Polygenic adaptation leads to a higher reproductive fitness of native Tibetans at high altitude.

The adaptation of Tibetans to high-altitude environments has been studied extensively. However, the direct assessment of evolutionary adaptation, i.e., the reproductive fitness of Tibetans and its genetic basis, remains elusive. Here, we conduct systematic phenotyping and genome-wide association analysis of 2,252 mother-newborn pairs of indigenous Tibetans, covering 12 reproductive traits and 76 maternal physiological traits. Compared with the lowland immigrants living at high altitudes, indigenous Tibetans show better reproductive outcomes, reflected by their lower abortion rate, higher birth weight, and better fetal development. The results of genome-wide association analyses indicate a polygenic adaptation of reproduction in Tibetans, attributed to the genomic backgrounds of both the mothers and the newborns. Furthermore, the EPAS1 -edited mice display higher reproductive fitness under chronic hypoxia, mirroring the situation in Tibetans. Collectively, these results shed new light on the phenotypic pattern and the genetic mechanism of human reproductive fitness in extreme environments. [Display omitted] • Deep phenotyping and genetic association of 2,252 mother-newborn pairs of Tibetans • Tibetans have higher reproductive fitness than lowland immigrants at high altitudes • GWAS results indicate a polygenic adaptation of reproduction in Tibetans • EPAS1 -edited mice display a higher reproductive fitness under chronic hypoxia He et al. conduct systematic phenotyping and genome-wide association analysis of reproductive fitness in 2,252 mother-newborn pairs of indigenous Tibetans, and they demonstrate that native Tibetans possess a high reproductive fitness at high altitude resulting from the mechanism of polygenic adaptation. [ABSTRACT FROM AUTHOR]