Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude

Overview

Journal Science

Specialty Science

Date 2010 Jul 3

PMID 20595611

Citations 766

Authors

Xin Yi

Yu Liang

Emilia Huerta-Sanchez

Xin Jin

Zha Xi Ping Cuo

John E Pool

Xun Xu

Hui Jiang

Nicolas Vinckenbosch

Thorfinn Sand Korneliussen

Hancheng Zheng

Tao Liu

Weiming He

Kui Li

Ruibang Luo

Xifang Nie

Honglong Wu

Meiru Zhao

Hongzhi Cao

Jing Zou

Ying Shan

Shuzheng Li

Qi Yang

Asan

Peixiang Ni

Geng Tian

Junming Xu

Xiao Liu

Tao Jiang

Renhua Wu

Guangyu Zhou

Meifang Tang

Junjie Qin

Tong Wang

Shuijian Feng

Guohong Li

Huasang

Jiangbai Luosang

Wei Wang

Fang Chen

Yading Wang

Xiaoguang Zheng

Zhuo Li

Zhuoma Bianba

Ge Yang

Xinping Wang

Shuhui Tang

Guoyi Gao

Yong Chen

Zhen Luo

Lamu Gusang

Zheng Cao

Qinghui Zhang

Weihan Ouyang

Xiaoli Ren

Huiqing Liang

Huisong Zheng

Yebo Huang

Jingxiang Li

Lars Bolund

Karsten Kristiansen

Yingrui Li

Yong Zhang

Xiuqing Zhang

Ruiqiang Li

Songgang Li

Huanming Yang

Rasmus Nielsen

Jun Wang

Jian Wang

Affiliations

Soon will be listed here.

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.

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References

Jain S, Maltepe E, Lu M, Simon C, Bradfield C . Expression of ARNT, ARNT2, HIF1 alpha, HIF2 alpha and Ah receptor mRNAs in the developing mouse. Mech Dev. 1998; 73(1):117-23. DOI: 10.1016/s0925-4773(98)00038-0. View

Beall C . Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A. 2007; 104 Suppl 1:8655-60. PMC: 1876443. DOI: 10.1073/pnas.0701985104. View

Albert T, Molla M, Muzny D, Nazareth L, Wheeler D, Song X . Direct selection of human genomic loci by microarray hybridization. Nat Methods. 2007; 4(11):903-5. DOI: 10.1038/nmeth1111. View

Moore L . Human genetic adaptation to high altitude. High Alt Med Biol. 2001; 2(2):257-79. DOI: 10.1089/152702901750265341. View

Acampora D, Mazan S, Avantaggiato V, Barone P, Tuorto F, Lallemand Y . Epilepsy and brain abnormalities in mice lacking the Otx1 gene. Nat Genet. 1996; 14(2):218-22. DOI: 10.1038/ng1096-218. View

Hentze M, Muckenthaler M, Andrews N . Balancing acts: molecular control of mammalian iron metabolism. Cell. 2004; 117(3):285-97. DOI: 10.1016/s0092-8674(04)00343-5. View

Niermeyer S, Yang P, Shanmina , Drolkar , Zhuang J, Moore L . Arterial oxygen saturation in Tibetan and Han infants born in Lhasa, Tibet. N Engl J Med. 1995; 333(19):1248-52. DOI: 10.1056/NEJM199511093331903. View

Kanno H, Fujii H, Hirono A, Omine M, Miwa S . Identical point mutations of the R-type pyruvate kinase (PK) cDNA found in unrelated PK variants associated with hereditary hemolytic anemia. Blood. 1992; 79(5):1347-50. View

Choudhury K, McQuillin A, Puri V, Pimm J, Datta S, Thirumalai S . A genetic association study of chromosome 11q22-24 in two different samples implicates the FXYD6 gene, encoding phosphohippolin, in susceptibility to schizophrenia. Am J Hum Genet. 2007; 80(4):664-72. PMC: 1852702. DOI: 10.1086/513475. View

10.

Gaetani M, Mootien S, Harper S, Gallagher P, Speicher D . Structural and functional effects of hereditary hemolytic anemia-associated point mutations in the alpha spectrin tetramer site. Blood. 2008; 111(12):5712-20. PMC: 2424163. DOI: 10.1182/blood-2007-11-122457. View

11.

Wu T, Wang X, Wei C, Cheng H, Wang X, Li Y . Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J Appl Physiol (1985). 2004; 98(2):598-604. DOI: 10.1152/japplphysiol.01034.2002. View

12.

Storz J, Runck A, Sabatino S, Kelly J, Ferrand N, Moriyama H . Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin. Proc Natl Acad Sci U S A. 2009; 106(34):14450-5. PMC: 2732835. DOI: 10.1073/pnas.0905224106. View

13.

To K, Huang L . Suppression of hypoxia-inducible factor 1alpha (HIF-1alpha) transcriptional activity by the HIF prolyl hydroxylase EGLN1. J Biol Chem. 2005; 280(45):38102-7. PMC: 1307502. DOI: 10.1074/jbc.M504342200. View

14.

Percy M, Furlow P, Lucas G, Li X, Lappin T, McMullin M . A gain-of-function mutation in the HIF2A gene in familial erythrocytosis. N Engl J Med. 2008; 358(2):162-8. PMC: 2295209. DOI: 10.1056/NEJMoa073123. View

15.

Shriver M, Kennedy G, Parra E, Lawson H, Sonpar V, Huang J . The genomic distribution of population substructure in four populations using 8,525 autosomal SNPs. Hum Genomics. 2004; 1(4):274-86. PMC: 3525267. DOI: 10.1186/1479-7364-1-4-274. View

16.

Henderson J, Withford-Cave J, Duffy D, Cole S, Sawyer N, Gulbin J . The EPAS1 gene influences the aerobic-anaerobic contribution in elite endurance athletes. Hum Genet. 2005; 118(3-4):416-23. DOI: 10.1007/s00439-005-0066-0. View

17.

Li R, Yu C, Li Y, Lam T, Yiu S, Kristiansen K . SOAP2: an improved ultrafast tool for short read alignment. Bioinformatics. 2009; 25(15):1966-7. DOI: 10.1093/bioinformatics/btp336. View

18.

Gutenkunst R, Hernandez R, Williamson S, Bustamante C . Inferring the joint demographic history of multiple populations from multidimensional SNP frequency data. PLoS Genet. 2009; 5(10):e1000695. PMC: 2760211. DOI: 10.1371/journal.pgen.1000695. View

19.

Bigham A, Mao X, Mei R, Brutsaert T, Wilson M, Julian C . Identifying positive selection candidate loci for high-altitude adaptation in Andean populations. Hum Genomics. 2009; 4(2):79-90. PMC: 2857381. DOI: 10.1186/1479-7364-4-2-79. View

20.

Hodgkinson C, Goldman D, Jaeger J, Persaud S, Kane J, Lipsky R . Disrupted in schizophrenia 1 (DISC1): association with schizophrenia, schizoaffective disorder, and bipolar disorder. Am J Hum Genet. 2004; 75(5):862-72. PMC: 1182115. DOI: 10.1086/425586. View