(en)Systems and methods relate to transgenic organisms and their use as biosensors are described. In some embodiments, the systems and methods include a first population of transgenic organisms that includes a first constitutively expressed reporter gene, and a first transgene that includes a first inducible promoter from a response pathway gene, wherein the first inducible promoter is coupled to a first reporter gene. Other embodiments are described.

1.ApplicationNumber: US-201213476790-A
1.PublishNumber: US-8937213-B2
2.Date Publish: 20150120
3.Inventor: HOPKINS CHRISTOPHER E.
GUNARATNA MILUKA

4.Inventor Harmonized: HOPKINS CHRISTOPHER E(US)
GUNARATNA MILUKA(US)

5.Country: US
6.Claims:
(en)Systems and methods relate to transgenic organisms and their use as biosensors are described. In some embodiments, the systems and methods include a first population of transgenic organisms that includes a first constitutively expressed reporter gene, and a first transgene that includes a first inducible promoter from a response pathway gene, wherein the first inducible promoter is coupled to a first reporter gene. Other embodiments are described.

7.Description:
(en)CROSS-REFERENCE TO RELATED APPLICATIONS
The application claims priority to U.S. provisional patent application No. 61/488,720, filed May 21, 2011 which is hereby incorporated by reference in its entirely.


BACKGROUND
One of the most difficult problems in drug discovery and toxicology is the ability to extrapolate results from early studies at the biochemical and cell-based level to effects in humans. The resulting inefficiencies in this extrapolation result in a high attrition rate in drug development and are an enormous drain of resources, effectively passing the buck on to consumers in one manner or another.
From the pollutants in the air we breathe to side-effects from drugs necessary for our health, we are surrounded by chemicals in our environment. It is important to determine which of these chemicals pose health risks and which are relatively harmless. Over 50,000 chemicals are in need of accurate toxicology assessment (Whittenberger J. Toxicity testing: strategies to determine needs and priorities. Washington D.C.: National Academy Press; 1984; and Kreweski D. Toxicity Testing in the 21st Century: A Vision and a Strategy. 500 Fifth Street, NW Washington, D.C. 20001: National Academy Press; 2007). Understanding the mechanism of action is becoming recognized as a critical parameter for accurate toxicology assessment (Lock et al. Toxicol. Lett. 2003 April; 140-141:317-322.). However, there are limited choices in the marketplace for comprehensive tests to report toxicology pathway activation. The currently available methods are tedious in application or removed from a whole-organism format. As a result, toxicology researchers are in need of fast and efficient high-throughput methods to detect toxicology pathway activation.
Methods using intact cells or whole organisms are challenging to apply in high-throughput formats. Whole organism approaches are the most reliable in capturing accurate correlative toxicity data because the tests are performed in a native-context platform. Yet these approaches are costly for high-throughput implementation with classical models such as the mouse. Tissue must be harvested and either RNA extracted for transcription analysis (microarrays (Shioda J. Environ. Pathol. Toxicol. Oncol 2004; 23 (1):13-31), RNA-seq (Kamb Res. Toxicol. 2011 August; 24 (8):1163-1168.), rtPCR (Walker J. Biochem. Mol. Toxicol. 2001; 15 (3):121-127.)) or metabolic analysis by specific biochemical assay (P450 (Guengerich Chem. Res. Toxicol. 2008 January; 21 (1):70-83) and MDR (Sarkadi Physiol. Rev. 2006 October; 86 (4):1179-1236.) transporter activity). Furthermore, tissue specific toxicity mandates careful dissection to allow accurate capture of toxicology data (such as sedimented-tissue lysates of liver, brain, and other tissues). As a result, intact organism toxicity approaches are difficult to implement in cost effective high-throughput strategies. In vitro analysis on cell culture systems is a method more amenable to high-throughput analysis. The common approach is to transfect primary cultures with reporter plasmids and detect gene activation as increased expression of reporter genes. These platforms are expensive, time consuming to maintain, and can be plagued with reproducibility problems. An additional drawback of cell culture transfection methods is the lack of native context. Frequently cell culture responses can give hypersensitive results and these results disappear upon whole organism analysis. Creation of transgenic immortalized lines can solve some reproducibility issues (Youdim et al. Drug Metab. Dispos. 2007 February; 35 (2):275-282), but these lines are even further removed from native context and can give misleading results. Better methods are needed both in the research setting and in the market place.
Other public health related areas are also in need of improved methods for predicting effects in humans and animals including air quality, cosmetics, apparel, infant food, drinking water, environmental toxicology, food additives, nutraceuticals, manufacturing, organic foods, plastics, pesticides, industrial toxicity, toys, and waste water. Just about any area where exposure of potential toxins to humans or animals occurs is an area where improved method for detecting toxicological liabilities would be a benefit.
BRIEF SUMMARY
The described systems and methods relate to transgenic organisms and their use as biosensors. In some implementations, the described systems and methods include a first population of transgenic organisms that includes a first constitutively expressed reporter gene, and a first transgene that includes a first inducible promoter from a response pathway gene, wherein the first inducible promoter is operably coupled to a first reporter gene.
In other implementations, the population of transgenic organisms further includes a second population of transgenic organisms having a second transgene that includes a second inducible promoter that is operably coupled to a second reporter gene, wherein the second population of transgenic organisms further includes a second constitutively expressed reporter gene, and wherein the first inducible promoter and the second inducible promoter each include a promoter that is derived from a different gene.
In still other implementations, the described systems and methods comprise an object that includes a transgene, a transgenic organism, or a construct, wherein the object includes a promoter region having a promoter, a fragment of the promoter, or a homolog of either the promoter or the fragment of the promoter, wherein the homolog includes at least about a 95% identity to the promoter or the fragment of the promoter, wherein the promoter region is operably coupled to a reporter gene, wherein the reporter gene encodes a protein selected from a fluorescent protein and a luminescent protein, and wherein the promoter region includes a promoter region for a gene selected from: C. elegans genes cdr-1, gcs-1, ugt-1, gst-38, hsp-60, hsp-16.41, mtl-2, hsp-16.2, gst-4, ugt-13, hsp-3, hsp-6, hsp-4, hsp-1, skn-1, dnj-13, daf-21, Hsp-17, cyp-13A7, cyp-14A3, cyp-35A2, zyg-12, ZK742.4, ZK742.3, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fmo-1, fmo-2, fmo-3, fmo-4, fmo-5, ftn-1, ftn-2, fzy-1, gen-1, glp-1, gsr-1, gst-1, gst-23, gst-25, gst-41, H01G02.2, haf-6, syp-2, T05A12.4, T05G5.3, T06E6.2, T07F12.4, Hsp-12.2, T05E11.3, Cnx-1, Crt-1, cyp-35A1, cyp-35C1, cyp-35A3, pqe-1, cyp-37B1, cyp-35B2, cyp-35B1, cyp-22A1 (daf-9), cyp-14A5, cyp-35B3, cyp-34A6, daf-16, exo-3, nth-1, pme-1, ung-1, xpa-1, mrt-2, ercc-1, ZK697.8, ZK287.5, haf-7, hda-1, hda-10, hda-11, hda-2, hda-3, hda-4, hda-5, hda-6, hdac-1, hif-1, him-1, him-14, him-3, him-4, him-6, hmg-3, hmg-4, hmg-5, hpr-17, hpr-9, hrdl-1, hsf-1, hsp-1, hsp-16.48, tbb-4, tnc-2, top-3, tor-2, trx-2, xpf-1, xpg-1, rad-23, mlh-1, msh-2, msh-4, msh-5, msh-6, brc-1, brc-2, rad-50, cku-70, lin-35, mei-1, cki-1, cki-2, cep-1, ced-3, ced-9, ced-13, vem-1, dhs-23, sodh-2, dnj-19, Xbp-1, hsp-16.49, hsp-2, htp-1, htp-3, hus-1, imb-3, ire-1, irk-1, K07C5.2, K07C5.4, K08F4.1, K11G12.5, kin-18, lagr-1, let-2, let-92, lig-1, lig-4, lim-4, lin-12, lin-44, lin-49, lrk-1, lst-3, M18.5, vps-41, W01A11.1, W02C12.1, W03G1.5, W06H8.2, Hipr-1, cdc-48.1, cdc-48.3, Ubq-1, Ubq-2, Gst-10, Gst-13, f25d1.5, fil-1, k10h10.6, hsp-70, f44e5.4, f44e5.5, hsp-16.11, hsp-16.1, nurf-1, aip-1, y43f8b.2, Dod-17, Dod-24, C55A6.7, F56D5.3, cyp-13A11, cyp-13A6, cyp-25A4, mac-1, mboa-2, mdf-1, mdf-2, mec-14, med-1, mel-28, misc-1, mnat-1, mre-11, mrp-1, mrp-2, mrp-3, mrp-4, mrp-5, mrp-6, mrp-7, mrp-8, mspn-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, ndx-1, Y55B1AL.2, Y56A3A.33, Y66D12A.15, Y66D12A.15, Y73C8C.10, cyp-29A2, cyp-31A1, cyp-31A3, cyp-33B1, cyp-33E1, cyp-34A10, cyp-34A9, cyp-35A4, cyp-35D1, abl-1, abu-1, acr-14, acr-22, agt-1, ahr-1, air-2, ama-1, apa-2, apn-1, apn-1, aps-2, arf-1, asp-5, atf-5, atgr-7, ndx-4, nft-1, nhr-6, nol-5, npl-4.2, nuc-1, odc-1, paa-1, pas-4, pat-10, pcn-1, pdi-1, pdi-2, pdi-3, pdr-1, pek-1, pgp-1, pgp-10, pgp-2, phi-37, phi-44, phi-9, pink-1, pme-2, pme-3, T08D2.4, T08D2.7, T08H10.1, T10B5.8, T13A10.2, atl-1, atm-1, B0222.9, B0432.2, B0495.2, B0563.7, brd-1, C01G5.5, C06A1.6, C06H2.3, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C25A1.5, C30G7.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C44H4.4, C56G3.2, catp-6, cbn-1, F17A9.5, F18A1.5, F19G12.2, F23C8.9, F36A4.15, F43D2.1, F43G6.5, F44B9.8, F45E12.3, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F55B11.1, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59F4.1, fan-1, fdps-1, figl-1, trxr-1, tut-1, uba-1, ubc-1, ubc-20, ccch-1, cct-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdc-48.2, cdk-7, ced-4, cel-1, cft-1, chk-1, chk-2, chn-1, cku-80, cle-1, clk-2, clpp-1, cmd-1, cnb-1, col-135, pme-4, pme-5, pmrt-5, pms-2, png-1, polh-1, polk-1, prx-6, ptl-1, R02D3.3, R03D7.2, R05D11.6, R05F9.10, R09H10.3, R10E4.9, R13D11.4, R151.6, rab-1, rab-7, srp-2, ssc-1, sti-1, sulp-7, sut-1, sut-2, wrn-1, xpc-1, Y110A7A.4, Y38F1A.5, Y38H8A.3, cps-6, crb-1, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, crp-1, csb-1, ctl-2, ctl-3, cul-1, cul-2, cul-4, cul-5, cyh-1, cyn-1, cyn-10, cyn-11, cyn-12, cyn-13, cyn-14, cyn-15, cyn-16, rad-51, rad-54, rbx-1, rbx-2, rcf-3, rcq-5, rec-8, rev-1, rfc-1, rfc-4, rfl-1, rme-8, rnf-121, rnh-1.0, rpa-1, rpa-2, rpn-10, rps-19, rps-26, T23G5.6, T26A5.5, T27E9.1, tag-353, tars-1, tbb-2, Y73F8A.24, ymel-1, ZC168.4, ZC395.10, ZC443.1, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, cyp-13A12, cyp-13A4, cyp-14A2, cyp-33C1, cyp-33C2, cyp-33C9, cyp-33E2, cyp-42A1, cyp14A2, cyp33C9, cyp34A6, D1081.8, D2023.4, daf-1, daf-14, daf-3, rpt-3, rpt-4, rpt-5, rpt-6, rtel-1, san-1, scav-1, scav-2, scav-3, scav-4, scav-5, scc-3, sdz-8, sec-22, sep-1, set-25, set-26, set-8, set-9, unc-11, unc-26, unc-57, uri-1, usp-14, vps-4, T15B7.2, T16H12.4, ugt-62, Y39G8B.1, Y39G8B.2, daf-5, daf-7, daf-8, dbl-1, ddb-1, dhs-22, djr-1.1, dna-2, dog-1, drh-3, drp-1, dut-1, E01A2.1, eft-2, egl-1, eif-2, emb-9, epg-2, eps-8, exo-1, F09E5.2, F14F9.5, F15E6.6, F16A11.2, F17A9.4, sft-4, sgg-1, sin-3, sir-2.1, sir-2.2, sir-2.3, sir-2.4, skr-15, slt-1, slx-1, smf-1, smk-1, sod-1, sod-2, sod-3, sod-4, sod-5, spas-1, ugt-61, Y43E12A.1, Y43F8C.13, Y48G1BL.2, Y50D7A.1, Y50D7A.2, Y54E10A.3, ufd-1, ugt-22, ugt-52, ZK1128.4, ZK1290.5, and Y39H10A.7; ABCE-1, ABCF-1, ABCF-2, ABCF-3, ABT-1, ABT-2, ABT-4, ABT-5, ABTM-1, acr-14, acr-22, ahr-1, akt-1, akt-2, apa-2, ape-1, apn-1, aps-2, ard-1, arf-1, arf-1.1, arl-7, asp-5, atf-5, atgr-7, B0222.9, B0432.2, B0495.2, B0563.7, bec-1, bmk-1, C01B10.7, C01G12.5, C01G5.5, C01H6.4, C03A7.12, C03A7.13, C04F12.1, C05C9.1, C06A1.6, C06E4.3, C06E4.4, C06E4.6, C06G1.1, C06H2.3, C07A9.13, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C16C8.14, C23G10.6, C25A1.5, C25A1.6, C27D8.4, C28H8.11, C30G12.2, C30G7.5, C31H1.1, C32D5.12, C33E10.10, C35B1.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C41A3.1, C44H4.4, C46H11.2, C55A6.3, C55A6.4, C55A6.6, C55C3.1, C55H1.1, C56G3.2, cah-5, car-1, catp-6, cbn-1, ccch-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdr-5, ced-1, ced-10, ced-12, ced-13, ced-2, ced-5, ced-6, CED-7, ceh-20, ceh-30, ces-1, ces-2, cgh-1, chn-1, cit-1.2, ckb-2, cle-1, clec-149, clpp-1, cmd-1, cnb-1, Cnx-1, cnx-1, col-135, coq-6, cpb-3, crb-1, crp-1, Crt-1, crt-1, csp-1, csp-2, csp-3, ctl-1, cul-1, cul-2, cul-3, cul-5, cyn-1, cyn-10, cyn-11, cyn-12, cyn-14, cyn-15, cyn-16, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, CYP-13A1, CYP-13A10, CYP-13A2, CYP-13A3, CYP-13A5, CYP-13A8, CYP-13B1, CYP-13B2, CYP-14A1, CYP-14A4, CYP-23A1, CYP-25A1, CYP-25A2, CYP-25A3, CYP-25A5, CYP-25A6, CYP-29A3, CYP-29A4, CYP-31A2, CYP-32A1, CYP-32B1, CYP-33A1, CYP-33C11, CYP-33C3, CYP-33C4, CYP-33C5, CYP-33C6, CYP-33C7, CYP-33C8, CYP-33D1, CYP-33D3, CYP-33E3, CYP-34A1, CYP-34A2, CYP-34A4, CYP-34A5, CYP-34A7, CYP-34A8, CYP-35A5, CYP-36A1, CYP-37A1, CYP-43A1, CYP-44A1, cyp14A2, cyp14A5, cyp33C9, D1007.16, D1054.8, D1081.8, D2023.4, dad-1, daf-1, daf-14, daf-21, daf-3, daf-5, daf-7, daf-8, DAF-9, dbl-1, DC2.5, dhs-1, dhs-10, dhs-11, dhs-12, dhs-13, dhs-14, dhs-15, dhs-16, dhs-18, dhs-19, dhs-2, dhs-20, dhs-21, dhs-24, dhs-25, dhs-26, dhs-28, dhs-29, dhs-3, dhs-30, dhs-31, dhs-4, dhs-5, dhs-6, dhs-8, dhs-9, djr-1.1, dnj-11, dnj-25, dnj-27, dnj-7, Dod-17, Dod-24, dop-1, dop-1, dop-3, dop-3, dpl-1, dpr-1, drh-3, duox-2, dut-1, E01A2.1, E04F6.15, eat-3, efl-1, efl-2, eft-2, egg-1, egg-2, egl-38, emb-9, eor-1, eor-2, epg-2, eps-8, exos-3, F02C12.2, F07A11.2, F09E5.2, F10D11.6, F10D2.12, F10D2.8, F10D7.3, F12E12.11, F14D12.1b, F14F9.5, F15E6.6, F16A11.2, F17A9.5, F18A1.5, F19G12.2, F20G2.1, F20G2.2, F22D6.15, F22E5.6, F23C8.9, F26D2.15, F28A10.1, F28H7.2, F30B5.4, F32A5.8, F36A4.15, F43G6.5, F44B9.8, f44e5.4, f44e5.5, F45E12.3, F46H5.2a, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F54C1.1, F54F3.4, F55A11.6, F55B11.1, F55E10.6, F56A4.4, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59E11.2, F59F4.1, fan-1, fasn-1, fdps-1, fil-1, fipr-24, fis-1, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fnta-1, ftn-1, ftn-2, gab-1, gad-3, gale-1, gdi-1, ggtb-1, gla-3, gld-1, glp-1, glrx-10, gsr-1, gst-11, gst-12, gst-14, gst-15, gst-16, gst-18, gst-19, gst-2, gst-20, gst-21, gst-22, gst-24, gst-26, gst-28, gst-29, gst-3, gst-30, gst-31, gst-32, gst-33, gst-34, gst-35, gst-36, gst-39, gst-40, gst-42, gst-43, gst-44, gst-5, gst-6, gst-8, gst-9, gstk-1, gstk-2, gsto-1, gsto-2, gsto-3, H01G02.2, H04M03.3, H06H21.9, H10D18.6, H23N18.4, HAF-1, HAF-2, HAF-3, HAF-4, HAF-8, HAF-9, hda-10, hda-11, hda-5, hi-14, hif-1, him-10, him-4, hke-4.1, hlh-2, hlh-3, HMT-1, hpo-15, hps-1, hps-60, hsd-1, hsd-2, hsd-3, hsf-1, hsp-1, hsp-16.1, hsp-16.1, hsp-2, hsp-60, icd-1, ikb-1, imb-3, ing-3, irk-1, irp-1, irp-2, itr-1, jkk-1, jnk-1, K02E11.3, K02E11.4, K02E11.5, K02E11.6, K02E11.7, K02E11.9, K04A8.10, K07C5.2, K07C5.4, K08F4.1, K10F12.4, K11D12.6, K11G12.5, kin-18, kin-4, lagr-1, lbp-1, lbp-2, lbp-3, lbp-4, lbp-5, lbp-6, lbp-7, lbp-8, lbp-9, let-2, let-23, let-60, let-92, lim-4, fin-1, lin-12, lin-3, lin-31, lin-44, fin-49, lip-1, lips-11, lrk-1, lst-3, M18.5, M57.2, mab-5, maoc-1, mca-2, mec-14, med-1, mei-2, mek-1, mek-2, mel-26, mev-1, misc-1, mlt-7, mpk-1, mtl-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, nas-39, ncs-3, ndx-4, nhr-181, nhr-6, nhr-64, nol-5, npl-4, npl-4.2, nrf-5, nsy-1, nurf-1, odc-1, paa-1, pag-3, pah-1, pas-4, pat-10, pax-2, pdi-1, pdr-1, pek-1, PGP-11, PGP-12, PGP-13, PGP-14, PGP-15, PGP-3, PGP-4, PGP-5, PGP-6, PGP-7, PGP-8, PGP-9, phi-37, phi-44, phi-9, pink-1, pkc-2, pmk-1, pmk-2, pmk-3, PMP-1, PMP-2, PMP-3, PMP-4, PMP-5, pmrt-5, png-1, polq-1, pqe-1, pqn-60, prdx-2, prx-1, prx-5, psr-1, ptl-1, ptp-3, ptp-3, pxn-2, qdpr-1, R03D7.2, R05D11.6, R05D8.7, R05D8.9, R05F9.10, R07B7.4, R07B7.5, R09H10.3, R10E4.9, R119.3, R11A8.5, R13D11.4, R151.6, rab-1, rab-5, rae-1, rcf-3, rcq-5, rfc-1, rfl-1, rfp-1, rgef-1, rgs-2, rgs-2, rme-8, rnf-1, rnf-121, rnh-1.0, rnp-2, rpa-2, rps-19, rps-26, rtel-1, scav-1, scav-2, scav-3, scav-4, scav-5, sdz-8, sdz-8, sec-22, sek-1, sel-10, sel-8, sem-5, ser-3, set-25, set-26, set-8, set-9, sex-1, sft-4, sgg-1, skr-15, slt-1, smf-1, smk-1, smo-1, sod-2, sod-4, sod-5, srp-2, srp-7, sti-1, sulp-7, sup-9, sup-9, sut-1, sut-2, syp-2, T01G6.1, T01G6.10, T05A12.4, T05G5.3, T06E6.2, T07F12.4, T08D2.4, T08D2.7, T08H10.1, T10B5.10, T10B5.8, T13A10.2, T15B7.2, T16G1.6, T19B4.1, T19C3.5, T19H12.3, T21B4.4, T23G5.6, T25G12.2, T26A5.5, T27E9.1, tag-124, tag-353, tag-63, tars-1, tbb-2, tbb-4, tbh-1, tnc-2, tor-2, tra-1, trx-2, trxr-1, tut-1, uba-1, ubc-14, ubc-20, ubxn-4, ugt-10, ugt-11, ugt-12, ugt-14, ugt-15, ugt-16, ugt-17, ugt-18, ugt-19, ugt-2, ugt-20, ugt-21, ugt-23, ugt-24, ugt-25, ugt-26, ugt-27, ugt-28, ugt-29, ugt-3, ugt-30, ugt-31, ugt-32, ugt-33, ugt-34, ugt-35, ugt-36, ugt-37, ugt-38, ugt-39, ugt-4, ugt-40, ugt-41, ugt-42, ugt-43, ugt-44, ugt-45, ugt-46, ugt-47, ugt-48, ugt-49, ugt-5, ugt-50, ugt-51, ugt-53, ugt-54, ugt-55, ugt-56, ugt-57, ugt-58, ugt-59, ugt-6, ugt-60, ugt-63, ugt-64, ugt-65, ugt-7, ugt-8, ugt-9, unc-11, unc-2, unc-26, unc-36, unc-36, unc-43, unc-43, unc-57, unc-73, uri-1, usp-14, vit-1, vit-2, vit-3, vit-4, vit-5, vit-6, vps-11, vps-16, vps-18, vps-33, vps-39, W01A11.1, W01B11.6, W02C12.1, W03F9.9, W03G1.5, W10C8.4, wah-1, WHT-1, WHT-2, WHT-3, WHT-4, WHT-5, WHT-6, WHT-7, WHT-8, WHT-9, Y110A7A.4, Y23H5A.2, Y38F1A.5, Y38H6C.17, Y38H8A.3, Y39G8B.1, Y39G8B.2, Y39H10A.7, Y41C4A.11, Y43D4A.2, Y43E12A.1, y43f8b.2, Y43F8C.13, Y45G12C.3, Y47D3A.22, Y47D3A.29, Y47G6A.21, Y47G6A.22, Y48G1BL.2, Y50D7A.1, Y53G8B.1, Y54E10A.3, Y56A3A.33, Y66D12A.15, Y71G12B.4, Y73B6A.3, Y73C8C.10, ymel-1, ZC168.4, ZC395.10, ZC443.1, ZC513.1, ZC513.2, ZK1290.5, ZK287.5, ZK550.6, ZK616.8, ZK697.14, ZK697.8, ZK742.3, ZK742.4, ZK829.1, and zyg-12; and homologous genes from an organism selected from Danio rerio (zebrafish), Drosophila melanogaster, Daphnia spp., and Xenopus laevis.
In yet other implementations, the described systems and methods include an object selected from a transgene, a transgenic organism, and a construct, wherein the object comprises a promoter region that includes a promoter, a fragment of the promoter, or a homolog of either the promoter or the fragment of the promoter, wherein the homolog has at least about a 95% identity to the promoter or the fragment of the promoter, wherein the promoter region is operably coupled to a reporter gene of an inducible reporter, wherein the reporter gene encodes a protein selected from a fluorescent protein and a luminescent protein, and wherein the promoter region includes a sequence selected from those found in SEQ ID NO:1 to SEQ ID NO:162.



BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1A , B, and C show a schematic representation of a transgenesis algorithm for generating transgenic organisms for use in the invention. The transgenesis algorithm involves, as shown in FIG. 1A , identifying a promoter response element, as shown in FIG. 1B , operably linking or fusing the promoter response element to a reporter gene to create a functional transgene and, as shown in FIG. 1C , inserting the functional transgene into the host organism's genome (e.g., C. elegans ). FIG. 1A comprises (1) toxicity profiling data analyzed for genes involved in response pathways (e.g., qPCR, microarray, RNA seq, and/or RNAi screens from literature), (2) promoter discovery (e.g., bioinformatic scan using ModENCODE ChIP-seq data and bioinformatics scan with MultiZ alignment for 5′ conserved elements), and (3) promoter isolation (e.g., design primers for region of interest and amplify from wild-type DNA). FIG. 1B comprises (1) reporter plasmid assembly (e.g., insert promoter into targeting vector/construct by standard molecular biology techniques) and (2) targeting plasmid assembly (e.g, having a positive selection marker (e.g., unc-119 rescue) and a homology arm for transposition (e.g., sequence flanking Mos1 site to yield transgene of interest—toxin sensitive promoter driving reporter gene). FIG. 1C comprises (1) microinjection of targeting plasmid into worm (e.g., insert targeting plasmid mix into gonad tissue of selectable background animals (e.g., unc-119 mutants)) and (2) genome insertion (e.g., array formation, Mos1 transposon insertion, homologous gene repair, transgene insertion, and array loss) to give the desired transgenic worm.
FIGS. 2A and B show a schematic representation of a plurality of representative populations of transgenic organism within the context of a multiwell plate. Each well has a population of worms from the indicated strain (as indicated by the abbreviation in the well which signifies the promoter region of the indicated gene that is fused, or operably linked, to a reporter gene). FIG. 2A shows the initial plate layout before addition of a selected agent. FIG. 2B shows wells highlighted in grey when the selected agent is one that selective induces cytoplasmic oxidative stress (e.g., induces promoter driven expression of reporter gene).
FIGS. 3A , B, and C show the fluorescence plate-reader sensitivity and toxin response. FIG. 3 A shows 2-fold dilutions starting with 200 worms per well, assayed in duplicate, were exposed to heat shock (34° C. for 1 hour) and allowed to recover for 16 hr 15 C. FIG. 3B shows Arsenic and FIG. 3C shows cadmium responses: 24 hr exposure, ˜600 worms per well, assayed in triplicate.
FIGS. 4A , B, and C show the population effects of chronic toxin exposure.
FIG. 4A shows chronic exposure was assayed for effect on population size during 72 hr exposure to cadmium at various concentrations. FIG. 4B shows raw data profiles show bimodal response in fluorescence intensity over the titration range tested. FIG. 4C shows population-normalized response curves show single-mode effect of cadmium on fluorescence intensity.
FIGS. 5 and B shows the results of the dual reporter configuration for population normalization. FIG. 5A shows uninduced vs. FIG. 5B which shows induced (30° C., 1 hr) nematodes (hsp-16::hRFP, unc-47::GFP) were imaged in green and red channels. FIG. 5A is the control worms (top panel is a photograph of the worm, the middle panel is the GFP expression, and the bottom panel is the RFP expression). FIG. 5B is the heat shock treated animal (top panel is a photograph of the worm, the middle panel is the GFP expression, and the bottom panel is the RFP expression). Expression of fluorescent protein shows up as lighter shaded areas in the images. The images show significant induction of RFP in the heat shock treated animals. The equation used for normalization using values in the control animals where R i is the value measured for RFP fluorescence in the induced animal, G i is the value from GFP fluorescence in the induced animal, R c is the value for RFP fluorescence in the control animal and G c is the value of GFP fluorescence in the control animal.
FIGS. 6A and B shows the NIEHS findings with hsp-16::hRFP induction in unc-47::GFP background. FIG. 6A shows confirmation of heat shock responsiveness in the larvae and adults nematodes. FIG. 6B shows representative COPAS biosorting profile showing nematode size-dependent effects on observe fluorescence. The lighter shaded areas in the images indicated fluorescence of GFP or RFP.
FIG. 7 shows expression response profiles using two-color nematode biosensors. The upper graph shows biosensors exposed to 34° C. for 1.5 hrs on seeded NGM plates followed by 4 hrs recovery at 20° C. The lower graph shows biosensors exposed to cadmium (1 mM, NGM plates) for 15 hrs. Responses are population-normalized changes relative to unexposed control. Error bars indicate average of 2 to 6 independent measurements. The label “2 line” indicates data derived from combining responses of two independently-derived MosSCI lines for the same reporter.
FIG. 8 shows a predicted set of results related to a panel or array of biosensors involved in oxidative stress and genotoxic stress. A 16 well microwell plate having populations of representative transgenic organisms for both oxidative stress and genotoxin stress are seeded into the wells of the plates. Exposure of organisms in the wells of the plates to a selected agent that induces oxidative stress or genotoxic stress gives digitized read-outs indicative of which toxicity pathway is being activated by the selected agent. The lower left plate shows activation of an oxidative stress pathway whereas the lower right plate shows activation of a genotoxin pathway.
FIG. 9 shows a predicted set of results related to a panel or array of biosensors involved in oxidative stress. A 16 well microwell plate having populations of representative transgenic organisms for both oxidative stress are seeded into the wells of the plates. Exposure of the wells in the plate with a selected agent that induces oxidative stress give digitized read-outs indicative of which oxidative stress toxicity pathway is being activated by the selected agent. The plates show activation of the indicated oxidative stress pathway by induction of the reporters in the highlighted rows.
FIG. 10 shows sets/formats of arrays or panels for different types of stress response biosensors and specific sub-groups.



