Origin and dispersal of Hepatitis E virus

Hepatitis E virus (HEV, genus <i>Orthohepevirus</i>) is a common cause of hepatitis worldwide. Human-infecting HEV strains (<i>Orthohepevirus A</i>) include human-restricted and enzootic genotypes. Viruses in the <i>Orthohepevirus A</i> species also infect rabbits (HEV-3ra), camels, and swine. Using a selection-informed method, we dated the origin of the <i>Orthohepevirus</i> genus at least 21 million years ago, whereas the <i>Orthohepevirus A</i> species originated in Asia, most likely from a human-infecting ancestor that existed ~4500 to 6800 years ago. In this period, the appearance of large human settlements probably facilitated HEV emergence and spread. The earliest events in <i>Orthohepevirus A</i> evolutionary history involved the separation of the enzootic and human-restricted genotypes, as well as the split of the camel-infecting genotypes, which occurred during the time-frame of camel domestication. The place and timing of HEV-3ra divergence also correspond to the circumstances of rabbit domestication. This study clarifies the origin and historical events underlying HEV dispersal.