgaggtgccagttgaaacaaaattctaatcaacatataattcagaaggatcttcatctgactatgacataaaaacaactt 18 - at tatacccagaaagttattgataagttcatacattgtacgaagagtatttttgacagaatatgtttcaaaetttggaacaagatggttctagcatggcatatttttcacatat ctagtatgaaattatataagtattctaaattttatatcttgtagctttatcaaagggtgaaaattattttgttcatacatatttttgtagcactgacagatttccatcctagtcact accttcatgcataggtttagcagtatagtggcgccactgttttgaatct tcatcaggctccagttattctccatctcccagctcagcttttctgtctgtaagcctgattttcaggaaggctctttcctagtgatggagatgaccaccatcagctccagg 159 206149 cttctatcctgctaacccagtaacccagtgggaagagatttacttattccaataattccaagtggagagtgtcattgacccgtttggggtctcatctctacttctagggg 19 - at aatgaaacactttgagtggccaggcctgtgtcatgtgctaattcctagagccagggaaataaggtetgaggattcaggatggggtgaaaggtggttgettaaagg aaaatgaaatacaattagcagaataaggggaaacgagtggtctgctctgctcgggcaaaacaagagatgcccattactgtgagggacccttgaagtctggact cttaaatgggtttttgctgatttcctgggtgcatgctagg

160 206198 accagcaacaacttcaatccggtggagaacaaagatattgtggttttaacctgtcaacctgagactcagaacacaacctacctgtggtgggtaaacaatcagag sat cctcctggtcagteccaggetgetgetctccactgacaacaggaccetcgttctactcagegccacaaagaatgacataggaccctatgaatgtgaaatacaga _s atacccagtgggtgccagccgcagtgacccagtcaccctgaatgtccgctatgagtcagtaca atattagttaccctggtgtgctgtattctctaaaacctttaaatgtttgcatgcagccattcgtcaaatgtcaaatattctctctttggctggaatgacaaaaactcaaata 161 206199 aatgtatgattaggaggacatcataacctatgaatgatggaagtccaaaatgatggtaactgacagtagtgttaatgccttatgtttagtcaaactctcatttaggtga 11 - at cagcctggtgactccagaatggagccagtcatgetaaatgccatatactcacactgaaacatgaggaagcaggtagatcccagaacagacaaaaetttcctaa aaacatgagagtccaggctgtctgagtcagcacagtaagaaagtcctttctgctttaactcttagaaaaaagtaatatgaagtattctgaaattaaccaatcagttta tttaaatcaatttatttatattcttctgttcctggattcccattttacaaaacccactgttctactgttgtattgcccagt cccaggaccctgaagacgaaattgcggtgctggcctttctggtggaggctggaacccaggtgaacgagggcttccagccactggtggaggcactgtctaatate 162 206208 cccaaacctgagatgagcactacgatggcagagagcagcctgttggacctgctccccaaggaggagaaactgaggcactacttccgctacctgggctcactc _at accacaccgacctgcgatgagaaggtcgtctggactgtgttccgggagcccattcagcttcacagagaacagatcctggcattctctcagaagctgtactacgac aaggaacagacagtgagcatgaaggacaatgtcaggcccctgca

163 206209 accacaccgacctgcgatgagaaggtcgtctggactgtgttccgggagcccattcagcttcacagagaacagatcctggcattctctcagaagctgtactacgac s at aaggaacagacagtgagcatgaaggacaatgtcaggccctgcagcagctggggcagcgcacggtgataaagtcggggccccgggtcggccgctgccc - - tgggccctgcctgccctgctgggccccatgctggcctgcctgctggccggcttcctgcgatgatggctcacttctgcac actgactggacgcacgtggaaaggagctattttggaggctttaagagtaaagaatctgtcccgaaacttgtggctgactttatggctaagaagttttcactggatgc 164 206262 attaataacaaatattttaccttttgaaaaaataaatgaaggatttgacctgettegetctggaaagagtatccgtaccgtcctgacgttttgaaacaatacagatgcct _at tcccttgtagcagttttcagcctcctctaccctacatgatctggagcaacagctaggaaatatcattaattctgctcttcagagatgttaaaaataaattacacgtggga gctttccaa gttggtcactgttatttgcctactgctggaagaaggacaaccgctggcaaggtagcgttccccaatctgaatacctgcaggetcccacatgagggagagggcag 206377 actcaggtgggaagatgtgccatgcgtaaggcatcaacgtgtatctgtgggatcttcgttgccttcagtaatcagggtgtgaaaaaagcagacaagttgtgtgtgtg 165at tgtgtgtgtetaagaaaaettgtgtgettttcaaaaaggcagtgetaagcacaagatttcaagaaagcctettettgttgcctagetgagtgggagagtcattttcccca -gacactacatttggatacaggtgccaaagaacattattaaggaattatttagaaacaatgtgtctagtttaagaaagtggttttcagtattgtgacaatacaacgttttt acaaggttgttttctaccaccatattttaaagatattttatgaccgtgtatactcacactttgctt aaagcccttcatctaatatttgttgctattgccaatttttcaatgaaatgacctaaaaacaacaaaaaaaaataacctatacggtagttgctttagggggtgggggga 206385 tgctatctgttagtgcttaaaagggggtaaatgcttgccgctttagaggtggatggtgctcataaaaggccccagtcgggggtatttaaaaaggactgaacagaaa 166 satt tccttagctagtagaatggcagcacgetgtaaaattattactgtattgtgtactggetataagatgtagacacetttcagtaagccaatcatttgtaaccattetagcagt gtcatattaggttaataaggctgctgtgttaaagggcatttttatttgggttttggtgaaattctttaatttgttgattatattcacataaaatcagcattcattgacacatag ctctaatgacatatgtatgaaaaaccatacactggatgacctagtcga ctgatggttctttctctgatgagatgaacaccattcttgataatcttgccgccagggactttataaactggttgattcagaccaaaatcactgacaggaaataactatat 167 206422 cactattcaagatcatcttcacaacatcacctgctagccacgtgggatgtttgaaatgttaagtcctgtaaatttaagaggtgtattctgaggccacattgctttgcatg 167 ccaataaataaattttcttttagtgttgtgtagccaaaaattacaaatggaataaagttttatcaaaatattgctaaaatatcagctttaaaatatgaaagtgctagattct _t gttattttcttcttatttggatgaagtaccccaacctgtttacatttagcgataaaattatttttctatgatataatttgtaaatgtaaattattccgatctgacatatctgcattat aataataggagaatagaagaactggtagccacagtggtgaaattggaaagagaactttcttcctgaaacctttgtcttaaaaatactcagctttcaatgtatcaa 168 206461 gccggctcctgcaagtgcaaaaagtgcaaatgcacctcctgcaagaagagctgctgctcctgtigccccctgggctgtgccaagtgtgcccagggctgcatctg 18 x at caaaggggcgtcagagaagtgcagetgetgtgcctgatgtcgggacagccetgetgtcagatgaaaacagaatgacacgtaaaatecgaggttttttttttetaca - - actccgactcatttgctacatccttttttctg ttccctgctggaggatcccaagattaaggagattgctgcaaagcacaaaaaaaccgcagcccaggttctgatccgtttccatatccagaggaatgtgattgtcato cccaagtctgtgacaccagcacgcattgttgagaacattcaggtctttgactttaaattgagtgatgaggagatggcaaccatactcagottcaacagaaactgga 169 206561 gggcctgtaacgtgttgcaatectctcatttggaagactatccettcaatgcagaatattgaggttgaatetectggtgagattatacaggagattetetttettegetga _sat aggtgactacctccactcatgtcccatttagccaagcttatttaagatcacagtgaacttagtcctgttatagacgagaatcgaggtgctgttttagacatttatttctgt atgttcaactaggatcagaatatcacagaaaagcatggcttgaataaggaaatgacaattttttccacttatctgatcagaacaaatgtttattaagcatcagaaact ctgccaacactga

170 206576 taagtccagtagtagcaaagccccaaatcaaagccagcaagaccacagtcacaggagataaggactctgtgaacctgacctgctccacaaatgacactgga s at atetccatecgttggttcttcaaaaaccagagteteccgtectoggagaggatgaagetgicccagggcaacaccaccctcagcataaaccetgtcaagaggga - - ggatgctgggacgtattggtgtgaggtcttcaacccaatcagtaagaaccaaagcgaccccat tgagcctggggttctggtgttagaatatttttaagtaggctttactgagagaaactaaatattggcatacgttatcagcaacttcccctgttcaatagtatgggaaaaat 206637 agatgactgggaaaaagacacacccacaccgtagaacatatattaatctactggcgaatgggaaaggagaccattttcttagaaagcaaataaactgattt 171 ttaaatctaaaatttacattaatgagtgcaaaataacacataaaatgaaaattcacacatcacatttctggaaaacagacggattttacttctggagacatggcat _a acggttactgacttatgagctaccaaaactaaattctttctctgctattaactggctagaagacattcatctatttttcaaatgttctttcaaaacatttttataagtaatgtttg tatctatttcatgctttact atttctttggcagttttcgtgctaatgtttttgctaaggaagataagctctgaaccattaaaggacgagtttaaaaacacaggatcaggtctcctgggcatggctaaca 172 206641 ttgacctggaaaagagcaggactggtgatgaaattattcttccgagaggcctcgagtacacggtggaagaatgcacctgtgaagactgcatcaagagcaaacc 172 at gaaggtcgactctgaccattgctttccactcccagctatggaggaaggcgcaaccattcttgtcaccacgaaaacgaatgactattgcaagagcctgccagctgc ttgagtgctacggagatagagaaatcaatttctgctaggtaattaaccatttcgactcgagcagtgccactttaaaaatcttttgtcagaatagatgatgtgtcagatc tctttaggatgactgtatttttcagttgccgatacagcttttigtcctctaactg gaagacactaccaacatgatattacgtattgatctgaccacacacaatgttactctagaagaaccaatagaaatcaactggtcatgaagatcaccatcaattttag 13 206664 ttgtcaatgggaaaaaacaccaggatttaagtttcacagcacttacaattttccctcttcacttggttcttgtactctacaaaatatagctttcataacatcgaaaagttat 173 tttgtagegtacatcaatgataatgetaattttattatagtaatgtgacttggattcaattttaaggcatatttaacaaaatttgaatagccctatttatecttgttaagtatca _a gctacaattgtaaactagttactaaacatgtatgtaaatagctaagatataatttaaacgtgattttaaattaaataaaattttatgtaattatatatactatatttttctcaa tgtttagcagatttaagatatgtaacaacaattatttgaagatttaattacttcttagtatgtgcattta 174 206710 attgcaatttcttaggtaaccttatatttacaataaatgaagattaccctcaaatgctagaagctgtctaggtccgtccggtgtgtcagatttcctcagattagatgtgcc 1- s at aataaccaagtttattcagtaaacaacttgtacttgtttcatctggtttattactctcacccataaacagtaatgactctctgaccetctggaaatatgtaatgottccaatc - ttg ttttggacctgcggtggtggccaaccactggaacttccactggatctactggetgggcccactcctggctggcctgcttgttggactgctcattaggtgcttcattggag atg 15 206784 atgggaagacccgcctcatcctgaaggctcggtgagcagagctcgtgggattcctgctgctccaggtgtcctcagctcacctgtcccagactgaggacagggga 175 gtctgcatttcctgccagggcagaggcccagaggagegaccccetgotcactgettgggcctgetttetcagatagactgactgetgaggaggetetaggtte _a ttggaattcctttgtgctcatcagagaccccagcctggggaacacgctgcccgcactgcccagagagcagtgcaaacaccacaacacgagcgtgtttcttgaga ggaatgtccccgagttggacaaggaggctgtttctgcacatcagctcatttcc gaggggtcaccgtgcaggatggaaatttctcctttctctggagtcagtgaagaagotcaaagacctccaggagccccaggagcccagggttgggaaactcag 176 207003 gaactttgcacccatccctggtgaacctgtggttcccatcctctgtagcaacccgaactttccagaagaactcaagcctctctgcaaggagcccaatgcccagga 16 - at gatacttcagaggetggaggaaatcgetgaggacccgggcacatgtgaaatctgtgcctacgctgcctgtaccggatgotaggggggettgcccactgcctgcc tccctccgcagcagggaagctctctcctgcagaaagggccacccatgatactccactcccagcagctcaacctaccctggtccagtcgggaggagcagcc cggggaggaactgggtgact 177 207080 tcgtctgcttcacaagctatcgctatggtgttcgtgcgcaggccgtggcccgccttgaccacagtgcttctggccctgctcgtctgcctaggggcgctggtcgacgcc s at taccccatcaaacccgaggctcccggcgaagacgcctcgccggaggagetgaaccgctactacgcctccctgcgccactacctcaacctggtcacccggca - - gcggtatgggaaaagagacggcccg 78 178 207126 tatttgaatatgtatcgtgccccctccggtgtettgatcaggatgacatgtgccatttttcagaggacgtgcagacaggetggcattctagattacttttcttactctgaa acatggcctgttgggagtgcgggattcaaaggtggtcccaccgtgcccctactgcaaatggcagttttaatettatettttggettctgcagatggttgcaattgatcc _x at ttaaccaataatggtcagtcctcatctctgtcctgcttcataggtgccaccttgtgtgtttaaa tgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgtccgtgacgacatgctgtgtgccgggaacacccggagggactcatgccagg gcgactccggagggcccctggtgtgcaaggtgaatggcacctggctgcaggcgggcgtggtcagctggggcgagggetgtgcccagcccaaccggcctggc 179 207134 atetacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaacc _x-at cctgctgtccaaaacaccactgcttcctacccaggtggcgactgccccccacaccttccctgccccgtcctgagtgccccttcctgtcctaagccccctgctctcttct x~gat gagccccttcccctgtcctgaggacccttccccatcctgagcccccttccctgtcctaagcctgacgcctgcaccgggccctccggccctcccctgcccaggcag ______ctggtggtgggcgct

atgatcacaaaatgttgcctgttttgtttccgaaagcttgccaaaacaggaaagaagaagaaaagggattagttatatcaaaagcctgaagtggaatgaccaaa 180 207245 agatgggactcctcctttattccagcatggagggttaaatggaggatttcctttttcctgcgacaaaacgtcttcacaacttaccctgttaagtcaaaatttattttcca 180 at ggaatttaatatgtactttagttggaattattctatgtcaatgatttttaagetatgaaaaataataatataaaacettatgggettatattgaaatttattattctaatccaaa agttaccccacacaaaagtactgagcttccttatgtttcacacattgtatttgaacacaaaacattaacaactccactcatagtatcaacattgttttgcaaatactca gaatattttggcttcattttgagcagaat caagtatcggggctctgctatcaaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatggagcaca 181 207266 ccatgtcactacagcccgcatcaatgatcagccetctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtcagctatg _x-at caaggagcctacttgccacagtatgcacatatgcagacgacagcggttcctgttgaggaggcaagtggtcaacagcaggtggctgtcgagacgtctaatgacc attctccatatacctttcaa tggactggtgtcgagccaagactcggggcctacgagcacgtcgacatccagaacttctcctccagctggagtgatgggatggccttctgtgccctggtgcacaac 182 207390 ttcttccctgaggccttcgactatgggcagcttagccctcagaaccgacgccagaacttcgaggtggccttctcatctgcggagatgctggtggactatgtgcccct 182 s~t ggtggaggtggacgacatgatgatcatgggcaagaagcctgaccccaagtgtgtcttcacctatgtgcagtcgctctacaaccacctgcgacgccacgaactg 207390 gcctcgcgcggcaagaatgtctagcctgcccgcccgcatggccagccagtggcaactgccgcccccactctccgggcaccgtctcctgcctgtgcgtccgccc accgctgccctgtctgttgcgacaccctcccccccacatacacacgcagcgtttga ggatgtgatagcattcctgctggcctgcgtggcaactgtgatatttatcatcacaaaattttgcctgttttgtttccgaaagcttgccaaaacaggaaagaagaagaa aagagattagttatatcaaaagcctgaagtggaatgactgaaagatgggactcctcctttattcagcatggagggttttaaatggaggatttcctttttcctgtgacaa 183 207392 aacatcttttcacaacttaccttgttaagacaaaatttattccagggatttaatacgtactttagttggaattattctatgtcaatgattttaagctatgaaaaatacaatg _x-at gggggaaggatagcatttggagatatacctaatgttaaatgacgagttactggatgcagcacgcaacatggcacatgtgtatacatatgtagctaacccttcgttgt gcacatgtaccctaaaacttaaagtataatttaaaaaaagcaaaaaaaaaaaataccaactctttttttaaaccaggaaggaaaatgtgaacatggaaacaac ttctagtattggatctg gccccggagtgcagetgcggggacccgctgctcgaccccggcctgccggagcccgaggccccgccccctgcgggtcccgaaccgcttaccctcatccetgg 184 207432 gcctgtcgagcccttcagcatcgtgaccatgcccgggccccggggtccggcgccaccctggctgcccagccctattggcgaggaggaggagaatctggcctg 14 - at agatcttagagcccagccccctaaggacagggaaccaggtccctgcacggcacccacgcaggtgtccoggtetgcataagcctcgtatgcctttgtaaagtcca cctacacttttgaccagctctcgctgcccgcatgtgtttggcgctgtgctaggggcgggagttcttccagactcttggaccagcccgccctgaccaccagctctactt cccaacccccactgcctgagaggtctctatcagtgtcctgcctgaattcttccttcaagtgaagatgtgactgactacctcctcgagttgtcatga gaacccagggagcgcgatgggctgcagggctgcgtcagggctcctgccaggagtggccgtggtcctcctgctgctgctgcagagcacacagtcagtctacatc 185 207502 cagtaccaaggcttccgggtccagctggaatccatgaagaagctgagtgacctggaggcacagtgggcacccagcccccgcctgcaggcccagagcctcct 15 - at gccogcegtgtgccaccaccctgetetgcctcaggaccttcagcctgtetgegcctogcaggaggettccagcatettcaagaccetgaggaccategetaacga cgactgtgagctgtgtgtgaacgttgcgtgtaccggctgcctctgagatagccctgggtaccctgagcccaccagggacacctcgcccttcagcccaccaccctg gcaggcttccatccccgtccatgctcaagatgggtc ttattcttagcgtcactggtctggctttcagaattaacatacaaggttgccacacctagttctgcccagctttatgtcttttattccagtattccaccaaagtttgttttcctgc 186 207761 attccagttctcaagtcttaagataaagattgtacttgacagtttagtatatccataaaactatttgaggtggttaaggttcttgggttcattttccttaatactttgotgaatat 16 s at tgtagattgtaggcaatgaaaaagtctactaaattaggaaaaccttgaataattaggtatcctaggtaagagcccctaaacatcaagcaatctgtgagtetgtaaa -t gaaataaatattttggattattcttatctaattccacccctgttggaagatgatttctttgttctttgcaactatggaagctgtgaaaatcatcacaagtgcctctgaaagc gagtgttaggttggttagagggt gtgacggtgctgaagaaggccctggatgaagagacgcggtcccatgaggctcaggtccaggagatgaggcagaaacacgcacaggcggtggaggagctc acagagcagcttgagcagttcaagagggccaaggcgaacctagacaagaataagcagacgctggagaaagagaacgcagacctggccggggagctgc 187 207961 gggtectgggccaggccaagcaggaggtggaacataagaagaagaagetggaggegcaggtgcagacactgagtttttagaaaaacatatccacggtaac _x-at cggtccctggcaattctgtttacatgaaatggggagaaagtcaccgaaatgggtgccgccggcccccactcccaattcattccctaacctgcaaacctttccaactt ctcacgtcaggcctttgagaattctttccccctctcctggtttccacacctcagacacgcacagttcaccaagtgccttctgtagtcacatgaattgaaaaggagacg ctgctcccacggaggggagcaggaatgctgcactgtttacaccctgactgtgcttaaa tagtggccgtgaggagcatcttcagtaagaaggaaggttctgacagacaatggaactacgcctgcatgcccacgccacagagcctcggggaacccacggag 188 207977 tgctggtgggaggagatcaacagggctggcatggaatggtaccagacgtgctccaacaatgggctggtggcaggattccagagccgctacttcgagtcagtgc 18 s at tggatcgggagtggcagttttactgttgtcgctacagcaagaggtgcccatattcctgctggctaacaacagaatatccaggtcactatggtgaggaaatggacat t gatttcctacaattatgattactatatccgaggagcaacaaccactttctctgcagtggaaagggatcgccagtggaagttcataatgtgccggatgactgaatacg actgt 189 207980 aatgtcatagacactgatttcatogacgaggaagttcttatgtcttggtgatagaaatgggtttggaccgcatcaaggagetgcccgaactctggetggggcaaa s at acgagtttgattttatgacggacttcgtgtgcaaacagcagcccagcagagtgagctgttgactcgatcgaaacccc ccccccaattgctgccaatagtggataacatgtatcactcactgccaaaaatagaaagtgaccatgaaaaataaattcgctggggaagggggetccatgctggt 190 208131 gtggccaaggctgagagctctctcttctctgttacaaaacgagataagcaagtnttagaattgccttaaggccacactggcatctccctgaccttctccagggaca 10 s at gaagcaggagtaagttetcatcccatgggegaccagggccatetectcccaccagtggcccccactcacagggagetggcaatgccctacctgcctgttetcc -t agatggagaaacaggctctgagatttcacaggtcttgcccaaagtcattgattttaatgattaaaaagaataaacacagtgtttcctgagtagcagtgattgttatgc cttgctatttta gatgtattaacctacctgtgaatcatatgttgtaggaaaagetgttcccatgtctaacaggacttgaattcaaagcatgtcaagtggatagtagatctgtggcgatatg 191 208370 agagggatgcagtgcctttccccattcattcctgatggaattgttatactaggttaacatttgtaatttttttctagttgtaatgtgtatgtctggtaaataggtattatattttgg 11 s at ccttacaataccgtaacaatgtttgtcattttgaaatacttaatgccaagtaacaatgcatgotttggaaatttggaagatggttttattctttgagaagcaaatatgtttgc -a ataaatgctttgattgttcatatcaagaaattgattgaacgttctcaaaccctgtttacggtacttggtaagagggagccggtttgggagagaccattgcatcgctgtc caagtgtttcttgt agggcaagtgttcccaaattgacgccacctaataatcatcaccacaccgggagcagatctgaaggcacactttgatttttttaaggataagaaccacagaacact 192 208383 gggtagtagctaatgaaattgagaagggaaatcttagcatgcctccaaaaattcacatccaatgcatactttgttcaaatttaaggttactcaggcattgatcttttca 12 s at gtgttttttcacttagetatgtggattagetagaatgcacaccaaaaagatacttgagetgtatatatatatgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgcatgtatgtgc -- acatgtgtctgtgtgatatttggtatgtgtatttgtatgtactgttattcaaaatatatttaatacctttggaaaatettgggcaagatgacctactagttttccttgaaaaaaa gttgctttgttattaatattgtgct ccgagccgagcttactgtgagtgtggagatgttatcccaccatgtaaagtcgcctgcgcaggggagggctgcccatctccccaacccagtcacagagagatag 193 208399 gaaacggcatttgagtgggtgtccagggccccgtagagagacatttaagatggtgtatgacagagcattggccttgaccaaatgttaaatcctctgtgtgtatttcat 193 t aagttattacaggtataaaagtgatgacciatcatgaggaaatgaaagtggetgatttgotggtaggatttgtacagtttagagaagegattatttattgtgaaactgt s~t tctccactccaactcctttatgtggatctgttcaaagtagtcactgtatatacgtatagagaggtagataggtaggtagattttaaattgcattctgaatacaaactcata ctccttagagcttgaattacatttttaaaatgcatatgtgctgtttggcaccgtggcaagatggtatcagagagaaacccatcaatgctcaaatactc 194 208450 ggagctgtcaccatgacgggggaacttgaggttaagaacatggacatgaagccggggtcaaccctgaagatcacaggcagcatcgccgatggcactgatgg at ctttgtaattaatctgggccaggggacagacaagetgaacctgcatttcaaccctcgettcagogaatccaccattgtetgcaactcattggacggcagcaaetgg at ggagcaacgggaagatcacctgtgcttcagcccagggtcagaggtcaagttcacagtgacctttgagagtgacaaattcaaggtgaagctgccagat gggcacgagctgacttttcccaacaggctgggtcacagccacctgagctacctgagcgtaaggggcgggttcaacatgtcctc

195 208581 gcgtgttttcctcttgatcgggaactcctgcttctccttgcctcgaaatggaccccaactgctcctgctcgcctgttggctcctgtgcctgtgccggctcctgcaaatgca 1 x at aagagtgcaaatgcacctcctgcaagaagagetgetgotcctgotgccctgtcggetgtgccaagtgtgcccagggetgcatctgcaaagggacgtcagacaa - - gtgcagctgctgtgcctga cccgaccatcgaatcttgcgaacaacacgatacttgttaagtggctaccccaaaacgatctgottggtcacccgatgacccgtgcctttatcacccatgctggttcc catggtgtttatgaaagcatatgcaatggcgttcccatggtgatgatgcccttgtttggtgatcag atggacaatgcaaagcgcatgg ag actaaggg agctg gag 196 208596 tgaccetgaatgttggaaatgacttctgaagatttagaaaatgetetaaaagcagtcatcaatgacaaaagttacaaggagaacatcatgegcctctccagcct -s-at tcacaaggaccgcccggtggagccgctggacctggccgtgttctgggtggagtttgtgatgaggcacaagggcgcgccacacctgcgccccgcagcccacg acctcacctggtaccagtaccattccttggacgtgattggtttcctcttggccgtcgtgctgacagtggccttcatcacctttaaatgttgtgcttatggctaccggaaatg cttggggaaaaaagggcgagttaagaaagcccacaaatccaagacc tgcagaggcctatgttttcactcctaacatgatctgtgctggaggagagaagggcatggatagctgtaaaggggacagtggtggggcctttgctgtacaggatccc 208747 aatgacaagaccaaattctacgcagctggcctggtgtcctgggggccccagtgtgggacctatgggctctacacacgggtaaagaactatgttgactggataat 197 att gaagactatgcaggaaaatagcaccccccgtgaggactaatccagatacatcccaccagcctctccaagggtggtgaccaatgcattaccttctgttocttatgat attctcattattcatcatgactgaaagaagacacgagcgaatgatttaaatagaacttgattgttgagacgccttgctagaggtagagtttgatcatagaattgtgctg gtcatacatttgtggtctgactccttggggtcctttccccggagtacctattgtagataacactatgggtggggcactccttt gggcctaaccagccttgggagtattgactggtcccttacctcttatggctaagtctttgactgtgttcatttaccaagttgacccagtttgtcttttaggttaagtaagactc 198 208763 gagagtaaaggcaaggaggggggccagcctctgaatgcggccacggatgccttgctgctgcaaccctttccccagctgtccactgaaacgtgaagtcctgtttt 198 satt gaatgccaaacccaccattcactggtgetgactacatagaatggggttgagagaagatcagtttgggettcacagtgtcatttgaaaacgttttttgttttgttttgtaatt attgtggaaaactttcaagtgaacagaaggatggtgtcctactgtggatgagggatgaacaaggggatggtttgatccaatggagcctgggaggtgtgcccag aaagcttgtctgtagcgggttttgtgagagtgaacactttccactttttgacacctatcctgatgtatggtc agatgtgtttagaacctcttgtttaaaaataatagactgcttatcataaaatcacatctcacacatttgaggcagtggtcaaacaggtaaagcctatgatgtgtgtcatt 19 208788 ttaaagtgtcggaatttagcctctgaataccttctccattgggggaaagatattcttggaaccactcatgacatatcttagaaggtcattgacaatgtataaactaattg 199 ttggtttgatatttatgtaaatatcagtttaccatgotttaattttgcacattcgtactatagggagcctattggttctctattagtcttgtgggttttgtttgaaaaggagtcat _a ggcatctgtttacatttaccttatcaaacctagaatgtgtatatttataaatgtatgtcttcattgctaggtactaatttgcagatgtctttacatatttcaatacagaaactat aacattcaatagtgtgctgtcaaagtgtgcttagctcacctggatatacctacattg gaagggagtgttgctcccagtccagaggcctgattctgttcggactgggttctcaagacacgaccaggttctcaagacacgagtccccttgttcctccccattaaag 200 208789 ggggtttgtcagaagcaagaacagcccctctccccagtcacagcctgaagggaggccccgagagottcctcctccccccacctgctccttaccttctctgccctg 200 etttftagaactgcagttcattgttttaagggattgggggagggagcctggggacacaaacettttatacaatacaaagetttgettttttttttttnnnnnnnecttttcc at cttctcggttctcttctctcctctgaatggctgaagacccctctgccgagggaggttggggattgtgggacaaggtcccttggtgctgatggcctgaaggggcctga gctgtgggcagatgcagttttctgtgggcttggggaacctctcacgttgctgtgtcctggtgagcagcccgaccaataaacctgctt ggctgcctgcggatgaaggaccagtgtgacaagtgccgggagatcttgtctgtggactgttccaccaacaacccctcccaggctaagctgcggcgggagctcg 201 208791 acgaatccctccaggtcgetgagaggttgaccaggaaatataacgagetgetaaagtectaccagtggaagatgetcaacacctcctcettgetggagcagetg at aacgagcagtttaactgggtgtcccggctggcaaacctcacgcaaggcgaagaccagtactatctgcgggtcaccacggtggcttcccacacttctgactcgga cgttccttccggtgtcactgaggtggtcgtgaagctctttgactctgatcccatcactgtgacggtccctgtagaagtctccaggaagaacccta

202 208792 agcagctgaacgagcagtttaactgggtgtcccggctggcaaacctcacgcaaggcgaagaccagtactatctgcgggtcaccacggtggcttcccacacttct s at gactoggacgttccttccggtgtcactgaggtggtcgtgaagctetttgactctgatcccatcactgtgacggtecctgtagaagtetccaggaagaaccctaaattt - - atggagaccgtggcggagaaagcgctgcaggaataccgcaaaaagcaccgggaggagtgagatgtggatgttgc 203 208894 1at cgatcaccaatgtacctccagaggtaactgtgctcacgaacagccctgtggaactgagagagcccaacgtcctcatctgtttcatagacaagttcacccca gatataccatgtattcacactttaaaaaatacacatagcagagtatcggaaagtatgtaccaaaacattgatctggetaccactgggagtcaggatcatgagttcat 24 208920 cttcttcntncttnnnactgcttttccaaacattctccagtaagcaggtactacatttataatggaaggaattttttaaaaaattttaagctgtacactttcaagtaagatct 24at - aattctaatgetggettgtgcctcttactatgtggtttggtcattatag ataatgcccagtttcagtttccccatetttg aaaagg agataatatgttatetettg gg agtag gttctgaatatgaagtgtgttgatacaagaagcactgacaatgtttctgtttcttaaatttaaaactggcctggtttgccttttttatcaagagagcttaacagataaaaaat gaaattagtctattttctacttgccagcagagtatctgtcttattttaggatgcagtgtgaaacttaccattcaactgaacaac gaaggetggattctatctacataagtcctttcaattccaccagggccagagcagctccaccactgtgcacttagccatgatggcaacagaaaccaagagacaca 205 209047 attacgcaggtatttagaagcagagggacaaccagaaggcccttaactatcaccagtgcatcacatctgcacactctcttctccattccctagcaggaacttctag 205 at ctcatttaacagataaagaaactgaggcccacggtttcagetagacaatgattggccaggcctagtaaccaaggccetgtetetggctactccetggaccacga ggctgatcctctcatttccagcttctcagtttctgcctgggcaatggccaggggccaggagtggggagagttgtgatggaggggagaggggtcacacccacccc ctgcctggttntaggctgctgcacaccaaggccctgcatctgtctgctctgcatatatgt agacagctgtttagggtcttctcccctcacccatgctttcatcatcccctccgcacagcctccccgtccaggccttctaaccacacctacccagggetgccgcattcc tgcactcagaagtctgcagcggtgcctcacaaacttgattgtgcataaaaatcactggggatcttgttaatacag attctaactcaatag atctgg gagatcctg cat 206 209074 ttctaacaagctcccaggtaaggcggaggetgotggtgtgaggaccatgetgtgagcagcagggcgagagtgcccagggetgatatatattggaaatatcacc _s-at cctgaagccatcgctggcccccacctcctgtggactg atgccccaggg attcccaccccacttctgcaaccccaggtatccttcattatccaccccatcccag act cccaccccagggattgcccgtgaagactttggcctagcaaattgtgttggttatgtgagtgttgttttaatcagagatgtacatgattgccaatctgcatttcttaccagt gtgaccacac 207 209101 atcatcagategactcttatacgagtaatatgcctgetatttgaagtgtaattgagaaggaaaattttagegtgetcactgacctgcctgtagccccagtgacagota at ggatgtgcattctccagccatcaagagactgagtcaagttgttccttaagtcagaacagcagactcagctctgacattctgattcgaatgacactgttcaggaatcg gaatcctgtcgattagactggacagcttgtggcaagtgaatttgcctgtaacaagccagattttttaaaatttatattgtaaatattgtgtgtgtgtgtgtgtgtgtatatata tatatatatgtacagttatctaagttaatttaaagttgtttgtgcctttttatttttgttttaatgctttgatattcaatgttagcctcaatttctgaacaccataggtagaatgtaa agcttgtctgatcgttcaaagcatgaaatggatacttatatggaaattctgctcagatagaatgacagtccgtcaaaacagattgtttgcaaaggggaggcatcagt gtcttg tacaccacaatggctgagcacttcctgacgttgctggtagtgcctgccatcaagaaagattatggttcccaggaagacttcactcaagtgtggaacaccaccatg aaagggctcaagtgctgtggcttcaccaactatacggattttgaggactcaccctacttcaaagagaacagtgcctttcccccattctgttgcaatgacaacgtcac 208 209114 caacacagccaatgaaacctgcaccaagcaaaaggetcacgaccaaaaagtagagggttgettcaatcagetttgtatgacatecgaactaatgcagtcacc _at gtgggtggtgtggcagctggaattgggggcctcgagctggctgccatgattgtttccatgtatctgtactgcaatctacaataagtccacttctgcctctgccactactg ctgccacatgggaaactgtgaagaggcaccctgggcaagcagcagtgatgggggaggggacaggatctaacaatgtcacttgggccagaatggacctggc ctttctgctcccagacttgggggctag

209 209116 gcagttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggtgcctttagtgatggcctggctcacctggacaacctcaagggcacctttgccac x at actgagtgagetgcactgtgacaagetncangtggatectgagaacttcaggetnctnggcaacgtgntngtetgngtgetggcccatcactttggcaaagaatt - - caccccaccag tctctgggctccaggetgaggacgaggctgattattactgctgctcatatgcaggtagttacactgtggttttcggcggagggaccaaactgaccgtcctaggtcag 209138 cccaaggctgccccctcggtcactctgttcccgccctcctctgaggagcttcaagccaacaaggccacactggtgtgtctcataagtgacttctacccgggagccg 210 tgacagtggcctggaaggcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaagcaacaacaagtacgcggccagcagc x t tatctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcaccgtggagaagacagtggcccctacag aatgtt tttggtgcagctgctagtcagtccctgactgacattgccaagtattcaataggcagactgcggcctcacttcttggatgtttgtgatccagattggtcaaaaatcaactg 21209147 cagcgatggttacattgaatactacatatgtcgagggaatgcagaaagagttaaggaaggcaggttgtccttctattcaggccactcttcgttttccatgtactgcatg 211 t ctgtttgtggcactttatcttcaagccaggatgaagggagactgggcaagactcttacgccccacactgcaatttggtcttgttgccgtatccatttatgtgggcctttct _at cgagtttctgattataaacaccactggagcgatgtgttgactggactcattcagggagctctggttgcaatattagttgctgtatatgtatcggatttcttcaaagaaag aacttcttttaaagaaagaaaagaggaggactctcatacaactctgcatgaaacaccaacaactgggaatcactatccgagcaatcaccagc gcacgccatcaatgccatcgtgcgcagcccgcgtggcggggcccggaggcacgcagagctgtccttcgtgttcctcacggacggcgtcacgggcaacgaca 212 209156 gtctgcacgagtcggcgcactccatgcgcaacgagaacgtggtacccaccgtcctggccttgggcagogacgtggacatggacgtgctcaccacgctcagcct _s-at gggtgaccgcgccgccgtgttccacgagaaggactatgacagcctggcgcaacccggcttcttcgaccgcttcatccgctggatctgctagcgccgccgcccg ggccccgcagtcgagggtcgtgagcccaccccgtccatggtgctaagcgggccc tgtttcctcatagctagttctcaagctgcatgtaagattttaacgggaagagaaaataggcctggacctgaaggtetcaaatatgttgagaagaaagtatgaactat 213 209167 aaggaacttgagatgtagatttattttgcaggaaatacgaggaaaataggaaagaagtgtttgccgcatcaagtgtaaagaatgatactgaggatttttacattttat 23 - at gaaatgaaataatggcatttacaaaatgaaaaatgtagtttcacaactaagttttgttaacagagactgcatgctttgcttatagttcttaatttggttttgacattcattta attttttccatgttaaatatgtagtttaattatttactcaaaataaacattgttcatgcttttaggcctttgggggaattgatttttatccacaggtagaaaatggtctttgcaca cactacacttatttcaaatatacaatgtgctcccgaacttcgcattagtctt gaaatatcactgacactccagactaaagcagagtctaggtttctgcaattttgttacagtaatttgtaaatagctttagtaaactcaccttgcatggtagattaataaga 214 209170 tgacttactgtacatgaattacacaataatgagatctggtggctatttccacattttgaaaaggattcagttatttactgacagtggtgagcatcctttttaaaataatgttc 214at tgatacttaaacattagagagcagtatctttaaatgaattattaacactttggaatacttacattttctgttatttttgattgcctgataaccagtttcaatgatgaaaatgaa sat aacaagtgctgaagatgaaatggaagagaaccgttttaatctggattttgttttgtcacacctggaaaatactttgcaaatatgtctaaatgaaaacaatttttttatg atcacatggttcactaccaaatgaccctcaaataagccagatg gatagtcggaatagagccgccccaactcagatcctacaacacgcaagttccttcttgaaccctggtgcctcctaccctatggccctgaatggtgcactggtttaatt 215 209191 gtgttggtgtcggcccctcacaaatgcagccaagtcatgtaattagtcatctggaacaaagactaaaaacagcagagaattgcgggttctacccagtcagaaga _at tcacaccatggagactttctactagaggacttgaaagagaactgaggggccacaaaataaacttcaccttccattaagtgttcaagcatgtctgcaaattaggag ggagttagaaacagtctttttcatcctttgtgatgaagcctgaaattgtgccgtgttgccttatatgaatatg tgtctccccgctatctaaaaaagtataagaacaagcagataacagcgagaatcttggaggcccatcagaatgtagotcagatgagtctaattgaagccaagatg 216216209209 agatttattcaagcttggcagtcactacctgaatttggcatcactcacttcattgcaaggttccaagggggcaaaaaagaagaacttattggaattgcatacaacag t actgattcggatggatgccagcactggagatgcaattaaaacatggcgtttcagcaacatgaaacagtggaatgtcaactgggaaatcaaaatggtcaccgta sat agttgcagatgaagtacgattgtccttcatttgtactgaagtagattgcaaagtggttcatgaattcattggtggctacatatttctctcaacacgtgcaaaagacca I_ aaacgagagtttagatgaagagatgttctacaaacttaccagtggttgggtgtgaatagaaatactgtttaatgaaactccacggccataa aaaatgctattagtccgtcgtgcttnatttgtttttgtccttgaataagcatgttatgtatatngtctogtgtttttatttttacaccatattgtattacacttttagtattcaccagc 27 2092 10 ataancactgtctgcctaaaatatgcaactctttgcattacaatatgaagtaaagttctatgaagtatgcattttgtgtaactaatgtaaaaacacaaattttataaaatt 217 ts t gtacagttttttaaaaactactcacaactagcagatggettaaatgtagcaatctctgcgttaattaaatgcctttaagagatataattaacgtgcagitttaatatctact aaattaagaatgacttcattatgatcatgatttgccacaatgtccttaactctaatgcctggactggccatgttctagtctgttgcgctgttacaatctgtattggtgctagt cagaaaattcctagctcacatagcccaaaagggtgcgagggagaggtggattaccagtattgtcaataatccatggttca gaccagttcttcggagagcacctgttggagtctgatcttttcccgacgtctacttccctgagtcccttctaccttcggccaccctccttcctgcgggcacccagctggttt 218 209283 gacactggactctcagagatgcgcctggagaaggacaggttctctgtcaacctggatgtgaagcacttctccccagaggaactcaaagttaaggtgttgggaga 218 tggttgatgtacgcatggaaaacatgaagagegccaggatgaacatggtttcatctccagggagttccacaggaaataccggatcccagetgatgtagaccctc _a tcaccattacttcatccctgtcatctgatggggtcctcactgtgaatggaccaaggaaacaggtctctggccctgagcgcaccattcccatcacccgtgaaaagaa Igcctgctgtcaccgcagcccccaagaaaaagatgccctttcttgaattgcattttttaaaacaagaaagtttccccaccagtgaatgaa

219 209301 tgaatctcgggtgtttccctttagctaagcacagatctaccttggtgattggaccctggttgctttgtgtctagttttctagacccttcatctcttacttgatagacttactaat 29 - at aaaatgtgaagactagaccaattgtcatgcttgacacaactgetgtggetggttggtgetttgtttatggtagtagttttctgtaacacagaatataggataagaaata agaataaagtaccttgactttgttcacagcatgtagggtgatgagcactcacaattgttgactaaa ctgtgtatccttcaaagacccagcccctgcagcaccataacctcctggtctgttctgtgagtggtttctatccaggcagcattgaagtcaggtggttccggaatggcc 220 209312 aggaagagaagactggggtggtgtccacaggcctgatccacaatggagactggaccttccagaccetggtgatgotggaaacagttcctoggagtggagagg x_at tttacacctgccaagtggagcacccaagcgtgacaagccctctcacagtggaatggagagcacggtctgaatctgcacagagcaagatgctgagtggagtcg ggggctttgtgctgggcctgctcttccttggggccgggctgttcatctacttcaggaatcagaaaggacactctggactcagcca agtcaaatgccaaacactagctctgtattaatccccatcattactggtaaagcctcatttgaatgtgtgaattcaatacaggctatgtaaaatttttactaatgtcattattt 221 209335 tgaaaaaataaatttaaaaatacatcaaaattannannnnanacaagcttaattgttaatattccctaaacacaatttatgaagggagaagacattggtttgttga _at caataacagtacatcttcaagtctcagctatttcttctacctctccctatctacatttgagtatggtaacttatgtcatctatgttgaatgtaagcttataaagcacaaa gcatacatttcctgactggtctagagaactgatgtttcaatttacccctctgctaaataaa ggcaaactgctaatcttgtggattttgtagatggtttcaaatgactgaactgcattcagatttacgagtgaaaggaaaaattgcattagttggttgcatgaactttgaa 222 209357 gggcagatattactgcacaaactgccatctcgctcatttttttaactatgcatttgagtacagactaatttttaaaatatgctaaactggaagattaaacagatgtggcc _at caaactgttctggatcaggaaagtcatactgttcactttcaagttggctgtcccccccgccgcccccccccacccccatatgtacagatgataatagggtgtggaat gtcgtcagtggcaaacatttcacagattattttgtttctgtcttcaacatttttgacactgtgctaat ctcctccatgagtctgacatctcggaaactgagcagctgccggacgcctgggtcaggaatccaagaccccacctcttaaggactggttcctcagaaagcaccct 223 209373 cagggaaaaaggtgaaaacattacatccgtggattctcctgccacaaccgcattggaagaaaaggctgccgcaacatctcagcgaggagtgaaggacccat 23 - at gtcccaggaaccgcgctgcgccacctgcactcacccccctcacattctcttaagcacccggtggccctccgaggcctggcggaatggtggtgcccacggggttg ggcaagggctcaccaggacctcaacgggcaaagttgtgcacactaaaatatcaaatcaaggtgcttggttttaaagtaaatgtttctaaagaaagctgtgttcttc tgttgacccagacgaatagggcacagccctgtaactgcacgtgccttctgtcattgggaatg

