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

作　　者：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 

机构地区：[1]Key Laboratory of Computational Biology,CAS-MPG Partner Institute for Computational Biology,Shanghai Institute of Nutrition and Health,Shanghai Institutes for Biological Sciences,University of Chinese Academy of Sciences,Chinese Academy of Sciences,Shanghai 200031,China [2]School of Life Science and Technology,ShanghaiTech University,Shanghai 201210,China [3]State Key Laboratory of Genetic Resources and Evolution,Kunming Institute of Zoology,Chinese Academy of Sciences,Kunming 650223,China [4]State Key Laboratory of Genetic Engineering and Ministry of Education(MOE)Key Laboratory of Contemporary Anthropology,School of Life Sciences,Fudan University,Shanghai 200433,China [5]The Eye Hospital,School of Ophthalmology&Optometry,Wenzhou Medical University,China National Center for International Research in Regenerative Medicine and Neurogenetics,State Key Laboratory of Ophthalmology,Optometry and Visual Science,Wenzhou 325027,China [6]Institute for Molecular Bioscience,Queensland Brain Institute,The University of Queensland,Brisbane,QLD 4072,Australia [7]Key Laboratory for Molecular Genetic Mechanisms and Intervention Research on High Altitude Disease of Tibet Autonomous Region,School ot Medicine,Xizang Minzu University,Xianyang 712082,China [8]Center for Excellence in Animal Evolution and Genetics,Chinese Academy of Sciences,Kunming 650223,China [9]Collaboralive Innovation Center of Genetics and Deve丨叩ment,Shanghai 200438,China [10]Human Phenome Institute,Fudan University,Shanghai 201203,China

出　　处：《National Science Review》2019年第6期1201-1222,共22页国家科学评论（英文版）

基　　金：supported by the Strategic Priority Research Program(XDB13040100 to S.X.);Key Research Program of Frontier Sciences(QYZDJ-SSW-SYS009 to S.X.)of the Chinese Academy of Sciences(CAS);the National Natural Science Foundation of China(NSFC)(91731303,31525014,31961130380 and 31771388 to S.X.;31501011 to Y.L.;31771389 to Y.Y.(Yuan Yuan);81522014 to Z.J.;31871256and 31601046 to H.L.;31460286,31660307 and 31260252to L.K.);the Program of Shanghai Academic Research Leader(16XD1404700 to S.X.);the UK Royal Society-Newton Advanced Fellowship(NAF\R1\191094 to S.X.);the National Key Research and Development Program(2016YFC0906403 to S.X.;2017YFA0105300 to Z.J.;2016YFF0202301 to Y.Y.(Yajun Yang));Shanghai Municipal Science and Technology Major Project(2017SHZDZX01 to S.X.);Science and Technology Commission of Shanghai Municipality(STCSM,19YF1455200to L.D.; 16YF1413900 to H.L.);NSFC Research Fund for International Young Scientists(31850410477 to A.K.);CAS President’s International Fellowship for Postdoctoral Researchers(2016 PB036 to A.K.);S.X.is Max-Planck Independent Research Group Leader and member of CAS Youth Innovation Promotion Association;supported by the National Program for Top-notch Young Innovative Talents of the ‘Wanren Jihua’ Project;the UK Royal Society-Newton Mobility Grants(IE160943 to S.X.)

摘　　要：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.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.248 C > T; p.Ala83 Val）, 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 × 10-5), red blood cell count(p = 5.72 × 10-7) and hematocrit(p = 2.57 × 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-rs116983452 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.

关 键 词：Tibetan adaptive genetic variant high-altitude adaptation next-generation sequencing(NGS) archaic ancestry expression quantitative traits loci(eQTL) tissue-specific expression hemoglobin concentration hypoxia 

分 类 号：Q987[生物学—遗传学]