Functional <i>EPAS1</i>/<i>HIF2A</i> missense variant is associated with hematocrit in Andean highlanders.

Abstract

Hypoxia-inducible factor pathway genes are linked to adaptation in both human and nonhuman highland species. <i>EPAS1</i>, a notable target of hypoxia adaptation, is associated with relatively lower hemoglobin concentration in Tibetans. We provide evidence for an association between an adaptive <i>EPAS1</i> variant (rs570553380) and the same phenotype of relatively low hematocrit in Andean highlanders. This Andean-specific missense variant is present at a modest frequency in Andeans and absent in other human populations and vertebrate species except the coelacanth. CRISPR-base-edited human cells with this variant exhibit shifts in hypoxia-regulated gene expression, while metabolomic analyses reveal both genotype and phenotype associations and validation in a lowland population. Although this genocopy of relatively lower hematocrit in Andean highlanders parallels well-replicated findings in Tibetans, it likely involves distinct pathway responses based on a protein-coding versus noncoding variants, respectively. These findings illuminate how unique variants at <i>EPAS1</i> contribute to the same phenotype in Tibetans and a subset of Andean highlanders despite distinct evolutionary trajectories.