Functional Diversification of Paralogous Transcription Factors via Divergence in DNA Binding Site Motif and in Expression 英文参考文献.docVIP

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Functional Diversification of Paralogous Transcription Factors via Divergence in DNA Binding Site Motif and in Expression 英文参考文献.doc

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Functional Diversification of Paralogous Transcription Factors via Divergence in DNA Binding Site Motif and in Expression 英文参考文献

FunctionalDiversificationofParalogousTranscription FactorsviaDivergenceinDNABindingSiteMotifandin Expression LarryN.Singh,SridharHannenhalli* PennCenterforBioinformatics,DepartmentofGenetics,UniversityofPennsylvania,Philadephia,Pennsylvania,UnitedStatesofAmerica Abstract Background:Geneduplicationisamajordriverofevolutionaryinnovationasitallowsforanorganismtoelaborateitsexisting biological functions via specialization or diversification of initially redundant gene paralogs. Gene function can diversify in severalways.Transcriptionfactorgeneparalogsinparticular,candiversifyeitherbychangesintheirtissue-specificexpression patternorbychangesintheDNAbindingsitemotifrecognizedbytheirproteinproduct,whichinturnalterstheirgenetargets. Therelationshipbetweenthesetwomodesoffunctionaldiversificationoftranscriptionfactorparalogshasnotbeenpreviously investigated,andisessentialforunderstandingadaptiveevolutionoftranscriptionfactorgenefamilies. Findings:Basedonalargesetofhumanparalogoustranscriptionfactorpairs,weshowthatwhentheDNAbindingsite motifsoftranscriptionfactorparalogsaresimilar,theexpressionsofthegenesthatencodetheparalogshavediverged,so ingeneral,atmostoneoftheparalogsishighlyexpressedinatissue.Moreover,paralogswithdivergedDNAbindingsite motifstendtobedivergedintheirfunction.Conversely,twoparalogsthatarehighlyexpressedinatissuetendtohave dissimilarDNAbindingsitemotifs.Wehavealsofoundthatingeneral,withinaparalogousfamily,tissue-specificdecreasein geneexpressionismorefrequentthanwhatisexpectedbychance. Conclusions: While previous investigations of paralogous gene diversification have only considered coding sequence divergence, by explicitly quantifying divergence in DNA binding site motif, our work presents a new paradigm for investigating functional diversification. Consistent with evolutionary expectation, our quantitative analysis suggests that paralogous transcription factors havesurvived extinction inpart, either through diversificationof their DNA bindingsite motifso