Evolutionary Analysis Provides Insight into the Origin and Adaptation of HCV

Abstract

Using a selection‐informed evolutionary model we show that the common ancestor of extant HCV genotypes existed at least 3000 years ago and that the oldest genotypes are endemic to Asia. Equine hepacivirus, HCV most closely related virus, originated around 1100 CE. These time estimates are not consistent with the possibility that HCV derives from a cross‐species transmission from horses and suggest a single zoonotic event with subsequent spread and diversification in human populations. Herein evolutionary analysis also support a role for hepaciviruses as drivers of CD81 evolution in Chiroptera and Glires, implicating these mammals as the HCV reservoirs. We describe a number of biologically‐important sites in the major HCV genotypes that have been positively selected and indicate that drug resistance‐associated variants are significantly enriched at positively selected sites. These results shed light on the origin of HCV and provide a catalog of candidate genetic modulators of HCV phenotypic diversity.