A positively selected APOBEC3H haplotype is associated with natural resistance to HIV-1 infection

APOBEC3 genes encode cytidine deaminases endowed with the ability to inhibit retroviruses and retrotransposons. These genes have been targets of natural selection throughout primate evolutionary history. We analysed their selection pattern in human populations observing that APOBEC3F and 3G are neutrally evolving. Conversely, nucleotide diversity was extremely high for APOBEC3H, and most tests rejected the hypothesis of selective neutrality in Eurasian populations. Haplotype analysis and the derived intra-allelic nucleotide diversity test indicated that positive selection has driven the increase in frequency of one haplotype (Hap I) outside Africa. Consistently, population genetic differentiation between African and non-African populations was higher than expected under neutrality. A case/control association analysis indicated that Hap I is associated with protection from sexually transmitted HIV-1 infection. Hap I carries a protein-destabilizing variant and a residue conferring resista...