| 1 | Prioritizing natural-selection signals from the deep-sequencing genomic data suggests multi-variant adaptation in Tibetan highlanders显示文摘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,w e 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 TMEM 247,a transmembrane protein-coding gene.The Tibetan version of TMEM 247 harbors one high-frequency(76.3%)missense variant,rsl 16983452(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 rsl 16983452-T is strongly and positively correlated with altitude and significantly associated with reduced hemoglobin concentration(p=5.78×10^-5),red blood cell count(p=5.72×10^-7)and hematocrit(p=2.57×10^-6).In particular,TMEM247-rs 116983452 shows greater effect size and better predicts the phenotypic outcome than any E P A S1 variants in association with adaptive traits in Tibetans.Modeling the interaction between TM£M247-rsl 16983452 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. | Lian Deng Chao Zhang Kai Yuan Yang Gao Yuwen Pan Xueling Ge Yaoxi He Yuan Yuan Yan Lu Xiaoxi Zhang Hao Chen Haiyi Lou Xiaoji Wang Dongsheng Lu Jiaojiao Liu Lei Tian Qidi Feng Asifullah Khan Yajun Yang Zi-Bing Jin Jian Yang Fan Lu Jia Qu Longli Kang Bing Su Shuhua Xu | 2019 | National Science Review2019，6，6： | 9 |
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