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Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude
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No Genetic Vertigo: Peoples living in high altitudes have adapted to their situation (see the Perspective by Storz ). To identify gene regions that might have contributed to high-altitude adaptation in Tibetans, Simonson et al. (p. 72 , published online 13 May) conducted a genome scan of nucleotide polymorphism comparing Tibetans, Han Chinese, and Japanese, while Yi et al. (p. 75 ) performed comparable analyses on the coding regions of all genes—their exomes. Both studies converged on a gene, endothelial Per-Arnt-Sim domain protein 1 (also known as hypoxia-inducible factor 2 α), which has been linked to the regulation of red blood cell production. Other genes identified that were potentially under selection included adult and fetal hemoglobin and two functional candidate loci that were correlated with low hemoglobin concentration in Tibetans. Future detailed functional studies will now be required to examine the mechanistic underpinnings of physiological adaptation to high altitudes.
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“For example, by studying genes that show population-specific allele-frequency differences between Tibetans and Han Chinese, a signal of positive natural selection was detected in EPAS1, a transcription factor involved in the response to hypoxia, which most probably helps the Tibetans to live at high altitudes [40].”
From Ancient DNA and the rewriting of human history: be sparing with Occam’s razor (2016) · cites this paper as [40]
In the citing paper
“Genome-wide searches for single-nucleotide polymorphisms (SNP), candidate gene approaches and exome sequencing have identified genetic variations in the HIF2A, PHD2 and PPARA genes that associate with lower hemoglobins in native Tibetans compared to Han Chinese and with high altitude adaptation in other populations.”
From Regulation of erythropoiesis by hypoxia-inducible factors (2013) · cites this paper as [173]
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“Namely, peroxisome proliferatoractivated receptor α (PPARA),18 egl nine homolog 1 (EGLN1),18–22 and endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1)19–24 have been reported to play important roles in high altitude adaptation in Tibetans.”
BackgroundInfluentialSelf-citationSurprisingly Low Limits of Selection in Plant Domestication
Allaby, R. G., Kitchen, J. L., & Fuller, D. Q. (2015) · Evolutionary Bioinformatics · doi:10.4137/ebo.s33495 · Cited by 28
The Unpredictable Species: What Makes Humans Unique
LIEBERMAN, P. H. (2013) · Project Muse (Johns Hopkins University) · Cited by 28
Targeted resequencing of coding DNA sequences for SNP discovery in nonmodel species
Förster, D. W., Bull, J. K., Lenz, D., Autenrieth, M., Paijmans, J. L. A., Kraus, R. H., Nowak, C., Bayerl, H., Kuehn, R., Saveljev, A. P., et al. (2018) · Molecular Ecology Resources · doi:10.1111/1755-0998.12924 · Cited by 31
Rapid local adaptation linked with phenotypic plasticity
Sun, S., Catherall‐Ostler, A. M., Pascoal, S., Jarrett, B. J. M., Miller, S., Sheehan, M. J., & Kilner, R. M. (2020) · Evolution Letters · doi:10.1002/evl3.176 · Cited by 28
“…elevated values of FST are indicative of a shift in allele frequency in one or both populations, elevated values of PBS allowed us to assign the relative divergence of each population to understand which population was driving divergence across the genome (Yi et al. 2010; Fumagalli et al. 2015).”
BackgroundAli, M. J., Xing, G., He, J., Zhao, T., & Gai, J. (2020) · The Crop Journal · doi:10.1016/j.cj.2020.06.008 · Cited by 28
Genetic and phenotypic differentiation of an Andean intermediate altitude population
Eichstaedt, C. A., Antão, T., Cardona, A., Pagani, L., Kivisild, T., & Mormina, M. (2015) · Physiological Reports · doi:10.14814/phy2.12376 · Cited by 30
“Remarkably, there are major adaptive differences between Andeans, Tibetans, and Ethiopians at the phenotypic level.”
