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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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BackgroundResultRapid Intrahost Evolution of Human Cytomegalovirus Is Shaped by Demography and Positive Selection
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The Mosaic Genome of Indigenous African Cattle as a Unique Genetic Resource for African Pastoralism
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Andean and Tibetan patterns of adaptation to high altitude
Bigham, A. W., Wilson, M. J., Julian, C. G., Kiyamu, M., Vargas, E., Lèon‐Velarde, F., Rivera, M. C., Rodriquez, C., Browne, V. A., Parra, E. J., et al. (2013) · American Journal of Human Biology · doi:10.1002/ajhb.22358 · Cited by 142
Genetic determinants of Tibetan high-altitude adaptation
Simonson, T. S., McClain, D. A., Jorde, L. B., & Prchal, J. T. (2011) · Human Genetics · doi:10.1007/s00439-011-1109-3 · Cited by 143
Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans
Crawford, J. E., Amaru, R., Song, J., Julian, C. G., Racimo, F., Cheng, J. Y., Guo, X., Yao, J., Ambale‐Venkatesh, B., Lima, J. A. C., et al. (2017) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2017.09.023 · Cited by 142
“found no statistical evidence supporting introgression similarly to that observed in studies of TBX15 in Inuit(46) or EPAS1 in Tibetans.(18)”
ResultInfluentialSelf-citationLi, Y., Xu, X., Song, L., Hou, Y., Li, Z., Tsang, S. X., Li, F., McGee, K., Wu, K., Wu, H., et al. (2012) · GigaScience · doi:10.1186/2047-217x-1-12 · Cited by 136
“Instead of utilizing a Bayesian estimation-based method called site-frequency spectrum (SFS) on population individuals [10], we used this SFS to calculate the somatic allele frequency in each SM site of all BC and BN cells respectively, based on the same methods of estimating allele frequencies from reads in one site…”
MethodSelf-citationGenetic evidence for natural selection in humans in the contemporary United States
Beauchamp, J. P. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1600398113 · Cited by 138
“However, new evidence that has been accumulating over the last decade suggests that natural selection has been operating in humans over the past few thousand years (2–4) and that a number of adaptations—such as lactase persistence (5), resistance to malaria (6), and adaptation to high altitude (7)—have occurred relati…”
BackgroundCreating artificial human genomes using generative neural networks
Yelmen, B., Decelle, A., Ongaro, L., Marnetto, D., Tallec, C., Montinaro, F., Furtlehner, C., Pagani, L., & Jay, F. (2021) · PLoS Genetics · doi:10.1371/journal.pgen.1009303 · Cited by 148
Li, S., Li, B., Cheng, C., Xiong, Z., Liu, Q., Lai, J., Carey, H. V., Zhang, Q., Zheng, H., Wei, S., et al. (2014) · Genome biology · doi:10.1186/s13059-014-0557-1 · Cited by 148
Self-citationExome Sequencing Identifies PDE4D Mutations in Acrodysostosis
Lee, H., Graham, J. M., Rimoin, D. L., Lachman, R. S., Krejčı́, P., Tompson, S. W. J., Nelson, S. F., Krakow, D., & Cohn, D. H. (2012) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2012.03.004 · Cited by 136
Petousi, N., Croft, Q. P. P., Cavalleri, G. L., Cheng, H., Formenti, F., Ishida, K., Lunn, D., McCormack, M., Shianna, K. V., Talbot, N. P., et al. (2013) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00535.2013 · Cited by 139
“Some of these reports demonstrated a correlation of genetic variation in these genes with hemoglobin concentration, such that among Tibetan natives, the putative selected haplotype in each gene is associated with lower hemoglobin concentration at high altitude (5, 36, 44).”
BackgroundResultComparative genomic investigation of high-elevation adaptation in ectothermic snakes
Li, J., Gao, Y., Xie, L., Deng, C., Shi, P., Guan, M.-L., Huang, S., Ren, J., Wu, D., Ding, L., et al. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1805348115 · Cited by 132
“EPAS1, one of the six members of the HIF superfamily, has been demonstrated to be under selection for adaptation to hypoxia at high elevations in Tibetan mammalian species, including humans (6, 36) and the Tibetan Mastiff (37).”
BackgroundSelf-citationTime Domains of the Hypoxic Ventilatory Response and Their Molecular Basis
Pamenter, M. E., & Powell, F. L. (2016) · Comprehensive physiology · doi:10.1002/cphy.c150026 · Cited by 169
“Both of these studies reported divergence of the endothelial Per-Arnt-Sim domain protein 1 ( EPAS1 ) gene, which is also known as HIF-2 α (23, 427), and which regulates the induction of erythropoiesis by hypoxia (334).”
