Selective Constraints in Experimentally Defined Primate Regulatory Regions 英文参考文献.docVIP

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Selective Constraints in Experimentally Defined Primate Regulatory Regions 英文参考文献.doc

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Selective Constraints in Experimentally Defined Primate Regulatory Regions 英文参考文献

SelectiveConstraintsinExperimentallyDefinedPrimate RegulatoryRegions DanielJ.Gaffney1,2*,RanBlekhman3,JacekMajewski1,2 1McGillUniversity,Montre′al,Que′bec,Canada,2GenomeQue′becInnovationCentre,Montre′al,Que′bec,Canada,3DepartmentofHumanGenetics,UniversityofChicago, Chicago,Illinois,UnitedStatesofAmerica Abstract Changesingeneregulationmaybeimportantinevolution.However,theevolutionarypropertiesofregulatorymutations arecurrentlypoorlyunderstood.ThisispartlytheresultofanincompleteannotationoffunctionalregulatoryDNAinmany species.Forexample,transcriptionfactorbindingsites(TFBSs),amajorcomponentofeukaryoticregulatoryarchitecture,are typically short, degenerate, and therefore difficult to differentiate from randomly occurring, nonfunctional sequences. Furthermore,althoughsitessuchasTFBSscanbecomputationallypredictedusingevolutionaryconservationasacriterion, estimatesofthetruelevelofselectiveconstraint(definedasthefractionofstronglydeleteriousmutationsoccurringata locus)inregulatoryregionswill,bydefinition,beupwardlybiasedindatasetsthatareapriorievolutionarilyconserved.Here weinvestigatethefitnesseffectsofregulatorymutationsusingtwocomplementarydatasetsofhumanTFBSsthatarelikely to be relatively free of ascertainment bias with respect to evolutionary conservation but, importantly, are supported by experimental data. The first is a collection of almost .2,100 human TFBSs drawn from the literature in the TRANSFAC database, and the second is derived from several recent high-throughput chromatin immunoprecipitation coupled with genomic microarray (ChIP-chip) analyses. We also define a set of putative cis-regulatory modules (pCRMs) by spatially clusteringmultipleTFBSsthatregulatethesamegene.Wefindthatarelativelyhighproportion(,37%)ofmutationsat TFBSsarestronglydeleterious,similartothatata2-folddegenerateprotein-codingsite.However,constraintissignificantly reducedinhumanandchimpanzeepCRMSandChIP-chipsequences,relativetomacaques.Weestimatethatthefractionof regulatorymutationstha