BackgroundMethodInfluentialApplying systems biology methods to the study of human physiology in extreme environments
Edwards, L. M., & Thiele, I. (2013) · Extreme Physiology & Medicine · doi:10.1186/2046-7648-2-8 · Cited by 28
“For example, two recent studies showed that Tibetans, whose ancestors have resided at high altitude for over 10,000 years, have acquired and maintained novel mutations in the gene encoding the oxygen-sensing hypoxia-inducible factor (HIF) molecule [64,65].”
BackgroundCardiometabolic risk factors in native populations living at high altitudes
Hirschler, V. (2015) · International Journal of Clinical Practice · doi:10.1111/ijcp.12756 · Cited by 29
Multi-ancestry genome-wide association analyses of polycystic ovary syndrome
Zhao, H., Xu, Y., Xue, B., Zhao, S., Zhang, M., Wu, X., Wang, T., Wen, Y., Li, S., Zhang, Q., et al. (2025) · Nature Genetics · doi:10.1038/s41588-025-02393-x · Cited by 28
“Pathway enrichment analysis showed that high-PBS genes in EAS were enriched in pathways related to kinase activity regulation, biological regulation and metabolic processes (Fig.”
InfluentialSelf-citationVariants of the Low Oxygen Sensors EGLN1 and HIF-1AN Associated with Acute Mountain Sickness
Zhang, E., Zhang, J., Jin, J., Qin, J., Li, H., & Huang, L. J. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms151221777 · Cited by 28
“Evidence of genetic adaptation at different altitudes was recently provided by genome-wide investigations in HL and LL populations [7–9] and these investigations indicated that the EGLN1 and HIF-1AN genes could be involved in AMS.”
BackgroundSelf-citationInferring Selection Intensity and Allele Age from Multilocus Haplotype Structure
Chen, H., & Slatkin, M. (2013) · G3 Genes Genomes Genetics · doi:10.1534/g3.113.006197 · Cited by 29
“…actively shaping the genetic diversity of human populations during the process of adaptation to new environments and infectious diseases (Sabeti et al. 2002; Bersaglieri et al. 2004; Tishkoff et al. 2007; Simonson et al. 2010; Yi et al. 2010; Peng et al. 2011; Xu et al. 2011; Kamberov et al. 2013).”
BackgroundConceptualizing the Tibetan Plateau: Environmental constraints on the peopling of the “Third Pole”
Madsen, D. B. (2016) · Archaeological Research in Asia · doi:10.1016/j.ara.2016.01.002 · Cited by 28
The Genetic Architecture of Chronic Mountain Sickness in Peru
Gazal, S., Espinoza, J. R., Austerlitz, F., Marchant, D., Macarlupú, J. L., Jorge Rodríguez, B., Preciado, H. F. J., Rivera, M. C., Hermine, O., Lèon‐Velarde, F., et al. (2019) · Frontiers in Genetics · doi:10.3389/fgene.2019.00690 · Cited by 27
“…as being under adaptation to high altitude (Table S4), even if we observed non-significant but small P values for EPAS1 (Simonson et al., 2010; Yi et al., 2010; Peng et al., 2011; Xu et al., 2011) and EGLN1 (Bigham et al., 2010; Peng et al., 2011; Xu et al., 2011) genes (P = 0.06 for both…”
BackgroundInfluentialMutation saturation for fitness effects at human CpG sites
Agarwal, I., & Przeworski, M. (2021) · eLife · doi:10.7554/elife.71513 · Cited by 32
Recent positive selection signatures reveal phenotypic evolution in the Han Chinese population
Luo, H., Zhang, P., Zhang, W., Zheng, Y., Hao, D., Shi, Y., Niu, Y., Song, T., Li, Y., Zhao, S., et al. (2023) · 中国科学通报：英文版 · doi:10.1016/j.scib.2023.08.027 · Cited by 27
Self-citationVerma, P., Sharma, A., Sodhi, M., Thakur, K., Bharti, V. K., Kumar, P., Giri, A., Kalia, S., Swami, S. K., & Mukesh, M. (2018) · Cell Biology International · doi:10.1002/cbin.10981 · Cited by 27
“EPAS-1 gene association with high altitude adaptation is well documented in humans and dogs (Erzurum et al., 2007; Yi et al., 2010; Gou et al., 2014) and has been related to the haemoglobin concentration in Andeans and Tibetans (Bigham et al.”
