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Science 329 (5987): 75-78

Copyright © 2010 by the American Association for the Advancement of Science

Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude

Xin Yi,1,2,* Yu Liang,1,2,* Emilia Huerta-Sanchez,3,* Xin Jin,1,4,* Zha Xi Ping Cuo,2,5,* John E. Pool,3,6,* Xun Xu,1 Hui Jiang,1 Nicolas Vinckenbosch,3 Thorfinn Sand Korneliussen,7 Hancheng Zheng,1,4 Tao Liu,1 Weiming He,1,8 Kui Li,2,5 Ruibang Luo,1,4 Xifang Nie,1 Honglong Wu,1,9 Meiru Zhao,1 Hongzhi Cao,1,9 Jing Zou,1 Ying Shan,1,4 Shuzheng Li,1 Qi Yang,1 Asan,1,2 Peixiang Ni,1 Geng Tian,1,2 Junming Xu,1 Xiao Liu,1 Tao Jiang,1,9 Renhua Wu,1 Guangyu Zhou,1 Meifang Tang,1 Junjie Qin,1 Tong Wang,1 Shuijian Feng,1 Guohong Li,1 Huasang,1 Jiangbai Luosang,1 Wei Wang,1 Fang Chen,1 Yading Wang,1 Xiaoguang Zheng,1,2 Zhuo Li,1 Zhuoma Bianba,10 Ge Yang,10 Xinping Wang,11 Shuhui Tang,11 Guoyi Gao,12 Yong Chen,5 Zhen Luo,5 Lamu Gusang,5 Zheng Cao,1 Qinghui Zhang,1 Weihan Ouyang,1 Xiaoli Ren,1 Huiqing Liang,1 Huisong Zheng,1 Yebo Huang,1 Jingxiang Li,1 Lars Bolund,1 Karsten Kristiansen,1,7 Yingrui Li,1 Yong Zhang,1 Xiuqing Zhang,1 Ruiqiang Li,1,7 Songgang Li,1 Huanming Yang,1 Rasmus Nielsen,1,3,7,{dagger} Jun Wang,1,7,{dagger} Jian Wang1,{dagger}

Abstract: Residents of the Tibetan Plateau show heritable adaptations to extreme altitude. We sequenced 50 exomes of ethnic Tibetans, encompassing coding sequences of 92% of human genes, with an average coverage of 18x per individual. Genes showing population-specific allele frequency changes, which represent strong candidates for altitude adaptation, were identified. The strongest signal of natural selection came from endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1), a transcription factor involved in response to hypoxia. One single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and Han samples, representing the fastest allele frequency change observed at any human gene to date. This SNP’s association with erythrocyte abundance supports the role of EPAS1 in adaptation to hypoxia. Thus, a population genomic survey has revealed a functionally important locus in genetic adaptation to high altitude.

1 BGI-Shenzhen, Shenzhen 518083, China.
2 The Graduate University of Chinese Academy of Sciences, Beijing 100062, China.
3 Department of Integrative Biology and Department of Statistics, University of California Berkeley, Berkeley, CA 94820, USA.
4 Innovative Program for Undergraduate Students, School of Bioscience and Biotechnology, South China University of Technology, Guangzhou 510641, China.
5 The People’s Hospital of the Tibet Autonomous Region, Lhasa 850000, China.
6 Department of Evolution and Ecology, University of California Davis, Davis, CA 95616, USA.
7 Department of Biology, University of Copenhagen, DK-1165 Copenhagen, Denmark.
8 Innovative Program for Undergraduate Students, School of Science, South China University of Technology, Guangzhou 510641, China.
9 Genome Research Institute, Shenzhen University Medical School, Shenzhen 518060, China.
10 The People’s Hospital of Lhasa, Lhasa, 850000, China.
11 The Military General Hospital of Tibet, Lhasa, 850007, China.
12 The hospital of XiShuangBanNa Dai Nationalities, Autonomous Jinghong 666100, Yunnan, China.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: wangjian{at} (Ji.W.); wangj{at} (Ju.W.); rasmus_nielsen{at} (R.N.)

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