Rapid Evolution of HERC6 and Duplication of a Chimeric HERC5/6 Gene in Rodents and Bats Suggest an Overlooked Role of HERCs in Mammalian Immunity.

Studying the evolutionary diversification of mammalian antiviral defenses is of main importance to better understand our innate immune repertoire. The small HERC proteins are part of a multigene family, including HERC5 and HERC6, which have probably diversified through complex evolutionary history in mammals. Here, we performed mammalian-wide phylogenetic and genomic analyses of HERC5 and HERC6, using 83 orthologous sequences from bats, rodents, primates, artiodactyls, and carnivores-the top five representative groups of mammalian evolution. We found that HERC5 has been under weak and differential positive selection in mammals, with only primate HERC5 showing evidences of pathogen-driven selection. In contrast, HERC6 has been under strong and recurrent adaptive evolution in mammals, suggesting past and widespread genetic arms-races with viral pathogens. Importantly, the rapid evolution of mammalian HERC6 spacer domain suggests that it might be a host-pathogen interface, targeting viral proteins and/or being the target of virus antagonists. Finally, we identified a HERC5/6 chimeric gene that arose from independent duplication in rodent and bat lineages and encodes for a conserved HERC5 N-terminal domain and divergent HERC6 spacer and HECT domains. This duplicated chimeric gene highlights adaptations that potentially contribute to rodent and bat immunity. Our findings open new research avenues on the functions of HERC6 and HERC5/6 in mammals, and on their implication in antiviral innate immunity.