224 209374 caccatcacgtgcctggtgacgggcttctctcccgcggacgtcttcgtgcagtggatgcagagggggcagcccttgtccccggagaagtatgtgaccagcgccc 2 s at caatgcctgagccccaggccccaggccggtactcgcccacagcatcctgaccgtgtccgaagaggaatggaacacgggggagacctacacctgcgtggtg gcccatgaggccctgcccaacagggtcaccgagaggaccgtggacaagtccacc ttctttttatattgtcctccacctccatcattttcaataaaagatagggcttttgctcccttgttcttggagggaccattattacatctctgaactacctttgtatccaacatgttt 225 209436 taaatcttaaatgaattgetttctcccaaaaaaagcacaatataaagaaacacaagatttaattatttttctacttggggggaaaaaangtectcatgtagaagca at cccacttgcaatgttgttctaagctatctatctanctctcagcccatgataaagttccttaagctggtgattcctaatcaaggacaagccaccctagtgtctcatgtttg tat ggaagcacaatttccaccttatttttgaactttggcagtttcaatgtctgtctctgttgcttcggggcataagctgatcaccgtctagttgggaaagtaaccctacaggg 226 209457 tttgtagggacatgatcagcatcctgatttgaaccctgaaatgttgtgtagacaccctcttgggtccaatgaggtagttggttgaagtagcaagatgttggcttttctgg 26at - atttttttgccatgggttcttcactgaccttggactttggcatgattcttagtcatacttgaacttgtctcattccacctcttctcagagcaactcttcctttgggaaaagagtt cttcagatcatagaccaaaaaagtcataccttcgaggtggtagcagtagattccaggaggagaagggtacttgctaggtatcctgggtcagtggcggtgcaaact ggtttcctcagctgcctgtccttctgtgtgcttatgtctcttgtgacaattgttttcctccct agagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccct 22722I 209458 x at ggagaggatgttcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggcc gacgcgctgaccaacgccgtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtca t acttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtg agcaccgtgctgacctccaaataccgttaagctg tggaggaatttcacaagcacccgcccgtgcagtgggccttccaggagaccagtgtggagagcgccgtggacacgcccttcccagctggaatatttgtgaggct 228 209496 ggaatttaagctgcagcagacaagctgccggaagagggactggaagaaacccgagtgcaaagtcaggcccaatgggaggaaacggaaatgcctggcctg 28 - at catcaaactgggctctgaggacaaagttctgggccggttggtccactgccccatagagacccaagttctgcgggaggetgaggagcaccaggagacccagtg cctcagggtgcagcgggctggtgaggacccccacagttctacttccctggacagttcgccttctccaaggccctgccccgcagctaagccagcactgagctgc gtggtgcctccaggaccgctgccggtggtaaccagtggaagaccccagcccccagggagaggaccccgttctatccccagccatgataata tttgtcaggaaaccttggcctctgctaaggtgtatttggtccttgagaagtgggagcaccctacagggacactatcactcatgctggtggcattgtttacagctagaa 229 209498 agctgcactggtgctaatgccccttggggaaatggggctgtgaggaggaggattataacttaggcctagcctcttttaacagcctctgaaatttatettttcttctatgg 229 at ggtctataaatgtatettataataaaaaggaaggacaggaggaagacaggcaaatgtacttcacccagtettctacacagatggaatetetttggggetaaga gaaaggttttattctatattgctacctgatctcatgttaggcctaagaggctttctccaggaggattagcttggagttctctatactcaggtacctctttcagggttttctaa ccctgacacggactgtgcatactttccc actggatgcgttaataacccatgttttacctttgaaaaaataaatgaaggatttgacctgcttcactctgggaaaagtatccgtaccgtcctgacgttttgaggcaata 230230209612 gagatgccttcccctgtagcagtcttcagcctcctctaccctacaagatctggagcaacagctaggaaatatcattaattcagctcttcagagatgttatcaataaatt t acacatgggggetttccaaagaaatggaaattgatgggaaattatttttcaggaaaatttaaaattcaagtgagaagtaaataaagtgttgaacatcagetgggga sat atgaagccaacaaaccttccttctaaccattctactgtgtcacctttgccattgaggaaaaatattcctgtgacttcttgcatttttggtatcttcataatctttagtcatcg aatcccagtggaggggacccttttacttgccctgaacatacacatgctgggccattgtgattgaagtcttctaactctgtctcagt gcagatttcttgcttcatatgacaaagcctcaattactaattgtaaaaactgaactattcccagaatcatgttcaaaaaatctgtaatttttgctgatcgaaagtgcttcat 231 209613 tgactaaacagtattagtttgtggctataaatgattatttagatgatgactgaaaatgtgtataaagtaattaaaagtaatatggtggetttaagtgtagagatgggatg sat gcaaatgctgtgaatgcagaatgtaaaattggtaactaagaaatggcacaaacaccttaagcaatatattttcctagtagatatatatatacacatacatatataca _at catatacaaatgtatatttttgcaaaattgttttcaatctagaacttttctattaactaccatgtcttaaaatcaagtctataatcctagcattagtttaatattttgaatatgtaa acacctgtgttaatgctttgttaatgcttttcccactctcatttgttaatgctttcccactctcgggaaggatttgcattttgagctttatctctaaatgtgacatgca ggatgccgctctgtgacaaatgtggcagtggcatagtcggtgctgtggtgaaggcgcgggataagtaccggcaccctgagtgcttcgtgtgtgccgactgcaacc 232 232209621 t tcaacctcaagcaaaagggctacttcttcatagaaggggagctgtactgcgaaacccacgcaagagcccgcacaaaacccccaagaggctatgacacggtc actctgtatcccaaagcttaagtctctgcaggcgtggcacacgcacgcacccacccacgcgcacttacacgagaagacattcatggctttgggcagaaggattg s t tgcagattgtcaactccaaatctaaagtcaaggctttagacctttatcctattgtttattgaggaaaaggaatgggaggcaaatgcctgctatgtgaaaaaaacata I cacttagctatgttttgcaactctttttggggctag ttcctgaagctcttcggctgacagcccgctcggctcgccctctcccccggaggccgcgccctcccggaaaagccgggtcctccagacccogaggccttgctctc 233 209651 agagcgggaggccccacccactggagagccccgcccctaaggtactatgagttctcaggggtcaagttcagaaacggcccagccagacctaaacccacac _at gcccacaaagtggattgcacacagacaagaactcccgtgcgggcctccactctattcccacccttgagggagccccttactgggggagggtccttgcaattcc agcgaatcggaggccaggccaggacgtcctgctccctgcaccctcactgttctgtgcactttttctacctacataaacacacgcatt gcagggctagttattccgatttcttgcacaattatttagctttttgtaagttcaacatgtaaattttaaagacataaatatagagagacttatgtgtttgaatataaatgatat 234234 209656 t atatggattagcatgtacctgtatattattaaacatgcaatgaactgactggtaagtgacgtctaattgtatggctagcaatgtaatttattcagactgtatttttgtacag agcagtgcactctaacctatgcctctgtgtcctctttaatgcctaaagctgtgcctagaaatttcatctgtcttaaaagtaaaatatacttcatgctgtttatgctattagtttc sa tgtactgctattctatatttattatttaaatatatgacatgtttactacttaaacatgaattcatggtatcctggttatttttaagtcatctgggggaaaacctgtttatcact ccagtgattttgagtttgcagtttcacaatcagttcttcat 235 209667 at caggccttttccactttgagggaggtgcttcgaagaatgttgcccacacctaagtgttagaagcctatgtccgttcatccctgagaggtctgaa tggcggactccatgtttgtgatccctgcactccaagtagcacattttcagtgttcccgggcccctgtgtacttctacgagttccagcatcagcccagctggctcaaga 236 209668 catcaggccaccgcacatgaaggcagaccatggtgatgagcttccttgttttcagaagtttctttgggggcaactacattaaattcactgaggaagaggagca 26 x at gctaagcaggaagatgatgaagtactgggccaactttgcgagaaatgggaacccgaatggcgagggtctgccacactggccgctgttcgaccaggaggagc -t aatacctgcagctgaacctacagcctgcggtgggccgggctctgaaggcccacaggctccagttctggaagaaggcgtgccccaaaagatccaggagctc I gaggagcctgaagagagacacacagagctgtagctccctgtgccggggaggagggggtgggtcgctgacaggcgagggtcagcctgctgtg gag agctcgctttg agtgactgggttttgtgattgcctctg aagcctatgtatgccatgg agg cactaacaaactctgaggtttccg aaatcagaagcg aaaaaatc 237237at 209687 agtgaataaaccatcatcttgccactaccccctcctgaagccacagcagggtttcaggttccaatcagaactgttggcaaggtgacatttccatgcataaatgcga tccacagaaggtcctggtggtatttgtaactttttgcaaggcattttttatatatatttftgtgcacatttttttttacgtttctttagaaaacaaatgtatttcaaaatatatttata - gtcgaacaattcatatatttgaagtggagccatatgaatgtcagtagtttatacttctctattatctcaaactactggcaatttgtaaagaaatatatatgatatataaatg tgattgcagcttttcaatgttagccacagt tgtggttctgtagcaacacttctcatgaccatctgttttgtgtttatgatgattttcaggtctgttggtcaatctcacaaccattgcatcttggctgtcatggettcagtacttc 238 209735 agcattccacgatatggatttacggctttgcagcataatgaatttttgggacaaaacttctgcccaggactcaatgcaacaggaaacaatccttgtaactatgcaac 28 - at atgtactggcgaagaatatttggtaaagcagggcatogatetctcaccctggggettgtggaagaatcacgtggccttggettgtatgattgttattttcctcacaattg cctacctgaaattgttattcttaaaaaatattcttaaatttccccttaattcagtatgatttatcctcacataaaaaagaagcactttgattgaagtattcaatcaagttttttt I_ gttgttttctgttcccttgccatcacactgttgcacagca gaacacgcagagagtttccctagatatactcctgcctccaggtgctgggacacacctttgcaaaatgetgtgggaagcaggagctggggagotgtgttaagtca 239 209763 aagtagaaaccetccagtgttggtgttgtgtagagaataggacatagggtaaagaggccaagetgcctgtagttagtagagaagaatggatgtggttettcttgtg _at tatttatttgtatcataaacacttggaacaacaaagaccataagcatcatttagcagttgtagccattttctagttaactcatgtaaacaagtaagagtaacataacag tattaccctttcactgttctcacaggacatgtacctaattatggtacttattatgtagtcactgtattctggatttt ctccagccccagagctgaaaacaccaagtgcctatttgagggtgtctgtctggagacttagagtttgtcatgtgtgtgtgtgtnnttggttaatgtgggtttatgggttttc 240 209791 tttctttttttttttttttttttnnagtctacattagggggaagtgagcgcctcccatgtgcagacagtgtgtctttatagatttttctaaggctttccccaatgatgtcggtaatttct 20 - at gatgtttetgaagttcccaggactcacacacccgttcccatetcacttgcccacccagtgtgacaaccetcggtgtggatataccccogtggactcatggetettccc cacccccactttctataaatgtaggcctagaatacgcttctctgttgcaaaactcagctaagttcctgcttccaccttgatgttgaaatatcttatgtaagagggcaggg gatgtcgtgaagatggc ggaatgacacttacttacgacccaactacagctgctatacagaacggattttatccttcaccatacagtattgctacaaaccgaatgatcactcaaacttctattaca 241 209868 ccctatattgcatctcctgtatctgcctaccaggtgcaaagtccttcgtggatgcaacctcaaccatatattctacagcaccctggtgccgtgttaactccctcaatgga _s-at gcacaccatgtcactacagcccgcatcaatgatcagccctctggcccagcagatgagtcatctgtcactaggcagcaccggaacatacatgcctgcaacgtca gctatgcaaggagcctacttgccacagtatg ggaacgaaaccagcgtcctattccagcgcctctacgggccccaggccctcctcttctccctcttctggcccaccttcctgctgaccggtggcctcctcattatcgcca 242 209948 tggtgaagagcaaccagtacctgtccatcctggcggcccagaagtagagccatccatccatgccataccacttgtcagggcacaggggactggctgggcccc cagggctgctccccacttgcagcacaatgccttctccacctgccctcccactcttccagtccaatccacgctgtcttctgttgcaggactaacctttgagaaatcctttt 242 at gtgaagtcatgcctgctcaagaatgtacagtggctccccaatgccttggagccataaggccagccagttctagotctctattacctgtccccactcaactgactcat acctgtttccggctgcatcactatgtgccccacagagaacgatgatcgtcacctctgtgcctgagttctccctgttgtctcaaagcggtacc ccggtcagcaggatcatcgtgcacccacagttctacatcatccagactggagcggatatcgccctgctggagctggaggagcccgtgaacatctccagccgcg tccacacggtcatgctgccccctgcctcggagaccttccccccggggatgccgtgctgggtcactggctggggcgatgtggacaatgatgagcccctcccaccg 243 210084 ccatttcccctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcatcc _x-at gtgacgacatgctgtgtgccgggaacacccggagggactcatgccagggcgactctggagggcccctggtgtgcaaggtgaatggcacctggotacaggcg ggcgtggtcagctgggacgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaaaa gccgtgagtcaggcctggggtgt 244 210107 ggccaaatcaccgacctgaaggcggaaattcacgggggcagtctcattaatctgacttggacagctcctggggatgattatgaccatggaacagctcacaagta I at tatcattcgaataagtacaagtattcttgatctcagagacaagttcaatgaatctcttcaagtgaatactactgctctcatcccaaaggaagccaactctgaggaagt ctttgtttaaaccagaaaacattactttgaaaatggcacagatcttttcattgctattcaggctgttgataaggtcgatctgaaatcagaaatatccaacattgcacg agtatctttgtttattcctccacagactccgccagagacacctagtcctgatgaaacgtctgctccttgtcctaatattcatatcaacagcaccattcctggcattcacat tttaaaaattatgtggaagtggataggagaactgcagctgtcaatagcctagggc accccttcagcgactagagagctacaggagaatcaccagtggcaaatgtccccagaaagctgtgatcttcaagaccaaactggccaaggatatctgtgccga

245 210133 ccccaagaagaagtgggtgcaggattccatgaagtatctggaccaaaaatctccaactccaaagccataaataatcaccatttgaaaccaaaccagagcct 245 at gagtgttgcctaatttgttttccettcttacaatgcatetgaggtaacctcattatcagtecaaagggcatgggttttattatatatatatatatttttttttaaaaaaaaacgt attgcatttaatttattgaggcttaaaacttatcctccatgaatatcagttatttaaactgtaaagctttgtgcagattctttaccccctgggagccccaattcgatcccct gtcacgtgtgggcaatgttccccc tgtgaagctttacgcgcacacggacaaaatgcccaaactggagcccttgcaaaaacacggcttgtggcattggcatacttgcccttacaggtggagtatcttcgtc 246246 210139 acacatctaaatgagaaatcagtgacaacaagtctttgaaatggtgctatggatttaccattccttattatcactaatcatctaaacaactcactggaaatccaattaa t caattttacaacataagatagaatggagacctgaataattetgtgtaatataaatggtttataactgtttgtacctagetaggetgetattattactataatgagtaaat sat cataaagcctcatcactcccacatttttctacggtcggagcatcagaacaagcgtctagactccttgggaccgtgagttcctagagcttggctgggtctaggctgtt ctgtgcctccaaggactgtctggcaatgacttgtattggccaccaactgtagatgtatatatggtgcccttctgatgctaagactccagacctttgt tctactgcgtgacttgccatgagaccaagtttgccaagcattgcgtgaagtgcaacaaggccatcacatctggaggaatcacttaccaggatcagccctggcatg ccgattgctttgtgtgtgttacctgctctaagaagctggctgggcagcgtttcaccgctgtggaggaccagtattactgcgtggattgctacaagaactttgtggccaa 247 210298 gaagtgtgctggatgcaagaaccccatcactgggaaaaggactgtgtcaagagtgagccgcccagtctctaaagctaggaagcccccagtgtgccacggga -x-at aacgcttgcctctcaccctgtttcccagcgccaacctccggggcaggcatccgggtggagagaggacttgtccctcgtgggtggtggttctttatagaaaaaatcg aagcttagcagctcctcgtggcccgggtttggtaaaggctccagtgtggtggcctatgaaggacaatcctggcacgactactgcttccactgcaaaaaatgctcc gtgaatctggccaacaagcgctttgttttccacc gcataggagataaaacccccactgagatgctctcatgcctcagctggacccaccgtgtagacacacgacatgcaagagttgcagcggctgctccaactcactg 28 210299 ctcaccctctctgtgagcagaaagaaccctactgacatgcatggttaactctcatcagaactctgcccttcccttctgttcttttgtgctttcaaataactaacacgaa 248 t cttccag aaaattaacatttgaacttagetgtaattctaaactg acetttccccgtactaacgtttggtttccccgtgtggcatgtttctg ag cctctactttaaag cat _at ggaacatgcaggtgatttgggaagtgtagaaagacctgagaaaacgagcctgtttcagaggaacatcgtcacaacgaatacttctggaagcttaacaaaacta accctgctgtcctt 249 210302 attcgttttgottttggttgcctgaatgttgtcaccaagtgaaaaaattatttaactatatgtaaaatttctcttttaaaaaaaagttactgatgttaaacgttetcagtgcc s at aatgtcagactgtgctcctccctctcctgaacctctaccctcaccctgagctgtcttgttgaaaacagt agccctttgctctggaggaagttctccagcttcagctcaactcacagcttctccaagcatcaccctgggagtttcctgagggttttctcataaatgagggctgcacatt 250 210495 gcctgttctgcttcgaagtattcaataccgctcagtattttaaatgaagtgattctaagatttggtttgggatcaataggaaagcatatgcagccaaccaagatgcaa 20 x at atgttttgaaatgatatgaccaaaatttaagtaggaaagtcacccaaacacttctgetttcacttaagtgtetggcccgcaatactgtaggaacaagcatgatettgtt -- actgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatctttctcttacctgttatttatcaatttttcccagtatttttatacggaa aaaattgtattgaaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgattattttttatactgtatgtgccaaagctttactactgtg gtgccatagtgcaggettggggagctttaagcctcagttatataacccacgaaaaacagagcctcctagatgtaacattcctgatcaaggtacaattctttaaaatt 251 210517 cactaatgattgaggtccatatttagtggtactctgaaattggtcactttcctattacacggagtgtgctaaaactaaaaagcattttgaaa'atacagaatgttctattg 21 s at teattgggaaattttctttctaacccagtggaggttagaaagaagttatattetggtagcaaattaactttacatccttttcctacttgttatggttgtttggaccgataagt -st gtgcttaatcctgaggcaaagtagtgaatatgttttatatgttatgaagaaaagaattgttgtaagtttgattctactcttatatgctggactgcattcacacatggcatg aaataagtcaggttctttacaaatggtattttgatagatactggattgtgtttgtgccatatttgtgccatt gtcaggactgttatggccctgttgtgctgagttagttggaacagaattcaagctccctgcactagtccacctgccccactgcttcttcgcttctctcttggaaagtccagt 252 210524 ctctcctoggettgcaatggaccccaactgctcctgegccgetggtgtetcetgcacctgegetggttcctgcaagtgcaaagagtgcaaatgcacctcctgcaag _x_at aagagctgctgctcctgctgccccgtgggctgtagcaagtgtgcccagggctgtgtttgcaaaggggcgtcagagaagtgcagctgctgcgactgatgccagga caacctttctcccagatgtaaacagagagacatgtacaaacctggattttttttttataccaccttgacccatttgctacattccttttcctgtgaaa caggaaggaccttgctttggaccctacacacttcggetctctggacacttgcgacacctcaaggtgttctctgtagctcaatctgcaaacatgccaggcctcaggg 253 210735 atcctctgctgggtgcctccttgccttgggaccatggccaccccagagccatccgatcgatggatgggatgcactctcagaccaagcagcaggaattcaaagct 253 t gettgctgtaactgtgtgagattgtgaagtggtetgaattctggaatcacaaaccaagccatgetggtgggccattaatggttggaaaacactttcatecggggetttg s_at ccagagcgtgctttcaagtgtcctggaaagtctgctgcttctccaagctttcagacaagaatgtgcactctctgttaggttgcttgggaaactcaacttctttcctctg gagacggggcatctccctctgatttccttctgctatgacaaaacctttaatctgcaccttacaactcggggacaa ttaccaatgacaaccctgagtgccgccttgtgaaagaaacccggatttgtgaggtgcggccttgtggacagccagtgtacagcagcctgaaaaagggcaaga aatgcagcaagaccaagaaatcccccgaaccagtcaggtttacttacgctggatgtttgagtgtgaagaaataccggcccaagtactgcggttcctgcgtggac 254 210764 ggccgatgotgcacgccccagetgaccaggacatgtgaagatgcggttccgetgegaagatggggagacattccaagaacgtcatgatgatccagtcetca _s-at aatgcaactacaactgcccgcatgccaatgaagcagcgtttcccttctacaggctgttcaatgacattcacaaatttagggactaaatgctacctgggtttccaggg cacacctagacaaacaagggagaagagtgtcagaatcagaatcatggagaaaatgggcgggggtggtgtgggtgatgggactcattgtagaaaggaagcc ttgctcattcttgaggagcattaaggtatttcgaaactgccaagggtgc aaattgtggagttagcctcctgtggagttagcctcctgtggtaaaggaattgaagaaaatataacaccttacaccctttttcatcttgacattaaaagttctggctaactt 255 210809 tggaatccattagagaaaaatccttgtcaccagattcattacaattcaaatogaagagttgtgaactgttatcccattgaaaagaccgagccttgtatgtatgttatgg _s-at atacataaaatgcacgcaagccattatctctccatgggaagctaagttataaaaataggtgcttggtgtacaaaactttttatatcaaaaggctttgcacatttctatat gagtgggtttactggtaaattatgttattttttacaactaattttgtactctcagaatgtttgtcatatgctcttgcaatgc 256 210946 aaggcaagaggatgcatetttcttcctggtgtacaagcctttaaagacttctgetgotgatatgcctcttggatgcacactttgtgtgtacatagttacctttaactcagtg at gttatctaatagctctaaactcattaaaaaaactccaagccttccaccaaaacagtgccccacctgtatacatttttattaaaaaaatgtaatgcttatgtataaacat gtatgtaatatgctttctatgaatgatgtttg gaaggagacggtctggcggettgaagaatttggacgatttgccagctttgaggctcaaggtgcattggccaacatagetgtggacaaagccaacttggaaatcat 257257210982 t gacaaagcgctccaactatactccgatcaccaatgacaagtcaccccaccagtggtcaatgtcacgtggcttcgaaatggaaaacctgtcaccacaggagtgt cagagacagtettcctgcccagggaagaccaccttttccgcaagttccactatctccccttcctgccetcaactgaggacgtttacgactgcagggtggagcactg sat ggctggatgagcctcttctcaagcactgggagtttgatgctccaagccctctcccagagactacagagaacgtggtgtgtgccctgggcctgactgtgggtctg gtgggcatcattattgggaccatc aatattggatatcaactgcttgtaaaggtgctcctcctttttcttgtcattgctggtcaagattactaatatttgggaaggctttaaagacgcatgttatggtgctaatgtact 258 211161 ttcacttttaaactctagatcagaatgttgacttgcattcagaacataaatgcacaaaatctgtacatgtetcccatcagaaagattcattggcatgccacaggggat _s-at tctcctccttcatcctgtaaaggtcaacaataaaaaccaaattatggggctgcttttgtcacactagcatagagaatgtgttgaaatttaactttgtaagottgtatgtggt tgttgatcttttttttccttacagacacccataat atctcatacccgcaaattttaaccttgtcaacctctggggtattagtatgccctgacctgagtgaattcacccgtgacaaaactgacgtgaagattcaatggtacaag

259259t 211372 gattctcttcttttggataaagacaatgagaaatttctaagtgtgagggggaccactcacttactcgtacacgatgtggccctggaagatgctggctattaccgctgtg tcctgacatttgcccatgaaggccagcaatacaacatcactaggagtattgagctacgcatcaagaaaaaaaaagaagagaccattcctgtgatcatttccccc sat ctcaagaccatatcagcttctctggggtcaagactgacaatcccgtgtaaggtgttctgggaaccggcacacccttaaccaccatgctgtggtggacggccaatg acacccacatagagagcgccta agotcgaaagagtttgcaaccccatcatcagcaaactttaccaaggtggtcctggcggcggcagcggcggcggcggttcaggagcctccgggggacccacc 260 211538 ategaagaagtggactaagettgcactcaagtcagegtaaacctetttgcctttctctctctctetttttttttgttigtttttgaaatgtecttgtgccaagtacgagatctat _s-at tgttggaagtctttggtatatgcaaatgaaaggagaggtgcaacaacttagtttaattataaaagttccaaagtttgttttttaaaaacattattcgaggtttctctttaatg cattttgcgtgtttgotgacttgagcatttttgattagttcgtgcatggagatttgtttgagatgagaaaccttaagtttgcacacctgttctgtagaagcttg gcttttttgttgtcagctatcttaagaatcattaaatacacctgctttgggtaaaactctttgcaagcagtaattaacactagtaacagtgaaagcacaagatttccaaa 261 26 211548 tcagtcgtttctcaaaaaaatatcgtataagtgactcatcctgtctgctaactccagacctcccagcttgaagccaaatcttccatgtgagattgatatggatttccta 2154 gaagtactggaatgttgtcatatettgccctattttaattetgetatagaaaacaattgccttcacttttaaggagtaattgaatattaataactctggtetagattttcatat sat aatgtattaaagacaaagtagtgaacatcaatgaacatctgatagagataaactgtaatcaggcataagctgtttgtatgttctggcagtgactaatcagtaaatg atgtcggtttgcccagtatcacttatcttctg cgtgaacggcaaagtggcgctggtgaccggcgcggctcagggcataggcagagcctttgcagaggcgctgctgcttaagggcgccaaggtagcgctggtgg attggaatcttgaagcaggtgtacagtgtaaagctgccctggatgagcaatttgaacctcagaagactctgttcatccagtgcgatgtggctgaccagcaacaact 262 211549 gagagacacttttagaaaagttgtagaccactttggaagactggacattttggtcaataatgctggagtgaataatgagaaaaactgggaaaaaactctgcaaat -s at taatttggtttctgttatcagtggaacctatcttggtttggattacatgagtaagcaaaatggaggtgaaggcggcatcattatcaatatgtcatctttagcagcccacc attgattgccaatggattgataacactcatgaagatgatgctttaaatggtgctattatgaagatcacaacttctaagggaattcatttcaagactatgatacaactc catttcaag gagtattacattggccttgggggacagaaaggaggaagttctgactttcagggctaccttatttctactaaggacccagagcaggcctgtccatgccattccttcgc 263 211596 acagatgaaactgagctgggactggaaaggacagcccttgacctgggttctgggtataatttgcacttttgagactggtagctaaccatcttatgagtgccaatgtgt s_at catttagtaaaacttaaatagaaacaaggtccttcaaatgttcctttggccaaaagctgaagggagttactgagaaaatagttaacaattactgtcaggtgtcatca ctgttcaaaaggtaagcacatttagaatttigttcttgacagttaactgactaatcttacttccacaaaatatgtgaatttgctgcttctgagaggca 264 211637 ggactggtgaagcctcggagaccctgtccctcacctgcagtgtctctggtggctccatcagtagttactactggagctggatccggcagcccccagggaaggga xat ctggagtggattgggtatatcaattacagtgggagcaccaactataacccetccetcaagagtcgagtcaccatatcagtagacacgtecaagaaccagttetcc _x at ctgaagctgagctctgtgaccgctgcggacacggccgtgtattactgtgcgagaacgatttcggggggtcg 265 211643 aatagtgatgacgcagcttccagccaccctgtctgtgtctccaggggaaagagccaccctctcctgcagggccagtcagagtgttcgcagcaacttagcctggta xat ccagcaaaaacctggccaggeteccaggetectcatctacggtgcatccaccagggccaatggtatcccagccaggttcagtggcagtgggtetgggacaga gttcactctcaccatcagcggcctgcagtctgacgattttgcagtttattactgtcaacactataataactggcctccgtggacgt 216g aattgtgttgacgcagtctccaggcaccctgtctttgtctccaggggaaagagccaccctctcctgcagggccagtcagagtattagcagcagtttcttagcctggta 266 211644 ccagcagaaagtggccaggtccaggtctcatctatggtgcatccagcagggccactggcatcccagacaggttcagtggcagtgggttgggacagac _x-at ttcactctcaccatcagcagactggagcctgaagattttgcagtgtatactgtcagcaatatggtagtcgc

267 211645 tcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagggcattagaaatgatttagcctggtatcagcagaaaccagggaaagc ccctaagogcctgatctatgetgcatccagtttgcaaagtggggtcccatcaaggttcageggcagtggatctgggacagaattcactetcacaatcagcagcctg 267 _xatt cagcctgaagattttgcaacttattactgtctacagcataatagttacccttg gcagttgagtcgtcatcacttttcagtgatgggagagtagatggtgaaatttattagttaatatatcccagaaattagaaaccttaatatgtggacgtaatctccacagt 26826 211671 2167 caaagaaggatggcacctaaaccaccagtgcccaaagtctgtgtgatgaactttctcttcatactttttcacagttggctggatgaaattttctagactttctgttggtg tatcccccccetgtatagttaggatagcatttttgatttatgcatggaaacctgaaaaaaagtttacaagtgtatatcagaaaagggaagttgtgccttttatagetatta _at ctgtctggttttaacaatttcctttatatttagtgaactacgcttgctcattttttcttacataattttttattcaagttattgtacagctgtttaagatgggcagctagttcgtagctt tccca tgaggagaagtctgccgttactgccctgtggggcaaggtgaacgtggatgaagttggtggtgaggccctgggcaggctgctggtggtetacccttggacccaga 269 211696 ggttcttgagtcctttggggatctgtccactcctgatgctgtatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggtgcctttagtgatggcctggc 2 69 x~t tcacctggacaacctcaagggcacctttgccacactgagtgagtgcactgtgacaagetgcacgtggatectgagaacttcaggetectgggcaacgtgotggt ctgtgtgccggcccatcactttggcaaagaattcacccaaccagtgcaggctgcctatcagaaagtggtggctggtgtggctaatgccctggcccacaagtatca Ictaagctcgctttcttgctgtccaatttctattaaaggttcctttgttccctaagtccaactactaaactg agagaa cccaccatggtgctgtctcctgacgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccct 270 211699 ggagaggatgtcctgtccttccccaccaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggcc 20 x at gacgegetgaccaacgccgtggcgcacgtggacgacatgcccaacgcgetgtccgccctgagcgacctgcacgegcacaagettegggtggaccoggtca aacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtg agcaccgtgctgacctccaaataccgttaagctg gggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaataccgctcagtattttaaatgaagtgattctaagatttggtttgg 271 211719 gatcaataggaaagcatatgcagccaaccaagatgcaaatgttttgaaatgatatgaccaaaattttaagtaggaaagtcacccaaacacttctgctttcacttaa 271 xatt gtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatattttaaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatct ctcttacctgttatttatcaatttcccagtatttatacggaaaaaattgtattgaaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgatt attttttatactgtatgtgccaaagctttactactgtg tcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcgagtatggtgcggaggccctggagaggatgttcctgtccttcccc 211745 accaccaagacctacttcccgcacttcgacctgagccacggctctgcccaggttaagggccacggcaagaaggtggccgacgcgctgaccaacgccgtggc 272 S att gcacgtggacgacatgcccaacgcgctgtccgccctgagcgacctgcacgcgcacaagcttcgggtggacccggtcaacttcaagctcctaagccactgcct gctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgcctccctggacaagttcctggcttctgtgagcaccgtgctgacctccaaata ccgttaagctggagcctcggtggc tacgcagactccgtg aagggccgattcaccatctccag agacaattccaag aacacgctg tatcttcaaatg aacagcctg ag agccg ag gacacggccg tat tactgtgcaagagagacttgtgtgattggggccaaggtaccctggtcaccgtgtcgagaggtggcggtggctcgggcggtggtgggtcgggtggcggcggatctt 273 211798 ctgagctgactcaggaccctgctgtgtctgtggcctgggacagacagtcaggatcacatgccaaggagacagcctcagaagctattatgcaagctggtaccag -x at cagaagccaggacaggcccctgtacttgtcatctatggtaaaaacaaccggccctcagggatcccagaccgattctctggctccagctcaggaaacacagctt ccttgaccatcactggggctcaggcggaagatgaggtgactattactgtaactcccgggacagcagtggtaaccatgtggtattcggcggagggaccaagctg accgtcctaggtgcggccgcagaacaaaaactcatctcagaagaggatctgaatggggccgcat ttgcacaagtttcctgggctggaccgtttcaacagagaggcttatttgactttatgctagaagatgaggcttctgggataggcccagaagttcctgatgaccgcgact 274 211813 tcgagccctccctaggcccagtgtgccccttccgctgtcaatgccatcttcgagtggtccagtgttctgatttgggtctggacaaagtgccaaaggatcttccccctga cacaactctgctagacctgcaaaacaacaaaataaccgaaatcaaagatggagactttaagaacctgaagaaccttcacgttgtctaccttcataacaacaata 274 t xa tctctgtagttggatcaagtgactctgcccacctggacacaacaccaaaaaggcttcttattegggtgtgagtcttttcagcaacccggtccagtactgggagatac I_ agccatccaccttcagatgtgtctacgtgcgctctgccattcaactcggaaacta tgtccatacagagtgtgcattccctggcaggggctcctgctcacagcctcgcttttaaccttctggaacctgccaaacagtgcccagaccaatattgatggtgtgcc 275 211848 gttcaatgtcgcagaagggaaggaggtccttctagtagtccataatgagtcccagaatctttatggctacaactggtacaaagggcaaagggtgcatgccaacta 25 s at togaattataggatatgtaaaaaatataagtcaagaaaatgccccagggcccgcacacaacggtcgagagacaatataccccaatggaaccctgetgatcca t gaacgtcacccacaatgacgcaggaatctataccctacacgttataaaagaaaatcttgtgaatgaagaagtaaccagacaattctacgtattctatgagtcagt acaagcaagttcacctgacctctcagctgggaccgctgtcagcatcatgattggagtactggctgggatggctctgatatagc tgcacagtactcctggcttatcaatggaacattccagcaaagcacacaagagctctttatccctaacatcactgtgaataatagtggatcctatacctgccacgcca 276 211889 ataactcagtcactggctgcaacaggaccacagtcaagacgatcatagtcactgagagacagaatctcaccatgttgcccgggctggactogaactcctgggct 276 xatt caagcaatcctcccatetgtttcccaaagtgetgagattacagataatgetctaccacaagaaaatggcctctcacctggggccattgetggcattgtgattggagt agtggccctggttgctctgatagcagtagccctggcatgtttctgcattcgggaagaccggcagggcaagcgaccagcgtgatctcacagagcacaaaccctc agtgtccaaccacactcaggaccactccaatgacccacctaacaagatgaatgaagttacttattctaccctgaactttgaagccca 277 211896 tcctccttcccttacggaattacatcttgatggcaacaaaatcagcagagttgatgcagctagcctgaaaggactgaataatttggctaagttgggattgagtttcaa 277 satt cagcatctctgctgttgacaatggctctctggccaacacgcctcatctgagggagcttcacttggacaacaacaagcttaccagagtacctggtgggetggcaga gcataagtacatccaggttgtctaccttcat 278 211959 tcacaccgtagcccacatggatagcacagttgtcagacaagattccttcagattccgagttgcctaccggttgttttcgttgttgttgttgttgtttttctttttcttttttttttga at agacagcaataaccacagtacatattactgtagttctctatagttttacatacattcataccataactctgttctctcc cactttccaatgccacagacaactcacattgttcaactcccnttctcggggtgggacagacgagacaacagcacacaggcagccagccgtggnnccagagg 211964 ctcganggggctcaggggcntcanggcacccgtccccacacgnagggccccgtngggtgggncctnggccctngctttctacngccnaatgnttatgnccag 2799 ctccatgtteteccaaataccgttgatgtgaattattttaaaggcaaaacngtgetetttattttanaaaacactgataatcacactgcggtaggtcattcttttgccacat ccctatagaccactgggtttggcaaaactcaggcagaagtggaganccnttctagacatcantgtcagccttgctacttgaaggtacaccccatagggtcggag gtgctgtcccc 280 211985 gaggcaaatggatctogatatttcagatgggettttgatgcactgttgccaaggaaggetttttgattttttgacaaatgaattttgcacactttcattggtgtetttegg s at caacttacacacattgaaaat

281 28t 211990 gaggacttaggagagatctgaactccagctgccctacaaactccntcncagcttttcttctcacttcatgtgaaaactactccagtggctgactgaattgctgaccctt caagctctgtccttatccattacctcaaagcagtcattccttagtaaagtttccaacaaatagaaattaatgacactttggtagcactaatatggagattatcctttcatt - gagccttttatcctctgttctcctttgaagaacccctcac 282 211991 gcactgggaggcccaagagccaatccagatgcctgagacaacggagactgtgetctgtgccctgggcctggtgetgggcctagtnggcatcatogtgggcacc s at gtcctcatcataaagtctctgcgttctg tgcagaagtcaaaccctcatgacaaagtaggcacaagtctacaataagctaaatcagaatttacaaatacaagtgtcccaggtagcattgactcccgtcattgg 283 212077 agtgaaatggatcaaagtttgaattaaggcctatggtaaggtaacattgetttgttgtacttgaacaagagctectcctgatcactattacatatttttctagaaaatct at aaagttcagaagagaatgtatcactgctgacttttattccaatatttggatggagtaagttttagggtagaattttgttcagtttggattaatcttttgaaaagtaaattcctt gtttactggtttgactataattctctgttatctttacgaggtaaaactgcaagctgactagcatgttctgtgaatctgccattcctaaaaattttataaacacttgatacttttc actgataatggatcgctcca tcacagcgggcaggacggaccccgcccacgacgtgcgggtggcggtggtgcagtacagcggcacgggccagcagcgcccagagcgggcgtcgctgcag 284284212091 ttcctgcagaactacacggccctggccagtgccgtcgatgccatggactttatcaacgacgccaccgacgtcaacgatgccctgggctatgtgacccgcttctac t cgcgaggcctogtoeggcgetgccaagaagaggetgotgetettetcagatggcaactcgcagggcgccacgcccgetgccatogagaaggcegtgcaggn s agnccagcgggcaggcatcgagatctcgtggtggtcgtgggccgccaggtgaatgagccccacatccgcgtcctggtcaccggcaagacggccgagtacg acgtggcctacggcgagagccacctgttccgtgtccccagctaccaggccctgctccgcggtgtcttccaccagacagtctccaggaaggt gaatttcacctgtaaacctgagtcgtacagaaagctgcctggtatatccaaaangctttttattcctcctgctcatattgtgattctgccntttggggnacttttncttnaa 285285212097 accttcagttatgattttttttncatacacttattggnaactctgcttgatttttgcctcttccagtcttcctgacactttaattaccaacctgttacctactttgactttttgcatta aaacagacactggcatggatatagttttacttttaaactgtgtacataactgaaaatgtgetatactgcatacttttaaatgtaaagatatttttatetttatatgaagaaa at atcactaggaaatggctttgtgattcaatctgtaaactgtgtattccaagacatgtctgttctacatagatgcttagtccctcatgcaaatcaattactggtccaaaaga ttgctgaaattttatatgcttactgatatattttacaattttttatcatgcatgtcctgtaaaggttacaagcctgcacaataa tcttccccttgagcttcagagaggagagttggcatggttaaatctgaatggttacctcactgctgaaaacccagaggggcgtggcacactcgcttgtgtggaaaag cctctaaatgcatcccttcctttctttcctgcttcctttgccttacaattgaagcagcccgtggtaccatcacagtatgcagagacttcctcacctttcatatctagggacc 286 212136 acccccgatgcattggtgagggtgggcactataaatgcctgctattgttaagccattccagcctcttcctctgaatagaccagacgccctttcacttagttcagtgcc -at agtccttttgccttcccaaccctgctgttaggcctgctgttccctttgctcttgattaggagagatggaaggagatgagotcccataactgaattggcctttggttcatgttt tctccccatatgtatatatgccatatgtgaatatgccatatatatgtgccaacaaatctatctacgttgttcttttcaaattagcacgcagataggaattttgagtttcttcttc t tatgtaaactttaacttccactttgtataaatttttaagtgtcagactatccattttacacttgctttattttcattacctgtagctttgggcagatttgcaacagcaaattaatgt 287 212158 gtaaaattggatattactacaaaaccgtttagicatatctatctaatcagatettcttttgggaggatttgatgtaagttactgacaagcctcagcaaacccaaagatg _at ttaacagtattttaagaagttgctgcagattcctttggccactgtatttgttaatttcttgcaatttgaaggtacgagtagaggttaaagaaaaatcagtttttgttcttaaa aatgcatttaagttgtaaacgtctttttaagcctttgaagtgcctctgattctatgtaacttgtgcagactggtg 288 212185 cgccggctcctgcaaatgcaaagagtgcaaatgcacctcctgcaagaaaagctgctgctcctgctgccctgtgggctgtgccaagtgtgcccagggctgcatct x at gcaaaggggcgtcggacaagtgcagctgctgcgcctgatgctgggacagccccgctcccagatgtaaagaacgcgacttccacaaacctggattt caactgttttgcgactttataggcaggtaaattttgctattactattgaatacaaatgacaattcatttatgaccactcaaacagcgttagtaaccatttagtgacaaag

