Natural selection on EPAS1 ( HIF2α ) associated with low hemoglobin concentration in Tibetan highlanders
Open accessAbstract
By impairing both function and survival, the severe reduction in oxygen availability associated with high-altitude environments is likely to act as an agent of natural selection. We used genomic and candidate gene approaches to search for evidence of such genetic selection. First, a genome-wide allelic differentiation scan (GWADS) comparing indigenous highlanders of the Tibetan Plateau (3,200–3,500 m) with closely related lowland Han revealed a genome-wide significant divergence across eight SNPs located near EPAS1 . This gene encodes the transcription factor HIF2α, which stimulates production of red blood cells and thus increases the concentration of hemoglobin in blood. Second, in a separate cohort of Tibetans residing at 4,200 m, we identified 31 EPAS1 SNPs in high linkage disequilibrium that correlated significantly with hemoglobin concentration. The sex-adjusted hemoglobin concentration was, on average, 0.8 g/dL lower in the major allele homozygotes compared with the heterozygotes. These findings were replicated in a third cohort of Tibetans residing at 4,300 m. The alleles associating with lower hemoglobin concentrations were correlated with the signal from the GWADS study and were observed at greatly elevated frequencies in the Tibetan cohorts compared with the Han. High hemoglobin concentrations are a cardinal feature of chronic mountain sickness offering one plausible mechanism for selection. Alternatively, as EPAS1 is pleiotropic in its effects, selection may have operated on some other aspect of the phenotype. Whichever of these explanations is correct, the evidence for genetic selection at the EPAS1 locus from the GWADS study is supported by the replicated studies associating function with the allelic variants.
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Genetic variations in HIF2A, PHD2 and PPARA associate with lower hemoglobins in native Tibetans compared to Han Chinese and with high altitude adaptation in other populations.
“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 [175]
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Genomic Control for Association Studies
Devlin, B., & Roeder, K. (1999) · Biometrics · doi:10.1111/j.0006-341x.1999.00997.x · Cited by 3,162 · see citing works
Demonstrating stratification in a European American population
Campbell, C. D., Ogburn, E. L., Lunetta, K. L., Lyon, H. N., Freedman, M. L., Groop, L. C., Altshuler, D., Ardlie, K. G., & Hirschhorn, J. N. (2005) · Nature Genetics · doi:10.1038/ng1607 · Cited by 444 · see citing works
A Gain-of-Function Mutation in the <i>HIF2A</i> Gene in Familial Erythrocytosis
Percy, M. J., Furlow, P. W., Lucas, G. S., Li, X., Lappin, T. R. J., McMullin, M. F., & Lee, F. S. (2008) · New England Journal of Medicine · doi:10.1056/nejmoa073123 · Cited by 314 · see citing works
Gordeuk, V. R., Sergueeva, A. I., Miasnikova, G. Y., Okhotin, D., Voloshin, Y., Choyke, P. L., Butman, J. A., Jedlickova, K., Prchal, J. T., & Polyakova, L. A. (2004) · Blood · doi:10.1182/blood-2003-07-2535 · Cited by 273 · see citing works
Moore, L. G., Young, D., McCullough, R. E., Droma, T., & Zamudio, S. (2001) · American Journal of Human Biology · doi:10.1002/ajhb.1102 · Cited by 194 · see citing works
Gale, D. P., Harten, S. K., Reid, C. D. L., Tuddenham, E. G. D., & Maxwell, P. H. (2008) · Blood · doi:10.1182/blood-2008-04-153718 · Cited by 157 · see citing works
Pathophysiology and epidemiology of chronic mountain sickness
Monge-C, C., Arregui, A., & León-Velarde, F. (1992) · International Journal of Sports Medicine · doi:10.1055/s-2007-1024603 · Cited by 153 · cited 1× · see citing works
“Chronic mountain sickness remains at that low level throughout adulthood among Tibetans but, in Peruvians, prevalence increases with age from approximately 13% in 20 to 39 y olds to approximately 36% in 55 to 69 y olds at 4,300 m (47).”