Population Variation Revealed High-Altitude Adaptation of Tibetan Mastiffs
Li, Y., Wu, D., Boyko, A. R., Wang, G., Wu, S., Irwin, D. M., & Zhang, Y. (2014) · Molecular Biology and Evolution · doi:10.1093/molbev/msu070 · Cited by 136
“Research on multiple species has revealed the identity of various candidate genes that may contribute to high-altitude adaptation, including studies on humans (Bigham et al. 2009; Beall et al. 2010; Simonson et al. 2010; Yi et al. 2010; Peng et al. 2011; Xu et al. 2011; Scheinfeldt et al. 2012; Xiang et al. 2013), dee…”
BackgroundInfluentialSelf-citationGenetics of human origin and evolution: high-altitude adaptations
Bigham, A. W. (2016) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2016.06.018 · Cited by 141
“Both genes exhibit compelling evidence of natural selection and variants in these genes contribute to the low hemoglobin concentrations observed among Tibetans [4,10,29].”
BackgroundThe Genomics and Genetics of Oxygen Homeostasis
Semenza, G. L. (2020) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-111119-073356 · Cited by 139
“F or p er so na l u se o nl y. formed an extended haplotype with a frequency of 46% in Tibetans and 2% in Han Chinese, and these were the only SNPs with P values 5 × 10−7, the threshold for genome-wide significance (4).”
BackgroundInfluentialHigh-Altitude Adaptation: Mechanistic Insights from Integrated Genomics and Physiology
Storz, J. F. (2021) · Molecular Biology and Evolution · doi:10.1093/molbev/msab064 · Cited by 140
“Compared with High-Altitude Adaptation . doi:10.1093/molbev/msab064 MBE a reference panel of control SNPs, the EPAS1 variants associated with low Hb concentration were present at a significantly higher frequency in Tibetans than in lowland reference populations.”
BackgroundResultInfluentialZhou, D., Udpa, N., Ronen, R., Stobdan, T., Liang, J., Appenzeller, O., Zhao, H. W., Yin, Y., Du, Y., Guo, L., et al. (2013) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2013.07.011 · Cited by 129
Self-citationZhao, Z., Xu, J., Chen, J., Kim, S., Reimers, M., Bacanu, S., Yu, H., Liu, C., Sun, J., Wang, Q., et al. (2014) · Molecular Psychiatry · doi:10.1038/mp.2014.82 · Cited by 132
Self-citationBorda, V., Alvim, I., Mendes, M., Silva-Carvalho, C., Soares-Souza, G. B., Leal, T. P., Furlan, V., Scliar, M. O., Zamudio, R., Zolini, C., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2013773117 · Cited by 54
“Natural selection scans were performed using population branch statistics (41, 83) and xpEHH from the package Selscan (42, 84).”
Methodvon Seth, J., Dussex, N., Díez‐del‐Molino, D., van der Valk, T., Kutschera, V. E., Kierczak, M., Steiner, C., Liu, S., Gilbert, M. T. P., Sinding, M. S., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22386-8 · Cited by 137
“Because of this, we also estimated population branch statistic (PBS) scores, which have been shown to have a high power to detect recent natural selection 49 and should not be confounded by deleterious mutations.”
BackgroundMethodGenetic substructure and complex demographic history of South African Bantu speakers
Sengupta, D., Choudhury, A., Fortes-Lima, C., Aron, S., Whitelaw, G., Bostoen, K. A. G., Gunnink, H., Chousou‐Polydouri, N., Delius, P., Tollman, S. M., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-22207-y · Cited by 129
The role of nitrogen oxides in human adaptation to hypoxia
Levett, D. Z. H., Fernandez, B. O., Riley, H. L., Martín, D., Mitchell, K., Leckstrom, C. A., İnce, C., Whipp, B. J., Mythen, M. G., Montgomery, H., et al. (2011) · Scientific Reports · doi:10.1038/srep00109 · Cited by 125
Physiology and pathophysiology of renal erythropoietin-producing cells
Shih, H., Wu, C., & Lin, S. (2018) · Journal of the Formosan Medical Association · doi:10.1016/j.jfma.2018.03.017 · Cited by 140
Suresh, K. S., & Shimoda, L. A. (2016) · Comprehensive physiology · doi:10.1002/cphy.c140049 · Cited by 174
“Indeed, a loss-of-function mutation in the Hif2a gene was identified in Tibetans and found to correlate with reduced P PA (42,58,583,644,716).”
