Role of APOBEC3 in Genetic Diversity among Endogenous Murine Leukemia Viruses 英文参考文献.docVIP

RoleofAPOBEC3inGeneticDiversity amongEndogenousMurineLeukemiaViruses Patric Jern1,Jonathan P.Stoye2,John M.Coffin1* 1DepartmentofMolecularBiologyandMicrobiology,TuftsUniversitySchoolofMedicine,Boston,Massachusetts,UnitedStatesofAmerica, 2DivisionofVirology,MRC NationalInstituteforMedicalResearch,London,UnitedKingdom The ability of human and murine APOBECs (specifically, APOBEC3) to inhibit infecting retroviruses and retrotransposition of some mobile elements is becoming established. Less clear is the effect that they have had on the establishment of the endogenous proviruses resident in the human and mouse genomes. We used the mouse genome sequence to study diversity and genetic traits of nonecotropic murine leukemia viruses (polytropic [Pmv], modifiedpolytropic[Mpmv],andxenotropic[Xmv]subgroups),thebest-characterizedlargesetofrecentlyintegrated proviruses.Weidentified49proviruses.Inphylogeneticanalyses,PmvsandMpmvsweremonophyletic,whereasXmvs weredividedintoseveralclades,implyingagreaternumberofreplicationcyclesbetweentheintegrationevents.Four distinctprimerbindingsitetypes(Pro,Gln1,Gln2andThr)weredispersedwithinthephylogeny,indicatingfrequent mispriming. We analyzed the frequency and context of G-to-A mutations for the role of mA3 in formation of these proviruses.InthePmvandMpmv(butnotXmv)groups,mutationsattributabletomA3constitutedalargefractionof thetotal.Asignificantnumberofnonsensemutationssuggeststheabsenceofpurifyingselectionfollowingmutation. AstrongbiasofG-to-ArelativetoC-to-Tchangeswasseen,implyingastrandspecificitythatcanonlyhaveoccurred priortointegration.TheoptimalsequencecontextofG-to-Amutations,TTC,wasconsistentwithmA3.Atleastinthe Pmvgroup,asignificant59to39gradientofG-to-AmutationswasconsistentwithmA3editing.Altogether,ourresults for the first time suggest mA3 editing immediately preceding the integration event that led to retroviral endogenization,contributingtoinactivationofinfectivity. Citation:JernP,StoyeJP,CoffinJM(2007)Roleo