BackgroundLee, M., Lindo, J., & Rilling, J. K. (2022) · Genes Brain & Behavior · doi:10.1111/gbb.12783 · Cited by 27
“The mediation effects were analyzed using a bootstrap estimation implemented in PROCESS macro on SPSS with 5000 bootstrap samples.54 2.2.4 | Test of positive selection for OXTR MPS across human populations Last, to test the evidence of positive selection for enhanced OT signaling in the ACC, we used PBS.37 PBS is a su…”
MethodResultInfluentialGenetic Adaptation of Schizothoracine Fish to the Phased Uplifting of the Qinghai–Tibetan Plateau
Zhang, D., Yu, M., Hu, P., Peng, S., Liu, Y., Li, W., Wang, C., He, S., Zhai, W., Xu, Q., et al. (2017) · G3 Genes Genomes Genetics · doi:10.1534/g3.116.038406 · Cited by 28
“These studies were initially focused on the native Tibetan people (Bigham et al. 2010, 2013; Simonson et al. 2010; Yi et al. 2010; Peng et al. 2011; Xu et al. 2011), and later on extended to various animal taxa endemic to the plateau, including yak (Qiu et al. 2012), frog (Yang et al. 2012),…”
BackgroundQuiver, M. H., & Lachance, J. (2021) · Human Genetics and Genomics Advances · doi:10.1016/j.xhgg.2021.100083 · Cited by 28
Adaptive cardiorespiratory changes to chronic continuous and intermittent hypoxia
Prabhakar, N. R., Peng, Y., & Nanduri, J. (2022) · Handbook of clinical neurology · doi:10.1016/b978-0-323-91534-2.00009-6 · Cited by 27
Genomic insights into the evolutionary history and diversification of bulb traits in garlic
Li, N., Zhang, X., Sun, X., Zhu, S., Cheng, Y., Liu, M., Gao, S., Zhang, J., Wang, Y., Yang, X., et al. (2022) · Genome biology · doi:10.1186/s13059-022-02756-1 · Cited by 26
“Firstly, by comparing the pairwise FST between designed compared patterns with a sliding window (500-kb windows sliding in 125-kb steps), we employed Population Branch Statistic (PBS) approach to detect incompletely selective sweeps over short divergence times [46].”
MethodSelf-citationGenetic explorations of recent human metabolic adaptations: hypotheses and evidence
Brown, E. A. (2012) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/j.1469-185x.2012.00227.x · Cited by 28
High altitude genetic adaptation in Tibetans: No role of increased hemoglobin–oxygen affinity
Tashi, T., Feng, T., Koul, P. A., Amaru, R., Hussey, D., Lorenzo, F., Ge, R., & Prchal, J. T. (2014) · Blood Cells Molecules and Diseases · doi:10.1016/j.bcmd.2014.02.003 · Cited by 26
Impacts of nucleotide fixation during soybean domestication and improvement
Zhao, S., Zheng, F., He, W., Wu, H., Pan, S., & Lam, H. (2015) · BMC Plant Biology · doi:10.1186/s12870-015-0463-z · Cited by 27
“the genomic regions showing artificial selection signals by genetic bottleneck model [18,19] and population branch statistics [27].”
