role of apobec3 in genetic diversity among endogenous murine leukemia virusesapobec3在遗传多样性在内源性小鼠白血病病毒.pdfVIP

Role of APOBEC3 in Genetic Diversity among Endogenous Murine Leukemia Viruses 1 2 1* Patric Jern , Jonathan P. Stoye , John M. Coffin 1 Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America, 2 Division of Virology, MRC National Institute for Medical Research, London, United Kingdom 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], modified polytropic [Mpmv], and xenotropic [Xmv] subgroups), the best-characterized large set of recently integrated proviruses. We identified 49 proviruses. In phylogenetic analyses, Pmvs and Mpmvs were monophyletic, whereas Xmvs were divided into several clades, implying a greater number of replication cycles between the integration events. Four distinct primer binding site types (Pro, Gln1, Gln2 and Thr) were dispersed within the phylogeny, indicating frequent mispriming. We analyzed the frequency and context of G-to-A mutations for the role of mA3 in formation of these proviruses. In the Pmv and Mpmv (but not Xmv) groups, mutations attributable to mA3 constituted a large fraction of the total. A significant number of nonsense mutations suggests the absence of purifying selection following mutation. A strong bias of G-to-A relative to C-to-T changes was seen, implying a strand specificity that can only have occurred prior to integration. The optimal sequence context of G-to-A mutations, TTC, was consistent with