Joint Effects of Balancing Selection and Population Bottlenecks on the Evolution of a Regulatory Region of Human Antiviral APOBEC3.

Human antiviral APOBEC3s are crucial components of the innate immune response, playing a key role in inhibiting viral replication and proliferation by inducing mutations in viral genomes. In this study, in a regulatory region of ∼16 kb in the APOBEC3 gene cluster on human chromosome 22, we identified three distinct haplogroups that are maintained at high frequencies in both African and non-African populations. Despite the long persistence of these haplogroups, one of which is shared by archaic hominins, the nucleotide diversity within each haplogroup was surprisingly low in non-Africans. Genome-wide empirical distribution and coalescence-based simulation tests showed that the simultaneous observations of low within-haplogroup diversity and high between-haplogroup divergence were incompatible with neutrality. We also identified an ancestral sequence group exclusively in African populations. To explain these features and elucidate the underlying evolutionary mechanisms, we performed forward simulations to model the joint effects of balancing selection and population bottlenecks. The results demonstrated the operation of balancing selection over the past ∼1 million years, as well as a hitherto unexplored reduction in within-haplogroup diversity. The only unexplained observation was the low diversity within African haplogroup I, which is unaffected by the non-African-specific bottleneck. We hypothesized that an extra haplotype turnover within haplogroup I occurred prior to the Out-of-Africa dispersal of modern humans. This study highlights the functional importance of the APOBEC3 regulatory region in terms of evolutionary conservation in Hominidae, a target of natural selection in modern humans, and its relevance in GTEx eQTL.