BackgroundSelf-citationCortical Thickness of Native Tibetans in the Qinghai-Tibetan Plateau
Wei, W., Wang, X., Gong, Q., Fan, M., & Zhang, J. (2017) · American Journal of Neuroradiology · doi:10.3174/ajnr.a5050 · Cited by 28
Self-citationJallow, M. W., Cerami, C., Clark, T. G., Prentice, A. M., & Campino, S. G. (2020) · PLoS ONE · doi:10.1371/journal.pone.0235141 · Cited by 26
Adaptive selection of an incretin gene in Eurasian populationsPreprint
Chang, C. L., Cai, J. J., Lo, C., Amigo, J., Park, J.-I., & Hsu, S. Y. (2010) · Genome Research · doi:10.1101/gr.110593.110 · Cited by 26
“Recent studies have revealed that genetic variation underlies a variety of diversities in human physiology and pathology (Sabeti et al. 2005; Voight et al. 2006, 2010; Sulem et al. 2007; Tishkoff et al. 2007; Genovese et al. 2010; Leslie 2010; Simonson et al. 2010; Yi et al. 2010).”
BackgroundThe “cancer–cold” hypothesis and possible extensions for the Nordic populations
Voskarides, K. (2019) · Scandinavian Journal of Public Health · doi:10.1177/1403494819831905 · Cited by 26
Cultural and demic co-diffusion of Tubo Empire on Tibetan Plateau
Zhu, K., Du, P., Li, J., Zhang, J., Hu, X., Meng, H., Chen, L., Zhou, B., Yang, X., Xiong, J., et al. (2022) · iScience · doi:10.1016/j.isci.2022.105636 · Cited by 25
Self-citationRace and IQ in the postgenomic age: The microcephaly case
Richardson, S. S. (2011) · BioSocieties · doi:10.1057/biosoc.2011.20 · Cited by 25
郑王山, Guo, Y.-B., 何耀喜, 崔超英, Baima, K., Duoji, Z., 彭忆, 白彩娟, 多吉卓玛, 龚嘎蓝孜, et al. (2017) · 动物学研究 · doi:10.24272/j.issn.2095-8137.2017.037 · Cited by 25
Self-citationOn the Distribution of Tract Lengths During Adaptive Introgression
Shchur, V., Svedberg, J., Medina, P., Corbett-Detig, R. B., & Nielsen, R. (2020) · G3 Genes Genomes Genetics · doi:10.1534/g3.120.401616 · Cited by 27
Self-citationSchweizer, R. M., Jones, M. R., Bradburd, G. S., Storz, J. F., Senner, N. R., Wolf, C. J., & Cheviron, Z. A. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab161 · Cited by 26
Time Domains of Hypoxia Responses and -Omics Insights
Yu, J. J., Non, A. L., Heinrich, E. C., Gu, W., Alcock, J., Moya, E. A., Lawrence, E. S., Tift, M. S., O’Brien, K. A., Storz, J. F., et al. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.885295 · Cited by 29
“…at HIF genes such as EPAS1 and Egl-9 Family Hypoxia Inducible Factor 1 ( EGLN1 ) exhibit signi fi cant associations with [Hb] (Beall et al., 2002; Simonson et al., 2010; Yi et al., 2010) but do not provide information about the direct modulation of this phenotype (reviewed in Simonson (2015)).”
Metadata
- Authors
- Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E., Xu, X., Jiang, H., Vinckenbosch, N., Korneliussen, T. S., Zheng, H., Liu, T., He, W., Li, K., Luo, R., Nie, X., Wu, H., Zhao, M., Cao, H., Zou, J., Shan, Y., Li, S., Yang, Q., Asan, Ni, P., Tian, G., Xu, J., Liu, X., Jiang, T., Wu, R., Zhou, G., Tang, M., Qin, J., Wang, T., Feng, S., Li, G., Huasang, Luosang, J., Wang, W., Chen, F., Wang, Y., Zheng, X., Li, Z., Bianba, Z., Yang, G., Wang, X., Tang, S., Gao, G., Chen, Y., Luo, Z., Gusang, L., Cao, Z., Zhang, Q., Ouyang, W., Ren, X., Liang, H., Zheng, H., Huang, Y., Li, J., Bolund, L., Kristiansen, K., Li, Y., Zhang, Y., Zhang, X., Li, R., Li, S., Yang, H., Nielsen, R., Wang, J., & Wang, J.
