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 TMEM247,a transmembrane protein-coding gene.The Tibetan version of TMEM247 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 (p =5.78 × 10-s),red blood cell count (p =5.72 x 10-7) and hematocrit (p =2.57 x 10-6).In particular,TMEM247-rs116983452 shows greater effect size and better predicts the phenotypic outcome than any EPAS1 variants in association with adaptive traits in Tibetans.Modeling the interaction between TMEM247-rs 116983452 and EPAS1 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.