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Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude
Open accessAbstract
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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BackgroundGenetic adaptation of skin pigmentation in highland Tibetans
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BackgroundCPT1A Missense Mutation Associated With Fatty Acid Metabolism and Reduced Height in Greenlanders
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MethodSelf-citationNext-generation sequencing applied to molecular diagnostics
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“Ge tive selecton for three HIF pathway related genes, ADAM17, the genome of yak ( [5,6,7].”
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“A careful reappraisal of six recent genome-wide scans in highland Tibetans and Andeans (Beall et al. 2010; Bigham et al. 2010; Simonson et al. 2010; Yi et al. 2010; Peng et al. 2011; Xu et al. 2011) together with the current adaptation study for lowland and moderate-altitude Eurasian populations, we identified EGLN1 a…”
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BackgroundHigh altitude adaptation in Daghestani populations from the Caucasus
Pagani, L., Ayub, Q., MacArthur, D. G., Xue, Y., Baillie, J. K., Chen, Y., Kozarewa, I., Turner, D. J., Tofanelli, S., Bulayeva, K., et al. (2011) · Human Genetics · doi:10.1007/s00439-011-1084-8 · Cited by 40
“Worldwide, three sets of populations living at high altitudes have received most attention: the Ethiopian highlanders, the Himalayan Sherpa and Tibetans, and the Andean Quechua and Aymaras (Moore 2001; Rupert and Hochachka 2001; Suzuki et al. 2003; Rajput et al. 2006; Zhang et al. 2006; Beall 2007; Erzurum et al. 2007…”
BackgroundInfluentialSelf-citationRu, D., Mao, K., Zhang, L., Wang, X., Lu, Z., & Sun, Y. (2016) · Molecular Ecology · doi:10.1111/mec.13656 · Cited by 38
“We calculated the Population Branch Statistic (PBS) for each locus (Yi et al. 2010) and examined whether some introgressed loci showed a high level of PBS based on the data set of P. likiangensis var. rubescens and var. likiangensis, and P. brachytyla var. complanata.”
MethodSelf-citationThe impact of genetic adaptation on chimpanzee subspecies differentiation
Schmidt, J. M., de Manuel, M., Marquès‐Bonet, T., Castellano, S., & Andrés, A. M. (2019) · PLoS Genetics · doi:10.1371/journal.pgen.1008485 · Cited by 35
“The Population Branch Statistic (PBS), [8] is a test of population specific natural selection.”
BackgroundMethodInfluentialDistinct Patterns of Selective Sweep and Polygenic Adaptation in Evolve and Resequence Studies
Barghi, N., & Schlötterer, C. (2020) · Genome Biology and Evolution · doi:10.1093/gbe/evaa073 · Cited by 39
Denisovans and Homo sapiens on the Tibetan Plateau: dispersals and adaptations
Zhang, P., Zhang, X., Zhang, X., Gao, X., Huerta‐Sánchez, E., & Zwyns, N. (2021) · Trends in Ecology & Evolution · doi:10.1016/j.tree.2021.11.004 · Cited by 41
Self-citationTracing Bai-Yue Ancestry in Aboriginal Li People on Hainan Island
Chen, H., Lin, R., Lü, Y., Zhang, R., Gao, Y., He, Y., & Xu, S. (2022) · Molecular Biology and Evolution · doi:10.1093/molbev/msac210 · Cited by 32
“Local Adaptation To investigate the potential population-specific adaptation of HNL.Main, we applied population branch statistics (PBS; Yi et al. 2010) to perform a genome-wide scan using the Han and CEU as the ingroup and outgroup reference populations, respectively.”
MethodInfluentialHe, G., Yao, H., Duan, S., Luo, L., Sun, Q., Tang, R., Chen, J., Wang, Z., Sun, Y., Li, X., et al. (2025) · Science China Life Sciences · doi:10.1007/s11427-024-2748-4 · Cited by 41
“We applied the PBS approach (Yi et al., 2010) to detect the signals of natural selection in NWCM populations.”
50,000 years of evolutionary history of India: Impact on health and disease variation
Kerdoncuff, E., Skov, L., Patterson, N., Banerjee, J., Khobragade, P., Chakrabarti, S. S., Chakrawarty, A., Chatterjee, P., Dhar, M., Gupta, M., et al. (2025) · Cell · doi:10.1016/j.cell.2025.04.027 · Cited by 36
Self-citationCardiovascular function in healthy Himalayan high-altitude dwellers
Bruno, R. M., Cogo, A., Ghiadoni, L., Duo, E., Pomidori, L., Sharma, R. K., Thapa, G. B., Basnyat, B., Bartesaghi, M., Picano, E., et al. (2014) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2014.06.017 · Cited by 36
“High-altitude natives, such as Tibetans and Nepalese Sherpa, developed genetic adaptations to their hypoxic environment, as recently demonstrated [25,26].”
