Natural Selection of the Common STING Allele HAQ in Anatomically Modern Humans

Abstract

The STING allele R71H-G230A-R293Q (HAQ) was positively selected in Anatomically Modern Humans (AMH) during the Out of Africa (OoA) migration. Here, we show that 51.61% of Native Americans (NAM) are HAQ/HAQ, while only 6.45% are WT/WT. HAQ individuals are defective in DNA-induced type I IFNs responses, such as smallpox-induced IFN-alpha production. 82.3% of NAM carry the HAQ allele, which helps explain the post-Columbus NAM population collapse from the smallpox epidemic. Similarly, in 12 sub-groups of Sub-Saharan Africans, we found 0% HAQ/HAQ, indicating ongoing negative selection reflecting Sub-Saharan Africa as the world's heaviest infectious-disease region. To understand positive selection of HAQ in non-Africans, we dephased HAQ haplotypes in 74 sub-populations worldwide, across more than 4,000 individuals. We found that the HAQ allele evolved faster than the neutral H232 STING allele and had more generations during the OoA migration, increasing its frequency in non-Africans. A mouse model of HAQ housed in a Specific Pathogen-Free mouse facility generates more surviving pups than the H232 mice. In summary, the HAQ allele was positively selected during OoA migration but is negatively selected in Sub-Saharan Africa, underscoring its essential role in AMH adaptation to diverse environments.