Abstract
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 mA3. At least in the Pmv group, a significant 5′ to 3′ gradient of G-to-A mutations was consistent with mA3 editing. Altogether, our results for the first time suggest mA3 editing immediately preceding the integration event that led to retroviral endogenization, contributing to inactivation of infectivity.
Highlights
Retroviruses that integrate into the germ line may be inherited vertically as endogenous retroviral sequences (ERVs) [1]
Vertebrate genomes are littered with remnants from earlier retroviral infections, in the form of endogenous retroviruses (ERVs)
We identified 49 endogenous murine leukemia viruses, divided into three groups; polytropic, modified polytropic, and xenotropic, in the sequenced C57BL/6J mouse genome
Summary
Retroviruses that integrate into the germ line may be inherited vertically as endogenous retroviral sequences (ERVs) [1]. A considerable fraction of mammalian genomes consists of ERVs [2,3,4], most with numerous inactivating mutations, presenting the only known viral ‘‘fossil’’ record. The role of human and murine A3 (hA3 and mA3, respectively) family members in inhibiting infection by exogenous retroviruses and retrotransposition of some mobile elements is becoming well established [10,11,12]. Less clear is the possible effect that these restriction factors may have had on the establishment of the many thousands of endogenous proviruses present in vertebrate genomes [13]. A3-induced G-to-A mutations can be readily detected in experimental infection, such mutations are difficult to discern in elements that have had long residence in the germline and that have suffered considerable postintegration mutagenesis
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