Cognitive Impairments at High Altitudes and Adaptation
Yan, X. (2014) · High Altitude Medicine & Biology · doi:10.1089/ham.2014.1009 · Cited by 128
Selection signature analysis reveals genes associated with tail type in Chinese indigenous sheep
Yuan, Z., Liu, E., Liu, Z., Kijas, J., Zhu, C., Hu, S., Ma, X., Zhang, L., Du, L., Wang, H., et al. (2016) · Animal Genetics · doi:10.1111/age.12477 · Cited by 131
“Some well-known genes, such as EPAS1 (a hypoxia pathway gene) (Beall et al. 2010; Yi et al. 2010; Peng et al. 2011; Wang et al. 2011; Xu et al. 2011; Jeong et al. 2014) and EGLN1 (Xu et al. 2011; Jeong et al. 2014), are linked to high-altitude adaptations in Tibetans.”
BackgroundThe Genomics of Human Local Adaptation
Rees, J., Castellano, S., & Andrés, A. M. (2020) · Trends in Genetics · doi:10.1016/j.tig.2020.03.006 · Cited by 132
Regulation of hypoxia‐inducible factor in kidney disease
Nangaku, M., Rosenberger, C., Heyman, S. N., & Eckardt, K. (2012) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.12005 · Cited by 130
Finding the lost treasures in exome sequencing data
Samuels, D. C., Han, L., Li, J., Sheng, Q., Clark, T. A., Shyr, Y., & Guo, Y. P. (2013) · Trends in Genetics · doi:10.1016/j.tig.2013.07.006 · Cited by 126
“Although the role of introns was unclear for many years, several studies have now established some functional significance for introns [11,16–19].”
BackgroundMethodInfluentialSelf-citationGenomic regions under selection in the feralization of the dingoes
Zhang, S., Wang, G., Ma, P., Zhang, L., Yin, T., Yan-hu, L., Otecko, N. O., Wang, M., Ma, Y., Wang, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14515-6 · Cited by 130
Self-citationA sheep pangenome reveals the spectrum of structural variations and their effects on tail phenotypesPreprint
Li, R., Gong, M., Zhang, X., Wang, F., Liu, Z., Zhang, L., Yang, Q., Xu, Y., Xu, M., Zhang, H., et al. (2023) · Genome Research · doi:10.1101/gr.277372.122 · Cited by 125
Self-citationKardos, M. D., Luikart, G., Bunch, R. J., Dewey, S. R., Edwards, W. H., McWilliam, S. M., Stephenson, J., Allendorf, F. W., Hogg, J. T., & Kijas, J. (2015) · Molecular Ecology · doi:10.1111/mec.13415 · Cited by 125
Towards Privacy Preserving IoT Environments: A Survey
Seliem, M., Elgazzar, K., & Khalil, K. (2018) · Wireless Communications and Mobile Computing · doi:10.1155/2018/1032761 · Cited by 127
“Wang [101] presents a nonlinear key algorithm based on displaced calculation to provide data encryption.”
BackgroundConvergent genomic signatures of high-altitude adaptation among domestic mammals
Wu, D., Yang, C., Wang, M., Dong, K., Yan, D., Hao, Z.-Q., Fan, S., Chu, S., Shen, Q., Jiang, L., et al. (2019) · National Science Review · doi:10.1093/nsr/nwz213 · Cited by 130
“Tibetans were found to exhibit characteristics contributing to improved hypoxic and hypercapnic ventilatory responsiveness including larger lung volumes, better pulmonary function, and greater lung diffusing capacity (Wu and Kayser 2006).”
BackgroundInfluentialSelf-citationA beginners guide to SNP calling from high-throughput DNA-sequencing data
Altmann, A., Weber, P., Bader, D. M., Preuss, M. H., Binder, E. B., & Müller-Myhsok, B. (2012) · Human Genetics · doi:10.1007/s00439-012-1213-z · Cited by 138
Glucose Homeostasis During Short-term and Prolonged Exposure to High Altitudes
Woolcott, O. O., Ader, M., & Bergman, R. N. (2015) · Endocrine Reviews · doi:10.1210/er.2014-1063 · Cited by 129
Selection and Adaptation in the Human Genome
Fu, W., & Akey, J. M. (2013) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev-genom-091212-153509 · Cited by 129
“The analysis of additional, typically understudied populations that have experienced unique environments obviously may still reveal novel loci that have been subject to classic selective sweeps [such as EPAS1 in Tibetans (163)], but such loci are likely to be the exception rather than the rule.”
BackgroundInfluentialWidespread phenotypic and genetic divergence along altitudinal gradients in animals
Keller, I., Alexander, J. M., Holderegger, R., & Edwards, P. J. (2013) · Journal of Evolutionary Biology · doi:10.1111/jeb.12255 · Cited by 125
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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