DETAILED DESCRIPTION
The invention described herein is a remarkable new paradigm useful for probing the effects of exposure to a stimuli (e.g., a chemical agent or heat shock), on gene expression at the organismal level in a rapid and efficient manner. The inventors have created biosensor organisms that are easily useable and provide robust reproducible results in an out-of-the-box format for testing the effects of exposure to various stimuli on gene expression levels as measured by reporter genes. Importantly, the compositions and methods described herein are unexpectedly useful for identifying gene expression responses to stimuli at the whole organism level.
In a specific implementation of the invention, the inventors have used nematodes (e.g., C. elegans ) as model organisms. Other organisms can be used as model systems, especially those that are translucent or partially translucent. A panel for oxidative stress response transgenic biosensor organisms was created based on the promoters of 7 genes induced by oxidative stress. Seven unique nematodes lines each corresponding to a different oxidative stress gene were created by genetic engineering technology (each line “representative” of a particular oxidative stress gene). More specifically, promoter regions for each oxidative stress response gene were identified and fused, or operably linked, to the coding region of a fluorescent protein gene to create a transgene promoter reporter construct using standard molecular biology methodology. Importantly, the promoter regions were identified/chosen to contain transcription factor response elements (e.g, transcription factor binding elements) that recruit transcription factors to help modulate transcription of genes under control of the promoter. Each transgene then was inserted into the nematode genome as a single copy (e.g., using single copy transgenesis procedures) to yield seven unique lines (also referred to as representative transgenic organisms e.g., seven representative transgenic organisms). Each line also has a constitutively expressed transgene encoding another fluorescent protein for normalization purposes which was introduced using standard techniques.
The seven different promoters used to create the lines were obtained from genes involved in oxidative stress response. Two genes used were alpha cystallins which respond to cytoplasmic heat shock (hsp-16.2 and hsp-16.41) (David et al. Environ. Toxicol. Chem 2003 January; 22(1):111-118; Hong et al. J. Mol. Biol 2004 November; 344(2):369-381; Candido EPM. Prog. Mol. Subcell. Biol 2002; 28:61-78; Dengg et al. J Pharmacol Toxicol Methods 2004 December; 50(3):209-214; and Strayer et al. FASEB J 2003 December; 17(15):2305-2307). A metallothionein gene was used to detect oxidative metal toxicity (mtl-2) (Sukaina Zeitoun-Ghandour et al. Aquatic Toxicology 2010 October; 100(2):140-150; Cui et al. Genome Biol 2007; 8 (6):R122; Roh et al. Environ. Toxicol. Chem 2006 November; 25(11):2946-2956; Liao et al. J. Biol. Chem 2002 November; 277(44):42049-42059; and Dong et al. J. Mol. Biol 2008 February; 376(3):621-633) as well as a uridine diphosphate-glucuronosyl/glucosyl transferases gene (ugt-1) (Cui et al. Genome Biol 2007; 8 (6):R122). The remaining 3 genes were chosen for unfolded protein response (UPR) oxidative stress in the mitochondria (hsp-6 and hsp-60) (Yoneda et al. J. Cell. Sci 2004 August; 117 (Pt 18):4055-4066.) and endoplasmic reticulum (hsp-4) (Vadim Kapulkin et al. FEBS Letters 2005 June; 579(14):3063-3068; and Urano et al. J. Cell Biol 2002). Promoters for these genes were selected to contain all clearly identified transcription factor binding sites and were cloned into expression vectors containing hsRFP, which is mCherry red fluorescent protein fused to the his-57 histone gene. The resulting hsRFP reporter construct expresses red fluorescence in cell nuclei. The reporter is injected into GFP expressing nematodes (unc-47::GFP) using the MosSCI method (Frokjaer-Jensen et al. Nat Genet 2008; 40(11):1375-83), which creates single copy insertions of the transcriptional reporter genes at Mos1 loci. The result is a two-color fluorescent nematode ( FIG. 5 ), where each strain contains both a ubiquitously-expressed GFP and hsRFP whose expression is driven by an oxidative-stress gene promoter.
Changes in expression were quantified with a plate reader assay. The 7-member oxidative stress response biosensor panel was heat shock exposed. Significant increased expression was observed in the hsp-16.41 and hsp-16.2 reporters ( FIG. 7A ), in contrast to the low to non-existent expression induction of the remaining genes. Exposure to metal toxicity elicited a different response in the panel. Cadmium primarily induced metallothionein gene expression ( FIG. 7B ) and only mildly induced expression from ugt-1, hsp-16's, and hsp-4. Thus, the simple 7-promoter panel was capable of distinguishing different types of responses. In particular, the panel differentiated between two types of oxidative stress responses: heavy metal ion induced oxidative stress and heat shock induced oxidative stress.
In addition, these results show the inventive methods and composition have 4 remarkable features. First, the system shows induction at significant levels over background. For example, the oxidative stress response panel has strong responses occurring at greater than 4-fold over background. Second, the system shows important levels of fidelity. The panel responses are highly reproducible, where less than 10% error occurs in the assays of 2 to 6 measures done on different days and/or different populations. Third, the method of MosSCI transgenesis creates independently derived strains with similar responses as indicated. Fourth, the arrangement of reports in a plate-reader panel provides an easy-to-use format that quickly reveals which genes are important for toxicity pathway response and can identify different types of response like one response pathway versus another response pathway.
In conclusion, the oxidative response panel demonstrated the system is feasible for sensitive and selective detection of changes in gene expression at the whole organism level when the organism is exposed to external stimuli. This system has advantages over cell culture methods because it is easier to use and amazingly less costly to implement. The inventive system is a whole organism approach, which detects cellular response in a native context. The ease of assay implementation makes the system ideal for high-throughput applications. In general, application of this technology in toxicogenomics is expected to be extremely valuable in the drug discovery sector (Yang et al. Chem Biol Interact 2004 November; 150(1):71-85). With this inventive system, pharmaceutical companies will decrease their financial exposure because better toxicology capture at the front end of drug development translates to lower frequency of drugs failing in clinical trials due to unwanted side-effect toxicity. Additionally, this technology has clear utility in a variety of other sectors, including screening potential pharmaceutical effects for wanted or on-target effects, or differentiating between types of on-target effects.
Definitions
As used herein, “operably linked” and “operably fused” may refer to the association of two or more nucleic acid elements in a recombinant DNA construct, e.g. as when a promoter is operably linked with DNA that is transcribed to RNA for expressing a protein. Additionally, the term “operably coupled” may be used herein to comprise the terms “operably linked” and “operably fused.”
As used herein, “percent identity” means the extent to which two optimally aligned DNA or protein segments are invariant throughout a window of alignment of components, for example nucleotide sequence or amino acid sequence. An “identity fraction” for aligned segments of a test sequence and a reference sequence is the number of identical components that are shared by sequences of the two aligned segments divided by the total number of sequence components in the reference segment over a window of alignment which is the smaller of the full test sequence or the full reference sequence. “Percent identity” (“% identity”) is the identity fraction times 100. Such optimal alignment is understood to be deemed as local alignment of DNA sequences. For protein alignment, a local alignment of protein sequences should allow introduction of gaps to achieve optimal alignment. Percent identity is calculated over the aligned length not including the gaps introduced by the alignment per se.
As used herein, the term “promoter” refers to a region of DNA which lies upstream of the transcriptional initiation site of a gene to which RNA polymerase binds to initiate transcription of RNA. An “inducible promoter” is a promoter that increases expression of its cognate gene or reporter when exposed to an inducing agent.
As used herein, the term “fluorescent protein” refers to proteins that fluoresce in response to excitation at a particular wavelength or range of wavelengths of light. As used herein, “RFP” refers to a class of proteins called red fluorescent proteins which are fluorescent proteins that fluoresce in the red region of the spectrum, generally in emitting light having a wavelength in the range of 600 to 650 nanometers. As used herein, “GFP” refers to a class of proteins called green fluorescent proteins which are fluorescent proteins that fluoresce in the green region of the spectrum, generally in emitting light having a wavelength in the range of 500 to 50 nanometers. The terms “RFP” and “GFP” are not intended to be construed based on the amino acid sequence of the underlying protein but are intended to be construed based on the wavelength of light they emit. For example, a RFP has been constructed by site-directed mutagenesis of a protein that was originally a GFP. As the term is used herein, this new protein is a RFP.
As used herein “detectably different” refers to measurements or observations that can be meaningfully distinguished from one another. In the context of “detectably different fluorescent proteins” this refers to proteins that fluorescent at different wavelengths of light such that they level of amount of the two proteins can be meaningfully determined. Detectably different can refer to no greater than 50%, 40%, 30%, 20%, or 10% of emissions.
As used herein, the term “transgene” refers to a gene in an organism that has been introduced, or is to be introduced, that is non-native. Typically transgenes according to the invention are created by genetic engineering technology and inserted into an organism to create a transgenic organism.
Thus, in one embodiment, the invention is one or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression in response to exposure to a selected agent. Each representative transgenic organism or population of representative transgenic organisms has a transgene which is an inducible promoter of a gene operably linked, or fused, to a reporter gene. Thus, a representative transgenic organism is a biosensor having a transgene which is an inducible promoter of a gene of interest operably linked, or fused, to a reporter gene. In a specific aspect, the transgenic organisms have a second reporter transgene that is a constitutive reporter that is used to normalize the expression level of the reporter driven by the inducible promoter. A population of transgenic organisms is 1 or more transgenic organisms each organism having as a transgene the same inducible promoter operably linked or fused to a reporter gene. In one aspect, the invention is a plurality of representative transgenic organisms or population of representative transgenic organisms where each representative transgenic organism or population of representative transgenic organisms has a distinct transgene that is a distinct inducible promoter of a gene operably linked, or fused, to a reporter gene. In a specific aspect, each population of representative transgenic organisms has 10 or more, 30 or more, 50 or more, 100 or more, 150 or more, 200 or more, or 300 or more transgenic organisms. A plurality of representative populations of transgenic organisms can be envisaged in the format of e.g., microwell plate with (a) each individual well having 2 or more transgenic organisms having as a transgene the same inducible promoter operably linked or fused to a reporter gene and (b) at least 2 wells differing from one another in the identity of the inducible promoter of the transgene (e.g., the inducible promoters in the transgenic organism in the first well and the inducible promoter for the transgenic organism in the second well are different i.e., from different genes). This concept is exemplified in FIG. 2 . According to a method of this embodiment, the plurality of representative transgenic organisms or population of representative transgenic organisms is contacted with or exposed to a selected agent, incubated for a time sufficient for induction of the gene driven by the inducible promoter, and expression of reporter gene is determined. In a specific aspect, the reporter gene driven by the inducible promoter encodes a fluorescent or luminescent protein. In a specific aspect, the constitutive reporter encodes a fluorescent or luminescent protein. In a specific aspect, each transgenic organism has an inducible promoter operably linked or fused to a reporter gene encoding a first fluorescent protein and a constitutive reporter encoding a second fluorescent protein wherein the first and second fluorescent protein fluoresce at detectably different wavelengths. Non-limiting examples of fluorescent proteins that fluoresce at detectably different wavelengths are GFP and RFP. Preferably, the inducible reporter expresses at least 2-fold greater, 3-fold great, or 4-fold greater than background levels (e.g., untreated organisms).
In a specific aspect of the embodiment described in the paragraph above, the invention is two or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is three or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In yet another specific aspect, the invention is four or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is five or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is seven or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is ten or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is fifteen or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. In another specific aspect, the invention is twenty or more (a) representative transgenic organisms or (b) populations of representative transgenic organisms as biosensors for detecting an alteration in gene expression as a response to exposure to a selected agent. Preferably, the inducible reporter is capable of expressing at least 2-fold greater, 3-fold greater, or 4-fold greater than its background expression level (e.g., untreated organisms).
The invention is a plurality of transgenic organisms for use as biosensors. The plurality of transgenic organisms includes at least two (a) representative transgenic organisms or (b) populations of representative transgenic organisms wherein the representative transgenic organisms or populations of representative transgenic organisms are distinct from one another in having transgenes comprising different inducible promoters operably linked or fused to a reporter gene (e.g., different strains) wherein the inducible promoter or promoters are chosen from SEQ ID NO:1 through SEQ ID NO:162, or a fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides of said promoter. For example, transgenic organism (1) has a transgene which is the inducible promoter of gene (1) operably linked or fused to a reporter gene and transgenic organism (2) has a transgene which is the inducible promoter region of gene (2) operably linked or fused to a reporter gene. The reporter genes used in the transgenic organism can be the same or different reporter genes. In a specific aspect, the reporter gene is the same gene in each transgenic organism. Typically, the inducible promoter is selected from a response pathway gene. Response pathway genes are genes from pathways that modulate an organism's response to an agent or stimuli at the gene expression level. In one specific aspect, the response pathway gene is a toxicity response pathway gene. In another specific aspect, the toxicity pathway response gene is a heavy metal, oxidative stress, endocrine disruption, xenobiotic, carcinogenic, genotoxic, neurotoxic, hepatatoxic, nephratoxic, or immunotoxic response pathway gene. In another aspect, the response pathway gene is an oxidative stress response gene, a carcinogen response pathway gene, an apoptosis pathway gene, an endocrine pathway gene, a genotoxin pathway gene, or a xenobiotic metabolism pathway. In one aspect, the response pathway gene is an oxidative stress response gene. In one aspect, the response pathway gene is a genotoxin response gene. In one aspect, the response pathway gene is a xenobiotic metabolism pathway gene. In one aspect, the plurality of (a) representative transgenic organisms or (b) populations of representative transgenic organisms comprise 2 or more, 3 or more, 4 or more, or 5 or more (a) representative transgenic organisms or (b) population of representative transgenic organisms having transgenes whose promoters are chosen from distinct oxidative stress response genes. In one aspect, the plurality of (a) representative transgenic organisms or (b) populations of representative transgenic organisms comprise 2 or more, 3 or more, 4 or more, or 5 or more (a) representative transgenic organisms or (b) population of representative transgenic organisms having representative transgenes whose promoters are chosen from distinct genotoxin stress response genes. In one aspect, the plurality of representative transgenic organisms or populations of representative transgenic organisms comprise 2 or more, 3 or more, 4 or more, or 5 or more (a) representative transgenic organisms or (b) population of representative transgenic organisms having representative transgenes whose promoters are chosen from distinct xenobiotic metabolism pathway genes. Preferably, the inducible reporter is capable of expressing at least 2-fold greater, 3-fold greater, or 4-fold greater than its background expression level (e.g., untreated transgenic organism or identical transgenic organism except for not having the inducible promoter reporter construct).
The invention is a transgenic organism, or a transgene, nucleic acid, or construct, comprising an inducible promoter operably linked, or fused, to a reporter gene to provide a biosensor functionality. In one specific aspect, the transgenic organism has the inducible promoter reporter transgene inserted into its genome by a single copy site specific insertion technology. In another specific aspect, the transgenic organism has a second reporter in its genome wherein said second reporter is expressed at a constitutive level. In one aspect, the constitutive reporter is inserted into the organism's genome as a single copy or using a single site insertion technology. The second reporter (constitutive) is used e.g., for normalization of the signal generated from the first reporter (inducible reporter). In one specific aspect, the transgene comprising the inducible promoter operably linked, or fused, to the reporter gene is inserted into the organism's genome in multiple copies, for example, 2 or more copies, 3 or more copies, 5 or more copies, 7 or more copies, or 10 or more copies. In one aspect, the reporter gene driven by the inducible promoter encodes a fluorescent or luminescent protein. In one aspect, the second reporter gene expressed at a constitutive level encodes a fluorescent protein or luminescent protein. In one aspect, the reporter gene driven by the inducible promoter encodes a fluorescent protein. In one aspect, the second reporter gene expressed at a constitutive level encodes a fluorescent protein. In one aspect, the reporter gene driven by the inducible promoter encodes a fluorescent protein which fluoresces at a wavelength that is detectably different than the wavelength that the fluorescent protein encoded by the constitutive reporter fluoresces. In one specific aspect, the reporter driven by the inducible promoter encodes a protein comprising a RFP and the reporter driven by the constitutive reporter encodes a protein comprising a GFP. Preferably, the inducible reporter is capable of expressing at least 2-fold greater, 3-fold greater, or 4-fold greater than its background expression level (e.g., untreated transgenic organism or identical transgenic organism except for not having the inducible promoter reporter construct).
In one embodiment, the invention is a method for detecting expression of a reporter gene operably linked, or fused, to an inducible promoter in a transgenic organism. According to this method, a plurality or array of representative transgenic organisms, or populations thereof, is provided wherein each representative transgenic organism, or population thereof, has an inducible promoter reporter construct integrated into its genome. A representative transgenic organism is one that has one type of inducible promoter reporter construct as a transgene e.g., a promoter from a specific gene. For example, a plurality of representative transgenic organisms can refer to e.g., a representative transgenic organism or population thereof (a) which has a transgene which is inducible promoter (a) operably linked or fused to a reporter; and representative transgenic organism or a population thereof (b) which has a transgene which is inducible promoter (b) operably linked or fused to a reporter. According to the method, each representative organism, or population thereof, is characterized by the identity of its inducible promoter (the organism “represents” a specific type of response characterized by the identity inducible promoter). Thus, each representative organism, or population thereof, has a distinct inducible promoter which is derived or obtained from a distinct gene. Each different representative transgenic organism can be present as multiple organisms to give a population of representative transgenic organisms (e.g., 3, 5, 10, 50, 100, 200 or 300 or more organisms) or as a single organism. The representative transgenic organism or population of transgenic organisms are exposed to or contacted with a selected agent and incubated with reagent and time sufficient to allow expression of the reporter gene. The reporter gene is detected or quantified. Optionally, the quantity of reporter can be normalized against the value for a second reporter gene, e.g., the constitutive reporter gene. Preferably, the reporter or reporters are fluorescents proteins. In one aspect, the inducible reporter encodes a protein comprising a RFP. In one aspect, the constitutive reporter encodes a protein comprising a GFP. Preferably, the inducible reporter is capable of expressing at least 2-fold greater, 3-fold greater, or 4-fold greater than its background expression level (e.g., untreated transgenic organism or identical transgenic organism except for not having the inducible promoter reporter construct).
In one embodiment, the invention is a method for detecting expression in a transgenic organism a first reporter gene operably linked or fused to an inducible promoter and a second reporter expressed at constitutive levels. According to this method, a plurality or array of representative transgenic organisms, or populations thereof, is provided wherein each representative transgenic organism, or population thereof, has an inducible promoter reporter construct and a constitutively expressed reporter integrated into its genome wherein the inducible promoter or promoters are chosen from SEQ ID NO:1 through SEQ ID NO:162, or a fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides of said promoter. A representative transgenic organism is one that has one type of inducible promoter reporter construct as a transgene. For example, a plurality of representative transgenic organisms can refer to e.g., a representative transgenic organism (a) which has a transgene which is inducible promoter (a) operably linked or fused to a reporter; and representative transgenic organism (b) which has a transgene which is inducible promoter (b) operably linked or fused to a reporter. According to the method, each representative organism, or population thereof, is characterized by the identity of its inducible promoter (the organism “represents” a specific type of response characterized by the identity inducible promoter). Thus, each representative organism, or population thereof, has a distinct inducible promoter which is derived or obtained from a distinct gene. The representative transgenic organism or population of transgenic organisms are exposed to or contacted with a selected agent and incubated with reagents and time sufficient to allow expression of the reporter genes. The level of the reporter gene is then detected or quantified. The quantity or level of the inducible reporter can be normalized against the quantity or level of a second reporter gene, e.g., the constitutive reporter gene. Preferably, the reporter or reporters encode a fluorescent proteins or proteins. In one aspect, the inducible reporter encodes a protein comprising a RFP. In one aspect, the constitutive reporter encodes a protein comprising a GFP. Preferably, the inducible reporter is capable of expressing at least 2-fold greater, 3-fold greater, or 4-fold greater than background its level (e.g., untreated transgenic organism or identical transgenic organism except for not having the inducible promoter reporter construct).
The combination of use of single site insertion technology for the inducible promoter reporter transgene and the use of second constitutive reporter for normalization in the invention has produced remarkable unprecedented results for whole organism biosensors. In one aspect, the transgene is inserted into a single site of the host organisms's genome using single site insertion technology and is present as one copy. In one aspect, the transgene is inserted into multiple sites in the host organism's genome using a site-specific insertion technology and is present in from 2 to 50 copies, more preferably 2 to 20 copies and even more preferably from 2 to 10 copies.
In an alternative aspect, the transgene is inserted into the organism's genome as multiple copies. For example, ballistic genes guns can be used to insert the transgene into the organism's genome in the range of 1 copy to about 50 copies. In another aspect, the transgene is inserted into the extra-chromosomal array of a C. elegans host organism. In this aspect, the host organism typically has from about 100 to about 1000 copies of the transgene.
According to one aspect of the invention, the transgenic organism is translucent or at least partially translucent. More specifically, the transgenic organism of this aspect is translucent or at least partially translucent to allow for spectrophotometric detection of one or more reporter genes in a medium or high-throughput fashion. In one specific aspect, medium or high throughput format refers to the ability detect the expression level of the reporter gene in a multi-well plate format using a plate reader that is capable of detecting and quantitating the level of fluorescence or bioluminescence of the respective reporter. In another specific aspect, the transgenic organism is a nematode, Danio rerio (zebrafish), Drosophila melanogaster, Daphnia spp., or Xenopus laevis . In one specific aspect, the organism is a nematode. In another specific aspect, the organism is C. elegans . The ordinary skilled artisan is capable of identify promoters in organisms such Danio rerio, Drosophila melanogaster, Daphnia spp., or Xenopus laevis to create the transgenic organisms in a manner similar to that described herein for C. elegans.
In one embodiment, the invention involves transgenesis of DNA into the worm genome (e.g., C. elegans ). This DNA is a transgene that contains an inducible promoter operably linked or fused to a gene encoding a reporter protein. The inserted DNA then allows reporter protein expression in the transgenic organism upon exposure to a selected agent or toxin that activates or induces its expression. The genetically engineered animal serves as a biosensor (e.g., for toxicity). According to one aspect of this embodiment, the transgene is inserted into the genome using MosSCI technology. The method involves (a) providing a strain of an organism having an insertion element site and a marker for positive selection (b) injecting the organisms with a vector having a transgene comprising (1) an inducible promoter reporter construct, (2) a marker for selection, and (3) sequence elements (e.g., homology arms) sufficient for effectuating insertion into the insertion element site or sites of the strain, a vector for producing a transposase compatible with the transposon and insertion element site, and one or more plasmids acting as markers for tracking the presence of extrachromosal arrays. Injected animals are transferred to plates, allowed to grow or incubate for a time sufficient to allow for transformation and recovery, and are then screened for insertion events by use of the selection markers in the strain, the transgene, and the markers for tracking the presence of extrachromosomal markers.
Inducible Promoters
A variety of inducible promoters are used to make different transgenic biosensors organisms of the invention. Inducible promoters are chosen from different genes that are selected for being activated or modulated in response to stimuli or conditions, e.g., like toxins or a drug or drug candidate. The promoters are chosen to include transcription factor response elements which are DNA sequences that enhance or drive transcription of a gene involved in a response pathway by serving as a template for the transcriptional machinery (transcription factors) associated with the response pathway. In one embodiment of the invention, the resulting transgenic biosensor organisms are arranged into a panel. A test compound (selected agent) is exposed to members of the panel and specific types of response (e.g., toxicities) are detected (see e.g., FIG. 8 or FIG. 9 ). In an alternative embodiment, the same representative transgenic strain, or population thereof, is duplicated in all wells of the panel and a population of molecules, like a library, are screened for one type of toxicity. In one specific example, a library of molecules designed to inhibit or modulate a specific target or that inhibited or modulated a specific target are counter-screened against one or more representative transgenic organisms, or populations thereof, to identify a molecule or molecules that have the least toxicology liabilities or have a desirable toxicity profile.
The inducible promoters used in the invention can be any promoter element or region that is involved in regulating gene expression. Promoter regions typically lie upstream of a gene, anywhere from about 1 to 10,000 or more base pairs (bp) upstream of the start site. In general, regions ranging from 1 to 4,000 bp upstream of start codon are chosen for promoter selection. In one aspect, the region ranges from about 1 to 2500 bp upstream from the start site. In one aspect, the region ranges from about 1 to 2000 bp upstream from the start site. In one aspect, the region ranges from about 1 to 1000 bp upstream from the start site. In one aspect, the promoter is within about 500 bp upstream of the transcription start site. See e.g., Gerstein et al. Science. 2010 Dec. 24; 330(6012):1775-87.
The genes chosen for the exemplary oxidative stress response panel are the following oxidative response genes (hsp-16.41, hsp16.2, hsp-6 and hsp-60, hsp-4, mlt-2, and ugt-1). To choose the oxidative-response gene promoters and any other promoters for use in the invention, a combination of modENCODE's TF-GFP ChIP-seq data (Niu et al. Genome Res. 2011 February; 21 (2):245-254) and multi-z 6-species alignment (Niu et al. Genome Research 2004; 14(4):708-715.) can be used to find the extent of conserved genomic regions containing TF (transcription factor) sites in front of the oxidative-response gene's start codon (or other response pathway genes). Promoter-reporter fusion constructs can be designed for Gibson (Gibson et al. Nat. Methods 2009 May; 6(5):343-345) reaction cloning using APE plasmid editor (biologylabs.utah.edu/jorgensen/wayned/ape). In general, regions ranging from 300 to 4,000 bp upstream of start codon were chosen for promoter selection. Other techniques for identifying, selecting and cloning inducible promoter regions for use in the compositions and methods of the invention are known to the skilled artisan.
Reporter Genes
Reporter genes for use in the invention include any reporter that can be expressed and quantified. Preferably, the reporter gene encodes a protein that can be detected spectrophotometrically. Some examples include fluorescent proteins (e.g., green fluorescent protein (GFP), cyan fluorescent protein (CFP), red fluorescent protein (RFP), mCherry, Tag-RFP, etc.), luciferase which is a luminescent reporter (Ranella, Firefly, etc.), chomogenic (beta-Gal, etc.), etc. See e.g., Pollock et al., Trends in Cell Biology 9:57 (1999). Useful fluorescent proteins also include mutants and spectral variants of these proteins which retain the ability to fluoresce. See e.g., Shaner et al., Nat. Biotech. 22:1567 (2004), Tag-RFP (Shaner, N. C. et al., 2008 Nature Methods, 5 (6), 545-551), fluorescent proteins fused to e.g., his-GFP or his-RFP which is histone H2B fused to the indicated fluorescent protein Essex et al. Mol. Biol. Cell 2009 February; 20 (4):1252-1267). Other fluorescent proteins that can be used in the invention include, but are not limited to, AcGFP, AcGFP1, AmCyan, AmCyan1, AQ143, AsRed2, Azami Green, Azurite, BFP, Cerulean, CFP, CGFP, Citrine, copGFP, CyPet, dKeima-Tandem, DsRed, dsRed-Express, DsRed-Monomer, DsRed2, dTomato, dTomato-Tandem, EBFP, EBFP2, ECFP, EGFP, Emerald, EosFP, EYFP, GFP, HcRed-Tandem, HcRed1, JRed, Katuska, Kusabira Orange, Kusabira Orange2, mApple, mBanana, mCerulean, mCFP, mCherry, mCitrine, mECFP, mEmerald, mGrape1, mGrape2, mHoneydew, Midori-Ishi Cyan, mKeima, mKO, mOrange, mOrange2, mPlum, mRaspberry, mRFP1, mRuby, mStrawberry, mTagBFP, mTangerine, mTeal, mTomato, mTurquoise, mWasabi, PhiYFP, ReAsH, Sapphire, Superfolder GFP, T-Sapphire, TagCFP, TagGFP, TagRFP, TagRFP-T, TagYFP, tdTomato, Topaz, TurboGFP, Venus, YFP, YPet, ZsGreen, and ZsYellow1 which are described in the literature or otherwise commercially available. hRFP and hsRFP are RFP's fused to e.g., a histone protein like H2B from C. elegans.
Isolated Nucleic Acids, Transgenes, Constructs, Transgenic Organisms and Transgenic C. elegans Organisms
The invention is nucleic acids and constructs and transgenic organisms comprising those nucleic acids as described herein.
In one embodiment, the invention provides a transgene, a transgenic organism, or a construct which comprises a promoter, a fragment of a promoter having 50, 100, 200, 300, 400, or 500 or more nucleotides of the promoter, or a homolog thereof having at least 95%, 96%, 97%, 98%, or 99% identity thereto operably linked, or fused, to a reporter gene wherein said reporter gene encodes a fluorescent or luminescent protein and wherein the promoter is for the C. elegans gene cdr-1, gcs-1, ugt-1, gst-38, hsp-60, hsp-16.41, mtl-2, hsp-16.2, gst-4, ugt-13, hsp-3, hsp-6, hsp-4, hsp-1, skn-1, dnj-13, daf-21, Hsp-17, cyp-13A7, cyp-14A3, cyp-35A2, zyg-12, ZK742.4, ZK742.3, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fmo-1, fmo-2, fmo-3, fmo-4, fmo-5, ftn-1, ftn-2, fzy-1, gen-1, glp-1, gsr-1, gst-1, gst-23, gst-25, gst-41, H01G02.2, haf-6, syp-2, T05A12.4, T05G5.3, T06E6.2, T07F12.4, Hsp-12.2, T05E11.3, Cnx-1, Crt-1, cyp-35A1, cyp-35C1, cyp-35A3, pqe-1, cyp-37B1, cyp-35B2, cyp-35B1, cyp-22A1 (daf-9), cyp-14A5, cyp-35B3, cyp-34A6, daf-16, exo-3, nth-1, pme-1, ung-1, xpa-1, mrt-2, ercc-1, ZK697.8, ZK287.5, haf-7, hda-1, hda-10, hda-11, hda-2, hda-3, hda-4, hda-5, hda-6, hdac-1, hif-1, him-1, him-14, him-3, him-4, him-6, hmg-3, hmg-4, hmg-5, hpr-17, hpr-9, hrdl-1, hsf-1, hsp-1, hsp-16.48, tbb-4, tnc-2, top-3, tor-2, trx-2, xpf-1, xpg-1, rad-23, mlh-1, msh-2, msh-4, msh-5, msh-6, brc-1, brc-2, rad-50, cku-70, lin-35, mei-1, cki-1, cki-2, cep-1, ced-3, ced-9, ced-13, vem-1, dhs-23, sodh-2, dnj-19, Xbp-1, hsp-16.49, hsp-2, htp-1, htp-3, hus-1, imb-3, ire-1, irk-1, K07C5.2, K07C5.4, K08F4.1, K11G12.5, kin-18, lagr-1, let-2, let-92, lig-1, lig-4, lim-4, lin-12, lin-44, lin-49, lrk-1, lst-3, M18.5, vps-41, W01A11.1, W02C12.1, W03G1.5, W06H8.2, Hipr-1, cdc-48.1, cdc-48.3, Ubq-1, Ubq-2, Gst-10, Gst-13, f25d1.5, fil-1, k10h10.6, hsp-70, f44e5.4, f44e5.5, hsp-16.11, hsp-16.1, nurf-1, aip-1, y43f8b.2, Dod-17, Dod-24, C55A6.7, F56D5.3, cyp-13A11, cyp-13A6, cyp-25A4, mac-1, mboa-2, mdf-1, mdf-2, mec-14, med-1, mel-28, misc-1, mnat-1, mre-11, mrp-1, mrp-2, mrp-3, mrp-4, mrp-5, mrp-6, mrp-7, mrp-8, mspn-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, ndx-1, Y55B1AL.2, Y56A3A.33, Y66D12A.15, Y66D12A.15, Y73C8C.10, cyp-29A2, cyp-31A1, cyp-31A3, cyp-33B1, cyp-33E1, cyp-34A10, cyp-34A9, cyp-35A4, cyp-35D1, abl-1, abu-1, acr-14, acr-22, agt-1, ahr-1, air-2, ama-1, apa-2, apn-1, apn-1, aps-2, arf-1, asp-5, atf-5, atgr-7, ndx-4, nft-1, nhr-6, nol-5, npl-4.2, nuc-1, odc-1, paa-1, pas-4, pat-10, pcn-1, pdi-1, pdi-2, pdi-3, pdr-1, pek-1, pgp-1, pgp-10, pgp-2, phi-37, phi-44, phi-9, pink-1, pme-2, pme-3, T08D2.4, T08D2.7, T08H10.1, T10B5.8, T13A10.2, atl-1, atm-1, B0222.9, B0432.2, B0495.2, B0563.7, brd-1, C01G5.5, C06A1.6, C06H2.3, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C25A1.5, C30G7.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C44H4.4, C56G3.2, catp-6, cbn-1, F17A9.5, F18A1.5, F19G12.2, F23C8.9, F36A4.15, F43D2.1, F43G6.5, F44B9.8, F45E12.3, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F55B11.1, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59F4.1, fan-1, fdps-1, figl-1, trxr-1, tut-1, uba-1, ubc-1, ubc-20, ccch-1, cct-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdc-48.2, cdk-7, ced-4, cel-1, cft-1, chk-1, chk-2, chn-1, cku-80, cle-1, clk-2, clpp-1, cmd-1, cnb-1, col-135, pme-4, pme-5, pmrt-5, pms-2, png-1, polh-1, polk-1, prx-6, ptl-1, R02D3.3, R03D7.2, R05D11.6, R05F9.10, R09H10.3, R10E4.9, R13D11.4, R151.6, rab-1, rab-7, srp-2, ssc-1, sti-1, sulp-7, sut-1, sut-2, wrn-1, xpc-1, Y110A7A.4, Y38F1A.5, Y38H8A.3, cps-6, crb-1, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, crp-1, csb-1, ctl-2, ctl-3, cul-1, cul-2, cul-4, cul-5, cyh-1, cyn-1, cyn-10, cyn-11, cyn-12, cyn-13, cyn-14, cyn-15, cyn-16, rad-51, rad-54, rbx-1, rbx-2, rcf-3, rcq-5, rec-8, rev-1, rfc-1, rfc-4, rfl-1, rme-8, rnf-121, rnh-1.0, rpa-1, rpa-2, rpn-10, rps-19, rps-26, T23G5.6, T26A5.5, T27E9.1, tag-353, tars-1, tbb-2, Y73F8A.24, ymel-1, ZC168.4, ZC395.10, ZC443.1, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, cyp-13A12, cyp-13A4, cyp-14A2, cyp-33C1, cyp-33C2, cyp-33C9, cyp-33E2, cyp-42A1, cyp14A2, cyp33C9, cyp34A6, D1081.8, D2023.4, daf-1, daf-14, daf-3, rpt-3, rpt-4, rpt-5, rpt-6, rtel-1, san-1, scav-1, scav-2, scav-3, scav-4, scav-5, scc-3, sdz-8, sec-22, sep-1, set-25, set-26, set-8, set-9, unc-11, unc-26, unc-57, uri-1, usp-14, vps-4, T15B7.2, T16H12.4, ugt-62, Y39G8B.1, Y39G8B.2, daf-5, daf-7, daf-8, dbl-1, ddb-1, dhs-22, djr-1.1, dna-2, dog-1, drh-3, drp-1, dut-1, E01A2.1, eft-2, egl-1, eif-2, emb-9, epg-2, eps-8, exo-1, F09E5.2, F14F9.5, F15E6.6, F16A11.2, F17A9.4, sft-4, sgg-1, sin-3, sir-2.1, sir-2.2, sir-2.3, sir-2.4, skr-15, slt-1, slx-1, smf-1, smk-1, sod-1, sod-2, sod-3, sod-4, sod-5, spas-1, ugt-61, Y43E12A.1, Y43F8C.13, Y48G1BL.2, Y50D7A.1, Y50D7A.2, Y54E10A.3, ufd-1, ugt-22, ugt-52, ZK1128.4, ZK1290.5, or Y39H10A.7. The transgene, transgenic organism, or construct is used for the gene expression biosensors as described herein. According to the invention, an inducible promoter or fragment thereof, or a homolog having at least 95%, 96%, 97%, 98%, or 99% identity thereto, of one or more of the genes listed above and is operably linked, or fused, to a reporter gene using standard molecular biology techniques as described herein and elsewhere. The resulting construct can be transformed into an organism to a yield a transgenic biosensor organism as described herein. In a specific aspect, the construct further comprises one or more of the following: a selectable marker, sequence elements sufficient for site-specific integration into the host organism's genome. In one aspect, the transgene is introduced into the organism with a technique that yields a site specific single copy stable insertion. In a specific aspect, the transgenic biosensor organisms are arranged into an array or panel. The panels can be arranged into kits useful for detecting a wide variety of toxicities or gene expression responses. In one specific aspect, the transgenic organism is a nematode. In another specific aspect, the transgenic organism is C. elegans.
In one embodiment, the invention provides a transgene, a transgenic organism, or a construct comprising a promoter, a fragment of a promoter having 50, 100, 200, 300, 400, or 500 or more nucleotides of the promoter, or a homolog thereof having at least 95%, 96%, 97%, 98%, or 99% identity thereto, operably linked, or fused, to a reporter gene wherein said reporter gene encodes a fluorescent or luminescent protein and wherein the promoter is from an organism chosen from Danio rerio (zebrafish), Drosophila melanogaster, Daphnia spp., or Xenopus laevis and the promoter is for gene that organism that is homologous to the gene in C. elegans corresponding to cdr-1, gcs-1, ugt-1, gst-38, hsp-60, hsp-16.41, mtl-2, hsp-16.2, gst-4, ugt-13, hsp-3, hsp-6, hsp-4, hsp-1, skn-1, dnj-13, daf-21, Hsp-17, cyp-13A7, cyp-14A3, cyp-35A2, zyg-12, ZK742.4, ZK742.3, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fmo-1, fmo-2, fmo-3, fmo-4, fmo-5, ftn-1, ftn-2, fzy-1, gen-1, glp-1, gsr-1, gst-1, gst-23, gst-25, gst-41, H01G02.2, haf-6, syp-2, T05A12.4, T05G5.3, T06E6.2, T07F12.4, Hsp-12.2, T05E11.3, Cnx-1, Crt-1, cyp-35A1, cyp-35C1, cyp-35A3, pqe-1, cyp-37B1, cyp-35B2, cyp-35B1, cyp-22A1 (daf-9), cyp-14A5, cyp-35B3, cyp-34A6, daf-16, exo-3, nth-1, pme-1, ung-1, xpa-1, mrt-2, ercc-1, ZK697.8, ZK287.5, haf-7, hda-1, hda-10, hda-11, hda-2, hda-3, hda-4, hda-5, hda-6, hdac-1, hif-1, him-1, him-14, him-3, him-4, him-6, hmg-3, hmg-4, hmg-5, hpr-17, hpr-9, hrdl-1, hsf-1, hsp-1, hsp-16.48, tbb-4, tnc-2, top-3, tor-2, trx-2, xpf-1, xpg-1, rad-23, mlh-1, msh-2, msh-4, msh-5, msh-6, brc-1, brc-2, rad-50, cku-70, lin-35, mei-1, cki-1, cki-2, cep-1, ced-3, ced-9, ced-13, vem-1, dhs-23, sodh-2, dnj-19, Xbp-1, hsp-16.49, hsp-2, htp-1, htp-3, hus-1, imb-3, ire-1, irk-1, K07C5.2, K07C5.4, K08F4.1, K11G12.5, kin-18, lagr-1, let-2, let-92, lig-1, lig-4, lim-4, lin-12, lin-44, lin-49, lrk-1, lst-3, M18.5, vps-41, W01A11.1, W02C12.1, W03G1.5, W06H8.2, Hipr-1, cdc-48.1, cdc-48.3, Ubq-1, Ubq-2, Gst-10, Gst-13, f25d1.5, fil-1, k10h10.6, hsp-70, f44e5.4, f44e5.5, hsp-16.11, hsp-16.1, nurf-1, aip-1, y43f8b.2, Dod-17, Dod-24, C55A6.7, F56D5.3, cyp-13A11, cyp-13A6, cyp-25A4, mac-1, mboa-2, mdf-1, mdf-2, mec-14, med-1, mel-28, misc-1, mnat-1, mre-11, mrp-1, mrp-2, mrp-3, mrp-4, mrp-5, mrp-6, mrp-7, mrp-8, mspn-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, ndx-1, Y55B1AL.2, Y56A3A.33, Y66D12A.15, Y66D12A.15, Y73C8C.10, cyp-29A2, cyp-31A1, cyp-31A3, cyp-33B1, cyp-33E1, cyp-34A10, cyp-34A9, cyp-35A4, cyp-35D1, abl-1, abu-1, acr-14, acr-22, agt-1, ahr-1, air-2, ama-1, apa-2, apn-1, apn-1, aps-2, arf-1, asp-5, atf-5, atgr-7, ndx-4, nft-1, nhr-6, nol-5, npl-4.2, nuc-1, odc-1, paa-1, pas-4, pat-10, pcn-1, pdi-1, pdi-2, pdi-3, pdr-1, pek-1, pgp-1, pgp-10, pgp-2, phi-37, phi-44, phi-9, pink-1, pme-2, pme-3, T08D2.4, T08D2.7, T08H10.1, T10B5.8, T13A10.2, atl-1, atm-1, B0222.9, B0432.2, B0495.2, B0563.7, brd-1, C01G5.5, C06A1.6, C06H2.3, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C25A1.5, C30G7.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C44H4.4, C56G3.2, catp-6, cbn-1, F17A9.5, F18A1.5, F19G12.2, F23C8.9, F36A4.15, F43D2.1, F43G6.5, F44B9.8, F45E12.3, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F55B11.1, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59F4.1, fan-1, fdps-1, figl-1, trxr-1, tut-1, uba-1, ubc-1, ubc-20, ccch-1, cct-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdc-48.2, cdk-7, ced-4, cel-1, cft-1, chk-1, chk-2, chn-1, cku-80, cle-1, clk-2, clpp-1, cmd-1, cnb-1, col-135, pme-4, pme-5, pmrt-5, pms-2, png-1, polh-1, polk-1, prx-6, ptl-1, R02D3.3, R03D7.2, R05D11.6, R05F9.10, R09H10.3, R10E4.9, R13D11.4, R151.6, rab-1, rab-7, srp-2, ssc-1, sti-1, sulp-7, sut-1, sut-2, wrn-1, xpc-1, Y110A7A.4, Y38F1A.5, Y38H8A.3, cps-6, crb-1, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, crp-1, csb-1, ctl-2, ctl-3, cul-1, cul-2, cul-4, cul-5, cyh-1, cyn-1, cyn-10, cyn-11, cyn-12, cyn-13, cyn-14, cyn-15, cyn-16, rad-51, rad-54, rbx-1, rbx-2, rcf-3, rcq-5, rec-8, rev-1, rfc-1, rfc-4, rfl-1, rme-8, rnf-121, rnh-1.0, rpa-1, rpa-2, rpn-10, rps-19, rps-26, T23G5.6, T26A5.5, T27E9.1, tag-353, tars-1, tbb-2, Y73F8A.24, ymel-1, ZC168.4, ZC395.10, ZC443.1, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, cyp-13A12, cyp-13A4, cyp-14A2, cyp-33C1, cyp-33C2, cyp-33C9, cyp-33E2, cyp-42A1, cyp14A2, cyp33C9, cyp34A6, D1081.8, D2023.4, daf-1, daf-14, daf-3, rpt-3, rpt-4, rpt-5, rpt-6, rtel-1, san-1, scav-1, scav-2, scav-3, scav-4, scav-5, scc-3, sdz-8, sec-22, sep-1, set-25, set-26, set-8, set-9, unc-11, unc-26, unc-57, uri-1, usp-14, vps-4, T15B7.2, T16H12.4, ugt-62, Y39G8B.1, Y39G8B.2, daf-5, daf-7, daf-8, dbl-1, ddb-1, dhs-22, djr-1.1, dna-2, dog-1, drh-3, drp-1, dut-1, E01A2.1, eft-2, egl-1, eif-2, emb-9, epg-2, eps-8, exo-1, F09E5.2, F14F9.5, F15E6.6, F16A11.2, F17A9.4, sft-4, sgg-1, sin-3, sir-2.1, sir-2.2, sir-2.3, sir-2.4, skr-15, slt-1, slx-1, smf-1, smk-1, sod-1, sod-2, sod-3, sod-4, sod-5, spas-1, ugt-61, Y43E12A.1, Y43F8C.13, Y48G1BL.2, Y50D7A.1, Y50D7A.2, Y54E10A.3, ufd-1, ugt-22, ugt-52, ZK1128.4, ZK1290.5, or Y39H10A.7. The transgene, transgenic organism, or construct is used for the gene expression biosensors as described herein. According to the invention, an inducible promoter or fragment thereof, or a homolog having at least 95%, 96%, 97%, 98%, or 99% identity thereto, of one or more of the genes listed above and is operably linked, or fused, to a reporter gene using standard molecular biology techniques as described herein and elsewhere. The resulting construct can be transformed into an organism to a yield a transgenic biosensor organism as described herein. In one aspect, the transgene is introduced into the organism with a technique that yields a site specific single copy stable insertion. In a specific aspect, the transgenic biosensor organisms are arranged into an array or panel. The panels can be arranged into kits useful for detecting a wide variety of toxicities or gene expression responses. In one specific aspect, the transgenic organism is a nematode. In another specific aspect, the transgenic organism is C. elegans.
In one embodiment, the invention provides a transgene, a transgenic organism, or a construct which comprises a promoter, a fragment of a promoter having 50, 100, 200, 300, 400, or 500 or more nucleotides of the promoter, or a homolog thereof having at least 95%, 96%, 97%, 98%, or 99% identity thereto operably linked, or fused, to a reporter gene wherein said reporter gene encodes a fluorescent or luminescent protein and wherein the promoter is for the C. elegans gene ABCE-1, ABCF-1, ABCF-2, ABCF-3, ABT-1, ABT-2, ABT-4, ABT-5, ABTM-1, acr-14, acr-22, ahr-1, akt-1, akt-2, apa-2, ape-1, apn-1, aps-2, ard-1, arf-1, arf-1.1, arl-7, asp-5, atf-5, atgr-7, B0222.9, B0432.2, B0495.2, B0563.7, bec-1, bmk-1, C01B10.7, C01G12.5, C01G5.5, C01H6.4, C03A7.12, C03A7.13, C04F12.1, C05C9.1, C06A1.6, C06E4.3, C06E4.4, C06E4.6, C06G1.1, C06H2.3, C07A9.13, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C16C8.14, C23G10.6, C25A1.5, C25A1.6, C27D8.4, C28H8.11, C30G12.2, C30G7.5, C31H1.1, C32D5.12, C33E10.10, C35B1.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C41A3.1, C44H4.4, C46H11.2, C55A6.3, C55A6.4, C55A6.6, C55C3.1, C55H1.1, C56G3.2, cah-5, car-1, catp-6, cbn-1, ccch-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdr-5, ced-1, ced-10, ced-12, ced-13, ced-2, ced-5, ced-6, CED-7, ceh-20, ceh-30, ces-1, ces-2, cgh-1, chn-1, cit-1.2, ckb-2, cle-1, clec-149, clpp-1, cmd-1, cnb-1, Cnx-1, cnx-1, col-135, coq-6, cpb-3, crb-1, crp-1, Crt-1, crt-1, csp-1, csp-2, csp-3, ctl-1, cul-1, cul-2, cul-3, cul-5, cyn-1, cyn-10, cyn-11, cyn-12, cyn-14, cyn-15, cyn-16, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, CYP-13A1, CYP-13A10, CYP-13A2, CYP-13A3, CYP-13A5, CYP-13A8, CYP-13B1, CYP-13B2, CYP-14A1, CYP-14A4, CYP-23A1, CYP-25A1, CYP-25A2, CYP-25A3, CYP-25A5, CYP-25A6, CYP-29A3, CYP-29A4, CYP-31A2, CYP-32A1, CYP-32B1, CYP-33A1, CYP-33C11, CYP-33C3, CYP-33C4, CYP-33C5, CYP-33C6, CYP-33C7, CYP-33C8, CYP-33D1, CYP-33D3, CYP-33E3, CYP-34A1, CYP-34A2, CYP-34A4, CYP-34A5, CYP-34A7, CYP-34A8, CYP-35A5, CYP-36A1, CYP-37A1, CYP-43A1, CYP-44A1, cyp14A2, cyp14A5, cyp33C9, D1007.16, D1054.8, D1081.8, D2023.4, dad-1, daf-1, daf-14, daf-21, daf-3, daf-5, daf-7, daf-8, DAF-9, dbl-1, DC2.5, dhs-1, dhs-10, dhs-11, dhs-12, dhs-13, dhs-14, dhs-15, dhs-16, dhs-18, dhs-19, dhs-2, dhs-20, dhs-21, dhs-24, dhs-25, dhs-26, dhs-28, dhs-29, dhs-3, dhs-30, dhs-31, dhs-4, dhs-5, dhs-6, dhs-8, dhs-9, djr-1.1, dnj-11, dnj-25, dnj-27, dnj-7, Dod-17, Dod-24, dop-1, dop-1, dop-3, dop-3, dpl-1, dpr-1, drh-3, duox-2, dut-1, E01A2.1, E04F6.15, eat-3, efl-1, efl-2, eft-2, egg-1, egg-2, egl-38, emb-9, eor-1, eor-2, epg-2, eps-8, exos-3, F02C12.2, F07A11.2, F09E5.2, F10D11.6, F10D2.12, F10D2.8, F10D7.3, F12E12.11, F14D12.1b, F14F9.5, F15E6.6, F16A11.2, F17A9.5, F18A1.5, F19G12.2, F20G2.1, F20G2.2, F22D6.15, F22E5.6, F23C8.9, F26D2.15, F28A10.1, F28H7.2, F30B5.4, F32A5.8, F36A4.15, F43G6.5, F44B9.8, f44e5.4, f44e5.5, F45E12.3, F46H5.2a, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F54C1.1, F54F3.4, F55A11.6, F55B11.1, F55E10.6, F56A4.4, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59E11.2, F59F4.1, fan-1, fasn-1, fdps-1, fil-1, fipr-24, fis-1, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fnta-1, ftn-1, ftn-2, gab-1, gad-3, gale-1, gdi-1, ggtb-1, gla-3, gld-1, glp-1, glrx-10, gsr-1, gst-11, gst-12, gst-14, gst-15, gst-16, gst-18, gst-19, gst-2, gst-20, gst-21, gst-22, gst-24, gst-26, gst-28, gst-29, gst-3, gst-30, gst-31, gst-32, gst-33, gst-34, gst-35, gst-36, gst-39, gst-40, gst-42, gst-43, gst-44, gst-5, gst-6, gst-8, gst-9, gstk-1, gstk-2, gsto-1, gsto-2, gsto-3, H01G02.2, H04M03.3, H06H21.9, H10D18.6, H23N18.4, HAF-1, HAF-2, HAF-3, HAF-4, HAF-8, HAF-9, hda-10, hda-11, hda-5, hi-14, hif-1, him-10, him-4, hke-4.1, hlh-2, hlh-3, HMT-1, hpo-15, hps-1, hps-60, hsd-1, hsd-2, hsd-3, hsf-1, hsp-1, hsp-16.1, hsp-16.1, hsp-2, hsp-60, icd-1, ikb-1, imb-3, ing-3, irk-1, irp-1, irp-2, itr-1, jkk-1, jnk-1, K02E11.3, K02E11.4, K02E11.5, K02E11.6, K02E11.7, K02E11.9, K04A8.10, K07C5.2, K07C5.4, K08F4.1, K10F12.4, K11D12.6, K11G12.5, kin-18, kin-4, lagr-1, lbp-1, lbp-2, lbp-3, lbp-4, lbp-5, lbp-6, lbp-7, lbp-8, lbp-9, let-2, let-23, let-60, let-92, lim-4, lin-1, lin-12, lin-3, lin-31, lin-44, lin-49, lip-1, lips-11, lrk-1, lst-3, M18.5, M57.2, mab-5, maoc-1, mca-2, mec-14, med-1, mei-2, mek-1, mek-2, mel-26, mev-1, misc-1, mlt-7, mpk-1, mtl-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, nas-39, ncs-3, ndx-4, nhr-181, nhr-6, nhr-64, nol-5, npl-4, npl-4.2, nrf-5, nsy-1, nurf-1, odc-1, paa-1, pag-3, pah-1, pas-4, pat-10, pax-2, pdi-1, pdr-1, pek-1, PGP-11, PGP-12, PGP-13, PGP-14, PGP-15, PGP-3, PGP-4, PGP-5, PGP-6, PGP-7, PGP-8, PGP-9, phi-37, phi-44, phi-9, pink-1, pkc-2, pmk-1, pmk-2, pmk-3, PMP-1, PMP-2, PMP-3, PMP-4, PMP-5, pmrt-5, png-1, polq-1, pqe-1, pqn-60, prdx-2, prx-1, prx-5, psr-1, ptl-1, ptp-3, ptp-3, pxn-2, qdpr-1, R03D7.2, R05D11.6, R05D8.7, R05D8.9, R05F9.10, R07B7.4, R07B7.5, R09H10.3, R10E4.9, R119.3, R11A8.5, R13D11.4, R151.6, rab-1, rab-5, rae-1, rcf-3, rcq-5, rfc-1, rfl-1, rfp-1, rgef-1, rgs-2, rgs-2, rme-8, rnf-1, rnf-121, rnh-1.0, rnp-2, rpa-2, rps-19, rps-26, rtel-1, scav-1, scav-2, scav-3, scav-4, scav-5, sdz-8, sdz-8, sec-22, sek-1, sel-10, sel-8, sem-5, ser-3, set-25, set-26, set-8, set-9, sex-1, sft-4, sgg-1, skr-15, slt-1, smf-1, smk-1, smo-1, sod-2, sod-4, sod-5, srp-2, srp-7, sti-1, sulp-7, sup-9, sup-9, sut-1, sut-2, syp-2, T01G6.1, T01G6.10, T05A12.4, T05G5.3, T06E6.2, T07F12.4, T08D2.4, T08D2.7, T08H10.1, T10B5.10, T10B5.8, T13A10.2, T15B7.2, T16G1.6, T19B4.1, T19C3.5, T19H12.3, T21B4.4, T23G5.6, T25G12.2, T26A5.5, T27E9.1, tag-124, tag-353, tag-63, tars-1, tbb-2, tbb-4, tbh-1, tnc-2, tor-2, tra-1, trx-2, trxr-1, tut-1, uba-1, ubc-14, ubc-20, ubxn-4, ugt-10, ugt-11, ugt-12, ugt-14, ugt-15, ugt-16, ugt-17, ugt-18, ugt-19, ugt-2, ugt-20, ugt-21, ugt-23, ugt-24, ugt-25, ugt-26, ugt-27, ugt-28, ugt-29, ugt-3, ugt-30, ugt-31, ugt-32, ugt-33, ugt-34, ugt-35, ugt-36, ugt-37, ugt-38, ugt-39, ugt-4, ugt-40, ugt-41, ugt-42, ugt-43, ugt-44, ugt-45, ugt-46, ugt-47, ugt-48, ugt-49, ugt-5, ugt-50, ugt-51, ugt-53, ugt-54, ugt-55, ugt-56, ugt-57, ugt-58, ugt-59, ugt-6, ugt-60, ugt-63, ugt-64, ugt-65, ugt-7, ugt-8, ugt-9, unc-11, unc-2, unc-26, unc-36, unc-36, unc-43, unc-43, unc-57, unc-73, uri-1, usp-14, vit-1, vit-2, vit-3, vit-4, vit-5, vit-6, vps-11, vps-16, vps-18, vps-33, vps-39, W01A11.1, W01B11.6, W02C12.1, W03F9.9, W03G1.5, W10C8.4, wah-1, WHT-1, WHT-2, WHT-3, WHT-4, WHT-5, WHT-6, WHT-7, WHT-8, WHT-9, Y110A7A.4, Y23H5A.2, Y38F1A.5, Y38H6C.17, Y38H8A.3, Y39G8B.1, Y39G8B.2, Y39H10A.7, Y41C4A.11, Y43D4A.2, Y43E12A.1, y43f8b.2, Y43F8C.13, Y45G12C.3, Y47D3A.22, Y47D3A.29, Y47G6A.21, Y47G6A.22, Y48G1BL.2, Y50D7A.1, Y53G8B.1, Y54E10A.3, Y56A3A.33, Y66D12A.15, Y71G12B.4, Y73B6A.3, Y73C8C.10, ymel-1, ZC168.4, ZC395.10, ZC443.1, ZC513.1, ZC513.2, ZK1290.5, ZK287.5, ZK550.6, ZK616.8, ZK697.14, ZK697.8, ZK742.3, ZK742.4, ZK829.1, or zyg-12. The transgene, transgenic organism, or construct is used for the gene expression biosensors as described herein. According to the invention, an inducible promoter or fragment thereof, or a homolog having at least 95%, 96%, 97%, 98%, or 99% identity thereto, of one or more of the genes listed above and is operably linked, or fused, to a reporter gene using standard molecular biology techniques as described herein and elsewhere. The resulting construct can be transformed into an organism to a yield a transgenic biosensor organism as described herein. In a specific aspect, the construct further comprises one or more of the following: a selectable marker, sequence elements sufficient for site-specific integration into the host organism's genome. In one aspect, the transgene is introduced into the organism with a technique that yields a site specific single copy stable insertion. In a specific aspect, the transgenic biosensor organisms are arranged into an array or panel. The panels can be arranged into kits useful for detecting a wide variety of toxicities or gene expression responses. In one specific aspect, the transgenic organism is a nematode. In another specific aspect, the transgenic organism is C. elegans.
In one embodiment, the invention provides a transgene, a transgenic organism, or a construct comprising a promoter, a fragment of a promoter having 50, 100, 200, 300, 400, or 500 or more nucleotides of the promoter, or a homolog thereof having at least 95%, 96%, 97%, 98%, or 99% identity thereto, operably linked, or fused, to a reporter gene wherein said reporter gene encodes a fluorescent or luminescent protein and wherein the promoter is from an organism chosen from Danio rerio, Drosophila melanogaster, Daphnia spp., or Xenopus laevis and the promoter is for gene that organism that is homologous to the gene in C. elegans corresponding to ABCE -1, ABCF-1, ABCF-2, ABCF-3, ABT-1, ABT-2, ABT-4, ABT-5, ABTM-1, acr-14, acr-22, ahr-1, akt-1, akt-2, apa-2, ape-1, apn-1, aps-2, ard-1, arf-1, arf-1.1, arl-7, asp-5, atf-5, atgr-7, B0222.9, B0432.2, B0495.2, B0563.7, bec-1, bmk-1, C01B10.7, C01G12.5, C01G5.5, C01H6.4, C03A7.12, C03A7.13, C04F12.1, C05C9.1, C06A1.6, C06E4.3, C06E4.4, C06E4.6, C06G1.1, C06H2.3, C07A9.13, C07D8.6, C08H9.3, C09D4.3, C11E4.2, C16C8.14, C23G10.6, C25A1.5, C25A1.6, C27D8.4, C28H8.11, C30G12.2, C30G7.5, C31H1.1, C32D5.12, C33E10.10, C35B1.5, C35C5.2, C35D10.2, C35D10.6, C37A2.4, C37C3.6a, C41A3.1, C44H4.4, C46H11.2, C55A6.3, C55A6.4, C55A6.6, C55C3.1, C55H1.1, C56G3.2, cah-5, car-1, catp-6, cbn-1, ccch-1, cct-2, cct-3, cct-4, cct-5, cct-6, cct-7, cct-8, cdc-14, cdr-5, ced-1, ced-10, ced-12, ced-13, ced-2, ced-5, ced-6, CED-7, ceh-20, ceh-30, ces-1, ces-2, cgh-1, chn-1, cit-1.2, ckb-2, cle-1, clec-149, clpp-1, cmd-1, cnb-1, Cnx-1, cnx-1, col-135, coq-6, cpb-3, crb-1, crp-1, Crt-1, crt-1, csp-1, csp-2, csp-3, ctl-1, cul-1, cul-2, cul-3, cul-5, cyn-1, cyn-10, cyn-11, cyn-12, cyn-14, cyn-15, cyn-16, cyn-17, cyn-2, cyn-3, cyn-4, cyn-5, cyn-6, cyn-7, cyn-8, cyn-9, CYP-13A1, CYP-13A10, CYP-13A2, CYP-13A3, CYP-13A5, CYP-13A8, CYP-13B1, CYP-13B2, CYP-14A1, CYP-14A4, CYP-23A1, CYP-25A1, CYP-25A2, CYP-25A3, CYP-25A5, CYP-25A6, CYP-29A3, CYP-29A4, CYP-31A2, CYP-32A1, CYP-32B1, CYP-33A1, CYP-33C11, CYP-33C3, CYP-33C4, CYP-33C5, CYP-33C6, CYP-33C7, CYP-33C8, CYP-33D1, CYP-33D3, CYP-33E3, CYP-34A1, CYP-34A2, CYP-34A4, CYP-34A5, CYP-34A7, CYP-34A8, CYP-35A5, CYP-36A1, CYP-37A1, CYP-43A1, CYP-44A1, cyp14A2, cyp14A5, cyp33C9, D1007.16, D1054.8, D1081.8, D2023.4, dad-1, daf-1, daf-14, daf-21, daf-3, daf-5, daf-7, daf-8, DAF-9, dbl-1, DC2.5, dhs-1, dhs-10, dhs-11, dhs-12, dhs-13, dhs-14, dhs-15, dhs-16, dhs-18, dhs-19, dhs-2, dhs-20, dhs-21, dhs-24, dhs-25, dhs-26, dhs-28, dhs-29, dhs-3, dhs-30, dhs-31, dhs-4, dhs-5, dhs-6, dhs-8, dhs-9, djr-1.1, dnj-11, dnj-25, dnj-27, dnj-7, Dod-17, Dod-24, dop-1, dop-1, dop-3, dop-3, dpl-1, dpr-1, drh-3, duox-2, dut-1, E01A2.1, E04F6.15, eat-3, efl-1, efl-2, eft-2, egg-1, egg-2, egl-38, emb-9, eor-1, eor-2, epg-2, eps-8, exos-3, F02C12.2, F07A11.2, F09E5.2, F10D11.6, F10D2.12, F10D2.8, F10D7.3, F12E12.11, F14D12.1b, F14F9.5, F15E6.6, F16A11.2, F17A9.5, F18A1.5, F19G12.2, F20G2.1, F20G2.2, F22D6.15, F22E5.6, F23C8.9, F26D2.15, F28A10.1, F28H7.2, F30B5.4, F32A5.8, F36A4.15, F43G6.5, F44B9.8, f44e5.4, f44e5.5, F45E12.3, F46H5.2a, F49E12.6, F52B5.2, F52C12.1, F53C11.5, F53F1.2, F53F1.3, F53F10.2, F54C1.1, F54F3.4, F55A11.6, F55B11.1, F55E10.6, F56A4.4, F57B10.5, F57B10.6, F58F9.1, F59A2.3, F59E11.2, F59F4.1, fan-1, fasn-1, fdps-1, fil-1, fipr-24, fis-1, fkb-1, fkb-2, fkb-3, fkb-4, fkb-5, fkb-6, fkb-7, fkb-8, fnta-1, ftn-1, ftn-2, gab-1, gad-3, gale-1, gdi-1, ggtb-1, gla-3, gld-1, glp-1, glrx-10, gsr-1, gst-11, gst-12, gst-14, gst-15, gst-16, gst-18, gst-19, gst-2, gst-20, gst-21, gst-22, gst-24, gst-26, gst-28, gst-29, gst-3, gst-30, gst-31, gst-32, gst-33, gst-34, gst-35, gst-36, gst-39, gst-40, gst-42, gst-43, gst-44, gst-5, gst-6, gst-8, gst-9, gstk-1, gstk-2, gsto-1, gsto-2, gsto-3, H01G02.2, H04M03.3, H06H21.9, H10D18.6, H23N18.4, HAF-1, HAF-2, HAF-3, HAF-4, HAF-8, HAF-9, hda-10, hda-11, hda-5, hi-14, hif-1, him-10, him-4, hke-4.1, hlh-2, hlh-3, HMT-1, hpo-15, hps-1, hps-60, hsd-1, hsd-2, hsd-3, hsf-1, hsp-1, hsp-16.1, hsp-16.1, hsp-2, hsp-60, icd-1, ikb-1, imb-3, ing-3, irk-1, irp-1, irp-2, itr-1, jkk-1, jnk-1, K02E11.3, K02E11.4, K02E11.5, K02E11.6, K02E11.7, K02E11.9, K04A8.10, K07C5.2, K07C5.4, K08F4.1, K10F12.4, K11D12.6, K11G12.5, kin-18, kin-4, lagr-1, lbp-1, lbp-2, lbp-3, lbp-4, lbp-5, lbp-6, lbp-7, lbp-8, lbp-9, let-2, let-23, let-60, let-92, lim-4, fin-1, lin-12, lin-3, lin-31, lin-44, lin-49, lip-1, lips-11, lrk-1, lst-3, M18.5, M57.2, mab-5, maoc-1, mca-2, mec-14, med-1, mei-2, mek-1, mek-2, mel-26, mev-1, misc-1, mlt-7, mpk-1, mtl-1, mus-1, mut-2, mxl-1, mxl-2, mxl-3, nas-39, ncs-3, ndx-4, nhr-181, nhr-6, nhr-64, nol-5, npl-4, npl-4.2, nrf-5, nsy-1, nurf-1, odc-1, paa-1, pag-3, pah-1, pas-4, pat-10, pax-2, pdi-1, pdr-1, pek-1, PGP-11, PGP-12, PGP-13, PGP-14, PGP-15, PGP-3, PGP-4, PGP-5, PGP-6, PGP-7, PGP-8, PGP-9, phi-37, phi-44, phi-9, pink-1, pkc-2, pmk-1, pmk-2, pmk-3, PMP-1, PMP-2, PMP-3, PMP-4, PMP-5, pmrt-5, png-1, polq-1, pqe-1, pqn-60, prdx-2, prx-1, prx-5, psr-1, ptl-1, ptp-3, ptp-3, pxn-2, qdpr-1, R03D7.2, R05D11.6, R05D8.7, R05D8.9, R05F9.10, R07B7.4, R07B7.5, R09H10.3, R10E4.9, R119.3, R11A8.5, R13D11.4, R151.6, rab-1, rab-5, rae-1, rcf-3, rcq-5, rfc-1, rfl-1, rfp-1, rgef-1, rgs-2, rgs-2, rme-8, rnf-1, rnf-121, rnh-1.0, rnp-2, rpa-2, rps-19, rps-26, rtel-1, scav-1, scav-2, scav-3, scav-4, scav-5, sdz-8, sdz-8, sec-22, sek-1, sel-10, sel-8, sem-5, ser-3, set-25, set-26, set-8, set-9, sex-1, sft-4, sgg-1, skr-15, slt-1, smf-1, smk-1, smo-1, sod-2, sod-4, sod-5, srp-2, srp-7, sti-1, sulp-7, sup-9, sup-9, sut-1, sut-2, syp-2, T01G6.1, T01G6.10, T05A12.4, T05G5.3, T06E6.2, T07F12.4, T08D2.4, T08D2.7, T08H10.1, T10B5.10, T10B5.8, T13A10.2, T15B7.2, T16G1.6, T19B4.1, T19C3.5, T19H12.3, T21B4.4, T23G5.6, T25G12.2, T26A5.5, T27E9.1, tag-124, tag-353, tag-63, tars-1, tbb-2, tbb-4, tbh-1, tnc-2, tor-2, tra-1, trx-2, trxr-1, tut-1, uba-1, ubc-14, ubc-20, ubxn-4, ugt-10, ugt-11, ugt-12, ugt-14, ugt-15, ugt-16, ugt-17, ugt-18, ugt-19, ugt-2, ugt-20, ugt-21, ugt-23, ugt-24, ugt-25, ugt-26, ugt-27, ugt-28, ugt-29, ugt-3, ugt-30, ugt-31, ugt-32, ugt-33, ugt-34, ugt-35, ugt-36, ugt-37, ugt-38, ugt-39, ugt-4, ugt-40, ugt-41, ugt-42, ugt-43, ugt-44, ugt-45, ugt-46, ugt-47, ugt-48, ugt-49, ugt-5, ugt-50, ugt-51, ugt-53, ugt-54, ugt-55, ugt-56, ugt-57, ugt-58, ugt-59, ugt-6, ugt-60, ugt-63, ugt-64, ugt-65, ugt-7, ugt-8, ugt-9, unc-11, unc-2, unc-26, unc-36, unc-36, unc-43, unc-43, unc-57, unc-73, uri-1, usp-14, vit-1, vit-2, vit-3, vit-4, vit-5, vit-6, vps-11, vps-16, vps-18, vps-33, vps-39, W01A11.1, W01B11.6, W02C12.1, W03F9.9, W03G1.5, W10C8.4, wah-1, WHT-1, WHT-2, WHT-3, WHT-4, WHT-5, WHT-6, WHT-7, WHT-8, WHT-9, Y110A7A.4, Y23H5A.2, Y38F1A.5, Y38H6C.17, Y38H8A.3, Y39G8B.1, Y39G8B.2, Y39H10A.7, Y41C4A.11, Y43D4A.2, Y43E12A.1, y43f8b.2, Y43F8C.13, Y45G12C.3, Y47D3A.22, Y47D3A.29, Y47G6A.21, Y47G6A.22, Y48G1BL.2, Y50D7A.1, Y53G8B.1, Y54E10A.3, Y56A3A.33, Y66D12A.15, Y71G12B.4, Y73B6A.3, Y73C8C.10, ymel-1, ZC168.4, ZC395.10, ZC443.1, ZC513.1, ZC513.2, ZK1290.5, ZK287.5, ZK550.6, ZK616.8, ZK697.14, ZK697.8, ZK742.3, ZK742.4, ZK829.1, or zyg-12. The transgene, transgenic organism, or construct is used for the gene expression biosensors as described herein. According to the invention, an inducible promoter or fragment thereof, or a homolog having at least 95%, 96%, 97%, 98%, or 99% identity thereto, of one or more of the genes listed above and is operably linked, or fused, to a reporter gene using standard molecular biology techniques as described herein and elsewhere. The resulting construct can be transformed into an organism to a yield a transgenic biosensor organism as described herein. In one aspect, the transgene is introduced into the organism with a technique that yields a site specific single copy stable insertion. In a specific aspect, the transgenic biosensor organisms are arranged into an array or panel. The panels can be arranged into kits useful for detecting a wide variety of toxicities or gene expression responses. In one specific aspect, the transgenic organism is a nematode. In another specific aspect, the transgenic organism is C. elegans.
Examples of preferred nucleic acids corresponding to promoters that are used in the compositions and methods of the invention are given below in reference to the pathways and gene abbreviations in SEQ ID NO:1 through SEQ ID NO:XX.
Cytoplasmic Oxidative Stress Toxicity






hsp-16.41





SEQ ID NO: 1





gattatagtttgaagatttctaatttcacaattagagcaaatgttgttcggtatttattttcaacggtatttatactattttccacctttttctagaacatt




cgagctgcttgttgcaaaaggagggcgactcacattcggtacatggaaaagtagtgtacacaataaagagacccagatacattttccgtctg



cgtctctttgcacccaccgggagtattttcaaacgaatgcatctaggaccttctagaacattctgtaaggctgcagaatgcgggtatataagg



aaagcgggctcagaggaagccaacacgctttgttctagtgcatctaaaaaacttcgaaa



hsp-16.2




SEQ ID NO: 2





tttcgaagttttttagatgcactagaacaaagcgtgttggcttcctctgagcccgctttccttatatacccgcattctgcagccttacagaatgttc




tagaaggtcctagatgcattcgtttgaaaatactcccggtgggtgcaaagagacgcagacggaaaatgtatctgggtctctttattgtgtaca



ctacttttccatgtaccgaatgtgagtcgccctccttttgcaacaagcagctcgaatgttctagaaaaaggtggaaaatagtataaataccgtt



gaaaataaataccgaacaacatttgctctaattgtgaaattagaaatcttcaaactataatc



hsp-16.1




SEQ ID NO: 3





tcttgaagtttagagaatgaacagtaagcacttgaacaaagtgtattggtttcctctgaacacgattggcttatatacccgtatcctgcagccgt




ttagaatgttctagaaggtcctagatgcattcatttcaaaatacaccccataggtgcaaagagacgcagattgaaaaagtatctgggtttcttc



agtacgcacactatttctcaatgttctgaatgtgagtcgccctccttttgcaagaagcagctcgaatgttctagaaaaaggtggaaatgagtat



aaatacagtgacaaaaccgaaccaaacaacattcactctaattgtgaaatcttcaaactacaatc



hsp-16.11




SEQ ID NO: 4





tcttgaagtttagagaatgaacagtaagcacttgaacaaagtgtattggtttcctctgaacacgattggcttatatacccgtatcctgcagccgt




ttagaatgttctagaaggtcctagatgcattcatttcaaaatacaccccataggtgcaaagagacgcagattgaaaaagtatctgggtttcttc



agtacgcacactatttctcaatgttctgaatgtgagtcgccctccttttgcaagaagcagctcgaatgttctagaaaaaggtggaaatgagtat



aaatacagtgacaaaaccgaaccaaacaacattcactctaattgtgaaatcttcaaactacaatc



hsp-16.48




SEQ ID NO: 5





gattgtagtttgaagatttcacaattagagtgaatgttgtttggttcggttttgtcactgtatttatactcatttccacctttttctagaacattcgagct




gcttcttgcaaaaggagggcgactcacattcagaacattgagaaatagtgtgcgtactgaagaaacccagatactttttcaatctgcgtctctt



tgcacctatggggtgtattttgaaatgaatgcatctaggaccttctagaacattctaaacggctgcaggatacgggtatataagccaatcgtgt



tcagaggaaaccaatacactttgttcaagtgcttactgttcattctctaaacttcaaga



hsp-16.49




SEQ ID NO: 6





gattgtagtttgaagatttcacaattagagtgaatgttgtttggttcggttttgtcactgtatttatactcatttccacctttttctagaacattcgagct




gcttcttgcaaaaggagggcgactcacattcagaacattgagaaatagtgtgcgtactgaagaaacccagatactttttcaatctgcgtctctt



tgcacctatggggtgtattttgaaatgaatgcatctaggaccttctagaacattctaaacggctgcaggatacgggtatataagccaatcgtgt



tcagaggaaaccaatacactttgttcaagtgcttactgttcattctctaaacttcaaga



hsp-12.2




SEQ ID NO: 7





acaattcagaaggagcaataattctgtgatatttaaactaatttctctttgtttctttgttatgagtatttatttttagttcttgttcatcatgctttttt




tgtcacttttccctccccaatcccatattcctctgcttttctctcattttcggttacgtgtattaattgaatgtatacgacgacgacagtcactagtttcgaa



ataactattttacgaggatgaataaacacactgatcgctgagcgacgctccgagcacttttcgagaagtttctaagaagccacttgaccgag



agagagggagaaagaaaagcttggcatagaaatgtgcttgtgtttatttgaactgttaaaagtgtttgacgggggcgaagtcactggggaa



acctcgagatcaataggacacgtggcaatttgaatttttggataattggaaaagcagtacccgactaaagatccgaatttgattttcagacattt



tactgcaaacttgattacacacggtaattttccaaaagttttgtgcattgaatcccgaaaaacttcacaaacgcataatattacaacccgatctat



gagcaaagtaaatagagagaatcaggctgaaagcttattgtgattaatgaacattaggaacaatgctgatttcaatttgaaacatttttttttcag



atcgaaaatcagttttttcagatcgaaaatcacattggatcttgacattttcaagagaattattaaaatttaaatggctatttgaaaagtattgatttt



ctgaaagataataactacttaccatctatgtcgtacctgactatgccaattattttcaacaattgtttattttaaaaaatttttgaagtaagcttaaaa



caaacccaggacctctgaaatgtaccaagtttggaaactaattccaagtactggtaataacaaaaattttgaattcgaggcggataagcgcc



agttgggagttttctgattataattatattaatagaattgccaaaaatcatgataaacccctccaatcattttttgattttcgaaaaagtttcaatgta



ggttttggtgagctgcgaagttttccaaaaatgtctaaaaactaaattcatatggttcaatttttgtcaaaaacgttcagctcatgaggagcttga



aactaaccaataaattttggtcattaaattggtcagttaaattgataattgaaattaaccggatatgtttggaaaaataaatgcaaaagttcatgat



catcagatcaaaaaccaaaaacttcccctacatttctatttccaaattgaagatttcttgaagcctacaaatagtacagtttacaaatatctctcct



tctttctctcgtcccttcttgcgcatcctcagagctcggagctcctatccgtcaatataaacaatcattgtttcttttcttctcctcgtaccttttttctt



cttcaaatccatttttcctccgcccccttatcctacagtccaattcctttcactctccactttctgagcttcttctccaactcgcaaaagcttcaaag



ctcacagagcattttacgatagtgcattgtaatgttctccaccctagagtgcatctccaacctgcgcatatgttttcgctctttgacattacattttc



ttccgattcacattttattcatccacccgataaatatattttcacacttttaattttctagagaaa



sod-1




SEQ ID NO: 8





tattctacgtcaataggaattgtcagaattatcagttttgatatcaaaaattgccagctttagtacagtagaataactatgcgattcatgctgcttat




tatttattcaaaatttaaattttaaccaactgtgagtttattttatagaacatttttcgaaataaaattcaaaaaaataaaaattgttatttttcaaaatct



taatcttaatttagcaccattaccgacaggcaatgatagaacaccaaaccggactgaccaagtgtcgtaccagtttcgagcaatcaagtattg



agagactgatattcttgctgatactatactcttaagatatgaaacgatatctacccctctagccccctactcgtgcgccctcagttacctacctac



cccgttacctaccctaccctacctacctactcagtctcctacctaccccgaccgtatcatatctttagaatatagtatcaacaagaataccaatc



acccaaccccaatcactcgaaaccgttaggcaccaggttagccagtctggattaatcgagagtaaaccacttgactccagacaactacatct



tatacttacttacgtctgggggacaatcttgggattctcaagatgacttccattacgaagtctcttgcaataaccaattaccacaattttggagca



gaattaaactcacccaccagtacaggatcaaagatgaataatgaatgagaggccctcctctcattgttgtgggcggggtcaaggggtcaaa



gttttttgaatttcgaaattttgaaattttggaattgttaaatttttggaaatctaatttttgaaagaaccacattttccgtttacaatttgagttcaattcc



gcaaccccgtcaaatttaagaagagaaagaaaaaaaacacaacgtgtttgcacctgtaaggtagtttttttttgttgccttcggcgttttgattca



catgaaagtttctacggaaaaactttcattgcataacgatcttcatatcttgtttctggaaacgaaaatttccaacatgaaagaaacccgacgct



atttattctcgcaacacaaaaatttcacatttaaataaccgcggtttttctcgaacagcatatttgacgcgcattgctcgtcaagtttgatgcgtgc



acactattttgctgttgtttttttcttttttctctaaattttctttacgctttcgtagtttctatagaaacgattctccactcccggttttcttccgattc



tcaaaattaattaaaatttagttattaaaaatcctttttcttgaaataatcgttcaatttcgagttttcaagagtggagacgttgaatttgtgagccgc



ttattttttctgtgtttttgttttgtggtttttaatcagtgtcataatcatactttccattgtttctttattattcaaagttgtagattcagtattttag



atcggtgatgtttatgaatcttctcactcaggtctccaacgcgatttttccgcaggtcagtgcttatccgaaacattcgtcattcgcaacttgggccta



tttgatctatggcgttgtgttgttgcctttaccttaattatcatcattttcatcagaaacccacaaaaactagagacatagctacaaaattctgcgacc



gagaggcgggtacacacacaatgttgtctatttcatctcgctccaccttctctctctctctctcgtgtttaccatttcttttttaattttgcatctatcga



ctgtgatctgcctgtttttttctaattctaaactttttgccgtgatattccttagagtgttccctagaaaattcgttgaatttacaggtcgaagccgct



caaaaag



sto-1




SEQ ID NO: 9





aaaaacttgatccgatcgaagaaaaaaccgaaaaaaaattcgaattgttgtgttgttcgtcagttggatggaatgatgatgaaggaagttgatt




aatggatatgactgatgattagtggtggaatatggaataattatttatttgatttattctgattattctgaattagaatgtattttcatatttcaggaaa



aatgattttatttcgaaacgaacttgttctagattaaaaaaattgaaatttaatatttagtgctatacaattacagtaccccatggaaatacacaaat



atcataaatacaagaattatcttcctggaagttaaacttatattttcgatgtaagtgaaaaagtttaaaagagaaatgatgtttgttgatcttcctgt



aagtggaaactggagaattcataagcttaaaaattccaaaatattaaaacttgcgtgttttttctgaaaatcgattaaaacagcaatattcagcat



gtttccagagccaaaaaaacctgcaagcatgggatacttttgcagttaaaaaatgtttcaggaacttgaatgaagttaggatgcatttgaaca



gagtaatgaaattatatgaaattcatatgtagactctcctactcagttgtttgtatgtgagttttgtatattataacttattttgaaattatctttaattact



tgtaatgttttttgtatgagttaaataataatcttttgaaaattctttttcaaataaccattttctgtttaaaaaaacagtgagcccaatataaacttgttt



tccatcaaaccgagcttctaccaaagttaacttaaattccataattttcacaaaccattcatagtttgtctacgtagccttatccttttttgaacattg



aaaaagtgaggagaaagtgcgaaaaacgagtttttttctttctcttcttcttggtcgtcacgtcaagacactctgaacgttggaatgggaaaag



catcgaagatcgaaaaattctgattttttctaaagtacacaacttatattgatattgcattgggatttaaaaaagctctactcgaacattttgattaat



tttaatatctcatttattcatctttcgataacagatatatcacattgttcggtaggataaaagggctaaaatcaagttttgaggaatgttcatttgtttg



gaaggtgatattatagtctgcgataactacataagtttggaaaccgaacacatgtttttttggcactttgctaaaaagttgtctgaaaacgttgga



aatcaatatttggtcatttatttaggtcattttcggaccattataagtgttttctaatacaaaactggcgctgctccgctatttaaaagactgaaagt



gacataaatgatctaatttccagatctcttataactttttttatagcggttccactcctaatttgatgtgtttacttgttgcatcagatcatttttcacttc



ttgtaattcttatcagttttctatattttctttcttatcaatttttcagcttttcaacattttccagttagttattcaatttttattccgcacgatcactgc



tgtttgaattcaaatattggagtattaaaattatacatttataaccattctaatgtctaccttctacacaaattacccttcctagtagaaaatatat



ttttggcttgaaatttgttctgtactgtccaa



gcs-1




SEQ ID NO: 10





tttctaagttcgcacattcctcgatttccacttgccgttacctttcattatctccttttactttaatctatcacagtttcatagatatcaaacgttaattttt




tgttgcgagctagtttgttttttttcctcttgttcggtccattcgctttaacttgtcacctattttttgttttctctacagtcctcttggttcatgatcctg



ttaattatcaatgctcttttctgtgatattcgatattcgaatcaacaatgtgtatgattagtgtcaaagtaacttatcggattttgaatataattcaattatt



cgtgtaataaataactattttttagtttactcatgtttgccacaaactagaaggtttatttattcataactacttgcaatttcacatttgaattctaactg



tatgattgcttcaactctctgcgattttttgcgctaaaatacggtacccggtctcggcgcgacaaaaaatttctagatttttagaaaattttacaga



tttattgcaacagctgttacctttttcacaaaaaaatcgactgaatttcgcgaagttatgatatctcaagcggccgcttgcgggaaaagccatat



tttttttcaaattttcgtagctgcacaatttttcataattttttcatttgttaaaaataaatgtattttaaataattgtcctatttcagtttttcaataaat



ttttttaacgaaaaactataaaaatagatgaattctagagccacgtaatttcagaattacagtactctttcaaggcgcatacccttttaacataaattttcg



cgtcgagaccgggtaccgtactttgacgcaaattttgcatctgggtaattcttgtttttgggttcttcactttccaccacttttttttcgaaagcatca



aatttcacatattcacgtcacaatcctagcaaagcccaatagctcattcaagtcatatttgtctctttctttctcattctcctgattagcaacactgtc



ttatcaaccactaggttccgtcttaatcgtccaaatattgatccgctcgctcgtgttttctcaacttctttatttgctgtgtttttctgtttctatagttctc



cattttccatctcctcttcgcttgttgaatggactttattttgataagttcattttaatttttctaacaatctcatcactagctcatgatgacaattgcaa



agaaattcgtcatatagaggggaaaaatgctgacaaatattgaaaagccttcaggagagatgtagagacgtaggagtagagacagaacat



aaatttgagaagcttgtagggagaatagacatagagttaccatgggaaaaacgctcgcattttccatttaacgagattttctagatcacaacat



tttgtgatccgttgtgcgaaaatcaagctttttatcaaacttttatcgtctgttcattctttctgacaatctttattatcttattaaacttgactaattgta



ttgaaagtatttttttagatgcgaacgaagttccatttttcatgacttaacatctcttaacgttagtgaaatttttgaattccaattaggactacggtag



gagttctgtagttgatttcctgaacacttgttttgtaacctttctgaacggattttaatatttctaaaattttaaattgcaaatctgagtcctattaaaag



atgtttcatccgtaaaaccaacaaacaaaatatcactttatcatcatgagatttaatgtttccttttgattttctgaattgttgtactttccttcaaacg



acttattgaactgatgtaactttccttctaatgttatcatttgtatttttttgcaga



hpo-15




SEQ ID NO: 11





aaaccaaatttactacttttactatatttttagttgaaaataaaaagagaaaaacatttattttctaaaaacagtaattttcctttagtcagtttatttctc




attgagatattgtgaactcctgttttaaaatcaaatgagaaaaattgaacacaaattttaaatttacataaatccccaaaaactatcaatatttcca



acctagacacactataattgaataagattctcgtgaccttcggacatacagtttgtcaaagacaagcactcccacatttgccggttaattgtgat



aaccctatcaacttggctccgtcttcactctcacttgcaattgcacaacttctttctttttggatgtaagtagcaacattttatcatcactctattggg



aaatttttaaaacaaaatttcttcaatacgattgccggtctcgccacgataaattgtaggtacatgcgaaaaaataatgcccatttaaagagtac



tgtaatttccatctctctttgttgcaggattttttgtcgatttttttagttgttcaatacaaataaattcattcgaaaactgtcatgtcacgataaacaaa



caaattttggtatttaacaaaaatttgtcgtgtcgagacctaagctagaatagtactataatttttgagctttaattttttcaagttttttacaaaattttt



ttttctgttgattaattgatgtatttttatcggagatctataaaaaaatcaatgaaattttcgaagaagccaaaaaagtactgttgatactacagtaa



tcttcaaaggcgcacacctttcggcatttaacaaaaatttgtcgtgttaagaccgggtaatttgttaggcaaatatttgaaaaaaaactgcttaa



atatttcatgaaaattctgttatctttaatcagatttttaaaaaattattatcaaatttcaaaaaattacctaaaataatgtctgaaattcttctttactca



cgcgaactgcaacttccagacattaattgaggaaatttcaaattaatcaataacaatgaatacgattttcagattaaacgagtattttcctacattt



ttattaatttttttgattaatattaatttttaaaatgaaatttttggataatcctactaaaataagcatgtcccgcaaggccctatttcaaaagtttagtg



cctgaaaaatcaatatttcgcaagaacagtctaccaatttttccaatttatacttccggcaattgccaccaattcggtgatctagaaaatacccat



ataggctctacagtaccttcccttatcacccacatccaattttgctatcagttagtcttcaatcacacttagtctttgaacaaatgaactcataactc



tcacaagatgtttgcaactatcatattgatgtcattcagttctcatatgagaaggcgggcacattgttgtatattgataaaccacccccattttcct



cttcttccagcaaaaaaaaataaaattaatattgtctcagacgcttgtgaaactggtgctctcaattgaaaagcaccattgacttcgcagaaact



ggcagttcatttggctttcggatacttacaaccatacgctcaca



dhs-18




SEQ ID NO: 12





tctgtatatatgcaaaaggaaaattaaatattatctatcgatggaaatgttagaaaagcgaattacttggcacggcagcaggtgccacaaagc




ctgcagctgaataaagttaagatacgattgcttgctgacaaataggacactaaattggaaaatacacaccacattttgatttttaatcagatcttt



tttaattttaattttagtcacatctagactactctgactactattctcacacgtgtggccaacaatcattcggactacgctgtaggcagtcaggagt



tttcaaatgataaggtgttcaacagtgtagtcttatttgtatcattttcacataaaacgcaatttcaaaaactcccaattttcttcagactgcggtaa



aata



gst-14




SEQ ID NO: 13





ccagttaccgagatctaatttttttctattttctttttctacttttcatgaaatacgcatttttgaaaacgaataataaagtatgatatgctgtcaaaaaa




tttcctgcattcttgcaaaaccggacgtcgaacaccaatttgccactttgatctacgtagatctacaaaaaatgcgggagaagatcttctcgag



acgcagaattctcaactgatttcaaatcgttaagaacgtgctgacgtcacatatttttgggcaaaaaattcccgcattttttgtagatcaaaccct



attgggacatcctggcatcacgtgatttgcctaaaaccaaaaataatgcgcattcagagaacatgcctattgtgcctacctatttattaactttga



cagtagataggcaggcggctgcttagagcctataagctagcctacctaggcaacccacatagcctacctttcaacttttcaaaagatcattgg



atcactaacacaatgtgactagttgtggtttgttacaaattgcctcattgtcaccctaaactccctattatttcccgtaaatgatgacgattttgatc



ttttgtagggttatcttgaagtgaaagatcactaagtacccagactgcactctagtctttttcccctttaaatagtctcgagaatgagtttgagaaa



ctaaaa



gst-32




SEQ ID NO: 14





tataattttttttcttaattttcatatgtttacattaaaaatttgagaaaataaagtagttcaagacaaaatcaaatatggtagagactgtggtttaagt




ttgggtttactagggaatggtcagcttaggggtgaggtacctagagacgccacatatgccaaacggaagctgagatcattggctacaagaa



tatgctttcaaattctgcaacggacctctgggagtctggaaattcttgtctgaaattatgcttttgaatgctcgaaagtggtaagaatttagaattt



attacagaaaaacgtttaattaataaaattagttttatacttgaaacaagtattgtatgcactgtatcaaaacacattttcatctttctaggtattcaa



cttcacgtttttctgtaataaattctaaattcttaccactttcgagcattcaaaagcataatttcagacaagaatttccagactcccagaggtccgtt



gcagaatttgaacgcatattcttgtagccaatgatctcagcttccgtttggcatatgtggcgtctctaggtacctcacccctaagctgaccattc