289289 212192 gattaaaacatccatctggatgttaattttgaagatgtaaatatatgttgtttaaattttccaggcatctgaaaaccttatctgctagacaatgtaagattcacacagag ttatctgggattetgatttttaaatagtacatatcattaaaccattttttaaatgtaagaagagcagaaaaaatettataagattatcagatttttctaatgacacaga at aatgtaagaaaaaaatccctttatattgaaaaaagatgcagtcaaagtctttcagacatgcccaaactttgagaatttcttcaaccatctaatgctataaagatttttg ttcttcctgttcacaaccagttgtataacagaaatactagctactgtttccttc gatgggtcgtgtgatgagatgcatttaaggccgatagtgatagatgttttttttatttcttgaacacaggctttgtctgaatgatgttcttttatctcttgaacacaagctttga 290 290 212195 atgataactacaggttttaagtgctgttacattaataccataatgtgatgtgttagaaacaaagggatattcaaaggtagatattgaaaattctctagtctcaatatgt atgtgtattgaatatactctaaaaataaatgtgcaatttgetagtaggacaatgcagtgactgactagcattaggtatgtttttatatectagctatgteccacttettc at taagtgcaatccttcatgttcacttgctgttttaccccatctactctaacttcatttggaaggcttgtctagagtatagcatgtatttttacctttgcagtgaattgcatgtgct aattgtaaccacagctatttttatgttgacataactccaaatgttatattaaatgttctattatatattagctctaatcccttaagtaaa acagtgttctctaatgttacagatgagatgcgcattgccaaagaggagatttttggaccagtgcagcaaatcatgaagtttaaatctttagatgacgtgatcaaaag 291 212224 agcaaacaatactttctatggettatcagcaggagtgtttaccaaagacattgataaagccataacaatetcctetgotctgcaggcaggaacagtgtgggtgaatt -at gctatggcgtggtaagtgcccagtgcccctttggntgggattcaagatgtctggaaatggaagagaactgggagagtacggtttccatgaatatacagaggtcaa aacagtcacagtgaaaatctctcagaagaactcataaagaaaatacaagagtggagagaagctcttcaatagctaagcatctccttacagtcactaatat caaggtcccactctaggtgatagacagggaccccttctactgaacctttgaggaaaggaggaaggaagaaatgcgtttagatcttggatgcagacctttcaaag 292 29 212230 ggttaaatgtaaccatatggatcaaccacatgcacatccttactacagaatccgtccttcattcaacttatagcaagctatgatttttatatataaatattatataaata a123 atgtataaaacattaaaagttaactatgtaagatattatttctgaaacaatttagctatatccactatgattataaactgtgtetcgacctgtgttatttacattagetgetta at aaaaagcattgagttaattttttaaatatcaactaaaatatcatagttctgtggtagacattgtttataatgaaataactgcaactagagaaaactgtataaaaacatt aaattgtcagtatttttgtaaggttccattttgtaaagagaataatattcaaagactttgtagcatacaaagtgaaaactgtatctgcgaaacta aagcagcctagggatgagcatttctttgaaagcaattaggttattcacctggtattaaaactatttactgttaaaaaatctgtgacttcatgaagttgattttaaaggca 293 212233 gcatcaaaaactgaaaaggnaagggaaaaaataggcagettctgcacttgtttggagetecccaaaacaggagccatggagaagtggcatcaagaccgg _at gctgccctttegagaacaccctgtggcagttcagagacacgcttttcctacactgcatgcagcccctctttccagcactggaaagaagtggtcttgagcccagctg agaagcacttcacactcctctctcttgttctgaatggtgtttgtgtcagtctgcagctgtgtatggtattatgtcttataatcctgcatcacttctatcctatccagtcatat gggtagatgggagtgtcgcttgtatgttatcgtacagctgacatgtatttttgtctattctttattatcttagtttcatgctatgtatgtaccataaccaacctattgcctatgag 294 212265 aaacatgtaagataatgtatttacagccattgttacaagtttataatgtatttttctatettgttttatatgtatgttatataacattcaaaaagaatttttttcttgattgagaaaa _at ggatacaaaatgcaaaatccacaattttgataactgaaaattgccaattgttttgcagtactttattatattgggtgtcttgtcttttttgggcttttagttagctaatgaatga atacattagacacttttgggttttagttgggattttacatagcttgcattttaattctttggttctttgctgtttctattaacccacagcattatt gaaggttgtcatgggctgttccttgggggttttatcctgctcaccgtggagataagcctgcggcttgtctaaccagcgcagcgcaaaggtctcaatgccttttggtaa 295 212288 catecgtcattgcagaagaaagttacacgacgtcaaaaagtgacgttcatgotaagtgtttttccagaaatattggtttcatgtttcttattggetctgcctcctgtgetta _at tatcatccaaaaactttttaaaaaggtccagaattctattaacctgatgttgagcacctttaaaacgttcgtatgtgtgttgcactaattctaaactttggaggcattttgc tgtgtgaggccgatcgccactgtaaaggtcctagagttgcctgtttgtctctggagat 296 212386 gagatttaccatgtatcagtgcctggetttttgttataaagetttgtttgtetagtgetetttgetataaaatagactgtagtacaccctagtaggaaaaaaaaaaaacta at aatttaaaaataaaaaatatattggctatttttcgcaggagcaatccttttataccatgaatatt gtttatacaactgtcagtccacccagtggtgcaactggttctgattcagtcttccgatncctttttattttcactttttcctatttctgaatttttttnattgtgatcttgattttga 297 212387 tgaggggttggggagtggggagggagtcgaaccaagacttggagttaagaggattcatcttttgcatccaacaggcagaatatgatctgtgtccaaaagtgaa ettgagtcaggaatgaatcaatttcagcataaacaagcacaaaaatttagtetgetggetgactggaagcaaaaaagtcaagatggaatatgatgaattccaac 297attacaatggggcaccaaggcctttaggcctctctttttattttgctttggttttgtttgtttttctttagagacatgctctttctcatgggacttgaagtggactcatctttgtgcagtg ctggttttgccatactcatttcaagtattatagacatatgtaatggtgaaaatatatgaactgtggcctttttcattctgtactgtg gaagtgactgttgtaccatggttgtgcacatgcttcagaatcctatggaagagaatattcctacttgcagtacatcaaaggaatggatggtggaccctactattcatgt 28 212397 tttgagacataaatgttcactttaaagcaattgcataatagataaaaacctgaactttcattggatttttgttaattttcctcattttgaattatgtgcactaccatagctacat 28at cagtttgatacagtattgaaaaattatcagttatattttgetgtttatgatctattgtagattaggattaaaatggatttaatccatttttaaggetgtgtgaatttttetaaaca - agaaccatttgcaatatggatttcttagagattaaaccaattataacttattagcagtcgcgagcacatgttcatatagtcaatgtaaaaatacactaatgagtatttgg taaatcccagtaggcttttaccattagca 299 212414 tccctcacttctcttaagccaagaagtttgotttccctagotgcagtgtagatggetettgttttgtttttgttttaatcatttggcattcacatgtggetgttaatatgtgottgt s at tttt tggtgggagggetctcaatcagcagggccccaggagggaagaagaagtggggcaaagcntggcctcgccgctcgggagctttgccatctgagccacgcctc ctccaggccatgctccttgaacttggaaatgtcaaccggagcccttacaccagccctccagcatctaatagacttgaatctactctaaacgaatatttaatccaacc 300 212419 tcactacattgtagotcagtecaacgactaaccetgaaatgggggtgttccagccttcagegagatggccaageggtccetgggggetgtggcageggnettat -at ccttctctgttgccaaccttgccgtccgacctcctccgcccccatgcggtgaccccgtccgtgtctgtgtctgtccatacgtgtgagtccagctaaaaagacaaaaca gaacccgtgggcccagctoggaaggtgcgtggagaaggctccgacgtctccgaagtgcagcccttgggatggcattccgttgtgtgccttattcctggagaatct gtatacggctcgcctatagaa cttctccaagcatcaccctgggagtttcctgagggttttctcataaatgagggctgcacattgcctgttctgcttcgaagtattcaatanccgctcagtattttaaatgaa 301 212464 gtgattctaagantttggtttgggatcaatanggaaagncatatgnncagnnccaanccaagatgcaaatgttgaaatgatatgaccaaaattttaagtaggaa _s at agtcancccaaacacttctgctttcacttaagtgtctggcccgcaatactgtaggaacaagcatgatcttgttactgtgatatttaaatatccacagtactcactttttcc aaatgatcctagtaattgcct glatcaaaatcttccaattatcatgctcacctgaaagaggtatgctctcttaggaatacagtttctagcattaaacaaataaacaaggggagaaaataaaactcaa 302 212592 ggagtgaaaatcaggaggtgtaataaaatgttcctogcattcccccccgcnttttttttttttgactttgccttggagagccagagettcegcattttctttactattcttttt _at aaaaaaagtttcactgtgtagagaacatatatgcataaacataggtcaattatatgtctccattagaaaaataataattggaaaacatgttctagaactagttacaa aaataatttaaggtgaaatctctaatatttataaaagtagcaaaataaatgcataattaaaatatatttggacataacagactt caggaggacacagcattattctagtgctgtactgttccgtacggcagccactacccacatgtaactttttaagatttaaatttaaattagttaacattcaaaacgcagc 303 212667 tocccaatcacactagcaacatttcaagtgottgagagccatgcatgattagtggttaccctattgaataggtcagaagtagaatcttttcatcatcacagaaagttet at attggacagtgctcttctagatcatcataagactacagagcacttttcaaagctcatgcatgttcatcatgttagtgtcgtattttgagctggggttttgagactnccctta gagatagagaaacagacccaagaaatgtgctcaattgcaatgggccacatacctagatctccagatgtcatttcccctctcttatttaagttatg 304 212671 accaatgaggttcctgaggtcacagtgttttccaagtctcccgtgacactgggtcagcccaacaccctcatctgtcttgtggacaacatctttcctcctgtggtcaaca 3 sat teacntggetgagcaatgggcactcagtcacagaaggtgtttetgagaccagetteetctccaagagtgatcattocttcttcaagatcagttacctcaccttcctccc - - ttctgntgatgagatttatgactgcaaggtggagcactggggcctggatgagcctcttctgaaacactgggagcctg cacatggttctagcctggacctggctgggctccatgagaatgagttgcctccaccctgtcccaacagctgacagccaggagccactctcccagetgcaggccttt gtggtccatettgtcctgcttcctcactgtggacccctgtctgggccaccctagtgtgctaagctgagcagtgcagtgtgaacagggcccatggtgtattctaggcca 305 212713 cagcccagcactcctetgggetgetetcaaaccatgtcccatettcagcatcceteccaccaaettactcccctgtggtgagtaccgtggaaccccagcccacotc _at actatcatactcagcttcccctgatggcccatcccagcccctgaagctntatgccaagaacacagctaccgcacaccaccctgaaacagccacagccaaggta ggcatgcatatgaggtcttccccataccctctgggtgttgagaggtttagccacatgagggagcagaggacaatctctgcagggctgggagtgggtagggactg aaggtctcaat tcagtgtctgggctcatgacttgtaaatggaagctgatgtgaacaggtaattaatattatgacccacttctatttactttgggaaatatcttggatcttaattatcatctgca 306 212730 agtttcaagaagtattctgccaaaagtatttacaagtatggactcatgagctattgttggttgctaaatgtgaatcacgcgggagtgagtgtgcccttcacactgtgac 306 at attgtgacattgtgacaagetccatgtctttaaaatcagtcactctgcacacaagagaaatcaacttcgtggttggatggggcoggaacacaaccagtetttttgta tttattgttactgagacaaaacagtactcactgagtgtttttcagtttcctactggtggttttgatatgtttgtttaagatgtatatttagaatgacatcatctaagaagctgat tttgctaaactcctgttccc gaactcatgtgatttacccttttcaactttttggaaaacgatttaatttattctaattagattaaccctattaatctatggattgggtatcaaaatgaatgccagtccagatgt 307 307212741 gcctagacacgaaattggagctgaggactctcacgatatgcaagttcatccaacgtgaagataccataagctttctctgaaccagagaaatgaaagtcagttta agaggetgatagatettggccctgttaaggcatccacttcacagttctgaaggetgagtcagccccactccacagttaggccaagaattagattttaaaacttcatet at gtctgtcccagttaactgtaaataaggcctcatcctccactgaagagtatggattgaaggattgtgaactatgtttagtgtgattgtgaacttggtgcctaatgttccat gtctgaagtttgccccagtgctacacgttggagta gatgcaattggttctcctgcattgagatttgatttaacagtgttatgttaacatttatacttgccttggactgtagaacagaacttaaatgggaatgtattagttttacaacta 308 212764 caatcaagtcattttacotttacccagtttttaatataaaacttaaattttgaaattcactgtgtgactaatagcatgatgotetgcagttttattaagaaatnagcetaacc -at atacaactctcatttccttagtaagccaaattaggattaacttctataaacagtgttgggaacaatgtttaacattttgtgccaatttgttcctgtattcatgtatgtaagtta cagatctgactcttcatttttaagttccttgttacatcatggtcatt cctatcctacttgcccatatgagcacggctccccatggccacatactcctgcaaagcttttatgctgcttcgcttttctctaaacagatctgatattgctgctcctgtggtttt 309 212814 ctcaaaattaactttgcegtggtttttaaaaaggaatcaaaatgcattgttgcattaagotttttcaataaaggaaaattacggaaggaaaataggcaacaccagca |_at aattatatgtggacaggttctaaactctatatatacatatatatatatatatctatatatctatatacgtaatcatctagttctgtcatcttactgaaaggaataacacttcta Iaagatcaccatttctgagaagttcttggaaatctttatgtctaa caccgcgcagagctcagggggtggtgcgcccggcccttctgcggcgcacagcccagcccaggaacgcgggcggtgcggactcagcgggccgggtgcagg 310 212859 cgcggagctgggcctctgcgcccggcccganctccgtctataaanagagcagccagtgcagggetcnantctgctttccaactgcctgactgottgtcgtctca 30 x at ctggtgtgagotccagcatcccetttgotcgaaatggaccccaactgotettgegccactggntggetectgcacgtgegccggetcctgcaagtgcaaagagtgc -- aaatgcacctcctgcaagaagagctgctgttcctgctnccccgtggnctgtgccaagtgtgcccagggctgcgtctgcaaaggggcatcggagaagtgcagct gctgtgcctgatgtgggaacagctcttctcccagatgtaaatagaacaacctgcacaacctggnattttfttaaaaatacaacactgagccatttgctgcatttc tactgatgcttctgatactggatgtttagcttcttactgcaaaaacataagtaaaacagtcaactttaccatttccgtattctccatagattgaagaaatttataccacata 31 212956 tcgcatatgaccatctttccatcaaatcaatgtagagataatgtaaactgaaaaaaaatctgcaagataatgtaactgaatgttttaaaaacagaacttgtcactttat 31 at ataaaagaatagtatgctctatttcctgaatggatgtggaaatgaaagctagcgcacctgcactttgaattcttgcttcttttttattactgttatgattttgctttttacagatg ttggacgattttttcttctgattgttgaattcataatcatggtctcatttcctttgcttctttggaatatttctttcaacacattcctttatttattatacattgtgtccttttttagctattg ctgct 312 213068 gacaggagggtgtccacatatgttaacatcagttggatctcctatagaagtttctgctgctctctttccttctccctgagctggtaactgcaatgccaacttcctgggcct at tctgactagtatcacacttctaataaaatccacaa gctccacatgagccatgcatgcttagcaatccaagtgcagagctctttgctccaggagtgaggagactgggaggtgaaatggggaaatggaagggtttggagg cagagctgaaaacagggttggaaggatttcctgaattagaagacaaacgttagcatacccagtaaggaaaannngnnnaggggccanggggaacccgtg 313 213071 aggatcactctcaaatgagattaaaaacaaggaagcagagaatggtcagagaatgggattcagattgggaacttgtggggatgagagtgaccaggttgaact _at gggaagtggaaaaaggagtttgagtcactggcacctagaagcctgcccacgattcctaggaaggetggcagacaccctggaaccctggggagctactggca aactctcctggattggncctnatnnttttggtgggaaaggctgccctggggatcaactttccttctgtgtgtggctcaggagttcttctgcagagatggcgctatctttcct cctcctgtgatgtcctgctcccaaccatttgtactcttcatta aagtgtgcataatttcatttaacgttaaagaaatagatccaattcctttcttgcaaccaaaaataaataaaatacgttgcctcaatataaggtttgggctattctgtgtttc 314 213317 tatagaagcaatctgtttttggtaaaatgtactttaaggatccagtcatctgaagtattatgtagagttagagatttcacaatattgactatacatatatttaaaatataa 34 - at attatccagctgatgtttgaatttgtcttactttcctggccacctcgttgtcctattttataagctggggagttaactagcttaacaaaagatgcttagcttttgtaaaagaac aagtgtttcatttacaaagacactccaaatgatagttacttgatttctcgagacctttaactatggtgatgaataacaggacttgctttcaagccttaataaatgtaaa atgccttttaatgaagatacagctgagtgttttcctcatgaatctgaaccaataccaatttgtgttccagtctgatt gaaaccaaggtcaggaggccgttgcagacataaatctcggcgactcggccccgtctcctgagggtcctgctggtgaccggcctggaccttggccctacagccct 315 213428 ggaggccgctgetgaccagcactgaccccgacctcagagagtactcgcaggggcgetggetgcactcaagaccetcgagattaacggtgetaaccccgtetg _s-at ctcctccctcccgcagagactggggcctggactggacatgagagccccttggtgccacagagggctgtgtcttactagaaacaacgcaaacctctccttcctcag aatagtgatgtgttcgacgttttatcaaaggccccctttctatgttcatgttagtttgctccttctgtgttttfttctgaaccatatccatgttgctgacttttc cacaggcaggtgactactccatgcgcgtggacctgcgggctggggacgaggetgtgttcgcccagtacgactccttccacgtagactcggetgcggagtactac cgcctccacttggagggctaccacggcaccgcaggggactccatgagctaccacagcggcagtgtcttctctgcccgtgatcgggaccccaacagcttgctcat 316 213451 ctcetgcgetgtetectaccgaggggcctggtggtacaggaactgccactacgccaacctcaacgggetctacgggagcacagtggaccatcagggagtgag _x-at ctggtaccactggaagggcttcgagttctcggtgcccttcacggaaatgaagctgagaccaagaaactttcgctccccagcggggggaggctgagctgctgccc acctctctcgcaccccagtatgactgccgagcactgaggggtcgccccgagagaagagccagggtccttcaccacccagccgctggaggaagccttctctgc cagcgatctcgcagcactgtgtttacag ccaatggcgagggtctgccacactggccgctgttcgaccaggaggagcaatacctgcagctgaacctacagcctgcggtgggccgggetctgaaggcccac 317 213509 aggctccagttctggaagaaggcgotgccccaaaagatccaggagotcgaggagcctgaagagagacacacagagctgtagctccctgtgccggggagga 317 xatt gggggtgggttcgetgacaggcgagggtcagcctgetgtgcccacacacacccactaaggagaaagaagttgattccttcattcacttcgccattcattcatacttc cgtccatccatcagaaagcatttattaagaatactcaggcatgatggcccatacttgtaatcccagctattgggaaggatgagatgggaggatggcttgaggcc agaggtttgagaccgaccagcc gggagagtccatctggaagctggagtatatcctgacccagacctacgacattgaagatttgcagccggaaagtttatatggattagctaaacaatttacaatccta 318 213624 gacagtaagcagtttataaaatactacaattacttctttgtgagttatgacagcagtgtaacatgtgataagacatgtaaggcctttcagatttgtgcaattatgaatctt 38at gataatatttcctatgcagattgcctcaaacagctttatataaagcacaattactagtattcacagtttttgctaatagaaaatgctgattctgattctgagatcaatttgt - gggaattttacataaatctttgttaattactgagtgggcaagtagacttcctgtcttgctttctttttttctttttgatgccttaatgtagatatctttatcattctgaattgtatta tatatttaaantgctcattaatagaatgatggatgtaaattggatgtaaatattcagtttatataattatatctaatttgtacccttgttgaaattgtcattta cttcgcttctctcttggaaagtccagtctctcctcggcttgcaatggaccccaactgctcctgcgccgctggtgtctcctgcacctgcgctggttcctgcaagtgcaaa 319 213629 gagtgcaaatgcacctcctgcaagaagagetgetgotectngctnccccgtgggctgtagcaagtgtgcccagggetgtgtttgcaaaggggcgtcagagaagt _x-at gcagctgctgcgactgatgccaggacaacctttctcccagatgtaaacagagagacatgtacaaacctggattttttttataccaccttgacccatttgctacattcc ttttcctgtgaaa

