Adaptive archaic introgression related to cellular zinc homeostasis in humans

AbstractSLC30A9encodes a ubiquitously zinc transporter (ZnT9) and has been consistently suggested as a candidate for positive selection in humans. However, no direct adaptive molecular phenotype has been demonstrated to date. Our results provide evidence for directional selection operating in two major complementary haplotypes in Africa and East Asia. These haplotypes are associated with differential gene expression but also differ in the Met50Val substitution (rs1047626) in ZnT9, which we show was adaptively introgressed from archaic humans. Although we found no significant differences in systemic zinc content between individuals with different rs1047626 genotypes, we demonstrate that the expression of the derived isoform (ZnT9 50Val) in HEK293 cells shows a gain of function when compared with the ancestral (ZnT9 50Met) variant. In particular, the ZnT9 50Val variant was found to avoid zinc overload in the endoplasmic reticulum and mitochondria, with an impact on mitochondrial metabolism. Overall, our results show that this adaptatively introgressed variant, which is prevalent in East Asians and present at intermediate-high frequencies in other non-African populations, is associated with functional differences in zinc handling by the mitochondria and endoplasmic reticulum. Given the essential role of the mitochondria in both skeletal muscle and brain, and that of zinc in glutamatergic neurotransmission, we propose that archaic adaptation to cold may have driven this selection event, while also impacting susceptibility to neuropsychiatric disorders in modern humans.