Preprint proposes STING HAQ allele was positively selected during human Out of Africa migration and may have worsened smallpox mortality in Native Americans

A preprint posted to bioRxiv investigates the evolutionary history and functional consequences of the STING allele designated HAQ (carrying the amino-acid substitutions R71H, G230A, and R293Q). The authors report that HAQ was positively selected in anatomically modern humans during the Out of Africa migration and is now present at high frequency outside sub-Saharan Africa.

Using population-level genotyping data, the team finds that approximately 82% of sampled Native Americans carry at least one copy of HAQ, with around 52% being homozygous (HAQ/HAQ), compared with 0% HAQ/HAQ homozygotes identified in twelve sub-Saharan African sub-groups studied. HAQ individuals show impaired DNA-induced type I interferon responses, including reduced IFN-α production following smallpox-relevant stimuli.

STING (Stimulator of Interferon Genes) is a central component of the innate immune pathway that detects cytosolic DNA and triggers antiviral interferon responses. The authors argue that the high frequency of the immune-attenuating HAQ allele in Native American populations may help explain, in part, the extraordinarily high mortality associated with smallpox epidemics following European contact in the Americas after 1492.

This is a preprint and has not been peer-reviewed. The proposed mechanism linking HAQ frequency to historical smallpox mortality is a population-genetic hypothesis; causal attribution of historical demographic events involves many interacting factors. The study is likely to attract significant scrutiny regarding its sampling strategies, statistical framework, and historical claims.