Retroviruses drive the rapid evolution of mammalianAPOBEC3genes

Abstract

APOBEC3(A3) genes are members of theAID/APOBECgene family that are found exclusively in mammals.A3genes encode antiviral proteins that restrict the replication of retroviruses by inducing G-to-A mutations in their genomes and have undergone extensive amplification and diversification during mammalian evolution. Endogenous retroviruses (ERVs) are sequences derived from ancient retroviruses that are widespread mammalian genomes. In this study we characterize theA3repertoire and use the ERV fossil record to explore the long-term history of coevolutionary interaction between A3s and retroviruses. We examine the genomes of 160 mammalian species and identify 1,420AID/APOBEC-related genes, including representatives of previously uncharacterized lineages. We show thatA3genes have been amplified in mammals and that amplification is positively correlated with the extent of germline colonization by ERVs. Moreover, we demonstrate that the signatures of A3-mediated mutation can be detected in ERVs found throughout mammalian genomes and show that in mammalian species with expandedA3repertoires, ERVs are significantly enriched for G-to-A mutations. Finally, we show thatA3amplification occurred concurrently with prominent ERV invasions in primates. Our findings establish that conflict with retroviruses is a major driving force for the rapid evolution of mammalianA3genes.