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

Abstract

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 <i>TMEM247</i>, a transmembrane protein-coding gene. The Tibetan version of <i>TMEM247</i> 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 (<i>p</i> = 5.78 × 10^-5), red blood cell count (<i>p</i> = 5.72 × 10^-7) and hematocrit (<i>p</i> = 2.57 × 10^-6). In particular, <i>TMEM247</i>-rs116983452 shows greater effect size and better predicts the phenotypic outcome than any <i>EPAS1</i> variants in association with adaptive traits in Tibetans. Modeling the interaction between <i>TMEM247</i>-rs116983452 and <i>EPAS1</i> 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.