Distinct haplogroups with star-like diversification in the APOBEC3 regulatory region indicate ancient viral pandemics before and during the Out-of-Africa migration of modern humans

Abstract

AbstractAPOBEC3s are powerful human anti-viral proteins that inhibit viral replication and proliferation by inducing mutations in viral genomes. We found that in the regulatory region of the APOBEC3 cluster on human chromosome 22, there exist three distinct haplogroups that began to have diverged nearly 1 million years ago and have since been maintained in both African and non-African populations today. Despite the long persistence time of the haplogroups, one of which is shared by archaic hominins, we also found that the nucleotide diversity within each haplogroup is extremely low. With a simulation-based method, the observed low diversity within haplogroups and large divergence between haplogroups suggested that these haplogroups have been maintained by special forms of positive Darwinian selection. Repeated occurrence of such selection entails the enhanced substitution rate in this regulatory region in both the human and chimpanzee lineages. The causal events of such positive selection, which are most likely viral epidemics, are shown to have occurred at least three times in the modern human population: one before the Out-of-Africa migration and another two in the common ancestors of non-Africans.