320 213746 cctggggctgagcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtnggggttcatggcccna 30 s at ngaccccetgegaggagnnnnngnngnagcacgtgggcagccggetntacagegtgtcetacctgotcaaggacaagggggagtacacactggtggtcaa - - atggggg gaaactgtatgggtagctttttgtttgtttttgttttgtttttgtttttgttttgtttttagttgtaggtcgcagcggggaaatttttgcgactgtacacatagctgcagcattaaa 321 213891 aacttaaaaaaattgttaaaaaaanaaaaaaagggaaaacatttcaaaaaaaaaaaaanngataaacagttacaccttgttttcaatgtgtggctgagtgcctc _s at gatttttcatgtttttggtgtatttctgatttgtagaagtgtccaaacaggttgtgtgctggagttccttcaagacaaaaacaaacccagcttggtcaaggccattacctgt ttcccatctgtagttattcg 322 213921 gctgctgccgcggggaagcaggaactggccaagtactcttggcagagctgctgtctgaacccaaccagacggagaatgatgccctggaacctgaagatctgt 3 at cccaggctgctgagcaggatgaaatgaggcttgagctgcagagatctgctaactcaaacccggctatggcaccccgagaacgcaaagctggctgcaagaatt -tcttctggaagactttcacatcctgttagctttcttaactagtattgtccatatcagacctctgatccctcgcccccacaccccatctctcttccctaatcctccaagtcttca gcgagacccttgcattagaaactga acaggaaattgctacttaccgccgccttctggaaggagaagacgtaaaaactacagaatatcagttaagcaccctggaagagagagatataaagaaaacca 323 213953 gnaagattaagacagtcgtgcaagaagtagtggatggcaaggtcgtgtcatctgaagtcaaagaggtggaagaaaatatctaaatagctaccagaaggagat 323 at gctgctgaggttttgaaagaaatttggctataatcttatctttgctccctgcaagaaatcagccataagaaagcactattaatactctgcagtgattagaaggggtgg ggtggcgggaatcctatttatcagactctgtaattgaatataaatgtttactcagaggagctgcaaattgcctgcaaaaatgaaatccagtgagcactagaatattt aaaacatcattactgccatctttatcatgaagcacatcaattacaagctgtagaccacctaatatca 324 214027 gagaaagccaggcaggtagccagggggactagcccctgtggagactggggggcttgaaattgtccccgtggtctcttactttcctttccccagcccagggtgga cttagaaagcaggggctacaagagggaatccccgaaggtgctggaggtgggagcaggagattgagaaggagagaaagtgggtgagatgctggagaaga _xxat at gaggagaggagagaggcagagagcggtctcaggctggtgggaggggcgcccacctccccacgccctcccctcccctgctgcaggggctctggagaga atgagccttcatacatggactgagagtcagagcttgaagaaaagcttatttattttccccaacctcccccaggtgcagtgtgacattattttattataacatccacaaa 325 214038 gagatatttttaaataatttaaagcataatatttcttaaaaagtatttaattatatttaagttgttgatgttttaaetctatctgtcatacatectagtgaatgtaaaatgcaaa _at atcctggtgatgtgttttttgtttttgttcctgtgagctcaactaagttcacggcaaaatgtcattgttctccctcctacctgtctgtagtgttgtggggtcctcccatggatca tcaaggtgaaacactttggtattctttggcaatcagtgctcctgtaagtcaaatgtgtgctttgtactgctgttgtt atgcctacaggtatgcgtgattgtgtgtgtgtgcatgggtgnacagccacntgtctacctatgtgtctttctgggaatgtgtaccatctgtgtgcctgcagctgtgtagtg 326326214091 ctggacagtgacaaccctttctctccagttctccactccaatgataatagttcacttacacctaaacccaaaggaaaaaccagctntaggtccaattgttntgctcta nactgatacctcaaccttggggccagcatctcccactgcctccaaatattagtaantatgactgacgtncccanaagtttntgggtnnnaccacactccccaacc satt ccccactcctanttcctgaagggccctcccaaggntacatccccaccccacagttctccctgagagagatcaacctccctgagatcaaccaaggcagatgtgac agcaagggccacggacc gcctctggcaatgccattcaggccaggtcttcctcctatngtgnagannatnnnnntggnggtggaaagcgattctctcattctggcaaccagttggnacggccc 327 214142 catcaccgccctccgggtccgagtcaacacatactacatcgtaggtcttcaggtgcgctatggcaaggtgtggagcgactatgtgggtggtcgcaacggagacc 327 tggaggagatctttctgcaccctggggaatcagtgatccaggtttctgggaagtacaagtggtacctgaagaagctggtatttgtgacagacaagggccgctatct _t gtcttttgggaaagacagtggcacaagtttcaatgccgtccccttgcaccccaacaccgtgctccgcttcatcagtggccggtctggttctctcatcgatgccattggc ctgcactgggatgtttaccccactagctgcagcagatgctgagcctcctctccttggcaggggcactgtgatgaggagtaagaactcccttatcactaac acaaggcccaggctggggccagggccagaggggaaggccctggattctcactcatgtgagatcttgaatctctttctttgttctgtttgtttagttagtatcatctggta 328 214164 aaatagttaaaaaacaacaaaaaactetgtatctgtttctagcatgtgetgcattgactctattaatcacatttcaaattcaccctacattcctctcctettcactagcctct x at ctgaaggtgtcctggccagccctggagaagcactggtgtctgcagcacccctcagttcctgtgcctcagcccacaggccactgtgataatggtctgtttagcacttc tgtat 214414 tcaacttcaagctcctaagccactgcctgctggtgaccctggccgcccacctccccgccgagttcaacccctgnggtgcacgcctccctgganaagttcctggett 329 t ctgtgagcaccgtgotgacctccaaataccgttaagetggagcctoggtagcegttennnnnncnngctnggenntccaacgggccetectcccetecttgcac cggcccttcctggtctttgaataaagtctgagtg cttcctcggaggcagcattgttaagggaggccctgtgcaagtgctggaggacgaggaactaaagtcccagccagagcccctagtggtcaagggaaaacggg tggctggaggccctcagatgatccagctcagcctggatgggaagcgcctctacatcaccacgtcgctgtacagtgcctgggacaagcagttttaccctgatctcat 330 214433 cagggaaggetctgtgatgetgcaggttgatgtagacacagtaaaaggagggetgaagttgaaccccaacttcctggtggacttegggaaggagccccttggc _s-at ccagcccttgcccnatgagotccgctaccctgggggcgattgtagctctgacatctggatttgaaggctccaccctcatcacccacactccctattttgggccctcac s~at ttccttggggacctggcttcattctgctctctcttggcacccgacccttggcagcatgtaccacacagccaagctgagactgtggcaatgtgttgagtcatatacattta ctgaccactgttgct ccatcggtgcggactccaaggaggtgcactataagaaccgcttctggcatgacacctgcttccgctgtgccaagtgccttcaccccttggccaatgagacctttgt 331 214505 ggccaaggacaacaagatcctgtgcaacaagtgcaccactcgggaggactcccccaagtgcaaggggtgcttcaaggccattgtggcaggagatcaaaac 331 satt gtggagtacaaggggaccgtctggcacaaagactgcttcacctgtagtaactgcaagcaagtcatcgggactggaagettcttccctaaaggggaggacttcta ctgcgtgactgccatgagaccaagtttgccaagcatgcgtgaagtgcaacaagggtttggtaaaggctccagtgtggtggcctatgaaggacaatcctggcac gactactgcttccactgcaaaaaatgctccgtgaatctggccaacaagcgcttgttttccaccaggagcaagtgtattgtcccgactgtgc ttgtcaaggggcttgcattcaaactgctttccagggctatactcagaagaaagataaaagtgtgatctaagaaaaagtgatggttttaggaaagtgaaaatattttt 332 214598 gttttgtatttgaagaagaatgatgcattttgacaagaaatcatatatgtatggatatattaataagtatttgagtacagactttgaggtttcatcaatataaataaaag 332 at agcagaaaaatatgtcttggttttcatttgcttaccaaaaaaacaacaacaaaaaaagttgtcctttgagaacttcacctgctcctatgtgggtacctgagtcaaaatt gtcatttttgtctgtgaaaaataaatttccttcttgtaccatttctgtttagttttactaaaatctgtaaatactgtatttctgtttattccaaatttgatgaaactgacaatcca atttgaaagtttgtgtcgacgtctgtctagcttaaatgaatg 214677 tcataagtgacttctacccgggagccgtgacagtggcctggaaggcagatagcagccccgtcaaggcgggagtggagaccaccacaccctccaaacaaag 333 xatt caacaacaagtacgcggccagcagctatctgagcctgacgcctgagcagtggaagtcccacagaagctacagctgccaggtcacgcatgaagggagcacc gtggagaagacagtggcccctacagaatgttcataggttctcaaccctcac gagtatacatcggtgcaggcttcctggatgacagttgggtgatatgtgtcatgtggcctaaaagcctccatgtcatttgacctacgaattctatctttgggaatttatcct 334 24696 aagaaantacttanggatttanttngtgataagatgttcatcccagcattgcaatggagaaaaatgggaagcaatggtttggttgggaatttattccttttctgctgtaa 334 2169 cgaaagtttgcaataggggattgcttaagtaaattattgtatctccatccagatggtggagtaccgcgcagacattaaaagtcatgtaaaagaacatctgactgaa _t agaaaaatgctccttgaatattaaaaggttgtaaaaatagtgcatgttatgtgatttcaattttgttttttaaaatatgggtgtatgcttgtatacgtagagcagataaaaa agacggaaggcatactaaaaaatgttgagtggttatctttgtatggtggaacaaagtcactgtaattttcatctttggtt 35 214752 tggggctgagcaaggcctacgtaggccagaagagcagcttcacagtagactgcagcaaagcaggcaacaacatgctgctggtgggggttcatggcccaag 335 t gaccccetgegaggagatectggtgaagcacgtgggcagceggetetacagcgtgtectacctgetcaaggacaagggggagtacacactggtggtcaaatg x~t gggggacgagcacatcccaggcagcccctaccgcgttgtggtgccctgagtntggggcccgtgccagccggcagcccccaagcctgccccgctacccaagc agccccgccctnttcccctcaaccccggcccaggccgccctggccgcccgcctgtcactgcagccgcccctgccctgtgccgtgntgcgctcacctgcctcccc agccagccgctgacctctcggctttcacttgggcagagggagccattggtggcgctgcttgtctcttggttctgggaggggt aatgctctgggtctctggatccagtggggnatattgtgatgactcagtctccactctccctgcccgtcacccctggagagccggcctccatctcctgcaggtctagtc 336 214768 agagcctcntgcatnntaatggatacaactatttggattggtacctgcagaagccagggcagtetccacagctectgatctatttgggttctaatcgggcctccggg _x-at gtcccngacaggttcagtggcagtggatcaggcacagattttacactgaaaatcagcagagtggaggctgaggatgttggggtttattactgcatgcaagotctac __ aaactcctcngacnttnggccangggaccaagntgganatcaaacgaactgtggctgcaccatct 337 214777 gcaagatggtgttgcagacccaggtcttcatttctctgttgctctggatctctggtgcctacggggacatcgtgatgacccagtctccagactccctggctgtgtctctg at ggcgagagggccaccatcaactgcangtccagccagagtgttttatacagctccaacaataagaactacttagcttggtaccagcagaaaccaggacagcct - cctaagctnctcatttactgggcatctacccgggaatccggggtccctgaccgattcagtggcagcgggtctgggacagattt gaggtgcagctgttggagtctgggggaggcttggtacagcctggggggtccctgagactctcctgtgcagcctctggattcacctttagcanctatgccatgagctg 338 214916 ggtccgccaggctccaggnaaggggctggagtgggtctcanntattagtggtagtggtnntancacatactacgnagactccgtgaagggccggttcaccatct 338 xatt ccagagacaattccaagaacacgctgtntetgcaaatgaacagcctgagagccgaggncacggccgtatattactgtncnnnagaaaatggtgtcagcagtt gganntnccaaganannaccccaacctatgttgactactggggccaggaaccctggtcaccgtctcctcagggagtgcatccgccccaacccttttccccctcg I_ tctcctgtgagaattccccgtcggatacgaagcagcgtggccgttggctgctc cgtcagtcatcctttattgcagtcgggatccttggggttgttctgttggccattttcgtcgcattattcttcttgactaaaaagcgaagacagagacagcggettgcagttt 215049 Cctcaagaggagagaactagtccaccaaattcaataccgggagatgaattcttgcctgaatgcagatgatctggacctaatgaattcctcagaaaattcccatg 339 t agtcagetgatttcagtgotgetgaactaaftttgtgtctaaatttcttcctatttctggaatggaaaaggaggccattctgagccacactgaaaaggaaaatggga at ttataacccagtgagttcagcctttaagataccttgatgaagacctggactattgaatggagcagaaattcacctctctcactgactattacagttgcatttttatgga gttcttcttctcctaggattcctaagactgctgctga 340 215076 ggggaatggagcaaaacagtetttgaatatogaacacgcaaggetgtgagactacctattgtagatattgcaccctatgacattggtggtectgatcaagaatttg s at gtgtggacgttggccct 341 215118 cttgctctgttgcagattggcagatgccgcctccctatgtggtgctggacttgccgcaggagaccctggaggaggagacccccggcgccaacctgtggcccacc _ssat accatcaccttcctcaccctcttcctgctgagcctgttctatagcacagcactgaccgtgaccagcgtccggggcccatctggcaacagggagggcccccagtac at tgagcgggagccggcaaggcacagggaggaagtgtggaggaacctcttggagaagccagctatgcttgccagaactcagcc 342 215125 gcataaattaatcagccccagagtgctttaannnnttctcttaaataccggtgtctttgatcaggatgacatgtgccatttttcagaggacgtgcagacaggetggca sa ttctagattactttcttactctgaaacatggcctgtttgggagtgcgggattcaaaggtggtcccaccgctgcccctactgcaaatggcagttntaatcttatettttggct _sat tctgcagatggttgcaatngatccttaaccaataatggtcagtcctcatctctgt 215176 ctactctggctccgaggtgccagatgtgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtc 343 t agagcattagcagctatttaaattggtatcagcagaaaccaggnaaagcccctangctcctgatctatgctgcatccantttgcaaagtggggtcccatcaaggtt tgcagtgatctgggacagatttcactctcaccatcagcagtctgcaacctgaagattttgcaacttactactgtcaacagagttacagtacccctca cat gccgagtactggaacagccagaaggacntcctggaagacnagcgggccnnggtggacacctactgcagacacaactacggggttgnngagagcttcacn 344 215193 gtgcagcggcgagtccatcctnaggtgactgtgtatcctncaaagacccagcccctgcagcaccacaanctcctggtctgntctgtgagtggtttctatccaggca 344 xatt gcattgnaagtcaggtggttncggaanggcnaggaagagaagnctggggntggtgtccacnggcctgatccagaatggagactggaccttccagaccctggt gatgctngaaacagttcctcggagtggagaggttacacctgccaagtggagcacccaagcntnacgagccctctcacagtggaatggagngcacggttga atctgcacagagcaagatgctgagtggagtcgggggctt aagatcctggagtttgtggggcgctccctnccagaggagacngtggacntcatggttnagcacacgtcgttcaaggagatgaagaagaaccctatgaccaact acaccaccgtccnccnggagttcatggaccacagcatctcccccttcatgaggaaaggcatggctggggacnngngnngnccacnttcaccgtggcgcaga 345 215299 atgagcgcttegatgeggacntatgcggagaagatggcaggncngcagcctcangettccgctntgagcngtgagaggggnnncntggagtcacngcaga _x at gggagtgtgcgaatcaaacctgaccaagcggntcaagaataaaatatgaattgagggccngggacggtaggtcatgtctgtaatcccagcaatttggaggctg aggtgggaggatcatttgagcccaggagttcgagaccaacctgggcaacatagtgagattctgttaaaaaaataaaataaaataaaaccaatttttaaaaaga gaataaaatatgattgtgggccaggcagagtggctcatgc ccggtcagcaggatcatcgtgcacccacagttctacatcatccagactggagcggatatcgccctgctggagctggaggagcccgtgaacatctccagccgcg 346346 215382 t tccacacggtcatgctgccccctgcctcggagaccttcccccogggnntgccgtgctgggtcactggctggggcgatgtggacaatgatgagcccctcccaccg ccatttcccctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcatcc xat gtgacgacatgctgtgtgccgggaacacccggagngnntcatgccagggcgactcnggagggcccctggtgtgcaaggtgaatggcacctggctncaggcg I_ ggcgtggtcagctgggncgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatcc gaaccacctcaatgcaaagattctacgggaaaatgtgggccccctccacctattgacaatggggacattacttcattcccgttgtcagtatatgctccagcttcatca 347 215388 gttgagtaccaatgccagaacttgtatcaacttgagggtaacaagcgaataacatgtagaaatggacaatggtcagaaccaccaaaatgcttacatccgtgtgta 347 satt atatcccgagaaattatggaaaattataacatagcattaaggtggacagccaaacagaagctttatttgagaacaggtgaatcagctgaatttgtgtgtaaacgg ggatatcngtctttcatcacgttctcacacattgcgaacaacatgttgggatgggnnnctggagtatccaactgtgcannnngatagaatcaatcataaaatgca cacctttattcagaactttagtattaaatcagttctaatttcatttttaagtattgttttactccttttattcatacgtaaaattttggatta tcttccaatttattatctgcaccaattattttgggcacttctcctgtgtatgtaaactttggagtttaggtctacgtcatttatataagagcctgtagacctgagtggatggac 348 215657 actgcctcttagaactagaacttagaacttatctgaaaatgtacnncnnnngcngaannncncacagagtatgtgtcaggtaggaaccaaattatgattgtt 348 215657 at atattcaaactggtttctgttccttgaaaatggttttattctgatcaaagcctaattaggagttattatgttcttgagtttattccatgtgtgtgaatattttgaatgaatccacta ataagatatgcatgtatgtctggannnnnnncnnnnnagaataaatatttaagtagactttaacaagtaaatggttgtaggcatcattaagtcttaaatagccttttc aaagtattgtgtctngttttaattattcagataattcctttaattctccactcaaatctgacttta gattcctgtgggtccagctttggaactgggaaacctttcggatccgcactcattccactgatgccagctgcccctgaaggatgccagtactgtggtgtgtgagtet 349 215867 cagcagccgcccacacgctcctaactctgctgcatggcagatgcctaggtggaaatagcaaaaacaaggcccgggctggggccagggccagaggggaag 349 xatt gccetggattcactcatgtgagatettgaatctetttctttgtetgtttgtttagttagtatcatctggtaaaatagttaaaaaacaacaaaaaactetgtatetgtttetag catgtgtgcatgactctattaatcacatttcaaattcaccctacattcctctcctcttcactagcctctctgaaggtgtcctggccagccctggagaagcactggtgtct gcagcacccctcagttcctgtgcctcagcccacaggccactgtgataatggtctgtttagcactctgtat 30 216207 ctctggctcccaggtgccagatgtgccatccagttgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcaagtcagg 350 t gcattagcagtgctttagcctgntatcagcagaaaccagggaaagetectaagetectgatctatgatgcctccagtttgnaaantggggtcccatcaaggttcag cggcagtggatctgggacagatttcactctcaccatcagcagcctgcagcctgaagatttgc ccaactgcctgactgcttgttggcctcaccggtgggagctccagcatctcctttgctcgaaatggaccccaactgctcctgtgccactggtggctcctgcatgtgcgc 351 216336 cggetcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagetgetgctcctgotgccccgtgggctgtgccaagtgtgcccagggetgcatctgca _x_at aaggggcgttggagaagtgcaactgctatgcctgacgtggggacagctctgctcccagatgtaaatagagtaacctgcacaaacctggattttttaaaaaataca acactgagccatttgcttcatt 216401 tcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggtgagtcagggcattagcagttatttaaattggtatcggcagaaaccagggaaagttcc 32 x at taagetectgatctatagtgcatccaatttgcaatctggagtcccatctcggttcagtggcagtggatctgggacagatttcactctcactatcagcagcctgcagcct -__- gaagatgttgcaacttattacggtcaacggacttacaatgccc tggaggaagttctccagcttcagctcaactcacagcttctccaagcatcaccctgggagtttcctgagggtttctcataaatgagggctgcacattgcctgttctgctt 353 216442 cgaagtattcaataccgctcagtattaaatgaagtgattctaagatttggtttgggatcaataggaaagcatatgcagccaaccaagatgcaaatgttttgaaatg 353 t atatgaccaaaatttaagtaggaaagtcacccaaacacttctgctttcacttaagtgtetggccogcaatactgtaggaacaagcatgatettgttactgtgatatttt _at aaatatccacagtactcactttttccaaatgatcctagtaattgcctagaaatatctttctcttacctgttatttatcaatttttcccagtatttttatacggaaaaaattgtattg I aaaacacttagtatgcagttgataagaggaatttggtataattatggtgggtgattattttttatactgtatgtgccaaagctttactactgtg ccgccatttcctctgaagcaggtgaaggtccccataatggaaaaccacatttgtgacgcaaaataccaccttggcgcctacacgggagacgacgtccgcatcgt 354 216474 ccgtgacgacatgetgtgtgccgggaacacccggagggactcatgccagggcgactccggagggcccctggtgtgcaaggtgaatggcacctggetgcagg _x-at cgggcgtggtcagctggggcgagggctgtgcccagcccaaccggcctggcatctacacccgtgtcacctactacttggactggatccaccactatgtccccaaa aagccgtgagtcaggcctgggttggccacctgggtcactggaggaccaa 355 216491 agtcgggcccaggactggtgaagccttcggagaccctgtccctcacctgcactgtctctggtggetccatcagtagttactactggagctggatccggcagcccgc xat cgggaagggactggagtggattgggcgtatctataccagtgggagcaccaactacaacccetecctcaagagicgagtcaccatgtcagtagacacgtocaa _xat gaaccagttctccctgaagctgagctctgtgaccgccgcggacacggccgtgtattactgtgcga 356 216510 agtgggtetcagctattagtgggagtgcaggtaccacatactacgcagactccgtgaagggccggttcaccacctccagagacaattccaagaacacgetgtat x at ctgcaaatgnacagnctgagagccgaggacacggccgtatattactgtgcgaaatccc 216576 tcctccctgtctgcatctgtaggagacagagtcaccatcacttgccaggcgagtcaggacattagtaattttaacttggtatcagaagaagccagggaaagccc 357 t ciaaagtcctgatctacgatgcatccaatttggaaacaggggtcccatcaaggttcagtggaagtggttctgggacagattttactttcaccatogccagcctgcag at cctgacgattttgcaacatattactgtcaacaatataatgatcaccccctcactttcggccctgggaccaaagtg atgaaactgattacaacaggctgtaagaatcaaagtcaactgacatctatgctacatattattatatagtttgtactgagctattgaagtcccattaacttaaagtatat 358 216834 gttttcaaattgccattgctactattgcttgtcggtgtattttattattgtttttgactttggaagagatgaaetgtgtatttaacitaagctattgctcttaaaaccagggatca _at gaatatatttgtaagttaaatcattggtgctaataataaatgtggattttgtattaaaatatatagaagcaatttctgtttacatgtccttgctacttttaaaaacttgcatttatt cctcagatttt 359 216984 catctcctgcactggaaccagcagtgacgttggtgcttataactatgtctcctggtaccaacagcacccaggcaaagcccccaaactcatgatttatgaggtcagt xat aatcggccetcaggggtttctaategottetetggetccaagtetggcaacacggcctccetgaccatetetgggetccaggetgacgacgagggtgattactactg _x at catctcatatacaagtagcaaccctctcgtggtt tcaagtgggaagagcgctgttcaaggaccacctgagcgtgacctctgtggctgctacagcgtgttccagtgtcctgccgggctgtgccgagccatggaaccatg gggagaccttcacttgcactgctgcccaccccgagttgaagaccccactaaccgccaacatcacaaaatccggaaacacattccggcccgaggtccacctgct 360 217022 gcegccgccgtcggaggagetggccetgaacgagotggtgacgetgacgtgcctggcacgtggettcagcccaaggatgtgotggtgetggetgcaggggt -s-at cacaggagctgccccgcgagaagtacctgacttgggcatcccggcaggagcccagccagggcaccaccaccttcgctgtgaccagcatactgcgcgtggca gccgaggactggaagaagggggacaccttctcctgcatggtgggccacgaggccctgccgctggccttcacacagaagaccatogaccgcttggcgggtaa acccacccatgtcaatgtgtctgttgtcatggcgga 361 217109 gctgtcaggattcttcaaggagaatgaatactgggaatcaagacaggactataccttatccataggcgcaggtgcacagggggaggccataaagatcaaacat 361 gcatggatgggtectcacgcagacacacccacagaaggacactagcctggcgegegtgcacacacacacacacacacacgagttcataatgtggtgatgge - cctaagttaagcaaaatgcttctgcacacaaaactctctggttacttcaaat 362 217110 gcacctgagcatgaaactcgacgcgttcttcggcatcttctttggggccctgggcggcctcttgctgctgggggtcgggacgttcgtggtcctgcgcttctggggttgc tecggggccaggtttctattoctgaaetcagotgaggcettgcettgaaggggcagetgtggcctaggetacetcaagactcacctcatecttacogcacattta 362t _ at aggcgccattgcttttgggagactggaaaagggaaggtgactgaaggctgtcaggattct 363 217148 catetectgcactggaaccagcagtgacgttgntggttataacnatgtetectggtaccaacannacccaggcaaagcccccaaactcatgatttatgnngtcag x at taatcggccctcaggggtttctaatcgcttctctg 364 217165 gcgctggttcctgcaagtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtagcaagtgtgcccagggctgtgttt x at gcaaaggg 365 217179 aggacagagggtcaccatetettgetctggaagcagotccaacattgggaagaattatgtatectggtaccagcaactcccaggaacagcccccaaactcctca _x at tctataaaaataataagcgaccctcagggattcctgaccgattctctggctccaagtctggcacgtcagccaccctgggcatcaccagactccagactggggac gaggccgattattactgcggaacatgggatagcagcctgagtggtggccgggggatat tgaggagaagtctgccgttactgccctgtggggcaaggtgaacgtggatgaagttggtggtgaggccctgggcaggctgctggtggtctacccttggacccaga 366 217232 ggttctttgagtcctttggggatctgtccactcctgatgctgttatgggcaaccctaaggtgaaggctcatggcaagaaagtgctcggttctttgagtcctttggggatct 366 t gtecactcetgatgotgttatgggcaaccctaaggtgaaggetcatggcaagaaagtgetcggtgcctttagtgatggcctggetcacctggacaacctcaaggg _at cacctttgccacactgagtgagctgcactgtgacaagctgcacgtggatcctgagaacttcaggctcctgggcaacgtgctggtctgtgtgctggcccatcactttg gcaaaga 217235 cagtgtccggatctcctggacagtcagtcaccatctcctgcaccggaaccagcagtgatgttggtggttataactatgtctcctggtaccaacagcacccaggcaa 367 agcccccacactcatgattatgatgtcattaagcggccctcaggggtecctgatogettctggetccaaatctggcaacacggcctcctgaccatetetggget _ _ _ ccaggctgaggatgaggctgattattattgcagctcaaatgcaggcagttttatgtct 217258 tcctgcactgggagcagctcctacatcggggcaggttatgatgtacactggtaccggcaacttcccggcacagcccccaaactcctcatctatggtaacaccgat 38x at cggccetcaggggtccetgaccgattttggetccaagtetggcatetcagcetcctggccatcactgggetccaggetgaggatgaggetgattattactgcaa -__- gtcctatgacagcagcctgag 369 217378 gatgtgacatccaggtgacccagtctccatcttccctgtctgcgtctgtaggagacagagtcaccatcacctgccgggcaagtcagggcattagcaatgggttatc x at ctggtatcagcagaaaccagggcaagcccctacgetectgatctatgotgcatccagtttgcagtcgggggtcccatctoggttcagtggcagtggatctgggaca - - gatttcactctcaccatcagcagcctgcagcctgaagatgttgc ggtccccacagactcagagagaacccaccatggtgctgtctcctgccgacaagaccaacgtcaaggccgcctggggtaaggtcggcgcgcacgctggcga 370 217414 gtatggtgcggaggccctggagaggcacttcgacctgagccacggctctgcccaagttaagggccacggcaagaaggtggccgacgcgctgaccaacgcc. 370 xatt gtggcgcacgtggacgacatgcccaacgcgctgtccgccctgagogacctgcacgcgcacaagettegggtggacccggtcaacttcaagctaagccactgc ctgctggtgaccctggccgcccacctccccgccgagttcacccctgcggtgcacgttccctggacaagttcctggttctgtgagcaccgtgctgacctccaaat accgttaagctggagcctcggtagcc 371 217480 gctgccaggtgccagatgtgacatccagatgacccagtctccatcctccctgtctgcatctgtaggagacagagtcaccatcacttgccgggcgagtcagggcat xa tagcaataatttaaattggtatcagcagaaaccagggaaaactcctaagctcctgatctatgctgcacccagtctgcaaagtgggattccctctcggttcagtgaca _xat gtggatctggggcagattacactctcaccatccgcagcctgcagcctgaagattttgc 372 217546 agtcgctccatttatcgcttgagatctccagccttaccgcggctcgaaatggaccccaactgctcctgcaccactggtgtctcctgcgcctgcaccggctcctgcaa 372_ at gtgcaaagagtgcaaatgcacctcctgcaagaagagctgctgctcctgctgccccgtgggctgtgccaagtgtgcccacggctgtgtetgcaaagggacgttgg aacgacgctgtgcctgatgtgggaacagctcttctcccagatgttaatagaacaagctgcacaacctggattttttttcaatacgatactgagccatttgct cctccagacctccttgaaatacaatattctcccagaaaaggaagagttcccctttgctttaggagtgcagactctgcctcaaacttgtgatgaacccaaagcccac 33 217757 accagcttccaaatctccctaagtgtcagttacacagggagccgctctgcctccaacatggcgatcgttgatgtgaagatggtctctggcttcattcccctgaagcc 373 aacagtgaaaatgcttgaaagatctaaccatgtgagccggacagaagtcagcagcaaccatgtcttgatttaccttgataaggtgtcaaatcagacactgagctt _a gttcttcacggttctgcaagatgtcccagtaagagatctcaaaccagccatagtgaaagtctatgattactacgagacggatgagtttgcaatcgctgagtacaatg ctccttgca ctattaccattctaactttcataaaaagttgggatcaagaagcagctgatttcctgccagggettatattagggggntgattcttaaaggacattaggattggtgctca 374 217762 gaaatggttaatcatgctgtgtgctagccagggccagctggtaccttctttgccatgagcattcaagggacngctaacctttattgacaatctatatngcaaaagtca 374 satt ggaaagaggttgtgagctgattggattaaagacctggcacttcagtaactcagcacgcttccacttcactcaacttaagagagttcattgacagtgttaggatgtga aggctgggaaacacttattttgcttcaagagttccactggtctcccaaataggtacctcaaaaactgttagcaagcggcatttggatgtcttgacaggggctttgc agggatttttagggttttttccacattgtccacattaatggttggcatgattgtgcttgcaggccaag gaatatgacgttaccttgcagactaaaaggttgaaggcccgaaactaacttttagctaacaataagggetgtgccccaatggaaactgagttcattttctgagaaa 375 217764 ggtttggatgactgaaatatttcctctacagtcaaggactttggcatgcggtggctgaaactgagcttttttgtgtgggctccagttctcactgttctgcaatgctcatggc 375 t aagttgaatggtgagctagettataaattaaagagotctgaactgtattcagaccgactgggtatetagettactgttttaacatcattgttgaaaccagaccctgtagt s~t ccagtggtgctgccctgttgtgcaaactgctccttttctcgtgttttgtaaagagcttccatctgggctggacccagttcttgcacatacaagacaccgctgcagtcag ctaggacctttccgccatgtattctattctgtagtaaagcatttccatcaacaatgcctaattgtatctgttattttggtttaacacacactgattcatact ggtctacgcctattacaacctggaggaaagctgtacccggttctaccatccggaaaaggaggatggaaagctgaacaagctctgccgtgatgaactgtgccgct gtgctgaggagaattgcttcatacaaaagtcggatgacaaggtcaccctggaagaacggetggacaaggcctgtgagccaggagtggactatgtgtacaaga 376 217767 cccgactggtcaaggttcagetgtecaatgactttgacgagtacatcatggccattgagcagaccatcaagtcaggeteggatgaggtgcaggttggacagcag _at cgcacgttcatcagccccatcaagtgcagagaagccctgaagctggaggagaagaaacactacctcatgtggggtctctcctccgatttctggggagagaagc ccaacctcagctacatcatcgggaaggacacttgggtggagcactggcctgaggaggacgaatgccaagacgaagagaaccagaaacaatgccaggacc tcggcgccttcaccgagagcatggttgtc cccctgcatatcttctcagcaataactccatgggctctgggaccctaccccttccaaccttccctgcttctgagacttcaatctacagcccagctcatccagatgcag 37 217897 actacagtccctgcaattgggtctctggcaggcaatagttgaaggactcctgttccgttggggccagcacaccgggatggatggagggagagcagaggcctttg 377 cttctctgcctacgtccccttagatgggcagcagaggcaactcccgcatcctttgctctgcctgtcggtggtcagagcggtgagcgaggtgggttggagactcagc _a aggctccgtgcagcccttgggaacagtgagaggttgaaggtcataacgagagtgggaactcaacccagatcccgcccctcctgtcctctgtgttcccgcggaaa I ccaaccaaaccgtgcgctgtgacccattgctgttctctgtatcgtgatctatcctcaacaaca ctcttttactactgacctttcacagagaaaaaatatttcccttgaaaaaaactgggcttgtcattttttcccttgtagctttaagcagagacataagtgccttgcattacac 378 27967 atagtaaactttctttaaaaaaaaaaaaaaaagattttggagactaccagggtaagattccaacttgtccaaaagctttctggccttacatattttattataaaaattct 37 2196 caagtctggtaatettctatgtcagagctagtgatttcaaaaggtttcacaattccccaagacaaaagtgattttcgttcattataataaggttaagtgatatgtgattcat _at aacaattttgatgtgaagaagggaaggacatcattgacttaataatagtatcagtcggtgcaacagttggcaacatgtgccttcacactttaccataaagagacgg gtttgagggtttgccttctaaagtctgcaacttcaagaaaaaaaatcgacactgtggattgactttcccggt aactttgtatagcccatgtacctaccttgtatagaaaaataattttaaaaatttgaatggaagggggtaaaggaagtcatgaagtttttgcatttttatttaaatgaagg 39 218087 aattccaaataactcacctacagatttttagcacaaaaatagccattgtaaagtgttaaaatttacgataagtattctattggggaggaaaggtaactctgatctcagt 39 s at tacagttttttttccttttaatttcattattttgggtttggtttttgcagtcctatttatctgcagicgtattaagtcctattgetagaataggttactacaaaaaaggttatattct gaaagaaaaataactgacattatatataaccaattaatttaaagtattgccatttaaattacacactgagagcatgtcctatgcagacatagatttttctgttcatttattt tcttcattgcagtggattgatttgataaatagatgtgttgaattactacattgctgtacatat ggagctagccttgttttgcatctttctcactcccatacatttatattatatccccactaaatttcttgttcctcattcttcaaatgtgggccagttgtggctcaaatcctctatat 380 218162 ttttagccaatggcaatcaaattcttcagctcctttgtttcatacggaactccagatcctgagtaatccttttagagcccgaagagtcaaaaccctcaatgttccctcct 30 at - getctcctgccccatgtcaacaaatttcaggetaaggatgccccagacccagggetetaacettgtatgcgggcaggcccagggagcaggcagcagtgttctto ccctcagagtgacttggggagggagaaataggaggagacgtccagctctgtcctctcttcctcactcctcccttcagtgtcctgaggaacaggactttctccacatt gttttgta gcgggtcttgctggctaaaatgcccaggtaaagggttggttggacacagcgcttagtgcacgctgtcatcatggacatcataatcagttgtgaaaaacacgcgaa 381 38t 218224 cctatgacacttcttattccacactgaatgtgaaattgcatgttcagatgtttnactacgaggcctggetcacaggaagtgttcagtaaaagtatgcactgttagattac tgataacgcggatagatttttgttnaccataaattgttccagatttatattaatggaaggaagtgtgcatttattagctattantcaactttacaangcaaacatcttatttct at catctttaaacatgtcgaccagtttaattgaaaagtattctgagactgcaaaatggggtgttaaaaaatactgcagttacggagctgtgtaaaccagtttctcattgca taagatacagatgtaaattgcatggagaggttgatatgcacctgtacagtaattcactcccccatttcacttctttgtcagagaatagttcttgttcatactgagtgt gcatccgaggggagccgccggatgtggaagaagactcggetttcctgcagccatttagtgccgccccatgctaggttatttgacattgtgcagtgtagagttgcctt 382 218312 aaagtgcgtgatctgccagtgctttctcaagtcacccttgccccgattcctcatgtttgcgctccccagggttgctcaagtggaaattttgtcagctgtttagccttttcgt _s_at acttggcgtgatgtcaacttcacttctaatctgcaaaagcagaagctgtttcctagtttacctcgcgtgtgtttacctatatggagtagotcgcagagatcacagaaat gcttgcagcctaaggcagggttttcagaccgtgggtcccagcccatttagtaaaatgggaaatcaattagcaagtggtcaccagcattacacagca tatacagtttaataagcctcttgcaagttacttgttctctcacctgaggtattttttcctccccaccttgcccctgttcctcccttcctcttctccctttgcaagaggaaatattt 33 218353 aacatatttgggtccaacttcaataatgtaataattaatacattaaaagcatttaacttcctttctagaaaaatgcacaggctaaggcatagacaaaacaaagaga 383 aatgetgagaaatttgccactggagacaagcaatctgaataaatatttgccaaaagttcftttatgtcatatagtgtcaggatttgaaggagetattttttttaatgttge _t aactagcaactcatcttcggaagacacagccaggagaatgaagtagaagtgaaaggtttataaatccatttgtaagcatttatcccatatattttaaattcaagaaa I aattgtgtttatctttagaattttgtattcaatactttatgtactatgtgactcatgcttctggataaataaagcaccaaatatgtatctgtaaccacaatcacacata ggettgatgtagactggettgctttgattttagtgaagggaatgtacgtaaaacaaaatagggettggetggtcaaaggagacaagcaggatggatggatggatg 384 218418 gatgaatagatagatggtgtttgcatgtaaattgcagagaaaacaaaaccaaagctgattggaaacaattaattgtgggtgtctgagggggaaggtcgcagcttt 34 s at gggcagctttgagaagcggtacaagagctctgtgcctgtgtgtccagccctggagccagccagtgcatttattttaagotcttagaagcaactccttggcccagga t atgcgtgacccctgagatgggtccacgcatctctctacacgtccttctctccgtgggatactggactcgtgcctctgcgcccattctcttctcacgcatatccatgagct ttaatttcactttctgatcacggtacgtccataaagccagt ggagatgacttaagttggcagcagtaatcttcttttaggagcttgtaccacagtcttgcacataagtgcagatttgccccaagtaaagagaatttcctcaacactaac 385 218468 ttcacggggataatcaccacgtaactacccttaaagcatatcactagccaaagaggggaatatctgttcttcttactgtgcctatattaagactagtacaaatgtggt _s_ at gtgtcttccaactttcattgaaaatgccatatctataccatattttattcgagtcactgatgatgtaatgatatattttttcattattatagtagaatatttttatggcaagagattt gtggtcttgatcatacctatt gaagctgacacaccgtatgttgttagagtcttttatctggtcaggggaaacaaaatcttgacccagctgaacatgtcttoctgagtcagtgcctgaatctttattttttaa 386 218469 attgaatgttccttaaaggttaacatttctaaagcaatattaagaaagactttaaatgttattttggaagacttacgatgcatgtatacaaacgaatagcagataatgat 386 gactagttcacacataaagtecttttaaggagaaaatetaaaatgaaaagtggataaacagaacatttataagtgatcagttaatgcctaagagtgaaagtagtte _a tattgacattcctcaagatatttaatatcaactgcattatgtattatgtctgcttaaatcatttaaaaacggcaaagaattatatagactatgaggtaccttgctgtgtagg I aggatgaaaggggagttgatagtctcataaaactaatttggcttcaagtttcatgaatctgtaactagaatttaattttcaccccaataatgttctatatagcctttgctaa gttcaaaatatttccaagcctgagtattgtetattggtatagatttttagaaatcaataattgattatttatttgcacttattacaatgcctgaaaaagtgcaccacatggat 387 218541 gttaagtagaaattcaagaaagtaagatgtettcagcaaetcagtaaaaccttacgccacettttggtttgtaagaggttttttatacatttcaaacaggttgcacaaa _s-at agttaaaataatggggtcttttataaatccaaagtactgtgaaaacattttacatattttttaaatcttctgactaatgctaaaacgtaatctaattaaatttcatacagttac tgcagtaagcattaggaagtgaatatgatatacaaaatagttataaagactctatagtttctataatttatttactggcaaatgtcatgcaacaa ggcagcccacaagtttctcgtggggagatggaggcagagcccagggtaggggacagagctgctggggcctttccttgcctgggaatctgtcccaggaagaget 388 218546 tccccactcccatcccccaaattggaaaaaccgtacattcaagcctgtttggccctgaaattcttaagaatctggttaagaattaactcactaatgtcaaaagtcaa 388 aacctcetaggggttgtcctgggagtcaggttcacgggtacagaagatgaatctcagatgtcactcaacctgagccgtcattctctgtggcagggetgccetgggtt _a tctcttactcaatccctggagtgtaagcatttggattgtgtcacagattacctttttaccttttctttctttftttttcttttttcaatatcagtgcccacaccttactgagtattgagtt ttagagctttcgcttgatgtgcttgaccaagagactcttttgtatccttttct tcaagtgcgttctttagaccaatgcattgcgtttctttccctgcttttgagatagtaggaagagttcttggtggtgtccccccccttcaattcttcagttgtatagtagttatag 389 218559 ggaagatatgggtgtttttctttattattacttttttttctgcaggtcagtaaaaggatttaagttgcactgacaaaaataccaaaataaaagtgtatttttaagttcccattt 389t sat gaaattgotggcgetgetggccggatgcatttttgagtttgtattagttgataaattaacagtaataacaagattgtatgaaccgcatggtgettgcagttttaaatattgt ggatattgtcctgcatcagaaacgagcttggtttttacagattcaactgtgttgaaatcaaacctgccgcaacagaaattgtttttatttcatgtaaaataagggatca atttcaaaccctgcttatg cctcctgcctctggatttaggtgttgatttctggatcacgggataccacttcctgtccacaccccgaccaggggctagaaaatttgtttgagatttttatatcatcttgtca 390 218756 aattgcttcagttgtaaatgtgaaaaatgggctggggaaaggaggtggtgtccctaattgttttacttgttaacttgttcttgtgcccctgggcacttggcctttgtctgctct 3 90 _at cagtgtcttccetttgacatgggaaaggagttgtggccaaaatcccatettcttgcacctcaacgtetgtggetcagggctggggtggcagagggaggccttcac cttatatctgtgttgttatccagggctccagacttcctcctctgcctgccccactgcaccctctcccccttatctatctccttctcggetccccagcccagtcttggettcttgt I cccctcctggggtcatccctccactctgactctgactatggcagcag ggcatgtgtgactgtttcagcgactgcggagtctgtctctgtggcacattttgtttcccgtgccttgggtgtcaagttgcagctgatatgaatgaatgctgtetgtgtggaa 391 219014 caagcgtcgcaatgaggactctctacaggacccgatatggcatccctggatctatttgtgatgactatatggcaactctttgctgtcctcattgtactctttgccaaatc 391 aagagagatatcaacagaaggagagccatgcgtactttctaaaaactgatggtgaaaagetettaccgaagcaacaaaattcagcagacacctcttcagettg _a agttcttcaccatctttgcaactgaaatatgatggatatgcttaagtacaactgatggcatgaaaaaaatcaaatttttgattattataaatgaatgttgtccctgaactt agctaaatggtgcaactagttctccttgctttcatatatcg agagaatgcccttctccttattgtaaccctgtctggatcctatcctcctacctccaaagcttcccacggcctttctagcctggctatgtcctaataatatcccactgggag aaaggagttgncaaagtgcaaggacctaaaacatctcatcagtatccagtggtaaaaaggcctcctggctgtetgaggetaggtgggttgaaagccaagga 392 219059 gtcactgagaccaaggetttctactgattccgcagotcagaccetttcagetetgaaagagaaacacgtatcccacctgacatgtecttetgagccoggtaa _s at gagcaaaagaatggcagaaaagtttagcccctgaaagccatggagattetcataacttgagacctaatctctgtaaagctaaaataaagaaatagaacaagg ctgaggatacgacagtacactgtcagcagggactgtaaacacagacagggtcaaagtgttttctctgaacacattgagttggaatcactgtttagaacacacaca cttactttttctggttctaccactgctgatattttct attaccttatcatgtcttagagcccgtctttatgtttaaaactaatttcttaaaataaagccttcagtaaatgttcattaccaacttgataaatgctactcataagagctggtt 393 219087 tggggctatagcatatgcttttttttaatatacctgatttaaaaatctctgtaaaaacgtgtagtgtttcataaaatctgtaactcgcattttaatgatccgctattataa 393 gettttaatagcatgaaaattgttaggetatataacattgccacttcaactctaaggaatattttgagatatccctttggaagacettgettggaagagcctggacacta _a acaattctacaccaaattgtctcttcaaatacgtatggactggataactctgagaaacacatctagtataactgaataagcagagcatcaaattaaacagacaga aaccgaaagctctatataaatgctcagagttctttatgtatt atggggctggggacttgaattggatgcttcaaaaccatcacctgttggccaacaagtttgacccaaaggtagatgataatgctcttcagtgcttagaagaataccta 394 219508 cgttataaggccatctatgggactgaactttgagacacactatgagagcgttgctacctgtggggcaagagcatgtacaaacatgctcagaacttgctgggacag 39 a19t tgtgggtgggagaccagggetttgcaattcgtggcatectttaggataagagggetgctattagattgtgggtaagtagatettttgccttgcaaattgotgcctgggtg at aatgctgctgttctctcacccctaaccctagtagttcctccactaactttctcactaagtgagaatgagaactgctgtgatagggagagtgaaggagggatatgtgg I_ tagagcacttgatttcagttgaatgcctgctggtagcttttccattctgtggagctgccgttcctaataattccag 395 219543 ggaattcttctcacttcaataaaatgggtttaacataacttaaattcagtaaatatacaatattgaatacctatagtgacttgggatggggactttttcaagtcata at agagtgtttgtttaaggtgatctcattgatggtagttetcagccgtetcaaaaactgcaagctaatcagtcagacattctttaatgaccccaattttttcactttaattgttac - catgttttctatttttactgatttttgctaaagcatgtaagagtgaatttattatagcagtaatcttgtgttctcctgatgtgca atcaacacatttagcttggcgtttattcattccatcacccttactgtaactactatggcaactcaaataattgtcatgggactatgtccatcttaatgggtctggatggcat 396 219607 ggtgetectcttaagtgtgetggaattctgcattgotgtgtccctctctgcctttggatgtaaagtgetctgttgtacccctggtggggttgtgttaattctgccatcacattet -s at cacatggcagaaacagcatctcccacaccacttaatgaggtttgaggccacccaaagatcaacagacaaatgctccagaaatctatgctgactgtgacacaa catctctcaggaggtgggctgtccaccaaaatgagcattcagggctgcgtggcccaaccttccagcttcttgttgaaccacaccagacaaatcgggatcttctctg 397 219669 cgcgtgagaagcgtgatgtgcagcctcctgcctctcagcatgagggaggtggggctgagggcctggagtctctcacttggggggtggggctggcactggcccc 397 agegetgtggtggggagtggtttgcccttcctgctaactctattacccccacgattcttcaccgetgctgaccacccacactcaacctccctctgacctcataacctaa _a tggccttggacaccagattctttcccattctgtccatgaatcatcttccccacacacaatcattcatatctactcacctaacagcaacactggggagagcctggagca tccggacttgccctatgggagag tccttgtccacaagcactatggcccccggctcaagtgctgctctggcaaagctccggagccccagccccaaggctttgacaaccaggcgttcctccctgaccac

398 219796 aaggccaactgggcgcccgtccccagccccacgcacgaccccaagcccgcggaggcaccgatgcccgcagagcccgcaccccccggccctgcctcccc sat s~t aggcggtgcccctgagccccccgcagcggcccgagctggcggaagccccacggcggtgaggtccatctgaccaaggagcggcggccagagggcgggt acaaggctgtctggtttggcgaggacatcgggacggaggcagacgtggtcgttctcaacgcgcccaccctggacgtggatggcgccagtgactccggcagcg _ _gcgatgagggcgagggcgcggggaggggtgggggtccctacgatgcgcccggtggtgatgactcctacatctaagtggccc 399 29799 accatcgctggtggtatcccagggtccctgctcaagttttctttgaaaaggagggctggaatggtacatcacataggcaagtcctgccctgtatttaggctttgcctgc 39 2179 ttggtgtgatgtaagggaaattgaaagacttgcccattcaaaatgatetttaccgtggcctgccccatgettatggtecccagcatttacagtaacttgtgaatgttaag _s at tatcatctcttatctaaatatt gaatactcataattcttatctctataatcaaaagtataatttactgtagaaaaataaagagatgcttgttctgaaagtaagatcagtgaactgcttttcagtctcaatctt 400 40 219948 gagaattgtaaatcatcaaataatgctacatagtaaaaatttaaggtattagaaaacctgcataacaaatagtatatatattaaatatttgatatgtaaagctcta 2194 cacaaagctaaatatagtgtaataatgtttacactaataagcaaatatgttaatettctcattttttactgtcatataatettagtgatatgcctattaatagttttaaataaa _at taaattggctcatctggctttttgaaaattttgaaattcttacagatgttgattaggtatatctacaaattaatttcaattttaaaatgatgatataaaaataaatataagtatt tttcttgtgtatgtata agtaactttgtttatccctcaagcaaatcctgatgacattgatcctactcctactcctactcctactcctgataaaagtcataattctggagttaatatttctacgctggtatt 401 401 220026 gtctgtgattgggtctgttgtaattgttaactttattttaagtaccaccatttgaaccttaacgaagaaaaaaatcttcaagtagacctagaagagagttttaaaaaaca aaacaatgtaagtaaaggatattetgaatettaaaattcatcccatgtgtgatcataaactcataaaaataattttaagatgtcggaaaaggatactttgattaaata _a aaaacactcatggatatgtaaaaactgtcaagattaaaatttaatagtttcatttatttgttattttatttgtaagaaatagtgatgaacaaagatcctttttcatactgatac ctggttgtatattatttgatgcaacagttttctgaaatgat ttccacttctattccacggagaaaaaaattgatttgtgtcacagaagtttttatggaaactagcaccatgtetacagaaactgaaccatttgttgaaaataaagcagc 402 220037 attcaagaatgaagetgetgggtttggaggtgtecccacggetctgotagtgettgetetectettctttggtgetgcagetggtettggattttgetatgtcaaaaggtat _s-at gtgaaggccttcccttttacaaacaagaatcagcagaaggaaatgatcgaaaccaaagtagtaaaggaggagaaggccaatgatagcaaccctaatgagg aatcaaagaaaactgataaaaacccagaagagtccaagagtccaagcaaaactaccgtgcgatgcctggaagctgaagtttagatga 403 220075 ctcaactoggccatcacatatcgaattaccaaccactcacacttceggatggagggagaggttgtgetgaccaccaccacactggcacaggcgggagccttet s at acgcagaggttgaggcc tccattaccaagagctcatgccacccggttcctgcatgccagaggagcccaagccaaagaggggaagacgatcgtggccccggaaaaggaccgccaccc 404 220266 acacttgtgattacgegggetgeggcaaaacctacacaaagagttcccatetcaaggcacacctgegaacccacacaggtgagaaacettaccactgtgactg -s-at ggacggetgtggatggaaattcgcccgctcagatgaactgaccaggcactaccgtaaacacacggggcaccgcccgttccagtgccaaaaatgcgaccgag cattttccaggtcggacc aaaacccattctttcagttacatctactaagagctcgtagttcaataacattccaaagaacgtagtttggaaaacactggcctatcggctgtaataggaagggtcta

