Intact, recombinant, and spliced forms of endogenous mouse mammary tumor viruses in inbred and wild mice.

Abstract

Endogenous retroviruses (ERVs) are chromosomally integrated viral copies that represent relics of past infections. Analysis of the sequenced genomes of 17 mouse strains, Mus musculus subspecies, and Mus spretus identified 29 ERVs of mouse mammary tumor viruses (MMTVs), termed Mtvs. The 15 laboratory mouse Mtvs are each present in multiple strains reflecting their common breeding history; most predate the development of inbred strains and were likely acquired by Mus musculus domesticus progenitors but have no orthologs in wild mice, whereas four, including the intact Mtv1, were likely endogenized more recently. One of the 14 Mtvs found in wild mice was distributed over a broad geographic range in southeast Asia. Most Mtvs are full-length, with multiple open reading frames, but Mtvs from many wild mice have an unusual envelope deletion corresponding to an intron of the viral rem accessory gene, suggesting its derivation from spliced MMTV cDNAs. These deleted envs have open reading frames, are found in globally distributed mice, and show subspecies-specific sequence variation consistent with their recurrent generation. The highly variable MMTV sag gene, responsible for resistance to exogenous infection, exhibits evidence of recombination as well as positive selection, consistent with its role in antiviral defense. In contrast, the spread of Mtvs in Mus musculus populations is not marked by an active arms race pitting the MMTV envelope against its cellular receptor. Thus, the acquisition of potentially disease-inducing Mtvs is a recent and ongoing process in Mus accompanied by recombination, positive selection, and a recurrent envelope deletion.

Importance: Endogenous retroviruses (ERVs) are copies of viral genomes inserted into host chromosomes, producing a fossil record of past infections and virus-host co-adaptations. ERVs of mouse mammary tumor viruses (Mtvs) were found in all common laboratory strains, all Mus musculus subspecies, and a sister species, Mus spretus. Most laboratory mouse Mtvs predate inbred strain origins and were acquired by M. musculus domesticus, but although widely shared among strains, none of these were found in wild mice. Among wild mouse Mtvs, only one showed a broad geographic distribution. All M. musculus subspecies carry Mtvs with a large envelope deletion corresponding to the processed mRNA for the viral rem gene; such Mtvs likely derive from spliced viral mRNA. The Mtv sag gene responsible for resistance to exogenous infection is under purifying selection and has been subject to recombination, whereas the Mtv envelope and its cellular receptor show no evidence of genetic conflicts.