cctagttaggcttaggcttcggcttaggcttacgattaagcttaggattaagcctaggcttaggctttgtctgagttcaactctccaccacggga



aaatttttttgcaaattttttcgtcccaaaaaaaaaaggaaaaaaaaactttatttttacttgatttttttcacttttttttcgagttcaactctccaccac



gggaaaatttttttgcaaattttttcgtcccaaaaaaaaaaggaaaaaaaaactttatttttacttgattttttcacttttttttcgagctcagctcgac



cgtccctcaatgaaaacaagcaacctgatgtattccagatactcccgtaccaaaggtcatttctcgttagtcacaaaatattctgattgaaaatg



gtgaaaaataacgagagagttgaaaattctacagactatggcctaaacgcagcaggtgagacacagtagagaacaagaggcagaagag



agagcagaaggcagaggaagaactaaagggtatataaaaagtgttttgttgatcagtgggatcaaatagtgtgctttttaaaagtttttttttcc



ataaatgtattgatatctagaatttttttcgagttcactgttgtttaacagtgtcacatggtgtcaggctgtctcaatacagtttgatctacaaaaaat



gcggaaatcttaaccatgcaaaatcagttgaaaactcttcgtattttctcccgcattttttatagatctacgtagatcaaaccgaaatgagatactt



tgatacaccgtgcagtgttaaaaaaaatacagttacagc



gst-38




SEQ ID NO: 15





tctcattctcttcaagacataacacaacgggctgacgaccatatcatcaacgacgattttttaggaactgtactttatctgtgtctgaccaacac




gtgtgaatgaagtttcaactggaaaatttgtttgaaacactgcaaagaatttcgaattttgatgataattttaaatgccattatcagttttaatacgc



cactctagtctttgattctttgcacacacacacacacacacacacacacacacactcacaaacacgcctgaaatttcgcaatatgctgatttaa



cgagaaaacatttgatgacaataaacttggcgtattaatataaaagggaaaattcaattcagattctcaacggtttattttctgtcacaactcttcc



taatattcacc



W06H8.2




SEQ ID NO: 16





Tacacagccaagtctcataaccaaaataatattgatagtaaaaacatgagtgaacacgtttcaaaacaacatgtcattgaaaatcaattttaat




gttcacgggaatttttttccaaaacagttttactcaaacatattttccatttgaaagtttgggaaactatccctggcacgttttcactgcattggtctt



tccagttgattcagccagagttggaaagcctgtacttttttcccaacaaccgtttctactgctcaacttgtaacctcaaatttgcctaattgactcc



gaagcttcaaaacttgctttaaagaactttgatgaaaatcgctgcggcgaaagaatcattgcggaatttttgccccagggatctaaatttccaa



cctactccactgaaccaaattttttcaaacttcaccaatttttttattttattttcacatgtcattaaaacactaagaattcaatacatgtatgaaaact



gcaaacaccaaagtacggtttggacttgtaagcaaaacaccggtagtctctttgacttatcatgtattgtcatcctatttcgtcagacggtcttgt



aagttcacattgacttactctgcgtctctcataggacacatactccgcatctttctcaatagatcaaatatattttgtcatcacctattatttaaactg



gttggtttttcacaatgtcacaactaattgaactctccacttattgaacttgacttgaaatc



cyp-34A9




SEQ ID NO: 17





accgccgagttacgacatcagattcaagcctttgaaagtttgaatctttaataattaaatgaataattaattgggagaaacatgtacataaataa




aatttccattaaacaatgttcatttgtttaagctggcacagaccacaaaagctgaaaccacaaagttttttaaaccttgttcttttcttaaattttgta



gtttcttatcttatcactcgtgtttcttgtcctccaaataattgtgaaaattgtagttaatgtgtcaaaaaagtcacatataagaagacgaacaactt



gattttttgttgacttcatttgaaaaaaaatagaaaac



ugt-41




SEQ ID NO: 18





agaacccatttttacaaattgtgttcttgtggtgttcgcgtattaactttttatagctgttttttacttataggatgattaagaaaaaagttccggcttt




ctcaaagtaaggtaaatattttgaaaataaagaacttgtaaaaggatacagctaactgattaaaaacaaaagacccatgttagttcacgctcg



gatttggagttcagctggaggggaaagaattcagcgttgaaatatttcagttggaatttcacctgatattatttaaaaaatgttatacgaaaattg



aaaaagcgcctcttaccccctcttcgcccgctttcctcttgcctactgtgcagttttttgtctttacggagttaacaagttgataacctgtttaagg



acaacagataaaaacagagaaaattaaaaaccactattggcgatttgaaatttccgttcccatttttcacttttcaatttcaaatatgtacttaacg



gtttccgatcattaacacgtaatccatcatttctagacaacaagtcacaccaatgccaatcaaaagtgcaaacatgctataacgaatctttttttt



caattaaactgtttacgatggaaattaggatagtgtcatagcattaattttcattgttcaaaaacagaaagaagtcacaaaatcttcacgtgaac



atgtttcgtttccataaacaaattgtattttcaaagacagccgggaattttcagaccaattcaggtgacaactatgggctaccacccacctaact



gtttgttcgcgattattctgactcacatcatgttttcaaaagtgactgtataattggagtgtagcataatcaacacaaactacagaatgggaaatt



tgtgacagtatcaatcacattaacagatctataaaagagactgggaaagttgttcagagacacaaattcgttgtctacttatcaaatc



dnj-19




SEQ ID NO: 19





aattttaaagtttatggattatttagaatttatgaatattttaaatatagcttgtaatagtagcattggcttttttattagttagaatgcagtatttatatag




attgtagttgtgtgcgtgctaagattattggagtattggtgttgtcacgtcttcagtctctctgccgtgcgctcacgagaatggggcaagcgaa



gttgcggctgacgcgttattggatgctggcgcgtttcgcgaccagcgttggttttatcgagaattttctctgcagtacaaagtcccaaattcgg



tggttttttatcgatttgacgcgcgtttgctcaatttctcgattttccgcgttttttattcagttctcattaattaacgttcgatgcttgttcacaaaattc



agtttttgttttcacttgctcgttggtgtcgttcgttgtgtaagaaaattgatttctaaatattttgtttaaattgctaaaaaataattcaataatttacatt



attgaattattaaaagttgtatttttcaaacatctcgcgcattctccgtccgtttctctcaatttttcactgtcatgtccgcattttaatattcattttttt



tcaggtaat



hipr-1




SEQ ID NO: 20





ttggttataggaatatcctcctaggatagacgtttttttctagtaatttttgttgtttttgttcgttacaataaatctcatttttattttctggattaatt




tgattaccaatcgtttccagcgattttcacatatttttccagaatttaatacagattaatattttcgaaaaatttaaacattttcttttcacattttaatt



catctctattcattatgcaatactcttttggttttcaagcatccgacattcctccgtttcatttatgtttgcatttctgctggcatgaatgcatttcattg



tgtctcgatgagaaaaaggacaatttcatgagcttatcagttacttcgttttcaaaattttaatgttgaccagccattgatgtcatattttgtctaag



aagctcaagaactattattttttgaagcttaatttcgaagagcaacattttttttcattaaaattcagcagtcattgttctttaaaaagttttgattctcgt



ttttaaacgatttttaattcagtcgagaattgaataacttcccgatttcccggccaccatcgtttaataccttttctttatgagactaacttccaagtat



gcaaattgcaaatcgacgcaaggggaatacactcgctcacttctcatcgaaattcgaaaccttttcccattttctttcatgtctttttcgcttttctcc



tctctgcccatttccatttatttctcaaacaccgttcagtgaacacgaaaacccttacggaaattgtgttgtaagaatacaaaaacttccgtagcatag



cgagaaagagtcaccattttgtagtgtttgcccccggtggtatagtttgcacaagtttctgaaagaagaagaagacacatttgaggtcttatgc



acataaaaatcaatgttagactatctttttcacgtagttttcttttgcaaagtggaaacttctcattaaacactttttgcttttcaattgtctgaacaagt



tttcgattaaacagctgtaaagcttttgcaagtttcatggtttatgaactatttcgaatcggttacattgctgaagttttagtgtttcttgaatatgtcg



tcactaccaggactggaccaaaaatcaaaaagaatttaaagtgaaataccaaaaaaaaaatcgtcgatttgcgatttttgaaggactgtaagt



gacttttttggcttcatttaggtcccaaaaaaccttttttttctcaaaaaatgtgactcaaaataccaaaaaagtcttaacctgatcacttcgccttct



caactcaagccatttttgctgtttagttcgaatatggaacaaatcataagaatcttgagtacctatatgcgatacccgattcattttcctctcttcta



aataacatcatttcctctctttttccctctctctctctctctgtttttgtttgtgactcactttgtccacaacgcgcgcggaaccggcttgttgccaca



cacacactgtgatgaaatatgcgggaggaaagcttttcgcctaatagttgacttacttttcatctatattcctcaattttgcaactaatagattgatt



tgtcatggttttgatttcagggttttgaatattctttgaaattggaatttttaacaaaaatgcaaattatgtgccaagtcatatctcctcctcacactttt



tctatcacatgcccccaaaaaaattaatttttttcagga



Ubq-1




SEQ ID NO: 21





gaatgcaggatataaatcacgattttcgttttcgaacacaactttaaacttcaatttttcctttgtttctctgaaaactttgcagtcattttcaagcttc




cacagaactttacaaaaaaactagattttctccaacgtggcgatattcccgagtttcgagaagaatccagcttgtcaatgctgtataaaaccttt



acttttctatcgtttccattatttctttcactgcacctgttactgccaggtgctttatttcgcctatcgtctattttgttttcctcctaccaaatttgacaac



cctccgcaaacactcattcctattttagcccggtgaaatttcgatatggagaaaaacaaaaacaagtgtgagcttccacttcggaataatttcc



ggagaatgagaattgtacaattttctcctataagaccatacaataaaattttatcagaaacatgaagctttggtcattatcattttttgttacccttg



aaatttgatcacaaggctttaatttttcatgagacgtcaattttttctgatgataaataacatagttcaaagtattgcgtaatgtttcaattttaacatg



acacataataaatcagaaactcgaaaaacgtatttaaatatagattttgtcgggaagtttaatgtgcaactgtctcgatatctttctttgaaaacat



ttaatttttattatattttccaaactggattcgagaattctcgtattcttaaacaaatttacaatgaaaatataaataattaatttaaaggaacatgttct



gcaatcctccctgggtcccgccacgaaaccgccacgcactaccatgaaaggcgcgttcgcattcgttctgccgctcgtttctgttttccagat



ctttccatcattttcttcattcattcgcgctctctcattatcttgagttgccggctattttcgctgctctctgctttttcgtatcgctttttcactctttcca



gcattcagaaaattgcattatttcggttttcatttaaaaaactcatagcaaagtattttgttattgatttcgcaatactttcgaaaagtatcggaaaat



tttaatgtttagtctgtgcgttcctcattccctgttctcgttgtactcttaactgatgtttttaaatttagttttccggggctctcttgaaaagacccaat



agtcgtattgaaccttcgcctgatcgccactagctcatcttttagtcttatgacgggctcacatgattctccccagtgtcctcccgttttctcactg



cacttgttttgtcgttcgttcatcagtacaaagtacaagcactttcgcgtctgtctgaaaattggttcgggtgccgttaggacattattcatactttc



ctgctagtcgcagattataaaaaaatgtccttgaccgtctgctctttcttatgttctccctatatatgcgtcaaacgaacaactgaccctgttcact



tttcctattcttcgtttcatcattttctgtaacaaaaatggaaacaatactttacacagacgtcactattattcaggcctatgatttctctatcgtttagt



taaagatgaaaagaaactggtcgacccagttgcatgacgagaaaaaagaacaccccgttcgattttcgttgtattccctctgcacacattgtc



cccttcttcctcatcatttctttccctacacagcactctagaatgttcttcttgtgcagaaagagtgccgtttgagtcagcgacccccccccccc



ccctcctttctcttgctcttcctcactggttctcgtaataggcgacttcttgctaacagaaagtgagcatagcaacattttttactttgtggccttca



ataatacgtgcgtcgtttaattagaatgtttgagtaaagttcaacgtgtagattcaatattcacgttttgggcgctctttaatttattactgtcaagaa



tcagtttaccaaacggtgagtttctttttttttgtctaattgtaagatttagcggggtaaaaccaacagaaatgtcatgcttttttgaataatctcaat



cagttgttatatgaattattttcccattttagcaatactgcttggtagttattttcggtcagagaaacgaggacatcagctgaacatctgcgtctct



aacaacactcggggaaggcggagtcagtgtgcgcgtgcgttgggggttttatcgatcgttgaggcgggcatacagcagtcatacacccca



ttcgaccagaacgctccgctcgcgtgccaccttgtctccattctcatttcacttgtctctactcggacattactcctcatcgattagctctttacta



ccattttacttttatgcctttcttttttcgtttgacttgcctatgacgagtggggatgaagtttgctttgttagtcttactagtgtatcgattttttgggta



atatttcgcaactttctaggactttctttcataatcacctcttctctcgcctcctcattccagttttattcgcactcattttctattttttcagcaatc



Ubq-2




SEQ ID NO: 22





aatcaataaaaaaacgttcgaaaaacgtttgaaacaaaaaaataatattcgaattcttctcccccttcccgtaaatcctgcagctctctaccgta




ctttcgccgtctctcaatttcgcggcgagacccatcaccacggcaatcctccatttgtgtcgctgggcctaaattttttccgtttttttgctcgattt



tcgccgtttctctgcgaaatttttccaaatttctgttcaatttaatcaaaatattgttctggacgcttgttcagcatagaaagtggagattctgttgta



ttttaagcttggaaaacgaatttattatgaaatttcatttttttgctaaataatttctctattcttgaatttttacagctttttaacgcaaaatattctttc



ctctttgttctaaatgggtagttacacacattatgcggtctataacgtcttttgtcacctttgaaactagtctctaaagaaaaatcaataatttttgccc



ctacgctctcctccaaatgtttcgctctcgccgtcattttctgacaattttactcggtttcttttcaaattatataatttcagtcg



sto-2




SEQ ID NO: 23





tgtaaacatttgttattatatttttaaactttgtgttgtggatgtgaatatgtggaatttaataaaacatttctcgatataataatgattttgttgaattag




aaaaattagaaaagtggacgattctaaaaacaaaagttacaacgaaaatcatcgaaggaaaaaacaactgaattccaaaatagttttcagag



gtgatcacaaaatgttctcaaacgatatatattctaccatcaataattttattggcactatatcacagtccataattcctgtgctttaattatacttttc



agtatagaacaatatgctatattatcaagttatgcgtccaataaacacaatttatttttcagactgaatttaagccatattgagaatagcgaaataa



aaacgtagaggaaatttgtgatcgccattcacaattaattcttagatcgcaatgataacaaacttcgattcaaaagtcatcatgcaaattcaccg



ttctcgtgtgtgtgtgtttttggaggaaataacacaattttgtgactgatttttttacaacatgtggtttgtagcatagttcaaagtcattctagaggg



ggctcagagggagttctttcgctatgtcatcgtttgtttttgcacaccaagaaaaatgaaaataaatgctctaggatgtcatggatcgtttccatt



cttaataagtagaagctaggatttcctatacaaaaataagtaatcttcgtttctacgtctatcaacttaaatttttgtatacaatccactttggtaatat



tcaaggccttcctgtaaaatgttttatgatcaatccgttacaccaagaaaacaagtgcaatttgtcatcatgtaggcttccgcctgtgtttacttcc



ttcccccagcacaacactgactatttataccaaattaataatgcagcattcctcatgtgataactcgtttgacttttatatctttctacgtgcatcttt



caagctcgaaaattaattttaaaaatttacattgcagaacaattgcggaacgaagaagcg



sto-3




SEQ ID NO: 24





attaatgaagaatccgaggttcctcactaaagattctcgctttatgatagagtcctcaagcttgtatattagagttttggggtgtttacctaaactt




atgcaaacggttttatcatggtttaactaaagtagtgaattgttggaccaatttaaaataacatcgatcgcttcctgcagatcatttgtggaattag



ttttttcaaaagagcaatatagtttgaggtcatcagcgtactgcatatatttaacagtttttggaatgtttgcaccaagatcatttgcaaatatgccg



aaaagtataggtgaaagtacgctcccttgggggacaccacatggggcgttcctaacagaagatagagaattgttcacttttactttgaacgta



cggttggagaggaatgagtccacccagcctatgagcatagaattgaacccggcctttattaatttttgcattaagagtgaatggtttactttgtc



aaatgccttactgtaatcaaaaaatacaacatctacttgattattgaaattaaaattttctatataggaacttgatatacccaatttctattaaaaaat



tgaattcgcgccgagcaaaatgtgatgtcaatttcagttttccaattttctcaatttttttgaccactaactaaaattttgataccaaaggatttttgct



caaatttcgaaataattgcggtaaaattggctctaaacactagtttttgacctagcgaattttgatgtcaatttcaatttatttacattttatttggaaa



ttttcttcactgcggatccctagcaaaatttgttaaacatcacttttccgagcaatttgtgatgtcgatttccgtgtctttacacggtttttgcctttttg



cttaaatttttcaaaaatttcagtaaaccccaaccaaaatgaattttactcacaaatttcgctcttcaattatttttttagtgaaattcacaaaatctga



cctcaccctaaattcccactgagcacatttggatgtcgatgtttgttcaagtttttggccaagttttaaacaattgcagtcaaattcaaccaaatca



cgtggtgtcagtttgtcccattacggtttgatctacaatgcgggcattttttgcccaatcaattgagaactctgcatcacagctaccacattttttg



tagatatacgtagatcaaacggaaattagacactctggcaccacttgccaaatcatatgcaaaactgctcaatggtagaatttgacaacccaa



attgctcatcaagtttttgtgtcattttccgcgcaaacagggattcaaatttctgccatcaaaaactcattttctacaaaagaactacaaatattatt



tcaaaaaggcggcagtggtggtcaaagaacaaacatctgaacatattgaagaaggtgtctctctctctctctctgtctttccctgctcacacaa



atctgtgtgtctctctccagaaaataacaacacttgaggttcacgggaggacggggggagctcccgcctgtgctccaactctcttgtcatgc



cactttatgttgctccagtgtttttgtctctctaaatctccagctagctgttctttcatgttcccttagccccaataccgccgcctttcgatcttttggc



tgttttttgggggatataagaagtttcgaggaggaagactagatctattcatcctaaaataaattttttttctttttttttaggctttatcagactctaa



aatgctcgtacgacaccaaattccagatttcagttttctatattttcggtcctataatactatattcaaaaaattagcgtcttcgaaggaatctgac



atctaaaagttctattggtcttttttccggcaaatcggcagattgccgaaatcaaaaatttccggcaaattggcaaaacggcaaattgagagat



tgccggaattgaaaatttccggcacagaggcaaaccggcaaattgctgatttctcagaaaaactgcaattgccgaaaattttcggctaattga



ggttttgcattttatttttggcaaattgcctgaattggaaatttctggcaaaccagcaatttgccaaaaatgaaaatttccggcaaattgccgattt



gccgaatttgctagaaaaaaaattaatcggcaaaattttacgcatctattttgaaaagaaagcaaattctatgaaaatatctaaagaaaatctttt



aaaaaaatgcacagttttaaatgtttcattcctttcaaaaatccctctaaccgcttccggcaaattaatatccggcaaagggcaaatcaccaaa



ccggcaaattgccaatttgccgaacaaaaacaactgaattatgctattaataattcctggttcctgatttccaatttttgattatttcttactcacttc



agtatcggaaaacgttcacaactttggaaagaatttgatgcccgtaatttgctgaataaatttaattttttcaatgtccag
























































































































































































































































































































































































































































































































































































































































































































































Mitochondrial Oxidative Stress Toxicity






hsp-6





SEQ ID NO: 25





gttttctgcaaaataatcattgattttaacacctcgtaaaataattttaaaaaaagaagttaaaattttaattgcaaccctatttgtaaaaagaaaac




tcattttcgccaaaaataaagcaaaaataattcaagagaaaaacgcgccgcgtgttgcgattggggcgtaactgcaatgtgtgcgcacaca



atctcaacaagcgctgcgagacccgccgcctgaccgtaatgtgaaatgggcggagacgagaagtttttttctgtttgaaagttgatgcaaaa



gcccgtgattctttttttcgagaaatttctcgagttttttccaacgaaaaattcattaaatttaaaccttttagctctcctttccaatattttgcatcatta



ttctcctaaaacttggcatattcagtggaaatgatgcaaaatgccctgacttttgttatcaaaaatacaagaaattgtcccgtttaacggttgaaa



agcaaattttgtgtcattttgtttaggaaatgtcaaaataagctcaaaaaccgattacaaattatattttactgctttttatcctattttctcgcgttttc



gttcatgatgcaattttctttcaggcact



hps-60




SEQ ID NO: 26





ttttcggctgaaaaattggttttttgagttttaaaatttatttttagcgggaaattacatgaaaacaacgaaaaaacccgaagaaacccgcgaaa




attcagaaaatgatcaaaaaaccaaaagaagcttcgagaaaaaaagcagaaaataaatgtgcggcgcgaaaaatctcgtgcggcaaactt



gcaaatctaggcgtgtcgggccaatggcagacaccgcgccgcaaattcagccaatcagcgcgctcagctccacctagaaaagtgtgcgc



accttgcaaaactgggcggagcgagtgaaatgatgcaaaagtctattctgatgtaaattagccattttacatcaaaatttgcgtcattttcgttat



ttttctctcatttttcatattttgaacgaaaaattgaggttttttgcttctattttcatcagaaaccattgaaaaatgcttatttttgggccatttttcgtcg



aaattaggggaaaaaactattctacagttttcccagctattttctcatttattcctgtatttttcagtcattacctgcttcccagacgataatgcaag



gcttctcgcttcattttcataaaaaacgattgaaaaatgcttatttataggccatttatcgtctaaattaggggaaatatctgttttaccgttttccca



gccgatttctcatccattctcgttatttttcactccttttctgcttctcagacgataatgcaaggcttctcgcttcattttcgatgagaaactctgatttt



gctcgcattttcgcctttccgctgcagattttcacacaattttcgtagtttttcagacacaaaag



mtl-2




SEQ ID NO: 27





agagaatacaaaaagagacgaaaatggttcagtggaacgaaacaaacgtgggatgtaaccatggaagtgagaataattgatggaatagct




aatgagctgaagctgagtagatcagagactactttattctaaaaagtacagtagttggaaaattacatgtttcatttctaattttcaaggaaaagc



tagtaattaccgtaatcttgtttgtacctgaaattttatgtactgcaggtgaccaagtatgtttgaggcatgacttcacacacctaactgataaag



gcctctatcacaaactagagttgtgacggaaaattcaacttctcagaatatagctcaaaatctatcaaattttattttcaaaaatccaaataattgt



gcacgcaatgtacttactgcttcataaagttcagaagaattggataaatttgaatgaagttttcaaagcttttatcagtgactgtacattgtgatag



gcttgtgctgttatcagctgcctcaaataggttgtcgcttgaaaatttatataaaaggcctaccagcagacatgagaatcaagcttcaaaggct



ctactcaaaa



mtl-1




SEQ ID NO: 28





ctgcgaggaagagaaaaaatcgtgctgtgaaggaaaaaccgagaagactgagcaaaagaaataaccaatgagcaagtgaacttttccca




cgtctactactaaattattgtcgatctataattctttcgcttatcaatcttgtcaattgaaataaaacaatatttttctaattctttttggaacgaacaca



cgtgtttaaatgaatgttgtgctaaaaacgtcacatcaatggtacgtgaatgttgcaaacaccttgtcaataactgataaaatcagaaactaga



gctgtgactgaatcgtatactagaacggagtctctctaaaaacgttctaaaaacaaacaaaaaattgtgcaaaggattagagtgctcaagatc



aatgagcaaactcacaatcaactatctgttattgttttgggtctcttctatatctctattcttttagtatcataagtttgtacattgtgacagggccac



cctcttttatcacatatttgaagtggtaaacagccagcaaaaaccaaataaaaaggcagtgagaaaaagaagaaggcagctcaatttgactg



ctgaaattaagaaatc



cdr-1




SEQ ID NO: 29





tctgctgatttatttgagcttctctgtgtgaccaagacgagagccgaagagtgaagtttccactgtcacaccatgtattttatactagttcagagt




atctttgaacacctgttttaaaaaggtacaataccaaaaggcgctcttaatgcacccggttacatttgtatttgtttgatcagatggatgtctgtct



gacaaacgtcggccaaagaatgcacttgcagactttactttaattttttgtctagtttgaaaattcttcggatttgttagtttcaagaactttcaatg



aaaccgaaagtttgttgagttagcgagaattacttctgattacctgaaaattaatttgactcaatcttttacctacttagaaagactaaagtttctgc



acaaatttgtttgaacaggtgcttcaaaatgttacagaattttcattttcatccacataaaaagttgattgacaaatagtgtgggcgacatgatttc



ttgaacaatttgtttcgcttttcaatttggactcagttcttcgaaatttagttattatccatattattactgttttgagttttatcgcagtaggaaatactg



gtgtatatacatattatatttttccgttttgtttacccagaaagcttaaaattcaagttggtcagaaaaataaaaaaacaacttttgcaagaaatacc



attttttcatcgtgcggaaagaacaattgaaaactaagtattttttgctaaactgcagtactgctacaatactaatactgtaccacgatagtcacc



caacagtacgaactcctactaaaaatttattaaaaaaagttttattattcaaattttgaaaatccataagttctaaatactttgttcagtatgctatact



taacacaaatggtattctgcaattgaaacagaaactacaataattttatcacaaaacacagttctccctactttcttatcacattatgtcatcgggg



tggcaagtatataaaggaatgctgtaaaaagatatgtactactgtctcaagt



sod-3




SEQ ID NO: 30





agaatttgcaaaacgagcaggaaagtcatattcgcagaaaaaagtcgttgcaaacattcgtttttatatgtttttctttgagaaagcgtggttcat




ttttgaaagtgaaaaatatttgcttaaaacttccaaatttaaatctgcagtgattcagagaggttgagaattattttcaaaaacattcaatgttttcc



cttggagtgactatgcaaatatgaaaatgttttccaaaaatatttggatgccctgataaaaagtaggtgaaatttcgcaggggaacatcatatta



aaatgttgaatttttagaagaaatggaaatgtttgtcggtggtatgctcgaatatttgagatattatatatttactgttaaatccgaaatttttgacaa



acggaaaaaatttgtgtcgaaatactacattttcgataacacaaaggtacttccataacacttataaaaactgtttgactatcttatttcaggaaa



aaaaaatccaagaataaacatttttcagaatttgaactttctaatggctgattaataaaacaaagttatacaactattcaaagcagttgctcaatct



ggcattttcttgtgtttttttttgaatatttcatcagcaagatgttgataattttgtgttaattctaattgttttctacaatttttcaaaccgaaaattgac



ctttgactttgtttactttgttctcgtgggttaactgttcactgatttctattgctgttgatgaggtctttgatcaaatttgtattgtttttatactgcata



ttgcttcaattctaaatcatctaatatattgtcaaacaacttcttgttttttttttcattcaaaacttctgcaaaaacgttctcttaacaaaggttcac



acaacaactctcctctccatctctttctctcaacaacaatgtgctggccttgcatgtttgccagtgcgggttgtttacgcgttttcaagatttttgg



tctcctatctaacgtcccgaaatgcattttttcctttcatttggtttttttctgttcgagaaaagtgaccgtttgtcaaatcttctaattttcagtgaataaa



eat-3




SEQ ID NO: 31





caattattataagaaaataaatttaaagttatccgagcaacaattatcaataaatattacttttttaaatgaaaacctttttaatttcagcagaaatctt




agaaatcagatgatcaataaataaaaacggctgactttttaaaggcgcatagaattttcttggtggcgggtcccgcaccgaagagccgttttc



taaataatatacactaatgattatttttattaaattttttcacggttttcgagagtattctttatataaattcaattttaaagcattctcgtcgagtttgaat



ccgaaattatcgattttcgtttttctctgctttctctaccgctgttttctctcctccgctgtcttcgcaagattatagagctcttttgaatcaatttgtttc



atgtttccgcttttgacgttattttaaacatatactgatataaataaattaagaatagagtagaaaatctagttcaagtaaagatgcaacatttctttc



tgcaaaatttctcgaaaacacctgttttccaaaacttttcaattacacaattagaatttcggaaaagttaacatatataagaacatattatatatata



tatatatatatatatatatagattaactctcacagttaaagaaatctgaatagtaatattgcgaaatagttttgcataagtttgtttgattaaattaaat



gtgaagcactaacgctattgaatccaggaaaaactcgaattatttgtttgatttttattaaacacactttgtgaacaattttcggttaagaggctttg



ttgtagtaaaaatcctaaatctacgattatcttcttaaaatttgacatacttcttacgtatgttacaggataaatcgagttttgatgtatttcgtaaata



gtttttaatcatgttatctttttatttcccatctctatgttttaatgttgtctttacactaattcacccgtaatgtccgtgcacaaaagaatttaacattca



gatattatggaaacaaaatcatcccaaacttcacatccgtggcttgttctactcattttcgccacttttgcggtctcaatttttgctgtatacagcaa



ttttcctgaagtctcggcagatgagaaggttcatttgaaatatcccaggaatctggaagacgctaagcagctgggcagagttctctcgaagta



caaggagaacaactattcagtagttctgtgcggtgtaattgtcgtctacgtatttctacagtccttcgctatccctggatctatttttctaacaattc



tatcaggatacctgtttccattctatgtggcaattgtgttggtgtgctcctgctctgcaactggagccgccatctgctacaccatttctaaacttttt



ggacgatcatttgttttgcaaaagtttcccgaaagaatcgcaaaatggcaggatgatctgagcaagcatcgtgatgactttctgaactatatga



ttttccttcgagtaactccaattgttccaaattggctaatcaacattgccagtcctgttctagatgttccactggctccattcttctggggaacattt



ctaggcgttgctccaccaagtttcctgtatattcaagctggctcaacactggaacaattgagccataccagtgtagcatggagttggagttcta



tcgttttacttacgggttcggcgattttgtcgctggctcctattttgctcaagaagaagctcaaatcggattaattttctctcttatttcctctttcgat



ctcattttttttccattgctttctgtgcaaaacttgtgatatttagagaatatagccgataactcatttctatactatttttatttatttttcgcctcc



ttttttgtcataataatcatattttcttcactaataaacaatttttaggtgatgaaacaatg



cyp-14A4




SEQ ID NO: 32





gaaactctcctggatttttctagattcttttccagttacatttcacatagaatctctaactaccggtgcatttgccaatcttcttactgaaattctgtgc




cttgttttgtcattaaaattttacaccgaataaattatttgtctttgtaatagcttatgactttaacaaggtcattttttctaactggctcattcgcgctg



aagtttaaaagaagtttgcttttttgtcggttaagccgttcatacattttttggcaatcttggtacaaccatctactacatttatatcaaaacgaaaa



aatgtataaattttccctcgtcttcatctacccgcaatcataaaggaatctcattccgtcccactcgccctttctttcttcaaccgaaattttttttccc



gcggcgcaaaccctcatgtgccgtcgatagctcagttggtagagcggaggactgtagagtcagcaggtatccttaggtcactggttcgaat



ccggttggacggatttcttttttattttctgtatcaagtgtaactcttcagaaaatcatcgggagcagtcgtacgaaattttaattataaaaattaaa



cattccagcatttttctttgggaggtgaagtagagtcagcgcggatttaccggatttacagttagtttgatacacattcaacattcaatattaccg



aatttcaaaacaaaacatttttacctaagtcttttagattattggaaaattacaggtaaagttttggtgaaatgccaaagtcataatgcgagatggt



ttttttttttgaaaaattcagatcaaaactacgtgtttggtttgtgataaaatattatgatgaaaaaaactcgaagaaatcataacccaaatgatatt



cagttcacaaacataagtatcatgatgcaaaatacaaagctgaatgtattttttcaagaccgcagatcacaattaagacatggtaaacacaaa



ctctactgcgtaccgcagtgaaatgtggtttgtagtatgactggtagagacacatcgacctatataaacatcaaaaaattgtttaaaaaaatatt



ccatcgagaattgcttcatttcaa



cyp-33C8




SEQ ID NO: 33





atattggaagtcaatgagaaggaggaattctggattgcaaacgagaatttggaagtgagtttggagatagtagcaagcctaagcctgggcc




tgagctgagtcaaagccaaagccgaagcctaagcctaaatctaagcctgagcctaagcataagcctcagtctaagattaagcctaagcctg



agcctgagcctgagcctgagcctaagcctaagcctaagccaaagccaaaacctaagcttaaacctaagcctgagaataagcctaagtctat



gccaaagccaaagccaaagcctaaagctaagcctatgcataaacctaagcataagccttaacctaagccttaacctaaacctataagccta



agcctaaattttcaggcactcactaccgaaaattttccattaatgttcaactcaatgctgtcgaccgtcctgaaaccaattgacaccctcattga



atgtttcaaaaaagaaggaccctacggcctggattactcggcctattcggattttgaagaaatgcagcaaaaattcactaaaatcgttcacga



gaagcatatcattccggatttggttccagccattggaaacgggatcaaggagaagctggaagctggtgggatccgagtgttggatgtcgg



gtgtgggggtggattccattcgggcttgctcgcggagcactatccgaaatctcagtttgttggattagatatcaccgagaaagctatcaaagc



agcgaggctcaagaagaaatctgatggcactgattttgaaaacttggaatttgtagtagctgacgctgcaataatgccaagttcatggaccg



actcattcgatttagtcatcctgtttgggtcttgccacgatcaaatgagacctgacttggtaatttttgtattcagtttcagagaggtatcccaatc



atttacagtgccttctcgaagttcaccgtgtggtgaagccagatggtttagtcgcggtcaccgacgttgatggatctagcaatgtgttcaccga



tcgtgagacctacgggaagatggctgcgatgaagtatggtggatcgatgcttcattgtcttccggttgggagcaataggccagatgcactat



gttgcggctcaatgtggggaaggaagagagcagttgagataatgaataagtgtggttttgataatatcgacattattccgactgactacttccc



tggaactgttttgtatttgatgaaaaaataaataaactgtagctagtgtttttttataattgtaatacttttttctatttattcaatcttttttcccgatt



ttcactgctttgttgtgactgtatcattatgatcctgatgaataaatatcaataaacaaatacagttttttttttatttgacattgatttttgattctga



gaatataatacatatctatgagaaattaattaattaataattaataagaattaataaatttaataagaattaaagtaaaatatagtgggaatatag



tggaaaaattgttttgtaattgtatgcaatatgtttataattttcaaaatcaaagagcagcacgacggagcccaatatcaaaagttcaagcgaca



cactcaaaatacgactcatacctgcgtctcctccctctcccaatttcgcaacatattttcgtattttgtggtttcttcagtcgtctatttctcgcacatactt



ccacctgatgcaatttcgagtcctcaccaaataaatagccggcaatgtttgccatttctcagttttcatc



glrx-10




SEQ ID NO: 34





ttttttttttttttggattttcgactttaaaattagcctaaatttatcctaaaattatcctaaaaattaaaatttcacatggttgacaaatttgcagtggag




cgcatttgcagaattttttttttgaatttttttttcataaaaagcgtaacattttccaaattaatgggatttttaaaggaaaaaattatcccaaaaatttt



aattttctaattgaaaaaagtgttattagcccaatttttaaaggttttttttgcaattttcatcagaaaaagcgttaaaaatatcaatttttcgtgaaaa



gttgatgaattctctcaaaaactcggcaaaaagtaccgccaaaaattcaaattctccaatttttcatctctaccagcaaattcgcgatggagcg



catttgcagagttttttcagaaaaatcgtaaaattttccgaattaacgagtttttttttaagtaaaagtgatcccaaaaattcaaaattttccgattttt



gaaatttttttggtgcaaaaaaactaattttcaaattaaaaaaaagtgatttgtctaaaataaaaagcgtttaaaaaaaccttttaaaaattttttttc



ccaaaattcacgtggtgccaggggctgtcccatcgacggtttgatctacaaaaaatgcgggagtttttcgcccaaaaatgttgtgacgtcag



cgctttcttaaccatgcgaaatcagtccccgcgcattttttgtagatcaaagtagatcaaatcgaaatgaggcattctgacaccacgtgaaaat



ttcaaattctccaatttttcatctctaccatcaaatttgcgatgaagcgcatttgcaaggcctttttttaaattttttaaaaactccttaaagttaaaaa



aaatcatttagctttagaaagcccaaaaattaaaaaaaaatttttttttaatcgaatatcaaaaatgcatttgtgctccaccgcacggcggtaattt



cgaaatttctttaaaattttttttataaatttctgtatttcacaactgtattttttcccgaattttcctcgcctaataacactatttgtcatgattcttacg



tcattgtcgccgccgtttctctttttctctcgccactctctcatttccatacactatttccactctcatttttatcatcattttcttcagtttttgctgctt



ttaaagcctatgttttccctttttatataatatcgcagaattttgtttttgtaaatttaatatatatatatatatattatttatttgatgataatgtgattt



ctaatttttttttccccaatttttttcaaattcaaattgtctctacgcttttcttatacttcattgcctttttttttcaacaaaaatttgagaaaaaacacc



aaaaaatttcagaaaaacc



F56D5.3




SEQ ID NO: 35





Gcacgtgtatttttttcggcacgtgaaaattttttttcaacatgtatatatatattttttcaaatttggaatgtcttatgaaaaacgtcgaaaaggagg




aactcatttagattaattgttatgcaaagtgcagatttttaacaacgaatttttgagatcaaattgtcacagttagctgatgttttcgaactctacac



atgtgtgaaggttcactcagtctgattggttcaaaagtggcggtacgagtcgctgatcggtcttgcagttctcaatttcgaggaaaatcaaaca



agaagattagccaaaattaaaaatttacgtttttgaacagtgttttcattgttattctcatttatgttatgaaaacattttcaaacgttttttcctggatg



gtaccattcattacatcaagaacttcctgtcactttaatgatcttttgtttttttgtagtttgaattaaaatgatgatatccattgaaattgagtgtagg



cgtatcatgatgacaattaattaattttgatcttttgctacagggttttccataggtcagttagtaagtgaaatctataaatttggattgtaaacgtttt



ttcaaccttgattttgtgttttttttcagttttttatttattttagatatttaacatttaaactattgaagcttttaaaaatcatagttttatgtaaaattg



aaaattgtggtaaatgacgttttaggccgaattagtttttcatttaagactacattttatttcaacatctaagaactttttgacatttttcgagccattgttc



aaaaaacatcattgaacactacacggttcaaaatgtttacactagatacacaaaccaatagagacactcttttaagaggcaaatggtcagagaat



tagacaatgagacattcttttcttctgtgaatttgtatgttatagtgattagacagttaggatgacatatatttgtcagcacaatttctcttataaatac



aagaaaattttcagagattctcatatccatttctatttcattgaaaagttttttcaaac



gad-3




SEQ ID NO: 36





tgactaacaatatgaaatgtgtataaagcttcatgatttcacaaaattgaagtctaaaaaatataagctttaattttttgctgtatgagcccctcaa




attctcttatatactttttcctgctaatggctacttctttgatcgaagatttggccaaccggttaagtttgccgacaccagcataaagaaattccgtt



catcgcattcaattgagttataggagcaaacattaaaaattgatggtataacttcttacaataacatgtgaacaaacagcacgtgggcataatc



aagaaaagaagcttttgattttgaagttgataagggaaacgatcaaggtgttcaagaccgaaaataatattttcagtttgagtaagttgaaaatt



atattatttttgaatactttttaaacagctaacagatattgcaatagagtgcttgaagttgtatgtcaatatagttttcgtgaatagacattaattaca



gtgcggctcataataaattttattgttttttttagtattctacaattccatcgagtagctcctgaaaatgtgaatagcctagatagtaaccgattgag



aaagtaaacgtgcgcttatgagttacgtttcgtattttcacaaaatcgcagtataatttttagtcatttcttcaaaaaccaaaaatctactgtaccct



tattgtaatcaaaaatgtgacggaatctcgcatgaaaccaaagattgtttacaatcccaaaaataatccaaaaattgccctgtttctctcaattca



ctgtacattttcaaagttttccacagatacattttcattcatctgtgaaatcgaatcttttagactatgtatttgtcataaaattttgtgattcttttttgt



tctgttcactctctgtcccttatcgttcgtatctctatttctctattctctcgttaccatcttatctattgttattccatttttttggtcatttgtttattg



aactccctttactcaactgcacacaaacatttctttttattttcttttgaatatatgctccatgctaaccagaactgacctgttgattctttttttttccc



aatatactagtccttttcttaagttttaccaatgtttttag



F17A9.4




SEQ ID NO: 37





Tcagcgatgagcacaccgttcaaagattttctgaagcattgggcttacatgtgaaacaagcagcactcgatattagtgaaggaaaaatacc




gaaagcaataattgcattcaactaaatactgtatttgcacttggtattacagaaacgcaaagttctgagaatgcgtactgggtaacatatttgac



gcgcaaaatatctcgtagcgaaaactaaaataatttaaaaaataattcgctttcgattagaaattcatttcgaaattcgagtatgtaaatcgacta



cagtagtcaataaaagtattactgtagttttcgttacgaaatattttgcgcgtcaaatatgttgcccaatacgcattctcagcatgttgtgttcccgt



aacatttaacctattttacataatctaggtgttttaaactttttataaaactttctcgtaatgctatctttgcctcttagaaaacttattcagcgacgtgt



atcataaccaattctaatcggcttgttagaaagaagaaatataatacttcggcgtctccactttgtgactgggcacaaaatgcaattcagattct



actttcgaaatagccataaaatcataagatcacagatctttcttcgtttctcaggcaaccaggtgcacaattgtcatcactcgaccagtgagac



cacaatagaacagcaaacgttgtcatctttttggttagacactttctttctgcctctgcgtcttttcataaggtgtgcatactcttgtttgcccaaca



acctagccgatcagaaaacgcactatatttgacctgcgtgtacactgctataaaagtaacattttgttctttcatttcttcgaaaa



C35B1.5




SEQ ID NO: 38





aatgcaaaaaaataagcctttccgaaaaaacgggcccttgggcctttaaaggacacaaaaacaggaaagcataagacaccaaagagtaa




ttggatttctacactttggttcctagaattatttataaggtgttattgcgtttttgtgagattgttctatttatccagtcaaaaattgcattttctttgttt



ttgcttcaaaaaaatacattttcagtggaaatttcagctgaaaagcagaattttgaggttttcgagtaaataacgtaaaacactaaattacaaatatt



gatttttgatgtcttagaccaaattttcgtaaacatgtttgtatttttggaaaaaataggttttttgtcgattttaacttaatttttcgaacaaaaaatgat



tttttctccgatttaccaaagttttgacttaaaattccgattttctgggtcatttttcccctaaaaatacgattttaattcaaaaaatctatattttcaaag



accaaagtaccataaccttcaaaaaacaaccactttctctattgcatcagcgaattgtcatcacccctctcaaaatatacaaaacgtcatcatttt



tctgtgttttctctaattctcctgaaaaattctataaaaccaacagtttttatcatcaaaaatgccttttgaccgactttttttaaagttgaaaatcgta



cagttttagcagaaattccagagtttcattttgaagtatgctggaaataataaaattattctaacatttattaatattttgtaaaactaattctatacaa



taaaaaagtaaaatttaatattaaaaaaaccggtttttctcaaatttccattccccaatgtcctgttctattatttgttccgattcggccacagaacg



cgcacacacacactttttgctgattctctgcctcctttctttgatttgaccgcattttatattgattttcggccacaattccactatttgttcagtttgtc



gatttgttggaaatttcaattccggcaattcgccgatttgccggaaatttaaattcagacaatttgccggtttgccggaaattttcagttccggca



attttttaatttgccggaagtttccatttcggcaacttgccaatttgccggaaattcgccgttttgccggaaattttcaattccgacaacttgcctat



ttcccggaaattacaattccgccgatttaccaatttgccagaaatttttaattccggcaatttgccgatttgtcggagatttcaatccggcattttg



ccgaaaatttcaatttcggcagttcgccgatttgtggaaaataacaattctggtcattcgccaatttgccgaaaatttcaattccggcaattcgc



cgatttgccggaaattttcaattccggcgattttcctatttggcgaatatttttaattccgccggtttgccgctttgccggaaatttcaattccggaa



ctttgccgatttgccgatttgccggaaaaaatcttttgccgcccacccctaataaagacttcaaaatatgcgtttttttttgcttttaacacgctaaa



actctctaaaaatccccaatttttcagcttaaaaaaccccaaaaaa



gst-4




SEQ ID NO: 39





ttttgcagactaaaaataactactctgccagtgtttaatttatagatgcaatttgtcactattttcattttatatcgaccaacccattcacacttcacta




atcgtgttaaaactcaattagtggaaaatttgaaattctatgaaactttcatttgcgacaaaagattgttgttttcttcaaaccaaaaatttatcaatg



ggaaaatgagatagacaagaactgggaaaaaagtcgaggttaataatttaaagaaatattgaatattcggcgccataatattaacgaaaata



accaaaatatgcccaattattatccaaaaagattagaagttggcaaaccttgggcaagaatttccagagattgcactaaagttgtagccaagtt



tgatccaactttatccaatcttttactaaaattatccttaagactatttaaattttagatagagaattggcgagagttagatcccacttggatatgac



ttatagttagcctaacctgaagctattgcttgcttgatcatttggtttatcgctttgctacttggataaccagctccaatagttgttatttttgcttttgt



catcatttttccacgatttacactctcaagtgaaaccaactgttctttgatgccagacgatgacattacacttgataagaaaatatatataaactg



gaattaaaaacaattgatacatcgattcaattactgaattctaatt




























































































































































































































































































































































































































































































Peroxisomal Oxidative Stress Toxicity






hps-1





SEQ ID NO: 40





atttcatttcttttttataaatacttcggctctattactgaatgaataaatgtataatgatgctctccaaatcctcttattattcgctcgaaccgcccgtt




cccatagataccgtctagttttgacaggtgttcaaccatctgccgggaattacgagaagagtcgaattaattgagatcctcgtctaaataaatc



tgaagtttaaaataaagccagaaatacctgaaaagagagaaaaagtgtgtccacgatgtctttgtttatgaccagtggtgtgttatcgagaaa



aactccaatgaatcacacaccagagaagaatcgagaaaggtcgggaaattaggaatgagaaataataaatgtgaggaagtaataaaaga



atcttcgagaactcattccacttttagatataaaacaagcagcaaacgggtttgtaggtattatatttatctattttaagtttaataaactatttttgct



aaacttaaacggttcaggtgttgaaaaagtcctaaaatttttgatattatcaaattcttttagcgtggcggttttcttttttttcgaaatattgagttttt



catctgaaaaatgcactattcgtgtccttcaaaagttcatgtgtcatcagtagccactcgaaagatcgatcagtccattttgatttcgaaagtaa



gaagagatcattactattcaagagacgcaggcacggagcctgttgcgccgcgaatcttccaggcattcttggcgctccgcccaaaaaattg



caaaaataaaagttgcttgaatcatgttgaatgtcacttaatcgtgtggctttcaatgttctctttcagaaaatgtattttttatttgataatgttaaga



attcgccgagttattcttcctcaaaatgtggtgcgcgctctctctcccccttttcgtcgcgaacattctctgcggaggcatctcttcttttaattcac



aattctcaacacttttctgtaggcaaaactctctaatattgctcctttttcagatttttgttcaaactttttttgtatttatcttgttcaagtgttttcca



ttcagcagttacagactatttaaggaaattttaggtttttagcacatttttctaattttttgacgaaattcgaattttctagaatcccgccacgcccagtcat



ctagtaaatttgttgaacttcatttctctatttttaatcattgttctcgacgtcctaattttttatctccatttgagtgactatttcttgatttttaaatt



attttttacagtaaaa



ctl-1




SEQ ID NO: 41





gctctgccagaagaagcattaaattgtttgatattcaaacttttgtatatagaatctcgttatttataaactcttttttttgtatttcttctggtttttgatg




ataagaaattttatgtgcacataaatcaaaaaagccggaaattaaatagcgttttatcaggcagaaaattggccacgtgacgtcatcattttcct



gtttgaagaaaatctggaaaattttttgtttcagtcaatttttaaagatgaaaacttaagttagactgtaaaagcaattttcgcgccaaaattacgg



tatcgggtctcgaaacgacagttttttatctattgcgaaaatatgtgcgcctttaaagagtactgtagttgcaaacttttgtcgctgtggagttttta



tcgattttttatattttttcgatgaaaacaactcaaatataacaataaaaacacaaaattaaaaaaaaaatcgataaaaaatccgcgtcaacgaa



agtttaaagttacagtatttgtcgtttcgagaccgggtaccgtagtttttggtgaaaacattgcaaaatttggtcaacaatttcatcgctgcgaga



ccgacacaacactttattttatttttgggtttcccttatcgcttatcataaacatgtgacgtcatcatctcttgtacagagcaccgcgactgggagt



ataagaatcgccggaaaacatcaataatcagttcggtagaagtgaaaattgagcgtaaaatatgatcatttttcgatgcaccatatttgacgcg



caatacttctacaagccgctgtgtactgctcgtggacaactttggattattttttgtttttaaaattcaaaatagtcaatatattgcttatttatagcgc



gcctttttgacagtaagtttgtcaaatttgcgcgtaagttatggtgtttgcacatatgcaccatacagcaacaccccgcggcccggctagtggt



acatccatgcaaatgcgctctactgataatttgagtttaaccaggtttaggcgcaagataagaaaaaagctttggaccaaaaaatttagagttt



atttttttcggacattttttatatacatcacaaaaatattgggccactcgtttttgataaaaacgacaagcccaaaagttcaggtatacggtagac



aaattgcgtacaggtaccacttttccacgtagtgccaggttgtcccattacgctttgatctatgaaaaatgcgggaatttttcgtccagaaaaat



gtgacgtcagcacgttctcaaccatgcgaaatcagttgaaaactctgcgtctattctcccgcattttttgtagatctgtagatttgtagatcaatc



cattccccgtataccctgacccataatcaatacctacctaatttttgtctttccccctacttttttgcctgtccaaaataagcgagactatgccgta



gtctggtgtccaacaacatgttccttatcagtgataacgctacaatcttctttcttttttctctgtttctcttgtctctcccaacccatattccgtattac



acctcgtcgtggtcatttttttgttcagagttttatttaattctaaatttcctaactaaaatttcagaaccaaa



ctl-2




SEQ ID NO: 42





aaactcttttttttgtatttcttctggtttttgatgataagaaattttatgtgcacataaatcaaaaaagccggaaattaaatagcgttttatcaggca




gaaaattggccacgtgacgtcatcattttcctgtttgaagaaaatctggaaaattttttgtttcagtcaatttttaaagatgaaaacttaagttagac



tgtaaaagcaattttcgcgccaaaattacggtatcgggtctcgaaacgacagttttttatctattgcgaaaatatgtgcgcctttaaagagtact



gtagttgcaaacttttgtcgctgtggagtttttatcgattttttatattttttcgatgaaaacaactcaaatataacaataaaaacacaaaattaaaaa



aaaaatcgataaaaaatccgcgtcaacgaaagtttaaagttacagtatttgtcgtttcgagaccgggtaccgtagtttttggtgaaaacattgc



aaaatttggtcaacaatttcatcgctgcgagaccgacacaacactttattttatttttgggtttcccttatcgcttatcataaacatgtgacgtcatc



atctcttgtacagagcaccgcgactgggagtataagaatcgccggaaaacatcaataatcagttcggtagaagtgaaaattgagcgtaaaa



tatgatcatttttcgatgcaccatatttgacgcgcaatacttctacaagccgctgtgtactgctcgtggacaactttggattattttttgtttttaaaat



tcaaaatagtcaatatattgcttatttatagcgcgcctttttgacagtaagtttgtcaaatttgcgcgtaagttatggtgtttgcacatatgcaccat



acagcaacaccccgcggcccggctagtggtacatccatgcaaatgcgctctactgataatttgagtttaaccaggtttaggcgcaagataa



gaaaaaagctttggaccaaaaaatttagagtttatttttttcggacattttttatatacatcacaaaaatattgggccactcgtttttgataaaaacg



acaagcccaaaagttcaggtatacggtagacaaattgcgtacaggtaccacttttccacgtagtgccaggttgtcccattacgctttgatctat



gaaaaatgcgggaatttttcgtccagaaaaatgtgacgtcagcacgttctcaaccatgcgaaatcagttgaaaactctgcgtctattctcccg



cattttttgtagatctgtagatttgtagatcaatccattccccgtataccctgacccataatcaatacctacctaatttttgtctttccccctactttttt



gcctgtccaaaataagcgagactatgccgtagtctggtgtccaacaacatgttccttatcagtgataacgctacaatcttctttcttttttctctgtt



tctcttgtctctcccaacccatattccgtattacacctcgtcgtggtcatttttttgttcagagttttatttaattctaaatttcctaactaaaatttcaga



accaaa



ctl-3




SEQ ID NO: 43





ttttattctgaactatatacaaaatgtgctcaatataacgagttttgtaattttgtgagaaagtcgtattgaaaattagtttaaatgtgatttaatatttc




gaaaaagtagtctaattttagctaaattctacaattttgacaacttttccgtgtcgcaaaacgaatttttgtagaggagtgtacctaagcgagtcg



gagaaacgtgcattcttccatttttttcccccggggagcccatagccagtttccggacgggcggtcttgttccaaacgtttttaaaatttaatatt



gcaatttaattatctattcagcatccgtagcccagccgcattgtggatctcagattggcgaatgcttgtgcgctccattggactccggagccat



tccgtctgttgatttcctgatttctgcggaattgtccggatcgacgagctctgtaaaaaattaatttaggaaaaatcaacattttttcgataagcaa



accttaattccttcgtcacacttctatggaatccagctgacggcggcggctgaaatatttttgcaaaaaaactcacttttcgacttttcctctttctg



cgatcggttttcgcctcgatttgcgttgattagcttaaaatagtttttatattttaactaataataaagaaaaacaaaaaaaaatgagaaaaaaca



atcaaaaactcgaaaaaaacattacgaaatcagcaaagaaaatgaagaaaaaatatatacagtaattttaaaggcgcacacacaaaagtttc



ggtacgcgtgccgagaccactcagcagaagtgtgctcctttgaatctggagtacggtcaatggggatttatttttgaaaatgcaaatgccaaa



atacaagaaaaataacaaattgcattaattttagtgaattttctgaaaatgagattttttgtgctttttttggaattgtgcaacttttagtgcattttcat



cgtccttttttctgaattcttgaagtttctggaatttttgttccccccccccccccaatctaagactaaacctaaggctgagtctaggcctacgcct



aagcctaagcctaagactaagcctattggtgtatgtgcacataaatcaatttttttaaaaattattattattttttgcaaaacacaaacgttttttttca



gattttttatttttcaccctttcaacctgcaaaacccatttttcttccaccaaaacacagctgttcttgccaccatttgcctgatggaaaatttatata



aattggctgtcctttgtgagaaaactagaacaataatgatgacattaagtactagagtataaatatatttttttttgctgacaattcctggcgtccc



ccgttgacattgaaaatgtataaaagaggcggccagacaccatccccgcaaatgtgtttttgttgttcacttttctttttttttccactctctctctct



cagctgtttgcatgttgtttttatggtgatctatggtctctaagaatttgtttataagctaagaactgctcgctgagaaggttttttttggttcgtagct



agttttttttacgtttatcgaaaaaaaattgaaaaaagtcgaaatttccatcttaaaaaattagtgaattttaatatttttgttaaataatcgccattgtt



tcgtgcttttctcgctctgtaaaattgaaaatctataaattttgggtaatttcgagtattacgggagcacaaaattttgagaatgcgttttgcacaa



cctatttgacgcgcaaaatatctcgtagcgaaagctacagtaattctgtagcgctggtgtcgatttacgggctcaagttttcgaattaatttttttt



cgaaaagttacatcgatatttcattttccttcgtgctattttcaaaaatcgagcccgtaaatcgacacaagcggtacagtaatcatttaaaggatt



actgtagttttcgctatgagatattttgcgcgtcaaatatgttttgtgtccccgtaatatttttttaaatcaaatttcacattttaaccataaaaaactct



ttcaaaagtgtaattttctacgcaaaaatgccgttcggatgaaaaattacttttgaaaaacaaactcgaaactacggtacgcaaaaaagtacat



cggtgtttgcacataagtgaaaacaatgttgtttttttgtaattaaaatcgattaattttttttcccggaaaacaaaaacgttttcagcgtggatttct



attgtttcttgcgtaaaaaaaaattatttaccaattttaaacgataatttccacgaattttcgccattaatctctcgattttgttgattcttgactccgag



caatctctccggttttcgcaaacgattatattatttatttgttttccttttcagtgccgattctcggaaattcaacagtaaatcttcaaa



