Single Nucleotide Polymorphisms Can Create Alternative Polyadenylation Signals and Affect Gene Expression through Loss of MicroRNA-Regulation 英文参考文献.docVIP

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Single Nucleotide Polymorphisms Can Create Alternative Polyadenylation Signals and Affect Gene Expression through Loss of MicroRNA-Regulation 英文参考文献.doc

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Single Nucleotide Polymorphisms Can Create Alternative Polyadenylation Signals and Affect Gene Expression through Loss of MicroRNA-Regulation 英文参考文献

SingleNucleotidePolymorphismsCanCreateAlternative PolyadenylationSignalsandAffectGeneExpression throughLossofMicroRNA-Regulation LaurentF.Thomas1,2,Pa?lS?trom1,2,3 * 1DepartmentofCancerResearchandMolecularMedicine,NorwegianUniversityofScienceandTechnology,Trondheim,Norway,2InteragonAS,Laboratoriesenteret, Trondheim,Norway,3DepartmentofComputerandInformationScience,NorwegianUniversityofScienceandTechnology,Trondheim,Norway Abstract Alternativepolyadenylation(APA)canforexampleoccurwhenaprotein-codinggenehasseveralpolyadenylation(polyA) signalsinitslastexon,resultinginmessengerRNAs(mRNAs)withdifferent39untranslatedregion(UTR)lengths.Different 39UTRlengthscangivedifferentmicroRNA(miRNA)regulationsuchthatshortenedtranscriptshaveincreasedexpression. TheAPAprocessispartofhumancells’naturalregulatoryprocesses,butAPAalsoseemstoplayanimportantroleinmany humandiseases.AlthoughalteredAPAindiseasecanhavemanycauses,wereasonedthatmutationsinDNAelementsthat areimportantforthepolyAprocess,suchasthepolyAsignalandthedownstreamGU-richregion,canbeoneimportant mechanism.Totestthishypothesis,weidentifiedsinglenucleotidepolymorphisms(SNPs)thatcancreateordisruptAPA signals (APA-SNPs). By using a data-integrative approach, we show that APA-SNPs can affect 39UTR length, miRNA regulation, and mRNA expression—both between homozygote individuals and within heterozygote individuals. Furthermore, we show that a significant fraction of the alleles that cause APA are strongly and positively linked with allelesfoundbygenome-widestudiestobeassociatedwithdisease.OurresultsconfirmthatAPA-SNPscangivealtered gene regulation and that APA alleles that give shortened transcripts and increased gene expression can be important hereditarycausesfordisease. Citation:ThomasLF,S?tromP(2012)SingleNucleotidePolymorphismsCanCreateAlternativePolyadenylationSignalsandAffectGeneExpressionthroughLoss ofMicroRNA-Regulation.PLoSComputBiol8(8):e1002621.doi:10.1371/journal.pcbi.1002621 Editor:RodericGuigo,CenterforGenomic