405405 220376 aagaaaattatttgctgagtcctcataatcaattggctataatcacaatttaataatttatcaatgcaaacagtacattaaaaactgtagcacaatctataatttttacctt catatgcagagaaattaagaatttacatettttacaaatatgtgtatctetgaaataatgaaatatattgatgggtgaaataatattetggtatttettcattataacacgt at ggaatgggacagtggctagaggtatggatggagcaaggtcaaatatgagctgatggagctgggcgctaaataagggtataatatgctacttctgtgtatgttgtgt atggtatagtatgctatttctgtgtatgttcaaattgtttatgtatataataaagttttaaaaatttgtatgtacttgacaattccttagaa agaggagacactttggcgttcttcaagcagaactgaggctgcgaaaaatccaagtctctacagagacactgatgaagttgaaagggtaattgtttttccatgccaa 406406220468 algaggaaatcaaattaatgagttgacaaacttttcctgagatgttatttcatctacatttagttaaacaacttagaatgatatctagaaaatatttattttcagccagga actttagcaaactgtggcaatgatcactgggaatgaaaacgtataatgttctacaattttgttatcacattggatgactttgaatatagtagtgacacttgggaccaaa at taaattattttatatgactactagaacaaagttttagtaagctgtctgctaatagagtcagaacttccagattgtttccagctgtaacaggtattgaatttccaccgtgct cctatgtaacagctgggtggtgtaaaaaatgaactcaaattatggagtggaagaagcgtaatgttaatatcttgtaaatcgtattccctat cattttccaggatctcagtgtgagtatcattgatgcctgggatataacaattgcatatggcacaaataatgtacacccacctcaacatgtagtcggaaatcagattaa 407 220645 tatattattaaactatatttgttaaataacacaaaagtetgaaattcattcacttaagtaaaaaaatttattgactgtctactagcaggccagatgetgtgtttggetetga _at attcccaactagcaagagcagagaatctacattatggctgatccataagccaccaattcagctaaatgagatgtttctaatctgggcttccacttaaaaataaaact aaaaatactcatgaaaagagcctaccctcttgatcagagccatacccctcttcaccaatgggaagt ggtattttagtctagttttatatgaacggttgtatcagggtaaccaactcgatttgggatgaatcttagggcaccaaagactaagacagtatctttaagattgctaggga 408 220812 aaagggccctatgtgtcaggcctctgagcccaagccaagcatcgcatcccctgtgatttgcacgtatacatccagatggcctaaagtaactgaagatccacaaa 408t agaagtaaaaatagccttaactgatgacattccaccattgtgatttgttcctgccccaccctaactgatcaatgtactttgtaatetccccaccettaagaaggtacttt sat gtaatcccccacccttaagaaggttctttgtaatctccccacccttgagaatgtactttgtgagatccaccctgcccacaaaacattgctcttaacttcaccgcctaa cccaaaacctataagaactaatgataatccatcacccttcgc gctggccaagactactgggccgtgctttctggaaaaggcatttcagccacgctgatgatcttctccctcttggagttcttcgtagcttgtgccacagcccattttgccaa 220834 ccaagcaaacaccacaaccaatatgtctgtcctggttattccaaatatgtatgaaagcaaccctgtgacaccagcgtcttcttcagctcctcccagatgcaacaac 409 tactcagctaatgcccctaaatagtaaaagaaaaaggggtatcagtetaatctcatggagaaaaactacttgcaaaaacttcttaagaagatgtettttattgtetac _a aatgatttctagtctttaaaaactgtgtttgagatttgtttttaggttggtcgctaatgatggetgtatctcccttcactgtctcttcctacattaccactactacatgctggcaa aggtgaaggatcagaggactgaaaaatgattctgcaactctcttaaa agcccaccagcaggagcttggagtttggggagtggggatgagtccgtcaagcacaactgttctctgagtggaaccaaagaagcaaggagctaggaccccca 410 221004 gtectgccccccaggagcacaagcagggtcccctcagtcaaggcagtgggatgggcggetgaggaacggggcaggcaaggtcactgetcagtcacgtcca _s-at cgggggacgagccgtgggttctgotgagtaggtggagctcattgctttctccaagcttggaactgttttgaaagataacacagagggaaagggagagccacctg gtacttgt 411 221305 gccactatcttgaagaaggtgcacagtgccctgctcctctttcctatgtccccagaattctcttagggttctcagatgccatgactttcaaggagagagtacggaacc 41 s at acatcatgcacttggaggaacatttattttgccagtatttttccaaaaatgccctagaaatagcctctgaaattctccaaacacctgtcacagcatatgatctctacag -- ccacacatcaatttggttgttgcgaacagactttgttttggactatcccaaacccgtgatgcccaatatgatcttcattggtggtatcaactgccatcagggaaagcc 42 221541 ctttatcatccccacaaacattttgaaactggaatatttgtcttcagaaaatggaaacaagactataaatgataagccctgtccctagcaccacctctcctgtgtgtgg 42 - at aatagaggcccctcgtgctaccaacacttaccctgtgtttaaaaagatcttgtaccaagccaacggcgttcctggctctcctgcccacaggatgaacattttcggctt ccttaggagttttgccctaccgtattccaaagcgtgtgctggtttctcatattgtctgtaggctcac gtgaggctcagtcagaacctccaccctcccccacaccaaagacaggggcagcgtagtattcaaaccagtattgtggtggggaataattgtatacatgtaaattat 43 221584 caagccctatgagtggaagaatttttcaaattatttttgtctctctatatattgatttatattatgtataactatctctttatataaactatatataattatatatatataactatat 413 t aattatatatatataactatatatataactatatatatgtatcccctagtattggatcatgaagagctcttcatgcattctttgcaaaggaggttataaagttacgccctca _at gaacatttataactataagaatgtgccagttaaagtgctcaacaggaaatatgacagtttaaaagcattgtaaaactcacatagcttacttctctctctaaagtgcaa caaggatgaatagaatgggccaaggtatgacaattaatggttctgcatgacctagccactgctgggggtttcttctataacgttgtccttgtga gggacttaacatttcacgttgtatcttacttgcagtgaatgcaagggttactttctctggggacctcccccatcacccaggttcctactctgggctcccgattcccatgg 44 221667 ctcccaaaccatgccgcatggtttggttaatgaaacccagtagctaaccccactgtgcttccacatgcctggcctaaaatgggtgatatacaggtcttatatccccat 414 t atggaatttatccatcaaccacataaaaacaaacagtgccttctgccctctgcccagatgtgtccagcacgttctcaaagtttccacattagcactccctaaggacg s~t ctgggagcctgtcagtttatgatctgacctaggtcccccctttcttctgtcccctgtttttaagtccggatttttacagaaggaactgtctccagacagctcatcaaggaa ccaagcaaaggccagatagcctgacagataggctagtggtaattgtgtatatgggcgggacgtgtgtgtcatta 45 221747 cctctgtcctcaaatgtccaaaatgttggaggacctctgttcatatcccacgcctgggctcttgccagcagtggagttactgtagagggatgtcccaagcttgttttcca 415 atcagtgttaagctgttgaaactctcctgtgtetgtgtttgtttgtgcgtgtgtgtgagagcacatcagtgtgtgcaggetgtgtttccccatttttctccettcagacc at catcattgagaacaaatgtaagaaatcccttcccaccaccctccctgcctcccaggccctctgcgggggaaacaagatcacccagcatcct 416 221748 atattttgtatcategtgcctatagcegetgccaccgtgtataaatectggtgtntgetecttatcetggacatgaatgtattgtacactgacgcgtecccactcctgtaca s at gctgctttgtttctttgcaatgcattgtatggcttta atccgacttgaatattcctggacttacanaatgccaagggggtgactggaagttgtggatatcagggtataaattatatccgtgagttgggggagggaagaccag 417 221841 aattcccttgaattgtgtattgatgcaatataagcataaaagatcaccttgtattctctttaccttctaaaagccattattatgatgttagaagaagaggaagaaattcag |_s-at gtacagaaaacatgtttaaatagcctaaatgatggtgcttggtgagtcttggttctaaaggtaccaaacaaggaagccaaagttttcaaactgctgcatactttgac aaggaaaatctatatttgtcttccgatcaacatttatgacctaagtcaggtaatatacctggtttacttctttagcatttttatgcagacagtctgttatgcactgtggtttcag atgtgcaataatttgtacaatggtttattcccaagtatgccttaagcagaacaaatgtgttttctatatagtccttgccttaa ccaatcctgaaggtactccctgtttgctgcagaatgtcagatattttggatgttgcataagagtcctatttgccccagttaattcaacttttgtctgcctgttttgtggactgg ctggctctgttagaactctgtccaaaaagtgcatggaatataacttgtaaagcttcccacaattgacaatatatatgcatgtgtttaaaccaaatccagaaagcttaa 418 221896 acaatagagetgcataatagtatttattaaagaatcacaaetgtaaacatgagaataacttaaggattctagtttagttttttgtaattgcaaattatatttttgetgetgat _ s at atattagaataatttttaaatgtcatcttgaaatagaaatatgtattttaagcactcacgcaaaggtaaatgaacacgttttaaatgtgtgtgttgctaatttfttccataag aattgtaaacattgaactgaacaaattacctataatggatttggttaatgacttatgagcaagctggtttggccagacagtatacccaaacttttatataatatacaga aggctatcacacttgtgaa tcgactctgctgctcatgggaagaacagaattgctcctgcatgcaactaattcaataaaactgtcttgtgagctgatcgcttggagggtcctctttttatgttgagttgct 419 222043 gettcccggcatgccttcattttgetatggggggcaggcaggggggatggaaaataagtagaaacaaaaaagcagtggetaagatggtatagggactgicata _at ccagtgaagaataaaagggtgaagaataaaagggatatgatgacaaggttgatccacttcaagaattgcttgctttcaggaagagagatgtgtttcaacaagcc aacta aataacgcaaatggcttcctctttcctttttftggaccatctcagtctttatttgtgtaattcattttgaggaaaaaacaactccatgtatttattcaagtgcattaaagtctac 222162 aatggaaaaaaagcagtgaagcattagatgctggtaaaagctagaggagacacaatgagcttagtacctccaatttcctttctttcctaccatgtaaccctgctttg 420 t ggaatatggatgtaaagaagtaacttgtgtetcatgaaaatcagtacaatcacacaaggaggatgaaacgceggaacaaaaatgaggtgtgtagaacagggt _at cccacaggtttggggacattgagatcacttgtcttgtggtggggaggctgctgaggggtagcaggtccatctccagcagctggtccaacagtcgtatcctggtgaa tgtctgttcagctcttct tcaaatggaacctgccctctaaagcactttctttcctttacttgcgtggtttcatgtaagctgtgctgtttagaaacaacatctcagactttacaaagaaatgacaaaga 421 421222453 aggcaattgcactttttaagggatatcgacaagcagtttctgttttctaaaggacaaaatacagagtgtgtgtcatttttaattagattctttcccctgctgagttggaaatt ccagtgcagcactgattgaccacagttgccaatctaaaagcacaaagacagaagtaaagctttatgctaattttatttcaatatgatagaaaatttatettggtatgtc at cttttttagataactccagcaggaaactgtaactgctatgtctttaggaaaacgtagaagaaagaacattattattctttaattcctacaaggtacttgaaaaccttaag tgaaaaagatttctatctttttatcttggcgcatt tgccactaattcattcacactaaggtgtaaatgattgataataggaatgagttacctcttcccacagacatttgtttttaagtatgacagagcagggccttaatcccaa gggaaaaggttatggaactggagggggtgagctttctgggtagaaggagacttcctgaatttccttaaaacccagtaagagtaagacctgttgttttggaaggtct 422 222513 gctccaccatctaagagcactgtttttttttgttgttgttgttgttttacggtctctgagggaatatagtaaaaatgcatatgcacgtgcaatttgcacggcagcatttca _s-at ccgattgtggactgtattggctaatgtgtttcctggtctttagatgcaaaccattaataacactatcttatctcatagttttttcaggggtgcttcttgattagtagggaattttg aacacctctttaaatacagctagaaaataaaaccaatttgtaaagccacatttgcatatgatgccagcctcacgcatttgtatatctccagaaattcaggtatgcctc accaatttgcccgtctttaataa taaactaacccttacattccatgtgatgtgatgtaggcttataagntgctaaaatctataggtntnggaagtgaaagattctattttttcttttttngtacataatgggaattt 42342 222717 catccagatatattatttacatattaatttcacagaatattaatattctaactctaaagcatgctagcgtttatgtatatgtacacatatattcagacagggtaatttt a221 atctgctgcctaacattgtactaaaatattgctttatctgtttttaattacaaaatgctaatgatttcttaaattatagtttaaagacaattggcccaggaagcaaatcccct at gccttagtatgaaccactataagtaaccttacaaatagagttaatccaagacaatattaacaaactgtgctttgtctttaataaaagggataggattaacaaacata ttgatggcataacctattcagctatgtccttatttttgcaataatgtaacctcaaatattggattgttgaaccaacaatggctgtgttaaa tttatgatgactcagtggtgccagagtaaagtttctaaaataacattcctctcacttgtaccccactaaaagtattagnctacacattacattgaagttaaacacaaaa 424 222722 ttatcagtgtttagaaacatgagtccggactgtgtaagtaaaagtacaaacattatttccaccataaagtatgtattgaaatcaagttgtctctgtgtacagaatacat 424 at acttattcccattttaagcatttgcttctgttttccctacctagaatgtcagatgttttcagttatctccccatttgtcaaagttgacctcaagataacatttttcattaaagcat ctgagatctaagaacacaattattattctaacaatgattatagctcattcacttattttgataactaatgatcacagctattatactactttctcgttattttgtgtgcatgcct catttccctgacttaaacctcactgagagcgcaaaatgcagctttatacttttacttt gataacctacatcaaccgagataccaaaatcatcctggagaccaagagcaagaccatttacaagctgaacggtgtgtccgaaagggacctgaagaaatcgg 425 425223121 t tgctgtggctcaaagacagcttgcagtgcacctgtgaggagatgaacgacatcaacgcgccctatctggtcatgggacagaaacagggtggggagctggtgat cacetoggtgaageggtggcagaaggggcagagagagttcaagcgcatctcccgcagcatccgcaagotgcagtgctagtcccggcatcctgatggetccga _at caggcctgctccagagcacggctgaccatttctgctccgggatctcagctcccgttccccaagcacactcctagctgctccagtctcagcctgggcagcttccccct gccttttgcacgtttgcatccccagcatttcctgagttataaggccacaggagtggatagctgttttcacctaaaggaaaagcccacccgaatcttgtagaaat ggtgcaactgtgacttgggtctggttggttgttgtttgttgtttgagtcagctgattttcacttcccactgaggttgtcataacatgcaaattgcttcaattttctctgtggccc 426 223122 aaacttgtgggtcacaaaccctgttgagataaagctggctgttatctcaacatcttcatcagotccagactgagactcagtgtetaagtcttacaacaattcatcatttt _s-at ataccttcaatgggaacttaaactgttacatgtatcacattccagctacaatacttccatttattagaagcacattaaccatttctatagcatgatttcttcaagtaaaag gcaaaagaatttataattgacttgagtactttaagccttgtttaaaacatttcttacttaacttttgcaaattaaacccattgtagcttacctgtaatI agggtacgagaacttgccaatgggaaattcatccgagtggcactggcagagaaggataggagtggaatgcccacacagtgaccaacagaactggtctgcgt 427 223235 gcataaccagctgccaccctcaggcctgggccccagagctcagggcacccagtgtcttaaggaaccatttggaggacagtctgagagcaggaacttcaagct _s-at gtgattctatctcggctcagacttttggttggaaaaagatcttcatggccccaaatcccctgagacatgccttgtagaatgattttgtgatgttgtgatgcttgtggagcat' cgcgtaaggcttcttgcttatttaaactgtgcaaggtaaaaatcaagccttggagccacag gagtccaaatgtcatcagtgctcattttgagataccctgctatcgatggtcgctacaaaccaggaaatactcaagttattatgtgtatacattggntttagntttatgaa 428 223343 acaattaccttcatgatctcatagtaaaatgtaataaattaggaatataaaggatcaatatgggaagcaaaatttctaaaggcagttctgttgttttaattagtattt 428 2234 gtgtagttcaaaccaggaaggatttgactatcattagattttgottaactttatgaaagotaaaatattetctgttataaaggggcaactccatetggtectatagcatett _ttactactgatttttttngtttaatttgaaaatgcaaagaattgttaaatgttcttaaatgttctcactacaaaaaaagaaaaaagataactacgtgaggtgatggatatg ttaattagctggattgtggtaatcattttggaatgtatatgtatatcaaaacatgtagtacaccctaaatatat 429 223395 agatacatttttacccaccataaatgttacaatatctgaatatgotttgtcaaactatccetttatgcaatcgtettcatattgtttttatgattctaatcaagotgtatgtagag at actgaatgtgaagtcaagtctgagcacaaaaagataatgcacgatgagattgcctaccattttataggatatttactatgtatttatacgttaagacctctatgaatga atgtatcagagaatgtctttgtaactgtttaattcaatctgtaataaaaatctaactaactaactcatttatttctattaaaaaggtattgtcctttaggcggggaatggga atccttgctgcactgttgcagtcattctgaaaggacctttccctgtacttacctttcaacatgcttcaatcttatcaacgctacat gaaaaccgatgtgatccttgatcgaaaaaaaaatccagaaccttgggaaactgtggaccctactgtacctcaaaagcttataacaatcaaccaacaatggaaa 430430223484 cccattgaagagttgcaaaatgtccaaagggtgaccaaatgacgagccctcgcctctttcttctgaagagtactctataaatctagtggaaacatttctgcacaaac tag attctggacaccagtgtgeggaaatgettgetacatttttagggtttgtetacatttttgggetetggataaggaattaaagg agtgcagcaataactgcactgt at ctaaaagtttgtgcttattttctgtaaatttgaatatgcatattgaaatttgtttatgatctatgaatgtttttcttaaaatttacaaagcttgtaaattagattttctttaataa aatgccatttgtgcaagatttct aattgtgttgtgatgctactcactttgattgcaatgatgatgtccaaggtaagctattaaaaggcaggttacttccaaatcgcactgaaggaaaaggttaagaataat 43 223551 acatgatcacagaaatgcataccactgtctgtaaacccaacaaaattcactgttctcttttggatttatttagcctgatgtatttaattcaatttttatggtgatgggcaaa 43t tcattcttggtaaatgtaaatcaaacatgattgatttaaaacttcatggaatttgtagaaaattatggacattttggtgagaaagaacaatagtcaaaactcacatgg at atagagtgtgtttgttttgccaaaaatgccccagaccttttcccaaacctcaaaaacgtcttggaaaaattgtaaaagtttgataacagaaacatctttaggatatttt tgtctgacgtattttgcttctagtatgtgcctactgtgatttttcatgtggaaaatgcaaaatttgtaacaaaatggttatatggaacatgcctattaaacgaa ggcatctggcacgtgcccaataagtcccccatgcagcactggagaaacagctccctgctgaggtaccgcacggacactggcttcctccagacactgggacata 42 223597 atctgtttggcatctaccagaaatatccagtgaaatatggagaaggaaagtgttggactgacaacggcccggtgatccctgtggtctatgatttggcgacgccca 432 gaaaacagcatcttattactcaccctatggccagcgggaattcactgcgggatttgttcagttcagggtatttaataacgagagagcagccaacgccttgtgtgctg _a gaatgagggtcaccggatgtaacactgagcaccactgcattggtggaggaggatactttccagaggccagtccccagcagtgtggagatttttctggttttgattgg agtggatatggaactcatgttggttacagcagcagccgtgagataactgaggcagctgtgcttctattcta gagaagcacctgttccaactaagactaaagtggccgttgatgagaataaagccaaagaattccttggcagcctgaagcgccagaagcggcagctgtgggac 433 223623 cggactcggcccgaggtgcagcagtggtaccagcagtttctctacatgggctttgacgaagcgaaatttgaagatgacatcacctattggcttaacagagatcga 433 aatggacatgaatactatggcgattactaccaacgtcactatgatgaagactctgcaattggtccccggagcccctacggctttaggcatggagccagcgtcaac at tacgatgactactaaccatgacttgccacacgctgtacaagaagcaaatagcgattctcttcatgtatctcctaatgccttacactacttggtttctgatttgctctatttc agcagatctttctacctact agctgccgggcaacgtgttgtgtaagtgaacatctgggaggtaaacactacacgtgaagagtggtgaaagggaacattgattactgaagtgccctggagaggg 434 223754 aaagcactggtcaacatcacatggacaaatttcattgttctaaagatggcctggaagtagtctttgccactgcttcctccacaaacagotcttcataacatgggctg 434 at catgaaatcaaagcaaactttcccatttcctaccatatatgaaggtgagaagcagcatgagagtgaagaaccctttatgccagaagagagatgtetacctaggat ggcttctccagtaatgtcaaagaggaagtgaaggaacctccagggaccaatattgtgatcttggaatatgcacaccgcctgtctcaggatatcttgtgtgatgcctt gcagcaatgggcatgcaataacatcaagtaccatgacattccatacattgagagtgaggggccttgaggctgtaggatgaca ggggctatactccatccaaatatgcagtggaaggtttcaatgacagcttaagacgggacatgaaagcttttggtgtgcacgtctcatgcattgaacgtctagacaa 435 223952 actgaaaggcaataaatcctatgtgaacatggacctetctccggtggtagagtgcatggaccacgctetaacaagtetettccctaagactcattatgccgetgga _x_at aaagatgccaaaattctggatacctctgtctcacatgccagcagctttgcaagactttattgttgaaacagaaagcagagctggctaatcccaaggcagtgtg actcagctaaccacaaatgtctcctccaggctatgaaattggccgatttcaagaacacatctccttttcaacc ggggctatactccatccaaatatgcagtggaaggtttcaatgacagcttaagacgggacctgaaagcttttggtgtgcacgtctcatgcattgaaccaggattgttc 436 224009 aaaacaaacttggcagatccagtaaaggtaattgaaaaaaaactcgccatttgggagcagctgtctccagacatcaaacaacaatatggagaaggttacattg 436 xatt aaaaaagtetagacaaactgaaaggcaataaatectatgtgaacatggacctctetecggtggtagagtgcatggaccacgetetaacaagtetettccctaaga ctcattatgccgctggaaaagatgccaaaattttctggatacctctgtctcacatgccagcagctttgcaagactttttattgttgaaacagaaagcagagctggcta atcccaaggcagtgtgactcagctaaccacaaatgtctcctccaggctatgaaattggccgatttcaagaacacatctcctttcaacc 224342 tatctgcggccccaggacagaaggtcgccatctcctgctctggaagcagctccaacattgggaataattatgtatcctggtaccaacaactcccaggaacagcc 437 t cccaaactcctcatttatgacaataataagcgaccctcagggattcctggccgattctctggctccaagtctggcacgtcagccaccctgggcatcaccggactcc x~at agactggggacgaggccgattattactgcggaacatgggatagcagcctgag ttttatttcaggcttccagctgtccctgtgagttatcctggacatttcgatggtttttggtaaggccaaactctgataagcaaaacagagaatactgacggtatacttaac 438 224352 catatgtgtaactgatacttggcaccatggaatttttcattgagttatttcctcattcttttaaaaaataagggactataaatcagttatttagtatcttttgtttttgtagctgatt 438t ccttaactttcttgtatgcctctagtaatttcagagattaaatattgctttaaactgtgatactttgatttgctagattgacaaaactgatactaatataattaagttcatctttg sat aaatacatctttgtgcgtagagccaaaaaaagagataaaattaataatagttcacttgttatttgagattaatttggcatttgaaatgatcatttatttacaatcatttata atgaatcaatgttccagttagctttaaaaggtatacggtgctaattagtaaaatattgaaggcaatatttactgctagcttgca taatcctgacattagctgacttgctagtgagcttgctttaaaaatctacactcttgcattcttaggcatacaggggaaatgttgaaaaggaaggtggaaaaccaaga 439 224412 atttagtttgccaatgattgcctetgattcttgtaagtttgagttocacaagggetaatttattcccettttacttgggttttggggtggtggaaagegggaaatttgggtgatt _s-at tgttgattggcaatgaggataaaatgttaatacttttttggggacttaacaactttatcctattctacaagtcagtaaaggaacaattggtactcacctcagtgctgcact caactatggaaagaggcagagtttgcttgcccaattgccaaactaaa attagtgtcattagtgtgttggaagagaaatactattcagtaagcttcgccaaagaaaagtgagtcaaagttaatgtgtgtgtgcatttatatgtaggcagctcgtaga 40 224480 ccacattttagccagcaactggtaacaaagagcttagttttccttgtttgaatgctgtagatctgtacctagtacccctcccatctactgatttgtttgtttttgtaaccaaac 440t acatttcagatagaaggagccttaaaaaaaaaaaaatcacattgagtaacttcagtatgaatgaatgagagtgtgtggagctacccctcaccetccacccetttg s~ttgctttttattcccgaatttcccagtctcttaaacagaaaaatgactgatataattatcttttggaaactgagccttaattttttttagagggggaaataagttttccccaact cacacagcataagcaatgtttgacagcaatataatgccgttgtaaactactgagagtattgtatctgttctggtaaccatgtaca ttgttttgacatcagctgtaatcattcctgtgctgtgtttfttattacccttggtaggtattagacttgcacnttttttaaaaaaaggtttctgcatcgtggaagcatttgaccca 441 224560 gagtggaacgcgtggcctatgcaggtggattccttcaggtctttcctttggttctttgagcatnctttgctttcattcgtctcccgtctttggttctccagttcaaattattgcaa _at agtaaaggatctttgagtaggtteggtetgaaaggtgtggcctttatatttgatccacacacgttggtctttaaccgtgctgagcagaaaacaaaacaggttaagaa | | gagccgggtggcagctgacagaggaagccgctcaaataccttcacaat ggtcagatggtcaacttttttcagtattatttatagttggcacttgattgcagttctgtgaggcttgagcattcatacacctcacctgccttggcaagcctattttagtgatat 442 224663 ggcagcacggatataacactatgcattaaaagcactttttgtaataagttaatatcctaaaaggaatgccaattaagttttgttaactgtgtcatcaacttatcctagta _s-at cctcagtgttcattcctgttacctgcatatcttcttaaaagaaatagctgttattaatgcctttttgttttccattgagtgtacactactgaataagtgtaggagttttatgtttac catgtgagtcctgcaacactaaagatattttgaatatcagtcatgatggcaatttctgtataaaagagccttaaatggaacattgttttgagatcaaactccccaccc gatatctggccatgggtaacctcattgtaactatcatcagaatgggcagagatgatcttgaagtgtcacatacactaaagtccaaacactatgtcagatgggggta 43 224694 aaatccattaaagaacaggaaaaaataattataagatgataagcaaatgtttcagcccaatgtcaacccagttaaaaaaaaaattaatgctgtgtaaaatggttg 443 aattagtttgcaaactatataaagacatatgcagtaaaaagtctgttaatgcacatcctgtgggaatggagtgttctaaccaattgccttttcttgttatctgagctctcct _a atattatcatactcagataaccaaattaaaagaattagaatatgattttaatacacttaacattaaactcttctaactttcttctttctgtgataattcagaagatagttatg gatcttcaatgcctctgagtcattgttataaaaaatcagttatcactataccatgctat gacctaatacatttcctctgtgtgtgtgtgtaacattccaaatacttttttcttttccactgtttgtaaggtgcaacaatttaatatttftaagggacttttaagagttccttaa 444 224823 gaaccaatttaaaattacttcagtgcaatcctacacagtatcaacattagaattttgatattagtcttatgttatcttccattctatttttatctgottttgctgctagtttcaaac 4 - at tgccagtatttttccttttgcttttaaaatagttacaatatttttcatgatagccacagtattgccacagtttattataataaagggttttatttgattagcgcattcaaagcttt ttctatcacttttgtgttcagaatataacctttgtgtgcgtgtatgttgtgtgtgtgcatgtgtggcgtatatgtgtgttacaggttaatgccttcttggaattgtgttaatgttctctt ggtttattatgccatcagaatggtaaatgagaacactacaactgtagtcagctcacaatttt gagtgagtcccagttacatcaaacagtgacttccagttattccccagtaagtctgagtggttccttcaagctgggtgtctttccagcctttgccagtctagccccagca 445 224836 gggcaccgtgtatgaatgcagtttggtgctgttttagagtatgcctgctccccagccccctgcctggaaccctctgagcaacttgctctgacctataatgtcttaggtgc 45 att aacacggaccccaccagagetettggatacccccctagatccatgtggetttatgtgaggggactgaatgcagacacaccatagccccettctactactttccetct cgccctgccacctagttccacatggaaccaacaagttgagtgcatccctgttgggtgttttgtgttgagactggctgaaatgaggagactttgaccatgtgacgtgtc aacagactcaaggagacaaccacctcaactgggtcatgtg ccccagtctcacctacgaaatatgaagagcaaaagctgatttgcttacttgctaaactgttgggaaagotctgtagagcatggttccagtgaggccaagattgaa 446 224840 atttgatactaaaaaggccacctagetttttgcagataacaaacaagaaagetaticcaagactcagatgatgccagetgteteccacgtgtgtattatggttcacca at gggggaactggcaaaagtgtgtgtggggaggggaagggtgtgtgagtggttctgagcaaataactacagggtgcccattaccactcaagaagacacttcacgt attcttgtatcaaattcaataatcttaaacaatttgtgtagaagtccacagacatcttcaaccacctttaggctgcatatggatgccaagtcag tcatgcgtcatccctaaaataataagatacatgggatcaaatagcccttgccttttcaacacaaatcagttggaaaattatggtttgagtcctgttgctgccatggcttc 447 224959 tgtttctcagaaatgagtgtgtatgaacataccaatctatgtaataggctaccttttgtcttctttggaactttgtacacaaaccaagacaatatcagggtgacaggt 47 - at gaatgaacttaaattctcagtcttgtctattcaccaaaaaagtatactgcctgttttttctttaattattcaaggttgatgacttttaggaacatgttttatactgtattttttaatta aagcaagtgccttgatgtaattccatgtaaatcattgcttaaccctcttatgggatgaggatgagttattaatgtattgcagcctactggaaaggagggggagttggtt aatagcagatacttttcttctagaagcttatgttttatgctgttattatgtaagatcctgtatgtgtgttgaga ataatgatccattcgagttctgtgatccttattgttcttaattgtgtttctctacgtattgttacagatgagccatacgtttctttgtatcaatgtagacatgacttcagatacctc 448 224963 tgaggacctacccagcagtctaggaccctgggccaagtgctgggactatggtactaaatccagtagatgggctgtgtagcaactctcccagggaacacactag _at ggtacttagggaggtgctttgtggagcatgttgaagctttgagatctgagcaggaggcagtgatgtccctggtctatcagggaaagatttcagtgtgaaatggtaa acatccaattgacaggattagatttgcttagttttctgctttttaatgtttctatcccccatctcagtgttttctttatccatcccagtgatgcct ataattttacatgatcctcaatatcaactccagtttaaaaagtgttatttttaaaacatttgaaaccaagtactgtttaatttcaatcagaagatgcaaatacatactttgat 449 224964 ctatgtttgattttgctaataatatttgaaggagattgcctaccaaggacaaaacaataaatttaaaaatcaaacgatttctccatacgctcatagtcacatatggaatt at 44 sat tgagaaaataaagcatgetgtetttaggaatttttatactictttgtetttcttccttaatatttgettctagetgotettggcaatgatgaattgttatgtatgcattaatgttttge agcccaaaagttgtcacattttcctatataagatctgtggagtgtgtgtttcaaagagagaactacagaaatgttaaagcaggaaaacctgaatgtgatgtgcac attttcatcccacatggaca catttctgtcacatgcacttagttgacattacatctacatatattagctttttcctacatgagccatctatttacttagtaaccagtgttcttaatgaagtatttagtcttgggttt 450 224989 cttgtaaaatttctctgcattccttagacagtgtactatacatgaaatattcttgttgacctagtaatttatattattccatttaattcttaaacctatggcctttttattgagcaca _at ctcttaaatcattattggcttgtaaacattcatctgaattgtggctacaatcctctttaaataatctaggaaaaaagaaagataaagcttacattttcacagttttggetct taaacacattccacaaatgccattaagaatttattttgttttaggccagtcatggt gagottctagaaatttcacttgcaagtttatttttgcttcctgtgttactgccattcctatttacagtatatttgagtgaatgattatatttttaaaaagttacatggggettttttgg 224990 ttgtcctaaacttacaaacattccactcattctgtttgtaactgtgattataatttttgtgataatttctggcctgattgaaggaaatttgagaggtctgcatttatatattttaaa 451 tagatttgataggtttttaaattgettttfttcataaggtatttataaagttatttggggttgtetgggattgtgtgaaagaaaattagaaccacgetgtatttacatttacottgg _a tagtttatttgtggatggcagttttctgtagtttnggggactgtggtagctcttggattgttttgcaaattacagctgaaatctgtgtcatggattaaactggcttatgtggcta gaataggaagagagaaaaaatgaaatggtgttactaattttatactcccatt ttgtgtgtaatttcatggtggcctagtgttgtggtgcttctggtaatggtaatagaagotcaactatttttttgtggatttcagtttttatcatcagaagtcctagacagtgacat 452 225207 ttcttaatggtgggagtccagctcatgcatttctgattatacaaaacagtttgcagtaggttatttgtcatttcagttttttactgaaatttgagctaaacatttttacatgtaaa 452 tacttgtatttaccaaagatttaaatcagttgattaattaattaactcaaatactgtgaactatctntaaaacactagaaaaaagaaatgttagtatetcaattacacca _a actgtgcaaatgaactttgataaaatagaaataatctacattggcctttgtgaaatctggggaagagctttaggattctagtagatggatactgaatactcaggccca cttaanttattaatgtatacattgtgtttttgtctttatgctatgtacag ggcgtgcaatttggtctgcgccacataaccattctgaagcttttaggcgttggagaggaagttgggggagtgttagaactgttcccaattaatgggagctctgttgtt 453 225242 gagcgagaagacgtaccagcccatttggtgaaagacattcgtaactattttcaagtgagcccggagtacttctccatgcttctagtcggaaaagacggaaatgtc 453 aaatctggtatcttcccacaaggctggtgatgtgtacgatttaattgatcgatgcaactggagacaggaaatggcgattcagcagtcactggggatg t _at cgctgcccagaagatgagtatgcaggctatggttaccatagttaccaccaaggataccaggatggttaccaggatgactaccgtcatcatgagagttatcaccat Iggatacccttactgagcagnnannnnnnaccttagactcagccagtttcctctgcagctgctaaaactacatgtggccagctcca aactgtgtacttgtctggtcagetgtgtatgatcagttatctacctcagagtctatttcttttgtgctgggacaggttgctggccctccctgtttccacagaccaaatcctcc 454 225269 tagctcaggagctagggctaagcagttatttctttcaagtattttttagttctaaattttatgcttgtatttgatgatagatgtcagtgacatttcatagtttcaaaagtccttgc 454 t tgotetgagaagtgtagattetagtgaaaattacatagtcataagagaaatgtgttttgttttgtttttgtttcatttttaaagttgtggtattattggttctatgetccetgga _at atattactgctttgtgaaagtccagactgaacgcagcaccctctgtgtacctagtacagttataaacctgggtctctcactacttgatatttttgcattagttaagacaga aatttgatagctcggttagaggggaggggaaatctgctgctagaaatgtctgaactaagtgccatactcgtctgggtaagatttgggaaacataacctctgtac gatgagagcaaaggggtcgcaccatatggaaatgttgaaaactattgtaaagtagtattatgaagtagcttttgtgtcattcatgtcgatgacatgaaagtgaagta aatttattctatgtaaattcacactaaaaccagtacagtaccataagtagaatacatgtaagaatcacctagtettcactatattgagtaaatataacatgctaattta 455 225275 caattaatgaaactaaactttaaacatetccattatatctacatecttttgaaggtatttatcatagttgccaatttaattttaggattgactttetettctgaatgacttcata _at aagttggtgtgaattttgaagacttgggttactaatgattgtatctttgctagtcaacaacttatgaaatatactcaatgcgtctgatgtgtcattaagtgcagaaataac taagacacaaataacctttgcaaaccttcaagctgtgtaatattccaatgttgttttttctttgtatatatacttatatcacgtaggatgtaaaaccagtatgaccttgtcta gtctccaaacttaa gccacacgtccaaaaccaatcaggtcaactcgggcggtgtgctgctgaggttgcaggtgggcgaggaggtgtggetggetgtcaatgactactacgacatggt 456 225353 gggcatccagggetetgacagogtettceggettctgetettccccgactagggegggcagatgegetegagncccacgggccttccacctccctcagettcc _s-at tgcatggacccaccttactggccagtctgcatccttgcctagaccattctccccaccagatggacttctcctccagggagcccaccctgacccacccccactgcac cccctccccatgggttctctccttcctntgaacttctttaggagtcactgcttgtgtggttcctgggacacttaaccaatgccttctggtactgcc gtatgtttgtaagtgcttctgcacgaatgtttatacatgactgtttccatagtacttatgtttttaaaaatattcagtcatttcctactataatcctcatgtatccatgtaactgac 45725381tcaaaaatacttcagccacagaaagctaaaactgagcaaatctcattcttcttttccatcccctttgcatgtggctggcatttagtaatgattaataatatggccagctg 45 a258 aataacagaggtttgagacacaatftttcaaaggagtcagctaagotgggtctacttatggacaaacatetaaatgtgtggaagtatetgatatttgacaatggt _a aaatttccacttagctagctagcattgtcagacttcaatctcctcatggctctggccgtcctgttttaagcatgataattgttggccacatctcacatagttctcattgagtg agttataataacagggttttttttaaagagcagccaagcacaaagtgtgactttgttgacattttatgtgactttgtcatatgttcctaacc agtgtcaggtgccttgcaggaaaataatctgagtcccaagctagcctgtgctcatccacaatcacaatgaacatgtcaaggaagaatttgcagagactcaaggg 458 225442 aagcacaatgggataaggtaatcactttcagtgaaaaactgttttcttgaaaacaggettggacacaattgaaagetggettcctgcaaacacaccaagagtetgt _at aatctagcctatccattatatgtcctttattattcatgatatcctattcttctaccttgttgcctggtaactttttctgaggactgagtttctgcagcgatgtggtgcactcttcctg tgatgaggaaacatctgggccccct ctggacacccggttaccaaagtcagcaaagaagatgcggtaatcgccgcctgatctccacatggtgaacacaacactcccaccaacacctccttgactggtcg 459 225458 gtettcagcaccgggggtgggcaggcaggtgttctgtgttgacgagaattgcacaggctaaacacaaacacggaaccagagtgagaacacctcactcacggc 459 agcccaggetgctccctaccaggtgacggagegegccggggetgtgggtgccaggggetgagtgctagggactogtcatgagtggggatccccacgttcctgt _a cactgctgtcaaacagaaggtaaacagtcttatgaatgtatttccttaggaaaacttgtaaaaactttattaggatatctatttaatactgaactttggcctactttgtgat agactataaacaaattgaggaaatcactattctcacttctgtattttctcaaaaataattttgttacagagttcaatatactgtgtaccattgatcttctattgtg gaaactgcggatcccaaactgttcccttttcatttcttgaaatgttaccactacagacatttttttaaggtgaataaacagttgtgatgtgctgtacntaaaatcatgttta 460 25575 alcgtataaggaaacatttcaatacacttatacaggaagaaaactatagatgaagtacatgtgtgtgattcagtctgattcacagaattctgagagtaatatggaat 46 a257 aaaacaactccacttagatgataaetgaagcatttcctgccttgtgaaaatttggatttaaattgetgttagaatgggaaatttggacactttatatcattgtataatttca _a gaatttagtttctgtatctttggaaaacatgattatagcaaaaacatagaaaataatctattactaaaacaccataaatgtaaaactagtatgcttggctgttaactcta aagatgttacttatgtctgttttta tgagggtgagcttactcagggcccccagaggaagccctcagcctctgccctccccccacacagggcgggagcccaggcctgttcctggcagctgtggctgca 461 225602 gctgtgctcctgctccctcctggaatgtgcgacaagcccaaatgttccngggnaggcggccggggcagggggettagaagtgctaatatggttctgtgttttgcctg 461 at aaacgataccaggttcccetgaatagcaactttacaaggtecatgtgggagggaccaacccagatgccctgetgagtgtcctgaaaccatggcagotecatet gtcaagatggcaggggccggagtgagggggctgctggctaacagcaggcatctgggcaggccagtcctcaaagcagctcctgaaggtctgtgttgcactgtc accagtctcaagctatgcctctaatttcaccagggatattg 462 225604 gtgtgatgcatgtgagegtetctggcacacacacttggacatacagttctgtgtgegctcattcttattacaggagtgagcaaaggaagcatttaccccgatggttac s at ctagaccacgaattggatggggggagg atccctgtattcatggcttgactttgtgactgctctacactgcatgtctgacattgcagagtgagctatgttgaggtaaactggttggttgtcattattttgcaatcagcctg 463 225626 gtetetccatgaagatgtcgtgtgcataagcacaatcatcactgattagaagatcacagcagaataccettggattagagagaagttcgtaccttgcatttetetga -at attctagtctctcataagcactgctttgctggatgattttcactgctttgtgttaatgactttgagcgatctctcacatgatggggttctttagtacatggtaacagccatgtc atcttacacacctagcattgtgaatgctgtagtgacatccttataggcaccttacagtcaaaacttttgtttcatttcatgccttacttatca agtgccatttattctagtttatcatgttttgcatgtttgaaagtatgaatgtgctctttcctaaaacatggcaaatgaatagatgtagagaataacaatattacttacaaga 464 46 2268 225688 tgaaatgatagatagaagtgtcccttattaaacttgtcagcctgactgggtacaattctttgttaattgcagtgtggttgtatacacgtatacgtgttatcaataata agattttgcaactggatgacacaagattttacttgaacagtgaaggacaaaaatcatgattgtggaagatattttaaaatctgattttgcagcgatcacttttaaaccc sa tgtagtgatgtaagactaaaatataattgtaagattttgttggttaatgtaaagatatgacttttctgcactgtactctcttcataggattgtaaaggtgttctaatccaatt gcatgatgtagtaagcctcttaaatatgtgtgtta tcctatgtcttctttcttaaatccagttgctgattttgtaaaatacagttgtgataaagcagcattacgggggggaaaaagctatattccaactggtgttaaatgtattcaa 465 225710 caaaatcttacatcatacagtattattcaattaatagaacttcagtgatatacttggtagatatctcaagccttgtcttttacacaatggtgctctatctattgttttcttt 4652271 teaaagaagcatctgaacacttgcatttctatttoctatccaaaggcatccacatetaagtgtgttttaaagttgattaaaattattttctgttaaagcattetgaaagtg _t tttgtctttacctagaatgatttgtacacactcgtggtcaactgaacatgaatgtcagtagtagtctaattatgggaagggtaaacgtgttagattaaggctcttaaagct ctaaaccatataaactatggacttgtatcatgatttaactgttcttagatctttcttacacagtgattcattcctctatttgtacagtggcttt 466 225720 tatcaaaggtttgccagccaataaagtgcatcccaagtatacaggggagaaagctagactcctacagggtectagagtttaagtaatttttttgttattaatataggta _at ataatttttctaatttttattttggttccaaatgtaaagctccttgtgttacctctgttatgtcattcttgacatgtttatctaaattatgtgtgctctgtgacaggtgaaatgtaa atctgggatccatagtcaagatatcataaggacctacttcccagcctacctttcttcctctacctgataatgataatactcaaaataacaacattcaaaggaaacac aaagaaatcctgctttcacatctcctatttcttgggctccttaataactactgatggtttgttcatgaaaaaaaatttttaaatcaaaagattgtacttggccctgagttgaa aaaatttcaaaaatcaaaagttgtactggccctgagtgaa cagaaacatgaccctcgctggtcttgggtccacatatcattggactctgggggacacaaagatgcctgtgacactttggtgttgccgagttagtcaacaattattctg 467467225721 ggaaaaagcagaattgaattcttctctagatgtcctaccagggttggccaagggccacaaagcaggctaataaattcccacaggatccagacaccaggcaaa attgetetaagaagccagttactgtcatccetctatggttagaaaaaatagtacaaaaatgacaggtcatectatgagegtcatgccaatgaaaccccatettg at gagaagcccttgaatcagaattatcttttttcttgatgtcgtcagatgcagccagtttcttaatttttaaaaactgtatgtttctgtggtatgtatatttgtacacctaactacc I_ tggcacttggaaatcacagcactact ttatcctgcgacaacactttcagcagantagcctctccttatctcacagatcacaagcacccctagatagtgtgattctgtcagatagcatttatgcaaaaatctatga

468468 225728 agttaaaagatcgtagaagccaaatgaaatgtacatatctactgactgatgacaagggaatttcattaggaagaaggtaaagaaacatcgttgagtagcctacct tgatttetgtcaagttcataaccagettcatattttaaaggettcaggtttgaaattaagtcaactgcatgcagetttgotgataaatgaataatttettgatgccatttat _a gagaaaagacttcaatatctgttgcctgtcatattaagaaaaattactgtttctactctctgtatctgattttaaaag aaaaaactattcatacctggcttccaggtaatt gactttga gaactgagtcaatatggcaaggtgtatgtgatctgtgggagttatgccatttaacataggaagtgcatgggactttccctctctgcactccagctcttactgtaccatta 469 225782 gaagatgcagaattetgttggtgtgcaaaaagtatagcctacattcaagcagaatggatetgaagaaagcagcaatatctgttactagagaacattcccatgtgtt _at taaactcttcacttcttagatgcatttaaattcttaatgcaaatgacgtagcaatttgaaaacttctccgtattacttgtgtttaaaatgtcttgctttaaatacaaaacaaat ggtaaaggggattatcttttgtttagatggttaaatattattttgccttagatagctttgtaataattttctccagacagtcaacactttga tactgactgactacaggggctgattgtgaagcacgaggaaccccatgtgtgtggagactgtagggtgagagcacacaattattagcatcatttctgagtgatctca cagattttttttcttgtgtttgttttgcttttgacaactgcttctcccacgttccttgcaattctattctctcaccttcactttactatttgtattcgatggaccaggataattcaggc 470 225894 aaggttacottgtaaacttnaattggccacacaccatgttgtcacccagotggetatgaagtgaataatggtactgaaagtaaacctgaagacctttetcagatctat _at tttaagtctgagtctgaccaaccatggaaaatattcgacatgaattaatgtagagaactataaagcatttatgacagctccaagaaaaatcatctactctatgcagg agatatgtttagagacctctcagaaaaacttgcctggtttgagggtacacagtaccattttaatcttctgaaaatatctgtattcctgctctttttctgctgtcactgtcaatc tgctatattttt ttcctgacgggaatgttgtgctataatgaatctgcataacgcttgggattctaggaggaaggaaggttccatggacatgtaagtacagcatattcccctcagtcttcta 471 225895 ggagggcagagtgaatcccagaactggtaagattgggaatctgagcattgccactttaatcttagaatatttatcattttgacacatcctgttttttagagaggaaaac 41 - at aaacacagtttctgcattggtagtgtaaagcataccttgttaggaacgtgttttgtaagacacatttgggttgtcattctagagcatgtcaaactttgtacttcaaaatata tttagtatgattgttagtggtaacatatatcaaggctttgaattaactgttttatttaatttcacaagaagcacttatttagccataggaaaaccaatctgagctacaaat agttctttaaaataagcccaggttattagctattctagaaagtgccgacttctttcaagaag ttaaatattcattccattacatctag actcaccaagaactacatgttatg atgttaagttg aagttgaaacatg atgttttgcattaaatttaag atatgcaaatttatg tag acaaa attg tttg 42 22600 1 ag a aa ata aatg ttatatacccta ta atctttcaccta attag tattta atta tatg g atttg ttttatattata aa ag atg ttttg attttg tcttttg atattg 472 gatatccttatgttctcaagtctgtatctgcctcccctgccttatttcttatgttttgccacagttaacccattgtgcttctttgtaatcaaacagtttgtgggagaatgggcttat at tgaatgtctaaaaaataagtttaaagtgtttgttaccctaagtttttacatttttaaactctaattacatatgtgaatgttattactctcagtgaattgttattgtttgcaaaaat gcactgggcagtaacattttgt gccggactggaaccgtctgagcggcctaacccgcgcccgggtagagacctgcgggggatgacagctgaaccgcctaaaggaggtgaaggctttcgtcacgc 473 226051 aggacattccattctatcacaacctggtgatgaaacacctccctggggccgaccctgagctcgtgctgctgggccgccgctacgaggaactagagcgcatccca 473 ctcagtgaaatgacccgcgaagagatcaatgcgctagtgcaggagotcggcttctancgcaaggcngcgcccgacgcgcaggtgccccccgagtacgtgtg at ggcgcccgcgaagcccccagaggaaacttcggaccacgctgacctgtaggtccgggggcgcggcggagctgggacctacctgcctgagtcctggagacag aatgaagcgctcagcatccc $47 aatggcttctatgatcagaactgggaaaacagtgnatcttatggtggaagaggtnctcagcaagtgtacagtatttaccttcctttgtcttacatnggctttttaaattttc cattaatttcaacataattatgggaacaagtgtacagaagaattttttttaagatatgtgagaacttttcatagatgaacttttaacaaatgttttcatttacaggaaatt 4.0 226084 gcaaagaaaattetcaagtgatagtettttttttaagtgtttcgtaagacaaaaattgaataatgttttttgaagttggcaagattgaagtetgatattgcagtaatgat _at atttattaaaaacccataactaccaggaataatgatacctcccaccccttgattcccataacataaaagtgctacttgagagtgggggagaatggcatggtaggct acttttcagggccttgacaagtacatcacccagtggtatectacatacttctttcaagatettcaaccatgaggtaaaagagccaagttcaaagaaccctagcaca aatttgctttgg ggaacctatcaatttgagtggactttttctttagtagtacaccatttnggttgtngtagtttcaaagtctttctgaagcagatatattgggattggagcggggtggggaaa 475 226103 actgtcactcctttcagaggaaaaggggaggagcatggagaaaaacaaaaattaaaggacttaaagaatggctatacagtgttgagtgttgaggatattaaac 475 atgttatttttcaaacgtatgtaatatatattaaatttataaagcaaatttatgttgtgatettgcctgaacaaattatattttaatgaaaaaactttctattaatagttcacgca at agagaaaacactttcaacatagtcgaaggcttcaagatctaagtgtatcagacttagggaaaaagtggcacaaccttcgatttaaaattctagtetttaaaatgagt I ttgtaaataattagctattacgttctattaagttgtt agggatctctctacaagagcccctgcccctctgttggaggcacagttttagaataaggaggaggagggagaagagaaaatgtaaaggagggagatctttccc 476 226147 aggccgcaccatttctgtcactcacatggacccaagataaaagaatggccaaaccctcacaacccctgatgtttgaagagttccaagttgaagggaaacaaag _s-at aagtgtttgatggtgccagagaggggctgctctccagaaagctaaaatttaatttcttttttoctctgagttctgtacttcaaccagcctacaagetggcacttgctaaca aatcag ggtaattatggaaactcctcaaagaggagaaagtaattttttccagacatttttctcattctgtgtctttcacacactagtttccatagttcgagaattctgttttttaccattg 477 226302 ggctgtgaatgttcacaatatcagtcctgtgaattcctatgaggtaatcacaatgtgtatatgttcattttctaggtatgataaaagaatgtatggctttttattctgtggaa |_at gtaaaatcctgaacgtttacaacttttcctaacttgtaaaa aattgtaagttttctttttttacagaaaacttagcttgtgtaattctgttagtttcagatttctctcctgt Itttgcaaattgtgggaaagattgacaatgcaaatgtgtcaaagacatactgttgggtgc acatgggtttatacaagttcctcttgagaaggcaaaaagaccaccatgtgtgagagotctttgacttggccaataggggcctatcttaatgcacttgtttggacacatt tctgatcttatttgtaaaggetgcaaaaggagaggatgaaatgctgtaaaagtaggaaatgaagtggaagctggaagaaaatgtaattggtggtacagctatgg 478 226303 gccagatggtggaggggagggtggggacccctgccggcaagcagagtgtcacagctggctttcctcacttgggaaaagggtactgccggtctagcagcctcct _at ctgtactcagccaggacacccagcgcgtgggacctgtttgtgtctgttttgcttccttgggaacggcacagtcactcaccctgccattgcggaaatgacctggtgca ctttgactgttaagcaatgcgttattgctgtagtcaaggttagtgcaagcaaggaaacattcccagtaaggtatttgtttccattttctgtctgtgcttctgtcagaaacttg ctaggac caaacgtcctggactgcacagacctcccactccagaccatccaggcctggttcccaagacccgatccttcccctgcaaccagacagtctacaactgccccctcc 479 226304 agcccattttctgccgtgaaaccccagccagccacaccagactctggaaccctttttcgactgccccaactcttggacaccaggccaactagaacacccaacac 49at - caaactgtacagactctcccaccccaacctccccagactctgcacggatgtectaggccccctccccaactctaaccagaccccatcccctaagtccettigtett gacccccaagtctcaaccagatatcctcggcaacccacctcccaccctcctcctcttctccttcaagacccaactgagcacccgctctgattccccacagcctttct ccctgccaccactcccttagtctttcccaggcttactctcccaataaatgtgctag ggtggagttggtggtcttaatttggagatgcaggggcaacctgtgaccctttgaggcaagagccctgcacccagetgtcccgtgcagccgtgggcaggggetgc 480480226333 acacggaggggcaggcgggccagttcagggtccgtgccaggccctcctcagtgccctgtgaaggcctcctgtcctccgtgcggctgggcaccagcaccaggg agtttctatggcaacettagtgattattaaggaacactgtcagtttatgaacatatgetcaaatgaaattctactttaggaggaaaggattggaacagcatgtcacaa at ggctgttaattaacagagagaccttattggatggagatcacatctgttaaatagaatacctcaactctacgttgttttcttggagataaataatagtttcaagtttttgtttgt ttgttttacctaattacctgaaagcaaataccaaaggctgatgtctgtatatggggcaaagggt atttttccatcttattcaagtcagagcacttttttaaatagcaatacaacaggcaagagaatactcaaaaatatttaaaactgtattgataccaagagtatgttttaaat