W01B11.6




SEQ ID NO: 44





tttgagaattttctcgggaaattaaacctgtgtttttcattaaatttgatgcaagcaacaagtcattatacaataaaattggtgaaaatatgattttttt




gaaatatttggggcgaggcttttagttttttgaagagcttacaaaaattagaatttaagaaattttcgaacacaaatttgagagaacttttgactttt



ttcaaaaaattgttttcaaaaattttaatattttcaaagacgaaagaatttgtttttttgtctaaatttacctaatcattatttttcaatcaaataattgcat



ctctgaaaacctgggaactttgaaaatgacgtcattcttttttccctccttttcttttccatttggttattgacgttttccaccccctcttgcaaaaaaa



actaaacaaaaaagaaaccattggcaactactaacgccaattttgtgttgcttcatcgggtttcttttagttttttttctgagagcgctgagattatt



tggaaatttgcattttctcacgttctagctcagaaagagatcagctttctgaaattgaaatttaaaaaatcgctctaaattgaaacagctgtttttta



tgtcgattgtctctgcaaatatatttttttcagaatatataagtatgtgtttgtttaagttttattttaaattttcttgaattttatgaacgacattagagc



ttatgttagtccaaatatttcaaaatttattaacttgaatcttgcgcaaaattatttgaaaaatcaatttccagccaaaatcttctttaaaattttatttgaa



ttgtcaaaaacaaatgcctcattattaattttatgccaatattaaaaaaaaattaattctcgataatcttaaaataagatttttagaaaaacaactttc



aaaagcttctatgcgaaaaaaattgtttttattcgaattaaaaaaaatgttttcttcaaaaaaaacaaatttcttaaatcatagatccgtgttgctca



actgctcaatgtttcccatgacaaaaagtccatgtctctctctatcatttctcatctctcttttttctctagccatcataaaaataaacacatgtttcaa



caatcattccttggttttttatctctcgattgctatatcatttttattttttttactattgggtaaattttgaagagggtactgattttttttcaaaatttt



tccaatccaaaagtcttttgaattgcgttaaatcatgtctattgtaccacaatgaccaaatgccatagtaaaacttttcaaaaaaatgtttgaattttttttt



gagcgtcagaaagtggcaattacagagttttttttagcactatgaaaattgaaaattttcggagtttttcaaaatgattttttgaaattggaaaaatt



acagaaaacaattttttgccatttttttggaagttgccgataaaaaaaaatttctttggattttatggttttattttgttgaaaatattaatattcaaacc



aggggtgtgcggcaaatctcaaaacttgccgagctcggcaaattcggcaaatctcttttttcaatatttgccgagcacggcaaattcggcaaa



tttgcctagctaggcaaattcggcaaattcggcaaatttgccgtgcttaacaaactcggaaaaatttgatactttttgatgttttttggagcacca



aaactactgaaatcttaacactcatctggtttctgaataagttccgtgtagtatgtctgcttaagcatcaaaataacgcaattttgtgtcattttact



aaatttttggcgaaaaaatcaatggttttagtcaaaattgcattgtcaaatttatgacgtgtgcggcaaatttcgaaatttgccgagctcggcaa



attccgcaaatctactgttttgaaatttgccgtgctcggcaaattcggcaaatttgccgcacacccctgattcaaacattgtaagggtttgaaca



tgttcttaaaatgtgacaaaaactcagtaataaaacatttaaattttttgaacacttttaccatgatatttggtcattttggcacagccttaaggttaa



agctttaacaatttccccactgacgctactccaccataattttgaaaatctaaaatattcagaaattcgaa



F10D7.3




SEQ ID NO: 45





ttttggaaatggtatcagaattgtttaaatatcttatctgaagtttatttaagtttgttacttaaaagtttgtcggtttcgcacaaaactttatttaagtta




ggggcacgaaaaaagtaaaatcacaaattatcaataattttaaaatcaaaccatcaaccagaaaccagaaaactaaaccttgtattttgaaat



gtgcccgtttgaagatctatgcaataaaaaaattacattttgaactgctatcaattttttaaaaccggcaattttgacatttgccggtttagtacattt



ttgaccgatctagataaattaaaaagctgataaatttgttaagtattcaacttttgagattcaaaattttaagaagcttttcggcattttgaaaacat



atgtgacgtatgtcaagtttgtttttgccgttcaaccgatgagcctgtatgaacatttgactaatgtttttttttcaatatcagatcattttaattgttta



aatttgataaacgaaattgaaaattttcgaaaatatatgtttcgaagttgtatacatttttaagagttttcactttgtggcagatttttctcttttcaattt



gaaagtgtcacgtaccttgaaatagtttgttttttttaagaaaatgaccaaaagaatattaaaattttgaattatggtaaagaatacaagccagca



aagaatctagttattgttggaaaactatgaacatcatgtcctcagttttcaagaaaacattaagatttcaaaactatgtattctgcatggcaatgtt



gcaacaaaccatttcctcataaaactagccaactaacacagttattcctaataaccacaatgttctcttttcatatgttgcctatgtaattctttctca



gaaacattatcatgaccataaaatagacaatgtattggtttctatgtttcttcttcctgccagtgtcctctcgcgttgtttgagtactattgttcccca



ctctccccccccggcgtgcgtattatcgctgaaaatgtcatattatctaatcgaacaatgcccattttttgggatgtttaatagcaaacatattcc



gattggaattgcaaaattgagttatcatctttttattgttggtcttgtgactgtgagtttatgtttggaatatagttttgataagtttgaaactattgtga



acttggaatttttgattctccaagtttttaaaacgctatgcacctaaacttggtattttttttcaatttaacaaaattctactttcaaaaaacactactct



tatttgcatgttccatagtatgtatttcttggcagtgtttttcaaaaatagaactccttccgatttaaacacataatgttgtgctttttaagcctagaca



cgacttccgatgtgatttttcttcgaattctccctgtctgtaagaaactcacatgctgactgcaaagaatgtgcctattgcggacctcaatcagtg



tcggctacacttttttagtgtcgtcccgaaagttgtggtgttctgagaaaacataatttttattgatttttaatgcagcaaaatttcaaataactgata



cccggttcaccctaattttcccatggatactccaaatatgttcagaaatgcatatttttgtacaaaatataacgttttctaaagtgtttgctaaaatgt



tattgttctaaaatcttttgaaagaaccagaaaatctcaaattcttaaaacatttttcatcgaaatgtgatatttgaccagccagtggcgcctaact



tctgaactttgcttcacgcaatctctgctttgatttctgtcgtttctctactgatttttgttcactttcacgtaagcgttcaactcgcggaaccaaagc



ctccgttcatatcatattaggctttcatatctaccatttttctactaatcattgttgttacaatcgttttttctctgtttcgaagaggcactctacttatga



ctacaacataaaagtagtatggaattcgcgtccttggtgaccagaggcgttcctatttcgaatctctattcgggtggaggcattatccgaatcc



cgagaaacattcttgtttgtgtaatctgtctaatcaatcccccttcctatttttctctgttcccttccttgtcttcaacatcgcccttcgatcatctgaat



tcagttcgttttcgctccgcccatgaagttgggctacataaaaagaggaactgaaatgacatcaggggaagttggatatatatttcattaagtt



gtactatcatttttttcttttttctctttttttcggtttgattctatcttttcaagatggcctcgcttatttctacgattgtcaagtcaacggtcaaagtt



tttgaattgttgcatttttctggttctttgattttgttcctttttaattccagttgtagtttaaattattttcaggaaagaaaaccgagaaaaaagata



ttacaaa



prx-1




SEQ ID NO: 46





agtttggccaatacctgtgaataaaaaataatttattattttaggaagttttataaatgcaaaaaaaggagtagaggaattgtattagaatattatt




aaatggaaatatgaaatagcaattggttgatattatacttcgaatctcagaatcactaaaatgaaaaccagaactgcttctgcttgatttttaacat



acttttatgttatttgcaatgattaaaaaatatatataatacgcgagaaatttgaaactggtttggctcgataaaaaattggtgagaaacccaaaa



tatcgtgaaagaagcggtggaattaaaatgatttgagaaagtaaattttgataatacgaattataattcgaaaaaatggtggtacttaaaatata



gcaaataaaacaggtgagaaaaagttttgaggtttttactatattttaatcaaaccgtttgttttatttattttcaggcatcgaaattttatgtactcaa



gcttatagtaaaaatacaaatatttgatatattaaacagagataaaacataaataacgagctctaaaaaattagcatattttgggaattaagaaa



accagtgaaagccgtaaaaatgatctgaagctatgaataagtttggttagagactctatttctagtagattactttattataataatgagcagaaa



cagatatttttttagcattttttcacttcatcattaaattaaaatcattacaaaaaatcgatagtccttgagaagagagacaccaatttacaagcag



gcaacaaacgagagagagcgtattatcgtgtaaacggtatatacgggagaagagtacgggagaccgacggaagaaaagcaatgggag



gtgtatagggtggtggctgtgttgtgcctaggaggcaggaaaatataacgttaaaaagtgcagacgcagacacaccaattgcccctcaga



ctccaattcagctgtctccgtctcttcctcgtcctcatcgcacacccttagaccggttgcttaaaaggaggagaagcaagtacgcaagcatta



caaacgacgacattactgacctcttataattaaagtaataaattgtgaaaatgtacaccgttttttatgaattgcataaagcgaatttatttataaaa



agttaatatatataaaagctacatgttcactgatctacaatttttggtttcagatttttttgaaatgttgttatcaacagtcgaactttaaatttttcttga



aaacttgatacataaattaaaaattgaacgataacatttggctaactttttccatgtttgcctttgtgcaaaggttatcacttgattatttatttttttga



aatctggagcaataaaaaaaaatagtaaggatagagataaatacaaactgaagcccttatgtttattacaagttatgacaatttcagtgtagtttt



gaaaatatcaagtattgcagttaaatttacaatgccaaaaaatctaagaaacattacgaagttttcatgaaaatacctcgaaaactatgaaaata



gatcaaagaatatccttaaatatgaaagaattcagacttcattgggttttgaaaaaaaatggaagggaaaaggaatctgattaaaatcagttttt



ggcattgtagaagtatacttcaataagtttgttttcaatgatagagcttagtcagttaacattcaagttaacttgtaattgtaacctggtaataaaaa



atcaaaagataaacaaaaaatattgtggaattatcaaatacaactaatcggaaaaagttgattttgaggcaaacatagcttcatctgctgtacat



tatgaaaattttattgaagaggagttaatgaagtggtacaaaacacgatgaaatgataaaacatgaacaaaatcgagttggtcactatacact



aaacaggacacgtaataagaaaagtcaataggcacggagagacaaaaaggtcatcctacaattgcggtggctaactgcatcttaactacgt



cgtagcattaaaaaagattgataagacagtgcgtgtatgaacgcacaaaaagaaaaacctagcaggacatcatgaggttttattttagcgtttt



tttgcatatcattttttattcattttgtttcagtaaaataagtttagattcattttttaaagcgaaagttaatagaataatttgatcttgaagttgaaaattg



ttgttaatttttaaaaactttgttttcaaattgcctaatatttttttgaaaacagaacataaaataac



prx-5




SEQ ID NO: 47





cttctacgtggaattctggaggttgaagcttctggtctaaccatcatcagtaagaatgtaaagaccatttcgtgtttcatatttatgccgtcaattg




tcagtacaaggggccgcccgttttcgtttcgtttcgtttaaattatagggaatacattataaaatcacaccttttgtgtatatcttcgtagttttattg



gacattttaataggccttgtttataaaagaaaatataataatgatgacattatacaaaaaagtattcaaggaatgttttatagttacaaaacctata



ggtatacagaatatgtcaaaataggggaaaaaactgaatgtatgcagtcgacgaataaggttgtcttgacatttttttggttaataatgtttttcct



gccagtttcgatatctttgaaattttgatccagatgacatcaatcctagctatggaataatgggggaactctctttaaattcacaacttcattcgag



caaaatttgtcttttgcacacgaaaaattattattattattgcacaatcaaatatttttcccccgtgcaagtgtgcaatggggcgacgggtcgagc



cagaaacccgtgttgttgaaaatcaaaccaagtgcaaaatatccattttgcttaatttaaaacgatctaggataactccactagcaactagaat



atctaattgaaggattgaaatttggaaacttacaataaggtattctattttattacgttttcaatcttgctaggaaaacttggaaaaaaaatccataa



acgtttcccggttatttcagaaatcgatagtcgacctccgttgttccttatctaaatttcatcaattgtatcctttttgataagacaatactatcttttta



tcactacgtctccttcactctaaatcctaatgtagtatcaatcaatttgatgaaaagactacactggggcccacttattttctttttcaatcaaaattc



acactttattttatatatttcttgtaaattgtatttttcttcatttttaattctactttttttcaacaattaactctcgaattcttcaattttttacaga



duox-2




SEQ ID NO: 48





aattttcaggagaatcaatcgacgagcttgaagatttcgacaccggtctactatcttccggaggatccgattattctttttaaaattttcttcttttaa




aaaatttcttttgaaataaataaattctcacctaggaatttcaacaattcaacttgaaaaaagttcgcgcaaactacgaacaaatgtgtgtcgag



cgggcggagccactgagaaagaggagcaaaatgtacacaaaaccatatttgagtgtaatttttcaaagtttggcgccgattttctgtgagag



atgagttttctcaatttatatttggttatttttattttagttcttactggtaaatttctgggtaagtcctgatgactttgaaaacgaaaaaaactctttcat



tgatgctagtgcgattgctaggaaagcaacttttcagttaccaagaaaaagtccaaggccatagggattagctgcgtggcataacaactcat



ccatcctcgcagatgcaaatccgctctattggcaaataacatggaagagtataaacattttctcttccacacggaaacctagtccccttgggg



agcggtagtgcccacaaccccgcatgtttaccaaactacacagacagcgctattgtctgcaagtggcaaaaa



prdx-2




SEQ ID NO: 49





agcgtttcgttttagaatcgccagtgtattttttgtgatagtcctatgtgctttaaattatttattttgaaaggttcaataaattatattttatgaccgaa




cacattatattctcagttgttatcttatatatccacaccggaatgttgaatatctgaccatatatatttagaatgttgcggtaatttttttgttgctgtgg



aattttattttatttttatttttcatagtttcaacattttacaatttattgaaatttatgggttttaattgttatatttggcgtttttcgtttactttttcg



ataaaaataaattcagttaaaaactaagttataacaatgaaaacacataaatttgaacaaatcgtagaaaaatcactacaaatttgacagattttatgggtt



ctatcgcgatttattgaaattaacgtcttttaattgttttattttagttttttagataaatactgttttcaaacgaaaaactttgaaaaatcgataaatctc



gcagtactcctgaaaggcacacactcgtttgtacttaagaaaaattgtcgcgacgagaccaactgtccaactacggtagttttcaaaatacgc



ggttcaccgcaaagtcaaattgcggacctgaacatttttttatttttcccgcaaactttttttttcaattttgcctaaagcgctcgaataaacatgaa



agtctcgtgtttccttccatccagacctctcatttttcaattttaaaactaaaagcactttttgacctactttttgtcgcaaccgccaaaactcgcttc



cagaattattccctttttaggattttcgacgcaacatctccaaccggttagttttttcgcagattttctcgcattcgcgtagtttcacttgtttacttcg



tggcgcctcgtttttttccgctctctcgtctgaccaccttcatatttattgatctgcgcctagcggcgcccgttgaaatactccacatttttttgcaa



tcttgtctgcgagttcaggttattttcgacttttatgaaagcttgctaggaagccatagcaaccggggaagaatacgctagccaaatgagaga



tagaatcgatcagctaaatttaagataaatagtgaattcgaattctaagacctgctcgaccagctgaaattctaaaactctgcgccaagatgta



tagacaggtaataatatttgaattttctttaaaagtgaccttgaaccctaagattttcgctcctcctaaacgttgtagtctgttactccctgccgcg



acaattgtcagcaaaaatcgcgtcacatgatgatgaaagtttgtggcaatgttataaaaagactgaccttatttcgtttcttggaagatgcaaag



aaatgtttattaaaaattgcagtgtgaaatcatgtctctcgctccaaaggtgcatttcttatttgttttttaaaaatatatttggttacttagatattaatt



taaatcacggaaaagtttaaacccctcgatttctgttatttaacatgatcactcacttttataacaattaatttggtttttcaaagatgttcccagaat



gttttattagttctcatttcgtcctccgattttttttctttcgtcgctctccaattttgccaatgtatttcattcccattagataagcaccgcccgtcacct



tattctccttcttttcacattgcaaacaaattcgttgccgttgggtttcaatatccttttcattttttgtcgtattgttgttcttgtgattgtggttgtta



ttttatcgcggtattatttttttttgttaaactaattaatttttag



pxn-2




SEQ ID NO: 50





tatcaaagttttgttgttacccacccaaactttgttttagttgcaacaagctcacttagaaggaaattgattttcagtatttattgaacacagcaaga




aaaatcagcaaacgtggtacttgtgtgttgcatgcgctcattttaataataatgttgttgaattataacaaataaaaacatgtagcatatttttgtatt



ttcaggcttaaataaccatttctaagcctaaagagaaaaaaaaatgtacaacacgttaaatttaaatggagaaagaaattaacaacatttgatt



ggatttagaaataagggcacgtaatacacaagtaccaaacgtgaactttaaaaatttgcgtacctaccatataatacaaaaccgtgaaaggt



ggaatagttttgaatggcaaattgtttgaattcatttctatagtgctaaactgaacaaatattagtttcagttttaaaaaaagtgtttgaaattcttcat



ttgcagtcaagcagtggcaattactcagcttttgacattcaagacaaccaagaaatatgttttcaaaaagtttttccgtattcagtcaagttctattt



tcctctgaactatagctaataatttataattgtacatatcaggaaaaattatgtggtttaagaatctctgaaattttttggaaattgggaggtgaaa



gaatacagtacacttttgtaattttagctaatacgttcgagagttattatcattatggcagcacacttgttggtgatttctattttttgacatgatatgt



ttgaatatgattttcctcgttatgtggaaaattttgtagaggcagatgctaaacgacaagctagactttttagtgaatttttgaatcaattatttataa



tggcatcaaacaaatcgaaaggatctgtgccttttgatatttttggttttgcaacaatttgtctttgttgttcaaacacgtatacatcaaaaactattg



tttatttcaacattttcagtgtatcttttaaagatcacatcaggttgttactaaaattagttttgaattcaaaaataaccaattaaatgttccaaacatat



aaaaaatatttcaaatatgtatcagcttcatgagtagtccataacaaaacccagaagttcatcggaggttgtatatctctgagagtgtcaaccc



acttcttatttttgcgataaaactaattaaaaactaaaataggaacaaaacattaattttatgcttcgagtgaaaattcgtatttattcactttttagg



gagtttctcaattattttaatacatagatacatagatattactttttaaataatatttacgttcaatccaaataagattttaaaacgattcagtaaaagtt



cttgcaaaacaatcaattagcaactgagtttggtttttaaactgtttaaatctgaaaacatttttaagaaaatgaaatccgtctaaattcattatattt



agcaggaacatgttaaaatttagtttctgaaatttaccaattatttggaactaatgtgaaataataagaatattattattcaatcattttcttgcagac



aaagggaattagaggcgtctggtcagcatttgtcgtggctcaactgttccgcaagatacattcgtcgagttgcgggtctcgtttgatattcaca



aaaggaggggttcatctgcgaagttacacacttcttctatcaaaccacattgcctcattttcccaataactgtctcatttttgaagaagatgcgat



caatcaccgtctaaaactgattgcgttgcaacaaatctgtgatgatatgatatgatggaacggacggaaaggttaaatttcgagtgaagaaaa



aatatagaagtaatatgaatgagtagatgaaagaaaaagacaaaagagaaattgatatgaccgcgcagcagacaggggcatctggtgtga



gcgtgcggttttttctgttacctctaacgcagtccgtacacttgtcggcgtttatttgtggctgtgggcccattgcgttgatgacggtccctctag



ctggctttcattgtgatccaattgcaccatttggtttttgagttttattctatttctatcgtcttttgtgataaattaattgagtgaatgaataatgtataa



gagcctcattatattctatttactaaacaaaactcaattatttcttttgaaaagataatgaaatttccagtcatcattccataaatataattattattttg



ccttcgcaataatcctaaagattttttatatccttcaagtttatcaaaattgtttaggt



mlt-7




SEQ ID NO: 51





attccaatttcccagccatccggaaattcgctgtaaaaattggaaagtaggacaaatagagaatataatacaaagattaaacactttttacgac




aatgttgacttcgtcatggtacattcagaagtgtctgggaaatgttcagcaggaaaacattgcagaagagaaaaacaactcggaatgtttgct



gaaaagttctgcttggaggtatttttaaacttggagaagatatcattgctctactttggcggcttctatcgcggtagtctttagtttgatcaaaaatt



tatcaactggcaaaatacgtacaaaatagttatatacattttgctagttgacaaatttctgataaagttgaagggaactgagaggttataacctgt



caatcaaggagcattatgtttttaggcgcacctacttacttcatgcctgcttggctacttacctgcctattacctgcagtttatatgtaggcactga



tgtaggcacgtagccatcaagtaggccgccttttgaggctcatttgacccatagaccttaaaataggccgttctagaacccttcttatctgaaa



caacaatctttcagacattttcgaatggtcaacaacttaagtttttattttgcaaaaacaaaaaacaacaagttttcaatgtttttttgccagtggaa



attattgttgttggataggtacagatgctaccgggttaccgagatcgtgcctaccaggcctacctattgcctgcctgccatgtgcctacctaca



cttcatttcggcaaaaggtcaggggccaatgaaaaaggagcatgaatagattcgcatcagaaattgatgtcggtgtaaggcaggtgcaggt



aaaatgaaggcaggcctgtggcaggcaaaggtcagcatggcaagcattttgggaataccaaccagtagttttcatcagagcacgattgcat



cgacgaaaaatttgaatttttgtgtattttgaagagtgccgtgaaaagtctaaatcttttgctattgcctctgattccttctcgaacctgaactataa



aactgatgtaaagaaaaaaagtttccaacttaagagatatcttatcaatttaaactttaccgagtgattctgtgatatctcaaatttcagtcgaaaa



tcacatgtggttttcccttttaattccgagagagagagagagagaaaggaatttcacctccacaacaacccataatcattcaattaggttctaa



acacatacaagaagaagacaggaaaatgttagccttttagtcataggtgctgctcgatcatgatgttgatgaaccaaacatcgcattttgtag



gaggggaagaggacaggagactgtccatttgaaagtgactactttgtcggatatttagagagtgacttacttacgaaagttataaagtttggtt



agcaggaaatctggtttttactgagaaaactctctgagggaaaagctcggggtgggtcatatacccgcgagatatctgccggtcattatttaa



gaatgtacagctctactttggcagatcatatctcggttattccagtacatatcaaaaattgactgaatatgaaaataaaggaaaatgttcaacct



gtattttaccagttgaacattttttgataaaaccaaaaataatcgaaattgtgcttaacggaaaagaagttagattaagattccaggctgggtcc



cgccacgataagctgcaaaattattttttggagctgtctgttcagaatcgtcgttattagaaggtggaagtgctgaaatctgaaaaaaagaact



caagaatctatagaatctctcatatatgagagatcggctccgtgaaaggcactaatctggaatacttcagaaattcggcgaaatcttggaaatt



gaaaactttgagatttttttcttgtagatcgaaacccgcgagatgtcagatgcttctgaattcagatttacaaaatgagctcttcagacactcctg



aaagatcagctgaccagaatatgcccacctaaggcaggcgtgacttacctgaaaggtgacctacgcctattctcttgccagaactcgaaac



tattttctaggaaaaacttttttgtagatcgcattccatgggagctataccttccctgtaggcacgcaggcactagtttccgtgcctacctggaat



ccacataaccggagcacggagcagcaacttcaccttcagaaatgattcagagctttacatatagtttcctgttcctgaaaagcatgttctacga



tgccatgattctcatttcgatgccacttctcaaccaacttttgccgagcttctgaacttgtcgagggagtctgaataccccccaccgcccacac



taaacttttttcctctgatccgtgagaatatcctcattatctcacaatcagtaatgtccaaatcaggcgggggaggaggggtaaaaaaacacg



gaaacgaggaggcgaaaagcgtctctgggttcccgcccttcctcccacacgtcttctctatgcgtctctctgacaatctctcgttaaagttgcc



ttttttgggaaaagcttctgtctctgtttctctctgtcaacgtgtttctcagcttgcgggcgccaaaccaccaccaccatcactgactgtcgattc



gcggtgtgttgtgtttcaattgcgtaaagagtgagagagaggaaaagatagagagagagagagaccccaaggttatacgtctgttatactt



gttacccatatactcttctacacctttaccttcaacctttccccacattgactccgcctctctctctcttacttcttggaagacactccccaccccct



cttatctattttttcgaaattctcgacccttcaccctccccccttacccgcaccggtcatcattctgactctgcgaactactggagaggaacacc



ZK550.6




SEQ ID NO: 52





catgaaggcgaccgaaaagtgtccagtgaagattttctaaaaatctcgaatctggaatcatgatgtgaaatatatgaataaagaatctttttaaa




atattttgaaaattctatacatctctaaaaaaatgcaatctcgttattacaaaaagcaaaatctttcaccttaagcctagatgtaggtaatgtttgat



gaacagtaaattttgaaacagtaaatttttgaattacaaattgaaatttttttaaaatctattcagaatccctatatccgcatgcatcagggaacgt



gccaaatttgaaaaatgtgtgtttctcaatctctaatcatttatcatatggtcatgacaacaactggtgtcaaggtgtacgataacggtacactgt



ggcaattgacactctttttttctttatttctctattcaacaagacttgtatttattaagaaaatgcaatgagagagcgtggtgataagacgggtaatt



ccctcgcttttctcattttttgcggtgttgtgttcgtgtcatttgagataatccatgttgattccacttttattgttgatttgatagatgttccaagttttta



ctgcttcctgaaagcataattcttaaaaataatgcttcatagcagttgtggcttcatacaattttcaaaaaaaaattcactgtttcaaaaaaattga



attcaatttcctgcattatgacgtacgtgttaaaaaaatatgttcacctaaaaattccgctcgaactgtcgcgaaatctgtgtttcagtgaaataa



aataaaaacatctagacaaaatacagttctcctcaaaaattgctgtttcaaaataataatttaaaaaaaaacaccaaagtgtcgtatttaaattta



aaaaaaaactatcgtttcaacaaaacaggttcaaatctattttagtattaaaatctataactttataaaatttgctatttaggttttacgaattgttgttt



tttactctgaattgtaaaattaccgtttcaaatatattcttctaaattcaaaaatttagtatacaatttttctagaaacattgaagtattaccaggaattt



ttggatatttcctataaattctattttgatcaatttgtagttgtcttatcatatattgcattggatgataataggaaatgatccgattctctttcctgttcc



aaaactaggtaaatgtacctcatatattttgttaattttgtagtcacaataacatgttatgataataatatcgataaaaaatatcgtgatgtttaaaca



ttaagtttcatttttttcggtactgttctaattgttcaaaacaatttaaaaaatttcggtcaatttatagacaataccgattttaataatgaatgtaaaat



tttcactgtttcactaattttataacaattttcattccttccaattcacattgtgttagtgtagtgatcattacttatatattttaaaaaaatagggtgtta



gttttttccgtttgtctgtttgtttccgtgacgtcacaacgcatgagacccattttggcgcaaattcaaatttcttcagaaaaattttggtgcaaact



caaatttcttcagaaaaattttagcgggaattcaaatttcttctgaaaattttggtgggatttcaaatttgttcagaaaaattttggtgcaaattcaaa



tttcttcagaaatattttggtggttttttcttccgcgccggaggcgcgatcagcagctagttttcaaataaatttactgtttcaaaaatacgatatttt



ttgcctaatttttgagaatatcactatgacgtctaaacgtaaagcgattccataatctacttcaaaattccaggctccccaa



C28H8.11




SEQ ID NO: 53





cagtgtaggccgtcttgctcatagagacaaataaactttttgagatggttttttaatagaaaatacattttatagaaatgagaaaaataaagtttta




ctattagaaaagcgtaacaaaaagcttccgtaattatttatatgaatgttccgatatttttagcgatgtgtgcatcgtgcactcacaatactaatgt



tatgagcttccttgcaataaacggtggggctggaaactgacaggaagtgggtttattcgatgattacaataccacaggactgatgacacgcg



taatcaaaagttgaaactagaaaacataaacacgcggctttcatctgaatcagagacgaatatccataaatcacggcccccaaatagaaac



cagtttattttatgtcacttcttttccccattaactttcctgtcacaatcatacaacagagttcgatcatacaggtccaaaggttttgggtatatcttgt



ggacatgtatgctgtgaaatgttgaacatttcatataaaattttaaaatcagactattagatcgaatagttctacgaaatttgtaaacagtttccatc



gaaatacctattttttgtaacacgaagtcgacctctctcccggagacgctgctacagaaaggtttgaattttgagcaaagttacggtattaggtc



tcgaatgaaaagtttcgaaagtacgcaaaactctacaatagggttaagaatcgataattttctagattgtccaaaaaagtagactaattttgcca



ttccgttcagtgccttcaagaagtacttgaagtctatacctcacctacttgtctgatatggtaatttactatcgagcttattagcaattttcttcacgg



gaaaggagttgtaggttaacttcaagtcgcgaggtaggcatatttgtgcctggcgataacaagagacgttccacaaacatcttactcagtttct



atttgaaacttggcgaagtagacatgaagttgaaccttcggaacgtcagtccaaaggtttgaaggaggggttccccgaactgtcatacactt



catttcatcgtcagctgtctgagatcaaacattcaataagcatgaagatctctgaacgaccgaaaagatatcgataaagtgatgataaaggtc



tgcagcagaatggttttgcagacatttcttcagaagttaaaacaacgttgtcgtacccaagtatcttatcaagggagaaaaagagtcaaaaga



taaattccgccatttgcccctccggtccgtaataacgagtatttcttatcacgtgtgctgatcttttttcttaacacacatacaatcaatcgatttgtc



agacatgggaaagaataagacgtgatggatgaatggaataatgtgaacgatgaacgagatacgtgacagtcagaaagttcactgtgaata



gagtatggtataaatggttgagagacgacggattacggaaagatcgaattatcacaacgtttttgatgtatctggaccgttcacatggaattta



gtaattgttacttcttgggcgacagagaaaattcggccagtctcatcaaatagagagtttttttgaaaatctgcattgcagggcgaacaaaatc



aatttccacattattttaggccggttttaaagagaaatggagagattttgagaactgtgaaataaggctggttaataaattgtgcataaaaaatct



agagagattggaaagccatgcctatttcactgcagcttcaccaacaatctaatcataattttgaaaatgaaaattacattagcatggtcctttact



cacatttttttaggatgtcgacacttttttcatttgaggtcgctacaactgttgctcaaagttggagcatgtgcgacctatttccactcctcctccac



agaccccgtttgattggtgcaaaagtgggcagagcgaaaagctgattggtcttgcagttttcattttgaagggaattaaaaaacggagttagt



aacaattgagaattaccgtttttaaatgtataacttttcaaatcttccgtttctgaatttattatatacatatattatatagactcaattacaaattatata



aatttaatttatatattatatagccttaattattaaactttttattttgagatatttttaaatttcaaactttttttcagtatttaagtaagcttcctattc



acgctactccacttttagtgtgtttcaaatgaatggacgttataccaaaattcaattgaaatatccagcttcataaatatattggcatgggaatgagcctc



gtcacgaacattttagaaaaacatcaggacaaacttatattgtactataacttgcaaacctgcagcagcagaactttgaacacccaaatccatt



tccgacggaagtattctacatcttgtggccgcgtatacccatgactactgtacccaaactggggaaaacccaaattgctagtaaacgcccac



taaataaactgttagcattgaaagtgtgaacacgtgaatcgtatgtcaagtgataggaagtgtgacgttttgtaattaatcttaacttccaagtgt



ttgtttccttgaaataagatgcctacacacggcggcgaaatggatactttttatgtctgcgcttattctctttgtcccccatcatcatacaatcttca



acgccttcacatatcagacagtccgtcgggcactgaccaaccattcaggctgcctgtctgtcatttataggctgtctagttatcttcaattaatgt



ttgaaaattcagaagc



C35B1.5




SEQ ID NO: 54





aattaattattttcacattttttcgaattttgtcgatttataggcgaaattttacgttaacctaacggaaatatgagtttataatgcatttttaatcgaaa




attcggttttttcaataaaatttgctatgaaatccgcaaaaacgcctggaaattgtctgaaaacgaagaaaaataaaaataaaaatccgaattct



gtgcattgtgacgtggcggtgtttgcgtacccgacatttaatttcacgacacttgtttttatgtttttattgttttctcgatttctgcaagttttccactt



aaaacgtgcggaaaaaatccagaaactgtaaataatactaaaaaaatataaattttccacaaaaaaggcatgaaaactaacaattacctcaa



atatcgtgaaaaatgcaaaaaaataagcctttccgaaaaaacgggcccttgggcctttaaaggacacaaaaacaggaaagcataagacac



caaagagtaattggatttctacactttggttcctagaattatttataaggtgttattgcgtttttgtgagattgttctatttatccagtcaaaaattgca



ttttctttgtttttgcttcaaaaaaatacattttcagtggaaatttcagctgaaaagcagaattttgaggttttcgagtaaataacgtaaaacactaa



attacaaatattgatttttgatgtcttagaccaaattttcgtaaacatgtttgtatttttggaaaaaataggttttttgtcgattttaacttaatttttcgaa



caaaaaatgattttttctccgatttaccaaagttttgacttaaaattccgattttctgggtcatttttcccctaaaaatacgattttaattcaaaaaatct



atattttcaaagaccaaagtaccataaccttcaaaaaacaaccactttctctattgcatcagcgaattgtcatcacccctctcaaaatatacaaa



acgtcatcatttttctgtgttttctctaattctcctgaaaaattctataaaaccaacagtttttatcatcaaaaatgccttttgaccgactttttttaaagt



tgaaaatcgtacagttttagcagaaattccagagtttcattttgaagtatgctggaaataataaaattattctaacatttattaatattttgtaaaact



aattctatacaataaaaaagtaaaatttaatattaaaaaaaccggtttttctcaaatttccattccccaatgtcctgttctattatttgttccgattcgg



ccacagaacgcgcacacacacactttttgctgattctctgcctcctttctttgatttgaccgcattttatattgattttcggccacaattccactattt



gttcagtttgtcgatttgttggaaatttcaattccggcaattcgccgatttgccggaaatttaaattcagacaatttgccggtttgccggaaattttc



agttccggcaattttttaatttgccggaagtttccatttcggcaacttgccaatttgccggaaattcgccgttttgccggaaattttcaattccgac



aacttgcctatttcccggaaattacaattccgccgatttaccaatttgccagaaatttttaattccggcaatttgccgatttgtcggagatttcaatc



cggcattttgccgaaaatttcaatttcggcagttcgccgatttgtggaaaataacaattctggtcattcgccaatttgccgaaaatttcaattccg



gcaattcgccgatttgccggaaattttcaattccggcgattttcctatttggcgaatatttttaattccgccggtttgccgctttgccggaaatttca



attccggaactttgccgatttgccgatttgccggaaaaaatcttttgccgcccacccctaataaagacttcaaaatatgcgtttttttttgcttttaa



cacgctaaaactctctaaaaatccccaatttttcagcttaaaaaaccccaaaaaa




































































































































































































































































































































































































































































































































































































































































































































































Endoplasmic Reticulum Oxidative Stress Toxicity






hsp-4





SEQ ID NO: 55





atccatttatttatgtccagtacaagacgaccgttcatatcttcttagtcattttctttcagccggtgtactctttgttcaattttctctttcttggtgcaa




cctttattcacgtgtatcttctccgagcttgtttgcatattttttttttgaaatttcatgtgctaatttattcatgtcatttttgaagttaaactcttcaca



tttcataataaatatttattgaacccgtttgactactccaaattcacgaagttaccaaaataaaagtgatatttgactttcagaaataccatttcaaattc



cctaagacgctcgggaaatattaattactgcaatttatattctgcttgtatttttcgaagttgggtccaactgtgtgaagtattgtaagaatcatatc



cttctccttcacattctacataaacaattcatttctattctgtaaattttttctgatgatttacggtaaaaacgagcgaaattcggtccgggacaagg



gtttctacgacgagtccatcgtggtgccgctcgcttgtttgaattcccgcgtgccgcattcctcgtgtcgagacccgatgtccaactgggggg



attaccaactcgggggattggccccgcccacagaaccgtggcttgcaattttttcttgttaattctcgctctattgagaaaaaataattttaaaac



cgtgcggcagtttcaaaaatgggcgtattgcaagccacggttctgtgggcggggccaatcccccgagttcttcgggtctctaaggaaagg



attcgtacattctggtcctttttatttatttttaacctctttttatttttttaaaccgcaatccattaccagttccattttctccgtactcgtcagtgtagcg



agtgacgagtgaaattgaccccatttcttatcttatcgaaaacaatctaaatagtttccgcattcgcataaccagaaaattcttcggtagtcgttc



tcatttgtttttatttcatgaacataaagtaacgccatagtctttttatgaaacgtggcgttaagaaagctctcgaaaagtctcgatttctccagca



ctaatacacgtcatctccgataagtacacgttgcataggcggtcctaataaaagcgaccgcggacgttcacattcagttctttgttttctttttgt



cgtctgcactccttctttgcgacgtgtattttgtgttcttctctgtgtttccacttctcgttagtattctcgcgcttctactctgaaaggtttttcttctta



aatgttctcatttttcagccactcagcgaacagttgaactgaccgctcatcaagagaaaaat



dnj-27




SEQ ID NO: 56





aaatttcaacttccggagcccgatacctataggccacgtgagaactttctcaggagagacgcagagagacacaaattgactgacgaggag




ccaggagaaatgagcagaaataaatcaaattgaagagtttctgaggagttcttttttctctcttccacttcatcctacccgcctgagccaccgg



gggaactgacaaaagagagctgtcacgtggttccagactgtcccattacggtttgatctacaaaaaatgcgggaatttttttcccaaaaaaaa



tgtgacgttagcacctatcggttagccatacgaaatcagttgagaagtctgccgcattttttgtagatctacgtagatcaagccgaaatgagac



actctgacaccacgtgagatgtgctcattgtggccgcgagagtggtgtcaaggaatatgagagtacatatggtaattggtgtataccataatt



agatgggaatttgagagcttttggaggaaggagagggtttttcggcgaaaaattagtgtccgaaatgagaaaaattgaaaaaaaatgcaag



ttttcactaaaaaactacactttttggagaaaaattggaaaatctgccagttttcagtgaaatcgagtttgaaaaaataaaaaattcgagaattttt



ttttttaatgaaagatttgtgctcgaaatagctgtaaaatcagcttaatttccgaaaaaaagatcgtgattttctcgaaattcattttttttaatttgtaa



ttttgatttttccacacaatttcaagctttaaaaatgttaaaagtcacctaaaaagtcgattttcataacaaaatacctagaaaattgtcgaaaacc



ggcaaatttcggcctaaatctacttttaggcagattttaagttgaaaaatgcacaaatatttctaaaacctgacaattcaacgattttttcctagaa



aaaatcgtcgaaatcgactttttcgacttttcagtattttttcagtagaaaagttcacaaaaatgtccgaattcgacggaaaattcaaatttttttttt



ccagaaaaagtgctgattttagccgaaattgggtggaaaaatcgaaatttcgacgaaaaaaatccaattgcaattgaaaaacattgattttcgt



tcatcgaagtatcctcttttgttattttccacttttttcccgcaggtattctctcgccattcaccaagacatcacacgaatcccggagacgcagac



aactgaagagacccactttttgtgtgattcaaaggggtcaacgcatatagccggccgattcgtgatgactcatctctgtgttattctataaatctct



tgatttttttgaggatttaactcttttttttcgaaaaaaacgtgtttttccgaattttgtatggttaaaagtatcggaatcaccgttttttgttgatttttt



tctcaattttcttttttgtttgagtaatgattaagaaataagaacggaaagaagagaagaaactgtgaaaaatgagagaaaatatttcaaaatca



ggaaaaaaaatcattttccaaattttcaggatattatgcggattattagggttagaacacattttaaattataattttaattatttttaacattgaaaaa



acaaaaaatcatccgaaaactactcttctttcacaaaaatcggtcaaaaataaaaaattgcgaaaaaaaaacaaaacaaattaaatgtagcaa



gcgcgctccattgacaaaatgccgaaatttttgcgagcgaagtttgaatttcgttgcaacatggggcatttttcgtgaaaaacaagatttaaaa



gaatttatactttattcttgctcaagaaaattaatttttccataaattctattaaaagtggcagttaaaacaacaatttctaagattttttcacttttttttt



ggcgtttgcttgtttttcagagtttggaatagttttatgtcaaattttgatttcttctcattactttcttcataaaaaaaaatgcaaaaaagcaaatttta



tcactaaatcgttcaatttccacctagaaaagacgaatttaacgcaattttccgattagagcgcatttgcattgtgcgggaaattcaaattattca



aaaattctcctctagtttccagttctagtacaatcggtggccgagtttttttctttttttttccagcggccacatagcaagagccaacctgtatacttt



tgcagttcttgtgcaaatctgagctccgccgagcacaaacaagtttggacagtccacttctctgcgtctctcgtgatgagtgtgctctctcgtct



aacctctaatccttcccagatatttgcacatctaccccagttccacatagccataaagacttgggtcatttttatcgattttttcggtttgctcacaa



tattgtgagtttcttaattaggtcttggtagctttttggagcattttgtgactttttatgcctaaaaaccagtttaaatatacttttttaatgcttaactag



atccaaacacctttgaaaattgtccaaaaaaattattttttggccgaaaatttcagtcgaaaaaagcattttttcggcctaaaaaaaattccaaaa



aaatccctaattttttctgtatctccagagccactttttaaggtataaatcagcaaaattttccgatcaaaattccatttccctatatcttttccctctct



ctatctcaccctatctcgtgcgttagccgacgtttactaagtcccagtcagtttaattctatcaaattcttcacttttacttacagaaa



dnj-7




SEQ ID NO: 57





atcacacggttgaaaaaagtcgaaatgaatgaaaacaagggcattttggaatttttttaaaagaagaagtaaggtgagttaaaagaatgaaa




agcggcgtgcttgagatctaatgaaacaagggaccgcccttgtttgtgatttgctaacaaccgctatcgtttgaaatattccgggcggagttct



agctgatttctacttggagtatcatagaattggaaacggaacgaaattgccatagtatgaaacttttaatttgtatatacaaatataatcgaccca



tttaataggcctactgcggattaatttcagtgctccttctaaaggcagacaatgaaacagttgtgtagtaaaaacaatgttcacaagacctgaa



acaattttctgaaaattgtttgataatattgttcaataaacataaaagatggttcacaaaattaaaactaaattaaaaattaataagaaaaccagtt



gtcacaaacgcattcgcaaccaaaaccgctaaacgctattccaactaaagttataattgcattttttgcaattaactgttttaccacaaaacaaa



acaaaattccagtttaacaaattatcaaaattccaataagatccttttttaaattaaaaaggtgagatttttctagagagtccgaatagaaaatggt



aaccaaaccgatgacgatgacaatggtaatcggatcaatgcagaagttgttttgaaattattttcaaagtcgttaattttgagaatatttgatttttt



ttagagtatgtactagatttgttctctacctcaaatgatcaaattctttgactgcattaaaacaaaattttggcaaaattatcgaaaatctcagaga



aaataaacaaacagtctatcacatttcaaatgaagaggaagccaaatttgaatatagacggtccgatgaagaattttttgacaatttattttaactcggaa



tggttattaaatttgatttttttaaatttatatttcccattattttaattttttaatttatgaaactttttatgtgaaaaaaaaatttatgtgtttttgatt



ataacagattttacgtcagaagccgaaccatctttaataaaaaatttgaaaaaaaaaatcacttctacaattttcatttttcaaatttgagccatca



aagtcaattaggaaaattaattctttcaatcgttgcagttacagtgctatttcaggatctttgagagctcgccgtgagcttggttctggagattcg



cagataaaaattcatgagtaaccgtttcaagacatgggctatcaaatggcataggtctcatatgcaagtccgattggcatcttctgatggttcc



ctagtgagtttattaattcacaagagcattgtatcggaattttggcaaactgttaaaacggaattatatgctttgttcagttttgtttcagtgtgttac



acagttaattgttttagaaaccattgcaagcaattataactttggtgttgaagtttagttgtgaatgagttcgtgacaactggttttcttattagtgtgtat



attaatcttgtagatcatctcacatgcttattaggcagtggtcatttctatttaattttgtttgaaagggttttaattttttgattttttttgttttgtttt



agcgaactcaaattgaaactaatcgccaaattttataataaggccttttcaaaacatttgatcaaacggaaaagttttttcaaaaaataaaattttgc



agcggcttaggcacacgaacatccgacaggcgattcaattgtatcaaatacttagtgcttctaggcaaaatgtagattttagatataaattaag



ccctttttcacagtttgtaacgccagggaaaacatttttgagcaaattttgaaaaatcttatcagaaaaatgttttgattgggttaaaaaaacacct



agaaactctactcctctttaatgaaagcttgtgtttcaaactctttttgtgcttaaataaatttttatgcaaattcataattttaccaacttttttcccact



gaaacatttcaaacataatgtcaagtcgtacaaaatcttataactaacgattttctaatcgtatctcctgttatcgttatctttacaatcgaagataa



acggctgagaaattttaggtccgaggtacaccactacgcacaattgcggattttgcactatttggagagttgagccaaaactgtcttacttttta



tgaaactgtggaatgttgtaaacaattggtgaatatatttattgtaaaatttttatttgaaaatcatattcttttgtatcgaattttggaattccacgttt



gaaaactgcaagagcgccttatgctgacgtgtgttagttagattgagagactcgcacggagtagacgcagacacaccacacagcacaaa



cagacgtcgacgtccgcaattctcgttggttatcgactcttttgtcccattccaccaccaaaacttgccacgatttgatgttgctaggacataaa



ggtccagtgggaaactgcaaattctttgttttcactggtttttttccatttgttagttactagcttgataatttaaaaatgaaacgtctcaaaactagtt



cacttgacctacttcgaacaccaatttgtatcgtgcgtcatattccttgccgttgcaatttcacgtgcacttttatgaatttcatagattttttttcaga



taattaaccgacaaa



Y41C4A.11




SEQ ID NO: 58





Ctgttgcggcgcacctcgaagaatagctcctgttgggacattttgtgatggctgaagtaggaaattatattaaatttacattaaaactaaagaa




aaaatacgaaaaattatgggaaatcagtggtaaatgcgaaaaaatgatttaaaaaaccgataaacgttgaaaacgcgacggtctccaaaat



aatgcaagcgtgctccactgcgaatcccctgctcatttgcgcgcgcattcaaatttagatttccccgatttatcgtgaaaatcgctgccatctga



caccgcattgcaccgaagatggccaaagataaccaaaaaaccaatgaatcattggtctatcgaaaatacattatattttgttgggagcagcc



ccacgaaagccacgagagcccgcaaaaaggtaaatattgacttaatatttgtggcggtctcttacttggttccacttacttttaccaataggca



gttatttttgcgttttgtcgaaaaaatcgatata



arf-1.1




SEQ ID NO: 59





atcgccaaccaaggaaagtagtgatctacaagttttctctgcaaaaaaaacaatcgtaattgcataacatctatcgaactcgagagtctccca




aaaaatccctccaaatctttactgcatttgcatgtaaagattttacctatttttctaaactgctgtgttcctgtattttcactctacctgtttcgtttattta



tttatttaagcatcaagtttattgaactctaataaattctcgggaaattcgtgtcttaattattcttgccagggaaagttacgtttccttatcgaacac



ctgttgcgaaaccagaaaagggcgggtctgactaagtgaacaaatatttcgtaataactttcttccaacagaaattaaaacacgcaaaaaac



ggccaactcactagctggaacgtggagccatggagatggataaaataactctgattgtcgacatagcttcaagaatatcgtattctgcattttc



aaaaagtctttttcgttcaaa



lips-11




SEQ ID NO: 60





gcataaaatgtttgaacttggcatattataatacaaaaacaaaaattgaaagagccaagaaatgggcggagcctattattgattatccttgtatt




ttgcaaaaattgttgacagatgattttttttccacactaactctattgggagtttttcaacaatttgatatccaaaaaaaagaggaaaatccgctaa



caatgtgaaaaactagcatcataatttgaattgccgcgcagtttcctggcgttccagaatgatctatttgtatttgaaagaagacctttgaaatag



gcatctcaaaatttgccgagcttggcaaattcggcaaatttctgtttccaataattgccgagcacggcaaactcggcataatcggcaaatttgc



ctggcttcgcaaactcggaaaaatctaagaattttgatattttttggagcacaaaaattactgttacactaagaacacgtttgcttggttggaaat



gtccgtgtggttcaatttcatgccagtttactagatttttggagccgaatcaagagttttagtaattgtttttctgttcaacttttggtgtacgcggca



aatcccgaaatttgccgaactcggcaaacagcaaaatatgaaacgtttatcacagaacttgttaggggatttttcaaatatatatatatttttttaa



ttcttggaaaaagcttgtctacctcgaaataccctaaaatcattcaaaaattttaaatattaccattgagagcaaatttacgggcctctgaaatag



tggaaaaatgaaaaattaactgaaagttaatacgaaaattttcaagcttgtaaaagatttttggttgttccggaaatcggataatcggaaaaca



gccacccttgtttctgactaatgagctaagaaattgattggtacttccatagttgatgaatgttatcagtaaaatgggtttggcaatgcttttgttat



tccaccgtgatataaactgaaaagcacaactgataagatgaggcacctgagtgtctagacatggcaacggaagtgggcgggattggaattt



ttgagacgtggcttaagttgtataaaactgaccggctaaattttaatttcagtgagtttttgagttttccaattctcacccaaattccacattttatgc



atcgcctaagttttttttttaattttaatttttttttccagatcccga



srp-7




SEQ ID NO: 61





gcttggagagcatctatggcgtcttttcggaatatcaagtcagtcacgaagtcttgtgccaattcctttaccaatcgttcgaatctggatcgagg




aatgagcagttcagtagactgttgttgttttcggatttctcgcagagcaactgtaccagaatgaaaaggatatgatcgtactggctgagtgcac



gatttgcggcatactcccgaaaggttctttttgccagccattgtttggtagatgtggtgtgaaatggagagattgtaaacccttctataggtgcc



aaaggtgagtgggcgtagcttcgaagtcaactgcggtgaagggggcgtggtttcttactattagagaaactgtatcagactaactccgataa



agccatagtcagtgaactctcaacatagttaggaagagttactcagattaaataaaatcgtcaaagaacaatcaggccaattctgggctagg



catagttcataggcagaacttggtagaggaaatcagagtaaagtaacgatgattttaatttttccgtctgaaaaaagatattgaaagcattttgc



cgatcgaacaagacacccaaagtctcatgacgacatcccagaaagagtttcagccaaattcccaacaacagcctaaaggaaaatctgaaa



agaacaaaacatttgaacgtgctagagcgtacttgcacatacttgcacatactgtaagtcaacatagaactctactcataagtgtgacaaattt



gttacaccaacagtacgaagccaagatttgattaaagacaattgttgtttaaactgcttgataaaaggtcacatggttgcaaagattgccagag



cgaacgcaaaaattgctctcgctgtgaaggtggtgaacactgactcagcaaagtcggaaaacatgatatgatttgtcttagtttattggttacc



tttatccgaaggtgcatcaagttgcctattggcgttatgttgaagatgactgatataatacattgtaacgatttcgggaaaaatacatatttaaca



agataattatttttttcgattttccgaaaaaatggaataaaagaaaaacggacattttcgatatttttcaaaatccaataaagatcagcatttttttgt



atttcaatttcaaaaaaaaaatcgaaattaattttttaaaattggaactcgagttcctgctcaatcctggtcaatgattaaattaaattatgctcgta



cagtaacttgttatttctgtgtttaattaaaggcgcattactgatgcgatttgggtctctccacgattgcactctgttgtgttatttacttttatttttaaa



tattttatttgttattttaattcattttccgcatcattttttcaaggaatttcattgatatttatgccattcgatttaaatttaattttttgtcgttatttt



acgtcgaacaatgagtcaaacacctaattctggttatgcaacgtggggttacacccttactatagtatatatatagaatacttgcaaaaattgttatattta



cacttcgaaaatcagtccgaaaaagacgtaaagcaactttgcctaatgaactttttttaattaataatttcacaaaaattgtgaaacttgttatttct



cttgttttttgcctttgaattttaaatatgtcgaatttttccaactattcagctgttcttgtcgatttttgttaatttcgaaactagttcagtaagaagtgc



gaattcagaaagaaaaacaaatcaagagtattttttatttcgtttttctctcaatttctcttcacttctctcccattttagtgcatgtattttcctcttctct



cttcttgttgtctagtttagacaacgcggtcactgttagagagtgcagacggttagcgtaacaaacaaaaaagtagaattcatttttggcgttgg



aaaccgcattaaatactgtcctcacagtttccgttcgtcttaatttcaaatctttgctcttg



ale-1




SEQ ID NO: 62





ctcgttttcattgttggcttcgattattggattttataaattatggtgatgtagttttgaatgtagacaataaattggaaatgaaatcgatgaaatgct




caagtttataaatagcaaaaaaaaaaacatcggtagactttatttgatctactgtgaaaatgttttccggcaaatcggcaaattgccagaattga



aaatttccggcaaatcggcaaaatgccagaattgaaatttccggcgaatcggcaaaatgccaaaattgaaatttccggcgaatcggcaaaa



tgccagatttgaaatttccgacaattcggcaaattaccacaattgaaaatttccggcaaatcggcaaattgtcagaattgaaaatttcggcaaa



tcggcaaattgccagaattgaaaatttcggcaaatcggcgaattgccagaattggaattcccggcaaaatgctagaatttaaattttcggcaa



atcggcaaattaccagaattgaaaatttcggcaaatcggcgaattgccagaattgaaatttccggcaaatcgcaaaataagcaaattctataa



aaaatatatagcgaaaaaatttcaaaaaggcactgttttaagtgtttccgtcttataaaaaatcccttgaaacattttcggcaaatctgatggcaa



accggcaatttgccgaaaatgaaaatttccggcaaatcggcaacatgccgaatttgtcgacaaaaaatttgccaaaaggcaattgatttaact



agttttaactaaatttgagtttttcatcgatttcatctcatttcccatcttcctgagttgtattaggcttcacattacccccttcaaagtacggtagcttt



gaagaccattttcattgacacatagctccgggtcgaataatgtatcgttttccaccacctttcgtcaataaatcatttacgtcatatcgttttttgca



agcttatacatatttctgtgtaggcggcaactgagactgataaaaaacgcattttctaaatggttttttgatgttgttggactgtgggaatggact



atggaattataacaatctggagagaaaagagtgcccgagagaagcagagaaacaagatgaacgtggcatacgtacacttccacaacagc



agccgtcttgtggcctatataaatgaccagattcaagcggccatttatacttttcgatcttcttcttttttcctttgtcttgagattgaaatttgagag



ataacgaatccaaatagacaatatgcacttaatttacttgaaaatgagcttaaaactcacaaaaaaaacaaataatttggacttttttgcacattt



cctgcaaaatttgatgtttatccagcttgtgatgaataatttttgcacagcaaaatgaattttgtggcaattttaatttcaatcttccatccattagtttt



cctggaatttttttgttgaaaattctgatgacttggagatttaatataagctttttagtcgaattcctccgttttagacgtctaactagttaaaaatcgt



tcaaatccttttaaattaattagtgagtaaaattcaaaaagttccagaaactttttatagttcattaaaaatgtattttttcacacctagttttaatttaa



aactcacgtggtgtcaggatgtctcataagggtttgatctacaaaaaaatgcgggaatttttttggaatcagttgagatctgaactcccgcatttt



ttgtagatctacgtagataaagccgatatagcacactctgacaccacgtgaaaacctataaattctcctaattcattttgttaatctgatcccagt



gacctctaatcttgatcattttatcaccacgcgtacttctattttgcaaagacctatgatatcagttgtctgacggtcagaaagtctcggaaaaag



gcgttgaccgagtaattacaataaaaaaattaacgatataaaacgtcgaatagccaaataggtagatagcgtcagaaaaaccaatcagtgat



ttgctccgcccacttttcaaccaatcagaagggtttactgggcggagctatacgttctcaatttggaaaaagttcaaatagtgagattttatctttt



tttttttgtagattcatgaataaatttcagactaattcgtgttttcattctcgctaatttagctttattacgcgaacactaggttctgagaatgcgtattg



cacaacatatttgacgcgcataatatctcgtagcgaaaactacagtaataattcgaatgattactgtagcgtttgtcacgatttacggggtcgat



tatcgaaacggattaaaatcatttagttatctataaaattaagcaagaaaatgaggaaataaaatggaaaatatattcatttaaataatcaaccc



cgtaaatcgacacaacagagctacagtagtcatttaaagggttactgtagttttcgctatgagatattttgcgcgtcaaatatgttgtgcaatact



caaaaattgtgtgactataataattagctatacaattctgtggtttttttgagcaaaaccgaaaaacgaaaaaatttcgtttttggcaaaacactcc



aaaatcggtatttttcattcaaaaaaccatattttttacggtttacgccctatttcctacaaacaacagaaattgaacgtggtgtcagagtgtctca



ttttggtttgatctacgttgatctacaaaaaatgcgggagaagagacgcagagttctcaactgatttagcatggttaagagtgtgctgacgtca



catttttgagcaaaaaattcccgcatttttttgtagatcaaaccgtaatgggagagcctggcatcacgtggcattagactttttgagcaagtttga



ccaaaatcttttttcttcgatttttcggttttccaaaaaaataacgccaggcttagcctccacctcaatattcttatgtgattgtttccagaacctcttc



cccactaaaaca



ckb-2




SEQ ID NO: 63





ttactggcatttaaaggaaagaactcggaaaatttatgaagatttgaagaaaggcacttgttaattgatgggttttcattgtgttttattaaatatga




agttgtgatagttttaatgtgattaaaataaaatttaaatcaactatcgtgaaaagtttaactacaaaactgtattaaatctgagaacacatacttta



taagttgggaaattgttgatcaagtctaagttgaactaatatattcttgatggaatcggaccgaaaaaatcaatttatcttattcagaaaccatctt



gagaatgcctacattttggcgcgagaatagcggcagaagagagagctagaacggtaggcattctcatgatctcatggtttttcttatacatttt



ctttttttctgccgtttagtttattgatctcaattggtttgttggtctccccctccccctgtctgcggtcatttagtccaataagtcaacgtgtactaac



tgcacctggactttgttcacttcctctataaaatgactttttgattgtcttctttcttattctatatctactttttgaatttgtaaattttatagctacaat



ttcactttgaaactgtttggtttttttttcagaaaccatacaattttgtttctccaaac



fipr-24




SEQ ID NO: 64





tggaatgggaatgagaagattcggatacgggtacccaatgtggggataagctgtgcaatcactactgtgtagttatgtataaactatgtaaaa




ttgaagaaaataaatattttgactacctcaatccatgttgtcacactgtaacaagaaaattaaaatctgataagcttcagctaaaaactcaaaact



aagattctcaggaagatatttgggtatttgaactaattttgaccgcttttcatgcacacgcaatggatttctaagtatccaagtatgattatttcata



tttcgccacttagaatccagaaatttcaggagcatatttttgtgatacaaaataacgtatttctgttgcattaaacttctgtctaaaactgttcggat



ctgaaattgaaattagcatttaactttttgttccaactgaaataatgtattactggacaaaaaaatattaccatgacatcttgcttcttttggagaata



ataaaataccttcagttatagattttaggtaacaaataccatatttattcacacaagttgatgaaactcgttcgatattttaaattaaactgcctttaa



atatctattagccagttgttgtatggtcctatgcacacactatcttgtatctatagtttaatatatgcggcctatattgtgacatatattcttcccgttt



gctctgttgttctccccttcctgtataatgggagattgtaaatgagagttgttctggtcccaatacctagccactgagaaccctcctcttctatcta



ctactcatttatattatcgtcattatttttatttttatttatacatatagtgggcttatcaacatatatgagggtaaaatacttataattaatcagcagttc



agaagaaaaaacaatgaatgataaggaaatttttagagaacggatagaaaagggatcttttgatttcttcagtgacactgttatcattttcgaaa



attgggtatgacaatggagacgccccacaatggaaataacttcaaggttatccatatatactgcatacatatccacaatattatgaggtttctct



aggaaactgaaagaatcctagtgtttgaatgtgttgagcatattaattttaagaagccaagaaaccataacttctgataatgactgatatctagg



ctgtcacgagggttgcttaaagtgttacagttgtgccagtaatattaatagctcaatttctacaacatacaaaccattatggtaccctacaaaca



ctacaaatggtttgaaaccttgttgtttattgtttttactgaactcttatccacctgatacctaaaaaacgtcatgttaagagaacaacaccgccca



ttttgaatcctttataaccactgggagatgaccggatttccaagtactcgtagttctaaaaacctttaaaaacccaaaaaaaag



arl-7




SEQ ID NO: 65





catgttttctctgcaaaaaaacaatcgtaattgcataacatctttcgaactcgatagtctcccaaaaaattcctccaaatctttactgcatttgcttg




taaagattttacctatttttctaaactgctgtgttcctgtattttcactctacctgtttcgtttatttatttatttaagcatcaagtttattgatctctaat



aaattctcgggaaattcgtgtcttaattattaatattatagttattcttgccagggaaagttacgtttccttatcaaacacctgttgcgaaaccagaaaa



gggcgggtctgactaagtgaacaaatatttcgtaataactttcttccaacagaaattaaaacacgcaaaaaacggccaactcactagctgga



acgtggagccccatgataactccatgataaaataactctgattgtcgacatagcttcaagaatatcgtattctgcattttcaaaaagtatttttcgt



tcaaa



F07A11.2




SEQ ID NO: 66





gcacaagccgccgtgagactcgacgataccacaaatttcaacgatttcttcacaagcttcaataatgacctcgggctcgatcaggaatggatgg




ttttcatcaaagctttctacgcagaactcaatctcaaagtcgaataatttttatttcattgtttttttgtttgatacctgttttgattaccattttttatca



ctatatttctgacttctttctcattttttttaaatttccggtcgatctttcacagacacgattgtatccgtgcagtatttgaaaataacaaatttttctgat



ttctgtgggtttcacgtgaagatcttcttcaagaagaggtcatcagattgcggaagatctatattaccgatctgacgcaagactaccatgtatat



ttggaaaggaaaaattttctgtgcagaggttgatggtttaaattttgatttagatattttcttcatttaatttgaaaatttccatgcctgaaaatatcct



cagtgaggattctcacctaccgtatacttaaaggcgcacacctgtctcaaccggagcgttgcgagacccgcggcatcaaactacacactgt



gttttgatgatctttcgatcgttctcgaaaaaagaaagagcagagttcattaaaacaaatggcggcaaaatgtctataaaggcgagtcgttctc



ttcattatcttttgattttcgatgtgttctccttattgttttgttcgttgaccccttatctgcattctcaccgctacgcaacgtatatttaacgtcagctttt



tcgcagaaaatttttctatattctcatgcaaatttactgttctcaatgctggacgtgtcgcttgtgctttgatctcaaatctaacattttcccttcaaat



attttatatctgcaacggtggggcagaaatttaaaagttgacctttgtcagccaactgctatcagttatcagttggccggagatctttctattttca



ctttcttgcaacgtattcagacattttttgatgaatcggttcacagaattttcgtcctgatgttggtcagtgatgcgccagccggaaattagaacc



gtatgccgttatcaatttttcaaaggctaaaaagttatgaggtgtatttattgttttaacacctgacctgctagtaggaaggaaattaattttatgttt



aaattgaaatgaaagagtcgagctccacgtgtcgtctccctagtttctctattcctcttcttctccgcctatctctcggcttctctcctttcgcgctc



ctctcacaattcctcctaatcgtgctgtttttggggtggtccaacacggcaaaaaaggcagcaaaaagtgtctgccgtctcgtgcctctttctta



ttgaaagggcacgagagaatagtatcaagaggctcctcgttcgggccgttgaagatggtatctggtgcttcggcggagacgggaggagc



ggccgtttctcgggtcatcacagcccattccttctaatgtttacactgaacttgtcgcaatccctcctctaaatctcattcatccattcattcatatt



cgtgttatgtgttcgcttttacataatttccattttcaccacgtttctcctcaaatttgcattatttaaatctctgccttttcataaacatttataattttc



agggtatcacctatactaaccatccaaa



C04F12.1




SEQ ID NO: 67





aggcaaacatcacgtttccgatatcaaaagacattgaataaaagaaaaccaatagaatgtaaactattaaagtgacaatttcagtgaaatttat




caaaatacgaaaataataaaattaaaaattagcgccagctaactatttagcagagcaaatacgttttgacccaatataaaaacaataatatgaa



aaaaaaaattaaaataaagttttaccaaatcgatattggcaaaacatcttgtttttgaggctccatatctctgcaggaaaaaatcgcactaaaaa



gtgatcaactagaaacttgttaaacacaatgtaatctaaaacttttcagttgaacactattttgtaaaaaatttcgttgccaagatatagatctttaa



ctatttagaatattcaaaaataatgaagctcaaatcaattggttccaactcggcaacgaaattttttacaaaaaagtgttcaactgaaatgttttag



atcacattgtgtttaacaagtttctagttgatcactttttagtgcgattttttcctgcagagatatggagcctcaaaaacaagatgttttgccaatat



cgatttggtaaaacgtcttgataaggcatcagaatcaatgattcggtcattgaaaataatgaaaaataggttatttgtgacactctaaaatatttc



atgcattttttaaaaaatttcaaaaaaaaatttttcgatcaaattttctcatggtggagaaaaaagtgacaattttcgaaaaaaattaaaatttctga



aaagtttccagggtaattatggttcaattaaaaagcaaaaaaattatgtaaaaccctcaaaaaaatgttctaaatacttgtttcccgttctgaaaa



ttttgtataaaaaaggccaaaagttaaaccatgtatgggaaccgaacccacaaacttctgctcaagaggcgaacgcgttcaccactcgacc



accgaaccgatgttttcgcccttccaccattgtggtgagacttctgttggcgccagagacaaaaatccactgttaaccataggaaatgcactg



atttcagtgtagaatttcagacgtaaaaatttcagatttccagcccgaacgggcaaaaatttcagtcatattcttatagtagagaatgtcagcttt



ccgatacaatatttttttttgaatatcgctccatttattctggtcattccctagtcagttgcctgcccgtggcggaggaagaacataataggagga



tacgcagagatgcagaaaaaaaacttccgtttgttggtaggtagtaatttctccttttgatctccaaagatgttgggaaattcgccttttggaatg



ttttatggcgcactttttaacagttaaatacatagccacactttctatagactaaacaagtactcttgacatatgtcattcatcatgtactctttagatt



ttccagccttaccaacctcctccacagtttatctcattgattgtactctttgaaggaggaccattggttctgacttttttgaccttatactgattcaaa



atgtcatcaaagacacgagcttcgtaatgagacttcagaaaaaaatttctgaacatttttatagcggttcaaaaattctaggaaatttagcaaatt



ttagctatagctataggctttacaaaaccttcaatttattttttttggtcagatacacgatctcatttcattttgctgattaagattcatttgaagctgag



aggtaaacaaaaatcgccggaaattgtaaaaatgccagaacctttatacaacctgtatgaaggttcaccttacaattatatctgtgtttttcactt



gtttagaggagtggtaggtggaagacattaaagtgtcgttctcgtagaactgttgtttggactgatagcttttaaatacgacttttttaaaaacttt



ttgagattatacaactaattgcaccatcatttattttttgccgatgtgcaactttcatattgttttttctcctcactttctccgttgtccttgttcataacac



aatttgcaaatcacattgaaatttcagatttccgattctcgaagctttactaacatctccaccactaaccaagcctcaac



hke-4.1




SEQ ID NO: 68





aactttttgcaattcctaaatacttaccattatttttgcccaatcaggttaatgatctctatcgtgtagttttccccttttagttccagttctgctgtgata




tttatttatttttgcgaatacatttcaattcctaacttttttcggaatacaaaccagtaactcataaaatgttcgatttatactcacatccgcgcgaac



acttcagtgccgggtgttataacacgtcagcgtttcgccagatgatgcaattggcgtttttccttggagaacaaatagcctcgtagagacgca



ttttatttccacactgcattggactcaattggtggtgtatttgctttgaaggtgaatttaaattcagacttttttttcgaaacttgcgcagaaaattgt



gaatttttcgatttttatagtggaaaataggtttttttcaaaatatttttattgaaaattaaaatgtttgctttctatgctctattattgccgaagaaatca



attttaatgaaatattcaaagaaatcgcggaaaattttcaaaaaatttccacgattttattttgtacgcaatcgcatctgcataccgtacccggttt



cgaatttcgaacttttcgaagcttttcttgaatttttttctgctttccaattagaattaaaagtgtaatttaatcaaattctagtaaatttcaaacaaattt



gggattaaatgttaaattttattaacattttcaggctttaaaaaaatatttcaaagttttgtgtcaaagtctgcaaacactctcgaataccgtaacctt



gcatcttttttaattttttgttttctttatttttatcactcctatactttttctataatttaaagcaattttataatatatttttacagaa



