Virus-Derived Domesticated Genes in Microglia and Resident Macrophages: Insights into Placenta-Driven Evolution in Mammals

Eutherian mammals possess 11 metavirus-derived genes, collectively known as the sushi-ichi retrotransposon homologue (SIRH)/Retrotransposon Gag-like (RTL) genes. Several members of this group function in microglia, where SIRH3/RTL6, SIRH8/RTL5, and SIRH10/RTL9 mediate innate immune responses against bacterial-, viral-, and fungal-derived pathogen-associated molecular patterns, respectively, whereas SIRH11/RTL4 responds to noradrenaline and is thought to contribute to stress-responsive brain functions. In addition, the retroviral Env-derived gene ERVPb1 has been implicated in yolk sac-derived resident macrophage lineages, suggesting that both Gag- and Env-derived domesticated genes contributed to the evolution of mammalian neuroimmune systems. Microglia are now recognized as central regulators of neural circuit formation, brain homeostasis, and neuroimmune function, and their dysfunction has been implicated in a wide range of neurological and psychiatric disorders. Here, we review current knowledge of virus-derived genes that have shaped the functional evolution of microglia. We also revisit the concept of “Placenta-driven evolution,” which proposes that the relatively hypomethylated developmental environment of extraembryonic tissues, including the placenta and yolk sac, facilitates the retention and functional co-option of virus-derived sequences, thereby accelerating eutherian evolution. Finally, by integrating recent advances in virus-derived genes and retroelement biology, we discuss how this evolutionary framework may extend beyond extraembryonic tissues to other hypomethylated developmental environments, including the germline and preimplantation embryos.