Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders.

Human genetic adaptation to high altitudes (>2500 m) has been extensively studied over the last few years, but few functional adaptive genetic variants have been identified, largely owing to the lack of deep-genome sequencing data available to previous studies. Here, we build a list of putative adaptive variants, including 63 missense, 7 loss-of-function, 1,298 evolutionarily conserved variants and 509 expression quantitative traits loci. Notably, the top signal of selection is located in , a transmembrane protein-coding gene. The Tibetan version of harbors one high-frequency (76.3%) missense variant, rs116983452 (c.248C > T; p.Ala83Val), with the T allele derived from archaic ancestry and carried by >94% of Tibetans but absent or in low frequencies (<3%) in non-Tibetan populations. The rs116983452-T is strongly and positively correlated with altitude and significantly associated with reduced hemoglobin concentration ( = 5.78 × 10), red blood cell count ( = 5.72 × 10) and hematocrit ( = 2.57 × 10). In particular, -rs116983452 shows greater effect size and better predicts the phenotypic outcome than any variants in association with adaptive traits in Tibetans. Modeling the interaction between -rs116983452 and variants indicates weak but statistically significant epistatic effects. Our results support that multiple variants may jointly deliver the fitness of the Tibetans on the plateau, where a complex model is needed to elucidate the adaptive evolution mechanism.