F22E5.6




SEQ ID NO: 69





tgctagcggtcaccactatcgactgagctatctgcccctaagaaagtttaaaaaacttaccgattttgagttccaacatcattttctcgctattttt




gataacgttttggttagcattgtactccggcagtattggtaggtcattctcgttgtttggagtctttatttcagactccacgacggctggagcaac



attctgaattatattttttaattattgttatactttttagcaaaaaactgacatttgaaatagatctactgttgcaaataatgtctggcaacggatccca



tctctcacttggcctgcctgagcctacatccaatcttgcaattgcttgctcacaatctctcactaatttcaccaatccgtaaaatctggcttcccg



gagcaactgatgtcgggttctgaaagttttatttaatttataaaactttaaacttctagcttaaaacatctaccatttcctgaatttcaggcaaattct



tgaagtatccatcgaactttgttagagtcgctttagaagtgacaaattccttgccacctacattgagccggagcatttactttcagaaacaataa



cagtttgagtttatctggaatttgttagataactttaggtagatttgaaatttttggtagatcggtttcatcaaatttatcaatgtcataaataaacttt



gtagctataaattttaaaatagctttttttacactttattcaaggaaacactgagaaatagctgcgaaaacaaaaaaaaacatttgaggggaga



acctagacgcaggagagaaagaacgtagaatctactagaaaaagtgtctgcgtctcttcaaaaaacaaatttaaacttagcaagatgacca



ccacagcaaaaatgaaaaagaggaacgcggagggacagggacagggttcagtgagaaaaaaattagaaattttggaaaaatgagataa



tttttaaactttttgcagtattccaaagtttttcggaaaattgagacaaaaattttaatcaaacttcccatgaaaatgacagaaaattttaaaattga



aattaaatgaaatttctttattttctggatttttaggagtttctggaaatttcttagcataagcataagcctaactacaaactaaaaacttcaaactac



caactgaatacaattaattacctcatgattttgttcccagcagccgtaacatgttaaaaactctatgggtcctgtgagatgtcggccgctctaac



tctgcacattgcagagattttcagacagtgtgtgaccaattttaggctgaaaatctgccgactgtactctttttggaaatgttttgtttcgaaattttt



tactcactctcactataactccaactcacctggttgcgaaattcagcgcttttcaacgtaatctaaaatgaaaaatattcattccatcactcctcca



actccccatttttgtttgaaattctctgaaa



pdi-2




SEQ ID NO: 70





aagaacgccgacgacaacaacaaacattttcatcgggagccctggaaaatgacgaatgtatgcattaccattgttgaaatttggactggaag




cgcaatggatgaaaaaaccacgctatttcgaagctcatttctgatgctggggcacaacacaaaattaaatgagacgaggagggggagaag



ggatggagagcatgcatgttttgttgttcactttcgaaaaaatgtatcgattttttctagcaaatgtttgaagtaaataacaactttcaaatgtgata



attagttatcaattcagtcagtttatcaaaaaaaagtacgtcattagcataactttgccgtatttgcatgtctaggaaattttagaaactagaattgc



taaaaagtggtttaaaagttgcgggacgccgaaaattggctgagaaattgtcaaaaatttccaagtgacggaaaaccgtatgttattgtgatta



gtaagacgatttcgcaattttatatatattttgtcacaaatctgaaatcactcgtgctattttaggtgtaaaagtcacatgttattgcacaaacacga



gcagaaaatgaattaaaattaccttctcggtttttcagacattgtcttcaactttgtctaggtatttcgaaatttcaaaaaaactccacctgaccca



caaatcaatactagtaagttagtaaacacaacagtatgggaattggttgatatgtacgttgcgagacttgtttgtgcttatctttttcccctctctac



ttaacaatcaaataacctgcaaaacactatggatttttctcttcagtttggggcaattcttccagaaaaccaccaaaaaagaccgcaattttgct



aacggtcttgttcacactggtagataagataacattgcgtaggtcgatcctaccgatcaaacgggagatatatggggggagtaggagagaa



attacgggaagaaggctatcgagcggccttgacacggtgcttgactttttggcgaaacgtatcagttgacctctattatttgggctatacagag



atgaggtatgatggacagaaacagaaaaacacacacaaagggtattgatgagaatcatagacggtgacaacgccaattcaatgagcagta



gatgtgcaggagacgtgtctcgttcagttggaaacgaaggcgagacgtgaaaagagtgcgtggttgcgagagacgcagtgatagagac



aaactggataggttatgagaacgagaaccactcggactgaggccattcgtagaatgaagaatggaagttgtatctgtcttttaatagactcaa



atgaaactgaagaaaaaaagtacaaaacataagacactatatattttttttcatattgaaaaagagtttgcaaattttcttgaaattcaaaaattct



gtttttcgtgacaacactttttgcttactcattttgtaaaattttaacgtgggctattgtttttgtgtttaaatatttatactacatttttgaaaattatta



ttttcacattgccacgtgaactcaaaatttattcatgcaaatttagaataaaatctgttcaactaagcctatacgcctcgtgcagaagtccaaatttga



aaggtaaacctaaacctaaatttgatcatgaacactgagcctgaaagcctgtaaaccataggcaaagcctaaaaacagcttacaaacctttct



ctgaaattatgtctgaatacgtaagtttattatatgaactaagctttacagctaaatctatgtttgcaggctcagttttgaacgttaataactttcgaa



tccacatggaaatttagatataattgaataaaaaagtcctcgttaatatttgaaaaaaaatgttgtcaatttacgaatccttttttttcgcctaaaaa



ggagaatgtcaaaagtactaaataaaaaaacaaaacattcaagagcaactaagcagtttttccgaaattttttccaaagttccaaagtcaacct



taaccttaagctgcagaatttctgatgtttaccagctactacgaaacaaaaacgattctcatagatgatttcccattttcgcacacaaaatgttgg



catcacaaacaaagtgagcacaagtatggagagagatttgagagcacagacatcaaagaataaactatgttctttgttctttttaaactactttg



aaaaaaaacaaatgaatttacatatttaaaatgttgcaattgcaatttcatgatggaaatattggaaaatgtctataaaataacgcagacagtgc



caatcaaaagcttttctcatctacccagtcggttgagtgaatgaaaggaaacatataatatcaaagctggcgtgccaattcctttttgtgctcgg



ctgcattatttacactgccggtgtttccgcgctccttctcatcgacataatttccctcatttcctctcagtcttccgcgcagttccatccatcgcaat



ccgccttcttgcctaaatttgtctgacccaatactctaactaactttcatttatgtccaatgcattattctctctgtaggtgacccagtgtccttccttt



tttctctctcaagatgtgagacccccccccccttttctcctcaacggcgaggggctacgtgagtttccgctgtgtgcgacgcgtccttgcccg



ctcttcccaaactgcacggccaatggggtgccgggaggcggggtaggggcgggccaatcgacgcgttccacgactaagtaagcgtgg



acaccccatcgtctgcagaagaggacactctcgatccattcgctattcatcgtg



pdi-3




SEQ ID NO: 71





gaacacgttgcatcgataaatcgagaatattctcgaagcgcaaaaagaaatttcgcaactatttcagaccgaataatgtaataatgtaatggg




tctcttcgatagaaaataaacgaagataaacgaagacacaattcttcctgacgcgcgagcttcaatatgcacgtgatgactaatttggtttcca



tggtgatctttttgttccttttatcgattcaaatttacaataaaaataagaaattaaagttctaaatggcgctccaatcaatttgccttccaatttaac



gtcgattccttctatatcaggtcataaaatgaataaaaaacaatgatcaataaaatgatgcggtagttgcgtaaatcgacacatgatggtcgcc



tcttccgtgcgagacccattgggcggagttctcacaagaatgaggccaatcggcacacaacacgcgtgcgacaggcagtgaacgacgtg



tttttggctcagttcctaccaatccctggtgtacacacgagcgccacgtggaccttaacaattcgggtctatttttatgcttctgctctgcattttct



ggattattagtaataatatcattaaaagtgatataacgctccccgagtctatataaaatttctcctccatacaacacatgttttttggctttcttcttct



aagcttaaaatttatagttatttactaactgtattttccacttattaaagataatttttgaaaagtgtttgtaaatacttaaaattgaacccgaaacaat



ctgtatttgtccattcacatgtgattcacagaaaagaatgaaaataaatgcgaaaaaaaaataaataaagtaaaggcgcattgattttaccgct



cgcggtatctcgccacgaaaacacgtttcgcgtcaagcggctcacgttttcgatgcgatcgcggtttgttaattgcgaaaacaccttcccttct



cttcaatcgttcgctcaatttctagaaaatatttctgaataatctgaaaacctctaatcttgtttcttagtttttaactttttgtcggtgttcccgataatc



tctcgccctctaaactcactcgatcgattgtcgtttataggtaaagtttttaggta



itr-1




SEQ ID NO: 72





aataaaagatgtgatggtcaatttaggatagtaaaagatgacaggtggattgagggaaaagagacaggttacttctgttgagtggacacatt




gcaacccccggccaccaccgccacggacacgccgcccacttttgcggtgtgaggtgcgaaactgtcttccgacagatttgtaaatattacg



aggaagttgatgtaatacggaagaggtccactggatttatgtgaatgaagaatcaaaagattgtaaaatgtttagatatgatgagctacaggg



tcaaaggtgatttgatacacgattttcgagcagaaatgctgacttttcgaaatctcattgttgtttaatcaatcacgggatgtacgaaagggatct



tggttttggatttttgaaaatcaaaatattacaggaaaatataatgcaaaactagtacagactgtgaaaatgtttctaaccttgatttctgctccgt



ccaactgtgaaattacattgtgtgtcaatttcaaaaacggtacgtgattttttagttctggtttttaagtgaactttatgtatatgagctctgaaaaca



ggaaaataagggaaaattaataaggtagtcagaatgaaatattgcaattcgaacataagcatttagtttgaaacaacccgtatttcccttattag



ttttgtagcttctagtttgtcatgcactgattttccgacagaccggctatactctgtgggaatttccgcaaaaattaaatttaaaattaatagatgag



atgtggtatgtagttttaaaaaagtcgatggattcagaaaatgctcagaaaaatccgcgcattaatttccaaaactatcacatttcagaaaagtatca



aacatcatatttttggagtccaatactacttcttcatttcttttttttttttcttttccactagttttacaataaaatatattgttttgtcctaatgaagca



catttcattttgtaatgttttttaactttctactgtaggatattctattccgtaatcgtacaaatcttctttctctcccaaatttaggctgcgccctgtttc



aaagctctgctaatagtacgcaaaacaaatgtattcgctaactctttcgctcatttcggtataagtgtcacttggagatctcttcgtctctcgcaa



cccgtatttgtattgtttatcttccaaaatggtagtcgactgctcatatgaattgaattactagcgggatatgaaagagacatgagatttataaaa



agtaactgaatatttcaacttttgaaattgaacttgtatcattttcgaaactaaaatggaaaaacaggaacgatattacttcatttttccacttaaag



atggagtagcaaaatttgggtgattgtttttagaatcaaaattgatcctaaatacctattgagacaacttgaaaatgtctcaaaaattattgtatta



ggttagtcattctctaaaagaaaacgggcaacccttcaagtattaaatcattttgagcttgaaaagagagaacattgttcattaaaattcatgttt



gggctcctaaatctacaaaaaatatcacatttatattttcggcaattctgatttcctgtaatcgacaatttcagcgattgccgaaatcgtcgaaaa



gtcgattaccgaacggcaattgctgcatgctatgtatcacaccgtttcagcgttgtgtatcgtatttgttcaaagataattttcttgtaaatctcgat



gttattgactactgcagctaatacatttgaattcccattaattcctttaatttgataagtgtgacttggttcccgttgcccaccatcttttgttcctttcc



tcctatcttcaaatcaaacgcatctggaatctatttttttcattgttgtctgtctaccgatgccaacgatctgacctttcttaattggtattcgcgctca



ttttgacattgtgtcaacttcaactatttgcgcgggtttacctgcaaaaaagtaaacaagaaaaatggagatgaaatgaaagaatttccaatag



aaatttgttgttgaaaactctctgaaccatgagaccgtccaagacgttaacatcaaatcttttcaattcagaaacgtttcctctttttctccttttgtg



acacgtttcctccgttcttttttggagagtcactatatttttaatacgattttgctttacaatttcttttttaaacttttattgattttgtgcttcttattt



tccatttttcataaaaagtattccaga



T05E11.3




SEQ ID NO: 73





gtcgcgaaaggtttgaattcccaactggaaaaactgagattaagaaatggaggtatattgcctgattgagatgagaaaccggtttatgagac




ggataaacaagtaagtttgctgagtaacgatcacaaatttcacaaattctcaagacaagtgagatgattaatttctataaggattaatttagatg



atccgaacattacttgagtgactgttataatagaaagactgaaaaatcgtcttttaaattaacatattccatattgctggatccggcaaacaaaa



acaatgttccaggacactcactccacgtgttctgagctgtcgtctcggtcgttgattggctgattccgcctctgtttgcaactagtaacgcgcc



gcagtttgcagttttcagtgaaggacaacgtgtttgcaagagacgcagacactgtgcggcacttgcaaattggggcgggacttttagggac



acgtcgagaaggggtgagccccggcgaaagaaagcaaacaagcggagagaaaaggggagtaattgaccgttggaaagacacctcatt



ccatttattctcggtcgttaggaagagacggcgatgagattccttttggtgggcttcgtcgcccttctggctgtttcaggtatgtctttttattgatt



ttcagagcttagtgagctttaaatagaaaaccgtagttttgaaattgtaaaaaaaatttttaagcttaaatgtacgctgaaaatattaaaactgtgt



tcacagaataaaaacattaggctttattttttcattctgtgcatacacgccacgcagtttttgaattcacgtttttattcccaacaatcatcacttttcag



ZK632.6 (cnx-1)




SEQ ID NO: 74





tctgcggttctgaaaatattaaaaccaatgatggaaaagaatttattcgggataaggatttttgacaaacggacatatggcatatcctaatgtga




gcagaggagctgtggtcggagcaaccgaccgcaccggctcacttctgctgtgattcggctcggcgccacgaaaagagtaagagagacg



tgacgacggcaatagatgaatcgaaatctatggatgcaagaaacctcttttcaaatcattcgaacggttagaattgtgcaaacacggcgacg



cacaaacgcacatatcgtggggacacgtgaacgatggccgacttgagaagaggaagaataacagacggcgggagagacgaggaaag



ggcacaaaactgagatgatggtggtcgcaggcgctgagcgtgatctcttctgttctatttcagacaccacgggattgtattcaacaacattttg



ttgtttctactgatcggatgggatgattgtaattaaccactatttatgtttctcacgaattgtgacactaaatgtgaaaaccaatagaaaacataat



cgtatttcttcaaatctgatattaaacgggtagttctaattatgaaaatattgccccacgacgaagaattaatattaataatatttcttatttttcacct



gcacagacactatagttatcgatgatcccagttttatttggtctaaaaataaaatttgaacttctgagggattgttgagcgacattgatatggaag



aagcgctatcgataaaaatttctatcgttccatgacaaccaatcacatgttcaaatgactgaatgccaaagaaaacctcgaaagcgaaccgg



tttttcttccggtgaccgtttagatttttataaaatcttttagttagctgaaaatgaaatttattgcagctccgtgagaaaaataatcagatatacgca



gaaatgactgagggacgatacgaaaatgcgaagaatctgccttgcaagaggacagatgtcggtactcaacacgtacccaacacagtctcc



tataggattgacaatttatcttcagagcagaccggaataatattaacaacaaaaagctaaacttaaaaaccgaaacgaaagcaattcaaactt



aaaatgaaaactaaaataaaaagcaaaaaccgaatgctgaaaaaaaaattgtctaccgtacacctacagtaagattctgcatatttgcgtgacagtgt



ttgcacatgtttattcgaaaaatgtcattgtttttttttcgtttttacttttttcgccaatcatttagctttaccctagattttcattcttattttgttttc



caaatcaatcaataaacaataaattttgtgaaaatttacctgcaaacctccattaaaatttgcaaacccggcaaactgtcacagagagaatgaa



aaattgattgaaaataataaaactgcttggccagtttgaaccgattttaacaattaagcttaatttttttgaagtatttgcatacacaccatgcagtt



tttttttaaagttttaccgtaaatccctactgagctaataaattaaaaaatttcgattaaaacaagcatttatcacgagttctaaactgatatgagac



atatttaatttattccgattcacttcaactgatgaaaacttttgttcaaattctcaaatatatttcaatcgtatcacattttttttcggcagctgcagcga



atttttcctttcatgagccatgggcaacggcttaattacaccaacagccgttgtcggtgtttggatgtattgccctaaatgaccgcccgtacgtt



gtcctctccatgcaacgacgctgaatattcttctgctctcacactcgtatactagttgtggttgaggcgcctcgatggacagcatgagagaga



gtgtatcctataataagacgtagacagacgcgctctagcaaattctttaccgcagcactccacagcgttcgtcagtccgccttgtttcacgttg



tcgattgcagacacaatgcccctcattttctattcacttctcattgtattctatctgtatgtgcatagtaacttgttttacagcgagtaatctcaaaaa



tcgatatatttttccttttcataatattgttctgttaccttggtaccctcattattattttttgaatttaggtaacc



Y38A10A.5 (crt-1)




SEQ ID NO: 75





aagtgatgttttggcaattggaaaagctagactaggaatgaggataaattatgacatcattaggacttgtaatttagaaattacacggaggcaaac




cgtaatgcgtttttttaaaataatattttcttaattttttccttttaatttctgctcaagtttgtttgttggcaaaataaattatttaaaacttctcaaaac



tatttaaataggttttttgaaaggatgtgaaattccttatggaattttagatgatcttcaatttgaaaactgttggcagagtatcgccagtgaaaaat



ttttctaaacaaaataactcaaaaaaaatcagatctttcaaagttgtcagtagaagtttttggtaaattgccaaatgttccaaaaatgtggacgttt



tgaaaatgttgagcatttcagatttaagctactgcaatcttcaaataaaaatatttgaaacatagctagaatatatgaatcgcaaaaagagttttg



gtaaattggtatatttttcacaactgtggtattggtctcattcagttatacatctttattcttaactttgatataccgtactctaaataaactttcctatta



caaccacacttttaaatttcatatgttttcactcttcagaggtcaaaaattggaagaaattattaacgaaaaaaataaaaaattagaaattaattatt



atgtttttatgttcaatttacgtttcaatttttcgtatttgaaacttggcaatttaccaaagctttcactataaatttttttactttttctacaaaatttta



gtgtgttttactacgttatcctgtcattttagactataataagtgagtacagtattgttttcatttagttcatatttctatgttctattataattgtctgta



tctgatattcgatttttttgaatgaacatgagttttaaagtatatcaaagttaaaatacggatgtatagctaaaggaggcagtaacacatatttgaaaactt



tgatttcatgttctcttccttcttttcccacggcgttatgtttgaccacagaagcatctatttttggaatcaatataatttttttcggtgcttttagcaaat



aatataaagtttgggaactacctctaatgttcattttcatttttgatattctcccttgacatatcaaaatatttcgagcagtatgcatttccttatcatttt



tcaactgtatttcctgattttagcttttcatattaatcaagtaggttcatggtttcaataaattgtgggttaattatagatctgcctaatcttcaagcca



atgccttctacggagtattgccagtgtggatttagtttgaaaagtattctaataaaatactccaaaattttaagttagttttggcaaattgccaacat



ttggactttttgagctatttccagcattgccacaggaactgtcagaatgtttgaatacaaacagttgaaaatataaaaattgtagaaaattgtttta



ggtctactttcaaaatttttataggttttattataactaaaattattatgactaatttttcaccataaaaaattaattgcaaataaaaaatttcaaaaatg



ttttgaaacgttttactattttatttggacatttaagcactaacgtgttcaaagctgaaatttcaaaacgtcataactttgctgaaacttgacttgggc



agctaaatttttcggagagatcataactaacagtcttctatcggatattcaacatgagaaccccaaacctacgggccccttcaaagatttccctt



gtgaatgggcaattttaaataatctctccatttacgatatttcaccttcaaataaacaatgaattattctagattacttgttgtcattcagtcaagata



ttctcaagtattccaagttctccattgtttaatgattttgctccaattctatccaatttccctttgttcgctgctttagtcccgccaccaccccctgtgc



aaagagataacgtgtgagtgaatctaatagccagaatctggaaatatatatatgtttagaatcacaaaaggaaaatgtgcaggcggggagat



caaaatcgaaactgtatttgtgtggaacaatgcaactattgagagaaacatgaagcatatggactacgagttgagtaggcttcaaaagtattc



aggaatctcaaccaacgagttttgcccagaaattaccaagaaaccagtgtaagtttcattttattttttggatttagttagattttttaaataatcaa



aaaccgatttcttgccgatgtcatactgtagacactgtgagaagtaggactacctcaatattgataagtgcctacctatgtgcctagaaggca



ggtgtggcttgcattgaacttaacagtagacgtaggtctcttgaagttttgcttccaggcaggcaggtaggcatttgaataatttaaagctatag



taaggagtacggtaaattacaatatcatttcgtgataaatttcaggcaagatcgaaatcattttgcaatgctctacacctttccttatattacgtca



acttgtgatcgtgtcagactttttgttcgaaatgcagtttcctggagttcagaggtctaaaaatattcctgaaaaaattataattctagatgttcag



gtgaaccgagcccgagtagcatgcgaatgtgaaaaaattgtggaaatgacgcgtggctaacgaggtacttctcgtcgccgatctttctcttg



accaggaccgaataaatatttgaaaatgcacttattgtttgttctcaatgccgaattgtttacaatgtaccttttggtaaagaggaactcgtttgta



ctggccagctaataaaatattcacattattcttcatactatgttttcatatagaatttatcaattttataatttagatgataacgagtgctgtactcctg



gagtccaccaggacttgataagagaattgaagcaccacttttataatgagcagtactaatttcgaatctggaaatgatatttcagaaacaatcc



aggaaacaccagaaaaatatcaccactttgaaaaatatgtgcatttattcaattatgctcaaatttcagctttggctcacgagtgatacggtcaa



ccacaattttctccagagtacgcaatttacgcaaacaccaaacgatggcgccaaagcgccattcaaattttattcatccgtttcagcctttttca



gtcttcttgtctctcattttcgccattttcattgttttatttacacaaacggtcgtttaaaatgtagtttccatctttttccgatggttcatcatttttgtc



atgcgtcttttgtgaaactggttttgcaaaacgaagcaaaaaatggataactgtgtcaagggcgatttttcgattcgtcatgtccacataaacgcg



ataatgtgtttttatcgttggtttcattcagaaattggttgataaatacattctactacattctggctgtgtgatccaatttttaaatccgaaagtctag



aaatttagtgcaaaataagcatggaaagttctaaaccccttaaagaatactgatctcagctgtttctgttcttttcaatcagattcccaattgcgat



aatatcaaaaagccctctgctggactgctgtccacccgcaagggcattatttccttatcccaaaatgctctccgtctgcatctcttcaactcact



cactctctcgctctcttcgcagtgcgaggccgacacgcaacgtggcctctcatcagacacgctccgcctattctcaatgtgtggcgaccgcc



gattggccagtcgctgacgtggaccaatagatacgcggcacctcgagccgtgtcagccacgcaagacacacgtcgacttactccattgtc



gtagcagacgagctcagttcaacatcatcagtttcagttttgctcttgttcggtttcatttctagtctttcttctctgaaattctcgaattttattctttg



gtatattctcattcaatttatctcttctttttccgattcatatgtttaattgttatatttactttttaatttcagattcaacttggtgtcgttttatcgaaa



aacgaa



hsp-3




SEQ ID NO: 76





ttcactccttgtctgcaacaaacgaataatagaatcaatagatggcaaaaatttgaaaacagcgtacagtcaagataagggtaatgtatgttttt




gtcgtcaacctctaaacgtcaaactgaaaacttaaagggcggcggttggttaaatggcgggcgtgtagtactaaaaacaaaggtttgagta



agtgcgccccattgataacaaggatctgaagaagtcttcttcggataatggaggtcagttctgatgggaaaatcgagaaatcgagttttttttat



ttgattgcaagctaatcacatttaaaacgcttacatgggaaagttggcgtttgaaaatcgaatgtaatatacatttttttgattttctgattacttttga



gctagcattttaccatttatatgaaaaataaaaaactaagttgcgatttggatgtggtcaattacccatttataaaactgaaaagtatgtttatttca



gttcaaaaacattagaattttagaacccttctagctaattcgacccttctccaagccatgcaataacctttgatgaatcttatctcaaccaattcac



attgcagagattcttatctccagcataacgtatctccaatcgctttctcccccatcgtccaacacagccgctattatcggccaaagtactacgtg



tctcgagtccgatcctgacctactttttatgtgtactttagttcaattgcgtctggttggatttgaatttgttgattcccaaataggagagattctgg



ataatttcttcgaaagcgttacaaaatgcgcagaattttgtgtatttttaaaacagttgattttagttttttggtttaaatatctagtgtatctgcttttag



caacaaaaaatgattctaaaactcgtttctttctaaatcatgtcaccacttatacacttggccttttccgatttttctttctctctttctatagctctttctt



actctcacctgccgtttccataacagtgctctctaaatttggtataaaacacgcagcgcaaccgcaacgcaacctagtaactgacgtgtccca



cggacaccctccactcacgacactctcgcacacaaacgcgcacacagggccacacgcggcgctcgccgattggccgaatgactctgcg



tctctgcgcgctgcacacggtgagccttcgctgtgctgacgttgccttgtcctatcgtcctaggccacgtcgacgattcggcagttcgttcctt



cgctctctccctctcgatgcgctcgtcgatccgtcagtttgctctcccttcaccactcccatcggttgacggtaccatttcggcctacagtcgac



cttgagcattcgggcggtctatcgggagagacgacctacaaacagaagcagtcctaggttttcctgcattccatttctctcaccgactggcct



tgtttcggttctttctttatctctttcttctcagcaattcaacaagtcgtttcatattttaggcctaataataatttttatttttacaggaaaataaatcaaa



cacaaagt



xbp-1




SEQ ID NO: 77





gccatttggtttgacaccacacttcacaaaaccaaagtcacaaatcatagaagttgagggaaatctttctattcgatggctttcagatctagtctt




aaatagcgacaatatttgttcaaaaagaaacagaatcgttcgaaattctgatatttatcttaaatcaaagcgttatttggcttttttttttaaagatct



ctattaacagaaacaccacgatgacgcgtgagtttataacttacaattggcaacaagaatagtgaataaaactgacaaggctacacttgacg



ggcagaccatctcggaagacgacgaaacggacagaatgatctagaagagtctcgtctgcgggatttcgactcagcgtcgtcatcccttcc



ggaacctccatatcaaatagcaccgtttctcgcttctccgcctccccaggcactattatgagctgttgtgtgtgtgcaagctcacatcatacaa



gaaatctcgaattcccactaataatagacaatgagactgatgttttgattgagttgagatcgtttgattagtcagaatagacggaaattggatgg



accaacagaaaaagagaggaacgcgaatcgaaaaatataactgtggaaatcggcaaaaaaaaagaatgataacaaaagggaaaagcg



cgtggcatattcttccaacaaaatatgtgtttttttggcgaccgactgtgcaactctctcatcatttatattctacacaaaaataattcggaatatcc



aaaaacatgcataaagtcgcggaaatgttacgaatgtcaatccgaaaacagaattgtgagtttacatgaatatatactcaaatctacttgaata



atgctgaaatgtgtattccaatacacttttttaatctcacaaaattcagtaaataatctcacactggagagtcaaagagttctacagctaaatttct



catttacgaatcaaattagagttttaaagcgttccttcgtattaatatcagtgtaaaaaaataattaagacaaaaaatatttcaaaaaaccagaaa



aagcgaaaaaatgaaaaaaaaaaaagaatgacaaaaacaaagcgaaacttttttctcagactacggtagatcttgttgtgtgcagcgtgtttg



cacagattgtcgaccgtacccggaacttttttatttgaaatattttcaaaaaaatatattttctctttccaaattattcacatttttcgatattttaatcgt



ttcttcatggttttgctgtttggaaaaagacgttcatcacagggtaagatttataattgtttaattctcagcaattaatttccatgagcagcgaacg



actaattgtcaaaattgagcgtgttttatattgattctgtctctgtgctattccatctttcctgcctaaaatgtatggcttttctcgttacatttctccaat



actttccaaagagacgcagacataaacgaatgtttgccctattgcgaaagaagtaaatgaatcacccttccttttcccttttttccactattttttat



tttttattttttgaagcaacatcggcgacc



cdc-48.1




SEQ ID NO: 78





tccattaatctatttgtttaatttattctaattctcgatcgggaataaataatttggaaattattcaacttattaaattcatagatctgggaaactatcaa




gaatcaaaatcttaagactattctcctctcgtctcgtttcacatctcttcgttctccgtctatcgatcgggtgatgctgcaaatcatttttatcgatct



acaaagtgctgcatttactaacggcatatcgtttcgagacccaaacgctgatgtgcgttattgcaaataacagttatttttccaaaccagcatta



cattacagtccactttttttccttttcatattttcatcctggacccagctacatacattaccgcaaacgtgcaaacggtagattttatttactagttcct



tttttccgaaaaatttcaaaaaattgtaaactgcgtttccgttttcaaagaacttttttgaagtttcaacgcttttcatcgcaaatatttacaaatacgt



ctcgttatttagaaattttaaaattttttgaacagtgaaaatccttttcaaacttcgcgctaaaattataaagcaaccgcgccctaacgtcagaatc



accaaacactttttgcgtacacttgttgaaaacacgcttctatatgcgtggatgatgacaattttcaaatctgtgtcgtttttagaaataatttcgtg



aacttttttaaaatctcaattttcttttatagtttcgttcccactatcattttggacactcattcttcttattttaggtcttaaattgtacata



cdc-48.3




SEQ ID NO: 79





atattcaattcattccaaaaacgatttttttaaagtttttttcaccagacacactttatttctctcaattttcaacagacacgatagttctgtccaacct




ccattcgatttgtgtagtccttttccggcattcgtacttcaagctcatacaacgtgtcgtctgtttcatttcgatgagccatcataaacgcacgtct



gtaaatgtgttcattatttcatgtcataaattatttgcaatatataccgttcgtttctttgttgaaccgatcgtttgatatactccaaatcttctggagtc



aattgatgacgaacatttggtcctgaatggattccaattcttatttctattattaatttattatctcaccattgataactggcttttcattctgatctttctt



tctcttcttttcatcagtattatcaacttttcttgccggttttgctttttctggtgatttttgtttttctccaattgtgggcattgggtagtaagtagatgtg



gcgaactgtttttgttggtaagtaggtgcaatagctgtatgaggatctgatcccattctttcaataggaatttcagatgcttgtctgaaatattcaa



ataattattttgttagttcggatgtttcgataagatattattcagatgcaaaatttttattctgcccgaaaactacggtactgtactataattttctcgc



gaaaatcacaaaatattgcatccaaataacatccaatacgccttcaaatttatgaaaaattacggtagcttatgagtaggttttggcacatgtac



attcgtgtgaacgactgtggttgtttcatgctttttgacttcttgcttgacttctgaaataaaaaaaaactttcataagatgctttgttcattcaacaa



aagccgtttaccttgcttcttgatacttttctctggaacgtgtgcactagtcttctgatgagttggctccacagtatcgttgagcaaagttttcgag



taatgcttcacatttagttcttctgattcaacacttgtcgattgacttgttggctgactgaatcatagaataattgataatctgaatatattaaaaagt



taactcacgtttcgtcgaaatgtgcaactcgattgtgatgaatcgatcgttccaatggatgctctttcttcagtatcgctgatttggactttgagttt



ttgtttttactatgactacagcccattcttgaatctttctctcttattgcacacgatacgatttcctggtattttgtcggcggaagaatatatgagtaa



aatcagaaatgaatctttttttatctaaagttttttattcgaagaaagaatcttcgcgaaacatgtttctgtcacagtttatctgaactacaaatctta



ggttcacgaacttacttacttgcttcgttaattaaaaaaaaattatattcttttgctttcgtttgcatgcaatttccaaaactataactcctattttcag



cdc-48.2




SEQ ID NO: 80





gcaaatgtgaatggaaccaagaagagaacgagcaaaaatgccaccgggaaactcattatatcattctggaaacaattatacttcaaaaaat




ggaagcaaaatataaaacaggagttgtgaatagagaaaacgacgctttatatcatcagttttggcattgaaatgaatcaataacataaattga



gcgagaaaaagagaaacagcaaaatagtgaaaaacgaatgattgaccgagagaacgggggaaggttggaatttttgtaaacaaacgag



ggaaacatcatgttgaaaacatatatatacacattttttatttaatgcgtcggaatattcagaaaatcgttcagatcatcgataatttttattgataaa



agaccaaaaatccagtttacatgaggaaaacaatacactgtgaattttaaagaaaattaaatattccaaaaaaatttaatttaatttgtaatttgg



gaaactgaaacaataaaacactatcgaaaacttaaaaaaaaacatggattgaagctcaaaaaaactgttttaatgtttcgttttgtagaacttta



gatttttgtaaagcgggagacaccacgaatccgcaagaagtttcttccagaagcagattcgctgaaaaaaaatgaagttgtcttaaacctgat



gcttttttttgataatttttatacattatgtggtttcctggttggccattttgttaaaatcattatttcctgtaataaaagtcaggcgttctcagttatttcc



agatatcggattcctaaaatagctgaactccaaaaaacggtcaagtctctgaacaccaaacgcgctccttcgaacaaaaaaagcagcgcgt



acgtttaacgaacagttttttcttctagaaattgttttctcattgcgcaatgcattgctcattataaataattatgttttaaacagttgctgggaggtttt



cgctatctcagtcgttgttaaacaattaccagagtgtgttatcgtatttatctttgccgtataatatcttttccatatttatgcgattgcggaaatttac



cactgactctgcggaaactgcggaaatttaccactgaaatatcactcatatcgtacgtttctttgaattcgtctccttgttattcaaattatgtcttc



gtttttgaacgagatatttacctctagctttctagatcgtcacatcacttaggttcgccttgaacttctgttccgctaaagacggctggttcacatat



atttttaacaatgtaattattacttatgacccgaataaaacggtagaacgctttgtgaaattattcgaaagcaaatgcgccccaaggagagagt



gtgaatgagaggctgcgttttgtcatcatgtagaggcagcattggggtgttctgtagagaacttagtctacgtgtctcatcttccatatttcttaat



tttgttctattggctctttttgcatctcttctttgattcgattctttaactgaattagatcagaaattatacttgaagttttatcttgaaaacctactgtaga



aaagtttgtccgtgttctactttcttattagactttcgcgtttcggcctttcctatgttctacccccatcttccgttcttttttattattccaagattttaca



gagaagtcgtttaacc



ufd-1




SEQ ID NO: 81





ccgggctcgaacaagacatggacgagccattcgatatgtgatcatctgttatcacaaaaatgatcaattttcttcataatttatcaaagtttctgttttcct




tccatttcatctgatgaattcctactttcttgttccttttcactaactttattattataattataattattcataatgttctttctttcccatcatcatat



ccatccttctatacattttgtttccatttgttgttgaaattttatatgctatttcattttttgtcgtcctttttttccgttcttcattttattgacttctct



gcgcgttcatgatttctggcattcagctcgataattcatttataccctgttctttctagtgttttttcgcgttgtttgtgacggttaaattcttccctctac



atctttttccacacaaaaatctgtacacgacattcggttttctcgttgttccatttcttttttgttcaacggagcgcgtttgtcgttgcaggaatc



ggttttaatatcatcatccattcacgcattctctttttcatgttgttcattgtgtttttcttcaatttttgtcaagtttccttcacacgtgcattttagta



atttctttctataataaattgcagtttgttaaatatttaaatgatcaatgagctctcttttcttggttggctcatcctctttgtattttttgaattatagt



tgaagaaaacgttaataacttttcagaaaaccaaaaataaaa



npl-4




SEQ ID NO: 82





atatagaaaaacggtctcttaatttcaaaaaaactaaatcaaataatgtgatagactctctcaattgaaatagataaaattgagagagaccgtg




gctattacatttgtaaattaattttcttaaactctacttctatctccagtgagccatactcgtgaattgatcgcattgaattcttctcttcaatatcacct



tgtccaataattacatcgtctcgtgagcacatcttctattaaacaaaattagcactaggctagttctcttctaaagtgagaaatgagaagaaatgt



gagttgtagagacgtgtataataaaatccataaaaattaaaaatattgtgagttcttctgagattacgtgaaggccgaataagaggtgacggt



gataatcacaagaatttaaaaataatttttccatagaacgaatatataattgcgtaaatggtcgtggttgctcagaatctcgagagactgtggca



aattgtcgaagttttggcattttgccaaaatttggtaaattgccaaatcatcgaaaatgtatattttcaaagtgatttcgagcagttttggaaactttt



actataatatttgagcacttgagaaaccgatttcaactatttccataccgtggaaaaattatgttttaagttttggcattctgccaaagttttgacatt



ttgccaaaatttggtaaattgccaattagttcaaggtgtgtacttttaaagtgattttgaacagttttggaaactattactgtgatattttagcacttta



ggaactgattttaactatttcaatactgtataataattctttcgacaacattctcatcgggccacatgcgatcacggaagaatctgaaattaaaag



ataaatagaaaacaatttgagattattaaatattacctctcggtgagatctggaaaagcttgatcgtagagagtcaaaatttccggcacattttgt



tcgtcaaccatgcgggaaaagtagaccaggtagtcggcgacctcatttggaactccatcctcatcggctgaagctgttaaaaattaagaaat



gagataagtttgtgttgttaacaagcacctaaataactaccataaatatgtttatagaattactctattgattgattatcaatttttcttttgaaaagat



ttcacaatgcacgatcattgatcctctgatactcaacttctctctcgggcttttaaatgattaacttcttatgaactcttatgaacaccttttcatttatt



atttctttcaaatgaataaagctgtgattcatttaatctgagatttgaggatattcgacaccgaaaaacactgaaaatgacaaaagtagtcatttt



catatacaatgagggagttctgagaattggcattgattcttcactgtaacagtatttggaaaatttggtttttctgaattttatgtattttgctcatgg



aatgttaatctgcagtttttatgcaaaattatttcagaccaaattctccaaatgtctgtttgccgaattaaaataaatcggttaatcaaaaaaggac



cgagtcttcagtcttttcgaactgtttcaaattttaacatttttcaactcattttactcttattcatcaattctgaaaaatagcattctgtgaacttacaa



gaaaaggtgttggtgcgacgacgatcagagtgatcttcagtggataaatcgaattccacgcgtcgagacattactgaaagaaggtttttatat



tgatattatttaaatgtcaaactaaattcgaaaaggtacgctaaaattaagagaaaacatttttttaattgtaaaatttgatgaaaggaattggaaa



atgtgatggaaaaaagaaaattgcaagcgttgcatgggatttcgcaagagtgccgcacggttttttgtgtacgcatttgctcgtcattcatgttg



tctaggcagttttgatgacattttttattctaaaaacaaaatgttttatttcatttgctgtttaatgtttgaatatgtatggaaactaatttgataccctttc



cgctgcattatttttgcaaaatctcaaaattatatatcttcaattcactacctagaaggcatatcttcctgcatttaaaaatctattttatttcagat
























































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Nuclear Oxidative Stress Toxicity






ugt-1





SEQ ID NO: 83





agatcaatggcactgaaaacgctcatttaaatgcaaaagatcgtgtcccgtaaaaattttctgtataattccgtgattattttcactcgggaatcg




ctcgcccactatgggggagtctacgcaaggacaacgcaaggacaaggacaacattctaatggaatggaaacgattgcccgactgcacca



attctagttcaagtgaacaatgataacttttgtattctgtattccttcacgtctcccagcgagcgtaataaattattattattattataaaaggagagt



tttgatcagataaatttattatcgttgaatatccactttctctgtttctcgtttcattctctaaacgacgtatggataatacatatgatgaaggtctaaa



aacttcaaagaaatgtctcctagttttgcaaatttccaccgaaaaaaaatttggtcggttctcggaccatttatgtattgtattttatttggcttatgtt



ttactcaggaaagtaaataacttttgctaaatgtacataaaatcagcaatgttttcaaaaatgttttgaggtaatccggcttctatgtgatatattaa



ttcaatcctaactgataagataattataaatttaaaacttactgctacctccaacttctggaacagcataagaattggttggtggaatggtaacat



atcttggctgcccatatccatgacgtggtggtaatttgattctatagactgcccgtttttctctaattgattcagttatcaaattccacgcatcatcg



gaatatttctacaaaacattgaattaaaaacttgaaaaattaattatggaccaacttcaaatgttttcagatcttcaagggaagtaatttcaaagttt



tcaatttcattaaaaaccgaaaaaattgaagcgagaatcgtaagaactgcaaaaacaatgagcagaatagtagcgaatagaaaatttgtgtg



cttcatttttgttttcagtttcagacaggtgtctatattttatacttttcaacacaatagatattaattattttagagagaaaaaaacaggaaacagct



acatagtgtgaagtgaaaatagaaatatgaaaaatgaaataacaatgactttgacgaatttatccctcttaccctaaattttcaataaaatcaaa



atacaacaaaagctccaaactctaaaattactaaattgtatttttgtaccaaaactagcttcccgacattgataagtaacgcactggcacaaact



ctaattttttagtgaacacaaaaacagtaatctgcaaaactttctttctcgtattctctgtttctctacataccgtacttaatatttcactatcttatctct



ctgtgtctcttgccgaccaaaaaactaatggtggatcgctatataaagaaatgttaggtaaggagttgaatgtcagttatttctgtaaaaactag



aagtttctaaa



ugt-13




SEQ ID NO: 84





attattatgttcctatttcttttatcaaataaatgcagttttaaaattttggacttttctgagaacgtacagcaataaataaaaatctaaaaccaatca




cattcaaaaggtcggagcaagttcggagctccgggattcaaggtcacaataatgaaattgtttttttattgcttgacattgatcgaaattaatttg



ttattttttgcaaaatcgaaaatgaatatttttgaattagaaatgtttttacaaaattttgaaccgccataaaaaatgttgaaaagttaaagttttatta



cgaaattcgtacatttgaaaaccttttgggtctacatgttcaaaatcgcccgaaccgttagtcttcctttaaagtcagttatgactgtgttctgtgtc



tcctcgactctgttttctgaattgtcatcacaccaaaagaccaatctttagatctttgtatttcttttcattacttgctatcaaattagccatgaaaaac



atatgtcatcatattactcactcaaaatactacaaactacactgacgaggttaccgtttgatcttatcatctcttaaattagtcggggtatataaga



agaacaaatcgagtacattgtttcaagaaaaattccca



hsp-17




SEQ ID NO: 85





gattattttcttatgctaaactggcagacagcagatctttttatatctgcacaaggggcggtgggatttatagaaacttaagtttactacgcctgc




cgcctaatccgtgaaaccttatttttatatttttccgcctcccgaaacagttgatacgtgaaaaagcacggaagagaaaaaagcttcttttggac



ttgattaatctgttggtcatgagaaagcgtgacacaaggtaggttacggtagcaattgcgtaattaatcggatcagtctatgcgcatttctgaaa



cattggggatttcaaatctagtttatcaaacagatacaaatcacattgacatctcgtggaaacagtctgtaaagtaccgcaaattttacaattttt



gatattattgtcgttaaacaagttccatttcaaattttttattgaatacggtaaaaaaacaagagaggcagctggttgaagtgagtcactcttgttgag



ttttcgttactggaaacctgaatgaagatagtttttaactttagcattacgcctcattattttcctatttcctttttactattttacttgtatttttaaact



ttgtttagcacattgagcacataaaaccaaatgttataaatatccttatcatcaacccatcggtttctttttaacttttttctttctcgaatttcaatgac



ccggaaaaccaccacatcatatgaaaatcgaatctaaaaatttgcagatacgcatctgtcctgctgcgctctttttttatttttgaatgtttttttttct



gcaaacgttgggaacagtcatccaatccttcaaccgttcgtctcgttttgaatgacaaacgttctctttccgtcctctgtttgagtatatttacattg



ctaattcaaaaaaaaatagtatagaatataatgatacttagagatagttctggcataaagtttaaacttgaatgaaatcatcaatgccattaataa



ctgtgtcactgcattagtttatcagcaagtgtgccagcaaaaaaaacgtttcgagacgattcgatacattcctgaaaaacttcgataaaaggg



aagtatccaaacaaccacacccaactttcatcattgactcgctgttttgctttttatttttgttaatcttccttacaattagttttaaagtttaaaacaaa



tattacatgttagaaagaactgtattttggtcagtttgttcgaataatttcgaaatctaaaaccttttctttttgatgattcgtcggagtagatgtttct



cgaaggaggtaaaaaaaaccgtgggcgattcttgtttgcattgaggataatagagcagtagtagaaaagcagggagtgtcaactcagtttt



gtcttcttcttcccctatttctgtcttactttcgttttgtttctttgaaataattagattttcagaaactattataaa



cdr-5




SEQ ID NO: 86





aggaaatttatccaaatgattttactatttgagaatgtattatgcggtaacttttttgaaataaactaatcgtgacactcaaaaacttagaatctattt




taaaagaatagataattccagtttttgatatccgggaatttatgattttttggaagaacgcaagaaatcgatacatttgggtacgcataataggta



ctcttgcacttggatcaaattcctagagaacgattagatgctttagacgcagaaacaaaaaaatgtgaccgatacaaaatcgaccacaatctc



aagaaaaataagtgcgcaacacaatccgaggtcaatctagacatttatgctcttcctgcgagacaaaaatgcattgtattttttcattcagattc



attcaggtgtcttgaagagatatcaaatcacatgtgacaaaattttgatcgaaaaataagttgcatcataataaaatcatcttatgatcttcctata



taatctttcttcaatttcggaaactacgattcgaatatatgttttattttaggcgaa



rnp-2




SEQ ID NO: 87





aaccttagggtaaagtttattttatttttttttctttacgatagggttatccaggctttctaagccgtaaataaacttccattttaaattttaaaatatttta




aagctcaagcttatagtatagggaacaaagctttctgatagtttagaactaacaaagagcttatgttctacaaaaacagggacgtttttatttata



gggggggaggtgtaaggattctaaccgtctctacacttctcccacttcccttttccccagtgatagaaggctaagagtgtatagggattaatg



cttttatttacaggatcaccggccagaaagtcagtcacgccatggatcaacccttcgctcttctccgaatacagctctgcaattgatccatccg



tgcacagtgccaaacgctccttacgcgttcgatccctgagataattgcaataattcccacacactcgatttattccaagcctctaaacttcctgg



ctaccgtaaccctgtgtgtgtgtgcgcacacttgtgtgcgcgcaccttgtttacgtcttctggacctttctgcggaggaatccagggctccgcc



ctgccaccgcagaggggtatataagacgtggattctatcactccagatcttctcttacttttctgttcccctttacttgttccctttgtctcatttctta



cttgtacccattccattggggttattaattcataataaatctattccttagcacataccttgttctgttgtagtatgggatgcaacaacttcggttgtc



ataatgataattgaggggaacacttaaacaattaccggtatacgcttaaacatttactatatgttcattcaatcaatcacatatcgacacaacaat



taacacaatccacaagtttttgcgcaatactccttcttctgttcctttgtgattcgtggatccgcacagaagccacgtcctgcccagagatggca



gctgtaatttttatgaatttttattatcaaattcgaattccccgtcattttttgttcataatcctatattttcaaagatctagctcaaaattgcgtgaaatt



ccatgtttgcggacttttggcgctacagtaacccggattatttttgaaaatcgagatggagctctgaaaatatgggagaaaaggtagaaaatc



atggaaaactcgaatttggcattgaattttttaaagaaaaaataaaatctgaaatttaaaaaattgaaaatttcacccaaagtttcaagcaaaatt



atcgaacaaaaatatcgatttttatccgttttgtaatatcaaattcgaattccccttcattttttgcccccaaccagagatctagctaaaaatcgcgt



gagattcggtgtttgcgtacttttggcgctacagtaatccggtaattttctgaaaattaagctatttagagctctaaaattttcggtttcgggcaaa



aaatggcagggaactcgaaaatttttaataaatttttaaaataaagtgcaggaaaaaagttacgaacgccccaaaacttactcaatattatcgt



gacatgacggagtggtctgagcactttcaaattcattcgggtggaaatttggaatactcatggcaaaattggtgccgaagagcacataaaga



gcagtaataatcagaaagaatcgcattctggaagcttctgacctgaaaatgctccagtggggagattttatactggaaaatttttaagtatttag



ataattaattgttcgtatttcggaactgtgttttatcaaaaagcactgtgttttgtgctcttaattctgtaatagtagatttttttccctaaaaattagag



tttttcattatcaaactttgattttttcatgatttttttctaaacatgcggttcaacaattccatgaactcaaaacaagccgaaatttgaagtaaattct



gtgaaaaatgatattttttctaatattattcaataaatctattttcttgtcctatatttggagcatttcaattgaagtttgctccattttctgcccgcggc



ctagaaacctccgtggccgaacaacaagcgcgctctactgcactctttttattttcgtattttcaatttaatttcaataatttttatcggttttcttcga



ttttttcgcacttccccccagtattttttcaatttttccgataaaaatacaaattttccagctaaca



dnj-13




SEQ ID NO: 88





ttttatacgaaaaatactttaaaatcagaggaaaatactttgggaccggtgaaaaagcatggaggttcgcacaaacttgtttaggaaaacaga




aatatgtctccgtggcaggaccatactgtgcgccgttgatgtccctttgatacagtactcttcgcattatttattttttttcggcgcgcctaggggt



tttcgagcgcagagttcaggaggccttctggattatggatagaggcttgatttttaaaattgtttaattcaatacagttttattaaagttttttctaaa



aatcttttctaaaaataatatctgattgctgtttatacacgagaacaaaactaatttcatggaaacaattttttctctttattttctcttcgaataatttaa



attttaacaattcaggttttaaataatcaatttttaaataagcaagtgaattttaagcataacttttcttcctagtgtacgtaaatcattctttccaacaa



acatattttttcgtgacgaaacttcgccttccagaatattcttttttcagaaaataaataccaaaaagcacaatttcttatctcttgctcattcttttctt



tgtatcgtgctcatgcttttattcattcctcatttttatcttgcgaaaccaatgtattttcaataaaaaaaacgagtgatgcatgtgcgctccaccgg



ccgacggaagatcgaacatgcactgcgcttcgcgagtaaatagaacgctctggaaagttccgcactcttctctctcatgattcggcgcactc



tctcttccatttctccgtgtttcctcttctgatgttgacccatatttattctgccgggtgtattctttttatctatctgttgcttcatttattccgttaacc



tgttactggttaatatttcaaaaattcatatgatttcttttcagattactttccaca



dnj-25




SEQ ID NO: 89





aactaaacattgaaatttctgcacttctttattgtaatgatgcttctgtgtctgacttggcattttcaaaaataatggaatggtggagaattgacag




cgcagaccattgttaagactatgactgtgcagtttatttgcacagcactgtctggcacactctcttcatatcacatggactctctcttgctcaccc



tttgacacggattaggttagaggcataccagtgggagtcagagtgctcagaaaagtagttgccatcgtggtaagagttctgaaaagcatcg



aaggttttttagggaccaaggaaatatgaatggagcatgtaaaaatacttgtaaaactgtaaaaaataactcagcccaaaactgagggaacc



gtactttctgaaagaaatatgtatgaataccgatgtttttaggttcaatcaaacaatttattcggatttttcacgaaatattacagagagtgtgacgt



tacataataatgttcactgtttgacgcagtcacgagcttccaaacaattttatattatcgagacgcaaagattcacaattttcgcgccagaatag



cacaacctggtctcgacatgacaagttttagttaaatgcgaaaagatgtgcgcctttaaagagtactgtaacttcgaatttttcttgttgcggaat



ttgtgaattttcatcgctttctcattgtatttcgaatgaaaaattggcttttttgacaaacttagacacaaaaataatgctcattaaattttaacaaatc



gaggaaaaaaaatattgtgaaatgtgaaaaattccgcagaaatgagacgctttccggtggcaactttcccacaatttttcactgatagaatgta



aatttttgaattaatatcactttcagaagtttttatacattattttctccttataaagtttgtgtgaatcacattttcggccgaaaaaaccggttttccat



ggaatgcatgcttccgatgcttttcgcttttattggcggatggttacgcaacctcaccgattttatctctattttccgcacttttcttctctatttccaa



aattttcagcctagtttatttttgaaatttcagcaaaataattaatttcctcacaaaactggcgaaagggcttttcgtttctctgccgtctctcttttcg



cacgctctataagcaagtgtccgtgaagcgcacttgcacccgtttattttcacaacacgttttcagataattttagctatttttcattgattttcagta



gtttttacagctattataatggtattttttagtaatttccagtataaatccg



pme-1




SEQ ID NO: 90





tttctctgcaaaaaattggagattttttcagtctctttcaactaatgtaaatacgctctcttgtgactaagcgcgcgcgtttgaaccagaggacaa




tttttttcctcagcgctagtagcccctgaaagagttattcatacttgaaaaaagaaacttttctatagatttctgcatgaaaaatcaatcctcagcg



cttcttctcttgcttttcctgattgtaatgaaattttagagtttttaaattgtaaaaaaaaaactaaacaagttctttttgaagggaaaattcgtttttaa



atgcttaaaatgcttcaaaaaaaaaacaaataaaaaaaattgtttctgtgcatacaccgtcacgacaaaatgcagacttgccattggtctcgcc



gcgaaaaaacatgtttcttttgaaagattgtcttaattttttgatttcaatcatgatttcaatcagaattttgcgatctttcagcatttttatctattttaaa



gctttataaattaaaaattaaatttttaaaaatcttccagattgtcatacgggtcccgg



tag-124




SEQ ID NO: 91





aaattattatataattttcaaaattactggttgatgaggttagattagtgataccttggaagtggtctatgtaataacaatttttgcacaaaaggag




atgagatttgatatggaagattggcaacacaaacgtcaaagaatggccattccattttcattacatctcctccattaacttgtaatttgttttgtag



aggtctgaaatatatttattttaaattcgaaaatatttttcaaaaaatacgtacgttcccataactcttttcttgacttcagcaatcattctaggatcga



tttcacatgcaattacagtttttgccacctccagcattttaaccgtcaagtttcctgttcctggtccgacttcaagcactgtatcggtggctttaag



agctgatttctcaacgattgcattcacaactccaggatttttgagaatatgttgtcctttgtcggtgttaaatggaagtgctataaaatcaatgttat



gaatagaaattttgcaaaaataacatacattgaacatttccagttgatgatcctgctttcgtctttttaactttactcgtttttcccattttgagttttttt



aaatctgaaaatgaacgaaaaataatagtatttctgaaaataggaaaataatgaaaagaaataaaggtagaatgatttgtccacgtgaagtac



aaaacgtgggactaaaaaacaattctagtccgcgcgtcgtgtactcctctcagacaaacagaagttgcacaattttttgaaatcgatccctttt



