Ancient Evolutionary Origin and Positive Selection of the Retroviral Restriction FactorFv1in Muroid Rodents

Abstract

The laboratory mouse gene encodes a retroviral restriction factor that mediates resistance to murine leukemia viruses (MLVs). Sequence similarity between and the protein of the murine endogenous retrovirus-L (MuERV-L) family of ERVs suggests that was co-opted from an ancient provirus. Previous evolutionary studies found orthologs only in the genus. Here, we describe identification of orthologous sequences in several species belonging to multiple families of rodents outside of the genus We show that these orthologs are in the same region of conserved synteny, between the genes and , suggesting a minimum insertion time of 45 million years for the ancient progenitor of Our analysis also reveals that was not detectable or heavily mutated in some lineages in the superfamily while, in concert with previous findings in the genus, we found strong evidence of positive selection of in the African clade in the subfamily Residues identified as evolving under positive selection include those that have been previously found to be important for restriction of multiple retroviral lineages. Taken together these findings suggest that the evolutionary origin of substantially predates evolution, that the rodent has been shaped by lineage-specific differential selection pressures, and that has long been evolving under positive selection in the rodent family supporting a defensive role that significantly antedates exposure to MLVs. Retroviruses have adapted to living in concert with their hosts throughout vertebrate evolution. Over the years, the study of these relationships revealed the presence of host proteins called restriction factors that inhibit retroviral replication in host cells. The first of these restriction factors to be identified, the gene found in mice, was thought to have originated in the genus In this study, we utilized genome database searches and DNA sequencing to identify copies in multiple rodent lineages. Our findings suggest a minimum insertion time of 45 million years into the genome of rodents for the ancestral progenitor of While is not detectable in some lineages, we also identified full-length orthologs showing signatures of a molecular "arms race" in a family of rodent species indigenous to Africa. This finding suggests that in these species has been co-evolving with unidentified retroviruses for millions of years.

Duplication and divergence of the retrovirus restriction geneFv1inMus carolimice allows protection from multiple retroviruses

“…Similarly, we and others have uncovered equivalent forces acting upon Fv1, (17,(31)(32)(33)) revealing a need for continuous or frequently reoccurring waves of retroviral infection in its maintenance over a ~45 my lifetime (33).…”

Convergent Co-option of the Retroviral gag Gene during the Early Evolution of Mammals

“…Moreover, a captured env gene was found to be conserved in spiny-rayed fishes (Acanthomorpha) for more than 110 million years (40). However, unlike retroviral env genes, few co-opted retroviral gag genes have been identified to date (22,24,25). In this study, we identified two new co-opted retroviral gag genes in mammals, that is, the wcs1 and wcs2 genes, which arose convergently in two major linages of mammals.…”

“…5). Both wcs genes are much older than the Fv1 gene, which integrated into the genomes of Muroidea ϳ45 MYA (24,25). The convergent co-option during the early evolution of mammals suggests that co-option of retroviral gag genes might occur more frequently than previously thought.…”

“…Sequence analysis has revealed similarity between Fv1 and the Gag protein of murine endogenous retrovirus L (MuERV-L) (22). Conserved synteny analysis dates the integration of the Fv1 progenitor into the genomes of Muroidea, a superfamily of rodents, back to ϳ45 million years ago (MYA) (24,25). In addition to retroviral gag genes, retrotransposon gag genes have also been found to be repurposed in mammals (20); for example, the Arc gene, a co-opted gag gene derived from Ty3/gypsy retrotransposons, mediates mRNA transfer between different nerve cells (20,21).…”

Coevolution of retroviruses withSERINCs following whole-genome duplication divergence

“…As part of this ongoing arms-race, while viruses have relied on acquisition and fusion of diverse genes (1), the host-defense mechanism has been made possible by the functional divergence of gene copies following duplication of genes as well as whole-genomes (2–7). Restriction factors being at the forefront of this long-term conflict (8–10), show clear molecular signatures of arms-race (11,12). In fact, the presence of these signatures has been proposed to be a hallmark of restriction factors (8,13), and has been used as a screening strategy to identify potential candidates(2,14).…”