481 226430 attttctaataaatacttgagcggttttgtctggcaggcttccaaatttgccaaaattaagcgttcagtattttcaacacatacgctttttactggtttatactgaactatctg 41 att atgagaattcctgtgttcccaaagcaactgatgtttacaggtcttgtgtttctcctcctcctttctaaggatgagggaatccacaacagactttctctagaaaacactaat gatggacaactttttggtgtcatcaatgagttggctactaccttgatgtaaaaatttgtaaggaaaattcaccatttcgagtgtcaagtgtatttttaactgtctggtttgta cttttatgacttttgtactaccaaagcgga agtgatctctggaagcgctaaagctaaaatttctgttcttgaaacacttcagctttgcaactaaaatattacagattaataataaattaaaccaaccaatgataaaca 482 226492 ctactcagtccaccaacaacaaacgtgtttgaattcaccttaccaatattaatcccagcgtgtgtaaaacagaacagtaactctatgtgaccccagataacattttgt _at aacattgtgcttccttgtagtttgtaatgtgagttcaatcagtatttatgttgaaatttctaacattaaatctagtctctatcctgttaatttaatttttaaatgctttatccatttgtg. caaaggtaaacgcagattgtatcttttttaatggtacggcataaaaagtaaccctcaagtgaagtgtctcta tgacgagacctcttcaaaaacccacagtaaaactcccctccctccagttggccaccagtctgccaccaaacatgaacaaattctgctgctaatcggtttcccttgtg 483 226594 atctggttcctgaggtcttcggatctgtgcaatgaattatttattgttttattaaaccgacagtggtgtcccagagaggaaccataaataaaatggaaatctggtgctgt 43 att gataaagtaataactagcattaatgagacctggtttcctttcagaaagtccagtatacctgtaacaaaggttaaagcaatttatatttaatttgcattctgatgttaacat ttaaacagcaattctaacaaaaatgcatcgagtctaattcttacctctatcaaaaaacaactgtataaatttatgaccaacattaaaacaaaaacaaaatgtaaatt ttctctttagaaatgattaactggaaatgagtgagacagcaccttgtgggttt tgctcgcattgatcatcctaatcatcttattcagcctatcccagagaaaacggcacagggaacagtatgatgtgcctcaagagtggcgaaaggaaggcacncct 484 226654 ggcatcttccagaagacggccatcngnnnagaccagaatctgagggagagcagattcggccttgagaacgcctacaacaacttccggcccaccctggagac 44 - at tgttgactctggcacagagctccacatccagaggccggagatggtagcatccactgtgtgagccaacgggggcctcccaccctcatetagotctgttcaggaga gctgcaaacacagagcccaccacaagcctccggggcgggtcaagaggagaccgaagtcaggccctgaagccggtcctgtctgagctgacagacttggcc agtcccctgcctgtgctcctgctggggaaggctgggggctgtaagcctctc gctgattctaattgtgtgtaggtcttgaggattaagcacacaaatttcacaaacttctgtttgagtaaacaaactcagccttctgtaaatatacatgcaagtttggaaac 45 226682 agtaatactgtacctataaatatatgctgtctgntttgtgtacagtatgtaaaaactccttttctgccacactaaaaatgcaagccatttatgggaatcctaaaactagta 45 - at ttgaactaaaactttgetaatgatctttattagaggatogtccaacttttcacttaccttgggttttcttttcaattcactcttacactagtetgettatttccagetgtttattttatt gagtcctgaatttaaaaaaaaaatattttgattcattttgtaaatacaagctgtacaaaaaagagagatttaatgttgtcttttaaatactccaattttcattctaatatgaa tgtgttatattgtacttagaaactgtacctttaatattacattacctttattaaaagtgcattgaacacatcaattttagatgtgctttatgtactgttatccta 486 226694 taagcattcagtgagetgccaattttgattttgtgttgetetttacccaaattattttctttgtttttctttttttgggggaggaggggaaaaaagcagcaatactgtgtttgga at aattatactctgtatctggttttcctgtgtatgttaaccacttaaatgttattatcctgctttggttttagagtgattgtgaggcattcaatgca agtgcctaaatcttgtttacctatcactttaaaaaaataattgaagtgtaagctaaataaaatgcttggagtttngcctgggetagtgagagttggtgcaaattcttgtgt 487 226811 gtgtttgcataggaaggtgagatgaccatctactaaagaggaagtagctaaatacagatctgtgggtgtttttaaaaaaactcaacctatctggtgttttattttaatgg _at ataaaaatgtaatttttctaaggtagcaacttatttccaaattaatatagatgaaaaatagataccaattagactaaattgaaagctttttgttctatatttgcatagccttt gaaatatttcttagtgcctaggaggtctggggattcctctttcgtggtggtcactaacctacttgatgcaga aacaccaattatgcaaactacttttttttccagcagaaagggagctgacatgatcaaatccatgttttcaaatgaactgaaaaaggcatccagcaccacttatanc acatttatttcagttccaggctgacagccntggggnatctagcaggatnnataattgtcatctggtgagagttgggactttgctcaattttaataccaatctctcctgatt 488 226818 gtaattacctccactactttcatgatccccctacaatatttttttaaatgatatatttattcactgaatcaaatgtcattaatgagttatcttctgtggaggatgactgttctcttt _at gttaatgttcacaatcaagatcttgggctgagaagaggcccttcacccaaggagtttgaagtatcacagcgtgtgggaaggtgggaaccaggatacccattcattt ccaaccgagacacagagaagtgagtcacagaatttgagccngctctcttgactgcccagccagagacactgatttctgtaacctcttcacttgatcctgcctcttaa gcatta tcatttctagagtacctgagccaaacaaatacacaacggaagctgcagctgtatcatcactagcaatttgctcatcattatttactacctttgaacctaaggtttcctgc 489 226834 ctatgettttgaaagcaaaaatcagtetectttgcatgaaaaagagccttagatttttaaacatgttagttaccagaatgctaaaataccagttgattacccaaattattt _ at tggaaatctatccataatggaagtctcacaaacacataaacagattacactaagagctgagaaatcaaaggaactgaagattctgagagataaactgttc aagtcttagcaatgatactgcacttctctttgacaggttctgggcttaagttagaggccctactggttccaaaccatattccactgactttgcaag cctctgagtgttttgtgggttctgggtgttttgtacattttagccaagctaaccacttgtctgcaagtactgactttcctatgaattctttgaagattattgagtcagaaagga

490 226841 aaaatatagccccaaattcccaggctttaatgcattacattaactgcctattgaaatgagaagttcttcacaaacttgtatacccactaacaagattgcacataaac 40 - at atgcattaaagtatatactaagaaaccctctgtecaacggetcatgcatatgaagtccgaacatgggagtttgccaattgcattcatcaagtcgttttgeggagtcag atccctgatggaagagtcacaggctctgcctccaagtcctgggtcctaactggtgaccttagcctggggtctgtggggagaccaaccctggcttccaagaaaa ccacattccatggactatcagaaatagacacagatttgggtgacaaagctggctctgtattgcatttt gcaagcgcgtgctgagcaagctgcagtctccatcgcgggcccgcgggncagggggcagtcccggggggctgcagaagcggcacncnngcgtcaccgtca 491 227006 agtatgaccggcggganctgcagcggcggctggacgtggagaagtggatcgacgggcgcctggaggagctgtaccgcggcatggaggcagacatgcccg 41 att atgagatcaacattgatgaattgttggagttagagagtgaagaggagagaagccggaaaatccagggactcctgaagtcatgtgggaaacctgtcgaggactt catccaggagctgctggcaaagcttcaaggcctccacaggcagcccngcctccgccagccaagcccctcccacgacggcagcctcagccccctccaggac cgggcccggactgctcacccctgaccctcttgcactctccctgccccccggacgccgcccagctgcttgtgtataagtgtatttaatggtctg cactgttccatggtcagcaagtcatatttcataatgtggattttccaaaataattattgaatacagctattctatggctacttttagtgttttgtggtatgtggtgtgggagtgt 492492227052 tatggaataccagtatcttaaattcaaaggaaccttggaagtctatcactctaaatgaaagtctgtcactctacatgaattatgtgctcaaatttgaccaactcagtt taagacacaaaacagtaatttgaagaaggaaaaatgaagagagtttctagtttaatgggttaaatttgttgttgcaatagtaagtttagtettcttataatatttctaaa at tgaaaaatcataggtatttgttaccatgtgtgaagatantttgtaaaagcaaaagtggtcgtgtgatatgctaaatgttaattactgattttatatgtttaaatcacgcca aacaaattatgtctgtgccatccagggtctgttgttaatctttttctgagtacttggattgggataaagggctgtactatgcactt acacttatagtctactgcccatgtaaggatcagctccggctaagaggccaaagatgggtgacatcgttatgctctgccntttattttttctttcttacccacttagcttcct aattggaggaaggaggcgtggtaaaggtatatgaagactatggtttaattagaccagaaaacactgtcataatctctggggtcatcagaatgtccagttttgtctttg 493 227061 ggccaagataagggcagtgggatttatgatgtgtgtttatagtetgaaactactctggtgatcanccagggtcagtttctttaatgatggtttccaactggcctaatac -at attaagtaagactggetgataacatgaccagacagacataaagaccctgttgggaatgacattgaactctcaaagtcaagatttcttacacaaatctatcagctgg agaaaatgaaggcagtgtggtatatgtgtgcaaataaggacattatgaagcttaaatatggaatgtctcttggacccccgatgtcatctgtattctctttttcttcttgtac tatatcctttgcctgtaaata 494 227099 tcccagtgcgaactctgctgtgagtgtgtgcggggaggcgcgcccgcgctgagtcggcggcgggtagccactccatgcccttgtccgatggtttgcaactccgatt 49 at tgcacaccgetccaccgtgccccccagegcacacccattcacactcacgccaacactctogetgaacacttttataattgttaggcgtggcegttgggactttggg _ ~t cgcagcgcggetgctactgcgtctggaggattgatatttatttttgcattgcgatggctgaaggcatttatttaacgatctttacctggatatgtctgtgaggetcctgaa gtgaagtaccatagaccatattgtctagatgggacaaaataataaattttgactaagaacttactgtttagagagaaaaaatagtaaataatgttcaaaatgagaa 495 227235 gacaataactgacaagtctgtgatttttgggttagatgagaccacttgatttgaggaataaaaggagttagttttttggtcctgatgtgtaaaatgattcatggggttt 495 cacatacagacaagtagttttcttttcagcaaatatttaacatatetetcaatatatttttcaccagtttttggtaaatatgcattgotataggiataccaagttttttttgttatgt at ttagtaactaatttcatttttctgtatatgtaaatatagctattggaccctgcattgaaaaccttcttagtactaacaacactccttttattatacctcatagttactttaaatg acatatttatttcgagttttacttctggctgagttgcaaagtctatgagaatgttacctcctgtctcagaagctgttagttattgtgccacc acatctgctagaaccttttgccttaactattcaccaatatatgctaatattcataaatatggattgactgtttacaaacattagaatcttgtcttggttccattttgatggctaa 496496227265 tatttgttatcttaattaagactatttctgaggtcatgatacttgaaaatattgactaaaactgggtccttagaaattccaggtggagctgatttacctatgactgagggg aaaaaaaaatcaaatttactgataatagtaatgetccaaatgaattaatgacacatctgttcaataaataaagagettaaatatacaaaacataagaaatetggg at caacaaaacttgtggtctttactttgaatagctacccaagaaaaggttttaaaggtaaaagttatgagtaatgtcatcacaataagctcttgtttaaaattcttttcttttat gtataattaggtttatgtttcatgtcttt atcccatgggcaataaagcgcattcaatgtgtttataagccaaacagtcactttgtttaagcaaacacaagtacaaagtaaaatagaaccacaaaataatgaact 497 227404 gcatgttcataacatacaaaaatogcegcctactcagtaggtaactacaacattccaactectgaatatatttataaatttacattticagttaaaaaaatagacttttg _s-at agagttcagattttgttttagattttgttttcttacattctggagaaccgaagctcagctcagccctcttccttattttgctcccaaagcctcccccaaatcatcactccctgc cccccttaaggctagaggtgagcatgtccctcacaattgcacatgtcaagccatcagcaaggcgcatcacacaaaaggcaccaag 498 227522 cagtgagtcgaggttgcgctactgcactccagcctggacaacagagggagactctgtctcnaaaaaaaaaaaaacctacagctgttcaaggaccagctgaca 498 ggtcaagtgtggccttttetggtetttgaacacatcatagaaagtgacaaatgetgcaaagccatgaagaacatgaactataaacgggtagactaactgcccagc _a ttagacacttatctatgccacaaaacagctgaatttgtcacatttatatattgcaatatgggaagtattgagatcaaaacaggattccattgacctaattat 499 227529 gccatcacagttgcgattccatgagtagctgctttatgactgctttttgtactatctggatgtgcccagagttacttctgtacaagctctgtatctatgtccgttgagaacatt 49 s at attttaacaagaagaacaccaacagtagcatgaaatataatactgttttataattctaaagetgotgttaatttatgaagtacataataatctaatgtaaactgcagaa - - gtcagagcaa gcaaccattggggaatgacctttcatttcagaagtggatgaggaaggtggtgtgagcatcaggtatattnctggaccatttcaagtgctggtgagaagaaagga 500 227561 actctttgcctgaactgggetggttttccaagtgetgetttggaaatgaagacccagagatgcagagettatggtagttcataaatettcatgttctattatetttcatctg _at ccaataaagttcattttcaataatgtccaccattgctgtgcccagaataaccacaggcaaacatcaaaacaatacgcataagttagacaagattaaatcttgtctg atatctgcacaaacagatatgcaccatgttggaaacatgtgttttcctagtcccatccaggcttcccacaagaaagccatgatgtgggtctaaacc attgtttcccatagcagaatgtcaatattcacagtacatttctgtaaagagcaaaccaatataatgttttgagtgttgaaaaaaattccagatttntgaagaattagaca 501 227623 actcttcatctaccttatttctagttcacacagttatctcaaatccactgaaactaatgggatactgtettgtgtagatgccagttgagtttataatgtgacctagtaaagc _at tgtcttttttgttgtgttgtatgagtgtcggatcatgcttttaggaatacttttattaaaatggtgtgcattcatgcaaaaggccaactggcttttgtgaacaatagatcttttctc ccctttattttgttctcttgacacttttgtgaaaattacctagcctgata aaagccttccctaaaaagagagcatgccagtcatagagacactaatttggcacttttcctccttcttaggtttaaatgttataccaatgcatgtgtttgaaatatccatta 502 27662 agatgatttaaaatttgtcttgtattttgagtttcttaaatgcgtggattcttgttcatttatctctgaatatgtctcttttatattttggcacaattatacacattggaaagggcca 50 a276 acctattagggetcaagtatgtatatgenaaaaaaaaaagttatatcaaacaggcacagttattacaactagagagaaattccagaaatatttgtttttttaagaga _a- aagtaaattttcacattagatttctattcaaagtactaatatctacatggtccacacttttctattttaaaaaattgtgttctcttgttaaatagattaacatttccacttctgttta tcacaa atctttccatattgaggacagcctctgcatataaaaatgttcattgggagaaaaattattttaaaactaaatttatagtagtcctccattactggcaattaaggagca