BackgroundGene Polymorphisms and High-Altitude Pulmonary Edema Susceptibility: A 2011 Update
Luo, Y., Zou, Y., & Gao, Y. (2012) · Respiration · doi:10.1159/000336625 · Cited by 37
Elevation of Circulating miR-210-3p in High-Altitude Hypoxic Environment
Yan, Y., Wang, C., Zhou, W., Shi, Y., Guo, P.-T., Liu, Y., Wang, J., Zhang, C., & Zhang, C. (2016) · Frontiers in Physiology · doi:10.3389/fphys.2016.00084 · Cited by 36
“Further, the ability of Tibetans to adapt well to high altitude hypoxic environments might be a result of natural selection (Yi et al., 2010; Huerta-Sánchez et al., 2014).”
BackgroundSelf-citationHypoxiaDB: a database of hypoxia-regulated proteins
Khurana, P., Sugadev, R., Jain, J., & Singh, S. B. (2013) · Database · doi:10.1093/database/bat074 · Cited by 36
Human Adaptation to Climate: Temperature, Ultraviolet Radiation, and Altitude
Beall, C. M., Jablonski, N. G., & Steegmann, A. T. (2012) · Human Biology · doi:10.1002/9781118108062.ch6 · Cited by 37
Genomic adaptation of Ethiopian indigenous cattle to high altitude
Terefe, E., Belay, G., Han, J., Hanotte, O., & Tijjani, A. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.960234 · Cited by 37
“PBS analysis was employed to detect genomic regions under selection with highly divergent haplotypes (Yi et al., 2010).”
MethodShi, J., Jia, Z., Sun, J., Wang, X.-R., Zhao, X., Zhao, C., Liang, F., Song, X., Guan, J., Xue, J., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-44034-z · Cited by 37
“The adaptation of Tibetans to high altitude provides an ideal model for studying adaptation during the evolutionary history of modern humans, given its well-controlled context 8 – 12 , but this adaptation remains insuf fi ciently studied at the population scale.”
BackgroundMethodSelf-citationZhao, H., Sun, L., Liu, J., Shi, B., Zhang, Y., Qu‐zong, C., Dorji, T., Wang, T., Yuan, H., & Yang, J. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2350151 · Cited by 37
Self-citationAncient genomics and the origin, dispersal, and development of domestic sheep
Daly, K. G., Mullin, V. E., Hare, A. J., Halpin, Á., Mattiangeli, V., Teasdale, M. D., Rossi, C., Geiger, S., Krebs, S., Međugorac, I., et al. (2025) · Science · doi:10.1126/science.adn2094 · Cited by 39
Xu, J., Yang, Y., Tang, F., Ga, Q., Wuren, T., & Ge, R. (2015) · Wilderness and Environmental Medicine · doi:10.1016/j.wem.2015.01.002 · Cited by 35
“17 The human EPAS1 gene is located on chromosome 2p21 – p16 and encodes the oxygen-sensitive alpha subunit of HIF-2, which is a key regulator of chronic hypoxia by regulating a large number of genes involved in the cellular and systemic responses to hypoxia.”
BackgroundSelf-citationZhan, X., Dixon, A., Batbayar, N., Bragin, E. A., Ayaş, Z., Deutschová, L., Chavko, J., Domashevsky, S., Doroşencu, A., Bagyura, J., et al. (2014) · Heredity · doi:10.1038/hdy.2014.59 · Cited by 38
“MC1R amplifications were conducted as described in Zhan et al. (2012).”
BackgroundMethodHuang, Y., Ochieng, J. K., Kempen, M. B., Munck, A. B., Swagemakers, S. M. A., van IJcken, W. F. J., Grosveld, F. G., Tibboel, D., & Rottier, R. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057695 · Cited by 37
“Recently, the EPAS1 gene, encoding for HIF2a, was shown to be associated with adaptation of living at high altitude [73,74,75,76].”
BackgroundSelf-citationA Comprehensive MicroRNA Expression Profile Related to Hypoxia Adaptation in the Tibetan Pig
Zhang, B., Qiangba, Y., Shang, P., Wang, Z., Ma, J., Wang, L., & Zhang, H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0143260 · Cited by 36
“Both EPAS1 and EGLN1 are closely associated with the high-altitude adaptation of Tibetan populations [37], and are involved in hypoxia pathways as key regulators during chronic hypoxia [52].”
BackgroundDeep History of East Asian Populations Revealed Through Genetic Analysis of the Ainu
Jeong, C., Nakagome, S., & Rienzo, A. D. (2015) · Genetics · doi:10.1534/genetics.115.178673 · Cited by 33
“Then, we prioritized windows with binomial P # 0.01 for both XP-EHH and PBS and merged adjacent windows.”