aatcactttttcctattcttctagcgtttaattattttctattgattttatttacaca



pme-5




SEQ ID NO: 92





aaaaaaaccggctggtttgctgaacggcaattgctgttcatccctatacctgcctacctaccgccaattcagataatgtggtgaaaaatttcac




gaaaaaaagagcaaaaagaaactataattttaaaaccggagtttgaaaccgtcatcgtcgttgtcattaataccattatcattattgacatcagg



aatcacgccattttgctccgttatcatacacatcgtcatcatcatcatcgtcgtcaacacccatcaaaaaaaatgtataaaaggtttcactcaaa



aagagggttttatcattttatcaagacttaaaaatgtcctcgtagtttgactatgatatcatttttccattatcaccatgtttgcgttttcctttttccaaa



catttcttttgcacggcgatgatgcttggcattttgcactcgtgaaagtttcagcttgccagtgcgccgccgcgttgtccatggcaatgcggca



tttgtattcaacggcagaaaattgagagatttgtttctctcgcgtacctcgcatgttttgatttttcgacctcggtttgtccctcaaacaaagagaa



tcgtttgtcgccctcaccgcgcacgcatatacggaaaaatgctacaatttcaaggcgtgatagagatcagctctcccgctgatttctatcgatt



ccaatagagatttattcacctcatacggcggcattagtttgggcggtgttttttggtgtttgttgtgtccaaaatacgaaaacggaaaaccttcat



ttcagcttagtttctaaaattgattttcttttatataatttttttcaataatgctgaatgcacgtgctcgccggctgcccttttgcaatgagactatgca



aacgcgcccgaatgcaaacgctgctggtggacccctctcggacataaaattatatttcttattttttcgaatctgtttttctttcatattttcgaaaa



aaaatgacaatattatttgatgaaaaaactacgaaaattggcaaaaccaaaaacaaaaccaaggaaggatttctggcttccctcataaattga



aataaaagagtttaccgaactaggccattttggctcggccatatctggggtagatttacggcgcgttgcttgtcgcgtcgcggctcgagttta



gttgtaaaactaaatgtatttgtccgtgtggagtatacaactttgccacgcgttgtccagcaggagatttgcaatagagcaagaaaaattcaat



gaggaaggccggaccccgtgaaaattcgcagaaaagtaatgaaatcgaaacagaaaactccgagaggactacacggccgaggatttttc



ctcgtccgctcttttgttaggccattttttgaattggtaaacggagttttctagtccccgaaaatataatttagaccaaccagcgagcacgtgctg



ccattgtcggaccaaaaaaaaaacgccaaaaaaccgtgtatttttttttcgttttttgatccaaatgctcatttcgtcaaaactgatgcctactttg



gctgcctacctacgcctacctacctacgtgcctacatatcgcctattctttgcattttggcgtccagtacttcactttccacagaatagataaaaa



agtgtattttgacaaaaaaatttatttgacctcggcgcatttgatctcgagaaaacgtggcgatttttgtttttaccagttccaaactacatgtaact



ttgccacgtctgccagatttgcgttccaacatgtcaaaatttggaaaaaaaaaccgttgtttaccgaatgacacacaaacacttttccccatctc



attgccctcttaatctttgcaaggtttcacaacattttgagaattctgctaaaccgtctgcgtctctcattcctccaccctattgtcacggttttgcta



tctgtttctctcgttttttcgtggttttttctctttttatgaccttgcgtgtatttgccaactattttttgtttgtgggcattttttttggggaaaaagttt



gatttctggatgatttgaatattcgtgtattttataagctttttcctaacttttctactttcgttcatttctgttgtttcagccgtaatccgaacagc



air-2




SEQ ID NO: 93





tatttcttgtgattcgcttcgattttctgaaaaaagatttaattgaatattaaaactacaaagaggttaaaaatgatttccgattttctcgattcaaatt




tagagaattccagattttagctcaattgttgtgaaaacaatttttagcttttgagaattaactttttctgccaaaaaaattacctggaggagccaatt



acaattagctccaagtgtttcaatacagtatttgagagctccatttggtccaagtccaagtcgatccattacatcattcacagtgatcatttcctaa



actttagtattttaaatgaaaaatatgaccttaagtattaaaataacattgatagatgatctgtaccacgtttcataattattgtcctatattcattgga



ataaaatacttacagtgatatttacatcaggtgcgtatgccattgtgtcattagcaggatcaagattgatagtgagaaatggtcgtttggtttgtg



agaaaatgtccgttaatcctgcacaaaatgtagattttccagctccaggagctccaattacaagaactccgtacatagtccaatgagtactga



aattttctagttgaatcttaattttctacggattgttttgataggaaaacatttaagaagaacaaaaatatataaatacaatttaatttaatttaaaaca



aacaaaaaagcaggataaacgggcctggcacagggccaagtacgcatttacaccgtacatgacgacatattgcggaccattgcattttgc



cgcgttaattttttatttaaacggcttgcatttctccttactatccagctgacaatttttagtttctttagaattatttgcaatcaaaactcgttttttgtaa



acatatttactcaggtaatgtgttgatttctcacttttttttgaaatcaaagcagaattagtcctatttttattctacataaatatctaaatgtattcaatt



aaaaattgggccattgaacttctaattaattcaatttataaatttatcgtgatgttttcttttagttaatttgtccttaatcgtgccgtctattttatttct



tcataaaaaacttttcagttccgac



mlh-1




SEQ ID NO: 94





caccagcatcaggagccaacatcagtgccgacaccatcgtcgcgaaacatgcaaagctgtggagtcgaaagcactcaacagccggacc




gtaaacaggtgagcatacagtactcggaggaagaaggctccgaatattttaccgatgagcttgacgatgttgatgatgagattgatgatgct



gctgctgcagcccgtgcggctgagaatattcgtattccggcgtgtctattacagacggctgctcaaaaatctgaggaagaggatgagtacg



atgtaagacactcattgggttacccatttttctttggttggccggagaaaaattatttactatgctccgatatttgttgatcgaaattttccaaaaaa



agagctgtaggaaattgagattgataaaattaatttttatgcatttttcgccaccacctgatgtcatggtttacaaaaaaccaaacagttaaaattt



aattagatacaatttttgaaaaaaaaaagtgttttgtacatttagaactaatccataagcgacgtgcatttcaatgaaattgtttatttttatttggcg



tatttctacgattttggacaaacttgtttgaaacaagacaacaattttcgaaatatcgtagcatcgtttgaacttatcatatttatttttaaaaaatttct



ttccgccaagaaaaatgggtaaccagcgtcgtcgaaaggctatgatcattaatttttataggtcatggagacgtatctttaattaatactctatat



actggtacgacgggtaagatacattaagttgtacaaaaattacagttttcctcctttattttctccaaaaaaccttttgtctagaaacatctcaacattatt



tagttaatttttttttagtttttcaaagtttataatttcaaaaaattatttttctgctttttcggtttttcttcatgttcaaaacttcttcctctctcgtca



tttttgtataatgcatcgcggcgatataaatttgcattttatctggttatggcttcatcatttttttttcaaacgaattttgggaaaaaagaatgctatagt



cattttaattacatccctcatatttgtggcgtactgtttcctttccctgctatcccgattgatgtttttaaaggcacaccgacgagaattttcgattaa



aattgtaaattagagtaaaatctatgacttgtcaatcgaaaatcttgtcggcgctctttaggaactccataaaaattgaaacaaaaattattttaaa



aattaccaattttttccaggtggccgctgcgtggtcgacaaaaatcgacgtggacacgcgcctcgaacaagatcaaatggagggtgtcgat



gaggcggaatgggacaaataggcgctactggaccatttcatattattttcagtcaagtagtgtacaatgaacacaattttctcacggttctgtaa



aaatgttttttctattgaaatgtttgatttttcgcccccatcaccaatccatcaccacctctccctctctcgctttttatttgtctcatgctttattcatcat



tttttatgattattattatgagtattattactattgtatagtctccaatttcgtgatttttggttttctagaaaattgcgcccgctcgcccgcccccacg



acttaccacctccccctgaatttttttgtgctcccatcgcctagtcgaatttattcttttgtatttttgtgtgtccactttctctctcggtcgatgtgtttt



aacatccatattttctgccccgcctcgtcccccctctcaatcgcccgctccccgccccgcctttacactgtgtttcgatgaaataaacagtaga



gaattgtaaaactatgtgcgtgagaatttggaaaattttagttttttgtgatatcggaagcttttttaggggaatttgaatttatttttaaaaattgttc



aaagataaattagctccgaaattggaaatcgtagtggaacatttgaatttccgccagccagacatgtggcattgcggttaccgtacccgcaat



tgtgatgaattttcaaaaatcggtgatcttctggattttcgctgtcaagcttgagtttaagggtctcctcactgatctatgtccattttgcggcagg



aattcttttttttttagtttcattcggatatctctaaaatatcaagaaaaatcgataatttcacttttcctgaaaactttcatattttcagaattttcacta



msh-2




SEQ ID NO: 95





tttcatagattttttaataatcagtctgctcactgataaacacgtcgattgccgcagtatcttggagaagagaactgaacttcattgtttgaaacct




agaaaatagtgaaaattagttagaaagagaaggagacggagaatgaaaaagggaaaatcgcgcgcgatggaagaaatttgaaaaaaga



ctttacttttgatatttttcgaaattttttaaaataattatgtttagagttaaaattgcaaggaaaaatgaaacaaaaattagtttaaaaataaaaacc



accgtatctctttccctgcgaaaccaattcaccgtattattgtatgtgcctttaatctttaacagtaagcataacatgtgattttcgccttctttttatta



aaatctaaattattacagaacttttaaataatttgattatattctttgtttaatttttaatcatttaaattcaatttagaaatgctaaaaatcccaaaacaa



tgagacactatttccctgcaggaccattttacagaaatactgtatgcacctttaatttcttttcaaaagtaagcggcctttctgtcgaatcatttttc



gttgatgaactcttttttcttcacttttactctatattatcacaaaaattcgaatttttcagcgaaaaaatcgaaa



msh-4




SEQ ID NO: 96





agaatgtctggtctccgaatcgtcaactcccttgcatattctttagctccaggacagctcggtgtagctgcaatttgcaacggaggaggagaa




gccacagcagtgctcatcaaaaaactgtaatatgaacctcttgcctaaatgttttctggtcttctattcatcattccttgattcacttttacaacaaa



tttcgattacgtatttataaatagttaaggttcttgtcacataaatgtttattctcaaatggtgcatacgtgttattgattgggaaatgaattaaggtta



atatgtacattatcaggaatggttttgagccatctcaaaagagatatactggaaaaatcggaaaagcatttttcttttgagatatatcattcattca



cgtcttcaaggcaaaacatataaggggagatcgtatacaaataatcacagggaagaattggtggatgataaaatgatcccataaaccattatt



agtttgagagatcaagttgggggaatgagaatattaaggggggaagaatttaaccgggaagcaaacatagagcgatttaatttttccgggat



ttgctttgctaggcggttccaggtggcgaggttggctctgaggaatcctttgtttgtttcgccaacagatctgagcatgtaggggtatcttgga



gttacagctttcttcaccgacgatgacacatttgggtagtggaagtttccagttatgatgttgtggtaggtgcgaaggatctgcaagacccgc



ctatattgcactgacttcaaattggcttgggccaaacgatcctcgtatgaagaatactttatgttgcagcgttggaagacgagcctggtgaag



aaatgagatgaatcaataaaggctatgaacgggtaactcaataaagtatcttcctggactgggatgattccgagaaaacaatcacaaacgat



acggtaatgaataggaatccattgatttcattttatctgtaatttcagtgtctgacaagagatcgtcgtttcggaattattacaggcccaaatatgg



ctggaaagtcaacatatctgaaacaagctgcccaactagcaatcatggcataggtaggatgcttcattccagcaaactatgcttcgttgccaa



gtaacctaaaagttttgatttgctattttctatcgtcgaattaatttcagtttttaatcgtatcttctccag



ahi-14




SEQ ID NO: 97





gatggtactgagaagaagaccgatttcgatgctccaacaacacttgcttaattattcacggagatgtcataattacagctttggttttcattatttg




tttggttattatttatatcacaaatttcgctaatcggcgagacccctctattgcttttctctcctatctcgtttttgttaacccagtttcttttgaatgaac



ccttgttatgacgattttatggttttccaacggtaattcaataaatgatattatatgtggaaatcttgaatctgatttgatcgatttagtctcgaaacg



ttcatgaaggcaacaaacaaacaaccgttgattaaattagttttttgaatttcgcgcacctaatattccagaggagcgggcttgcattatctttttt



acacgaatttcttatttacagtatgcactattctttctcctctcccattaatttcttgtcaatcccatccctttttgtag



msh-5




SEQ ID NO: 98





gcgagccgtttttttgagaccctgaaattcggaatttctttttattttatatttttaaattcatttaaatataaaaatagagcacaaacctcatcaaatg




tgctcactagaaaattacacgtcctgcatttttcgtttttgatggtgacttctttttgtgacgtggcaccaattaatacagcaagcaggagcagtat



ccggctcattttcaccctgaaaaatggaaaaaattggatttttatgtagctttaagacacgacaaaccgttattttagagaaattacacgcagaa



taagcgaatgagcgcggccgaatgcactgcaaattgtctacgttgtccagtttctcggccctgtgagcggagaaaagagagggagaaaa



gaaaaatgaacaaatattggctttgaccgggattactagcaaaagaggtgactgatggaagagggaacaattaaatattagaaaaattcga



aaaagttaattattttcgctggaaatcaccttaatttggggagtttcgaaagaaattttgataaaaatagaattatccactttttatttcgtgaaaaa



aacaacaatttcgactgaaaatccagctttaattcgagaaataacaaatatttatttatttaattaaattaaattaaattaaagaaaataattgaatta



ctgtagtgatcgttgcgggacccgatgaaccgaaatcggtatgcgccttgtagttacggtaagaaaaacgggcggtgtcgagaatttaattt



aaattgcatttccaaaacaattttcctcgtttgaaaataaattttacgagtttttggttagtttaaatgctaaaaacttgatttaatttaataaaacgta



cctaaaaattcagtttcgtagcagaaaacacgaaaatttcagtttttagtaaaattttcggaatttctattttcaagtcttgtttatagttactttttatg



gtgttcaatcaactttttgaagtttaaaatgtttaaaacgtttaaaattactttacaagaaccgaaaaaaaccgaaaatatttcaatttttagtttttca



gcaaccttttcttaaatcagaaataattttatgaaattttggttcaa



tag-63




SEQ ID NO: 99





cgagaaacatcaaccatcgaagagcagcttccttggccagagtgtcgtctgataggtcgatgtagtcgagcaggcacacgactgctctgc




acagttctccgttgtaaaagtagaaaaagcagagtttcgcgggaatactcgcgaaaatctctcgatctttgctccgacactccatcgcctcctt



tcgtagagtttgccacgtgatgaacattttgcatgcggttcgttgatacttcgcaagtccttgaaagtattcggacgaggcgtagtatgaggtg



attcgagccaatttgctcagcgagttcatgtcaatcggtccattgacgccgaattcggcgataaaaagctcggaaatctcctgttgcaactcg



gcagtttgttcggcaaacccgatcaccgtgcagctcacatttttgcgtagctcatctagtttttcgatgtgctgcttgtcaactgacttgtttgtga



tcttcatgaaagtttatctagaaaaattaaaattaaactgttttaatggaattaacattattacatacataaaaagcaagttttttgattgattttcatta



aaaatcgaggaaaaattgaaaatgaaagggtttcaacgcacgttatcttctaaaaaatttaaaaaattttcttctagatgatacgcttcacatac



gcgacgcgtaacattggagcaacgttgtcactttttcttaaaaatctcttataagagttggcacggtgccagatccggaattccaccagatctt



gaattaaaataagtttttttgcaagttttagcaagttgaagcaagtttttttattgattttcaccggaaatcgaggaaaattgaaaatgaaacgattt



tcgaggcaaaaataaaaaatttccctccgattttgaagtccgtgaatgcgcgtgcggtgcaactgcgtacaaaacaccaaactttacgacag



tgcggtaaattctacttttcaaagtttgagccccaaaattcgtttaatttttgtttaaaacttttcttgtttattgaattatttacattttttcagtcgac



polq-1




SEQ ID NO: 100





ttgaccaagatactttgaaatcatccgcggatcatacacaattagtacaacgtttgacatttctcctgaaaaatggaatttcagttctaaaaacac




aaaaataaagttagaaattgttaaaaacaaaaaagtttatttgaattcgccgaagagcgcgccaaaacatgtgacatttctcggccgtgaaaa



ctaggccaccgcggccacaaacaaattttagttttcttcgctgaaaaaaacatgtttttcagtctgaaatcagagtttttagtatgaaacaag



him-6




SEQ ID NO: 101





ccctaaatatattcacaatatctcatatttctagatatgcagtttcttcttctggaactacacatcgttggccattatgcttcgcccatttggtaatga




tttggatacttgcgttgcaccttgggtcttctatctaactcatccggtttttcggaagaaagttgttcagagaatatttatttttaggcctgactcatg



ataataaagtttcgatttattttctataagtccgcagagattgaaaagtggcaaatttgattttgcttattccataaaagttatctctacttaattaattt



tatcatgttttatgcaattttcaaagtaatgttggtgcgccaaaaaattctacttaagcttgaaaatttgagatgaaactctaaattgtatgcagttat



tttggtaatacagctttcaaaacacagaacttgcatcttttgatcatttctaacaatgtagccttcacctaattttagttcccagaagttaactcaga



cggataatgagcgttttaaatttttgaatttctggttttgccgccaatacttaacaagagcacacgctatcttgaggaaaacaactacctgaaaa



ggggcgtagtcatttagttcacacttctctgtgcgtttttttaaataatgttagtttccaaaaatttttagagacccgaagaactcgggggatgtcc



aattggggggattaccaactcgggggacacggttttaaaattattttttcttgttaattctcgctctattgagaaaaatacagttttaaaaccgtgc



ggcagttgcagaaatgggcgtattgcaagccacggttctgtgggcggggccaatcccccgagttggtaatccccccaattgggcatcccc



cgagttcttcgggtctcaatttttagaattgtttaaaaataataatgccaacccaaagcacaaaatccctgcctcttaagtgacagtcttcattctc



cgagttttgaattccaggcgtgtgtgacgactcattcaaattattgtttttgtttttttttcagattctcactcaattttgaaattttctgcgtttcaaaag



gttttttcggaatattttttaattctaaagcttcaaaaactgaattaaaagaattttctcctaaaaagtcgccgaagaaacgcagagaaaatcggc



aaaaggcggcaaacattttattttcaaattttatccgctttcccttgtgtttatctttattttccctcaatttgcttaaccgaaacgtctgttttcagaat



ataa



xpa-1




SEQ ID NO: 102





ggacgtgcggcgaattgcaccaattggtgcatgttcaaaaaggaacggagaagagccaccctgtgaccactcgagcactaatttgaatga




atcaacctccccaagtagtaacatactaaccgagaatagtttgaagttctgggggtataaacaagaatggagatagcaaaactaacgcccg



agagtaagtaaatacttatatggtgagcctaagtctcgcgtcgatttattgttttctgttcagaacacaacgtgcatatctagaaattttcgatgat



tcatgcaaaaatgttttcaaataatttttcaaaaactgaagaaagtttgagaaataatataaatttaggctttccttcagataaatttaaatataaaa



aatcatatatattttcaagatgcgagaaaaatatggaagcggccagcagagatacgctatagcgctaaacaatgtgtgcgattcacaagagc



ttctgaaagataaaaattgtgactacgattcaataattgattcaaagtttgataagtcaatcgatttcaagtgaaaagaaagagcttgagaacat



gatgagtagcaggtgtagaaaacgcatcgacgcgattttttgttttgtttggcgccactaaacacacagacattcggtcatacactcttccaaa



tatagtcaatatacagtgtgttcgagtgagagagaatggaacatgtcgaaatatagtgtctgaagacgagacactggattattttgacgggaa



agcgtgttccttccggttgcaggatgctggtgcagcaaagtgtcaaaatcgatgggaacagggaaggaccccaaggataattgaaagatg



agcgaggagaaagagagcgactgaatgagttattacgagcggcagatagccggaatagctggcctattttacattgcggtcgtcgctttttg



cggaacgggtcgaacggttttcaatgcaattagacgattcgtcatctttttgacattttttagatacaaaaaatacttatcaataaaaaagtttttta



gaaaaacttaaaatatcgaatttatctttagaaaatgaattaaagaagatgaaaaataaaatgaaaatctaaaacagattccataccgtagtttc



acacaaagggacatttatagttctcaaatttgtgtcccgccgcgaaatcaaaacaaaagaaagttagtccgtgtactccactcggacaacattgtt



tcgcaacacttttttctgcgaacattaaaaaatataaatttgttcaacttccattttttaatgttatcaaatgtttcaatttttcttaatttttatgatatt



ttcagctgaaatttttgtttcgattagatcacaaacttttttttgatgtttaattgaaattttagagatgtattagaaagttttttaatcttcaaacaaaaa



acatttttgtcaaatcgagacctcaaaataatttatcttttcaatacaatttagtttccttgcttttaacgttcaaatcttgatcatttctttttttttgtt



tataaacgattgtttcagataa



nth-1




SEQ ID NO: 103





actgggtcgacgagaagttttggaagtgagaatttactaaaaaaaagaattaaaattagaataattctgtagacatccacaaatcacctgttttt




cagtcgatgaaaacttgaaagtttataatcgtctactttatcctccttcttttcaaagtcaattagaacaccatcagctcctgaacatcgattttttat



atatcgatcactgggaaagaatctgaaatcactgatataatagagacattgcattgttgacataccttgtcagtcgaactcgaatcaacgatct



gatcttcattttttgtgttagttggttagtcgttagtagattataaattcggtaataaatttatagtggtagaaattaatgagaattatatccacgaatc



cgcgtgtactgcggaaatattcattttatatttataaaaaatgttacaagtgagatcaaatttttttttaatgtatcatagaagagaagcgccaaat



caatagaatgctgcacattttaccgcatccaatcgttccattttctgaatttgaaataattattcatagctccataacggttgagtaacgtgaatga



taattctgttttaaattattaagactaattcccctatttgaattccctccaaaataagaactgcaagactagcgatttgatttgagcaatttgcatcg



cctactttccaaccaatcaaattaagtgtgcgaagttcgaagtcgcctacctaccatatacttcccatcgggtctcttaacaatcattggcttga



acgaaacttctctacaaactctcgttggtggcgacagaaaccgtcttgtcattttgccacgtagcaatagatccgccaatgcttcaggaatctg



atttgatttcagtgcttctgatggaatacttccaaagcatcgatgaaatgcctgtgggactccatcaatgtcttcgaattggaacttccatagaca



acatggttgttctctgaattttaaaaaaatgattatgattaatgattgagtataagttcctgagccagttgggcaacctacattccaagagaagg



atcgcactcctttccaaatgtgatccttggaagtatggactttgtgtcaaggattgctcgagcatccagattccgtggtagaagatatcgattgt



tccaaaaatcatcgagaaccactagaatctctctgatcctagacctctcattatatgaatttacgatagaagttgtccgaaatctggcattttctc



cccaatccatcggttttgtttcaattgggtgaatttttagaaacgtctcacctgaatcaagaggatgtgatgaagatcttaaatctctgcagttca



ccttcataacatacgtacatcagtggagacctacttccagggtctctgaaccatcgatcaggaatatgaattgttaaactgaacacgtgggtta



ctgtagttatatttatatttctcacttaacaacaggaatcggtatctgtttgatagggttgaagtgtattccatctcgaaaatgaatcggaacatgg



aagaattgtttcctggctagagatccacaaaagttcgagacgttgtcaccggtaatccgatctccgagaagaacaatctgtaagaggtctcat



ctgggagaagcttatttcagtagttaccttctgttcagactctgcgattccttgactataatagtcgatcccttcaagattctgatgaattgcatcc



gaaaatgcttctttaacaacttcgtgcaaatgaaaacgtaattcgttttgatcatcatactgaaacttcggaaagattttaagtattaccccgatcc



aaatgtttcgaattaaagttataaatacggtacccggtttcgacacgatttttgtcaaactcgaggaaactacagtagtccttaaaggcgcatac



taatagcgcaaaatctcaaccttcgcttaccaacttacccgcacaccttcctttctctgcgaatcaataataaaattcgaaatcggcgtcatcatt



ctataaccagtacaatgaataatcaaactaaatagaaaggcagcttgaaacatttctttaatcttctcgcaacgaaatgtgctccggctctcca



ggcttatcagtgttagaagagaagagaaggataaaacaacaataaaaacagttttcatttgtctcgtttcttgcttcttcccccacgatctgctg



atctgaaaatgcattctttcagt



sir-2.2




SEQ ID NO: 104





caagtggtatgccaactcatttgagagatctaaacatcgaagcccatcctctacttcgacagcccgtagaagttgtgtagcacattttgaacat




gtgagcctgtacaaaagccataatacttctcaactactatcatcgtcatctctccgtcaccaatgatctctactcaaaacggttatggacggtttt



tttgcataaggattcaactagccctacacgattgctttgatctctgtacatttttgcgtttaatatggatatttgctttttaatggattttcgatcttcta



cttttattgttgatttttctggttttgtgggggttgtgtacaaattttgtttatttgttgtcggtaaccacgggtaccatattatgtgaatcgtttatcatc



gtattaaatcatgtatacatgcattgtacagagtttttgaatataataaatgaacatgacgtcatttgcacctactttgtgcttttgaactttcactgtt



tcagatattttttatttatgaaaaaaggtatctatgaacaagcttttcaatacattataactttgttgtatctggtctgatcctcaatatttttgagtcttc



aaaagaaacaattataaattgcaatacatctcaacactgttttatggcgtctcaaattttgaaaaaaaaaattattttataaaaattgatttgcagc



agacatgttgaaaacggtgcttttcttttaaattatttttgttgtgataatgtaattaactacaactttacataaattgaactgaatatacgggtcattc



atttttacaaaccttatctattctatcaataccatgacttttttcgcgaaaagtcagccgacatgacatgactcttatctcttttttttttgttaattcttt



ttttgttgcgacaaattagtgtcaaaaaacgtgaacccattcgatcacataacattttgaacttcaagaaaatcacacaatcgataaatgatgaag



tatggtaagtcaaaattttctaatattccaactgattaatagttagtgtgtttgagttttactttttcaaattaatgtttacattaaaacaactataacaa



tcctcaattgaaatattgtacacgaaataaaaatcaaaacatatgtatgaacatatttctcttatctttttgtattctgtcaaaggggtctaatttttttg



accatttttttgtcagttagaaccaaataaaatcatgccgcatgtctgtgaaaaatcaccttattctttctctttgagattgataaaaacgttctgta



ggttttccaaaatgttaactaaaaaatcaaatttaagccgtcggtatagtattacaggctaggtataggatgctcggataatattaattttaaaaat



tcgaaaatgcatcatacataaaactttttaatacaaaatatagatgttttctttttatttatttattaatataacgtatctatataattttcaattaagcaat



aaatatttttgaagatttgaggataaaactaagcaaattctaaaactgcaatgttcaatgaaattgcgttattcagtgttacctataaagatttttca



aaacgttactctcttattcttctcccattcacgtgttgcactttctgccagccgccttctcggagaaactaggaaatatctgtgactttctctagcc



actctctactctctcgtcagtgcaaatagagcgcgaatgctttaaaatgacgcatcaatcactctgtcggtcatttgattttacacttttcactgat



agcttaaagctcggaagcggaactatagtgaaacattttataaattacgatttagatttttttgaattctgtatcatgctgcctaatttttaataatttg



aatatttttaggc



exo-3




SEQ ID NO: 105





tgcccagagagccgtcgaccaattcaacggagtcgatttcaacggaagagctctacgcgtcaacttggctcaaaacagaaacaactaattt




tcatatcggtactttgttacttgtttgatctttaatgatctcaataataataaacccatgaaatcgttatcataaatatatatgctctatttttttatttcga



atcttcatttggggtcaatctgatggcaagcgttgaggctagaagcttgaaggaacggcttcggttcgagcaagttttgaatcctgggctatg



cgcagcccaatgtgagcttacaactgaaaattcaagtttcaacactcttcgcggtcttattttggactaattcctcatattttcagcttgaaatgga



aaaaatctgtcgaaatcgatgctattcgaggggcggggccaaaacgcaaccctggcacggtttttacgcaactgccgcacgttttctccaa



ggcagggtgagcggaaaaattaaaccgtcataaattttctgctacggcctaaaatcgtcatgtctggaatcttctctgtttacggttagtttttta



ataatttattttaagtattaaacaatcggaaactggttaaaatagccaataaaactcgatattgtcctgaaattttgggatttttcggaaaaatcga



attcgcgaagttttccctaatattttcatttgaaaaggcaattttaagtgtttagattcaaatttggttgcgaaatatttaaatcaattaaaattttccttt



tttttagttggaaacgctccattccagaccaccgaggaggagcttggaaacttcttcagcagcatcggacaaatcaacaacgtcaggtaact



ctcccagccagcccgagcttcatgatttctaacgcaatatctctttcagaatcgtctgtgatcgcgaaaccggacgtccacgtggattcgcctt



catcgagttcgccgaggaaggatccgcacagagagccgtcgagcagatgaatggagccgagttcaatggaagaccactccgcgtcaac



ctcgccaacaaataagttgatcttcatatcgggtttttgttacttttttgctcttcactgatctcattattaataacaatccaatgaaactatcgattta



attatttaattcaatttcaactattctctaactaatctgttcaacattcggggaagtttctctatttgtcatccttccatccgccgacctgattcaacttt



cttcttccccagctgctccgttcaagagcctactcgactactaacctgttgctgaaa



ung-1




SEQ ID NO: 106





tccggcaaatcggcacatttccggaattgaaaatttccggcgaatcggcaaattgccggaattgaaaattttctgcgaatcggaaaatagtg




ggaaattgaaaatttccggcgaatcggcaagtttgccggagtcgtaaatttctggcaactcagcaaattggaggaataaaacatttgcagac



cggaaattgtcgcccacccctgttttgcactacgctttgacaagtgtgaatttattcgctttttttatttgcctgaattttgccgataaagaagatttc



cggcaaagtggaaaattgccggaatttaaaaatttccggcaaatcggcaaaatgcccaatttgccgcccacgcctgcttcacaaattgatta



attgcagcctcttccgtagctgaacctctggaagaagccactacaacgagtgtgccagagccaacagagtttcaattgtcacgggacattta



tagcactgtaaagccgactgatgaggctcatagcccgccgattcaagcccaaccgaagaaaaaagccacgccaagacggaagaaagc



agatgacgtggaaactgtagtagctgacggaacagcgacgatcccgaagccgaagagaaaaaggccgccgaggaagaagcctgagc



cgaagccgaatatcgtttttgaaacaacgccgaatcctccgacagaaagcttcgcagccaacaacaatttccagcagttccagtttcaaaat



cagcctggtagttggacctacaacaatggattcggcaatggatatgggtacggcggtggaaccactggatacatggataatcttgttggca



gagggtttgacacggtttctcagcagcctggatttcagaatcaaggtacattttttaaaaggaattgagaaaaatgtgccaaaaaattttaaag



gtggactacgctttgtggggaaattgctttaaaatacgcctatggtaccacaatgaccgaatatcatgattaaaaaattcaaaaattttttctaaa



ttttatatgattttttgaaaattggaaaaatcacagttttcccctaattcctatttgaattaccgccaattgaatttgttcgatggggcgcgcttgcac



gtttttaaatttatttattttattttttgttattttccaccgatttttaatgttttcggtgtatttttgctcgaattttagagaaaaagtcaaaataaatgc



aaattttcgattaaaaagtgcgcttacaggcgtaaatcagtgaaattaattaattcaggttcgaaatcgtttaaaagcgttactttttcatttttacgcct



gtaagcgtgctttttaatcgaaaatttgcatttatgttgattttttctctaaaattcgagcaaaaatacaccgaaaacattaaaaatcggtggaaaa



taacaaaaaataaaataaataaatttaaaaacgtgcaagcgcgccccatcgaacaaattcaattggcggtaattcaaataggaattagggga



aaactgtgattttttcaattttcaaaaaatcatataaaatttataaatttttttttgaattttttatcatgaaattcggtcattgtggtaccataggcatgtt



ttaaagcaatttccccactagcgctaccccacctttaaaggaattgtgaaaattgtgaaaaaaaaaatcaaaatttcgaaaaaaaaagcgcta



attttaactaaaatctctaattttggccacttttccgtgctgcagcgtccgaaagtgcactttttttgaattattattcttattattatacattaaaaacc



cccgtactcctccaataacgccaatattatcgaccatctggacgtgaccgcgtgcaaccacggcctagctgccgccaccccattcaaacga



gacatttcggcgggagagtcctttttttcgataattcggatttttttgtctgtttcaagtaattttcgccataaaaattaccattttcttcttcggtgcc



atttctaatgattttccagtgcgttttgagtctgaaagtttgaaaataagagtttttgcacaaaaatgtgtgagaaaagttcaagaaaatcgtcga



aaaattcaataaattaattttaaaatttaaaaaaaaattaattttttttaaaaatcaattctgtgcatacaccgccacgcaaaagtgcacacaattac



ctaccgtagtcaatgcgaaattaaatgatttttatcgattttcttcattttcaggttacgaattcaccggtttgcctgcaaataactcgaataatttcc



catttttgtgatttaatttttcaaatatccttatctatgccctcaggtttattttatctcatttccactcgtgttttttgaataaaaattctttttttttct



tctagatttccgtttatttcaga



mrt-2




SEQ ID NO: 107





atttttcgaatattttgtctgaaagtttcacgtgatgtcagagtgtctcatttcggcttgatctacgtagatctacgaaaatgcgggagttgagac




gcagagttttcaactgatttcgcatggttaagaacgtgctgacgtcacattttgttgggcaaaaaatgcccgcgtttttgtagatcaaaccgtaa



tgggacagcctggcaccacgtgaaattccagaaaaaatgtctgaacctactgtagttcacaatttaaaggcgcataccaaaaaattatagcg



ggaattaaatttttatttaataattttttcagttacagagcaattaaaaaattcaatttcatcaaaattttatagaccaattttctcgctttatagctgag



ctccgcgagccaaaataggaaggggagcacgaaaaaaaaacagaaaaatgagctcgacagagcccatagcctcaagcgctaacgaac



caaaaaatgcacacacacacaggaggcggagtcgtggaaatttcgaaaaaaaaaacaagattttcttctctctcggctcaaatttgaatgcg



gagcaagaatattacgggaacaaaaaattctgagaatgcgtactgcacaacatatttgacgcgcaaaatatctcgttgcgaaaagcaaacta



cagtgattctttaaatgacatttgtagtgtcgatttacgggatctcgattttcgaaatgaattcatttatcattgatcgagcccgtaaatcgacaca



cgcactacagtagtaatttaaagggttactgtagttttgttttcgctacgagatattttgtgcgtcaaatatgttgcccaatacgcattctcaggatt



ttttgttagcgtaataaaataacagaaaacacagaaaaaggcatgaaatttaatttgaaataccgcgctgagttttctaggccacgtgtcgtgt



actccccgtggacaagcggtttttgccttatttttctgaagtacaaattctcaagtacaagtaaaaaagtacaaattttaccaaatttgaggaaaa



gaactagcatgacaaaaatagaattagaaaaattctagagaaaaactacggatttctggcttccctcataaaatgaaatggaagagtttgccg



aactaggccattttggctcagccatatctggagtagatttacggcgcgttccgtgtcgcggctcgattttagttgtaaaactaaatgaatttgtc



cgtgtggagtacacgactttaccacgcgttgtccggcaggcgattgtcaatggagcgcgaaaaattcaatgcaccagatttgacgcgcaaa



atttgaattttcaagttgtaaatcccttttttcttcccattgtcccatcaaatatccttcttcaaaaaaacccctgcgtctctcaggccatatctgcgg



tagatttacggcgcgttgcgtgtcgcgtcgcggctcgattttagttgtctggcgggcgattatcaatgaagcgcgaataaatcaatgaggaa



ggccagaaccccgtgaagatccaagaaaagttttctaggccacgttccgtgtactccacgtggaaaatgtcctttccggcaggagattgtca



atggagcgcgaaaaattcaatgcaccagatttgaccacgcgtcgtgtactccacgtggaaaatgtggacactagggatctactaaatgcct



ggaaaatcgtaaaaatctcgaaacttcctaaagaaaaaaaaagcaaatacacaaaaacgcattgatgtatgaacaaattgccctccccgtct



cccaccaaaaactcccaaaaattgctcttttttcatgtttatatgggggaccgcgggatttcataatagctccgtggtccgctcagctcatccg



gagccaaaaagagcacacacacacacgcacacataaaagttgtaaactagtttcgagcaaaaatgatacgacggatgagtgtgtcacgca



atcagtgagcttctctcgctttcgaaagaaaaatctttttcgcaaaaagaaaaagtactttacactggccacagtgtaaaataagggtgaaaa



gatcgaaaatcggaggtttcaaatttgaatttccgcgcaaatgagagggacgaggtgcgatggcctacaaaactccgcaggtgtactcctc



tcggaaaacggtgcgagaattaattttttaatttatatttaattttcagcgatttttctcagttttccggttaaaatttaaattttttcaggaaaa



rae-1




SEQ ID NO: 108





aaactgcaatttcgtaaacgattgaaaattgagaaagatcaggtatctgaacaaaaacttgtacatttgaaatctcaacttcatttattccaggat




acctacaaatatgaatcctatgtgcttcaatgaattctacaggaaaatattcaataaatgaccaaatcgaaaaactttatttatgatcccaattatg



ttttctttgattatgctacaaattcaagaatcggcaaataatgggaaaatacgatttttttttcacaatcaatatatactgcttgatctctctgttagaa



tttcctccaaaatctgaactgtatgaccaaaaatcaatttttttgaaaatgcatttgtcccaatatttcctttctaccattctgctttgatcttttttaacc



tttttattcgaataaaaatatattccgaattaaatacaattaatgtgtttccaccaactttacacataaaaattcattttctgatgtaaagattttttctaa



catacatgcattaacttatttctggagaaatatttctctggtttaaaaaaaaaaacttctatttagttatgatttttccttttcacaacgtgaaaagttg



caaaacttctgcgaacgacgccacttctccacggtgttgtttctccggaacatttttccccagtgggacgccacgcgcaactgcgctctactg



ccaattttcaaaaacggaattctttcgctgaaattttctttaattttctttcgtttttcaacgtttttcattctctaaacttaaataatcgaaatatttcgaa



atgattaatgaagaaaggtaggcgttataatatttataatcaaaatttctcaatatcatgttagatattcatttttggcgaatattcaacaattgaaa



atcaaaataccattatttatcgactggcgttatttttattgtttcagaaaagctgaaataaagcgaatgttggaaaaatgccgtaaaacggaaaa



ccgacagaaattttggcgatggttgcccaattttcagttgaacagctggcagactcctgttgtcattggtgttgcagctgtttctgctgcaattat



ctatcactatttttcctaattacccttattcctattgttcaatttttcttcatcctgattttgtgatctacctcatgtaataattttctcttcttctttatt



attttctgcgctctgtactttcttaaaactgtataaattaaaattgcaga



rad-23




SEQ ID NO: 109





cccacacagccagaagatttttatgggcggcagacattttcttaaatccaataatgttttaatttgataaaatcgaagataaaagttcacgataa




acacaagtgaagttaaaaaataaaaataaaacattcaaaaaagaaataaacgcattctccgtaaatcgacacaatgacaattctggcaggtc



tcgccacgaagagtgttcaaatcatgtgcgcctttaagacgccaagccattttctcttctgttttttaccacttattttgttcttcaaaatggttttttt



gttttgttcttttattaataatcaaatgtttgtttattttatacatatatactgcttgttttgcattaatatcaatctgttatcgatatttatttctttttc



tttcaatacatgactctattcgtaacatttcacaattttttgcagg



brc-1




SEQ ID NO: 110





gaacgtccgacatgatgagatgcaataacctgaaaatgaggcactttatgataagaaaatgcggtaaaacatgcgaaatatggcaccataa




accgtgagcaggacaaagaacaaacacttggaaaagaaaagaaaatagaaagaaaaaaaggaaaactggagaaaacaaactcaataa



cacaacgcgagaaatacaatttcgtttcgttttttcttctatttattagatttctcacaatttgttaccagtaaagtcacgttctatatttcaaactactc



ctaaaattcggtttgaacagttctctgataaacgaatttcgaagaacgatcagaaaacaaatctacggttgtgtgtgatcaatggggtcaaac



ggtggacgaaaggggacggcggagagaggaaaaagtgagagaaaataaataaaattgaccttcgagtgcagagttttgctggtattttgg



tcagaattgattatgaaaatctgaaaattaccgccgggaaagttgaaaatttgacgtggaaacgtttaaaaaaataagatgagaaagttagta



ctgtagatgtcgtcggatcaagtgcacagtacgcaagcaccgttacgaaaaattgcactaattgctcaattaaatttttttaaaaaattaattttta



tagtgtgttttgtgttttttttctgcttttttaatgatttttaaaggcttgattatgtttttttctcaaaatttgaataatcaataacattaattaattact



ttattaaaaaaccacatttggcattttaataaagcaagttatcgcgacaaacggcaaaaatgtctctttttataaaaattgtttttttttgagttaagagaa



gatgtggagttttttgaactacattagttttctaaaaattttatcatctagattttgaggaaaaaagcagattatatatctttaatcttggttttaaaattt



ttttaaaaagcagaatattaaagtaaaatattataaaaagaaaaattcgtgtttgcaaaatttgtttgaacggaaccttgcaaaaatgatatttagc



agctaaactaactgaaaactactgcataaagctttcccaaaaagagctaccatccagaaaatgttttttttttcaaagccgaaaaagaagaaa



aaaagatagaaaaccgaaaaagcagcatcgttttcgcgcactctttcttctttttttctttctttttctaaaaaaaaatattctccgtagcttgaagtc



tcaggatttccaaagggaatttccttgatagaatatggaaaaacaagagagtcatcagagaagggagaggaaaagcggggatgctggcg



aagaccgggggcaccgactgaaatataggcaccggcggggaggcggggcgctctctcctctccgctttactccgccccgattgtcagtg



gagcaggtttgcaatgagtgttctctgatgccccctcagcgcgggagttttgaaatcaaatattttgtattttaacctactttattgatttttcaatta



aaatgaaatgttatttgtttaaaatttaatttcag



brc-2




SEQ ID NO: 111





tgtaggtctaaaaatatttgtttgagaataaatattcgaaatcaatctaacgtttttccaatctacaggtggcacgacacgctcacaaccaataa




gtttcttgccacgctcgtcgattttttgtagaattcccatttctgagagtgtttcttcgctttctgcttgctctggaacttctgaaataactttcccgcg



attatttggatttctatatattttcaaactacttacctattttcgttttccaaagtctcgaattgtgtacttgtcgacgttggttccagatttgagcattat



gaagaattccaattttaaaatcacaaactggctcaaaatctatacgctcgaatagagaattgtgtgatgtaagagcctgaaaattatatttgattt



tctttccatctttttttattttcgggaataataaaacattcaaaaagggctgagatctatctatttttcacatgcgacccatttctatttcacgtgaagc



acatgattctgaagggcaatggaaatgaaaacccggaaaaacaaaatctttcagtttaaattgtatcaaaacaagtttttctagattacaaatgt



acctgaatagtgatccatgaattgggacagaccacatcgaaataacatttcacacgtggcaatggagccattttgaagtttggctgaaattaa



atttatgtcgagaaattaaaaaaaatcagagcgtcatcatgagaaaataggaaaggtttagactgtaaaatcaggttttcatggcgggaatga



cattaaaatggtgataaggtgattattttatcaaaagaattttttgaatgattgcacctaaaatcgagtgctttttctttaatttgattatcaaaagaa



aatacccaagaaatggaaaatgaaaatttaagagatgaaaggaaaaagcgacccggaaaaacatcaagctgggaagaaatctcaactag



ttagaccaaagcttcgaactctgcgagcatgtattttttttcctcactttctccttttcttctctatttctctagatctttattactgcgggggcaaaaa



gagtaagagatagaaaagaatgacgcaaaaaatacacggatttaatatttgctttgcttttttattcagagaggaaaggtcaattgggggtttc



ccctcgttttatgaatgaaaaccgcacataaatataattatttccacagttttaaacggcagaaacggttcgtgttataatttgtgagataattgat



tttgcattacgaaattagaagaaaaggcggaaataaataaattagtgtcgcaatttttttctcaaaaaggaaataatgcaattacgctccaccg



gacagtaaaattctcagtttatttgaaaaacaaaaatttaattttttccctttttttcaattgaaatctcaaatttctgaactcaaaatgaaattttcaga



ctttaccagaatattgtgacatcgaccg



rad-50




SEQ ID NO: 112





atcgcagaaatgtgaaatcataaaatccatagtgagattgagttgtttattattttatgaaatgagataatcagttggataactactgct




cacgccgtattcgatctatcattcgattctccgattctggaacatcaaattttaatcatagggagagaggttcgggtacttgagaaaa



aaatgtcgtgtttcgagaggttttgaaaagtcagttgttaactggttcggtcaacatgtagagattgtagagaaatatgagaacttag



agaattgacgtatgaagagaaaaaagtgggaaaggggagccgctgttgttttcgaaagaagaaaataagacagaaaaaatcgg



agaggaacataacaacaagttaagttgacttttgaactggaaatttgtcaatattgaaaaaaggaacagtgagaaatatcgatttcc



acgtcgctcgattctatgaaaagaaattatgcacacacaagcttcacagtgagcatgctgaatgattgagcaaatacatgagaga



ataagagaggaatgagatgaaaagaagcgttcaaatcaaaagaaaccagacaaaatggcgattttttacgggaatatgaaccta



ctgattggcagtggacagctggaagaataagaagatactgaaggaaggttgaagttgaagcttggaagacagatgatgagaga



gaggaaaacctgtttctttttgattacgatcggacggaaatgagaaggaagtaagtgttttcacacgtaggtgggcattgagatcttt



gaaggtgcattcgacaggttaataatcattctaaataccaggtgacaatggaggatacttttaaacagtaaatatattggaataaaa



cataaaagttagtcttactcagaatttctaaaatttcagccttctggaacgaaaggtaaaatcataataataatacaagtggggctgtt



agtagccctaaatacaagtaaaatgaccgaacacagccgttaaagaatgttgcagaaaattgcgaaatatttccttactcttaagaa



caacattcgatgtgacgcaatatgatgcatttccttagacaaaaacgttcagttcaaaataaacaacaataaaaccgtttgtacgatt



tctagaatacgagtttatcagttgttcggaaaatatcttatcaatcgtttgactgatgttttttaaccatgtgagaatttgaaaaaaaattt



catgattgccaaaaattaaaataaacaggaagcttttaccgagttttcgtgattttcagaatgaagaaattaatatgaagctcaaaatc



aaaagcagagggaaaagaaaaaatcgaaatcttctttcggttaaacaacacgcgcttgcggaacttcggagcatcgtattttgtttt



tgcgctctatttttgaatcggaaactgtttttttgtcagttttcgaaattgttttttttctgtttttttacttcatgcaagagtttaactttacgca



aaaattaattaaaaatacgcagaaggcccactttacacaggaattaattgaaaatactcaggaatttcactttacttagtcctttttcca



gagtttccaacggaatcaatatattaatttaatttcgcaacatttttctttgaataaacctatttgcaaatgagaatgtttcagatatttgct



tatcgaagcctgggaattgctt



Y47D3A.29




SEQ ID NO: 113





Gcgtaaattggtttctataaattcttgacaaactcattccgaacggctgaaaatattgattgaactgaattcacattattcattaaaaaaaatagg




ttagcctgttatgtagagaaatttagtgaataaaaaactgaatatgtatttatttaatagatttctcggcacacaggaattaggaataactcccaa



aaaatagatatttggcaggagggccgaacagctgtgttttccgtgacgtcatacaggtcaatggacacaggatgtagtcatattacgggaac



acacaattctgagaatgcgcactggggcatttgatttgacgcgcaatatctcttagcgaaaactatttacagtaagaatttaaattctaccgtagcgg



gctcaattttcgaaaatatattttcttatcgaattttgagagcagtttttcagttttccatgcttgattttattattttatctttaaataaatttttttcat



tgaaaaaacgggaaaaacaccgggagaaattgatctggtgagaaaattataatatttctgctgttttcctgttgacaactttagaaatgtcaatt



aaacaactatattttaaaataatcatttatttttttaattacgtcaactagaaaacattaactttttgcgaaaattcacttctaccacactcatcatccc



gaaaacagcgaggtctcatgaaattgcaagcgcgctctactgcaaggaaaggcagcgcgcgaagcaaattttcaaacaattttttgaacgt



tttaccgcattttctcactttctcgcttaattttgctatgttttttgcgatttttttgtaatttttcttcgtttttcag



cku-80




SEQ ID NO: 114





tcactaaacaaaaaacatatatttgtaaaataccatttttcttttcatcaacagcttcaaaactatctgaagtgctggattttcgttcagctccgtcg




atcagctcgaagtcttgctcctgttctggagtatcgctcattctggaaagatttaaatacaaccgaggaaccagaagagcgcatgaaaatata



gagcgtgtaatttaacgtcagttattgacagagaaaatagaattacgaaagaccaaatcgggcaacgaggaaaacgtttaacacaaacaca



acactgaaaataagcaagaaaaggaggaagttatcggaaaaccgaagaactttcaacttcggaaagaaccgtttaatttatgtttaaaatca



aacaaaaaattcccgaaacatcccttttaaactttgattttcacgaaaaacaacgaatgaccgaaaaatgtgatcaatctctgagagtgtgcac



ttttgcgtgacggtgaactgtccgcgtgcaccagattcgacgcgcaaaataatcggcgcgaggttcgaacgaacgttcgtgaatttgtggg



agcggtttttaatgtttaaaaatcagttttggtttattttatttgaaaaaaaaaacgataaaagctatattccagcagtatctaaaatgatcttctttta



atattctaattttaatgttttaaaattcatttttcgctgcagcaaaaagttggtgtttgcgtacaaaacccgcgccagtcttgaaaaacgcacgcat



tatttattcacatgtttcgcaatatttccatatgaacttctcaacatcaccaatttaaattaagttacagga



him-10




SEQ ID NO: 115





cttgtttcatactaaaaactctgatttcagactgaaaaacatgtttttttcagcgaagaaaactaaaatttgtttgtggccgcggtggcctagttttc




acggccgagaaatgtcacatgttttggcgcgctcttcggcgaattcaaataaacttttttgtttttaacaatttctaactttatttttgtgtttttagaa



ctgaaattccatttttcaggagaa



polq-1




SEQ ID NO: 116





ttctcctgaaaaatggaatttcagttctaaaaacacaaaaataaagttagaaattgttaaaaacaaaaaagtttatttgaattcgccgaagagcg




cgccaaaacatgtgacatttctcggccgtgaaaactaggccaccgcggccacaaacaaattttagttttcttcgctgaaaaaaacatgtttttc



agtctgaaatcagagtttttagtatgaaacaag



lin-35




SEQ ID NO: 117





ctcttcttttactaatccatcaagcgacttttcacggagtaatctgaattaataatatttatcagtgcatatctctgaaaactaacttgacgacaaat




gcttcgacatcaaaatccggctttgtgacgtccaaaacactagacattttacattcaatactgaaaaattaaagaaaattcaggaaaactcgag



aatgaaaaaaaacagatttgagacaccatcaatacaaagggaacgaaatttgggggaaatgctggttgccgaaaaaataagtagaaggta



agatgtgttcaactggaacatacattttctgaattgcaaactcgatttctctcacattcacaatttttaatcacatttaatgcttcagttttagaaagtt



ctgaagtatcctcttcttcctattcagtttctcaaaatcgatggtgtctccaggacgtgcacaaatgcgctctattgcgaattgtggaacatcatt



gcgcgcgcgactagaaaaaaatgagcgcgttcttgaaaattattttgctttctctaattttaaacgatttcgattacattttatctgaactttcttgg



gtttaatcgaataaaaaacacaaaaatattcttcagactggtaaaaacttcttcaat












































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Xenobiotic Toxicity Genes






cyp-13A6





SEQ ID NO: 118





gtctagtttcaaaaaaaattaaattaaattaaattgtgtaatatgtggcattatttatatacttttttgtcgatcatctgttaagttagtttttagtcttatc




ttcttgtcgcacaaaacattatggtttgtgtttaatagaacaagaaagtgggtgacaagaatcgtatgatttggagaaacccagcaatcaaga



agattttgtttcaaaattcgtagtctggatactttagaatgtattctcaattttcgaataaagtttagaggatgttttttcaaacttttatcaatttttgaa



aactatctgatggttttataattattacagtcacatatttgtagcttgtgaatctaaacctattatgtatattctcgttttaaaaaaattaattgccgaaa



aaaagcaaaaaattttaatcttacgaaaaaaagttttttttttggatttatcagcttcagtgctcattttcatccctaactttctttcaagaaattttaga



tatgaagaacaattttaaaattctagatcaaccaaatctctgaaacaaaactagttttctattgtttctacatattgatattttttttaaactccattatc



atttttaattttttaaaaagttttctaactaccatctgctctccatcacctctttatgttttttgcatttgagcagtgaaaagtttgaagaatattggtaca



acttttataccttccaaaaagtgcttgccccattctctatgttctcttatcagtacactatatctcaacagtcgacacatttgtgtggaaaagtgttg



tttgtgtctgactgttgtttctaccaccgatactatttataaggtggtctaccgaaaaacatcaatacgtttcttttttattcctgaaaataaaaac



cyp-13A7




SEQ ID NO: 119





gtttttattttcaggaataaaaaagaaacgtattgatgtttttcggtagaccaccttataaatagtatcggtggtagaaacaacagtcagacaca




aacaacacttttccacacaaatgtgtcgactgttgagatatagtgtactgataagagaacatagagaatggggcaagcactttttggaaggta



taaaagttgtaccaatattcttcaaacttttcactgctcaaatgcaaaaaacataaagaggtgatggagagcagatggtagttagaaaacttttt



aaaaaattaaaaatgataatggagtttaaaaaaaatatcaatatgtagaaacaatagaaaactagttttgtttcagagatttggttgatctagaat



tttaaaattgttcttcatatctaaaatttcttgaaagaaagttagggatgaaaatgagcactgaagctgataaatccaaaaaaaaaactttttttcg



taagattaaaattttttgctttttttcggcaattaatttttttaaaacgagaatatacataataggtttagattcacaagctacaaatatgtgactgtaa



taattataaaaccatcagatagttttcaaaaattgataaaagtttgaaaaaacatcctctaaactttattcgaaaattgagaatacattctaaagtat



ccagactacgaattttgaaacaaaatcttcttgattgctgggtttctccaaatcatacgattcttgtcacccactttcttgttctattaaacacaaac



cataatgttttgtgcgacaagaagataagactaaaaactaacttaacagatgatcgacaaaaaagtatataaataatgccacatattacacaat



ttaatttaatttaattttttttgaaactagac



cyp-13A11




SEQ ID NO: 120





gaatcttcgatgttcattgtgaattttgtatcactgccttgcctttattcacttcaggaattttatgttttacttgtaatctcaataaaaatgaactttcaa




attaataataacaaactaattttctagttttacatcagatatctgctgagcttctgctcctcttccgtcaaaattaaatcaaattggctgagcagcg



gcccagtcaactagcgaagttaggacataggttttcttttttttttttgttgaaatgggcaaattgccggaattgaaatttctggcaaattggcaaa



ttgccggaattgaacatttgcccaaatctgcaaattgccggaattgaaatttctggcaaatgggcaaatcgccagaattgaaatttccgccaa



attgtgattttgcacttttttctggaaatttcagaatttcaatttcaatcggcaaatttgtacgcatcctattttgaaaagtaagcaaattctatgaaaa



tatctaaagaaaacgggaaaaaaactcaaaaagacactgtttttagtgtttccgttttataaaaaatgcctctaaacatttccgacaaatttgatg



atccggcaaacgacacaccggcaatttgccgacgaaaaaagttgccaaacggcaattgttactggatcttatagtgatcaaattttggaaaa



ctcaagtacagtcagaaaagcagtcagaacccagggtctattaaaacatcttttacacattgaaaagttacatatacttgaaaaaaggagaca



tagagaaaaactcagatactgtctctgacaatttttctgctttgtgccactgaatggtaaacaagctgaaaggtataaaaactattgcaatttttg



acagaatggtatttgaaatcaagg



cyp-14A3




SEQ ID NO: 121





atgtaaccccaataatttttttttgttgcattttactacttatatccgtttccattttttaattttatgttgtcacgttttgtctaaatagtgtaatcttctt




gtactaattattccaattattttaacccgtaagcgataaatgaaacaacactttttggtttttatttgctaattttaaataaattgtcatcaattctgaaaa



ataataaattttaaaaaaataccgaagaggcaaacaagacattttggaaattctgatccggataaatattccgttagatttttattagactcgaaatt



gcctgaaacccccgattttataacgaaacctcttgaaaacttctcaaaaaagagaagttaccaaactttaccaaatttggtctcccatcgacctt



caatgtacctaactctagttgaatacgcaagataattaattgctacaaccaaaattaaacggcggtttcaaaaaaatattgttttcagccgctgc



aacattgacaagtgggaaaaatttcaaattttaactaattttaggtcattttttgagccgccataactttttttgagaagttttcaagatattttattttg



aagttcggagttttcagacaacttcgagtcaaataaaaatattttttaagtcgacgacaccacctcggagataatctttaaaaaaatcttttcaga



aatgcaaaaattccaataagtgtcaaaactcccgagtagcgcttaagcagtggcacgtctgtatttatgtatttttgttttttttttttactttattatttt



gtgctttattactgttttttttttaaatttattttgtttcatgaaattttaggactaacgtgaaactcaacataaaaaagctagaaaagtttcgcgtactg



tattctatttttctttgattttattaatgtaatacatcacttttatatcttgagtgactaaactcttgttaagtgtgtttcaataatgttttgattttttga



ctttacttatacgtgctttgtagttttagtgacattagtgaccgaaagtgagacgataacaaattgggagcggtatataagtgaactacgaaacttct



aaaaaaacaaaggctgtttcaca



cyp14A5




SEQ ID NO: 122





tgtgggaaaagttggaggtttttgcacattttaggtgagcgaatatcccgttgaaattatagaaattaccgattgccggacagttttggaaattg




tcaaatccatctatttttcgaaaaattaatagaaaactacattggttttcagtatttgataagtctacgagacaaaaatgtctacgagacaaatgta



cacaaattatcaaatttacacttccggcaattctgattttcggaaattgtccattccggcaattttgcaaaatttgaaattttataaaaataattctct



acctgcctgcctacaggcatgccgcaactaaccttgaaaactttaaaagaaactccgaatttcttaaaattttaagtcggctggaaacttagaa



atctcttgccaagataaaaaacatcgagaacatcgtaatcaattttatttgatttgatacgttcacaaagtgaaattccaatattgaaaatcaaatt



caattaatcaattaagagttcagtgagtcgtccttgaaatgtaccaatttcacttgagcgctcagaatttcgttcaaaatcatcaatttctcgtcca



aaaatcgatgaaattttgcgagtaggtacaagtttgtgctggaaattaatttattggttgtatggatatttttttttaatttaagaattaaaaatttacc



atgaaaataaagtatgaaatattacaactatcagggtaaaccaagcaacgcgagatccagtcaaactgtacacgactaaactttaaatagca



atactaatctaaaaagcaaatatttttctttaagtagaagcaaggcagaagtttgacattttttccgaccagttgaattgtgattctatatacatctg



gttcactcgaatttcagacaaacaactccacattcctcaatttctgtgatagaacaataacttattttcttcacatttctctttcaattatgcattttcat



tctttaagtgtctttttttaaaatttgacaccatttgcccgcgactcgttgtccggaggtttcctcttacctcggagaaattccgctaaatctaccat



gcatgagtctcaccacgtggacaacgagttactgtaacttgtgtcaatttacgggccgctatcctttttttaaatgatatgtaccaattgatacaa



agaaatacttgttttgttatcaaaatagagtataaaatataaatgaaataattcaaaaattattctcaattgggccagatacaataggatagtggg



gaagttcaaggatgatattgtgtcagacaaggagcaaaaatgcattaggccagtttttacagaattcattccaagtacagaatttttcaaacatt