503 227682 acccacaaaatgtcattatgtggttctttgattaggcataaaaagtattgcaaacagcttttctattcctttggaatatgaatctttttaatgtctaaagttaacctgcaaca 53at - ttttctagtaggacaagtcaatgtaaattaggtaatttttgcctgtttataccttctgtngcatttgttcaaatgaaaacattttaaaacatgattgaatttttacttetcaga taattggtttgagtgtggaatttcttttttaacactttgatatgtaagttagtgtaaattaatacttttataacactactaggctttatatttttatggaatgtttaaaatttgaaatt tttgaantgttaatttagcagtactttatcattatgtgccaatactgacaag tttactccagtcattcgatgttgotgagatttacatatgactcttgtcaacatctcatcttttgacccaatcttattcatttaataagaggtctcattcatttgcatggaaaaat 504 227705 gctcattgtatattgcaaagtgaaaataacgagttgcaaaacagtgtatacatatatgtgtgtatatatgtacactttatttgtacatttctatgtgacataatgcaaagg _at aaagtgtctgattttattatacaccaaaggttaacagtgaatctctgtgtgatctctttttttftctttttgcctatctgcatcttctcacttgccaaaaaatgaatatatgtttatgt ggaatcttgtcacaaaaaaccctaaagtagacagtaaaagaacttgtcaatcgcctttggaaggcaatgaaacacttaataaactctcaataa agccaagaactgaccggggccagggnctgccatggtctccttgcctgctccaaggcacaggatacagtgggaatcttgagactctttggccatttcccatggctc 505 227725 agactaagctccaagcccttcangagttccaagggaacacttgaaccatggacaagactctctcaagatggcaaatggctaattgaggttctgaagttcttcagt 55 - at acattgetgtaggtectgaggccagggatttttaattaaatggggtgatgggtggccaataccacaattcctgetgaaaaacactcttccagtecaaaagettcttga tacagaaaaaagagcctggatttacagaaacatatagatctggttgaattccagatcgagtttacagttgtgaaatcttgaaggtattacttaacttcactacagatt gtctagaagacctttctaggagttatctgattctagaagggtctatacttgtccttgtcttaagctattgacaactctacgtgtt gggctgttccagagattcgatcctcttaaggcattatcagtgagcaaatgtgaaggaaatggtgtctggaagaaagttctggttcacatgccttgtagctaagtctttc 506 227727 tgcaaacaacctcccttccccccgtcgagtcatttggtgactttgatggggggatttctggttatgtcaaggctctggagacaggaanggcctttggccgccttgggt 56 - at agttgacctgccttttetgactccgggacgagccagtectaggetgcctcngggagcacttgaggtatcccgcaggccatgaggacccactgggcagotectgg acagcctcttggtccagcccccacccgaaagtggnacactgnntccgccctggccacctggggactggcactgtggtgcacagtggcccaatgtggccaac ggaagtttt 227735 cacaggtgtagcactcccaaagcaagactccaganngnnnnnnacctcatgcctggcacctgaggtacccagcagcctcctgtctcccctttcagccttcaca 57 s at gcagtgagetgcaatgttggagggettcatctcgggetgcaaggaccctgggaaagttccagaactccacgtccttgtctcaattgtgccatcaactttcagagcta - -at tcatgagccaacctc 508 227736 caccatgaccggtcacagctacaaatccagagaccatcaatcctgctagagtgcagggnggcaagcacccaagggtggctgaccaagactgcagagtctcc at tocatettcaggtecattcagcctcctggcatttaactaccagcatccagtggtcccaaggaatccettoctagcetectgacatgagtetgetggaaagagcatcc - aaacaaacaagtaat 509 227826 ggtagattccgttgactgettggtatctcatgtaagcatttcccagggacactacacagtetttataattatgatcactacatettttggataaettaggettttgcacta s at ttttgtcacgatgcctcaaacttttctatcattgtctgtaattactcctataatcttttatt aatatctcaagatttctaggcattttcctatgtctaatagtaggatgttctctctgaatttatttattacaaaaataacattacaacaataaagcaaaataatatttaaaag taatacctttgta act 50 227827 aaagaaaaaacaaacagtcgcaataccag aacaccattgtagtcgtttgtgtatgtgtg acttctttactgtgttcatgcag agacaagctttg 50 - at actgtacaggtgcgtggttagattccgttttgactgettggtatetcattgtaagcatttcccagggacactacacagtetttataattatgatcactacatettttggataa cttaggcttttgcactattttgtcacgatgcctcaaactttctatcattgtctgtaattactcctataatcttttattataaaatattgaaacaaagtcacatcactaaaaaca ctgtgagtataatttattagtaagtgtagactgtgtatcattagcaaa ggagctgcttcaagaagaaacccggcagaagctcaacgtgtctacgaagctgcgccagctggaggaggagcggaacagcctgcaagaccagctggacga 511 228133 ggagatggaggccaagcagaacctggagcgccacatctccactctcaacatccaggtgcctgccccgtgtccttgcttccttcatgggtcctctcaacttctctgcg 51 sat ctgagatcccccgcaggcagategcggtggagtgttggtgcgatggtgettgaccccccagettcccctgetattgggtttctccaacgaggagacatggtettege -a tctcagagtetgtggggccagggacaggggccantcatggtccccctctcaccctaccctggacgctgtccttgtagctctccgactcgaagaagaagctgcag gactttgccagcaccgtggaagctctggaagaggg tgttacctttcagttacatgcctttgatcctaaaattctctacttttgntgccttatcagttctttgcaatctgcctgtggttatcagcacttaaagcacaattttgaaggggaa 228195 aaaaatgataatcaccttagtcccaaagaaataatttntgtcaaactgccttattagtattnaaaacagacacactgaatgaagtagcatgatacgcatatatccta 52 - at etcagtatcattggccttttatcaaatggggaaactatacttttgtattacatagttttagaaatcgaaagttagagactetttataagtaatgtcaaggaacagtaattta aaaacaaagttctaacaaatatattgtttgcttaatcacaatgccctcaacttgtatttgaataactaaataggacatgtcttccttggagctgtgggcattagttcaga agc gtttacacctatactgcataatccaacaattttaatttcagttgaagacatgttactaatataactattattaaaagagtagaggatgtgtaattaaccatatcttctaaaa 513 228202 catggttactaaaagaatatgtaacatcaatattgaccttggttcttacacaagtgttgctaactcaatagtgaaggagacactattaaattctgaacccatgaga 53 - at gatactagagatggggagtggaaagtgtttggttcagggatatetgaagaacagaagggcagagatttettaagtgacgcetcatetacaagetggaaattccta aaaacaagtagaaagcttataaacaacaggtgatacactcacctcactggttttagtaaattaccaatacagaaagtatccctagtcttaaaaacaagtggaaa atttgaactgattagtcatattcctttgattacactgtt 14 228232 cagtcagagtggacaaacctctgtgggaggctctactgcactgagatgcagctcttccgagggggctcctaagccagtgtacaactgggtgcgtcttggaactttt 514 satcctacaccttetectggcagcatggttenagatgaggtgtetggccagctcattetcaccaacctctccetgacctcctogggcacctaccgctgtgtggccaccaa -- ccagatgggcagtgcatcctgtg gcctcctcagacactctcaagaggatggggagatgacatcacttgggtacaaacttatgaagaaggtctcttttatgetcaaaaaagtaagaagccattaatggtt 515 228241 attcatcacctggaggattgtcaatactctcaagcactaaagaaagtatttgcccaaaatgaagaaatacaagaaatggctcagaataagttcatcatgctaaac 515 cttatgcatgaaaccactgataagaatttatcacctgatgggcaatatgtgcctagaatcatgtttgtagacccttctttaacagttagagetgacatagetggaagat atactctaacagattgtacacatatgagcctogggatttacccctattgatagaaaacatgaagaaagcattaagacttattcagtcagagctataagagatgataga I_ I aaaaagccttcacttcaaagaagtcaaatttcatgaagaaaacctctggcacattgacaaat 516 228469 aaggttatagccacattcaacttgaatggtcccnaatgttaaatttaccatgaatactgtgtettacaatgotgagotctcgactagactaaccagaataggaacac at agtctcaaaggataccataagacaaacagtatttagacatataaaaaactacagagatgataacttgaagaataaataacgtgaaaaactactatattcttgaat gggagtagaatgtaagctctttgagggcagggactttgactgtettgttcattgctatatgataatgcctggcccaacagcaggcattctgtagtgtctgttgaacaaa catctaaaatctggcaaagtgaacaatggttcctgaggataagtatttaaataacaaaattaactttcactacaaaagctgccaacttacctttatettctggtgctatc ccctgagctttcttaagatca gaatgcatgatctcaagccttaactactataatcttttctgcccctcagaaattgaataacctaaccaagatgcctttaggggatgccctaagtaaatgtaatttcag 517 228504 atttcagggnttttttttcctctctaagtgttccttccetttttctgotetccatcatgttatggagaccagtgaggaaccagtgttaacttggtgacaatgtgacag _at ctggtgctttatctaagctccgttttctatttcttgggaatgctttattgtggaaactgcttcagatacttaaattgaatcataacttgcttctgtaaattgcgtaaagacaaca aactgattttagtttgaaaagtttatcttttacttgtaaaccttgtttgccagttacct agccccaggtgtatttctgagtgtcaacagtgttaatttcaagcatgctaataaaatgtnnnnncggnnnatannnnnnnnnnaannanncnttnaaantnnn 518 228507 ggtttccnntgntaaaancanconcntttgcttttgttagctgtaatattgtcatttagataagacctggtttggctctcaataaaagatgaagacagtagctctgta 518 at cagggatatatctatattagtettcatctgatgaatgaagaaatttetcatattatgttcaagaaagtatttacttcctaaaaatagaattcccgattctgtctattttggttg aataccagaacaaatctttccgtgcaatcccagtaaaacgaaagaaaaggaatatcttacagactgttcatattagatgtatgtagactgttaatttgcantttcccc atatttcctgcctatcttacccagataactttctttgaaggtaaaagctgtgcaaaaggcatgagactcaggcctactcttgtttaaat 59 228640 aatcttgtgagttgtgacctaggtgaaggtntaatgataacatctggaggaagcatcatttgttcagctacctagggtttactttcagacttttcctacagtttaaagcac 519 _at ttgegttcagtgtggtacgatetgtttgtaatgttaatcattgactattgttgetacttggatgttgatagtgaagcagagaacaatttatcategtttattatgagtcactat gcacgcaactatgcttaacatggcgaaatgtattaaacactcgtccaactatt aaagggtggcatttgcgtcacgtggaccagggacagtgctgaaatcagcagtgctcagaaacaatttaacatgttgaaacgacaatattctaaaatactgatga 520 228706 atettgcatcaatataattattgggtttttttctttttcctgotgtataactccttgccatgcaaactctcaagaggccaatatattcctggccatgtttgaatgagcctettaa -s at aataaacttagagccatgcaaatgccagcagcttaatggatttcatggaatgaaataccgtgattaactcatagctacatatcattgcataaatgggatttatcttttt ctcacttatttttgcggtgaaa 521 228707 agagccatgcaaatgccagcagcttaatggatttcatggaatgaaataccgtgattaactcatagctacatatcattgcataaatgggattatcttttttctcacitatttt 51 at tgeggtgaaagtcgagggcatgcaagagtttetetcagaagccaagaggagaacaaaggtectaatgetgtactatcaccetttggacgcctcatccagga - cgcagaggactctaggtttaacatttt gacccagagtcacctaagagaactcttccaacttaaatgactagggtgtgtaatcagttgcttcttattctgtgtctcagatttcctagtccatgacatttaatagtgagt 522 228750 atagagtaggatattctatacattttagtatttggcccttggaaacaaagttaaataccatgtcactcagaagactctcaaagtttgtgtataaatggcgaagtatgca 522 at ctatgagagattctaatccattcacatcattcttgagttgtgcaaatacacttggetttgatttcacttggtgatctaaatttgtttatttaagotgcaagaaagttacattaat tggaatgtgtcatcactggacccagtatatcagattttattgagtaaaatgttaaaaataataagtgtaactcagattctggatgttcgagtttacaatacattgcctgt aataaaagctgattctgaagtgcatttttcttgacttactttggcag atgcacgtacaaatttcttaacctgttatcaatgtctgagctacataattatctttctagttggagtttgttttaggtgtgtaccaactgacatttcagtttttctgtttgaagtcc 523 228766 aatgtattagtgactctgtggetgctctcttcacctgccccttgtggcctgtetacaattctaaatggattttgaactcaatgtcgtcgettctggtttoctgcatataccaat _at agcattacctatgactttttttttcctgagctatttcactgagctgagctaatgaactaaaactgagttatgtttaatatttgtatcaaatacataaaaggaatactgcttttt ccttttgtggctcaaaggtagctgcatt ggaatcttttccaataaccagctaaagatttgcactgaaatacaacttgtatgccttttgcatttttaaagcctgcttcctggatttaagcagagtgatagtgttcaaaga 524 228846 gccagttcagcctgtaacatatttgaaaaagatatgtctgcactttgaggtcccttgaatgccattcactagacctctcaagcattttgtttcattgctacatccaagcg 524 _at cctcacaagtecacaatgcgggacagcatcaaaagetcaagactttgnaaaaagettgtgggettgcactgggggagggaagggaacaaaatttgtgtacttet ttgtttaatagaaataaggcatccaagagatgccattattttctgtgtttcaattgttgtgcctttgagttaaactgcatttttgtcttttggttgaaatctgaaatgtactgtcc caatat ctccttatctgttctagttccgaagcagtttcactcgaagttgtgcagtcctggttgcagctttccgcatctgccitcgtttcgtgtagattgacgcgtttctttgtaatttcagt 525 228854 gtttctgacaagatttaaaaaaaaaaaaaaggaaaaaaaaagaaaaaatgaatttactgetgcaggtttttttctctctccatgtgtcactaagtgaagtttgtgcett _at ctatagcaaagagaatatttttacatcctactaacagtagattttttgtagtgaacattttttgtatttttatttataagtctcataagaaaaatagcaatgttcagttgtata ccttgaatctgcagttaga aataggtcttgcaggtttccttttgaatttaagtatcataaatatttfttaagtaaataatacggggtgtcagtaatatctgcagaatgaatgcagtctttcatgctaatga 526 228885 gttagtctggaaaaataaagtettattttctatgttttattcatagaaatggagtattaatttttaatattttcaccatatgtgataacaaaggatctttcatgaatgtccaagg 526 gtaagtcagtattaattaatgetgtattacaaggcaatgetaccttttatcccctttgaactacctttgaagtcactatgagcacatggatagaaatttaacttttttttg _a taaagcaagcttaaaatgtttatgtatacatacccagcaactttataaatgtgttaaacaattttactgatttataataaatattttggtaagattttgaataatatgaatt caggcagatatactaaactgcttttatttacttgtttagaaaattgtatatatatgtttgtgtatcctaacagctgctatgaa gagaacatcagatctaatagagcatagtgatactatttaatttaaccaaagtctctagtgaatatttcanctttgaatgtaaactaacaaataaacctgaccaccaa 527527228961 ggagattgtttgcccagagtttcaaagcacattgtctacaaatggaaattgaaataatttataaaatattgacgttactatgttttttaaaaagttcctaattttttcactaa atggaggaaactattagttttattgttaaatatggtagatattaatattcctcttagatgaccagtgattccaattgtcccagtttgaaataagtaccetgtgagtatgaga at taaattagtgacaatcagaacaagtttcagtatcagatgttcaagaggaagttgctattgcattgattttaatatttgtacataaacactgattttttgagcattattttgtat ttgttgtactttaatacctggtgtacagttccagaaa gaaggatgctgaggacctagatgagaagttacctgcaaaaggcaaaagggttacttagtgtcagaaccaaggcaatgacttctctctcccagatctcctagcta 528 229070 ctggtectgggccanntttttttaaataatcccaacntttetttaaaagacaagcatttcagtaagotagttattttcatgggttgetcatccatttttttcagtgatetaaa _at aatgtagggagatggctactactgaagttgtetgtctacttgggataatagcaaattaattgaagacaatgggaaagtaagttataaaaaatactgggaaatctgttt ctcttctgagcaagcattcagggcaggtataaacatcaaacatagtgacattgtcaaaacctcttccatt 529 229254 ggaaagagaaacgtggctcaagtgctggctcaccttctagctgtgtggccctgggcaggttactgaggctcttccaanctcacttttcacatgtaaaatggcatttct 2at _a aaata tacacctacctcagagatctgaaaaaagtaagtgaatttgtnannnaagcaaagcactcacaatatgcctgacacacaaactgctttaat gtagtaatttttaaaacctcctcataagcggcttagaaattattcatgttggtacatatttattgcaagtcaagcagatccaactttttgaaagctggtggtctaggagt atagttttaattatatttgtaaatactcaaaagtattagatgccagtctaatttaaatgcagtctgactgtagcgagtaactgacctgggcaatg gggactcagttcttagagaagtcttttggtcttagagttcatcaagcagagaaggggaaggacatggtccaggaaaataaatcagcacacaaagagatggggt 530 229530 ettgagggtgcatagtacattctggacagccagttacctgggatgagttgggagggaggagaataaggacaaaagaccatctgggcaaaaatcacgaaggg _at gtatgtgtgtcatgtaaaggtgtgccatgatagttattcatattgctattgtaatattaatatatagtaattaactacacatgacacagctttacatgaccttaagtagttatc I aacattaccataatagtaatattaataactacaataagagccattattatcactgagg gttagcaagtgccagcttgtaggctggttgaagtacagaactcagaggaaaaaagaaattaaattttagcttctggagagcagcccctctctggcaccatcaaa 531 229659 cacttctttgtttcccttcaacttggaactettcaaacatcaggggttgtgagggtttggccattcttttatettgggtecatgtgagtgacagaaatggtgeggcctggga _s_at aagatctccctcctttacattttctcttctccctcctcctccttattctaaaactgtgcctccaacagaggggcaggggctcttgtagagagatccctggcccaggacag gagatgccaaatctaattatctcactgagggc tttcctaccaatttcacattttgcagaaacttgttcacatttccaacaatatcagaattagaaaacagttcagataacaagaaagattaaaaattagggaaattctgat 532 229831 atcaccataaagcactattttacatttagagattacattaagataaagtcatcatacacaaaaacaataaatatttataactttctctataaggtccgcatatactgtat 532 at atattgaaacaatctgaatgactagtagatttcatatgaccattgttatttccactttctccaatacttgtattttatgotacatgtaatgaagttggaccttttattatttagta atcctatatgttcctatacttttcattttcaanatgattgctctattgtttcatgttgtttctagcaatatatctccatgagatatgcacttgtttcatattgaaaagtataaaattt I_ atctttcaattcctgtgtgtgtatcctatggttatctgtatgtat 533 229839 tcccaacccggttctggcaaagaatccagttatcccttccatgaagacgcacataactctcttacttggtctttccattagggacaacataagtcttgttttacatcaaat 53 at aaaaacaatgttaaaaagtgtgtgaaccttaaaaatggaagtctactagtttacatacctacttcagaggacatggaaatgaccatgggcctgcatttcagggac at caaagcaaattaggcctggcctaaaatacatcagacctttg gttgaccccaactttggaactcagatcataggatctcccagaggtttcaggtgttcctaagaagcttctaaaggaagttttggaagaaagactaataggtgtaaac 534 230087 atataaacatatatattatatatagctatatatatttaaagagatctctacatatatatatatataaatacaactactgtactctctgcatctgtacaaagtatgagttaaac 54 - at tgcccaggtagtgtgagatacgtaatgcatgaatgtgaatatcctgaaatctgccttcttagcaacgtgccgcgtgtactggagagaggacagttgetectgggagt tctctcaatgggcaaatgtacaagttgatgccgtcttatccaccaacaagccattaaggttggtttcctgctgagacttttgtaccggaagcgagaccggcagcact gggggtgtccatatgccacttatgagg ggccaaggcacatttgactcctgagatgaattttttgtggtcataatcaaatacttagttgttttgatgccccaaaataaagtgagaatggtaatttgccaggaattctt 535 230264 cataacagtatcttacaaaaaacgtgttgctctcttcacagtattatgtgtaaagtcattgtttaaagcacgaatgttccctctggggtacttgttaaagctaaatttatttt 535t sat gettccctccacttagaagtgetgcacactttacagcagettttettccatngcactgcctagttaacagaagtettataaaaatttaaaaagacacatttettaca aaaaagagttgaatgaggtaaaatggcatagatggctctatattttttaaagctatgtaattgttcagcgtcacttttctaagtacttatacatatctaaacatgtcttcat ggtttatattttcacttatatatgctgggctggattaagctttgt ggggcagagggactatgttgtgagcctngcnaaagaagnttgtgtggggactgtgggcagtgaatgcgttgggaacaatatggaaaactgggagctgccttgg 536 230595 aatctacagggccgnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnnggctgaagaaaagaagaatggtattcatgcagttcccattttacagatgaaaa 56 - at caagaggactttttctgtgaagtcaagaaagtggttacaatggtactttcagcctgtccgaattatgtattgcccctcccctttttattaataacattgaagtgtgatggga caaccactgaagccgtctgttgaaacctgctgggactttttagccattctcttcaacataaagaatgggtgtttttggagggggtgagaggaatggggaaatgttgtc aaagagtacaatgtttagttgagacaggaggaatatatttgttgagatctacagcacagcat 537 230788 gatagcgaatgcactcagggtcagcagtggagtttaaaaattgtctcttttcaacttatttaaatgacagcacctgagaagaggaaccgttttacactggatgtttctc at atgtagaacaagaaatetttctggaattgatgtttacatgtctgttgttggtcatctctcctgtgtettaaatactttaatgttggaagagcatagtgtttgggetagtgggttt - ctgacagcccatgggaatgccctgaaactactgtatctgatgttgttttcgatgaggtccatgtttgtttc gcagctgtggtggtcattataagcatngtccntcctgggaagaagcatccaggcaagcagaaaagaaaagatgcagccaccagaaaaagaaactccagaa 538 230830 gtcctgcatttggatgaggccaaggatcacaacagcctaaacaacctaagagaaactttgctctcagaaaagccaaacttggcccaggtggaacttgagttaa _at aagagagagatgtgctgtcagttttccttccggatgtaccagaaactgagagctagtgagggttcagagaagccccatcctaagccagacacatgatgtgggct cagctcagtggcctgaaacctctcaggttttagagtctctcccaagaagccgcttttttc tactagttgttttacactctcttttcttattcttagggcttttgtgtatgtctnactnntntttnaannanntncncnnnnanncagaccttaanttttatatttttttaaagtngct 539 231120 aacatagcngnaggcacttaagcatttagtcaatgatattggtagaaatagtaaaatacatcctttaaatatatatetaagcatatattttaaaaggagenaaaata _x-at aaaccaaagtgttagtaaattttgatttattagatatttagaaaaataatagaattctgaagttttaaaaatgtcagtaattaatttattttcattttcagaaatatatgcatg cagttatgttttatttgattgttgacttaggctatgtctgtatacagtaaccaa gagtaggttcggtctgaaaggtgtgggcctttatatttgatccacacacgttggtcttttaaccgtgctgancagaaaacaaaacnggttaanaananccgggtgg 540 231579 nnagntgacagaggnaanccgctnaaataccttcacaataaatagtggcaatatatatatagtttaagaaggctccccatttggcatcgtttaatttaaatgttatgtt 540 sa t ataagcacagetetettccaattttcatcctgcaagcaaetcaaaannnttnaaannaannttnnnntgtagttattttcaaatetttgettgataagtattaagaaa tantggacgctgccgtaatttaaagctctgttgantttgttccgnttgganttttgggggaggggagcactgtgtttatgctggaatatgaagtetgagaccttccggt gctgggaacacacaa ggaacctataaatgtagtttcatctgtcgtcaattactgcagaaaattatgtgtatccacaacctagttattttaaaaattatgttgactaaatacaaagtttgttttctaaa 541 231773 atgtaaatatttgccacaatgtaaagcaaatcttagctatattttaaatcataaataacatgttcaagatacttaacaatttatttaaaatctaagattgctctaacgtcta 541 gtgaaaaaaatatttttaaaatttcagccaaataatgcattttatttataaaaatacagacagaaaattagggagaaacctctagttttgccaatagaaaatgettctt at ccattgaataaaagttatttcaaattgaannngtncctttcacangtnnatgattaaatctganttcttaatnatatatcctatgctgattttcccaaaacatgacccata gtattaaataca tctttttgagtgatagtgccattgaatgagcagtatggaaacagtgttacttgatattttgagctttctcaggttatctaaatcagtggtagcttaacaaaacccagacta 542 231925 attgtgtgtaattgtatttttaataaaaggaaagtacatttcctataatagcatagtactgtttgcatgtaagagtatgcaaaaccttgtgtgtgtgtgtgtgtgtgtgtgtgt _at gtgtgtgtcttagtgtgtgtaaggcatggcagccaactttgtatctgctatttttagtacgagcagagcttcataattgtggtcactagaactgtacitaccatggacagtt ,aaaact tctctcagtttaaacatcttaacagagaatttgttactgtttattaaaagaattgcatttggaagcaagaaaacaaccggatttgcaatcatgtgaagaaacaataatg 543 231975 cctttattatcaagtgttaagcacaattettataacaaactgtgataaattetttgtttttcctttgccccattattttcttatgaacaaaccaaaaattcatggtgagca _s-at gttgcagtgttggctgatatatcttttatgtacagggaatttgaaaaggacagtggattcatttagaagtgtaactggtgctgtgattatagcaatacatttgttagttgtac ttcatctttttcatgctagctttttaaatgtttagttttcctcttgtcatggtcagctgctgaatttacttgaag agattctggccacggetgggaacgttgtcaccctgaccatcatccccagtgtgatctacgagcacatggtcaaaaagttgcctccagtcctgctccaccacaccat ggaccactccatcccagatgcctgaagccactgcagggcagggcaggcagggggggcttcccgccctcctgcagcaaagggcaaccaccctcggatgatg 544 233565 ggttgcagccggcctgetgettaaggtgggggetgccatgaggggggcgtgtccaggagggtgaccatgggatggettatacacacaggcctccttggagcctc _s at agactccaagctaggctgaggctcaggcagggcccacaggcagccgattctcttgtgctgatttaaatgctggacacggaggcaggetgtttaaacgctgcttaa agtcgcaactgggcccctttcaagaaattttgctctaccaggaaaacagttacacatttaagagaacagagctacgttctttgtgagagcttttccttgccttgacttg ctctttgtcacagactgca 545 234764 gtcaccatctcttgttctggaagcagctccaacatcggaagtaattatgtatactggtaccagcagctcccaggaacggcccccaaactcctcatctataggaata xat atcagcggccctcaggggtccctgaccgattctctggetccaagtetggcacctcagcctccctggccatcagtgggetccggtccgaggatgaggctgattatta x at ctgtgcagcatgggatgacagattgagtggttttat 546546234987 gtttactctgagattctgtagtcctaatattgtatcattgtgctgtctgcaaaacaacttgaatctattttgnttgcatcttttgttacatgtaacgcagctgtactttatgttctttg caactgtttccattatgagaacgetgtgetatttacaaggttacatttttcttggccaggcgaggtggtcatgcctgtaatcccagcactttgggaggccaaggtgggc _a ggatcacttgaggtaaagagttgagaccagcctggctagcatggcgaaacccagtctctactaaaaatancaaaaattagccgggtgaaattagccgggcg ggtgtttaaggttagcacatgcacaaaggaacgagttggtttaaaaagataaatcactgcaaagaatgaaattggettattcacatcaaaactagataagatgct 547 235146 aaaaaaaaaagatataaacagaactaacctatagtttcctgaaatcagtacagtttaatttataagaagctagaaagtaatgcaccttgattgttttaggaatgatt 547 tatgtgttgcaattttaatttatttaaagcatgtctactgtgtttgtcctaagagaaatatttcaacaaaacgtgotctgtgtttaagatatgtttaggcagtagttagcaactc at tgaaagtagaaactggaaatgtttattgtgaggcttgttgcagaatttccattgtgagttactacttagtttcatgtcagcctaaaattgtaaattccctgtagatcttcac cccattgtggtgtcatcaatgaatccaaagcaggtgccattattt gcagggtcataatcacacagcagtgccttatatagttgccataagacttcagtgcagtacaacatanttttacngctacatatcagggcatattctatatggtgtatttg 548 235766 tgttagaataacacattaaatgtetttaaacataaaaataagaatgtttgcatgtttcagttttcaagaaccaaatgagtaattagctatagattccactggccttaaac _x-at atacaattaagtgtatacatgatatagtgcacacacaaaagccacctttaattattgaaataacctgtattcttttggaaatcatttaagtttggtattgaagtactatattt tttgtgcatcaatgtatttttctatttacaagcctatgt ggagategtgttctgcttttacatgaggagcagaactgggccatacacgtgttcaagaactaggggagctacctggtagcaagtgagtgcagacccacctcacc 235849 ttgggggaatctcaaactcataggcctcagatacacgatcacctgtcatatcaggtgagcactggcctgcttggggagagacctgggcccctccaggtgtagga 549 acagcaacactcctggetgacaactaagccaatatggccctaggtcattcttgettccaatatgettgccactccttaaatgtcctaatgatgagaaactctctttetga _a ccaattgctatgtttacataacacgcatgtactcatgcatcccttgccagagcccatatatgtatgcatatataaacatagcactttttactacatagctcagcacattg caaggtttgcatttaagttaaaaaaaaaaagaaaaaaaacctaagggtgaaacgatgccactttgacgc tgactttcatacacacccagtacatctcaaaggatgctaagggacattttctgccagtagagttctccccctttttnggtgacagcaatattattatgttcacatctaact 550550236300 ccagagcttacttcctgtggtgccaatgtatttgttgcaatttactacatttttatatgagcctattataggtgccattaaactcaggtetttcaaatgaaagagtttctagc ccncttagggaaaaagataattgtttagaaaaccataaaatcaatggtaggaaaagttggaactggttacctggatgccatggttctctgttaaataaagtaagag at accaggtgnannnnnaannnnnannanngntattttcagcatgctaataaatgtctttccggttatatatctatctaaaattaacctttaaaatattggtttccttgata aaagcaccactttggcttttgttagctgtaatattttgtcatttagattaagacctggttaggctctcaataaaagatgaagacagtagctctgtacagcggataatatc gctagttgcattatactgggtcatgaaaaattatcccttgaaatagatatgaaacatgttacttcatttctggtttaaataacttgtggaatctttcctaatgacaacntgat 51236313 attaagggaaactaaagaaaatgttattgtggatcccacagtactatattacactgtttttttttgttgttttgttagtttttttttatttaaagcaaacctcaaacattattgggt 551 atcaattaccacctggttgtattaaaatagtaacttatcaatgccatgtaaaaattaattccattttegaagccacctggcagacaggtttagotgtttcatcagcagcc _a taatatatactgttaaatttgttaaggatttcactttgaaggatacatgcaaaacatatagttactatttcatgagtcctgcttctagctccattgtggaatacagaaaatt aaatatacctgttaagttcgtatctaaacctaagacattaccaaggtttgtacaaattctactacctgacatttattccaaga ctcccctgaagaacgtgtccagcaacgcagagtgccctgcttgttatgaatctaatggaacttcctgtngtgggaagccctggaaatgctatgaagaagaacagt 552 238143 gtgtctttctagttgcagaacttaanaatgacattgagtctaagagtctcgtgctgaaaggctgttccaacgtcagtaacgccacctgtcagttcctgtctggtgaaaa _a52 caagactcttggaggagtcatetttegaaagtttgagtgtgcaaatgtaaacagettaacccccacgtntgcaccaaccacttcccacaacgtgggetccaaaget tccctctacctcttggcccttgccagcctccttcttcggggactgctgccctgaggtcctggggctgcactttgcccagcaccccatttctncttctctgaggtccagag I caccccctgcggtgctgacaccctctttccctgctctgccccgtttaactgcccagtaagtgggagtcacaggtctccaggcaatgccgacagctgccttgt tttgtccatagaggcttcaagatagataggtaagagnccagtagtgttcataagaagccaatagagagcaggagccactttatcaggtggcaggtgtcctgggc 554553 238750 ctccctgctggtagtcccaagcggtggtgttgccaggatgtcttggaggtgataatgggacacacagaggcactgagtctccataggttaaaatgccaccaaaa ctggcctttgcctaatatccetcattgactatttagcatttaatttatttatttcctgacatttetgcaagetttgtatttatatttccactttatagatgaggaaatttgaggetett _a agaggtaaaatgacttgcccaggtcacacaggaagtggcagagacaagctttttaaataagaaaaaattaataaaatataatatgagagtaacttaaaatatta ataaaccacaattttaaattaattaaccgtgataaccaacattaataaaagttaagataccaaaacactggtgtctaattctttcaac gttctgttgtttatccatgaagcctatatatttctagtgcaaaangcccagtgggtctcaaaacattcttggaggggtttgacacactgctattagtagtgactcataattc 554 238751 cacgattccctgggatacagagaaggcaggggggtagtactgtttgaacaaaaatettcccaagaccctggcaaagagatcttccttaggaatcagtggcatat at gcgtttatgttctttaacagggaaagtaaaagtgagcgcactttttgaagctcataaatactcatgtgactgtaaattagaaatgttaattaattgggcctaatgtttga tctggaaaagtacttagcagtcaccaggaatttgccttgaactgactcgaaccacaaatcagaaccgtattccacaattta 239272 gcactgttaaaatccggctaggccaagatttcccaatgtcttgaagccaatggctaggaaaacagctgagcctgggactggactttgtcagtaacctctcttcccta at gggcacgggaggagtngggtgaataggacctcttggettgaggaccatgattgtgaatacagacatttaattcagaatgacacctacattgatgaattttcattgta - caagtgtttttccagatcaaacacaaaacccatgtaattccttgataaattttcaatgcagggcagataaactgttgctaac gtgatcttggactgtcaattcccctncctgtgatccattttactgcaaacataagggttgcagtaaagggttgtetcacgtcttctgctttaaaagcctataaatatatga 556 241994 cctgaaaactccagtacataaaggatctgcagctatctaaggettggttttcttactgtcatatgatacctgggtetaatgaactetgetgagatcacctcaagtttetg _at cggttggtaaagagaacaagggaagaacaaacatcccttttattgctccaaatggtgatttaatccctacatggtgctgggtggacaatgtgtcactgtcacatgcc ttnactgtataaatccaaccttctgccagagagaatctgtggttctggccatggagggaggatagtggaaatgatatagttggactggtgcttgatgtcacta atgtgattatacttctctttgacttgtcagcttagctttagnngatacactctggtgcccaactattattgtatcagtgaacttnccactttncttttnccttttnctctcaatttttg 557 242317 tgtatcattcctaccttgtgaggacatataatatttacattgttgtcatectcacatttcttagttccacagtttaaatgtatttgaaactcaaaacattcccattaatetett _at ggtcagctgaaattaatgatttaatagtttccttaaaaaagactcatggaacaattccctaaatttttgccatgtcaaatatgtttatctgtagcctttacacagtaaaaa caatttggctagataatacaattctcagttcatat agggcacttctcaacattaattttggaattattcaccatttaaaaattgtcactgctcttttcattactgtagataactgagagttagctgttctaggaaaaggccatgtttc 558 242447 agttagtgetatgacttcttttttcgataaggttgaagcagtgtttttagtagcctgaacacttctcaaagcgacttatcactagcggetttaatattgagettctatatc _at gttgtgtccacctcactttttaaggctgttcatacctggcaatattcactactctgctatttaaaaactatttaaagttttaagcacaatgttgactcttctgtaatttccta aaattatattgttttcctacagacagctcaacttccttgatatgt 59 242601 ctcattattcctttacatgcagaatagaggcatttatgcaaattgaactgcagtttttcagcatatacacaatgtcttgtgcaacagaaaaacatgttggggaaatattc 59 - at etcagtggagagtcgttctcatgctgacggggagaacgaaagtgacaggggtttcctcataagttttgtatgaaatatetetacaaacctcaattagttctactctaca ctttcactatcatcaacactgagactatcctgtctcacctacaaatgtggaaactttacattgttcgatttttcagcagact ataaatgaccagactttttctaagaaaaatgttgctttaatgcatttcatgaatttttactcttatatcattgcttgctagtaatagcaaatctgcttttctgcatctgctttgcgt 560 243278 agctattgtaaggetttgaactaatgtatgtatttattgcttgaacttctgtgcataccttataaagcataatgtetgacaatttaaatggetcatgtattcttgettntatcata _at agctgattatggggactatgatcttttgtatacagcaaattttaaactgtagcacaaacatctgtttatgtattggtggaatatacctgttttatttatctttttgaggtaaact aatttttgatacttttcattactgtgtactatgttcatactttgaattctctgacgttagaagtcatggttgagaattgtaacagctgttattcgttctgtattcatggctttc 561 200832 aaaagegaggtggccatgttatgctggtggttgccagggcctccaaccactgtgccactgacttgetgtgtgaccctgggcaagtcacttaactataaggtgccte _s-at agttttccttctgttaaaatggggataataatactgacctacctcaaagggcagtttgaggcatgactaatgcttttagaaagcattttgggatccttcagcacagga attctcaagacctgagtattttttataataggaatgtccaccatgaacttgatacgtccgtgtgtcccagatgctgtcattagtctatatggttctccaagaaactgaatg aatccattggagaagcggtggataactagccagacaaaatttgagaatacataaacaacgcattgccacggaaacatacagaggatgccttttctgtgattggg tgggattttttcccttttatgtgggatatagtagttacttgtgacaagaataatttggaataatttctattaatatcaactctgaagctaattgtactaatctgagat 562 201147 gagtcggagatgatgcagcacacacacaattccccagcccagtgatgettgtgtgaccagatgttcctgagtetggagcaagcacccaggccagaataacag _s at agctttcttagttggtgaagacttaaacatctgcctgaggtcaggaggcaatttgcctgccttgtacaaaagctcaggtgaaagactgagatgaatgtctttcctctcc ctgcctcccaccagacttcctcctggaaaacgctttggtagatttggccaggagctttcttttatgtaaattggataaatacacacaccatacactatccacagatata gccaagtagatttgggtagaggatactatttccagaatagtgtttagctcacctagggggatatgtttgtatacacattgcatatacccacatgggg 563 201162 ggaatgtcactggtgcccaggtgtacttgagetgtgaggtcateggaatcccgacacctgtectcatctggaacaaggtaaaaaggggtcactatggagttcaaa _at ggacagaactcctgcctggtgaccgggacaacctggccattcagacccggggtggcccagaaaagcatgaagtaactggctgggtgctggtatctcctctaag taaggaagatgctggagaatatgagtgccatgcatccaattcccaaggacaggcttcagcatcagcaaaaattacagtggttgatgccttacatg 564 201163 aggtgaaggtgcegagctataaacctccagaatattattagtetgcatggttaaaagtagtcatggataactacattacctgttcttgcctaataagtttettttaatcca s at atccactaacactttagttatattcactggttttacacagagaaatacaaaataaagatcacacatcaagactatctacaa 565 201185 ctcaaagactctcccgtggatgacggatgaggactctgggetgetggaataggacactcaagacttttgactgccattttgtttgttcagtggagactccetggccaa _at cagaatccttcttgatagtttgcaggcaaaacaaatgtaatgttgcagatccgcaggcagaagctctgcccttctgtatcctatgtatgcagtgtgctttttcttgccagc ttgggccattcttgcttagacagtcagcatttgtctcctcctttaactgagtcatcatcttagtccaactaatgcagtcgatacaatgcgtagatagaagaagccccac gggagccaggatgggactggtcgtgtttgtgcttttctccaagtcagcacccaaaggtcaatgcacagagaccccgggtgggtgagcgtggcttctcaaacgg ccgaagttgcctctttt 566 201261 tctctctttctgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtgtettgtgottcctcagacctttetegcttctgagettggtggcctgttccctccatctctccgaacctggc _x at ttcgcctgtccctttcactccacaccctctggccttctgccttgagetgggactgcttctgtctgtccggcctgcacccagcccctgcccacaaaaccccagggaca gcggtctccccagcctgccctgctcaggccttgcccccaaacctgtactgtcccggaggaggttgggaggtggaggcccagcatcccgcgcagatgacaccat caaccgccagagtcccagacaccggttttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggg gctgcttctgaggtcggtggctgtctttccattaaagaaacacc 567 201792 ccaccgctggctgggaggagtcggagactgagacctacacagaggtggtgacagagtttgggaccgaggtggagcccgagtttgggaccaaggtggagcc at cgagtttgagacccagttggagcctgagttcgagacccagctggaacccgagtttgaggaagaggaggaggaggagaaagaggaggagatagccactgg ccaggcattccccttcacaacagtagagacctacacagtgaactttggggacttctgagatcagcgtcctaccaagaccccagcccaactcaagctacagcag cagcacttcccaagcctgctgaccacagtcacatcacccatcagcacatggaaggcccctggtatggacactgaaaggaagggctggtcctgcccetttgagg gggtgcaaacatgactgggacctaagagccagaggetgtgtagaggctcctgctccacctgccagtctcgtaagagatggggttgctgcagtgttggagtaggg gcagagggagggagccaaggtcactcca 568 202237 ctactacatgattggtgagcagaagttctccagcctccccctgggccgggaggcagtagaggetgotgtgaaagaggetggetacacaatcgaatggtttgagg at tgatctcgcaaagttattcttccaccatggccaacaacgaaggacttttctccctggtggcgaggaagctgagcag 569 202238 tegtcactgactactcagaccagaacctgcaggagetggagaagtggetgaagaaagagccagaggcctttgactggtocccagtggtgacetatgtgtgtgat _s-at cttgaagggaacagagtcaagggtccagagaaggaggagaagttgagacaggcggtcaagcaggtgctgaagtgtgatgtgactcagagccagccactgg gggccgtccccttacccccggetgactgcgtgctcagcacactgtgtctggatgccgcctgcccagacctccccacctactgcagggcgctcaggaacctcggc agcctactgaagccagggggcttcctggtgatcatggatgcgctcaagagcagctactac 570 202310 tggcctacatggaccagcagactggcaacctcaagaaggccctgctcctccagggetccaacgagatogagatecgcgccgagggcaacagccgettcacc | s at tacagcgtcactgtcgatggctgcacgagtcacaccggagcctggggcaagacagtgattgaatacaaaaccaccaagacctccogcctgcccatcatcgat gtggcccccttggacgttggtgccccagaccaggaattcggetgacgttggccctgtctgcttcctgtaaactccctccatcccaacctggetccctcccaccca accaactttccccccaacccggaaacagacaagcaacccaaactgaaccccctcaaaagccaaaaaatgggagacaatttcacatggactttggaaaatatt tttttcctttgcattcatctctcaaacttagtttttatctttgaccaaccgaacatgacca 571 202311 getccccatttataccaaaggtgctacatctatgtgatgggtggggtggggagggaatcactggtgetatagaaattgagatgcccccccaggccagcaaatgt _s-at tccttttgttcaaagtctattttattccttgatatttttntttnttttttttttgtggatggggacttgtgaattttctaaaggtgctatttaacatgggaggagagcgtgtgc ggctccagcccagcccgetgctcactttccaccctctctccacctgcctctggettctcaggcctctgctctccgacctctctcctctgaaaccetcctccacagctgc agcccatcctcccggctccctcctagtctgtcctgcgtcctctgtccccgggtttcagagacaacttcccaaagcacaaagcagtttttncccctaggggtgggagg aagcaaaagactctgtacctattttgt 572 202404 actttcccatgagtgtgatccacattgttaggtgetgacetagacagagatgaactgaggtcttgttttgttttgttcataatacaaaggtgetaattaatagtatttcag _s-at atacttgaagaatgttgatggtgctagaagaatttgagaagaaatactcctgtattgagttgtatcgtgtggtgtatttttaaaaaatttgatttagcattcatattttccatc ttattcccaattaaaagtatgcagattatttgcccaaagttgtcctcttcttcagattcagcatttgttctttgccagtctcattttcatcttcttccatggttccacagaagcttt gtttcttgggca 573 202450 gaacaacgcctgtggcattgccaacctggccagettccccaagatgtgactccagccagccaaatccatectgetettccatttcttccacgatggtgcagtgtaac _s-at gatgcactttggaagggagttggtgtgctattttgaagcagatgtggtgatactgagattgtctgttcagtttccccatttgtttgtgcttcaaatgatccttcctactttgctt ctctccacccatgaccttttcactgtggccatcaggactttccctgacagctgtgtactcttaggctaagagatgtgactacagcctgcccctgactgtgttgtcccag ggctgatgctgtacaggtacaggtggagattttcacataggttagattctcattcacgggactagttagctttaagcaccctagaggactagggtaatctgacttctc acttcctaagttcccttctatatcctcaaggtagaaatgtctatgtttctactccaattc 574 202859 gtacccagttaaattcattcagataaacaacaaataattttttagtataagtacattattgtttatctgaaagttttaattgaactaacaatcctagtttgatactcccagt _x-at cttgtcattgccagctgtgttggtagtgctgtgttgaattacggaataatgagttagaactattaaaacagccaaaactccacagtcaatattagtaatttcttgctggtt gaaacttgtttattatgtacaaatagattcttataatattatttaaatgactgcatttttaaatacaaggctttatatttttaactttaagatgtttttatgtgctctccaaatttttt actgtttctgattgtat 575 202878 atccgaattctccatatattcactaatcaaagacactattttcatactagattcctgagacaaatactcactgaagggettgtttaaaaataaattgtgttttggtetgttt -s-at gtagataatgcccttctattttaggtagaagctctggaatccctttattgtgctgttgctcttatctgcaaggtggcaagcagttcttttcagcagattttgcccactattcctc tgagctgaagttctttgcatagatttggcttaagcttgaattagatccctgcaaaggcttgctctgtgatgtcagatgtaattgtaaatgtcagtaatcacttcatgaatgc taaatgagaatgtaagtattttaaatgtgtgtatttcaaatttgtttgactaattctggaattacaagatttctatgcaggatttaccttcatcctgtgcatgtttcccaaactg tgaggagggaaggctcagagatcgagcttctcctctgagttctaacaaaatggtgctttgagggtcagcctttaggaaggtgcagctttgttgtcctttg 576 202917 ggcatcatgttgaccgagetggagaaagccttgaactctatcatcgacgtetaccacaagtactccctgataaaggggaattccatgccgtetacagggatgac s at ctgaagaaattgctagagaccgagtgtcctcagtatatcaggaaaaagggtgcagacgtctgg 577 202998 gccagtettgaccgggatgaggcccacagacaggttgtcatcagettgtcccattcaagccaccgagotcaccacagacacagtggagcegegetettetccag _s-at tgacacgtggacaaatgcgggctcatcagcccccccagagagggtcaggccgaaccccatttctcctcctcttaggtcattttcagcaaacttgaatatctagacc tctcttccaatgaaaccetccagtctattatagtcacatagataatggtgccacgtgtttctgatttggtgagctcagacttggtgcttccctctccacaacccccaccc cttgtttttcaagatactattattatattttcacagacttttgaagcacaaatttattggcatttaatattggacatctgggcccttggaagtacaaatctaaggaaaaacc aacccactgtgtaagtgactcatcttcctgttgttccaattctgtgggttttgattcaacggtgctataaccagggtcctgggtgacagggcgctcactgagcaccatg tgtcatcacagaca 578 203083 caggaaatagtcactcatcccactccacataaggggtttagtaagagaagtetgtetgtetgatgatggatagggggcaaatctttcccctttctgttaatagtcatc _at acatttctatgccaaacaggaacgatccataactttagtcttaatgtacacattgcattttgataaaattaattttgttgtttcctttgaggttgatcgttgtgttgttttgctgca ctttttacttttttgcgtgtggagctgtattcccgagacaacgaagcgttgggatacttcattaaatgtagcgactgtcaacagcgtgcaggttttctgtttctgtgttgtggg gtcaaccgtacaatggtgtgggaatgacgatgatgtgaatatttagaatgtaccatattttttgtaaattatttatgtttttctaaacaaatttatcgtataggttgatgaaac I_ gtcatgtgttttgccaaagactgtaaatatttatttatgtgttcacatggtcaaaatttcaccactgaaaccctgcacttagctagaacct 579 203325 cccacctggagetgaatcacatgacctagetgcaccccagcgcctgggcccgccccacgetctgtecacacccangcgcccogggagcggggccatgccte _s-at cagccccccagotcgcccgacccatcctgttcgtgaataggtctcaggggttgggggagggactgccagatttggacactatattttttctaaattcaacttgaaga tgtgtatttcccctgaccttcaaaaaatgttccaaggtaagcctcgtaaaggtcatcccaccatcaccaaagcctccgtttttaacaacctccaacacgatccattta gaggccaaatgtcattctgcaggtgccttcccgatggattaaag 580 203570 ctggaggacagcacctgtgactggcaacctcaagcgctatgcatgcacctctcatacccagggcctgagcccaggetgctatgacacctacaatgcggacat _at cgactgccagtggatcgacataaccgacgtgcagcctgggaactacatcctcaaggtgcacgtgaacccaaagtatattgttttggagtctgacttcaccaacaa cgtggtgagatgcaacattcactacacaggtcgctacgtttctgcaacaaactgcaaaattgtccaatcctgatctccgggagggacagatggccaatctctcccc ttccaaagcaggccctgctccccgggcagcctcccgccgaggggcccagcccccaacccacaggcagggaggggcatccctccctgccggcctcaggga gcgaacgtggatgaaaaccacagggattccggatgccagaccccattttatacttcacttttctctacagtgttgtttgttgttgttggttttatttttatactttggccata ccacagagctagattgccc 581 203878 tgccagogactgtetcagactgggcagggaggetttggcatgacttaagaggaagggcagtettgggacccgctatgcaggtcctggcaaacctggetgccctg _s-at tctcatccctgtccctcagggtagcaccatggcaggactgggggaactggagtgtccttgctgtatccctgttgtgaggttccttccaggggctggcactgaagcaa gggtgctggggccccatggccttcagccctggetgagcaactgggctgtagggcagggccacttcctgaggtcaggtcttggtaggtgcctgcatctgtetgccttc tggetgacaatcctggaaatctgttctccagaatccaggccaaaaagttcacagtcaaatggggaggggtattcttcatgcaggagaccccaggccctggaggc tgcaacatacctcaatcctgtcccaggccggatcctcctgaagcccttttcgcagcactgctatcctccaaagccattgtaaatgtgtgtacagtgtgtataaaccttc ttcttctt 582 204006 gagtacaggtgccagacaaacctctccaccctcagtgacccggtgcagctagaagtccatatcggetggetgttgetccaggccceteggtgggtgttcaagga s at ggaagaccctattcacctgaggtgtcacagctggaagaacactgctctgcataaggtcacatatttacagaatggcaaagacaggaagtattttcatcataattct gacttccacattccaaaagccacactcaaagatagcggctcctacttctgcagggggcttgttgggagtaaaaatgtgtcttcagagactgtgaacatcaccatca ctcaaggtttggcagtgtcaaccatctcatcattctctccacctgggtaccaagtctctttctgcttggtgatggtactccttttgcagtggacacaggactatatttctctg tgaagacaaacatttgaagctcaacaagagactggaaggaccataaacttaaatggagaaaggaccctcaagacaaatgacc 583 204051 aaccagccagteccaagaagaacattaaaactaggagtgcccagaagagaacaaacccgaaaagagtgtgagctaactagtttccaaagcggagacttcc s at gacttccttacaggatgaggctgggcattgcctgggacagcctatgtaaggccatgtgccccttgccctaacaactcactgcagtgctcttcatagacacatcttgc agcatttttcttaaggctatgcttcagtttttctttgtaagccatcacaagccatagtggtaggtttgccctttggtacagaag 584 204320 gaaaatgtaccttggtgccaccaacccattttgtgccacatgcaagttttgaataaggatgtatggaaaacaacgetgcatatacaggtaccatttaggaaatacc _at gatgcctttgtgggggcagaatcacagacaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctc aactctcctttcctatttgaatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgctcattctcatccatccaggatgtactaaa acagtgtgtttaataaattgtaattatttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattccgctgactctaatttatgaggatgc cgaactctgatggcaataatatatgtattatgaaaatgaagtatgatttccgatgaccctaagtcc 585 204475 gaagaactgtetattttetcagtcatttttaacctctagagtcactgatacacagaatataatcttatttatacctcagtttgcatatttttactatttagaatgtagccetttt -at gtactgatataatttagttccacaaatggtgggtacaaaaagtcaagtttgtggcttatggattcatataggccagagttgcaaagatcttttccagagtatgcaactct gacgttgatcccagagagcagcttcagtgacaaacatatcctttcaagacagaaagagacaggagacatgagtctttgccggaggaaaagcagctcaagaa cacatgtgcagtcactggtgtcaccctggataggcaagggataactcttctaacaca 586 204620 tgcegtgoteccaaaacattttaaatgaaagtattggcattcaaaaagacagcagacaaaatgaaagaaaatgagagcagaaagtaagcatttccagcctatc _s-at taatttctttagttttctatttgcctccagtgcagtccatttcctaatgtataccagcctactgtactatttaaaatgctcaatttcagcaccgatggccatgtaaataagatg atttaatgttgattttaatcctgtatataaaataaaaagtcacaatgagtttgggcatatttaatgatgattatggagccttagaggtctttaatcattggttcggctgctttta tgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagctagaaaacacaaaatcttgtaggtcattgcaccta tctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaaggactccaatgtcgaactcttcttgctgc 587 204811 ggggaactgagggcaaggggatatagtgatggggetcagatggactgggaggagggggagggtgatgcattaattaatggettcgttaattaatgtcatgttgett _s-at gtcgctttctcagtgtgtgtgtgtggtccatgcccactgotggtgccagggtgggtgtccatgtgcacccggcctggatgccagctgtgtccttcgggggcgtgcgtgt aactgtagtgtagtcaggtgctcaatggagaatataaacatatacagaaaaatatatattttaagtttaaaaaacagaaaaacagacaaaacaatccccatcag gtagctgtctaacccccagctgggtctaatccttctcattacccacccgacctggctgcccctcaccttgggctgggggactggggggccatttccttttctctgcccttt ttttgttgttctattttgtacagacaagttggaaaaacaacagcgacaaaaaagtcaagaaactttgtaaaatatcgtgtgtgtgatccttgt 588 205479 cccgaccggtgggcatttgtgaggcccatggttgagaaatgaataatttcccaattaggaagtgtaagcagetgaggtetettgagggagottagccaatgtggg _s-at agcagcggtttggggagcagagacactaacgacttcagggcagggctctgatattccatgaatgtatcaggaaatatatatgtgtgtgtatgtttgcacacttgttgt gtgggctgtgagtgtaagtgtgagtaagagctggtgtctgattgttaagtctaaatatttccttaaactgtgtggactgtgatgccacacagagtggtctttctggagag gttataggtcactcctggggcctcttgggtcccccacgtgacagtgcctgggaatgtacttattctgcagcatgacctgtgaccagcactgtctcagtttcactttcaca tagatgtccctttcttggccagttatcccttccttttagcctagttcatccaatcctcactgggtgggg 589 205765 caccacctacctatgatgccgtggtacagatggagtaccttgacatggtggtgaatgaaacactcagattattcccagttgetattagacttgagaggacttgcaag _at aaagatgttgaaatcaatggggtattcattcccaaagggtcaatggtggtgattccaacttatgctcttcaccatgacccaaagtactggacagagcctgaggagtt ccgccctgaaaggttcagtaagaagaaggacagcatagatccttacatatacacaccctttggaactggacccagaaactgcattggcatgaggtttgctctcat gaacatgaaacttgctctaatcagagtccttcagaacttctccttcaaaccttgtaaagaaacacagatccccttgaaattagacacgcaaggacttcttcaacca gaaaaacccattgttctaaaggtggattcaagagatggaaccctaagtggagaatgagttattctaaggacttctactttggtcttcaagaaagctgtgccccaga acaccagagatttcaacttagtca 590 205828 gaaaatogatgcagccatttctgataaggaaaagaacaaaacatatttctttgtagaggacaaatactggagatttgatgagaagagaaattccatggagccag _at gctttcccaagcaaatagctgaagactttccagggattgactcaaagattgatgctgtttttgaagaatttgggttcttttatttctttactggatcttcacagttggagtttg acccaaatgcaaagaaagtgacacacactttgaagagtaacagctggcttaattgttgaaagagatatgtagaaggcacaatatgggcactttaaatgaagcta ataattcttcacctaagtctctgtgaattgaaatgttcgttttctcctgcctgtgctgtgactogagtcacactcaagggaacttgagcgtgaatctgtatcttgccggtcat I ttttatgttattacagggcattcaaatgggctgctgcttagcttgcaccttgtcacatagagtgatctttcccaagagaaggggaagcactcgtgtgcaacagac 591 205927 tccacacacggccaggcctgtttatctacactgctgcccactcctctctccagotccacatgctgtacctggatcattctgaagcaaattccgagcattacatcattttg _s-at tccataaatatttctaacatccttaaatatacaatcggaattcaagcatctcccattgtcccacaaatgtttggctgttttgtagttggattgtttgtattaggattcaagca aggcccatatattgcatttatttgaaatgtctgtaagtctctttccatctacagagtttagcacatttgaacgttgctggttgaaatcccgaggtgtcatttgacatggttctc tgaacttatctttcctataaaatggtagttagatctggaggtctgattttgtggcaaaaatacttcctaggtggtgctgggtacttcttgttgcatcctgtcaggaggcaga taatgctggtgcctctctattggtaatgttaagactgctgggtgggttggagttcttggc 592 207173 gaacatccaagtetttctttttaagttgtcaaagaagottccacaaaattagaaaggacaacagttetgagetgtaatttegccttaaactctggacactctatatg _x-at tagtgcattttaaacttgaaatatataatattcagccagcttaaacccatacaatgtatgtacaatacaatgtacaattatgtctcttgagcatcaatcttgttactgctga ttcttgtaaatctttttgcttctactttcatcttaaactaatacgtgccagatataactgtcttgtttcagtgagagacgccctatttctatgtcatttttaatgtatctatttgtaca attttaaagttcttattttagtatacatataaatatcagtattctgacatgtaagaaaatgttacggcatcacacttatattta 593 207191 aatctcttctagagcacctgctatccccaacttctagacctgctccaaactagtgactaggatagaatttgatcccctaactcactgtetgcggtgetcattgetgctaa _s-at cagcattgcctgtgctctcctctcaggggcagcatgctaacggggcgacgtcctaatccaactgggagaagcctcagtggtggaattccaggcactgtgactgtc aagctggcaagggccaggattgggggaatggagctggggcttagctgggaggtggtctgaagcagacagggaatgggagaggaggatgggaagtagaca gtggctggtatggetctgaggctccctggggcctgctcaagctcctcctgctccttgctgttttctgatgatttgggggettgggagtccctttgtcctcatctgagactga aatgtggggatccaggatggcttccttcctcttacccttcctccctcagcctgcaacctctatcctggaacctgtcctccctttctccccaactatgcatctgttgtctgctc ct 594 208063 aagaagctaagcctgatctcetgtaaaaacatcattccetgatggacaccageggcaatgggaagetggagttgatgaattcaaagtgttetgggacaagetg