- Affiliations
- BGI Group (China) (CN)
- Department of Integrative Biology and Department of Statistics, University of California Berkeley, Berkeley, CA 94820, USA.
- Tibet Autonomous Region People's Hospital (CN)
- University of California, Davis (US)
- University of California, Berkeley (US)
- University of Copenhagen (DK)
- The Military General Hospital of Tibet, Lhasa, 850007, China.
- The hospital of XiShuangBanNa Dai Nationalities, Autonomous Jinghong 666100, Yunnan, China.
- Corresponding author
- Yi, Xin
- Liang, Yu
- Jin, Xin
- Cuo, Zha Xi Ping
- Pool, John E.
- ORCID
- Yi, Xin
- Liang, Yu
- Jin, Xin
- Pool, John E.
- Xu, Xun
- Jiang, Hui
- Korneliussen, Thorfinn Sand
- Zheng, Hancheng
- Liu, Tao
- He, Weiming
- Luo, Ruibang
- Wu, Honglong
- Cao, Hongzhi
- Zou, Jing
- Shan, Ying
- Yang, Qi
- Tian, Geng
- Xu, Junming
- Liu, Xiao
- Wu, Renhua
- Zhou, Guangyu
- Tang, Meifang
- Qin, Junjie
- Wang, Tong
- Wang, Wei
- Chen, Fang
- Li, Zhuo
- Yang, Ge
- Tang, Shuhui
- Gao, Guoyi
- Luo, Zhen
- Gusang, Lamu
- Zhang, Qinghui
- Liang, Huiqing
- Bolund, Lars
- Kristiansen, Karsten
- Li, Yingrui
- Zhang, Yong
- Zhang, Xiuqing
- Li, Ruiqiang
- Li, Songgang
- Yang, Huanming
- Nielsen, Rasmus
- Wang, Jun
- Wang, Jian
- Venue
- Science
- Published
- 2010-07-02
- Volume
- 329
- Issue
- 5987
- Pages
- 75-78
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC3711608
- OpenAlex
- W2147575903
- Cited by
- 1,611
- References
- 35
- Citations by year
- 2026: 92 · 2025: 95 · 2024: 90 · 2023: 123 · 2022: 113 · 2021: 123 · 2020: 101 · 2019: 106 · 2018: 84 · 2017: 88 · 2016: 105 · 2015: 111 · 2014: 95 · 2013: 97 · 2012: 90
- FWCI
- 50.78
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- The HKU Scholars Hub (University of Hong Kong) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (124318)
- U.S. Public Health Service (R01-MHG084695)
- National Institute on Alcohol Abuse and Alcoholism (R21AA022707)
- National Institute of Mental Health (R01MH084695)
- National Human Genome Research Institute (R01HG003229)
- Topics
- Health Sciences › Medicine › Physiology (medical) › High Altitude and Hypoxia
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Keywords
- high-altitude adaptation, Tibetan Plateau, EPAS1, natural selection, hypoxia response, allele frequency change, single nucleotide polymorphisms, Han Chinese, population genomics, exome sequencing
- MeSH terms
- Acclimatization, Endothelial PAS Domain-Containing Protein 1, Altitude, Bayes Theorem, China, Erythrocyte Count, Ethnicity, Exons, Female, Gene Frequency, Hemoglobins, Humans, Male, Oxygen, Selection, Genetic, Genome, Human, Sequence Analysis, DNA, Tibet, Polymorphism, Single Nucleotide, Asian People, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Genetic Association Studies
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