MethodInfluentialEvidence for positive selection on recent human transposable element insertions
Rishishwar, L., Wang, L., Wang, J., Yi, S. V., Lachance, J., & Jordan, I. K. (2018) · Gene · doi:10.1016/j.gene.2018.06.077 · Cited by 37
Self-citationFrom Summary Statistics to Gene Trees: Methods for Inferring Positive Selection
Hejase, H. A., Dukler, N., & Siepel, A. C. (2020) · Trends in Genetics · doi:10.1016/j.tig.2019.12.008 · Cited by 36
Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes
Childebayeva, A., Goodrich, J. M., Lèon‐Velarde, F., Rivera, M. C., Kiyamu, M., Brutsaert, T. D., Dolinoy, D. C., & Bigham, A. W. (2020) · Genome Biology and Evolution · doi:10.1093/gbe/evaa239 · Cited by 37
“First, our previous work (Childebayeva et al. 2019) demonstrated that Quechua individuals born and raised at low versus high altitude have significant differences in DNA methylation of the repetitive element LINE1 and the gene EPAS1, a well-known high-altitude adaptive gene that has been shown to be under genetic sele…”
BackgroundInfluentialArchaic inheritance: supporting high-altitude life in Tibet
Huerta‐Sánchez, E., & Casey, F. (2015) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00322.2015 · Cited by 35
Identification of Multiple Loci Associated with Social Parasitism in Honeybees
Wållberg, A., Pirk, C. W. W., Allsopp, M. H., & Webster, M. T. (2016) · PLoS Genetics · doi:10.1371/journal.pgen.1006097 · Cited by 33
Schlötterer, C. (2023) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2022.0046 · Cited by 37
Genomic structural variation is associated with hypoxia adaptation in high-altitude zokors
An, X., Mao, L., Wang, Y., Xu, Q., Liu, X., Zhang, S., Qiao, Z., Li, B., Li, F., Kuang, Z., et al. (2024) · Nature Ecology & Evolution · doi:10.1038/s41559-023-02275-7 · Cited by 34
Self-citationHypoxia causes reductions in birth weight by altering maternal glucose and lipid metabolism
Määttä, J., Sissala, N., Dimova, E. Y., Serpi, R., MOORE, L. G., & Koivunen, P. (2018) · Scientific Reports · doi:10.1038/s41598-018-31908-2 · Cited by 34
Limited evidence for selection at the FADS locus in Native American populations
Mathieson, I. (2020) · Molecular Biology and Evolution · doi:10.1093/molbev/msaa064 · Cited by 34
Detecting adaptive trait loci in nonmodel systems: divergence or admixture mapping?
Crawford, J. E., & Nielsen, R. (2013) · Molecular Ecology · doi:10.1111/mec.12562 · Cited by 34
“…from both theory and empirical evidence that adaptation to novel environmental factors across heterogeneous environments is a major evolutionary force generating and maintaining phenotypic divergence (Fisher 1930; Haldane 1930; Lewontin & Krakauer 1973; Kaufman 1974; Via 1991; Yi et al. 2010).”
BackgroundSelf-citationLiu, X., Cai, X., Hu, B., Mei, Z., Zhang, D., Ouyang, G., Wang, J., Zhang, W., & Xiao, W. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.745471 · Cited by 34
“On the other hand, change of the allele resulting in gain of function has also been suggested to respond to either hypoxic adaptation or hypoxic sensitivity (56, 57).”
BackgroundSelf-citationGenomic Approaches in Landscape Genetics
Storfer, A. T., Antolin, M. F., Manel, S., Epperson, B. K., & Scribner, K. T. (2015) · Wiley eBooks · doi:10.1002/9781118525258.ch09 · Cited by 34
Genomic and functional evidence reveals convergent evolution in fishes on the Tibetan Plateau
Yang, L., Wang, Y., Sun, N., Chen, J., & He, S. (2021) · Molecular Ecology · doi:10.1111/mec.16171 · Cited by 33
“…years with the rapid progress in high- throughput sequencing, including mammals (Beall, 2007; Ge et al., 2013; Li et al., 2014; Qiu et al., 2012; Yi et al., 2010), birds (Cai et al., 2013; Hao et al., 2019; Qu et al., 2013), ectotherms (Li et al., 2018; Liu et al., 2018, 2019; Ma et al., 2015;…”
Self-citationIncreased blood‐oxygen binding affinity in Tibetan and Han Chinese residents at 4200 m
Simonson, T. S., Wei, G., Wagner, H. E., Wuren, T., Bui, A., Fine, J. M., Ga, Q., Beltrami, F. G., Ma, Y., Wagner, P. D., et al. (2014) · Experimental Physiology · doi:10.1113/expphysiol.2014.080820 · Cited by 32
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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