Differential Evolutionary Fate of an Ancestral Primate Endogenous Retrovirus Envelope Gene, the EnvV Syncytin, Captured for a Function in Placentation

Abstract

Syncytins are envelope genes of retroviral origin that have been co-opted for a role in placentation. They promote cell–cell fusion and are involved in the formation of a syncytium layer—the syncytiotrophoblast—at the materno-fetal interface. They were captured independently in eutherian mammals, and knockout mice demonstrated that they are absolutely required for placenta formation and embryo survival. Here we provide evidence that these “necessary” genes acquired “by chance” have a definite lifetime with diverse fates depending on the animal lineage, being both gained and lost in the course of evolution. Analysis of a retroviral envelope gene, the envV gene, present in primate genomes and belonging to the endogenous retrovirus type V (ERV-V) provirus, shows that this captured gene, which entered the primate lineage >45 million years ago, behaves as a syncytin in Old World monkeys, but lost its canonical fusogenic activity in other primate lineages, including humans. In the Old World monkeys, we show—by in situ analyses and ex vivo assays—that envV is both specifically expressed at the level of the placental syncytiotrophoblast and fusogenic, and that it further displays signs of purifying selection based on analysis of non-synonymous to synonymous substitution rates. We further show that purifying selection still operates in the primate lineages where the gene is no longer fusogenic, indicating that degeneracy of this ancestral syncytin is a slow, lineage-dependent, and multi-step process, in which the fusogenic activity would be the first canonical property of this retroviral envelope gene to be lost.

Author Summary

Syncytins are “new” genes encoding the envelope protein of captured endogenous retroviral elements. Their unambiguous status of “cellular gene” was recently demonstrated by knocking them out in genetically modified mice, showing their absolute requirement for placenta formation and embryo survival, via formation by cell–cell fusion of the feto-maternal syncytium interface. These genes are remarkable, as they are “necessary” for a basic function in placental mammals and yet they were acquired “by chance” on multiple occasions and independently in diverse mammalian species. We proposed that syncytins have been pivotal for the emergence of animals with a placenta from those laying eggs via the capture of a founding retroviral env gene, then subsequently replaced in the diverse mammalian lineages upon successive and independent germline infections by new retroviruses and co-optation of their env gene, each new gene providing its host with a positive selective advantage. This hypothesis would account for the diversity of the captured syncytins that can be currently found, concomitant with the diversity of placental architectures. A consequence of this paradigm is that evidence for “decaying syncytins” in eutherian mammals should exist, and this is precisely what we sought—and found—in this study.