Fine-Scale Variation and Genetic Determinants of Alternative Splicing across Individuals 英文参考文献.docVIP

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Fine-Scale Variation and Genetic Determinants of Alternative Splicing across Individuals 英文参考文献.doc

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Fine-Scale Variation and Genetic Determinants of Alternative Splicing across Individuals 英文参考文献

Fine-ScaleVariationandGeneticDeterminantsof AlternativeSplicingacrossIndividuals JasminCoulombe-Huntington1,2,KevinC.L.Lam2,ChristelDias2,JacekMajewski1,2* 1DepartmentofHumanGenetics,McGillUniversity,Montreal,Que′bec,Canada,2McGillUniversityandGe′nome Que′becInnovationCentre,Montre′al,Que′bec,Canada Abstract Recently,thankstotheincreasingthroughputofnewtechnologies,wehavebeguntoexplorethefullextentofalternative pre–mRNAsplicing(AS)inthehumantranscriptome.Thisisunveilingavastlayerofcomplexityinisoform-levelexpression differencesbetweenindividuals.Weusedpreviouslypublishedsplicingsensitivemicroarraydatafromlymphoblastoidcell linestoconductanin-depthanalysisonsplicingefficiencyofknownandpredictedexons.Bycombiningpubliclyavailable ASannotationwithanovelalgorithmdesignedtosearchforAS,weshowthatmanyrealASeventscanbedetectedwithin theusuallyunexploited,speculativemajorityofthearrayandatsignificancelevelsmuchbelowstandardmultiple-testing thresholds,demonstratingthattheextentofcis-regulateddifferentialsplicingbetweenindividualsispotentiallyfargreater thanpreviouslyreported.Specifically,manygenesshowsubtlebutsignificantgeneticallycontrolleddifferencesinsplice- siteusage.PCRvalidationshowsthat42outof58(72%)candidategeneregionsundergodetectableAS,amountingtothe largest scale validationof isoform eQTLs to date.Targeted sequencing revealedalikely causative SNP in most validated cases.Inall17incidenceswhereaSNPaffectedasplice-siteregion,insilicosplice-sitestrengthmodelingcorrectlypredicted thedirectionofthemicro-arrayandPCRresults.In13othercases,weidentifiedlikelycausativeSNPsdisruptingpredicted splicingenhancers.UsingFstandREHHanalysis,weuncoveredsignificantevidencethat2putativecausativeSNPshave undergonerecentpositiveselection.WeverifiedtheeffectoffiveSNPsusinginvivominigeneassays.Thisstudyshowsthat splicing differences between individuals, including quantitative differences in isoform ratios, are frequent in human populations and that causative SNPs can be identified u