Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes 英文参考文献.docVIP

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Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes 英文参考文献.doc

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Ancient and Recent Adaptive Evolution of Primate Non-Homologous End Joining Genes 英文参考文献

AncientandRecentAdaptiveEvolutionofPrimateNon- HomologousEndJoiningGenes AnnDemogines1,AlysiaM.East1,Ji-HoonLee1,2,SharonR.Grossman3,PardisC.Sabeti3,TanyaT. Paull1,2,SaraL.Sawyer1* 1Section of Molecular Genetics and Microbiology, and Institute for Cellular and Molecular Biology, The University of Texas at Austin, Austin, Texas, United States of America,2TheHowardHughesMedicalInstitute,ChevyChase,Maryland,UnitedStatesofAmerica,3FASCenterforSystemsBiology,DepartmentofOrganismicand EvolutionaryBiology,HarvardUniversity,Cambridge,Massachusetts,UnitedStatesofAmerica Abstract Inhumancells,DNAdouble-strandbreaksarerepairedprimarilybythenon-homologousendjoining(NHEJ)pathway.Given theircriticalnature,weexpectedNHEJproteinstobeevolutionarilyconserved,withrelativelylittlesequencechangeover time. Here, we report that while critical domains of these proteins are conserved as expected, the sequence of NHEJ proteins has also been shaped by recurrent positive selection, leading to rapid sequence evolution in other protein domains.InordertocharacterizethemolecularevolutionofthehumanNHEJpathway,wegeneratedlargesimianprimate sequence datasets for NHEJ genes. Codon-based models of gene evolution yielded statistical support for the recurrent positive selection of fiveNHEJ genesduring primateevolution: XRCC4,NBS1, Artemis,POLl, andCtIP.Analysis of human polymorphism data using the composite of multiple signals (CMS) test revealed that XRCC4 has also been subjected to positiveselectioninmodernhumans.CrystalstructuresareavailableforXRCC4,Nbs1,andPoll;andresiduesunderpositive selection fall exclusively on the surfaces of these proteins. Despite the positive selection of such residues, biochemical experiments with variants of one positively selected site in Nbs1 confirm that functions necessary for DNA repair and checkpointsignalinghavebeenconserved.However,manyvirusesinteractwiththeproteinsoftheNHEJpathwayaspartof their infectious lifecycle. We propose that an ongoing evolutionary arms r