ccattaggaaatggtgaagaaaaccaatacatttcaacttccaaatttttgaaatggatttaaagcttccctataaaatttgtttatgaaaataattt



taacgatttcatttacaatcaccacattttttagaattctcagcacaggttgaattgttcagtaccttttttcaacatctagttcacctacatatgagtt



cttaatttaattacgttttttgaaaagtaaatatgttatttggcaagtccattcaaacaaaagacgtcgaccacttataatcaaaaagtacacttgc



ggcagacatctcgatacttgttttctctgcctgttgtcactgatcttatcgatatgtaatattgtgaaatgttgcgcagtgttgaaaaataagatata



aaattaggaaagaattgtataaaaatcagacaaaactattctgtccaacaaagatcatt



cyp-25A4




SEQ ID NO: 123





gatgagatgcaataacctgaaaatgaggcactttatgataagaaaatgcggtaaaacatgcgaaatatggcaccataaaccgtgagcagg




acaaagaacaaacacttggaaaagaaaagaaaatagaaagaaaaaaaggaaaactggagaaaacaaactcaataacacaacgcgaga



aatacaatttcgtttcgttttttcttctatttattagatttctcacaatttgttaccagtaaagtcacgttctatatttcaaactactcctaaaattcggttt



gaacagttctctgataaacgaatttcgaagaacgatcagaaaacaaatctacggttgtgtgtgatcaatggggtcaaacggtggacgaaag



gggacggcggagagaggaaaaagtgagagaaaataaataaaattgaccttcgagtgcagagttttgctggtattttggtcagaattgattat



gaaaatctgaaaattaccgccgggaaagttgaaaatttgacgtggaaacgtttaaaaaaataagatgagaaagttagtactgtagatgtcgtc



ggatcaagtgcacagtacgcaagcaccgttacgaaaaattgcactaattgctcaattaaatttttttaaaaaattaatttttatagtgtgttttgtgtt



ttttttctgcttttttaatgatttttaaaggcttgattatgtttttttctcaaaatttgaataatcaataacattaattaattactttattaaaaaaccaca



tttggcattttaataaagcaagttatcgcgacaaacggcaaaaatgtctctttttataaaaattgtttttttttgagttaagagaagatgtggagtttttt



gaactacattagttttctaaaaattttatcatctagattttgaggaaaaaagcagattatatatctttaatcttggttttaaaatttttttaaaaagcaga



atattaaagtaaaatattataaaaagaaaaattcgtgtttgcaaaatttgtttgaacggaaccttgcaaaaatgatatttagcagctaaactaact



gaaaactactgcataaagctttcccaaaaagagctaccatccagaaaatgttttttttttcaaagccgaaaaagaagaaaaaaagatagaaaa



ccgaaaaagcagcatcgttttcgcgcactctttcttctttttttctttctttttctaaaaaaaaatattctccgtagcttgaagtctcaggatttccaaa



gggaatttccttgatagaatatggaaaaacaagagagtcatcagagaagggagaggaaaagcggggatgctggcgaagaccgggggc



accgactgaaatataggcaccggcggggaggcggggcgctctctcctctccgctttactccgccccgattgtcagtggagcaggtttgca



atgagtgttctctgatgccccctcagcgcgggagttttgaaatcaaatattttgtattttaacctactttattgatttttcaattaaaatgaaatgttat



ttgtttaaaatttaatttcag



cyp-29A2




SEQ ID NO: 124





accatgtacccaatttctccagatgtctcaaaaagtccttcttcttgttaatatagctcgcctcctcaaattttgatcttccaattcctctccgccca




atatattctagtccgtgtcttaccccttgacaaaaatgagcttttctcagattccgactaattccaaaaaaattccctacgttttgaataattgtcgcttt



gtatttttttttctcgttttcatacgggtgttcatcattcattttacttttttaaaaattttcctctcgtttcttttgaacgtcccatttttattgcaatcg



ttcattgtctagggtctatccttctaatcattcttcttctcagaaatatcacaaaccgtctgtgttgcattcaaatttttaagtaaaaataataaactaaa



gaaccacaatgaaggtctaagttggcaaaattgaaaagccgaaagcttttcccggaataatagtaattactggagtgcatcccgaactgtct



aaaagtagagaaaagattaagtggatatatattttttatattttttaatatagtaatctgtttgaactgttatacaaaccgaaatcgtgttagtttgga



caaagttttgcatcaaattttttttgagttttagatcgaactattgtgtttttaatgtaccagtcaatatttggcattcacaagcggtatagccaaatgt



acccagagttgatcagatagcgtttttcttcactgtgttccgttgttatcaaataaattatgcaaaaactgcgaaaatttgagttcaaacattaaaa



aaaatcatatttttctaggttattgcgagtttttagcaagaacaactaatgttttcatgtttaaacaaaaaaactgagtgagtgagaaaaaatctca



tgtatgccatgggatcaagccatatattttccatagactaaaattatttagagatggaaaattgaaaacaggagacgggttactgtaggaagat



ttttttaagactattgcaaatacataaatcttttgaatatattttacttcttcgaccgccgctttgaaacagtgcgttactgtgaacgttgaaaacca



aacatttgaactcttcacctcacttgtccattttgttaattgtctagccaactgtagccacctttgatcaggtagaccttttccaatctgcgtctctca



ttctctcaaattcacttagccatgttttgtacggacatcatttctgatacattaactacgataatagttgtgcacgctgtggtcatttgattaactttttt



tcctgttgcagcagttcgcgagtatataacctgtctttaactgataaatcgtttgcattggtcgtttgaaggaaacaacaatacgctttccaaaaa



cyp-31A1




SEQ ID NO: 125





tacagttacaattgaaataaatggaaatctctcttatttttacattgaaatttcttgctggtcacttcttccaatccaccgtagttaaccgactgggt




ggtctactacccgtttctggttttctctgcactctcttcggagagagtgcagacaaaattctccgcgttcgcagtcctggttctgtttcgagacgt



tgacgtcgcccgacaccactcctacaactgttcggacagcgtctgcaattttcgattagtaatatagttttggttgtgaatataatataaattgtg



aaaaattgcattgagaattaggaaaagagcatgtgagaagaggaggggaatttttagaataactgagaatataatttagagaaacacgatta



cttcgcatcaattcagaatatcttttaaaatctgagaaattttggttaaaaaataacacagggcgcttagtttgtggttttctcaattctgtttaattttt



aaaacagtaattcttatttcgataaactaaaatgaatatgaaattttcttacgattaaaaaatgcatgaaaccagatataacaaattgaaggaaa



actgaaaaacttcagaaagtgtttttttctgaaaataaaagcagaaaaattcgaagctcgcgcaaagaacgtaaacgcgctccattgctaact



catttgaacattagtttttttcattgggctttcaatcttgtaagtgatgtttaggcatctaaaagttttataaattgacaaaatccagcttaaaagatg



ctatcaaaaactaacttttcagaatatttatttggctaatgtttgacccatacgttttttgccgaaaagaatttcaaaaatgaaaagtatcttgaaat



gcatcaaaatccgggaatattgccgatggtcagtttttcagcatttctaaattgagagactgaaatgggaatttatttatttttattcatctgctttttt



atttcatgaatatccgcatctgaaatcagctttttttttcaggaaaattgattgaaagaagacaataacagctcgttgttcaacatctcgattcttcc



atatgaatcgatgaatggaaaaaccgtggcatttggtaaagttttggctggaaccgaagttgtctcccgcatcgccttcaataaatcaaacac



gaagggttccaaggcttgcgtcatcaccgactgtggagaagttatctgaaaggttttatcatagattttcaaattttttggtttattattatttctttct



ttttgttccgataagtccatatatgaaatttgtccagtttttatgaaaataaacatttattttatttaatatttttttattcatcatatgc



cyp-31A3




SEQ ID NO: 126





tctgaaaaacgttgatttaaaattttataaaaaatttgaagcaaaaatgaaagagaaaactaaaaaaaaagtaaatgtactgaagtgattggca




gattaataataatttatcgataaaaccattttttaaaaaacttcatcagtttttgtgagtgtcagcaaagaagaagaagattcacgatcaaaaattc



gttgagcctatatgaaatagttgcgctggtttttcgacggggggatcaaatacgtcaaataggtcaaatagacgaagcattcataaaaagtac



aatattcattgaaaaatagttttggatttgtttttttgttttcttcatttttttgttgaaaaaataatggtaattaaaagtttttaataattatttaaatca



agattgaaatatcagaaaacgacaaaaattcgttcgagaactttctcaagactaccgtactctttaaagacgcatgacgattttcacatgggtctcac



cacgacttgtctgaaatttgaatgttcgttcaaaaacttttttttttgcgattttcaaaaccaaagcttaacaaacaattttcctcaagttttcaacgct



ttttgctcgtttttttcgctcaaataaattatttcagaaggttttgca



cyp-33B1




SEQ ID NO: 127





tatattcaaaaaaatatattttttgtaaatgttcttgacaaggtgtcaggaaatcagaataaacattcaacaggtgtttatgttttttttgtatcattcta




aaaatcctaacccgtgcctgattttcataaaactaaaacactaaatgttgtcaatctgtgaccctggagcctagaataagttttccaaaatctgat



tattaaaaacacaacaacagattttaaatagatttgagcacaagtcatgcattgagcataagccacaaatgaaataacgagagtgaatttttag



agtctaattgaattgcattagcttttctaaaaactttttttcggctcaaaatcatttccacaaaaaaaacagttttaaaataataagagttggccttc



agagcggttttgtgtttaacaaattataattcttattgtcagctcgattacgtttttttttcagtatctttcgttttgctttttgtttttagttactcgcca



cgagagagggtttccctccaaatttcgcaaaaactagcacaaattatatgtatgtaccggaactaacctataatacttccgggttcatgccaaattc



taatttctaaatccccagacagacacgctctcaacttcctccctctttttgtttatgaatgaatttagtttgtgacaatcagctaaaagtcgtgattt



gaaaagttcaagaaatcgtcaagctcgtgaccacgaaaaagttctagtcacaatacatcatagactagaaagcatttctcgatcaactagttg



acagctttttgtgaataaagattgagaattcgagttgttttcgaaccatgattacatggcttaacaataatacatgcagctcattgagtctatacaa



acacaaaatacgggtctgcgtctaattatttcctacaatatttttgttattattcacaaaaaacgggagatagtcgacagctctcaaccggttgaa



gagttgtgtcgtgaagaaacaatataaaaacattgaaaagtaataactgataacaacagttctcaaacaatattatagtgatcaa



cyp-33E1




SEQ ID NO: 128





agcaaataaaataattttatggtttttcatttgaaaaaaaagttattaaccttccggcgcaaatgaataaaataataaaaatgattaagttattgca




cggcccaattcatcgttgctatacttattgactacagaatatttttacttctatcaacaatgcaagtttgaaaatttccataaataagatttttcttatc



actacctttttgcttattttcattttaatttcgtggtctctgctctcccttttctgacctgctgacagtttgaatcgtcttcaaactaaatactcggtatgt



ttgcctaaatctcttgtaagagagtagtctctcattcagagaatttcactcttgttgttagaacaaacttcactggcgtgtattttgggaaaataga



ttatatatatttaagagattaatacgatttctaattttagttgtccatcaaattgaatttttttgtgtcgtttttctgaataaacatctgaaattgattcacc



atttttcaga



cyp34A6




SEQ ID NO: 129





ttattaatattattgtatttctgaatgtaccgtattgtatttctacatattgaatcaataaattgttttgtacaataattctttggctgagactggtcgga




caaattcaatgcaagcctgcaaacttattagactctaatagaaaattttctcaaattggaacaattattctataattccttgccggttttgcagaaa



aaatgtttttttaagaattaaaaattttaattatgttccaattaaacctacatcaatgctctagaattctccaaaacatcaaaaaaatttgttgacaag



attggaaaatctgaaatatttttaattttttaatatcaaacccccttcaaatgctacacaacttaaaaataaaaacaaaaagtgtggtcaacaactt



tcaaagcgtagaacacgcattttgtgttgtgtgtcttatttcttttctacctcttatctatcgtctcattcgcgcgcttttcaattttgggggtaggctg



agttagtataagaaaagttaataaaaaatattagtttctaattttcgagtttctaatctagcagtattttaaaata



cyp-34A9




SEQ ID NO: 130





atctttaataattaaatgaataattaattgggagaaacatgtacataaataaaatttccattaaacaatgttcatttgtttaagctggcacagacca




caaaagctgaaaccacaaagttttttaaaccttgttcttttcttaaattttgtagtttcttatcttatcactcgtgtttcttgtcctccaaataattgtgaa



aattgtagttaatgtgtcaaaaaagtcacatataagaagacgaacaacttgattttttgttgacttcatttgaaaaaaaatagaaaac



cyp-34A10




SEQ ID NO: 131





tactgaattttgcaaaaatgaggagtataggaaaactcgctcagaaaatcgaaaaaaaattagttccgttttgtaacactcagactttacaacta




ccaattagaaaaaataataatacactaaaagagaagaatagaaatcagaagaagtcagtatcatgggagctcatgagttaattgcctgaaat



gcgtattcccagaaataaaaatgcggtttcttagctctgagatctgaagtgtaagactgccaatagattccatgagattcgttgtgacaaggg



gttctgaaaaaaggaatcgcgcaaatttatttattgcacagttgtagatgataaagtttctttcagatttgaataatttttaaaagcttctaaaaatta



tcttgcagctaattgtccaaaaattattaaacatttgaatatttttctttgcttccaacaggttttatggaaattattaacaactgtaaaacgttaacgt



agaataaagtaaatcgatcttgaaaacccaaaagaaccggccctatatttttggcaggtggaaattttgaatgaaatttaataatatagctcctg



aacttttaaacgatgatattagatgttgaatgatcaatttccttgtagtcataaccatacggtttttgaaacatcataattttatcgaaatcacttgta



aatcccccgggtacagctataaccaaccctattcgacaatttcaatttcggatattgtaaaaaaaaattttaaaggtggtgtagtcgaatttttttt



attgctttattaggttcaaaattgtctgaaaaaaaccgaatttcataatgaaacttcttgaaaacttctcaaaaaaagttatgacggctcaaaaaa



tgacctaaaattagttaaaatttgaaatttgaccgacttgtcaatgacgcagctgctggaaacaatttttttttgaaattaccgtccaatttgggtat



ttaagttaattatctcgcgttttcaacttcattataaagcttataaacagcgagaattttaaattttttttaccaaatctcgccgtccatcgaattcaaa



atacataaatggtgttgaaaacgcaaaatacataattacatgctatactcacaatttgacggtgatttcaaaaaaaaattgtttccagccgctgc



gacattgacaagtcggtcaaatttcaaatttaaacgaattttagaccattttttgagccgtcataacttttttttgttgagaagttttcaagaaatttc



attatgaaattcggctttttcagacactttttagtctaataaagcaatcaaaaaattcgacttcaccacctttaacttagcaattgccaaaatttttta



ttgcagtacatataaaattagaaacacacaatgtctcaaacctggaattactaggaatttttaagaaaatgactgaaaaaacaaactatgccaa



ggacaaatttaatgtttttttcaaagtatagcatgtcgaaaatactgtttttgataattaaactgtttaatactactaatttttcacattctcatacgact



atgaaaataagtgtaggaaatgtaacctgtgtgatgaacattctactttgccttatcaaattggaaaaacctcgtataaaatggtcaacaaaaa



atgaaactgatttaacttctgatc



cyp-35A1




SEQ ID NO: 132





aagttcacaatttattcattcatccatgtaaactgtatattttgaatttgtgttgtaaagaatttatcttcgaataaaatgtttttaaaggtttttaaattgt




attctggtgagattgcttaaatagagtccttcggcgataaaaatgctaaaaattatatgaaaaaaactatacaaagaatatgtctcgaagtgttt



cattccagatcaaagtcgaaaattagcttagaaaaaggatcttcgtcaaaacccctgatttaacaccaagacgaataggaaaaataaagtaa



tttaaaataaaataaattacaagtgcgctccattgtaaaaacgctagaatttgcaaaaactgaacaatatttgattttcgactggaaaaaaaactt



gttggtaaattgcatgaacagttttaaaatgtcattaagaaaactgatgccaatttttggttgttttctctcgtttaggaaattaaaattccctcttatt



tttttagcatgaaccgtcaacgatttctggtcagataaattatggttattatagtgtgtagttttttgagtttaaaccaatgtttcgaaatttttatcagt



aaacagaaactacggtttgctgtatataagttaattccgatagcaaaagtagaaatccaaa



cyp-35A2




SEQ ID NO: 133





cttctgtaataaaaaaaaattgaaatgtttagtgaggagagtgatagaaaataaaaaaagccgagactaaacattttccctgtgctgccctgttt




ataaacgtttcaaaggaaaattctgaaccctgtaacaactgtcgtcgaccttcgaatagctcaaaaacatttggtctgcttgtggatcgcacgtt



tgtttcacaaaattcattgtgatttgtcgtttgagatatatcccttctatcaatcaacatgttgatgccggaacttttaatcccaagaaatctgttaca



caaagatcggaaaatacctttaattgcttacaacttttattaatagtcgatagatacacttgcttttgacttgccagaaatttaagtatgatgcttat



caaataattacattgattacaattattaaataattgaataattgctaactacaactaaaaaattattcgaaacttttttgtaaaactaagaatcagtcc



gcggatgaatggtaatattgttcaaattcgtctagaaaaaaaaccaaaaaaataattaaaaaatgagaaactgcgcaaaatatatatatttaaa



atgaaacacaacgaggcggctctcgttaaccagcattgtgcaaataacccaaaaactctgttcacgccaaagtgctgaaaagagaaaaga



ggctggcgtgaagccgacaggtataggtcctgaaaccgcgccccactggttactcgaatttgcgaatcattcttcttttttttttttcaaagcaa



cttccctttattaatttcagattattgaacattcaatttttttttgttgtaaaaatcaattgtttttctccgaatagttaagaaaaatgtatgttttgaaa



attatctgttcttgggaaataatagagttctgcaaacaaacttactatcagtcgattcgcctaattcgacccttctatcaaaaacgttgtgctgaatgt



ataaattgtgaatttttgagtgaaaataactgataagagcttttttatcagtcaactgacagtgtgcatgttttgtataaaaacagtccactgatttc



gaaaaatcaaatcagaat



cyp-35A3




SEQ ID NO: 134





ctttgtaaattattttcaattaatttatttgcacatgtgaactattagaaaagaaaaagtttacttttatatttggtgctatattggtgataaatctatgc




aattggtaataaatcggaaatacgtttattttctgcaattgaatataataaaaggtaaataaatgatgagtgcgagaaatttgagttccataattgt



acaagccagggagttttgaaaaataacagaaccggtacctatttctctttttataacatataacatctgaaaccgacatgttaaataaaaaatttt



gagaaagaaagttgttaattctcgttaatttgcgatatgtctataataaacctcgtagcatttctatcgactaaaaatttgttataatcagaaaaaa



ccatcgaagttttcaagtcaaatttcaaaatactcttcacatcaaaacttgcaaaattaaactcacagactggaaaaggaaattcgaaaatgtct



gaagaataacggttttggaaaccgagctgtacttttttccaggaagatcgttcacaaacaaaatcaaatagccataaattgaaatacttgcaca



acttaaaaaatacgagaacattgaagaaatatcgatgttcttcaatacacataaaatgttgttgtcatattgtttccatgagcaaatggctgaaat



ctgggcaataataatatttgataaatgtccattactcacttggtatagcaactttatgaactaaagaaattataaaagaattgataattataaatgc



aagacatcggggtcgaaacctaacgaatgatcgaaaatttggaaatttcaatgatatgactttttgtattgctagtagaaacatggaaacagc



gaaaatattcgggaaaacggtattttgagaatgtgctattagagccataatggactgaacgatagcccaatttgtaattagaatcttacgattta



catttctgaaaatttatagatattaactttaaaacatatatgaatggatcttacaatccattaattacaatcaatacaataacattgttcatattaatta



aaaataaagtaatgctcattaataaagacatcaaatgattaatttttaaaatgtgacatgatttatgtctcaaataatgtgtcttgttgtgattccatg



aacggcagtaaaatataaaaacgatactatttgtagaagcaaaaaccatcaataaagttatttcaaagtcaatatgacttgttgctaagttctga



aaagtctgaaatacttgcatagcttaaaagcgtaaaagtgaattactatgcataagtctgtgggcgaaatgcatgtgacaacatttgcacctgt



ttggtttttaatagcctccaaatttaagactatgaaaattcattctgcggtccttcctgaacaatggcacgtccaaacgtctacaacatttgaatat



ttatatttaatacaaaagtagaccataaaaatagaattaacatttttttgatcgacaatttccaaaaaaataacaaaaactgagattgttccaaattt



tttttccaaaagttatataaaattttaaaaaaatttcaaaacttttactatgatatatttacagccccccccccccacaaaaataacggatttcatcg



ctttgaatttttaataaattttcaatgaaaatttatggaatagacacgggaccaggcggaagtcttgatactttttggtactgtgtaccaaccaaa



aattgcagatacaaaaagaataaaaacattttttttaaatttttttattcaattttccgtatttttgaaccacacttaaataaactctatttgaagcaca



gtcttatttccgtgttttcatcagagaccacagttccttatccttgcgttatcaattttcattacatctttacatcaaatcttttgtggcaaatgtacaaa



atgtacattttgaagtaaatatacccgataagaattagttatcggtcaagagactgtttgattgctttatataaaatcagatatttcaattttaattctc



aaatcgaa



cyp-35A4




SEQ ID NO: 135





ttgtcttatattttattaaaatcggggcgaagccctgattttaaatccatattgttttttttgtcttccactatccctacaaataggaaagagaatgtgt




tctttctgatgaagtaaaaacggcgcagccagccgacagccgaaattttcacgattttcggctggtagcgccagccgaaaaattaaaagaa



gtcggctggcggcgccagccgacagccgaaccagctttttgtcggctggtagctttaaatttttttccagttttttacagaaaattcgtccagtt



cttacagaaaattcgcgtttctatgttttaaatttgataacatttgcagtaacggagactgctgacccggcgtttcccatgagaaaagagagag



agagagagagggggagacagtgagatatacggcagagacatagacaggggagacaccattagagatcgtctcctatagagtgctgccg



gcagggggcgttgtggacctgtgggaagaaggggggagacaaccgcacactgtgcggttgtaaatgcggaataatccatttaaaactaa



ggaaaatagtggtctaatgcttaacagtgagccgcctagataaaacaaaaaaaagtcggctggctgcgccagccgacagccgaaattttc



actattttcggctggtgccaccagccgacagccgaaaaattgaagtcaatcggctgtcggcgccagccgacagccgaaaaaatcagcca



gccgctcagccctggtggggtggcgatgtgttggcagccaacccttcaacgaactgtatctcccgcctgtatctcccttcaaagtgagatcc



tgtaacagtaattagagaccatatttacagccagcctacatgcatcactggagactctgtggagagggaggaggcaagagaaaggggag



gcaagagggggcgggcgggcactgctgaaccttgaaagcgccgtagctccgctcacaattggaattgaaaaatgaaaagtatatatttga



agtcaacgttaaaaggagaatatgatagcatttgaaattttggaaattggtgaagaatgaaaaaaaaagcctctggagcaaggcttgaagct



cacaacttcaggaacggggctcgaggaactcatggccaaaaactttttatttgtctcgcttctcatagcaaaaataataagatttaaaacataa



aattgattatccaacaaaaaactggtccaggaaaagagggaaactgaaaattcgaggtcaaaaattaaataaactaaaattgtgaaaaatgg



tcgtagagagctgtgctttcagctggcattcggaatttatgcacttattacgaatttaacataaaatcccatttgatagtggaaaaattttcattttt



ccagcaaaaacgtcatttttttgagaaaatgcagcaatttgcgatttctgaagttatttttaacttttttgaaaaaaaaaaatatttttgaagagaaa



atttcctgaaaaatacgtttttcaaaaaatttacctcaaaaagtgccaaactgaccgacttatggacgaaaaaccatcaaaaatcgctaatttgc



acaccaaaaaaaagggggggggggggaaatgcaattttcgatttcacactaaagagcccacttctatagcaatttttgagtttcactcaaaat



atctcggctcaatgagctccaatctttctgaaaacaagaatacagaggtggggcaagctttttgaagagacagcaaaaaactgcatcaaaat



ccatccacccaccgtcaagttacacgcgcgttttcatttaccacttttgtcggattttgaagcttaatatctcggctcctgtaaatcgaaatcggc



tgaaaattcacaagaaaacttacttcactacgatcctcctgtcattaaattttcgtgagcttagaccgaaaactgacaaaacgccaaactttgct



aacgctcgccactgacgccaagccttcagacacgctttcactaaatacagtctatttttccgtgttttcatcagagaccacagttttaaaataat



gcgttttcaatttatttgatgtgatttatacattttcccatcagaaatgctgtgctaaatgtattcaatgtgtctttttgagtgaaaccactcttaatttat



cagtcaacagataatgttgctttgtataaaaaggattcatcgaatttgaaattttcaatcaaa



cyp-35A5




SEQ ID NO: 136





ggccaaaaatagtaaaacttgatcgttttctgccattgaaaactgcgttactatcatgcttggtttttgggggcgctggtatagaatatgtgctca




aggaagtgccggatatcagaaaactgatagttttgatcaaaaagttgtgtatgcctgtctttctgtctgtctgttgacactccctccgagaggca



gccagagcctcagagtgacaaatgcgaacggcagacggaatggaggaaaaggatgagcggtgctaataacagtacacagtttgacgaa



aatccaagtttattgagcagggcagctttaagctgggaataaacaaggcaaaaacgtagagaatatttagggaattgggcacgaagatcag



caacgagcagccatggcgttgggagaacgaagaaaagaagtgaagaatggctacattttaggccagaattaatatgagcaagggaataa



acagcgcgcgctacgacactccgatgtgtacaatggcgcgcgcttgcatccttggcggcaaattcaaatgagaattatttaatttaattaattt



aaatggtggaatgattattaaagaacgaacaaacggaattgtgtgagtaaattaccggcggatgattatcgctggattgtgggcaattcttgc



cgataattataatccgcaaagttggggcggaggacctctactgaggccaagtcacaacactgtctaccgtctgtctattctatatctagaagat



gtcaacattcagtggttattttttagtaataaaagtgtaaaacaaaacaattcagatctgcaaagctgaaaagtgatgaaaattgatatcttcaat



tataatttatagtacttttttaataattactctaattacaccccactgctttactttgaaatctcatatctcgctccattctgaagtagtcaactagaaa



cggtaaaaaatccatagaaaattgtttttccaggtgacaatttttaaataaaaatggggtgcaatagtaatagagcaattatgctaattttgtgaa



actgtagtttcaatactttaaactctatctgtacgttgttctctattgaaaaatacataccagatcagttatcaatttcatttctcatatgtcaatcgct



attaattttactgataagaacacgctgtgtcagttgtgtcagttgtagttgcaacgagaaatacaatttctttttgggtttcttcttaagtttctcggc



ttgaataatgggaaaactaattaacagttgactaaattatttaattttattatcccgcccttaaaaagttacccaaaaagatttagtgaagttatgtc



gttctaatataatacttcgaacaacttgtgtcagttgtagtcagttgttaaaatctaaatttggtgataagatagtcgtatcactagttctgcaacgt



tattatttaaatagccggagattgacaaaaatattcattcataatttttaaaaa



cyp-35B3




SEQ ID NO: 137





tctttaatgataatttatgggatctgtatttctctttctgtcaataaaaattgaaaatgatttttacattctcaatattttctaaatcatgtttcgtgaagct




gaagagtaaaattcgacatttagaaggtttcgttagaaaaatgaaaagtgtagtgccagaggggactttatctaaaacaggcctgaaggttc



gacccgcgttacagttccagtctaaagtaataacactaattcaaaataatatatacgaaaaaaaaacacttgaatattatttgatttttaaagattt



tcaattttgaaattatcaaatttccttgaatttgggaatttttgaagaagtttcagatgcaggtttgaaatcctagaatgtgcaagtatgaaaactg



aaacaaaatgtatttatacgacttttttggtcactgccaaacttataatcggtcaaaactatgtttgcacaaatttctaacattaaaaataaacgatt



ttaatttttttttgaaaattatgcctgtatacatttcagcattataagagcgtttttaagcgattccctactgatgatactgtagcattctaaaattattg



tagcttaatagctatctaatttgtaaaattaaatttaaaaaaataaatttgaagtggatctattagaaccttcatacaatatttcctactcttttaaattt



gaaatttttcgagtcagtgctagtgatagatagaatacatccattccgtagttatctacgctttcctcttggaatcaacacatcaaaactcaaagt



acgcctttattaaagaaccgtgctttgtagttttaaattacttgcttccattgtttgtagcctttccttataaaagatagcaggttctgtttaactatctc



aatttcaaa



cyp-35C1




SEQ ID NO: 138





atttttgaactaaataatatttcaaattgcacccgcaaatatcgtcacttttataccgataaacaaataaagtttagtgatgacttatgataagaac




ctctttgagtctatatgtacgtgaaacaaacgttaaagaataacggctttacgtgttagtcattcataaaatttcataagttgatctggaaatttgtg



ttatggacgttacgccattatttctcgtcactcaacgtctcgtcaatggtaattgtttttcagagacggtgaatcatgtttcagttgatgattttagg



aaacgcatgccatgttgagacaccataataatttaaatttttgtgggtaccttttattgggattttctaacatttcagtcagaacttttagtagaattttttt



atagatctttttttttcagcttaaaattagtgttctaattactgtttaaaaaatgaaaactgaaacgtttgatgattttgtttttaaaaaattttcaattttt



ttcgatatgtttttattgattgtaagatcaactcttttaaagtttacttttcattttttgttaataaataagaaaattttaccgactttttagaaatttaa



tttattgaaaaactgataaacgtcttgttttgatcaattttccaataaagaatacttttagcgttagtcacaacatatactcaaaatgtgtcaaaaaaca



atgtttcgaacagttttattgttttttttagcttcatcccgaacaactaaaaattgactttcccgataacttaagacgaataagtttaaaatttgaaat



ctagttatttttcacgattttgacttttgttctgtccgcgccgaatctgaaacttgaacactaattcaatgtacacataagaatagacaagtagtga



atatgcccattatcacacagactacatactttgactgttccaagcgtcgcaagcgtcgcaagtgtagcattttgagtcagtgataacaatgtaa



gaaagtatataaagaacatgcatttgttcatttctattgcaaaaca



cyp-35D1




SEQ ID NO: 139





tgattccaaatgataattggctagtcttaaaacattttatattttagggaattcgaaatcaaaactatgcacgtcatatcaaaatcaatttttgttcaa




tattaatgttatttattcatttgacagctatcaataattatatttattaaaatagctgatagaactatttagggcattcacaaacatttcagaatgtttcc



gaaagttcgcaacagcggattcgccacaatgcttcctcataacccatttgtaacaccatttttcaattgtaaacatgcttgtcaaaaatgcagta



tcattgggttgcaaaacataactcgggcatttgtatttaaatatattgaagttagaagaacggagctttgacaaacaggcaatgaatggagttt



gtttcaaataaatgaaatcacatccaacaaaaaccaactctgtgtatcaatcgcctcttggcaaacatttatcggagaaactctgaaacgggta



ctatttctagtttagttttggtatatttcacaactgaacaccttcacactgtttacttatttccactatatcagcattatttctcgagttccgataatcgt



ccaacattctatgagctttatctccaaactggctatatcgtaaatgcttgaaaaaataaaaaggatcatagcaatccgactcattagcaggtgtt



gtgggaatattatcaagaaatgcgttgtaattctccgtagtattttctgtttttagcttttcacaaatgtttcttatagtatccgaaaagcatgtctttc



catcttctaattgatcactgatatcatcaatctgaaaatattagattgattttttgctgagaagaacctcaaaaccaactatgaaaaaatcatttagt



ttgatgcagccgtcacggtagtttaacaaatgtgtacaagcaacttggacacaaggacgagggtcattgatgtagtaagattgcaaaaaag



gaactcagaacagtaagaaagccaaagttaaaagcattgttgtcctgaaaaatccttattagtgtgtgataaaaataaatttcacaagttggac



agttattatttcacaaaataaaatattattttgttgtgtgtactttacaattgacgaaaagatcaaaccgacgcaaaaatgatcaatataatccgttc



atatttgtttggtaaagcatttttctgctaatcaaaaactgttggtgcaaaataatcgcacgttttttcgttttttttttaattttttggtctcaaaattaca



taaattttcggaaacatttctaacgctgaaaaaaacatttaattgtgtgaagtgtagccgtgaaaatgtgttaggtgttgctaccctcttatcttca



atcttatcatgtttttgtctcctttataaagaattgccggtgaacttgaagttcagatgtataactgtttctatc



vem-1




SEQ ID NO: 140





tcccttgttatttgatttttaagatttgcccttatgtcagtgtcttctgcatgagtacatgcatatttgcatattattagaatgttatgtataaaaagaaa




aagagagccacctcttaacgataatccaatttcttgttacgcagaaacgcctcgttttcctgtggactttcgatatcttcaacatgctgctattatc



actcccatgacccgtttcctatctgtttttatttcgattactacacatctgctagaaacacacgtcacgtgtgatttgtactcaccgttttctcctttc



atactttttagcctacaaaccacgaattgctttgtgacttgactcaattttctcccgaaactttttttcgtcctcaattcccactacccattttcttgctt



ctccctgttgcaatattttcaatttcccatccaaaaacggcccgagcacgggttttcttttcctttttgtaggttcacttcttctttttcttcttcgtttct



atttttttacacaatcattgttcacctttgggcaccccagtgaaacatttgtttgataaaaattgtgtgttccacggcactaaccacaaaatctttgc



tacaaatactactcgtattgtttgtgatgactgtggtgaaagtaagaagaatcgagagacattaggggacaaatataaaatagaaacgataag



gcgacgaaaacgcacattcttctcgatttccgaccgtcaatcgctgagtgaataattgttgacggcaactgggaaaatctgtgagaaaataat



gtaccatgttttcgaatttctaaaattagagataatttcttccgttttctcttttacatcttgttttcttcattttacaacaaatccttcttctttctctta



ccgctttgtgcacttgcactgtaaatgacggcaacttacggacctagcgttcgacgaacacagtcaaggacgctcacacatcgtcgacgggttc



acctgctctgttgcagtgatttttgatgtttttattggtgactagtttttgactttttacaaa



dhs-23




SEQ ID NO: 141





atttgaggactgggatgtcattaggactgaaattattctaaattagataatatattttaaggtaaaacgtctgtttaaattatttgtataagcaacaa




aaaataaacgaaaactaaaattctacctgaagttcaggtcctgaacaataacataaaaaatttgggaaaacacgaaaaaataaacttaaaaa



attaattaaaaaattaaagattaaaattaaagattaaataatctctagaacatagatctctaaaacacttcccgtagcggttcatttttgttcgagtc



tgactggcgttttctatgggaaacagaaaacaacacgctgtttgctcagtttcgagaattttggaattcacagacttattttgttttgccgtatatg



atcttaatcatagacatataatatttatgacaatgctttgctataattctgtgtggtgagcgttcgcagaaggttctgcacaattctttcaatgaaaa



aaaaaagaaaattataagaacttattagaaaattataagatgtagaaagttattcataaaagttagtattcccaagaaaaatcataaagaaagg



ttttttttcaaggtttttttcagatttttggcgttgttcaacttgtattgcaatcattattattgcgatcattagtaatttaatataatttgctccagagca



tttgtaagcaatgaaatccaattttccctctgtggtgtttggtttagaaacttttgcaatttcgtcttgatgtgccgcggcatgccgcaaaaatcata



ggggatttgatttcccagtagttgaagttggcagagttaactataaggatgacctaaaacaagttttaggctacttgttatagacatggacttcg



atttctaatttggacagcatccgctacagtgaaagtctgcggattgatttcaaactctctaaaatcgaacgagttttcaatttttttttcaattttgat



gcctaatttagtgaacacggtaattatagtttcttgtatataaaacccgtttaactccttaaattactgtttacgtttcgtgttgtaataaacgatctct



tgatcttcattcaactatgctggcacaaaaatagacacaattcgaagaggcgcagagggagtaacagacacaaaaaatgttaggacgtctg



cgatctcgccggtaagaaacactgaaaatactctctgcgtagtcacgaaagctacaaactttaatgtattcaaccaaataatgttaactgtata



aaaagaaacaaagaaaaaaaagtataaaaagaaactttaaaccaaaactaatcatcagattcaatatcttctatctgtttgacattctatttctgt



aagctcgaaaat



sodh-2




SEQ ID NO: 142





agtagagtcaatatcttgaaatgtttagaattctcgcgtatctcacatgttgaggtgagatatttgtaatgaatagtttcatagtctttggccaaaat




atgattatacgttaaagcaaattttgatgttacgccgtttgaagaaatgtttttagcatgtttaacagagattcagactaaatttattctacacagttt



ctgaagggatattttttgccagagtcaattttcttgtaaaccagtgagccttaggtacatagaaaattttgaaaaatatccaagaataaaatttttt



ctgcatgccttattctgggcttattttttgcggttttcaattcaattttatcgtatttcaaaaaattaaattagaacaaatgcatattcatttttacatcctt



ttctaattggtaattataatttcaaaaatcttctttgcttatcatttgtaacaacaactacaaaaactgtactcgtagttttatctaaccgtattctttga



ccgcatcctcccttttgaccattcaagtaaaaagatgacaatcgccgtctacatattgccacgtgacgcaaattacttataaaaccattcgtata



aatatttcattgatttcttgaattcaaaaagc



ugt-16




SEQ ID NO: 143





cccgaatttttttatcgcagaaaaccaagatggaataaataaatggataatctaattaaaaattgtaatttactatttggaatcaaaaataaataaa




caaatcttataatatgtcagcaataaaaataataaaagaacaattgaaagttcaatgtgttgtcaagaaatccattaaagtatcgtcatcaacgg



ggtcatcaatttccatgttgttgttattgtcttccataacatctatttccatgaagtcttagagtactgacaatagtttatttagtaaattaatttttgag



aaagtttcttgacacattgctttgagactttgattaaatcacaaatgactcactattatcataattttctatccaaaatgttgatttcatttcaatttcca



ttgaatcagctattccattacatccatcagttggtttacaaaatgggaccagtggcctcaatatctgtattttcttccttttttgtgaaaatcgtacttt



tgaaaatactaatggattctcgttctgatcgaaatgaggaaactgtgctgttttctaagaacacttgagacgtggattttctttgttgttcttaaata



cgaaaatcaaatttactgacaaaatatctaaaacttacaatcacttcgttgctgtagggataatcacaaaaatttgacatgattttctggttttcatt



ctgaaaaactgggagcattttaatttgaaaaaaacgaaccgtagtctgccccaattgatttgttggtaaaggaagtgaattaaagcgacaagg



aatacatttatctgttgaaagtgaatgcatttttctggaaagacggaataaattgaaattaaaacaatattcagttaaagggaaactgaattatcc



caaacccgggttatttcaaaacggaatctacatcttactttaattctgattgtcagccctataacaactatttcatctattcaaaaagatacaaaaa



taaaccaattaacattacttcgtagatacctcatcacatgaccaccctctcaagttgatataattaactttctaaattgaccaaaagtgtttgctaat



gtgtatagggtatagtaaataggaaggagttcggaagttcgatgagagtaaatatcttttgtgaaatatctattggaaattagcggaaaaaaga



taaattttctcctgaagtgcacaactaataacgaatatcttaatgtggaaataaatcaaatcaaatcaatatacatcccaatcatgacatccaag



aaccccacaaaaatatgttcctaaaaactaactgataattaatttgaatgtttccaacagaaccttgctcgctttttgcacatttttccactttgtttc



gctctacacgcttgtatttttttaattaattatattttttcggcctcaataaaaattaaaattccagattgaacacatttaatgtcagaatataattaca



gtacctttttatgacaaaacatatttcggtataatctcagatttccacttcttgtttcatggcccaagtttttctcaatgctcacttgtaacggaaaat



ggagtcagtgaagctgttcaattctagataatatgatgctatcaaaggtcttaaaatttagataaaatgatgaaaatgacgacattaaagtgtag



ccttactgaaaaaaccaattattgaactttaagaaaaaaaacattttggaaaataaaggtaattcatttttcgtacacctaaaatttgaaaaaccg



aaatttcagtgagaacgtcttcaactgcatcaaaaaaattgtgaagaaaatcgaattgaaaagagaggctaaattggcttcatatctttaattta



gccgattatacacgtcgggccagtcttttttaaatgactgtcatggaggacttgatttcaagattggaagtgatgaactacaaaaaatatcaaa



caatttttaactgcataaaaacggtttttctccgggatcaaagatgttttcggtatcaagtcacattcatggttcattaaaacatactatttttctagt



cttaaaatgtaatctgtataattttatgttgttgattgaactcataatatgacaggattttttttgtgatttctgtaatgaagtacagtcttacacgaaa



actagagtaatacaagtcataaattttattcgtcttttttcccgtagtcctttcaataatgtatgaaaagcatttacaaactacaactctttcaaaaac



tagagttcttatcatacaaaccacacattttttgcagctctatataaaccaactgataatgaggttttgtctactctcattactcaatt



ugt-63




SEQ ID NO: 144





gtgaataccacaactgaatgtctcgaatatggagccaatgattcggaaatctatgaggaaatggcatcgatttgcaagtatattgtacgggatt




cgagagctcacggggactcggttccagagtgatttttgttgttcgccaattttatgattgtttcttgttgttaagttttctaaaaaataaattctttgat



tttaataaatttcgaaaattcaaatattatggggacgccgagggaatcagggtgcaaaggcgctctaacgccaaatgacaaccgagcattg



ggtctcgttaggaaatggcggcaaacgagacatttaaattttttattacgggaacacaaaattctaataatgcgtattgcacaatatatcttacg



cgctaagtatctcgtagcgaaaactacagtaattttttaatgactacgcttgtgtcgatttacgagctcgattttagagatgaatttattttcgaata



gtgtcagcgatatttcgctttaatttcgaatcgagcccgtaaatcgacacaaacgctacagtagtcatttaaagaaattactgtagttttcgctac



gagatattttgtgcgtcaaatatgatgcgcaatacgcagtctcagaactttgtgttcccataataaaaagtgagagttttcatgcgcccttggag



cgctactgcacctcaatttcaaaaaacgcatttttctgcgtccccataatacaccgggattttcttttctcttcgtctgaaaaacaatcaatcatca



ttaaaatcatcatctatcaccaatacagaatccatagatcaaacagatcaaaaaaccaacttgaacgcttgcaggcaactacgataaaaatat



attttgtagtgtagtcatcatatcaatcatctagctataataatgcctgccgtataaatacaaaacacgatgatgatctttttgcgaaa



gst-5




SEQ ID NO: 145





attagagaacttttcgagaagtctaccgttgtagttttcgaaatagtaatttatttagtgacgtttataaaggtttacatgatttggtttggaaatttttt




aggagtttattcataaaaacaaagtaaccatggacattccagaagtctatagtacacgcgatcctaccgtacccttcagtatttctatcagattg



atagctttcggtagtcaggtacagcctaaaaaattcctgcttgcctttttgcctacatgtctgcctaccttcagtcataatgcctacataatgatttt



ttccaattgaaacttgcagacagaaattcaaatggcaaaaagaaacaaacaccgaaacattaatcacatttcttttcatatcagttttcctgtcaa



agcacatttctggagtctgtgtgtatttttttgtgtctttatgtgatcggtgttgtgaaatttgtagttgatgttgataacatacttttttttgaaacaaa



aagtgattgattaggcttgaattcagagatatgttcgtgatactttgcgattctcgagccaaaaacacggtatccggtctcgacacgacaacttt



ttcgcaaaatacaagctgatgtgcgccttgaaagagtactgtaatttcaacctttcgttgttgcggaattttcatagtttctcgttcaaaatatatgt



atttattaaacaaaaaactaaaacaaaacaattgagaacacataaattgtgaaaaatcaatgagaccacagcaaaaaattttgtatctacagta



ctctttaaaggcgcacatccgttcttattttcagcaaaaatgtcgcttcgagaccgggtaccgtatttttttttgtgcaaaactttaggtctaggta



atattaaaaaaaaattccacaaaactagaatctagagctttccattaaattttttgatgacatttgaaaattcatgatgatttttttccaacaatttcg



aaatatccctcttttcacctggtccactgaattctctttccgaaagaccaccacaatttcagggctccgcccatttcgtggtttgtagccttcccg



accctacgtttttgatgacaattgtgagagaagtgagaggttcagacacaaaaagcgacgtggtcgaatgagtataaatagagagtgaagtt



tccaatttccctcacaattgtttgtttgcaatccactttccaaaaaaacacaacttcaatcaaaaatcatt



T16G1.6




SEQ ID NO: 146





Gctaaactttcgtattcgactgataatgagaacgtggaggagtatcgtgaggttctcactgaaaaagctgaacgtctcatggaagacttaaa




gcgatggcacttgtacagtaaagatgtgacaaaggatttagaaacggcggaaaagttgactttatgataagaataccgataaaattatgaaat



ttctcgaaacttttgaattgtgaagcaacttcttaataaagtaactcattgactttaatttttaaaccacggcttagagaaaattaaaaatcaaaca



ctgcagcttttttgatgcgaaaattcattgatatggaacaaacctcaaatttgataaataatacaataatttgtcaagaaatcacaaaaacgttctt



ttgaaatgcaagttataagacatacgcaagatgttatgtcggtggctggttttaactataaaatacgaaacaattgacctcctgacacaaaattt



ccgagcttgatttgtctgatatcatttgtgctttggaattattgtttcatgtgcataaaatctacactgtgttcattcacgataagaagaatttcagac



agaaaccacaggaggttcatcgatataaaatgctaatcatttgatttaaagaaccatactctttttactctcgtcgttaagaa






























































































































































































































































































































































































































































































































































































































































































































































































































































































































































































Cell Division Toxicity Genes






mei-1





SEQ ID NO: 147





cagctatcccgaattctcgagcgacatccgtcatctgaaagagatactaatgtcatgtgaagtggtattaaaaatatagtaagcacggtagaa




acattaacttataaaattgagatttctgataaataaaatttttccgggagttctgtaaaacttcttacggttttaacttgataattccatagggtttaaa



atttccttttgtttcttgagtttcttctcggaatttgaacaaaaataacgcgtttaatctcgaatcagtacaatgatggactacacggcagttttaaa



aaaccaattaataataataatcctaaaaaatgagaagaatatttaagaaaatgtaaaagttttccgcggaattccgctaaaattcgaaaattgaa



agtgttcaaattgcaagcgattgtgcattcagacgtgacagtgtctggggtgtattgcgtactcgacattttaactgacgacacttgtacttttgc



gccatacttccggagctccagctccgcggagccctgagcaattatttttttactttttatgaaaagctttctatagatatcttttaagaagttacact



ataattgtgcaaatcaaactggctccggacaacacaaatttcgtctatacctttatgatctttttttgttaaacaagtgaaacaattatttccttttca



aactgctcttgtttcttctctttattaatcaatttttttttttttgctttgtgtaaattaattgtttgtcgcggatgagctaattctgaggtttgaccagcag



aaatctgttttctgaaaaatcaataactcgccgcttaattttggttttattcaagtgatatgcaattagaaggttctaatcatttatatctcgctgaaa



gatctcagatttcaagccttttgctaaggatttaattcctaaaactttttttgacctatcattttttgtgtgatctaccgctgtaaatacttgttgttttgc



ggctaaactctttcaatgtttccaacaagtgagccaatatcaagtaaaaaaagaaaaatcgttttctattcaaccattttattctgtaaataatatta



aattcatcttcacggtacaatcttcttctcccatctaataaagtccacgcacactccgttccgtcgtttccctattcgttatcattcatcatcttgcca



ttttcttctccgccaaatcccattgtcttatactaaatttcatcctctcgtctgtagaagtgtatattattgaaaaattaaagtatattttcagg



mei-2




SEQ ID NO: 148





cgcttcattttccaacaaaccaagtactggagccatttactataagaactaaattaaatattaaatatatcgtttcaagaattcattggaatgagg




caaaagtaaatacttaggattaaaaaatccagctttatattaaaaactttaaaggcgcatatgagatgttattcgggtcccgcagcgctcatgc



ggggtacgatagtacttcaaagaattacgcgggaatttcttttatgcgggaaaacggttttttcttgtttactagttcctttctttcgtctaattttgat



atcttgtgtttttttccaattataaaatgtttgtctcttcttaaatttgaaattttgaaatttttcag



mel-26




SEQ ID NO: 149





ctctccttctttcatattctgtgtccacttctcactcattgaatcatacatctctatgttttctcatagtcatcatatattgtcagctgcagaaatctcat




catttttccaaacgaaaagctcttaagagaaatgcttgttttctgtggggtacagcgaatggcttctgtgggaatgcagtttgtgaatgtaaata



gattgttatgcagtcttgcaaatgtgtcggaggccaaaagtagagtagacatatttgaaatttatagctttgagtgtccttagtctattttgatattt



catttctgctttcctcagtctctcattccagctgcaaaaaataaaaataagaaaaaacacgaatcccgtccattcgccattcaacatagatcata



ttcctcagattttttgcagaatatgtaatttttgctgaatgctcgctctattgtccttcattggttatcaatctttttgcattaatagctttaatttttgat



gttttcgaaagattagggaaaaattttttaatgtgtcttttgtgacttgagattatatgctacactgaaaaaattggtcgcataacatttcagagttcaa



agtgttttttctttcgattgtgtaagcggcaaaattctactttatcatgcatttttgtttcaatcaaaaatttgatgtgatttgtacatggcgtcggtttg



gtactagttgtccacttcctcagccatgaaaagtgtgagtaagtgataacgtttattatcttttttgaattcattctatgtttaagctacacgtatttaa



ctagctgactcatttccaccaaatatgccaaaagacctccgagatttttttttgaagataatttcgatttcgcagaaaaaaaaacatataagtgat



gtgggggtgtgtcgccttcttcagctttccatagtgaaagtttcgtaaaaacaagcttgctatttcatttttccccgttctaataccttgtcgccca



gaaaaaatatttatatgatctttttcaactctttttttgtaaaaatggccaaagattagctaatatttgtataccatcaaagttctgccaaaatctcgtt



gaaacatccatcgtagaacactcattgggttccatcaatacattttttgtgtaacatcagtcgattgttatcattcgtatatgcatggtcatctcaac



cgcccttacgacgtcttcaaccattttctcttctaactctctttctctcaatttcacttctcactactctagtctattcaattctttgaaaaggcaaaaa



aaaatgcataaaaagatgaagaagacattcaacagacgggtgtcttccttatttttattcaaatcaaaacaaatggcgaccttcttattcttctctt



ttgcccgatgattcattttctttttccattaattttgttatctattgctgaataacccgctttactgaatgtgtggactggcatttgccacgttgcatttt



ggaaaagagccgatgtagttcttccgggtatatgtattcacagaacgattcataagatcagacatatagacataaaattcagcgcattctgcct



tgtggtttgtcaactacttccgtcttttttctgcatattcatttcccgcttctgctgtcttgttcatgaactcttgaactttgcactttgccctctttttaag



tttctctcgattgatgcagcagcagcagactgtcattcatatttgtctagtgatttcgtaggttcaaacaacttattaagcggtttcacctaaaattt



cgcatcccaaaataaaagttcaattgcgaactagaagtacccagaagcgaaatttttttgcttcaaaaatacggtacccggttttcaacaaaat



cgttttcaagtgacatgagcgattttcctttttatggaaaatttctaattcaaaaataaatatttgaaataccttttttagattattatatttattcttggta



ttttctctattcccactaaaatagactgatacgagaacagttcttgtttgcgcaaactcacattttctctctctatctctccgtctcttcttccgtatct



ctctgacggtcccatactctctcactcatcgtcagacaccaccacttatcgatctattttcgacgagtgagcggctgttcgtcgcatgtttttttat



aacttgattcgatcaatttcatcatatcttcttcacttatttgaatttccgttttgaacatcatttttccgtcggaaagttgaagcatttgtttgattttctc



ggtggaagattagatttcaaaactttcgaaatttaacaatagaaaaagagaaaaaagtgtagttattaggaaatattttagacaattttgttggca



attaattgaaattaatttcttctttctacatattttaaaaatgtatctttttttctatttatatttcctttccggggatgagcgacaattattttcggcagc



tctacaaaatgactgcttgagataaaatttctacttaaaatttattgtcgaaagatagaaaaatgttgcctcaaactgtaattttgtcgagttgcccaa



aataattgtcgcacacctcagatttttttttctattattttttaaataattaaaattacagtggaa



cul-3




SEQ ID NO: 150





tattttgacttttgaattttggaggttttcaagaataggcaaacgttttggcatctttttgaaaaaatctgattttttggtagattctatccactttctaa




aaattctacatgctctgaacaaagtggaaaatacactgaaaatttcagatcgaagtttcaggtgtttgaatttgtgtaatagtctgaaaaatctga



atataagctttcaaatgagacatctcgaagaaaatgaatttgtgaaaaaatccaatttttttctaattcgagcacaaaatgatgtcggtctatcac



acctccttgttgttaggtgaataattgttaaattcttaatctttatgatataacaaagataggcttctaactacgtcacgcctacatattcaatgaaat



tttgtagtgctactactatttgtgcaagccggaatatgaatgtcctttcattttttttcgtcccaaaagtatataaaatatctcacgatatactcagag



attgggcaacaaagttcaggagaacttttgatgcacaccggaaataaaagggcttcactgctttttttgttgaattcatattggttttggcggga



aatattgaatcattattgatacttttgaaacaggaatagacagtatttttcgtacggaaattcgataatttccgaaaatgttcggttgcctccctcg



ccccctttgaaattacaggagactaaaattcgaagaatgcgtattacgaaacgtatacgcgcaaaatatctcatagcgaaaactacagtaatt



ttttaaattactactgtagcgcttgtgtcgatttatgggctcgattaaaattgagcaaaaaatttagaaaatactatgcaggcgcggaggaaaat



aaaatatcgatatcactattcggaaacaaattcatttcaaaaatcgagcacgtaaatcgacacaagcgctacagtagcaatttttaaaaaaatt



actgtagttttcgctacgagatattttgcgcgtcaaatttgctgcgcaatacgcattctcagaattttgcgttaccgtaatatacacggtgaagaa



cacgagccaccaggagtacggtagccctgactttaattgcaaaaaaagagaaaacagtgaaaaaaatctgtatataattgctattatttttaaa



tttcgcaaaaaaaattagaaatgaccacattaattttgaattcctgcgcgaatgaattctattttttgcgtattcctgcaatatttattggattttctctt



agcctaaagcctaaaacgcagaaatttcgaaataataaattgaccatttttgaattattggtgcaaaattgagaaaaattgtgaaaaattatacc



attttttgaacaattacgctcagcttactaattgtaagattactcagatttatggcaaaacacgatttttacgccttcaaaaaatcctagcttttggc



aaaacttacaggaaattaaaaaattcagaataaaaagtaataagatccaggaagccatgactcgaatcattgtagttgaactgtatgaatgatt



tgatcccagcttcttccgccaccctaaacaccccataatttccgttttccgcttgaataggaaatgttgtatatttctgtactccttcctgaagtattaaaa



ctcgttttcgtttattaaactgtttcttttttcagatcactcaacttcctcttctcaacgtcaacttcgactcggctaattataattttatttatttttctga



tttttttaaaattcttgttttttctcaaatttccaatttcaacatcatcttattttcaaataaaaatatttattttgcgactttctattaatttgaaacagc



gaatattgttaatttattaagtaaatttaatcattttagatcgttttcaaccgattttcgagggctttccacaaattttgtacttttaaataaatttaaagt



ttattctaccgaaaacactatttatttttccacgtggacaccgccaattttctctgaaaattctaaaattctggttgaaaattaatttttaaagcttcct



cacgagaaaagcgccaacgcacgaggagcgcgccagcaaacccgcattgacgcagtctcggtgcacttctgaactccaaaacacactg



ttcccgttcgatttttctcgcatttttcatagtttttttcgaaattgaagcttttaaaggtgttttagacttgattcgaagtgaaatattgattgattgag



ccggaaaataggcaaaaagttctggaaaaacgcgcgaaattaaaattccagtgactttcgagataatgatattgatttttccgagtaattaagt



tgatatccagctatttatttttgcgtgacattctaattaccggattttcaaagttttttcgaaaaaaaaacaaagcaaaatcgatttatttcgaattac



tcgcgacttctcaactttgaagctgaaaatagttagttttgttttttctgttatcagtgcgcgctttttctgcaataataacattccgcagtacgatttt



ttcaaattttttgcttttcgagaacggaaaatcaagtttatttcagtgtgcacgaaaaacgagcgagattctgacttgaccagttcgttcggaatc



gactcatttttggag






















































































































































































Cell Cycle Toxicity Genes






cki-1





SEQ ID NO: 151





gatctgttctttccgaaaagaagtagttaacaggtgcggcttcactgggtggtctcatttttcattttaacctgttaatttattccggcttcacctcta




atccttaatgacattaacatcttcctaatgtgtctaagcttttcccacggaaagctaatttcctctctcttatttttctcattaccgttctggttgagctt



catcttataccgtgaatggtttcataattacgtgctacataatttgttatgctggtcgaggctcaacgtttcgaacatctggctcttttccttcagct



aaccacaccactcttcgttacaatcccttctgcgcacacatatcctatctaccagccggacagatgctcgtttctcggtgcaaaacgttgaga



gttgagatcgagcagccggttggtagttcttaatgacaaattgccaagactttttctgaattattttaggatttaaaacttttctaaagtattacgat



agttcataatttctttcttttttaaaaattggctcttttttgtaatgtatggtatctaactaaaactaggcctcatttccataactattctttaaattgagtt



gagctcaaagagttagacagaactggtgtgaatcatagaacccacctgtgtttttactttctttgaaaaatgtcggtcacttagtcgtctctctgt



ctgttccttttcctaatcacaagtaacaacacacagtcttctttcacatatattatttgttgaccaatcgtagggtcaactatctagtactcgagacc



gcctatttgaacagagctcctcactgtcaccaaatgtaccgtattgctttccggctgttattgttgttatcactgcttcttcttcctatcatgttaccc



atccaactatacaccttagactagtcatcttattgatatacattcctcccatccaacacaacggtattctatttatttatccaattagtcatagtcgta



ccaccatccagcacgaaggtgcctctttagtaaagagtagaaagaagaaccggatgggaaatgtttttgttacaaaaatgacacatattgta



gtggacagaaggagtgagacagacatgagcaagccaatttgtttataatttctcttctagaaaaaaatacatttttccatacttcactagtcaaa



acctttcacctttctaatacatctcgtaaaccataatcttgatagttctgagcatttcaatacgaaagcttctcactgtctagatctctgactgagtg



ccctcatcaaaagtgcaatctgtcatctgtttcctcataatcacggagcactaatttttctctctgcgtctctataatcagatatctctcgtcactaa



gaactttccgaaatgtttatgcttctcatctgaccacttcggttccgcacaaaaaagtacggcattccaaaagaaatctgatccccctccgttca



ttcgtggtccgagtcggtgccaccagtcgttgcgcattgaatatttgtttggtccgttccccttcttctccgactgctgacctcgggcactttgat



gaccgggccaccacctcagtacccctctattacaccctctttgcctccgcgcatatgactccaccccttctcgtggaaggcgtgtatctcccc



tcttttccgctattccctcgatggatatatattcaaatgtatgtgtgttcctgacgggagggcgtctcgcttgagagcatcgtcacatcttttacaa



ttttacttatgattttacttcatcttcttcttcttactgcgattttgatatgcattcttatgtaaactattattattccaggtttcctcactcttttcaa



cki-2




SEQ ID NO: 152





taggttaacactgataaatcttgcagaactgttttattttattaaatgagacattaccgatctaaataaatttacaatcccatcaaactttctcctttat




cctccagaatcccatcattttcatcggcacttcttcaaaagtttaaatgtgagtgaccgcccgtctcgctctactaatcgtatatgcaaattttcttt



gatatcatagaacctgtcatacttctccaagtatatgaaagacaattaaaactactgagagaaagaagtagttcgcgataaaaaagtacatat



aatacaccttttcacctagaagagatgctttcaacttctacttttctggtcatatgtaaatagttgggttttttgacagtttgacaggtttacggcagt



