Functional Characterization of Variations on Regulatory Motifs 英文参考文献.docVIP

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Functional Characterization of Variations on Regulatory Motifs 英文参考文献.doc

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Functional Characterization of Variations on Regulatory Motifs 英文参考文献

FunctionalCharacterizationofVariationsonRegulatory Motifs LapidotMichal1.,OrnaMizrahi-Man1,2.,YitzhakPilpel1* 1MolecularGeneticsDepartment,WeizmannInstituteofScience,Rehovot,Israel,2StructuralBiologyDepartment,WeizmannInstituteofScience,Rehovot,Israel Abstract Transcriptionfactors(TFs)regulategeneexpressionthroughspecificinteractionswithshortpromoterelements.Thesame regulatory protein may recognize a variety of related sequences. Moreover, once they are detected it is hard to predict whetherhighlysimilarsequencemotifswillberecognizedbythesameTFandregulatesimilargeneexpressionpatterns,or serve as binding sites for distinct regulatory factors. We developed computational measures to assess the functional implications of variations on regulatory motifs and to compare the functions of related sites. We have developed computational means for estimating the functional outcome of substituting a single position within a binding site and appliedthemtoacollectionofputativeregulatorymotifs.Wepredicttheeffectsofnucleotidevariationswithinmotifson geneexpressionpatterns.Incaseswheresuchpredictionscouldbecomparedtosuitablepublishedexperimentalevidence, wefoundverygoodagreement.Wefurtheraccumulatedstatisticsfrommultiplesubstitutionsacrossvariousbindingsites in an attempt to deduce general properties that characterize nucleotide substitutions that are more likely to alter expression. We found that substitutions involving Adenine are more likely to retain the expression pattern and that substitutionsinvolvingGuaninearemorelikelytoalterexpressioncomparedtotherestofthesubstitutions.Ourresults shouldfacilitatethepredictionoftheexpressionoutcomesofbindingsitevariations.Onetypicalimportantimplicationis expectedtobetheabilitytopredictthephenotypiceffectofvariationinregulatorymotifsinpromoters. Citation: Michal L, Mizrahi-Man O, Pilpel Y (2008) Functional Characterization of Variations on Regulatory Motifs. PLoS Genet 4(3): e1000018. doi:10.1371/ journal.pgen.1000018 Editor:GregGibson,Nort