Baton pass hypothesis: successive incorporation of unconserved endogenous retroviral genes for placentation during mammalian evolution

Abstract

It is well accepted that numerous RNAs derived from endogenous retroviruses (ERVs) are expressed in mammalian reproductive structures, particularly in the uterus, trophoblast, and placenta. Syncytin 1 and syncytin 2 in humans and syncytin A and syncytin B in mice are membrane proteins originating from Env genes of ERVs. These ERVs are involved in the fusion of trophoblast cells, resulting in multinucleated syncytiotrophoblast formation. Evidence accumulated indicates that syncytin-like fusogenic proteins are expressed in the placenta of rabbits, dogs/cats, ruminant ungulates, tenrecs, and opossums. The syncytin genes so far characterized are known to be endogenized to the host genome only within the past 12-80 million years, more recently than the appearance of mammalian placentas, estimated to be 160-180 million years ago. We speculate that ERVs including syncytin-like gene variants integrated into mammalian genomes in a locus-specific manner have replaced the genes previously responsible for cell fusion. We therefore propose the 'baton pass' hypothesis, in which multiple successive ERV variants 'take over' cell-fusion roles, resulting in increased trophoblast cell fusion, morphological variations in placental structures, and enhanced reproductive success in placental mammals.

Endogenous Retroviruses: With Us and against Us

“…Notably, integration of ERV-W and ERV-FRD into the genome occurred prior to the divergence of Old World (Catarrhini; Cáceres et al, 2006) and New World (Platyrrhini) monkeys (Blaise et al, 2003), respectively, thus Syncytin-1 and Syncytin-2 are only present in higher-order primate (Haplorhini) species, although functionally similar yet distinct ERV proviral proteins have been discovered throughout most mammalian genomes, as reviewed in Imakawa et al (2015). The ERV-V env gene present within Old World monkeys has also been implicated in trophoblast fusion activity, possibly alleviating the lack of functional Syncytin-1 within these species, while the ERV-V reiterations present within the human genome are not functional in this capacity (Esnault et al, 2013; Supplementary Table 2).…”

Genome-Wide Screening of Retroviral Envelope Genes in the Nine-Banded Armadillo (Dasypus novemcinctus, Xenarthra) Reveals an Unfixed Chimeric Endogenous Betaretrovirus Using the ASCT2 Receptor

“…This could have enhanced the fusogenic capacity of Dasy-Env1.1, as observed for several gamma-and beta-type Env proteins, which can be rendered fusogenic via C-terminal truncation (71). In this respect, dasy-env1.1, thanks to future modifications and provided that it confers a selective advantage, could progressively replace an existing, but asyet-unidentified, syncytin gene in Dasypus and contribute to the turnover of these genes throughout evolution (27,72,73).…”

Evolutionary Medicine of Retroviruses in the Human Genome

“…40 The syncytin-1 and -2 sequences are believed to have integrated 12-80 million years ago, and at the same time these sequences obtained mammalian-specific placental function. 41 As in this case, HERVs acquired essential functions that can be evolutionarily preserved.…”