Positive Epistasis Drives the Acquisition of Multidrug Resistance 英文参考文献.docVIP

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Positive Epistasis Drives the Acquisition of Multidrug Resistance 英文参考文献.doc

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Positive Epistasis Drives the Acquisition of Multidrug Resistance 英文参考文献

PositiveEpistasisDrivestheAcquisitionofMultidrug Resistance SandraTrindade1,2,AnaSousa1,KarinaBivarXavier1,3,FranciscoDionisio1,2,MiguelGodinhoFerreira1, IsabelGordo1* 1InstitutoGulbenkiandeCie?ncia,Oeiras,Portugal,2DepartamentodeBiologiaVegetalandCentrodeBiologiaAmbiental,FaculdadedeCie?ncias,UniversidadedeLisboa, CampoGrande,Lisboa,Portugal,3InstitutodeTecnologiaQu?′micaeBiolo′gica,UniversidadeNovadeLisboa,Oeiras,Portugal Abstract Theevolutionofmultipleantibioticresistanceisanincreasingglobalproblem.Resistancemutationsareknowntoimpair fitness, and the evolution of resistance to multiple drugs depends both on their costs individually and on how they interact—epistasis. Information on the level of epistasis between antibiotic resistance mutations is of key importance to understandingepistasisamongstdeleteriousalleles,akeytheoreticalquestion,andtoimprovingpublichealthmeasures. Hereweshowthatinanantibiotic-freeenvironmentthecostofmultipleresistanceissmallerthanexpected,asignatureof pervasivepositiveepistasisamongallelesthatconferresistancetoantibiotics.Competitionassaysrevealthatthecostof resistancetoagivenantibioticisdependentonthepresenceofresistanceallelesforotherantibiotics.Surprisinglywefind thatasignificantfractionofresistantmutationscanbebeneficialincertainresistantgeneticbackgrounds,thatsomedouble resistances entail no measurable cost, and that some allelic combinations are hotspots for rapid compensation. These resultsprovideadditionalinsightastowhymulti-resistantbacteriaaresoprevalentandrevealanextralayerofcomplexity onepistaticpatternspreviouslyunrecognized,sinceitishiddeningenome-widestudiesofgeneticinteractionsusinggene knockouts. Citation:TrindadeS,SousaA,XavierKB,DionisioF,FerreiraMG,etal.(2009)PositiveEpistasisDrivestheAcquisitionofMultidrugResistance.PLoSGenet5(7): e1000578.doi:10.1371/journal.pgen.1000578 Editor:JianzhiZhang,UniversityofMichigan,UnitedStatesofAmerica ReceivedApril20,2009;AcceptedJune25,2009;PublishedJuly24,2009 Copyright: ? 2009 Tr