Duplication and divergence of the retrovirus restriction gene Fv1 in Mus caroli mice allows protection from multiple retroviruses

Abstract

Viruses and their hosts are locked in an evolutionary race where resistance to infection is acquired by the hosts while viruses develop strategies to circumvent these host defenses. Forming one arm of the host defense armory are cell autonomous restriction factors like Fv1. Originally described as protecting laboratory mice from infection by murine leukemia virus (MLV), Fv1s from some wild mice have also been found to restrict non-MLV retroviruses, suggesting an important role in the protection against viruses in nature. To begin to understand how restriction factors evolve, we surveyed the Fv1 genes of wild mice trapped in Thailand and characterized their restriction activities against a panel of retroviruses. An extra copy of the Fv1 gene, named Fv7, was found on chromosome 6 of three closely related Asian species of mice (Mus caroli, M. cervicolor and M. cookii). The presence of flanking repeats suggested it arose by LINE-mediated retrotransposition. A high degree of natural variation was observed in both Fv1 and Fv7, including numerous single nucleotide polymorphisms resulting in altered amino acids, as well as insertions and deletions that changed the length of the reading frames. These genes exhibited a range of restriction phenotypes with activities directed against feline foamy virus (FFV), equine infectious anemia virus (EIAV) and MLV. It seems likely, at least in the case of M. caroli, that the observed gene duplication confers protection against multiple viruses not possible with a single restriction factor. We suggest that EIAV-, FFV- and MLV-like viruses are endemic within these populations, driving the evolution of the Fv1 and Fv7 genes.\n\nAuthor SummaryDuring the passage of time all vertebrates will be exposed to infection by a variety of different kinds of virus. To meet this threat, a variety of genes for natural resistance to viral infection have evolved. The prototype of such so-called restriction factors is encoded by the mouse Fv1 gene, which acts to block the life cycle of retroviruses at a stage between virus entry into the cell and integration of the viral genetic material into the nuclear DNA. We have studied the evolution of this gene in certain species of wild mice from South East Asia and describe an example where a duplication of the Fv1 gene has taken place. The two copies of the gene, initially identical, have evolved separately allowing the development of resistance to two rather different kinds of retroviruses, lentiviruses and spumaviruses. Independent selection for resistance to these two kinds of retrovirus suggests that such mice are repeatedly exposed to never-before-reported pathogenic retroviruses of these genera.