_s at aagcagtggattaaccttttccttcggtttgatgctgacaagtccggcaccatgtctacctatgaactacggactgcactgaaagctgcaggcttcagctgagcag ccacctcctgcagctgattgtgctcaggtatgcggatgaggagctccagctggacttcgatgacttcctcaactgcctggtccggctggagaatgcgagccgggtg ttccaggctctcagtacaaagaacaaggagttcattcatctcaatataaatgagttcatccatttgacaatgaacatctgaggctgccttgtagagatgcagcctgcc cagctgaatcttggcttctggaccttgaccttcagaacttctcttggtgtggaaccattacgcccagggttcactc 595 208782 actcccaagagcaaatccacattcctcttgagttctgcagettctgtgtaaatagggcagetgtcgtetatgccgtagaatcacatgatctgaggaccattcatggaa _at gctgctaaatagcctagtctggggagtcttccataaagttttgcatggagcaaacaaacaggattaaactaggtttggttccttcagccctctaaaagcatagggct agcctgcaggcttccttgggetttctctgtgtgtgtagttttgtaaacactatagcatctgttaagatccagtgtccatggaaacattcccacatgccgtgactctggact atatcagttttggaaagcagggttcctctgcctgctaacaagcccacgtggaccagtctgaatgtetttcctttacacctatgttttaagtagtcaaacttcaagaaac aatctaaacaagtttctgttgcatatgtgtttgtgaacttgtatttgtatttagtaggcttctatattgcatttaacttgtttttgtaactcctgattcttcct 596 208850 gaagcctcaagttccagtgcagagatcctacttctctgagtcagctgaccccctccccgcaatccctcaaaccttgaggagaagtggggaccccacccctcate _s _at aggagttccagtgctgcatgcgattatctacccacgtccacgcggccacctcaccctctccgcacacctctggctgtcttttgtactttttgttccagagctgcttctgtc tggtttatttaggttttatccttcctttctttgagagttcgtgaagagggaagccaggattggggacctgatggagagtgagagcatgtgaggggtagtgggatggtg gggtaccagccactggaggggtcatccatgcccatgggaccagaaacctgggagagacttggatgaggagtggttgggctgtgcctgggcctagcacggac atggtctgtcctgacagcactcctcggcaggcatggctggtgcctg 597 208851 aaagcagcgetagtggagggttggagaaggaggtaaggatgagggttcatcatccctccctgcctaaggaagctaaaagcatggccetgetgcccctccctgc _s-at ctccacccacagtggagagggctacaaaggaggacaagaccctctcaggctgtcccaagctcccaagagcttccagagctctgacccacagcctccaagtc aggtggggtggagtcccagagctgcacagggtttggcccaagtttctaagggaggcacttcctcccctcgcccatcagtgccagcccctgctggetggtgcctga gcccctcagacagccccctgccccgcaggcctgccttctcagggacttctgeggggcctgaggcaagccatggagtgagacccaggagccggacacttctca ggaaatggcttttcccaacccccagcccccacccggtggttcttcctgttctgtgactgtgtatag 598 208937 ttcagccagtcgccaagaatcatgaaagtcgccagtggcagcaccgccaccgccgccgcgggccccacgtgcgcgctgaaggccggcaagacagcgagc -s at ggtgcgggcgaggtggtgcgctgtctgtctgagcagagcgtggccatctcgcgctgccggggcgccggggcgcgcctgcctgccctgctggacgagcagcag gtaaacgtgctgctctacgacatgaacggetgttactcacgcctcaaggagctggtgcccaccctgccccagaaccgcaaggtgagcaaggtggagattctcc agcacgtcatcgactacatcagggaccttcagttggagctgaactcggaatccgaagttggaacccccgggggccgagggctgccggtccgggctccgctca gcaccctcaacggcgagatcagcgcc 599 209218 gattccctgcatcaactaagaaaagcctgttttttatttcaaacttggtggcgaatgtgttgcgggtcctgttgggetgetttctgtattgtetectaaccctetagttttaat _at tggacacttcttgctgttgcaatctatgccgtgtatttttgctttaagtcagaaccttggattacaaaacctcgagcccttctcagtagtggtgctgtattgtacaaagcgt gtctgtaatatttcctctaatttactcagaaatgaagtatatggttcattaagcttaaaggggaaccatttgtgaatgaatatttggaacttaccaagtcctaagagactt ttggaagaggatatatatagcatagtaccataccacttata 600 209395 gctgtggggatagtgaggcategcaatgtaagactogggattagtacacacttgttgatgattaatggaaatgtttacagatccccaagcctggcaagggaatttet at tcaactccctgccccctagccctccttatcaaaggacaccattggcaagctctatcaccaaggagccaaacatcctacaagacacagtgaccatactaattata ccccctgcaaagccagcttgaaaccticacttaggaacgtaatcgtgtcccctatc 601 209396 tcaccaatgccatcaaggatgcactcgctgcaacgtagccctctgttctgcacacagcacgggggccaaggatgccccgtccccctctggetccagotggccgg _s-at gagcctgatcacctgccctgctgagtcccaggctgagcctcagtctccctcccttggggcctatgcagaggtccacaacacacagatttgagctcagccctggtg ggcagagaggtagggatggggctgtggggatagtgaggcatcgcaatgtaagactcgggattagtacacacttgttgatgattaatggaaatgtttacagatccc caagcctggcaagggaatttcttcaactccctgccccctagccctccttatcaaaggacaccattttggcaagctctatcaccaaggagccaaacatcctacaag acacagtgaccatactaattataccccctgcaaagccagcttgaaacctcact 602 209596 tccaacctccttcaaattcagtcaccactgttatattaccttctccaggaaccctccagtggggaaggetgegatattagatttccttgtatgcaaagtttttgttgaaag _at ctgtgctcagaggaggtgagaggagaggaaggagaaaactgcatcataactttacagaattgaatctagagtcttccccgaaaagcccagaaacttctctgca gtactgctttcatctggtctaaggtggctgcttcttccccagccatgagtcagtttgtgcccatgaataatacacgacctgttatttccatgactgctttactgtattttt 603 209875 gaatggtgcatacaaggccatccccgttgcccaggacctgaacgegccttgattgggacagcegtgggaaggacagttatgaaacgagtcagetggatgac _s-at cagagtgctgaaacccacagccacaagcagtccagattatataagcggaaagctaatgatgagagcaatgagcattccgatgtgattgatagtcaggaactttc caaagtcagccgtgaattccacagccatgaatttcacagccatgaagatatgctggttgtagaccccaaaagtaaggaagaagataaacacctgaaatttcgta tttctcatgaattagatagtgcatcttctgaggtcaattaaaaggagaaaaaatacaatttctcactttgcatttagtcaaaagaaaaaatgctttatagcaaaatgaa agagaacatgaaatgcttctttctcagtttattggttgaatgtgtatctatttgagtctggaaataactgatgtgtttgataattagtttagtttgtggcttcatggaa 604 209955 acagetttccaaggtgacaaactcctctatgcagtgtatcgaaagetgggtgtttatgaagttgaagaccagattacagetgtcagaaaattcatagaaatgggttt _s-at cattgatgaaaaaagaatagccatatggggctggtcctatggaggatacgtttcatcactggcccttgcatctggaactggtcttttcaaatgtggtatagcagtggct ccagtctccagctgggaatattacgcgtctgtctacacagagagattcatgggtctcccaacaaaggatgataatcttgagcactataagaattcaactgtgatgg caagagcagaatatttcagaaatgtagactatcttctcatccacggaacagcagatgataatgtgcactttcagaactcagcacagattgctaaagotctggttaat gcacaagtggatttccaggcaatgtggtactctgaccagaaccacggcttatccggcctgtccacgaaccacttatacacccacatgacccacttcctaaagcag tg 605 210095 tcttttgtectccttagcacaatgtaaaaaagaatagtaatatcagaacaggaaggaggaatggettgetggggagcccatccaggacactgggagcacataga -s-at gattcacccatgtttgttgaacttagagtcattctcatgcttttctttataattcacacatatatgcagagaagatatgttcttgttaacattgtatacaacatagccccaaat atagtaagatctatactagataatcctagatgaaatgttagagatgctatatgatacaactgtggccatgactgaggaaaggagotcacgcccagagactgggct gctctcccggaggccaaacccaagaaggtctggcaaagtcaggctcagggagactctgccctgctgcagacctcggtgtggacacacgetgcatagagetct I_ I ccttgaaaacagaggggtctcaagacattctgcctacctattagc 606 210511 aaaggagcagtcgcacagacctttoctcatgotgcaggcccggcagtetgaagaccaccetcategceggcgtcggcggggettggagtgtgatggcaaggte s at aacatctgctgtaagaaacagttctttgtcagtttcaaggacatcggctggaatgactggatcattgctccctctggctatcatgccaactactgcgagggtgagtgc ccgagccatatagcaggcacgtccgggtcctcactgtccttccactcaacagtcatcaaccactaccgcatgcggggccatagcccctttgccaacctcaaatcg tgctgtgtgcccaccaagctgagacccatgtccatgttgtactatgatgatggtcaaaacatcatcaaaaaggacattcagaacatgatcgtggaggagtgtgggt gctcatagagttgcccagc 607 211571 acaagcatectgtetcacgaagaacaaatgtttgtaatcgtgtgggccatgattatcagtggataggcctcaatgacaagatgtttgagcatgacttccgttggact _s-at gatggcagcacactgcaatacgagaattggagacccaaccagccagacagcttcttttctgctggagaagactgtgttgtaatcatttggcatgagaatggccag tggaatgatgttccctgcaattaccatctcacctatacgtgcaagaaaggaacagttgcttgcggccagccccctgttgtagaaaatgccaagacctttggaaaga tgaaacctcgttatgaaatcaactccctgattagataccactgcaaagatggtttcattcaacgtcaccttccaactatccggtgcttaggaaatggaagatgggcta tacctaaaattacctgcatgaacccatctgcataccaaaggacttattctatgaaatactttaaaaattcctcatcagcaaaggacaattcaataaatacatccaaa catgatcatcgttggagccggaggtgg 608 211966 tggtgatgtetgctactatgccagccggaacgacaagtectactggetetetaccactgegccgctgcccatgatgcccgtggcegaggacgagatcaagcccta -at catcagccgctgttctgtgtgtgaggccccggccatcgccatcgcggtccacagtcaggatgtctccatcccacactgcccagctgggtggcggagtttgtggate ggatattccttcctcatgcacacggcggcgggagacgaaggcggtggccaatcactggtgtcaccgggcagctgtctagaggacttccgcgccacaccattcat cgaatgcaatggaggccgcggcacctgccactactacgccaacaagtacagcttctggctgaccaccattccogagcagagcttccagggctcgccctccgcc gacacgctcaaggccggcctcatccgcacacacatcagccgtgccaggtgtgcatgaagaacctgtgagctggcgcgtgccaggaagggccattggtgc ttattcttaacttattacctcaggtgccaacccaaaa 609 211980 gaaagactgtgetgtcctttaacataggttttaaagactaggatattgaatgtgaaacatecgttttcattgttcacttctaaaccaaaaattatgtgttgccaaaacca _at aacccaggttcatgaatatggtgtctattatagtgaaacatgtacttgagcttattgtttttattctgtattaaatattttcagggttttaaacactaatcacaaactgaatga cttgactcaaaagcaacaaccttaaaggccgtcatttcattagtattcctcattctgcatcctggcttgaaaaacagctctgtgaatcacagtatcagtattttcacac gtaagcacattcgggccatttccgtggtttctcatgagctgtgttcacagacctcagcagggcatcgcatggaccgcaggagggcagattcggaccact 610 211981 tcggetactcttgtgatgcacaccagegetggtgcagaaggetetggccaagccetggcgtcccoggetectgcctggaggagtttagaagtgcgccattcat _at cgagtgtcacggccgtgggacctgcaattactacgcaaacgottacagcttttggctcgccaccatagagaggagcgagatgttcaagaagcctacgccgtcca ccttgaaggcaggggagctgcgcacgcacgtcagccgctgccaagtctgtatgagaagaacataatgaagcctgactcagctaatgtcacaacatggtgctac ttcttcttctttttgttaacagcaacgaaccctagaaatatatcctgtgtacctcactgtccaatatgaaaaccgtaaagtgccttataggaatttgcgtaactaacacac cctgc 611 212344 ggaaaacacctcatttgaccttgccagetgaccttcaaaccctgcatttgaaccgaccaacattaagtecagagagtaaacttgaatggaataacgacattccag _at aagttaatcatttgaattctgaacactggagaaaaaccgaaaaatggacggggcatgaagagactaatcatctggnaaaccgatttcagtggcgatggcatga cagagctagagctcgggcccagccccaggctgcagcccattcgcaggcacccgaaagaacttccccagtatggtggtcctggaaaggacatttttgaagatca actatatcttcctgtgcattccgatggaatttcagttcatcagatgttcaccatggccaccgcagaacaccgaagtaattccagcatagcggggaagatgttgacca aggtggagaagaatcacgaaaaggagaagtcacagcacctagaaggcagcgcctcctcttcactctcctctgattagatgaaactgttaccttacccta 612 212353 aatatccttgttgtgtattaggtttttaaataccagctaaaggattacctcactgagtcatcagtaccctcctattcagctccccaagatgatgtgtttttgcttaccctaag _at agaggttttcttcttatttttagataattcaagtgcttagataaattatgttttctttaagtgtttatggtaaactcttttaaagaaaatttaatatgttatagctgaatctttttggta actttaaatctttatcatagactctgtacatatgttcaaattagctgcttgcctgatgtgtgtatcatcggtgggatgacagaacaaacatatttatgatcatgaataatgt gctttgtaaaaagatttcaagttattaggaagcatactctgttttttaatca 613 212354 gtgtgcacacggagactcategttataatttactatctgccaagagtagaaagaaaggetggggatatttgggttggettggttttgattttttgottgtttgtttgttttgtac _at taaaacagtattatcttttgaatatcgtagggacataagtatatacatgttatccaatcaagatggctagaatggtgcctttctgagtgtctaaaacttgacacccctgg taaatctttcaacacacttccactgcctgcgtaatgaagttttgattcatttttaaccactggaatttttcaatgccgtcatttcagttagatgattttgcactttgagattaaa atgccatgtctatttgattagtcttattatttattttacaggctatcagtctcactgttggctgtcattgtgacaaagtcaaataaacccccaaggacgacacacagtat ggatcacatattgtttgacattaagctttgccagaaaatgttgcatgtgttttacctcgactt 614 212488 gaaaggegatetettcactgtgaaaagttgcccgggtgcagegcctttccttctaccatgggaaatgcaggetgggccettggggtgagcctgcggggetetggt _at gctgtccccgacccccaccaccaccagaatgcagttccagcttaggaagccacaaacaagccacccaggaggaacaaaacaccgccagcgtggattttcc aaatttccctggaaagtaagtctcgctcttgccaaagaaaagtctggcttggagagtctctggagcccaggatgccagcatgtgccaatgactgtcaccttcatctc ttcaaaagaaaagccatagccgaggactgtcccgcgacccccgtggactgcgtctaggtcatgtgattctgattcatttctcatcccatccaatttgtccttttctcctgt cattttcttcctctgtggtcccttcaaagttgttataatttgtactgaacttcaaaatgtgtcccgttctccccagaccactctagccacagtatatt 615 212489 attgaaaagcaggtaccagtgcccettttcagacagtttttgatgetetagacnttttttnttttttaatagggagggaaaaaatttgataattttettntttctacatgcac _-at ttaagactaaaacacaggtttgg attaattttatttgcttcctttttccgcetttcttcccgcag agcctgatgg gag aatgtccagggcaggg aaaccacattttttgtag gtgataactcaatgaaaattggtgcttatttttacacttctctcttgtggetctcttgtggtgctatctgttttaaggtctccttgaaggcgcactggggtccctggccatgcc tcgttctccctgctttctttatcctgttattgcctccacagtctgttgccaaggactctaagatcaatgcacgtcactttcctttccactgggcaggatagccaagcacact ccctcctgcgctctcccgccccggtgcgtccactcccgagggctgttatgaggactgggttgtgcctacttgatttgaaaacacacac 616 213106 acttetcagcaaataaateteccttaagtaggaaanctagatttcatattngettnctttgaattaacagcaactttccacaggtaaatctgttcttgcaaagatgtgag _at cagaatagttaaaaataatatttttatgtttcatggttctaaatggaagccataaatgcagtaaatactatctgttgtttaactactttaatcgtcattttttacattttcaagttt attaggttaagaaaaacagggcagccttggaaggcagctactacagaaaactgcagttttgcgttaaagataaagtagtattttcagctccctgaaaaaccattcc tgctgaaactgctgtagaaattgtgaagctgcatgagtggagagtattgaatctgtggttatagtagttttctcaggtttgtttatcttgatgtttgatgcactgtgttttatagt I tattaaaattgagtaatattatttctatgcagtgttatgtgtcattggccttttgtgaatgtgcatgttttaaactgcaaattttaaacattttgtcctctaattgttat 617 213125 gaatgagtattcctatacgacccagatagactacaaccccaaggaccgcctgotctatgcctgggacaatggccaccaggtcacttaccatgtcatctttgcctac at tgacacccttgtccccacaagcagaagcacagaggggtcactagcaccttgtgtgtatgtgtgtgcgcgcacgtgtgtgtaggtgggtatgtgttgtttaaaaatata tattattttgtataatattgcaaatgtaaaatgacaatttgggtctatttttttatatggattgtagatcaatccatacgtgtatgtgctggtctcatcctccccagtttatatttttg tgcaaatgaacttctcctttgaccagtaaccaccttccttcaagccttcagcccctccagctccaagtctcagatctcgaccattgaaaaggtttcttcatctgggtctt gcaggaggcaggcaacac 618 213524 gtgeteggcctgatggagactgtgtgcagcccettcacggcogccagacgtetgegggaccaggaggcagcegtggeggagetgcaggcegccetggagog sat acaggctctccagaagcaagccctgcaggagaaaggcaagcagcaggacacggtcctcggcggccgggccctgtccaaccggcagcacgcctcctagga actgtgggagaccagcggagtgggagggagacgcagtagacagagacagaccgagaaggaagggagagacagagggggcgcgcgcacaggagcct gactccgctgggagagtgcaggagcacgtgctgtttatttggacttaacttcagagaaaccgctgacatctagaactgacctaccacaagcatccaccaaag gagtttgggattgagtttntgctgctgtgcagcactgcattgtcatgacatttccaacactgtgtgaattatctaaatgcgtctaccattttgcactagggag 619 213869 cacagcctccaagtcaggtggggtggagtcccagagetgcacagggtttggcccaagtttctaagggaggcacttcctccentegcccatcagtgccagcccet _x-at gctggctggtgcctgagcccctcagacagccccctgccccgcaggcctgccttctcagggacttctgcggggcctgaggcaagccatggagtgagacccagg agccggacacttctcaggaaatggcttttcccaacccccagcccnccacccggtggttcttcctgttctgtgactgtgtatagtgccaccacagcttatggcatctcat tgaggacaaagaaaactgcacaataaaaccaagcctctggaatctgtcctcgtgtccacctggccttcgctcctccancagtgcctgcctgnccccncttcgctg gggtctccacgggtgaggetggggaacgccacctcttcctcttccctgacttctccccaaccacttagtagcaacgctaccccaggggctaatgactgcacactg ggcttcttttcagaatgaccctaacgagacacatttgcccaaa 620 213905 cacaaaaccccagggacagcggtctccccagcctgccetgetcangccttgcccccaaacctgtactgtcccggaggaggttgggaggtggaggcccagcat _x-at cccgcgcagatgacaccggtttcctagaagcccctcacccccactggcccactggtggctaggtctccccttatccttctggtccagcgcaaggaggggctgctt ctgaggtcggtggctgtctttccattaaagaaacaccgtg 621 214234 gaatgaagaaaagtcgcctcaacgacaaacaaaagcaccgactagatttccttcagetgatgattgactcccagaattegaaagaaactgagteccacaaag _s-at ctctgtctgatctggagctcgcagcccagtcaataatcttcatttgctggctatgaaaccaccagcagtgttctttccttcactttatatgaactggccactcaccctga tgtccagcagaaactgcaaaaggagattgatgcagtttgcccaata 622 214235 ggtgaggggatgacccetggagatgaagggaagaggtgaagccttagcaaaaatgcctcctcaccactccccaggagaatttttataaaaagcataatcactg _at attccttcactgacataatgtaggaagcctctgaggagaaaaacaaagggagaaacatagagaacggttgctactggcagaagcataagatetttgtacaatat tgctggccctggttcacctgtttactgttatcacaata 623 214247 acttaggtaattgtagggcgaggattataaatgaaatttgcaaaatcacttagcagcaaetgaagacaattatcaaccacgtggagaaaatcaaaccgagcag _s-at ggctgtgtgaaacatggttgtaatatgcgactgcgaacactgaactctacgccactccacaaatgatgttttcaggtgtcatggactgttgccaccatgtattcatcca gagttcttaaagtttaaagttgcacatgattgtataagcatgcttcttgagttttaaat 624 215646 tetcacctatacgtgcaagaaaggaacagttgettgeggccancccctgttgtagaaaatgccaagacotttggaaagatgaaacctogttatgaaatcaaetcc s at ctgattagataccacntgcaaagatggtttcattcaacgtcaccttccaactatccggtgcttaggaaatggaagatgggctatacctaaaattacctgcatgaacc 625 217430 agggcctaagggtgacagaggtgatgotggteccaaaggtgetgatggetetectggcaaagatggcgtcegtggtetgaccggccccattggtctcetggccc x at tgctggtgcccctggtgacaagggggaccccattcccgaggagctttatgag 626 217763 aacattgtaatggccategetggaaacaagtgegacctctcagatattagggaggttcccetgaaggatgetaaggaatacgetgaatccataggtgccategtg _s-at gttgagacaagtgcaaaaaatgctattaatatcgaagagctctttcaaggaatcagccgccagatcccacccttggacccccatgaaaatggaaacaatggaa caatcaaagttgagaagccaaccatgcaagccagccgccggtgctgttgacccaagggcgtggtccacggtacttgaagaagccagagcccacatcctgtgc actgctgaaggaccctacgctcggtggcctggcacctcactttgagaagagtgagcacactggctttgcatcctggaggcctgcagggggcggggcaggaa atgtacctgaaaaggattttagaaaaccctgggaaacccaccacaccaccacaaaatggcctttagtgt 627 218211 gccacaccttcgcgaaacctgtggtggcccaccagtcctaacgggacaggacagagagacagagcagccctgcactgtttccctccaccacagccatcctgt _s-at ccctcattggctctgtgctttccactatacacagtcaccgtcccaatgagaaacaagaaggagcaccctccacatggactcccacctgcaagtggacagcgaca tcagtcctgcactgctcacctgggtttactgatgactcctggctgccccaccatcctctctgatctgtgagaaacagctaagctgctgtgacttccctttaggacaatg ttgtgtaaatctttgaaggacacaccgaagaccttatactgtgatcttttaccccttcactctggcttcttatgttgc 628 218638 ctgccccgagctegaagaagaggetgagtgegtecctgataactgegtetaagaccagagcccogcagcccetggggcccccggagccatggggtgtcggg _s at ggctcctgtgcaggctcatgctgcaggcggccgaggcacagggggtttcgcgctgctcctgaccgcggtgaggccgcgccgaccatctctgcactgaagggcc ctctggtggccggcacgggcattgggaaacagcctcctcctttcccaaccttgcttcttaggggcccccgtgtcccgtctgctctcagcctcctcctcctgcaggata aagtcatccccaaggctccagctactctaaattatggtctccttataagttattgctgctccaggagattgtcctcatcgtccaggggcctggctcccacgtggttgca gatacctcagacctggtgctctaggctgtgctgagcccactctcccgagggcgcatccaagcgggggccacttgagaagtgaataaatggggcggttteggaa gcgtcagtgtttccatgttatgg 629 219955 gaagttgcaacattcgtttgataggaattccagaaaaggagagttatgagaatagggcagaggacataattaaagaaataattgatgaaaaetttgcagaacta _at aagaaaggttcaagtcttgagattgtcagtgettgtcgagtacctagtaaaattgatgaaaagagactgactcctagacacatcttggtgaaattttggaattctagtg ataaagagaaaataataagggcttctagagagagaagagaaattacctaccaaggaacaagaatcaggttgacagcagacttatcactggacacactggat gctagaagtaaatggagcaatgtcttcaaagttctgctggaaaaaggctttaatcctagaatcctatatccagccaaaatggcatttgattttaggggcaaaacaa aggtatttcttagtattgaagaattagagattatgttttgcatatgcccaccttgagagaattactggggaataatataccttagcacgccagggtgactaca 630 221011 gagtggtcatccatactctcattccctogcctcccettgtggacgggggtettgccttcaattcctgtgttttggtgtettccettatetgetaccetgaatcacctgtcctg _s at gtcttgctgtgtgatgggaacatgcttgtaaactgcgtaacaaatctactttgtgtatgtgtctgtttatgggggtggtttattatttttgctggtccctagaccactttgtatga ccgtttgcagtetgagcaggccaggggctgacagctaatgtcaggaccctcagcggtggagcctgctggggggacccagctgctcttggacaagtggctgagc tcctatctggcctcctcttttttttttttttcaagtaatttgtgtgtatttctaactgattgtattgaaaaaattcctagtatttcagtaaaaatgcctgttgtgagatgaacctcctgt I_ aacttctatctgttcttttttgaggctcaggga 631 221729 tggaattagaccatttggcctttgaaetttcataggaaaaatgacccaacattttagcatgagctacctcatetetagaagetgggatggacttactattettgtttata _at ttttagatactgaaaggtgctatgcttctgttattattccaagactggagataggcagggctaaaaaggtattattatttttcctttaatgatggtgctaaaattcttcctata | aaattccttaaaaataaagatggtttaatcactaccattgtgaaaacataactgttagacttcccgtttctgaaagaaagagcatcgttccaatgcttgttcactgttcct ctgtcatactgtatctggaatgctttgtaatacttgcatgcttcttagaccagaacatgtaggtccccttgtgtctcaatactttttttttcttaattgcatttgttggctctatttta attt 632 221730 tagattccggtatatcgttcttcaagacacttgctctaagcggaatggaaatgtgggcaagactgtctttgaatatagaacacagaatgtggcacgcttgcccatcat _at agatcttgctcctgtggatgttggcggcacagaccaggaattcggcgttgaaattgggccagtttgttttgtgtaaagtaagccaagacacatcgacaatgagcac caccatcaatgaccaccgccattcacaagaactttgactgtttgaagttgatcctgagactcttgaagtaatggctgatcctgcatcagcattgtatatatggtcttaag tgcctggcctccttatccttcagaatatttattacttacaatcctcaagttttaattgattttaaatatttttcaatacaacagtttaggtttaagatgaccaatgacaatgac cacctt 633 221731 tttcagcaccgatggccatgtaaataagatgatttaatgttgatttaatcctgtatataaantaaaaagtncncaatgagtttngggcatatttaatgatgattatggag _ x-at ccttagaggtctttaatcattggttcnggetgcttttatgtagtttaggctggaaatggtttcacttgctctttgactgtcagcaagactgaagatggcttttcctggacagct agaaaacacaaaatcttgtaggtcattgcacctatctcagccataggtgcagtttgcttctacatgatgctaaaggctgcgaatgggatcctgatggaactaagga ctccaatgtcgaactcttctttgctgcattccttttcttcacttacaagaaaggcctgaatggaggacttttctgtaaccaggaacattttttaggggtcaaagtgctaat I aattaactcaaccaggtctacttttaatggctttcataacactaactcataaggttaccgatcaatgcatttcatacggatatagacctagggctctggagggtg ggg 634 221874 ctggcctacgtgttcaattttctatgaacaaaggetttagtcttgacccagggetaaagtggtetgiccaagetgttgttggtagagggagtatgataaaatgtttaaa _at tctcatttggttaccttgagtcctggaacacgcagtaactgtcatgctatagtcntcatctgtatttggctgggaatacaaatgaagattgtggtgtattcaagcagtag ggttttgcttgtttgttagtgccaacaaaacttgtctgactacattaaagataagactgactatatttatacaacagaaactttgtaatagattttttcagctttgt gaaatcgaattttttttcatcagggctggttggatttcctttttaccctgtaatccaagcgttaatagttgttagaagatgggtatgcatgtcactt 635 223969 gaagatcaaggatgttctcaacagtetagagtacagtccctctcctataagcaagaagetctcgtgtgetagtgtcaaaagccaaggcagaccgtcctcctgccct _s-at gctgggatggctgtcactggctgtgcttgtggctatggetgtggttcgtgggatgttcagctggaaaccacctgccactgccagtgcagtgtggtggactggaccact gcccgctgctgccacctgacctgacagggaggaggctgagaactcagttttgtgaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaa acgtcccacttcatttgttccattcctgattcttgggtaataaa 636 223970 ggagotcagagatetaagetgetttccatetttteteccagccccaggacactgactctgtacaggatggggccgtectcttgcctccttetcatectaatcccettetc _at cagctgatcaacccggggagtactcagtgttccttagactccgttatggataagaagatcaaggatgttctcaacagtctagagtacagtccctctcctataagcaa gaagctctcgtgtgctagtgtcaaaagccaaggcagaccgtcctcctgccctgctgggatggctgtcactggctgtgcttgtggctatggetgtggttcgtgggatgtt cagctggaaaccacctgccactgccagtgcagtgtggtggactggaccactgcccgctgctgccacctgacctgacagggaggaggctgagaactcagttttgt gaccatgacagtaatgaaaccagggtcccaaccaagaaatctaactcaaacgtcccact 637 224724 gcctgagaaagcaagcacgcactctcagtcaacatgacagattetggaggataaccagcaggagcagagataacttcaggaagtecatttttgcccetgetttig _at ctttggattatacctcaccagctgcacaaaatgcatttttcgtatcaaaaagtcaccactaaccctcccccagaagctcacaaaggaaaacggagagagcgag cgagagagatttccttggaaatttctcccaagggcgaaagtcattggaatttttaaatcataggggaaaagcagtcctgttctaaatcctcttattcttttggtttgtcaca aagaaggaactaagaagcaggacagaggcaacgtggagaggctgaaaacagtgcagagacgtttgacaatgagtcagtagcacaaaagagatgacattt acctagcactataaaccctggttgcctctgaagaaactgccttcattgtatatatgtgactatttacatgtaatcaacatgggaacttttaggggaacctaataagaaa tcccaattttcaggagtggtggtgtcaataaacgctctgtggccagtg 638 225664 ggaacccagagetgetgtgtattgagegggcagtttatettttgetatacttatttcaattcaattacaccacgattcaaataattcccetectaaaaccaaaaagg _at agggaaacgtcaactccattgcaattacttatcttcctcttctatctctgttatacgccggggcatagaatgctcgtatacatctctttaacaaccacaaaccttaagcc atgtagatgaagttagtgcatcaacgggatacagttccatattgccttaaacctccttgttttagacacactaacatttataccaaattgcagattattctgcagagagg gaattgcatgtttgtgttgta 639 225681 aattaatattcategcacttcttctgtggaaggactttgtgaaggaattggtgetggattagtggatgttgetatctgggttggcacttgttcagattacccaaaaggaga _at tgcttctactggatggaattcagtttctcgcatcattattgaagaactaccaaaataaatgctttaattttcatttgctacctcttttttattatgccttggaatggttcacttaa atgacattttaaataagtttatgtatacatctgaatgaaaagcaaagctaaatatgtttacagaccaaagtgtgatttcacactgtttttaaatctagcattattcattttgct tcaatcaaaagtggtttcaatattttttttagttggttagaatactttcttcatagtcacattctctcaacctataatttggaatattgttgtggtcttttgttttttctcttagtatagc atttttaaaaaaatataaaagctaccaatcttgtacaattg 640 225799 aaatgactggatggtcgetgetttaagtttcaaattgacattccagacaageggtgcctgagcccgtgcctgtettcagatettcacagcacagttectgggaaggt _at ggagccaccagcctctccntgaataactgggagatgaaacaggaagctctatgacacacttgatcgaatatgacagacacngaaaatcacgactcancccc ctccagcacctctacctgttgcccgccgatcacagccggaatgcagctgaaagattccctggggcctggttccaaccgcccactgtggactctgaggcctctgca tttgcgggtggtctgcctgtgatattttggtcatgggctggtctg 641 226237 gaagaggagcaacatctatgccaaatactgtgcattctacaatggtgetaatetcagacetaaatgatactccatttaatttaaaaaagagttttaaataattatctat _at gtgcctgtatttcccttttgagtgctgcacaacatgttaacatattagtgtaaaagcagatgaaacaaccacgtgttctaaagtctagggattgtgctataatccctattt agttcaaaattaaccagaattcttccatgtgaaatggaccaaactcatattattgttatgtaaatacagagttttaatgcagtatgacatcccacaggggaaaagaat gtctgtagtgggtgactgttatcaaatattttatagaatacaatgaacggtgaacagactggtaactgtttgagttcccatgacagatttgagacttg 642 226248 tgaaagtgggcatetetgcaggcacctgtactgccatectgetcaccgtettgacctgctacttttggaaaaagaatcaaaanctagagtacangtactccanget _s-at ggtgatgaatgctactctcaaggactgnnnnntnncngnngctgacagctgcgccatcatggnanncnnnnangnanngnnnnnnnncancnnnnnnc anntgcgccatcatggaaggcgaggatgtagaggacgacctcatctttaccagcaagaagtcactctttgggaagatcaaatcatttacctccaagaggactcct gatggatttgactcagtgccgctgaagacatcctcaggaggcccagacatggacctgtgagaggcactgcctgcctcacctgcctcctcaccttgcatagcacctt tgcaagcctgcggcgatttgggtgccagcatcctgcaacacccactgctggaaatctcttcattgtggccttatcagatgtttgaatttcagatctttttttatagagtacc caaaccctcctttctgcttgcctcaaacctgccaaatatacccacac 643 226311 aaacgacgcaaatetetgagetggggaccacttggagaaccggettagtaacagtcetgatetgcaagccagettettetgcatetgaggggetectggegcc _at cagaggaggcagacagatgtcttctagctgagtttctaaccgcatgatgagactcagaccttccgctgcactagaaaatctgcaacagtgtccctgagtcacttct ccttagtgggcagactcgtgttagatttgtggaacccagctctctgatttactccttttggaaaacccatggaatttcatgtataaggctttcatttgtattttaaggtttttctg Itttgttttgagtatatacatggtgctcaatagcaacatcttagcagatgaagcagtttatgattccactccctcctgtatgacaggtagccactatactgaatcaaggtg ctgaactcaaatcacaaaattctggcttaccgatacaacaaccaatac 644 226777 tataaggtaactctttagtcctccatttagcacattttaaatcctccaaagaataagtatcatgtgattattagctttacaaaaaaaaagttgaatggcgtttattttcat _at ggcctataagcaggtaccttagtagggcagatataggaaaaacaaattagagcaaaacaaatcctctacaaatccaaggcaggaaaagtggtggcagagtg actcattctcctgtccctcccatcaggtcaaatcaggaggetgcagtgaatgcctgttctttgaatgtgtagcagttgttncctgtaactctttaaaacttggctatagget gtttagcacagtacagattaaagatacagttacgtaaacagcaaagtaattttatagtgettcatccatttatcatgctttggtttgctaatttttcacatacctttttctatca cagtctgttgcttttgtacacatttctcatattggggttcgaca 645 226930 ggtgccaggaaggtcacagatggacactggccattggtcatetcagtetggaactcagtoccactettggcctggacaatgaacaggattcagttttgetgttaa -at ctttgcttctctacttttttftgtttgtttgtaatagcacatcccagagacatcagaaaccagcaactgattcagtgtgatttccagactttttaggcatgaaattcggacact tcagtatttccaggaatagcatatgcacgctgttcttgcttcatggaatgctacatgctttctgtttttctcatttggatttctccaaaactaactgaatttaagcttcaggtcc ctttgtatgcagtagaaaggaattattaaaaacaccaccaaagaaaataaatatatcctactgaaatttactctatggacttacccactgctagaataaatgtatca aatcttatttgtaaattctcaattttgatatatatatgtatatatgcatatacatatccacactgtctgcaag 646 227140 ttaccetctatttaaatgotttgaaaaacagtgcattgacaatgggttgatatttttctttaaaagaaaaatataattatgaaagccaagataatctgaagcctgttttatt _at taaaactttttatgttctgtggttgatgttgttgtttgtttgtttctatttgttggttttttactttgtttttgtttgttttgttttgtttgcatactacatgcagttctttaaccaatgtctgttt ggctaatgtaattaaagttgttaatttatatgagtgcatttcaactatgtcaatggtttcttaatatttattgtgtagaagtactggtaattttttatttacaatatgtttaaagag ataacagtttgatatgttcatgtgtttatagcagaagttatttatttctatggcattccagcggatattttggtgtttgcgaggcatgcagtcaatattttgtacagttagtgg acagtattcagcaacgcctgatagcttctttggcctt 647 227566 ccacacaccaggcactaatcacctggtgaggatttggcatatccaccaaaaaatgcatccgatttaaccaacatetccaccagegetacggactcctcccaatte _at tgacatctcttgcagacaatactatgctctctacacactgtttagaaatggaaaggtgatctgcactgtatcttgggtttgttggctatgcttcctttgatgacatatattata cagtatatatatacatatattttttttgttagagttctagccattttatttctccgcagggtcctttctcagacattactgcatgctgtatatggcgttagctgtgtgttgatttcta aaagatgatagagtttactggtaatgtgtaatcagctcctgcctttttatt 648 227676 caggaaactcttttgacttggggagttcctacgeganacaaetgggettccgggacagetgggtettcataggagccaaagacctcaggggtaaaagcccet _at ttgagcagttcttaaagaacagcccagacacaaacaaatacgagggatggccagagctgctggagatggagggctgcatgcccccgaagccattttagggtg gctgtggetcttcctcagccaggggcctgaagaagctcctgcctgacttaggagtcagagcccggcaggggctgaggaggaggagcagggggtgctgcgtgg aaggtgctgcaggtccttgcacgctgtgtcgcgcctctcctcctcggaaacagaaccctcccacagcacatcctacccggaagaccagcctcagagggtccttct ggaaccagctgtctgtggagagaatggggtgctttcgtcagggactgctgacggctggtcctgaggaaggacaaactgcccagactgagcc 649 227719 cacttgatagactgtaagcacctgettaactttgtgteccaaatatttagtgtgtatatatatatatatatannoncacacacacacatatatattcaacaaataaagca _at aaatataacatgcatttcacattttgtctttccctgttacgattttaatagcagaactgtatgacaagtttaggtgatcctagcatatgttaaattcaaattaatgtaaaaca gataacacacaaagaaactgtctatttgagtgaagtcatgctttctattataataacttggcttcggttatccatcaaatgcacacttatactgttatctgattg 650 229218 gccaaaaggcctggettgataggaaactggtaagaaaetettcatgaaaacacatcactaatattegetattactctcctggtetgaagicagottttetgaaccat _-at taaggtatttcatcacaagttatattttataatatcagtttaagaggcttttattcatgtgaacaccagnnccctttcaggggcatggtetttttgaaaaaaaaaaaanaa aaaaannaacagttttagccacatatcagatatttctatatctaattatcctttatggctaacattctgcctccattgttaaggtataattgttcctgaatttaaaggtggttt ggcctctaatttaattctgattcagactctcctgtcaggactcaagaaaatttaattaattaccaaggattaagtcttctggttaaggtttctgggaaaaaaaaatagca aagatgtgatttcttggaatccttttacaggttcataacagaaaaatctcatccctgtaggcatttaattaaacctagttgagaagtgtgtgggattcctcaattatga acaaaacacgtatattggcttcttt 651 229802 gacatgattgtctataatctogetagccttgtactgtgtgtgcatagcaattacagggaagtaatctagctectgactattatgttgaactatgtcgctgctttttacaaact _at tgtcttgatccaaagcagtcacaatgataaccctgcatatctgggaatcataagtcaactatgtatctctgtgtgtgtatatatatgtatgtatgtatctattttcaaactgt gatttaatatttaaatattcctactgccatattgtgactgaaaaactacacatgaggaaacgtcttagaattttccaatagaggaaaaataacacttgggcaatctgtc atgtttcacaacagttctcatttttctcatgatttgtgtagcgtggaatgtgtttgctcaatgtgaagggttttcattgctcaattctctgtgtaa 652 231766 ggttccggetaacacattttctaagtcgccagtgetgettacagtttgaatacatgaaaatectgtttctnagatgtttgegcacgtgettattaggaaatgagtetgtatg _s-at gaaatctcaccacagataatggttaacgaaccgggtcgacatcacaaaggagggtggagactctttttactaacttgaatgagacaaaagcagtggtgtcagttt ataatcctgatgcatttcagtaataatgtagaaaaacattattttaaaaaagttccaacacacagccatgaggagccnnnnnnnnnntcagttttgaaagaggtg cataataaaactactaaccagaggagtctatgccatttt 653 231832 gagtttcaactttaaatgttcactatgtcatttagtgtecanctttacggataggttgactatetaaataggcatttttagtcattaaaaaaaantctagtcaccaggagg _at atccctataactcaaaataacttgtttgtaaaagaaaatttgtttacttacccattagtaagttcctgcatattcattataagatggcaaatcaaacttttctaggatgaag acagttatttttaagttgtatagtcttagttggtttagggtctcaatttaataataaaatacttggtttttatttgcttgtccttttgaattcctgttttaataatttaaaatgagc acaaagaangttgaagtcagattaatctctctgaatgatgtttttttcctctgtgatgagtgtttctg 654 231879 tgetgtagtcactggtgtetcacccaccagetgtaaetcagttgtgtgaggtacagccacagaagatgtcatgtactgtatattacctggtgatagttgettttcacc -at ccccgagttcagtttctaggagccaatgaaacttcccctcacctcctcatctttccaagttgttctttgaattgaggagtttgaaggcataaacagttacttggggatttg cgaaaatcctacttagttactgcgtttacagttctttggcccagtctctgacccttcccnagtatttgtgcnatgattgtgtttactgctggatttttgaaggttttttttttnnaa gaaagtgccatttcattatttgatt 655 232176 gggatcactgggagaagccatggcattatettcaggcaatttagtetgteccaaataaaataaatecttgcatgtaaatcattcaagggttatagtaatatttcatata _at ctgaaaagtgtctcataggagtcctcttgcacatctaaaaaggctgaacatttaagtatcccgaattttcttgaattgctttccctatagattaattacaattggatttcatc atttaaaaaccatacttgtatatgtagttataatatgtaaggaatacattgtttataaccagtatgtacttcaaaaatgtgtattgtcaaacatacctaactttcttgcaata aatgcaaaagaaactggaacttgacaattataaatagtaatagtgaagaaaaaatagaaaggttgcaattatataggccatgggtggctcaaaactttgaa 656 232458 gattcctggattgatgtettatctacaggettctttttaaaaatnnnnnnngattggetgtgagtttaccaggattatagttgaggetaaaggacagctectcaggaaa -at gcccctgttctacatctacggtcacatgctggaccttgagttgtcactcagagaaaagagtgccatctaccgaaactccacagtttccattgtgaatggettctttggt IgcagagttccaaaaattatgtagcccagotctttaattttgtaacatctaatgatatcaccgccttgaagtgattaaagtagattgcttaaagaattaaagctttaaagaI tgaaagatgttattgcttttgctggacatgaggaacagttgtaaagtttccaggtctacaataactttctgganccctctcagtgaactgtttcttgta 657 232481 gaagtecatectttggtccaaagcatctggaagaggaagaagagaggaatgagaaagaaggaagtgatgcaaaacatctccaaagaagtettttggaacag _s-at gaaaatcattcaccactcacagggtcaaatatgaaatacaaaaccacgaaccaatcaacagaatttttatccttccaagatgccagctcattgtacagaaacattt tagaaaaagaaagggaacttcagcaactgggaatcacagaatacctaaggaaaaacattgctcagctccagcctgatatggaggcacattatcctggagccc acgaagagctgaagttaatggaaacattaatgtactcacgtccaaggaaggtattagtggaacagacaaaaaatgagtattttgaacttaaagctaatttacatg ctgaacctgactatttagaagtcctggagcagcaaacatagatggagagtttgagggctttcgcagaaatgctgtgattctgttttaagtccataccttgtaaataagt gccttacgtgagtgtgtcatcaatcagaacctaagc 658 233555 getgetcaagegcctgcagaacaacgacacgtgcagcatgccaggcctcacgtgettcacccacgacaaccagcactggcagacggegcctttetggacact _s-at ggggcctttctgtgcctgcaccagcgccaacaataacacgtactggtgcatgaggaccatcaatgagactcacaatttcctcttctgtgaatttgcaactggcttcct agagtactttgatctcaacacagacccctaccagctgatgaatgcagtgaacacactggacagggatgtcctcaaccagctacacgtacagtcatggagctg aggagctgcaagggttacaagcagtgtaacccccggactcgaaacatggacctgg 659 234994 acaatcggctaacctgacatttctttttaccttcatatgccactatctcggtagttcaaaaaaatttagttcttgataaattgcctgaagtttaccttgtgetggagagcct _at tatgataactccaaagactttcttacggtataatacatgttgtttaggattgtgtttcttagtcactgaagataataaatattaaaatggatgttttcatcagaaaattttcat gttttcctttaaggtaacataattgtaagaattgtttaataaaatactcaggaaattctaaaggtttctccnaatacctaaacatttctgaacatcagtattgcagttgtgg aagagcagaaggaggatacattgtttgtgttgctccccaaaattccacctgcatttgcatcacaaacttccctcaattgaggcagttttctttg 660 235976 cagtgetgotgtgaactaaagtatgtcatttatgetcaaagtttaattettettettgggatattttaaaaatgctactgagattetgetgtaaatatgactagagaatatatt -at gggtttgctttatttcataggcttaattctttgtaaatctgaatgaccataatagaaatacatttcttgtggcaagtaattcacagttgtaaagtaaataggaaaaattatttt atttattgatgtacattgatagatgccataaatcagtagcaaaaggcacttctaaaggtaagtggtttaagttgcctcaanagagggacaatgtagctttattttaca agaaggcatagttagatttctatgaaatatttattctgtacagttttatatanttttggttcacaaaagtaattatcttgggtgcctttcaa 661 236894 aaagtatatgtgctagcttgtctaagaataaactnnatactgtgggggagggctgcacctgtcaagataacctgtcaatgtagtaggaaaacaggaggggac _at agtaacagaaaagcacgggaaaagatggcaaggttagttaaaatagaaaagtgctcagttcctcatacctgtaatcccagcagtttagggggccaaggaagg tgggtcacttgagcccaagagttcaaggccatcctgggcaatgtggcgaaagtgtctacaaaaaaatacaaaaagaggaagaaatgatatttcacaagtttgta tcatttgtcat 662 237521 cagtccaaaatccatagacacagacagtagaaaggtggttatncaagggnctggtaggagagggagttagtatttagtggtatagagttttagtgtttnccgggta _x-at aaaatgttnctagagatctgttgcaaccatgtgaatatacttaacactaccgtactgtacactgaaaaaatggttaagaggataaatttaaatggttaagaggaaa I aatggttaagaggataatgttgttttgttaccacagtagtaacttttaaaaaccctcatgtatgttcttt 663 37892_ caacccatttgtgccacatgcaagttttgaataaggatggtatagaaaacaacgetgcatatacaggtaccatttaggnannancngatgcctttntgggggca at gaatcacatggcaaaagctttgaaaatcataaagatataagttggtgtggctaagatggaaacagggctgattcttgattcccaattctcaactctccttttcctatttg aatttctttggtgctgtagaaaacaaaaaaagaaaaatatatattcataaaaaatatggtgcteattctcatccatccaggatgtactaaaacagtgtgtttaataaat tgtaattattttgtgtacagttctatactgttatctgtgtccatttccaaaacttgcacgtgtccctgaattcc

TABLE 7: MSP primers and PCR conditions

Gene Probe set Gene Name Forward primer 5'- 3' Reverse primer 5'- 3' Re-anneal Temp

CA4 206208_at Carbonic anhydrase TCGTTTTTCGCGTTTAGTT GCGCACCGAAAAAACCG 61.0°C IV GTC (SEQ ID NO:664) (SEQ ID NO:665) CXCLI 209687_at Chemokine,CXC CGGTTACGGTTAGTATTCG AAAATACGACGATAAAAA 64.0°C 2 Motif, Ligand 12 GTTTC (SEQ ID NO:666) ACGCG (SEQ ID NO:667)

DF 205382_s complement factor CGAGGGTTTTTTAGCGATT AAACGAACCGCTCCCCG 64.0°C at D TGTC (SEQ ID NO:668) (SEQ ID NO:669) MAMD 228885_at MAM domain- TTCGGCGThTCGTTT A CCCCTTAACAACATAATCG 60.0°C C2 containing protein 2 C (SEQ ID NO:670) CG (SEQ ID NO:671) precursor MTIM 217546_at Metallothionein-IM GATGGTGCGTTCGGTATTT GCTTACACCCGCCCGACTA 62.0°C ATGT (SEQ ID NO:672) (SEQ ID NO:673) CAGE Control unbiased GTITGTGATTGGTTAGGT CCRTCACCTTCTACACCAA 61.0°C amplification assay TATTAAAGT (SEQ ID AAAATA (SEQ ID NO:675) NO:674)

TABLE 8: COBRA Primers and PCR conditions

Gene Probe set Gene Name Forward primer 5'- 3' Reverse primer 5' - 3' Re-anneal Temp, Enzyme ADAM 206134_at ADAM-like, TGTGGATTTATTFTATAA ATAACTCATTAAAAACT 61.00 C DECI decysin 1 GGATATTGAAT (SEQ ID CACATCTAAACACTA NO:676) (SEQ ID NO:677) BstU I

GPM6B 209170_s Neuronal membrane TTAAGAAAGAGAGTAAG AAAATCCCAATTAAAAA 60.0°C at glycoprotein M6-b GAGGAAGAGTT (SEQ ID ACAACCA (SEQ ID NO:678) NO:679) Hinf I

P2RY14 206637_at Purinergic receptor CAAAATAATAAATCCCTC GGAGGAAAGGAATTAG 60.0°C P2Y, G-protein TACTACTATTATCAA TTFAGAAGTTAGTT coupled, 14 (SEQ ID NO:680) (SEQ ID NO:681) Acl I

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Affymetrix. GeneChip expression data analysis fundamentals. Affymetrix, Santa Clara, CA USA, 2001. Alon et al., Proc. Natl. Acad. Sci. USA: 96, 6745-6750, June 1999 Ausubel, F. et al., "Current Protocols in Molecular Biology", John Wiley & Sons, (1998) Bonner et al (1973) J. Mol. Biol. 81:123 Clark et al. 2006, Nature Protocols1:2353-2364 DeRisi, et al., Nature Genetics 14:457-460 (1996) Germer et al., Genome Res. 10:258-266 (2000) Guo et al., Nucleic Acids Res. 22:5456-5465 (1994) Heid et al., Genome Res. 6:986-994 (1996) Hubbell E.W., W. M. Liu, and R. Mei. Robust estimators for expression analysis. Bioinformatics, 18:1585-1592, 2002. Irizarry R.W., B. M. Bolstad, F. Collin, L. M. Cope, B. Hobbs, and T. P. Speed. Summaries of affymetrix genechip probe level data. Nucleic Acid Research, 31, 2003. Kraus, M. and Aaronson, S., 1991. Methods Enzymol., 200:546-556 Maskos and Southern, Nuc. Acids Res. 20:1679-84, 1992 Moore et al., BBA, 1402:239-249, 1988 Nielsen (1999) Curr. Opin. Biotechnol. 10:71-75 Nielsen et al. (1991) Science 254: 1497-1500 Pease et al., Proc. Natl. Acad. Sci. USA 91(11):5022-5026 (1994) Pevzner et al., J. Biomol. Struc. & Dyn. 9:399-410, 1991 Schena, et al. Science 270:467-470 (1995) Smith et al., Science 258:1122-1126 (1992) Smyth G.K. Bioinformatics and Computational Biology Solutions using R and Bioconductor. Springer, New York, 2005. Smyth G.K. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Statistical Applications in Genetics and Molecular Biology, 3(l):Article 3, 2004. T. Sano and C. R. Cantor, Bio/Technology 9:1378-81 (1991) Urdea et al., Nucleic Acids Symp. Ser., 24:197-200 (1991) Wedemeyer et al., Clinical Chemistry 48:9 1398-1405, 2002) Weissleder et al., Nature Medicine 6:351-355, 2000

Claims

CLAIMS:

1. A method of screening for the onset or predisposition to the onset of a large intestine neoplasm or monitoring the progress of a neoplasm in an individual, said method comprising assessing the level of expression of: (i) the gene detected by Affymetrix probeset ID 212265_at; and/or (ii) QKI in a biological sample from said individual wherein a lower level of expression of the genes or transcripts of group (i) and/or group (ii) relative to control levels is indicative of a neoplastic large intestine cell or a cell predisposed to the onset of a neoplastic state.

2. The method according to claim 1 wherein said neoplastic cell is an adenoma or an adenocarcinoma.

3. The method according to claim 1 or 2 wherein said control level is a non neoplastic level.

4. The method according to any one of claims 1-3 wherein said cell is a colorectal cell.

5. The method according to any one of claims 1-4 wherein said biological sample is a faecal sample, enema wash, surgical resection, tissue biopsy or blood sample.

6. The method according to any one of claims 1 to 5 wherein said level of expression is mRNA expression or protein expression.

7. The method according to any one of claims 1 to 5 wherein said level of expression is assessed by screening for changes to genomic DNA.

8. The method according to claim 7 wherein said changes to genomic DNA are changes to DNA methylation.

9. The method according to any one of claims 1 to 5 wherein said level of expression is assessed by screening for changes to the chromatin protein with which said gene is associated.

10. The method according to any one of claims 1-9 wherein said individual is a human.