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

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 IFNα 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 regions. To understand the positive selection of HAQ in non-Africans, we dephased HAQ haplotypes in 74 sub-populations worldwide, over ~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.