caagacgacaaaaatggttatcaaaaggagctggcatacagccaataccaccagttctgatctttttacgattatcaaattgtacatgggggg



ttaagttgaattttagtttcattttttcaaaagtttaaactcgaaaaataactgaattgaaatatagtgaagttggcaatataccaagggtagaaaa



tcagacgagtgattttatttctagacaatcttaaattgctcaaattgtggtcttttctatatttgaacttttaaatgcagcaatttgtgaaacatacaat



tgaaacaaatttcctcaaaaactgccaccagctgaggtatcatgaagccttctgttcacacatgttgccacctaatcggtcacttatcctaatta



acattcttccactaaattgtcccctagtcacccccacttgaacgatatacacaccaactgttctcgttcactaatacacttcttccggagggattc



aactggttatattctgcagttgtcggcaggtgtgtggtagacggtgacgtaatattgcacagggtgtcggggaatgattatgaagtcgagatg



cgcaacagctggtaattgaagccacgagagaaaatggaaaagactatgatgagggcacaaggatagaaaaattgactgggagtgacca



aacaggcgaggtcacaatgaaattggtgaaaatggaaaccctaaaagtaactttagattttagaaaatagttggacgatttttcgttttcaaagt



tcaaagcatgcattattatcatctgaagatgcacgatttgacttgtgtgactgatatctcgtcgcgatcttaccgtaacctacagtacttccatatt



aactaaagttggttcgcttcgagacatcgggaacgtgagttatgtatttggcattattcgtcattttatattctagaaagatttacattctgtcaagt



tggaatattttttcttagccgtgcaatagaacttttgttgaatttctcagagtacaatttttatgaccgccgatttcctctcgataagcattacgttatt



tacctatggttttcaactatttaatgagatttatcaggacctcccgtagttttatcttctatttttactcaaattttgagctcaaaaataacaggaaag



atttaatcgaaaaaaacatatttctgaaatccaagagcaatcgcgcgctattgataatctggtttgccgcatttctcgcggcaacaacaaagag



tttgaatcgaaacgcctttttatttgaaaaaaaaccttttttgttttaaaatttagtctatacgtgaatctaacacacacaaactgttcactaatttctct



ttgttcgtctttttaccatttcatttcgaaactcgctgtcgtctcgtttctctcaccactcttcacacttttgccgcctaatcgatcgatcttgccgcg



gcgcactcacatttttctcttattttcttaccggcaaaaaatgtacgttttaccgcacttttcgcttacattactatttcaaattctcttatcaaaattatt



tcagaaacgaagtaacacaa



pcn-1




SEQ ID NO: 153





catgaagaaacagtggccgtattgggaaaaatgaacgatttttcggcgggaataatttatttttttatgtttttctatgcgttttcgggtgttttcgg




gttgctaagcgattggttgcctttttgaatcactagtcttggtttttgttgtttctgtgaatgaataattggtttttcgaggtttttttgtcaaacatgcct



aaaaaataaattatgacgttttagttgatttgtttgttctttaaacgtctgaaaataaggtttaaatctaatttattaattataaaattcgtcaaaataag



ttgcgcgtcaaattatatgtattgtacgcagtgtcaaactccaggcctcagttttcatgaatttaccagcgatttttgttataaatttttttattgaaat



ttaaaatttttatttttcaaccaatttgcctcgaaaattcgttatttccccattaaaaaccgcttttctaaagtgttgcgcgtcaaataaaatgcctgg



tacgcaatgcacggagaatgcgcaaaggacgactgctggcgcactttttgaatgcggtaaattgaggcgcgaagtttcattcgaaaacgc



gcgcgaaacttcattcatcgcactttctccgttcatttcgtcctatttttttgtggtttttcgcgattttttcgcttttctgagtgaaaaaataattttcctt



cgttttttcaatgaaaatccgcggaaaacccattttttcccgtgaaaatccgcatttttcgctgtatttcataatttttattcagatctcccgtcaaa



smo-1




SEQ ID NO: 154





ttgctgttcttaattgatttcataaatatgtataaagcattaaatttgaatatatttttaataaagaaaaatcgatattcacattagagcgcgcttgca




atttcacgatgagacctgacgataccgcgcgaattaaatcgatcgctttttggcctaaaatgctcattaacaattgtttttgtagtttttagcttaaa



attatattttaaaatccagtttgccttgttacatattggaaaacggtatttttagagtttttcctcaaaaaccaagcgaaaaccttgaattttgttccg



aaaacttgttcaaaacatttttttcgttgaaaactcaaataattcaccaatttatctattttaggccgaaatctcttattttttcagtccaaaaagcacc



aaatttggtcaaaaacctgtccaaaatctaccgtaccctcgtgttgctcgtgaaatgcggtgcattgtgtgcaaacaccgcggcgtgaacatg



cacactctgcaacgcgggaaatcatttcgaaaaggtttttaggcgcgtattgcccgatttttcggctcatttcgtgtgttttcatttatttttgccttc



tttctccggtcgcgatgcgtttaattaagttttgcttctaaatttcgtcaatttcgctgaaaaaccacgtagaaaacttgataggaactggatatcc



taaaaaaaaggatttccttgagaaaaatgggttttttttctgaatttcgcagtgatattcttgaaattctcagcgcagcgctccccagacaatcga



tattcctaatttttcaagcatcttgtggctcagccagctgttctgtaattatcgattttatttgttacagcgtctatataaataccctagaaagtcatca



ttctgcactcttaatacctttcactcgtgtgagttgcattctccatagcaactctacctctctccttctatctctttttctcttttcaaatctaatttcgttt



cagagactcccgctataaacg



rnf-1




SEQ ID NO: 155





ttcgctttaactcctccagaagttgacggtccgccagtgcctccactagtcgtcgggagtttatggttcagtttcgcctttttcatgtcctccggc




ttcataatcgtatcatttaggcgtttgtgttttttacgttccattatttataagattctaaacgagaaactcttaagattttccggaaaataatgataaa



aacggttgtgaaattgaatgagaataaaaaaacgaaacaagcacgagtgaggcaggtgcgctccaatgcgaatttctttgcgcggatgttt



aaatggttatttttttatgggaatcgacaagtcacatgctacgctagagagagttttacattttacagtctttttggaatttaataatatatatattatc



ataaaatcgaataaaaattgtttcgaataatgaatagctttgttttttcgtcttgacttctgaaataattttaaatttgagaaaaatttgtgtcgcaata



tataattattaatattattaataatgtaatttttttataataaactgatttatattttaaaaacaaaaaaggaatgacaattcagtttagttttatgaaaaa



ctttgaaaagacaaaaataattacagtaaacgcgctccgctagactccccaaatttgtttttgttttccaggcttgtgtccaggcaaattccagct



ttctttttgtttcagaatttctaggtatttatctccgtgaaa




















































































































































































Apoptosis Toxicity Genes






egl-1





SEQ ID NO: 156





gaaaacttcgattcttatggttaaaacgagccttgttagtaaaaattattgagtgaataaataaattagatcaagtattttcacttctgccaaaattc




aactaaatagaaatggttggaattaagttacaagctaccagtttacaaaacaataattgacaggtaatcggagtgaagacagttttttgcctttg



ataattttacattcacatttaattttacattcacataaaaaaagaatcacacatttttttcaattgacaagtttttgataaagtggaagacatcggag



atatgacccgtcaaagttgctcagcagggtgcaaaactaaaagaggaaatactgtgaaacattttgacaatttagagaaatacacagcgaa



agaatgaaatctaaaaaagcgtattaactttaactagataaacatactaacttattgaggtaaatctgagcagatcctcttcctattcccaatattt



acccaattagtcttctgattgcgcacctgcatatcttaagtactcaaatacaacacacatcttgagaaatgatgactccacactcagaatgcaat



tcacactattagaagccatgtgcaatatgaaaacaagcttatcctgaagctgcaaacccatttacctcatcaattatttgcgatgtgccgacctg



ttgcatggcttccgacactgtaaggggataatctgtttgtcggcacgcttcaaccgattaattggcgtgtgaaacgatactaatccagtcgatt



ctcgactaactgtaaacactttgatgctaaccgacgtgccggctaatatactctctgtgttacgtcagaatcctttaaatatgcaaatatggataa



ggtggaatgatctcaagaggtgtgattgggtcaaattggattacgtaattcttaagtgggctaaaggtatactgtaactggggtgcaatttatgt



gggaagtgcggcgaagttatattggggttttatagattctataacttgttacattgattttgaatagatttcaattttcagaaaagtgggaaaactg



tatttacattttgaaagaaatttaatgcaacagaaaatagtgattggctggaaaagtgcccctatgttataaactttttgttgaagctttgaaattttt



cacaaattattcaactgaagtctcacacgtcgaaaaatggccaaacaaatttttaaaaaatagaggcctgatcatagtttctgccatttcatggc



cgtctgtgacgtcacatgaggtttttcgactatttggcttccagggttttacctgtttttaatttcaaaattatatattcttcagtaaatctctgaaagt



cacagtcgtttcagcgaactttcaaggccgcgtgtgacgtcacactcttgcaaagaaagctgcacgtggtgtcaggttgtcccataacggttt



gctctacgaaaaatgcgggaattttttcatcaaaaaatgtgacgtcagcacgttcttaaccatgcgaaatcagttgagaagtctgcgtctaagt



tcccgcgttttttgtagatcacaacggaatgggacattctgacaccatgtgaagctggccttgagatagttttgtagattcaaaatatttttaatgt



ccaatatttgttttcaaaacattcgttaaaatgtgcagaatatgttaaactgaaggttcctaggtttaaaacttcaagctaaagctttccggctcag



ttctcaggttcaggtctgtaatctttctgtaagcttgtaatcttgttagttcctcagacagacttagctgctaaatttatttcatgtctaatattacactt



caagagctatgagtttgtcttcataaaagttttggctcccatataggaactttggaacatcatttgatccccgtttcgaaaacgttcgaaaattgtt



ttgtttctttatttaaacccgacagttcaaattctttatcttgatcaaacccttttttttcatctgtccattcctcggccttaacctaatttatacagtttcg



caataacctcccccgtgcttgctccagtaccagctgttgcgtcacgacttcttattttcaaaactcaaatcttgcatcacacctcatcaattaatc



atcctcatcaagcctgcaaacttatacccccttctctagacccctctcctgacatttgacactcctgtggtagaggggtgtggccttgcctggg



cggggcgtgcaatgagaagctgtgcacgcacaccattcattcacacccaaaacattcacaccgattagtcgtattctaacttctcttttcaattc



agttgatatgctggtaagtctagaaattatttatttttgatctacatacctgtccaatattgttcgtctccccctccccctcctgagaaacaaattttt



gtttttgtctgctcgcctcaccctcaacctctctctctctggatgtgttcgtggtgtagaaacaaaaacagatttttgtttttttgttttttgtttcttgttt



tagaacttgtatcctagtaattgttagacatctccctactatctttcccctatataaacccccttcaaaaccttactaatttccag



cep-1




SEQ ID NO: 157





aacagaactcacccgtttctagaacaacgtttgctatcaactccaccccgaaagaatccaggtggttcgtctgacattatgctgcaattttatg




agaatattcagacgcaacaacaacgtgacaaacgacgagataaaaatctatcaaggctgaaacaatgacaaaaaagaaatcccgacaaa



tgaaaatggcgcctaaaacaaacttttttaaaggacgtcgggtttcattcacagatgggtctcggaacgaaatcatggagtacggtatcacac



acttgaatttgaaagtgaacttctttatttgtttctcttgcaagtttaaacttaagtttttaattttttctgcttgtttctcaataaaataaaaatattact



tgatttgtagcgcaga



ced-3




SEQ ID NO: 158





ttctgcgtgaaatgtgatgtttctacagtaacccgtacaaccaaggcatcgaacttcacgacatttacgaattcaaatttgaattgcaaacttttt




aattttatcgattttctttctttttgagctttatcaatagctctaagcgattattcaacagaatttcacttttttacgcctaaatgattgaaaatttgataa



aatatcaataatttacggttatcctcttcgtaatcttcgctttcttcccagagtagtgaaaatatcgactttttgatagaaactggattttttaacttcc



ctgttcgaaaaactatttttccttaaatgagatctgaaataaggtgataaattaataaattaagtgtatttctgaggaaatttgactgttttagcaca



attaatcttgtttcagaaaaaaagtccagttttctagatttttccgtcttattgtcgaattaatatccctattatcactttttcatgctcatcctcgagcg



gcagcgtctcaaagaattgtgagagcaaacgcgctccattgacctccacactcagccgccaaaaacaaacgttcgaacattcgtgtgttgt



gcctccttttccgttatcttgcagtcatcttttgtcgtttttttctttgttctttttgttgaacgtgttgctaagcaattattacatcaattgaagaaaagg



ctcgccgatttattgttgccagaaagattctgagattctcgaagtcgattttataatatttaaccttggtttttgcattgtttcgtttaaaaaaaccact



gtttatgtgaaaaacgattagtttactaataaaactacttttaaacctttacctttacctcaccgctccgtgttcatggctcatagattttcgatactc



aaatccaaaaataaatttacgagggcaattaatgtgaaacaaaaacaatcctaagatttccacatgtttgacctctccggcaccttcttccttag



ccccaccactccatcacctctttggcggtgttcttcgaaacccacttaggaaagcagtgtgtatctcatttggtatgctcttttcgattttatagct



ctttgtcgcaatttcaatgctttaaacaatccaaatcgcattatatttgtgcatggaggcaaatgacggggttggaatcttagatgagatcagga



gctttcagggtaaacgcccggttcattttgtaccacatttcatcattttcctgtcgtccttggtatcctcaacttgtcccggttttgttttcggtacac



tcttccgtgatgccacctgctccgtctcaattatcgtttagaaatgtgaactgtccagatgggtgactcatattgctgctgctacaatccactttct



tttctcatcggcatgcttacgagcccatcataaacttttttttccgcgaaatttgcaataaaccggccaaaaactttctccaaattgttacgcaata



tatacaatccataagaatatcttctcaatgtttatgatttcttcgcagcactttctcttcgtgtgctaacatcttatttttataatatttccgctaaaattc



cgatttttgagtattaatttatcgtaaaattatcataatagcaccgaaaactacaaaaaatggtaaagtcttttaaatcggctcgacattatcgtatt



aaggaatcacaaaattctgagaatgcgtactgcgcaacatatttgacgcgcaaaatatctcgtagcgaaaactacagtaattctttaaatgact



actgtagcgcttgtgtcgatttacgggctcaatttttgaaaataattttttttttcgaattttgacaacccgtaaatcgtcacaagcgctacggtagt



catttaaaggattactgtagttctagctacgagatattttgcgcgccaaatatgatgcgtaatacgcattctctgaattttgtgtttccgtaataattt



cacaagattttggcattcctctttaaaggcgcacggatttattccaatgggtctcggcacgcaaaaagtttgatagacttttaaattctccttgca



tttttaattcaattactaaaattttcgtgaatttttctgttaaaatttttaaaatcagttttctaatattttccaggctgacaaacagaaacaaaaacaca



acaaacattttaaaaatcagttttcaaattaaaaataacgatttctcattgaaaattgtgttttatgtttgcgaaaataaaagagaactgattcaaaa



caattttaacaaaaaaaaaccccaaaattcgccagaaatcaagataaaaaattcaagagggtcaaaattttccgattttactgactttcacctttt



ttttcgtagttcagtgcagttgttggagtttttgacgaaaactaggaaaaaaatcgataaaaattactcaaatcgagctgaattttgaggacaat



gtttaaaaaaaaacactatttttccaataatttcactcattttcagactaaatcgaaaatcaaatcgtactctgactacgggtcagtagagaggtc



aaccatcagccgaag



mev-1




SEQ ID NO: 159





aaattcgaggaattttagatttcatcttgaaatttgcaatggaaaaaataattattcaaagaaaatcacagaaaatgcaacaaaaaaaacaaaa




aaagaacaaaaaacaagtcgaaaagtgcgcccgggtcgtttgctgacgcatctcttcaaacgagacgcgctgctggcgcacttctcgtgc



cctgtgcgtgcatttccgcaacaaaattcaacacttgttttgaaacgcaccgccctgtttcttttttcaattttgataagaaaatcagcattgtttca



gg



ced-13




SEQ ID NO: 160





tagaaacatgtttcccgtaagtgacctatccagtgaaacaaaaacatgtttctgtccgccttccttccatcggtggaggtgcatgctagattgc




ctcctaaactctaatacctaaaattttaataatttattgacaacatacagtttcaccgataaccgacactcttattttttctgatcctgactattctgtt



cattatttcagctcctatcatagaacgatctttccagatcttggacaagtcacagttacaggtaattttttcaacaggtgtttgtataatgtcttagtt



tctgtaaaattgttttatcatgtaaaatatttcagattattcgagggcagaaaaacgtgatattactattggagaggaattgacaaagttgtgtgat



aaatttaattttgag



bmk-1




SEQ ID NO: 161





cgagtttcttgtgagaaccaaaaactattcctctgcaagaaaaaatttattaatccggcataaaatactttttattacaataggaacttcacagtc




gcttcctccgacgctttgagcggtacatcgatgcttatcaccatgctgattgttacctttcttacccgtttgactttctgcaatttttaactgcaaag



atgtttaatgcagatactcgaaagaaacgaaaaaatgataaaaaagtgaaaaaccccaaaaataaatttgaaaactccgcgtaagcttgctc



gatcgctgcgagaccattgcataccgtactacttctttaaaggcgcacacatcaaatctagctgtttcgtgacaggacccagcaatgttcagc



cgcgaagttttgaatcgccatttttttttaatttctagaatgtttatagttttgctttcgatgagatttttaagcattatgaggaacaaatttttttaaaaa



ctttagaagttttaaaatttaattttgcgattatgctttgctttcgcgtgtcctttccgttgttcctcgctccaaatatatcacagtaattaaccactact



tatgtagttatcacgtttctaaaaatataaattcatttttatttctctattgattcggtttgttgctcttcttgtctcaatcttgtgctactgccgaataccc



tgctaatttttcgttttcagtcattcgattcacttgggttgttgtttaaaatggtaagatttttgcaggttactttctttcccatgaggtaaatgcatttat



tgcgggtgcgctctatcgcacgacgccgcgaatcattgtatttcaaattgattttcctgttgcacttttattagttacaatttttattagttatttttagt



tggattcgaca



rad-51




SEQ ID NO: 162





gaaaacctaaaatgaacaaaattttttgtcattaaataacaacgcttcggttaacgcttgaaattgatattcggaaaataaaaagcctgatttttgt




tcgatttctgaaatatatttcatgctttacccgtttttaattgcgaacaattctaaatttgaaatataattttcaatcaacgaaaaacaattttcaagat



aaaaaattattatataaatttaagctaagtattaataaattaataagtaatagtattcaaaaatcatagaatcttgcaagaaaaaatgttttaaagat



ttaatagttcgagtgattgaaaaacgaatagtactttaaaaaataatgctttaaggcagaaaagtgatataaaaattaagctcaaaagggcaaa



agataaggttaatgtccagttttggttttaaaatggttcggacacaatgtacatagtagacatttgggtgtcctcttccttctcttttccccattgcg



tccactgaccctccttgctgtatgtctgcgcatcgtctttttctacactttttccttttccctggcccgttcctatcggtgcctttcacacacgcgag



cggcagtggacgagacgggagggcgaggtgttgaacaagagtacagcaagtgcgcgccatcgaaaaagcggaaaaaaaaatttcaaa



tggcgctactttgaaaattgagaattctgtatttactgccagttttacttgcatttaaatttccatgttttctattctaaaacgaaaatctatctaagaa



aacccttaataaaaacctataaatcataaattgtgattcttaaattcgaaaatatgttcgttcaacttgacgcctagaaatatgtggacttaatcct



gttataaatcagtagttgacgacaaaaatagtagagcagcaaaagcagttctaacttgtgaaaaacatgaaagttcttgttttcgtcaagcgaa



cgggggctcgaggaaggacttggcacgtgtctctaggccatgtttttctcaatttttgttgctctagagaaagcttttgctattgattatgggaca



atcttggggatatgaaggtaacattttaaaaataagtttaggtaaatgtgtagcataatttttgaaaaaaaaagctccactgttaaaaatgccgat



tttagggattgcgaaacgttcactatgtacacataaatggctatataatttgaatttgcattcaataaatcttttccttccaattgtatgttttaactta



aaaataattaattaaaattatctcaggagtcaaaa






















































































































































































































































The invention is a nucleic acid comprising a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked, or fused, to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a isolated nucleic acid comprising a nucleic acid having a sequence 95%, 96%, 97%, 98%, or 99% or more identical to the sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked or fused to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a nucleic acid comprising a fragment of a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked or fused to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a nucleic acid comprising a fragment of a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked or fused to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgene comprising a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked or fused to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgene comprising a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked or fused to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgene comprising a fragment of a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter is and operably linked or fused to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgene comprising a fragment of a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a construct comprising a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked or fused to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a construct comprising a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% or more identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked, or fused, to a reporter gene. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a construct comprising a fragment of a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a construct comprising a fragment of a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgenic organism comprising transgene which is a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein said nucleic acid is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgenic organism comprising transgene which is a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein said nucleic acid is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgenic organism having a transgene which is a fragment of a nucleic acid having a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
The invention is a transgenic organism having a transgene which is a fragment of a nucleic acid having a sequence at least 95%, 96%, 97%, 98%, or 99% identical to a sequence as in one of SEQ ID NO: 1 through SEQ ID NO: 162 wherein said fragment is 50, 100, 200, 300, 400, or 500 or more nucleotides in length which is an inducible promoter and is operably linked, or fused, to a reporter gene wherein the nucleic acid fragment is capable of promoting transcription of the reporter gene as described herein. In one aspect, the reporter gene comprises a gene encoding a fluorescent protein.
Inducible promoters for use in the nucleic acids, transgenes, constructs and transgenic organisms of the invention are typically chosen from those present in the host organism and are involved in promoting expression of its cognate gene in response to stimuli or an agent. Examples of stimuli or agents include, but are not limited to, stimuli or agents that cause oxidative stress, stimuli or agents that are genotoxic, stimuli or agents that cause xenobiotic stress.
Exemplary inducible promoters, constructs comprising the inducible promoters, transgenes comprising the inducible promoters, and transgenic organisms comprising the inducible promoters of the invention are described in more detail below.
The invention is a nucleic acid, transgenic organisms, transgene, or construct comprising a promoter of a gene involved in oxidative stress response fused, or operably, linked to a reporter gene where the oxidative stress response gene is from a pathway of cytoplasmic oxidative stress, mitochondrial oxidative stress, peroxisomal oxidative stress, endoplasmic reticulum oxidative stress, or nuclear oxidative stress (Zhong, M. et al. PLoS Genet 6, e1000848 (2010)). In a related aspect, the invention is a nucleic acid, transgenic organisms, transgene, or construct comprising a promoter of a gene involved in oxidative stress response fused, or operably, linked to a reporter gene where the oxidative stress response gene is from a pathway of cytoplasmic oxidative stress induced by juglone or other quinones or phenazine; mitochondrial oxidative stress induced by paraquat, mitomycin C, antimycin A, or maesanin; peroxisomal oxidative stress induced by aminotriazole or antimycin A; endoplasmic reticulum oxidative stress induced by tunicamycin, menadione or plumbagin; or nuclear oxidative stress induced by belomycin.
The invention is a nucleic acid from a gene involved in oxidative stress whose promoter is used in the transgenic organism, transgene, construct, or nucleic acid of the invention and is chosen from those involved in cytoplasmic oxidative stress that can involve pathways such as heat shock, phase I and phase II xenobiotic response, or proteasome. In one aspect, the gene is hsp-16.41, hsp-16.2, hsp-16.1, hsp-16.11, hsp-16.48, hsp-16.49, sod-1, gcs-1, hpo-15, dhs-18, gst-14, gst-32, W06H8.2, cyp-34A9, or ugt-41, where the promoter for the gene is fused, or operably linked, to a reporter gene.
The invention is a nucleic acid from a gene involved in oxidative stress response whose promoter is used in the transgenic organism, transgene, construct, or nucleic acid of the invention and is chosen from those involved in mitochondrial oxidative stress that can involve pathways such as heat shock or electron transport. In one aspect, the gene is hsp-6, hps-60, mtl-2, mtl-1, cdr-1, sod-3, eat-3, cyp-14A4, cyp-33C8, glrx-10, F56D5.3, B0222.9, F17A9.4, C35B1.5, or gst-4, where the promoter for the gene is fused, or operably linked, to a reporter gene.
The invention is a nucleic acid from a gene involved in oxidative stress whose promoter is used in the transgenic organism, transgene, construct, or isolated nucleic acid of the invention and is chosen from those involved in peroxisomal oxidative stress that can involve pathways such as heat shock or oxidative metabolism. In one aspect, the gene is hps-1, ctl-1, ctl-2, ctl-3, W01B11.6, F10D7.3, prx-1, prx-5, duox-2, prdx-2, pxn-2, mlt-7, ZK550.6, C28H8.11, or C35B1.5, where the promoter for the gene is fused, or operably linked, to a reporter gene.
The invention is a nucleic acid from a gene involved in oxidative stress whose promoter is used in the transgenic organism, transgene, construct, or nucleic acid of the invention and is chosen from those involved in the specification of apoptosis as in endoplasmic reticulum oxidative stress that can involve pathways such as heat shock, ERAD, or disulfide exchange. In one aspect, the gene is hsp-4, dnj-27, dnj-7, Y41C4A.11, arf-1.1, lips-11, srp-7, gale-1, ckb-2, fipr-24, arl-7, F07A11.2, C04F12.1, hke-4.1, or F22E5.6, where the promoter for the gene is fused, or operably linked, to a reporter gene.
The invention is a nucleic acid from a gene involved in oxidative stress whose promoter is used in the transgenic organism, transgene, construct, or nucleic acid of the invention and is chosen from those involved in nuclear oxidative stress that can involve pathways such as heat shock or oxidative base damage. In one aspect, the gene is ugt-1, hsp-17, cdr-5, dnj-15, dnj-25, pme-1, pme-2, pme-5, air-2, mlh-1, mlh-2, polq-1, him-6, xpa-1, nth-1, or cep-1, where the promoter for the gene is fused, or operably linked, to a reporter gene.
A promoter region for an oxidative stress response gene (hsp-16.41) has the following DNA sequence (SEQ ID NO:1) and activates transcription of its cognate gene (or a reporter gene fused or operably linked thereto) in response to or by e.g., heat shock. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:1 operably linked or fused to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
A promoter region for an oxidative stress response gene (hsp-16.2) has the following DNA sequence (SEQ ID NO:2) and activates transcription of its cognate gene (or a reporter gene fused, or operably linked thereto) in response to or by e.g., heat shock. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:2 operably linked or fused to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
A promoter region for an oxidative stress response gene (mtl-2) has the following DNA sequence (SEQ ID NO:27) and activates transcription of its cognate gene (or a reporter gene fused or operably linked thereto) in response to or by e.g., heavy metal ion toxicity like cadmium. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:27 operably linked, or fused, to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
A promoter region for an oxidative stress response gene (ugt-1) has the following DNA sequence (SEQ ID NO:83) and activates transcription of its cognate gene (or a reporter gene fused or operably linked thereto) in response to or by e.g., heavy metal ion toxicity like cadmium. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:83 operably linked, or fused, to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP
A promoter region for an oxidative stress response gene (hsp-60) has the following DNA sequence (SEQ ID NO:26) and activates transcription of its cognate gene (or a reporter gene fused, or operably linked, thereto) in response to mitochondrial stress by e.g., paraquat. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:26 operably linked, or fused, to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene is encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
A promoter region for an oxidative stress response gene (hsp-6) has the following DNA sequence (SEQ ID NO:25) and activates transcription of its cognate gene (or a reporter gene fused, or operably linked, thereto) in response to mitochondrial stress by e.g., paraquat exposure. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:25 operably linked, or fused, to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
A promoter region for an oxidative stress response gene (hsp-4) has the following DNA sequence (SEQ ID NO:55) and activates transcription of its cognate gene (or a reporter gene fused, or operably linked, thereto) in response to endoplasmic reticulum stress by e.g., exposure to tunicamycin. In one embodiment, the invention is an isolated promoter reporter construct nucleic acid comprising SEQ ID NO:55 operably linked, or fused, to a reporter gene. Preferably the reporter gene is one that encodes a fluorescent protein or a luminescent protein. Preferably, the reporter gene encodes a fluorescent protein comprising a GFP or RFP. In a related embodiment, the invention is a C. elegans line or strain having the promoter reporter construct stably integrated into the C. elegans genome at a single site or using a single copy insertion technology. In one aspect, this C. elegans line or strain has a constitutive reporter gene stably integrated into its genome in addition to the above construct wherein said constitutive reporter is detectably different than the reporter of promoter reporter construct (e.g., different fluorescent protein). Preferably, the constitutive reporter comprises a GFP.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene induced by heat shock, heavy metal ion toxicity, mitochondrial oxidative stress, or endoplasmic reticulum oxidative stress which is fused, or operably linked, to a reporter gene. In a specific aspect, the heavy metal ion stress is induced by cadmium or arsenic. In another specific aspect, the mitochondrial stress is induced by paraquat. In yet another specific the endoplasmic reticulum stress is induced by tunicamycin.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene chosen from hsp-16.41, hsp-16.2, mtl-2, ugt-1, hsp-60, hsp-6, and hsp-4 which is fused, or operably linked, to a reporter gene.
Apoptosis pathway genes: Apoptosis activation is important for understanding toxicology and in the creation of drugs to battle cancer. A compound that activates apoptosis leads to cell death is advantageous for combating cancer. However, activation of cell death would be a detrimental property for apoptosis occurs by either the intrinsic (DNA damage and unfolded protein response) or extrinsic (Ras/MAPK signaling) pathways. Cell death is initiated by activation of the caspase pathway. Caspases activate pathways leading cell corpse engulfment and DNA fragmentation. Thus, the invention relates to transgenic organisms and in particular, nematode strains for monitoring apoptotic gene activation. An apoptotic gene's promoter is used to drive expression of a reporter gene. In one specific aspect the reporter gene is one that expresses a fluorescent protein. Preferred fluorescent proteins are a protein comprising RFP or GFP.
Examples of genes involved in apoptosis whose promoter regions can be used in the transgenic animals, transgenes, constructs, or nucleic acids of the invention are chosen from those involved in the specification of apoptosis as in cep-1, lin-35, jnk-1, pmk-1, mpk-1, ces-2, ces-1, atl-1, atm-1, brc-1, dnj-11, chk-1, cki-1, rad-52, cki-2, dpl-1, ceh-20, efl-1, hlh-2, or daf-16; those involved in the execution of apoptosis as in cps-6, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, cyn-13, nuc-1, bec-1, ced-1, ced-10, ced-12, ced-2, ced-5, ced-6, ced-7fnta-1, gdi-1, or ggtb-1; or those involved in the core of apoptosis as in drp-1, egl-1, ced-9, ced-4, or ced-3 wherein said promoter is operably linked, or fused, to a reporter gene.
In another aspect, the invention is a nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene induced in apoptosis which is fused, or operably linked, to a reporter gene. In a specific aspect, the gene induced in apoptosis is in the extrinsic pathway. In a specific aspect, the gene induced in apoptosis is in the intrinsic pathway. In another specific aspect, the gene induced in intrinsic apoptosis pathway is a DNA damage gene or unfolded protein response gene). In yet another specific the gene induced in extrinsic apoptosis pathway is a RAS/MAPK pathway gene.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene chosen from cep-1, lin-35, jnk-1, pmk-1, mpk-1, ces-2, ces-1, atl-1, atm-1, brc-1, dnj-11, chk-1, cki-1, rad-52, cki-2, dpl-1, ceh-20, efl-1, hlh-2, daf-16, cps-6, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, cyn-13, nuc-1, bec-1, ced-1, ced-10, ced-12, ced-2, ced-5, ced-6, ced-7, fnta-1, gdi-1, ggtb-1, drp-1, egl-1, ced-9, ced-4, or ced-3 which is fused, or operably linked, to a reporter gene.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, or a nucleotide 95%, 96%, 97%, 98%, or 99% identical thereto, which is a promoter for a gene chosen from cep-1, lin-35, jnk-1, pmk-1, mpk-1, ces-2, ces-1, atl-1, atm-1, brc-1, dnj-11, chk-1, cki-1, rad-52, cki-2, dpl-1, ceh-20, efl-1, hlh-2, daf-16, cps-6, crn-1, crn-2, crn-3, crn-4, crn-5, crn-6, cyn-13, nuc-1, bec-1, ced-1, ced-10, ced-12, ced-2, ced-5, ced-6, ced-7, fnta-1, gdi-1, ggtb-1, drp-1, egl-1, ced-9, ced-4, or ced-3 which is fused, or operably linked, to a reporter gene.
Genotoxin or Carcinogen Pathway Genes
Genotoxins are compounds that cause DNA damage. Carcinogens are compounds that cause genotoxicity or other procancerous activity such as, stopping cell cycle arrest, stopping cell-cell inhibition signalling, stopping apoptosis induction, etc. The arrays or panels of the invention can include 1 or more representative transgenic organisms, or populations thereof, having a promoter from a genotoxin or carcinogen response pathway gene operably linked, or fused, to a reporter protein.
From the Gene Ontology database, there are 162 genes involved in the C. elegans response to DNA damage stimulus (GO:0006974) (Ashburner et al. Nat. Genet 25, 25-29 (2000)) This group was compared to a meta-study cataloging the genes highly expressed after carcinogen exposure (Waters et al. Mutat Res (2010)). 24 genes were identified pathway-specific genes (carcinogen and/or genotoxin responsive genes). In particular, the genes identified corresponded to enyzmes base excision repair, nucleotide excision repair, mismatch repair, recombination controlled repair. Additional genes for inclusion in panels related to carcinogenicity include, but are not limited to, those involved in cell cycle control and apoptosis. To reveal which sections of the promoter contain transcriptional control sequences, data from two sources, 1) the Model Organism ENCyclopedia Of DNA Elements (modENCODE) project, and 2) related species alignments are compared and optimal sequence regions are selected. Once identified, the promoters for these carcinogen and genotoxicity pathway genes can be used to generate the promoter reporter transgenes, constructs, isolated nucleic acids, or transgenic organisms of the invention using genetic engineering technology, such as those described herein.
In one aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides of a promoter for a carcinogen pathway or genotoxin pathway gene which is fused, or operably linked to a reporter gene. A carcinogen pathway gene is a gene whose expression is altered (e.g., induced) in a cell, tissue or an organism upon exposure to a carcinogen or genotoxin. In another aspect, the invention is an isolated nucleic acid or fragment thereof which is a promoter for a gene induced in base excision repair, nucleotide excision repair, mismatch repair, recombination controlled repair, cell cycle control or apoptosis which is fused, or operably linked, to a reporter gene. In a specific aspect, the promoter for a gene induced in base excision repair is promoter for exo-3, nth-1, pme-1, or ung-1. In a specific aspect, the promoter for a gene induced in nucleotide excision repair is the promoter of xpa-1, mrt-2, ercc-1, or rad-23. In a specific aspect, the promoter for a gene induced in mismatch repair is the promoter for mlh-1, msh-4, msh-5, or msh-6. In a specific aspect, the promoter for a gene induced in recombination controlled repair is the promoter of brc-1, brc-2, rad-50, or cku-70. In a specific aspect, the promoter for a gene induced in cell-cycle control is the promoter for lin-35, mei-1, cki-1, or cki-2. In a specific aspect, the promoter for a gene induced in apoptosis is the promoter for cep-1, ced-3, ced-9, or ced-13.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene encoding a protein in a DNA damage response pathway that is induced by irradiation with UV or X-ray exposure which is fused, or operably linked, to a reporter gene.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene encoding a protein in a DNA damage response pathway that is induced N-ethyl-N-nitrosurea which is fused, or operably linked, to a reporter gene.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene encoding a protein in spindle formation that is induced by taxane which is fused, or operably linked, to a reporter gene.
In another aspect, the invention is an isolated nucleic acid or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, which is a promoter for a gene encoding a protein involved in regulating cell division or checkpoint control which is fused, or operably linked, to a reporter gene.
Endocrine Pathway and/or Xenobiotic Metabolism Genes
In one embodiment, the transgene, transgenic organism, or promoter reporter construct of the invention has a promoter or fragment thereof having 50, 100, 200, 300, 400, or 500 or more nucleotides, derived or obtained from a CYP P450 gene, ABC transporter gene, SDR/Redox gene, GST gene, or a Sol. Transporter gene, which is fused, or operably linked, to a reporter gene.
Examples of CYP P450 genes include, but are not limited to, the following C. elegans genes: cyp-13A1, cyp-13A2, cyp-13A3, cyp-13A4, cyp-13A5, cyp-13A6, cyp-13A7, cyp-13A8, cyp-13A10, cyp-13A11, cyp-13A12, cyp-13B2, cyp-14A1, cyp-14A2, cyp-14A3, cyp-14A4, cyp-14A5, cyp-23A1, cyp-25A1, cyp-25A2, cyp-25A3, cyp-25A4, cyp-25A5, cyp-25A6, cyp-29A2, cyp-29A3, cyp-29A4, cyp-31A2, cyp-31A3, cyp-32A1, cyp-32B1, cyp-33A1, cyp-33B1, cyp-33C1, cyp-33C2, cyp-33C3, cyp-33C4, cyp-33C5, cyp-33C6, cyp-33C7, cyp-33C8, cyp-33C9, cyp-33C11, cyp-33C12, cyp-33D1, cyp-33D3, cyp-33E1, cyp-33E2, cyp-33E3, cyp-34A1, cyp-34A2, cyp-34A3, cyp-34A4, cyp-34A5, cyp-34A6, cyp-34A7, cyp-34A8, cyp-34A10, cyp-35A1, cyp-35A2, cyp-35A3, cyp-35A4, cyp-35A5, cyp-35B1, cyp-35B2, cyp-35B3, cyp-35C1, cyp-35D1, cyp-36A1, cyp-37A1, cyp-37B1, cyp-42A1, cyp-43A1, cyp-44A1, dpr-1, coq-6, fmo-1, fmo-2, fmo-3, fmo-4, fmo-5, pah-1, tbh-1, C01H6.4, C46H11.2, F30B5.4, R07B7.4, R07B7.5, T19B4.1, Y47D3A.22, and Y71G12B.4.
Examples of ABC transporter genes include, but are not limited to, the following C. elegans genes: abce-1, abcf-1, abcf-2, abcf-3, abch-1, pgp-1, pgp-2, pgp-3, pgp-4, pgp-5, pgp-7, pgp-8, pgp-9, abt-1, abt-2, abt-3, abt-4, abt-5, abt-6, abtm-1, cft-1, haf-1, haf-2, haf-3, haf-4, haf-6, haf-7, haf-8, hmt-1, mrp-2, mrp-3, mrp-4, mrp-6, mrp-7, mrp-8, pgp-10, pgp-11, pgp-12, pgp-13, pgp-14, pmp-1, pmp-2, pmp-3, pmp-4, wht-1, wht-2, wht-3, wht-4, wht-5, wht-6, wht-8, and wht-9.
Examples of SDR/Redox genes include, but are not limited to, the following C. elegans genes: dhs-1, dhs-2, dhs-3, dhs-4, dhs-6, dhs-7, dhs-8, dhs-9, dhs-11, dhs-12, dhs-13, dhs-14, dhs-15, dhs-16, dhs-17, dhs-17, dhs-18, dhs-19, dhs-20, dhs-22, dhs-23, dhs-24, dhs-25, dhs-26, dhs-28, dhs-29, dhs-30, dhs-31, ard-1, fasn-1, maoc-1, qdpr-1, sdz-8, C01G12.5, C06E4.3, C06E4.4, C06E4.6, C27D8.4, C30G12.2, C33E10.10, C41A3.1, C55A6.3, C55A6.4, C55A6.6, C55A6.7, D1054.8, DC2.5, E04F6.15, F02C12.2, F12E12.11, F20G2.1, F20G2.2, F25D1.5, F26D2.15, F28H7.2, F32A5.8, F54F3.4, F55E10.6, F59E11.2, H04M03.3, K10H10.6, R05D8.7, R05D8.9, R119.3, T01G6.1, T01G6.10, T25G12.2, W03F9.9, Y47G6A.21, Y47G6A.22, ZK697.14, ZK829.1, Y47G6A.21, Y47G6A.22, ZK697.14, ZK829.1, hsd-1, hsd-2, hsd-3, and C32D5.12.
Examples of GST genes include, but are not limited to, the following C. elegans genes: gst-1, gst-2, gst-3, gst-4, gst-5, gst-6, gst-8, gst-9, gst-10, gst-12, gst-13, gst-14, gst-15, gst-16, gst-18, gst-19, gst-20, gst-21, gst-23, gst-24, gst-25, gst-26, gst-27, gst-28, gst-29, gst-30, gst-31, gst-33, gst-34, gst-35, gst-37, gst-38, gst-39, gst-40, gst-41, gst-43, K10F12.4, K10F12.4, R11A8.5, W10C8.4, Y45G12C.3, Y53G8B.1, Y53G8B.1, F55A11.6, F55A11.6, F56A4.4, gstk-1, and gstk-2.
Examples of Sol. Transporter genes include, but are not limited to, the following C. elegans genes: vit-1, vit-2, vit-3, vit-4, vit-5, vit-6, egg-1, egg-2, irp-1, irp-2, lbp-1, lbp-2, lbp-3, lbp-4, lbp-5, lbp-6, lbp-7, lbp-8, lbp-9, nrf-5, cit-1.2, C06G1.1, C05C9.1, F10D11.6, T19C3.5, ZC513.1, ZC513.2, C31H1.1, T10B5.10, D1007.16, C55C3.1, F14D12.1b, F46H5.2a, and ZK616.8.
Specific Panels of Representative Transgenic Organisms or Populations of Representative Organisms
In one embodiment, the invention is a panel or array of transgenic organisms as described herein. The panel or array in one aspect is provided in a multiwell plate wherein at least 2 or more (or 3 or more, 4 or more, etc. as described in more detail below) has a transgenic organism or population of transgenic representative organisms representative of one-type of response gene e.g., having a distinct transgene that is distinguishable by the identity of the gene from which the promoter of the transgene was obtained or derived.
Panels or arrays of the invention include 2 or more representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include 3 or representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include 4 or more representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include 5 or more representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include 6 or more representative transgenic organisms or populations of representative transgenic organisms. Preferably, the panel or array has a control organism or control population of organisms.
Panels or arrays can include from 2 to 384 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 2 to 96 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 2 to 48 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 2 to 24 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 2 to 12 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 2 to 6 representative transgenic organisms or populations of representative transgenic organisms. Preferably, the panel or array has a control organism or control population of organisms.
Panels or arrays can include from 3 to 384 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 3 to 96 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 3 to 48 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 3 to 24 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 3 to 12 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 3 to 6 representative transgenic organisms or populations of representative transgenic organisms. Preferably, the panel or array has a control organism or control population of organisms.
Panels or arrays can include from 4 to 384 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 96 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 48 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 24 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 12 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 6 representative transgenic organisms or populations of representative transgenic organisms. Preferably, the panel or array has a control organism or control population of organisms.
Panels or arrays can include from 5 to 384 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 5 to 96 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 5 to 48 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 5 to 24 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 5 to 12 representative transgenic organisms or populations of representative transgenic organisms. Panels or arrays can include from 4 to 6 representative transgenic organisms or populations of representative transgenic organisms. Preferably, the panel or array has a control organism or control population of organisms.
Selected Agents
A “selected agent” refers to a chemical, object, or external stimuli that is contacted with or exposed to the transgenic biosensor organism. The selected agent can be given or exposed to the transgenic organism. In one aspect, the selected agent is dosed in a range at concentrations below a lethal dose and at or above levels where a therapeutic effect is expected to be observed. Such ranges can be determined in dose finding studies. Acute assays can be conducted using the compositions and methods of the invention and can range from about 2 hours to about 24 hours, more preferably from about 2 hours to about 18 hours and more preferably from about 2 hours to about 10 hours.
Typically, chemicals are given to the animal or organism in the range of 1 picomolar to 10 millimolar. In other aspects, the organism are exposed to an agent like a physical object e.g., in their growth medium, lining the vesicle or microwell plate or as a gas.
In one aspect, the selected agent is a chemical. In one aspect, the selected agent is a drug candidate or an agent which is a component of a formulation for a drug product. In one aspect, the selected agent is water. In one aspect, the water is a drinking water. In one aspect, the water is wastewater. In one aspect, the selected agent is a food product or liquid or an additive of either. In a specific aspect, the food product, liquid, or additive of either is intended for human or animal consumption.
Methods for Creating Transgenic Organisms
The transgenic organisms of the invention and for use in the methods of the invention can be produced by any technique. Preferably, the transgenic organisms of the invention have single copy inserts of the desired transgene at defined genomic loci and are stable. The transgenic organisms of the invention have a response element (e.g., promoter) reporter gene construct stably inserted into the host organism's genome.
In one specific aspect, the transgene is an inducible promoter reporter gene construct. The optimal promoter and gene-intron sequences of target genes are identified from publicly or privately available databases. For example, one such public database is found at www.wormbase.org. Gateway-compatible PCR primer sets are created for both the promoter and gene intron regions. PCR reactions are gel purified and cloned into a targeting vector (e.g., a MosSCI targeting vector) containing the desired reporter gene (e.g., tag-RFP, RFP, his-RFP, mCherry, or his-mCherry). Desired construction is verified by PCR and/or restriction enzyme digestion.
MosSCI integration (Frokjaer-Jensen, C. et al., 2008 Nat Genet, 40 (11), 1375-83). Plasmid DNA mixtures are injected into MosSCI targeting strains. These strains have a Mos1 element at a specific genomic site on chromosome II and contain the unc-119(ed3) mutation, which is used for positive selection of the transgene. The injection mixes for MosSCI transgenesis contain three types of vectors: 1) the gateway reporter construct containing the unc 119(+) positive selection marker gene and sequences for homologous recombination into the C. elegans chromosome, 2) a transposase-producing plasmid, and 3) three plasmids acting as markers for tracking the presence of extrachromosomal arrays. Three injected animals are placed on each plate and transferred to 25° C. for 8 days.
After the 8 days at 25° C., the worms are screened for MosSCI events. Candidate insertion strains are homozygosed by clonally picking 8 Unc-119(+) animals that do not carry mCherry (RFP) arrays to individual plates. MosSCI typically produces one integrated transgene from ten injected animals. Thus, the 25 injections/construct are expected to yield 3-4 independent lines.
Desired insertions are verified by PCR with one primer annealing within the insertion and a second primer in reverse annealing outside the insertion. Outcrossing (2×) of the candidate lines confirms their chromosomal integration by observation of Mendelian segregation of the integration locus.
Validation of reporter construction. Candidate lines are imaged by confocal microscopy to record basal expression profiles. Animals are anesthetized on agarose pads on glass slides with glass coverslips. Laser confocal imaging is performed on a Pascal LMS system. Each worm is imaged with a fixed set of laser intensity settings and the level of RFP expression is quantified with NIH ImageJ.
Kits
The invention relates to a kit having one or more biosensor nematodes and materials for use thereof.
Thus, the kit of the invention has:
One or more transgenic biosensor nematode cultures and reagents necessary to reconstitute healthy populations;
Incubation buffer for delivering agent;
A control nematode culture that is similar to the transgenic biosensor nematode culture but does not have the inducible promoter reporter transgene; and
A vesicle or reaction plate for containing and culturing one or more transgenic biosensor nematode cultures and the control nematode culture.
The reagents necessary to reconstitute healthy populations include a medium. In one aspect, the medium is M9, S-media, or CeMM.
The incubation buffer allows for delivery of the selected agent to the transgenic biosensor nematode culture substantially affecting the nematodes in a negative manner (the incubation buffer minus selected agent desirably does not kill the nematodes). In one aspect, the incubation buffer contains DMSO. In a more specific aspect, the incubation buffer has about 2% DMSO. In another aspect, the incubation buffer has acetone. In a specific aspect, the incubation buffer has about 5% acetone. In another aspect, the incubation buffer has methanol. In a more specific aspect, the incubation buffer has 2% methanol. In some aspect, the incubation buffer comprises 2 components which are a solvent for the selected agent and a buffer. The solvent for the selected agent in is chosen from a solvent comprising DMSO, DMFO, acetone, or methanol. In one aspect, the buffer contains detergent. One detergent for use in the incubation buffer is 0.01% triton x-100. The incubation buffers for use in the kits have capacity to increase uptake of the selected agent compounds.
The vesicle or reaction plate for containing one or more biosensor nematode cultures is of sufficient height, size and depth to contain each transgenic biosenor nematode population separate while allowing for the additional of appropriate reagents for growth and exposure to selected agent. Additionally, the vesicle or plate desirably does not interfere with reporter assay.
Typically, the vesicle or each well in a plate has a number of organisms sufficient to yield an adequate signal of the reporter gene. In one aspect, each vesicle or well has 10 or more organisms. In another aspect each vesicle or well has 50 or more organisms. In another aspect, each vesicle or well has 100 or more organisms. In another aspect, each vesicle or well has from 10 to 1000 organisms. In another aspect, each vesicle or well has from 50 to 1000 organisms. In another aspect, each vesicle or well has from 100 to 1000 organisms. In another aspect, each vesicle or well has from 300 to 1000 organisms. In another aspect, each vesicle or well has from 300 to 800 organisms.
Generally, the nomenclature and the laboratory procedures utilized in the invention include molecular, biochemical, microbiological and recombinant DNA techniques. These techniques are explained in the literature. See, for example, Molecular Cloning: A laboratory Manual Sambrook et al., (1989); Current Protocols in Molecular Biology Volumes I-III Ausubel, R. M., ed. (1994); Ausubel et al., Current Protocols in Molecular Biology, John Wiley and Sons, Baltimore, Md. (1989); Perbal, A Practical Guide to Molecular Cloning, John Wiley & Sons, New York (1988); Watson et al., Recombinant DNA, Scientific American Books, New York; Birren et al. (eds) Genome Analysis: A Laboratory Manual Series, Vols. 1-4, Cold Spring Harbor Laboratory Press, New York (1998); Cell Biology: A Laboratory Handbook, Volumes I-III Cellis, J. E., ed. (1994); Oligonucleotide Synthesis Gait, M. J., ed. (1984); Nucleic Acid Hybridization Hames, B. D., and Higgins S. J., eds. (1985); Transcription and Translation Hames, B. D., and Higgins S. J., Eds. (1984); Animal Cell Culture Freshney, R. I., ed. (1986); Immobilized Cells and Enzymes IRL Press, (1986); A Practical Guide to Molecular Cloning Perbal, B., (1984) and “Methods in Enzymology Vol. 1-317, Academic Press; “PCR Protocols: A Guide To Methods And Applications”, Academic Press, San Diego, Calif. (1990); Marshak et al., Strategies for Protein Purification and Characterization—A Laboratory Course Manual” CSHL Press (1996); all of which are incorporated by reference as if fully set forth herein.
Reagents useful in applying such techniques, such as restriction enzymes, coding sequences, fluorescent proteins and the like, are widely known in the art and commercially available from such vendors as New England BioLabs, Boehringer Mannheim, Amersham, Promega Biotec, U.S. Biochemicals, New England Nuclear, Life Technologies, Roche and a number of other sources.
References are provided throughout this document. The procedures therein are believed to be well known in the art. All the information contained in these references is incorporated herein by reference.
EXAMPLES
The examples below describe the construction and use of representative compositions for detecting and screening for response to exposure of whole organisms to selected agents e.g., a chemical or toxin. In these examples, the use of panels of transgenic nematodes as biosensors of toxicity pathway activation is described. The panels are composed of promoters of toxin-responsive genes fused to genes encoding reporter proteins. The promoter-reporter fusion construct is inserted into the nematode genome as a single copy gene insertion (e.g., using single copy or site specific insertion transgenesis techniques) at a defined genomic locus. The result is a set of transgenic nematodes strains or lines where each type of transgenic animal functions as a biosensor for a specific toxin (e.g., a representative transgenic organism). Toxins can be typed e.g., for their class of toxicity by observing which subset of strains show reporter activation.
The unique use of single copy insertion allows direct comparison between strains, where intensity of toxin response is de novo normalized between strains. This allows easier determination of the primary mode of toxicity (or other gene expression effects) when analyzing novel compounds. The transgenic strains or lines can be configured into panel sets (or arrays). It is contemplated that the arrays can be configured to be specific to various types of responses (e.g., toxicity), such as heavy metal, oxidative stress, endocrine disruption, xenobiotic, carcinogenic, genotoxic, neurotoxic, hepatatoxic, nephratoxic, immunotoxic, and others.
Example 1
Studies in C. elegans Having a hsp-16 Promoter-Red Fluorescent Protein Transgene
The results described herein demonstrate remarkable responses of the whole organism biosensor to toxic insults (such as: heat shock, cadmium, arsenic, etc). For instance, a protein homeostasis reporter was created by fusing heat shock protein to a nuclear localized red fluorescent protein (hsp-16.42::hRFP) (the materials and methods for the construction of the transgenic organism are described in more detail in the examples below). Exposure to heat toxicity generates induction of nuclear localization. This heat shock gene reporter was screened for gene induction capacity using a heat-shock protocol. The hsp-16::hRFP construct is exposed to a 1 hr incubation at 30 C. Gene induction was screened 4 to 24 hrs after heat shock. Significant red fluorescence is observed in the nuclei of heat-shocked worm relative to control ( FIG. 5 ).
Toxin sensitivity of hsp-16 was confirmed with exposure to heavy metals and metalloids. To develop a rapid screen for the hsp-16::hRFP expression, a fluorescent plate reader assay was developed. To test the sensitivity of this assay, a titrating concentration of nematodes were exposed to heat shock. The worms were transferred to a 96 well plate and red fluorescence was quantified. Good sensitivity for a red fluorescence signal occurs at concentrations of 50 or more worms ( FIG. 3A ). Next, the toxin dosage sensitivity was measured. The Phsp-16::hRFP reporter shows higher sensitivity to cadmium chloride relative to sodium bis-arsenite ( FIG. 3B vs. FIG. 3C ). The EC 50 for cadmium occurs near 0.2 mM while arsenic sensitivity is near 1.5 mM. Thus, the Phsp-16::hRFP reporter shows greater sensitivity to cadmium.
Example 2
Control Reporter
Advantageously, the transgenic animals described in these examples can have a control reporter (e.g., constitutively expressed). Exposure to some selected agents or toxins can lead to shortened life-span, lower brood sizes or other effects that need to be controlled. The problem becomes most pronounced in chronic assays. For instance, exposure to cadmium for 72 hrs leads to significant population effects ( FIGS. 4A , B, and C). Thus, it was determined a control for population mass differences between assay wells is desirable. Introduction of a second constitutively expressed reporter gene can be used to control for various population differences.
To create a population control in the fluorescence reader assays, the hsp-16::hRFP was crossed into a line containing a constitutively-expressed neuronal marker (unc-47::GFP). Expression of the control reporter remains constant, while the inducible reporter responds to heat shock ( FIGS. 5A and B). The use of a constitutive-expressed reporter allows normalization of induction reporter responses—a toxin's effect on population dynamics is controlled.
Example 3
COPAS Cytometry
The fluorescent expression patterns of individual nematodes was rapidly quantifiable using flow cytometry. The hsp-16::hRFP construct in unc-47::GFP background was sent subjected to COPAS biosorting analysis. Induction of the red fluorescence was observed ( FIG. 6A ) and COPAS biosorting generated size-dependent profiles for red and green fluorescence expression ( FIG. 6B ). As expected, the levels of fluorescence increase proportionally with nematode age.
Example 4
Gene Selection and Transgene Construct Construction
The genes chosen for an oxidative stress response panel were the following oxidative response genes (hsp-16.41, hsp16.2, hsp-6 and hsp-60, hsp-4, mlt-2, and ugt-1). To choose the oxidative-response gene promoters, a combination of modENCODE's TF-GFP ChIP-seq data and multi-z 6-species alignment was used to find the extent of conserved genomic regions containing TF sites in front of the oxidative-response gene's start codon. Promoter-reporter fusion constructs were designed for Gibson reaction cloning using APE plasmid editor (biologylabs.utah.edu/jorgensen/wayned/ape). In general, regions ranging from 300 to 4,000 bp upstream of start codon were chosen for promoter selection.
Example 5
Nematode Transgenesis
To make transgenic nematodes, the MosSCI transgenesis procedure was used. Briefly, using the custom transgenesis platform provided by Knudra Transgenics (www.knudra.com/product/custom-transgenics), promoters are positioned in front of a red fluorescent protein fused to histone H2B. The gene is cloned into a vector pNU142, which contains left and right homologous recombination arms of the Mos1 locus (2094 bp and 1825 bp, respectively). The pNU142 plasmid (Amp r ) contains CBunc-119 gene obtained from the C. Briggsae genome for use as a positive-selection marker. The resulting construct is inserted as a single copy into the Mos1 ttTi5605 site in C. elegans strain COP66, which is homozygous for ttTi5605 and oxIs12 (unc-47::GFP) alleles. Strains obtained with the MosSCI transgenesis procedure are verified by PCR for single copy insertion at Mos1 locus. Verification oligos for insertion at Mos1 site are forward SEQ ID NO:163 (GATTCCATGATGGTAGCAAACTC) and reverse SEQ ID NO:164 (CAGATGATGAGCCAAGAAGAGTT), which gives a 325 bp product specific to strains homozygous for insertion at Mos1 loci. The resulting nematode is a two-color worm acting as in vivo transcriptional reporter of gene activation. For the results herein, the 7 types of two-color worms used are hsp-4, hsp-6, hsp-60, hsp-16.2, hsp-16.41, mtl-2, and ugt-1.
Example 7
Nematode Preparation
Two-color worms are grown to high density (0.5 ml worm pellet/plate) using Perfect-GROW HB101 plates (www.knudra.com/product/perfect-grow). Worms are recovered from the plate and cleaned by sucrose sedimentation. Animals are distributed on 5 cm NGM plates (seeded with HB101, (www.knudra.com/product/perfect-seed) at densities of 200 adult animals per plate. For heat shock, plates are exposed to 34° C. for 1.5 hr, and then allowed to recover at for 4 hrs at room temperature. For cadmium exposure, fresh seeded NGM plates are pre-incubated for 24 hrs with 700 ul of 10 mM CdCl 2 . Cleaned nematodes were added at 200 adult animals per plate and incubated for 15 hrs at room temperature.
Example 8
Plate Reader Assay
Each strain is transferred with 1 ml of M9 into a 2 ml deep 96 well plate. Plate is allowed to stand for 5 minutes to settle worms. Excess M9 is siphoned off and a repeat wash/siphon step is performed. Settled worms are transferred (about 200 ul) to a black 96-well read plate (Corning, Inc. #3651). The plate is read in a fluorescence plate reader (Biotek, Inc., Synergy 4, with optical cubes for GFP detection at ex. 485/20, em. 528/20 and RFP detection at ex. 575/15, em. 620/15 with reading set as endpoint from bottom well at sensitivity of 50). Reads are normalized as RFP/GFP ratio, which adjust for population differences between wells. Fluorescence intensity readings of the reporters in the panel are calculated as ratio of induced RFP/GFP ratio divided by control RFP/GFP ratio.
In conclusion, the oxidative response panel demonstrates the inventive system is feasible for use in testing the effects of external stimuli on gene expression at the whole organism level. As shown herein, the exemplary toxicogenomics studies is remarkably sensitive and selective for detection of oxidative stress toxicity. Furthermore, a simple 7 gene panel can differentiate between different types of oxidative stress e.g., heat shock and metal exposure. The inventive system has advantages over cell culture methods because it is easier to use, less costly to implement, and is believed results more translatable to more complex animal studies like mammalian studies. Importantly, the inventive system is a whole organism approach, which detects cellular response in a native context. The ease of assay implementation makes the system ideal for high-throughput applications. With respect to a specific implementation, toxicogenomics is very valuable in drug discovery. With this invention, pharmaceutical companies will decrease their financial exposure because better toxicology capture at the front end of drug development translates to lower frequency of drugs failing in clinical trials due to unwanted side-effect toxicity.
Those skilled in the art will appreciate that the concepts, specific embodiments, and Examples disclosed in the foregoing description may be readily utilized as a basis for modifying or designing other embodiments for carrying out the same purposes of the present invention. Those skilled in the art will also appreciate that such equivalent embodiments do not depart from the spirit and scope of the invention as set forth in the appended Claims.