<i>Apobec3</i> shows rapid evolution in house mouse subspecies and unusual hypermutation patterns of endogenous mouse mammary tumor viruses

Apobec3 (A3, apolipoprotein B editing complex 3) is a cytidine deaminase with broadly antiretroviral activity. A3 is packaged in virions and converts cytidines to uracil (C > U) in viral minus-strand DNA during reverse transcription, resulting in guanosine to adenosine (G > A) mutations in the viral plus strand. Mouse Apobec3 (mA3) mutagenizes numerous infectious retroviruses and some families of endogenous retroviruses. Here we show that endogenous mouse mammary tumor viruses, termed <i>Mtvs</i>, show a range of mA3 hypermutation from trace levels to an extreme example, <i>Mtv21,</i> that sustained a catastrophic, genome-wide reduction of G content to 10.8%; this level is associated with the contemporaneous generation of new preferred trinucleotide target sites by mutagenesis of consecutive cytidines. Although newly inserted proviruses have identical long terminal repeats (LTRs), mA3 can disproportionately generate G > A substitutions specific to the <i>Mtv</i> 3' LTR. Individual hypermutated <i>Mtvs</i> display two different mA3 target site context preferences that correspond to those of the two mA3 alleles found among inbred strains of laboratory mice. <i>Mtv-</i>positive <i>Mus musculus</i> subspecies screened for these mA3 alleles unexpectedly revealed 20 distinct mA3 haplotypes with different combinations of replacement mutations at the 15 sites that distinguish the two inbred strain alleles, 11 of which show signatures of positive selection. These data show that mA3 deamination can have a major impact on the genomic integrity of <i>Mtvs</i>, and that mA3 is actively evolving within this single mouse species suggestive of high-impact genetic conflicts over a short evolutionary time frame.IMPORTANCEThe antiviral cytidine deaminase Apobec3 (apolipoprotein B editing complex 3) mutates retroviral DNA copies generated during new infections. Although such mutagenesis of replicating mouse retroviruses has been reported to be modest, here we show that many germline copies of mouse mammary tumor viruses (<i>Mtvs</i>) have sustained significant to massive levels of mouse Apobec3 (mA3) editing. mA3 hypermutation can also disproportionally affect one of the two otherwise identical viral long terminal repeats and can create new preferred target sites in the viral genome substrate by mutating successive cytosines. The edits in individual <i>Mtvs</i> correspond to the different target sequence preferences of the two inbred mouse strain mA3 alleles, but examination of allelic variation in wild mice of the species <i>Mus musculus</i> identified 18 additional variants and signatures of diversifying selection, a display of unusually rapid evolution within a single species over a short time frame.