BackgroundNovel exon 12 mutations in the HIF2A gene associated with erythrocytosis
Percy, M. J., Beer, P. A., Campbell, G., Dekker, A. W., Green, A. R., Oscier, D., Rainey, M. G., van Wijk, R., Wood, M., Lappin, T. R. J., et al. (2008) · Blood · doi:10.1182/blood-2008-02-137703 · Cited by 127 · see citing works
Chronic Mountain Sickness in Tibet
PEI, S. X., CHEN, X. J., SI REN, B. Z., LIU, Y. H., CHENG, X. S., HARRIS, E. M., ANAND, I. S., & C.HARRIS, P. (1989) · QJM: An International Journal of Medicine · doi:10.1093/oxfordjournals.qjmed.a068349 · Cited by 90 · see citing works
Flagged first, then by citations
Cited by
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Hypoxia-inducible factors in physiology and medicine
Semenza, G. L. (2012) · Cell · doi:10.1016/j.cell.2012.01.021 · Cited by 3,645 · see citing works
Hypoxia-inducible factors and the response to hypoxic stress
Majmundar, A. J., Wong, W. J., & Simon, M. C. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.09.022 · Cited by 2,380 · see citing works
Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA
Huerta-Sánchez, E., Jin, X., Asan, Bianba, Z., Peter, B. M., Vinckenbosch, N., Liang, Y., Yi, X., He, M., Somel, M., et al. (2014) · Nature · doi:10.1038/nature13408 · Cited by 1,208 · see citing works
Self-citationRegulation of erythropoiesis by hypoxia-inducible factors
Haase, V. H. (2013) · Blood Reviews · doi:10.1016/j.blre.2012.12.003 · Cited by 787 · see citing works
Tracing the peopling of the world through genomics
Nielsen, R., Akey, J. M., Jakobsson, M., Pritchard, J. K., Tishkoff, S., & Willerslev, E. (2017) · Nature · doi:10.1038/nature21347 · Cited by 728 · see citing works
High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq
Schödel, J., Oikonomopoulos, S., Ragoussis, J., Pugh, C. W., Ratcliffe, P. J., & Mole, D. R. (2011) · Blood · doi:10.1182/blood-2010-10-314427 · Cited by 724 · see citing works
Prabhakar, N. R., & Semenza, G. L. (2012) · Physiological Reviews · doi:10.1152/physrev.00030.2011 · Cited by 641 · see citing works
Evidence for archaic adaptive introgression in humans
Racimo, F., Sankararaman, S., Nielsen, R., & Huerta-Sánchez, E. (2015) · Nature Reviews Genetics · doi:10.1038/nrg3936 · Cited by 521 · see citing works
Chen, N., Cai, Y., Chen, Q., Li, R., Wang, K., Huang, Y., Hu, S., Huang, S., Zhang, H., Zheng, Z., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-04737-0 · Cited by 403 · see citing works
Self-citationGenetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism
Jain, I. H., Calvo, S. E., Markhard, A. L., Skinner, O. S., To, T.-L., Ast, T., & Mootha, V. K. (2020) · Cell · doi:10.1016/j.cell.2020.03.029 · Cited by 224 · see citing works
The HIF pathway and erythrocytosis
Lee, F. S., & Percy, M. J. (2011) · Annual Review of Pathology Mechanisms of Disease · doi:10.1146/annurev-pathol-011110-130321 · Cited by 177 · see citing works
Uterine artery blood flow, fetal hypoxia and fetal growth
Browne, V. A., Julian, C. G., Toledo-Jaldin, L., Cioffi-Ragan, D., Vargas, E., & Moore, L. G. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0068 · Cited by 127 · see citing works
Hypoxia: Adapting to High Altitude by Mutating <i>EPAS-1</i> , the Gene Encoding HIF-2α
Tissot van Patot, M. C., & Gassmann, M. (2011) · High Altitude Medicine & Biology · doi:10.1089/ham.2010.1099 · Cited by 119 · see citing works
The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions
Mastrogiannaki, M., Matak, P., & Peyssonnaux, C. (2013) · Blood · doi:10.1182/blood-2012-11-427765 · Cited by 116 · see citing works
Human evolution: a tale from ancient genomes
Llamas, B., Willerslev, E., & Orlando, L. (2017) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2015.0484 · Cited by 100 · see citing works
Goldstein, D. S. (2019) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00396.2018 · Cited by 96 · see citing works
Signatures of archaic adaptive introgression in present-day human populations
Racimo, F., Marnetto, D., & Huerta-Sánchez, E. (2016) · doi:10.1101/045237 · Cited by 200 · see citing works
Hypoxia, AMPK activation and uterine artery vasoreactivity
Skeffington, K. L., Higgins, J. S., Mahmoud, A. D., Evans, A. M., Sferruzzi‐Perri, A. N., Fowden, A. L., Yung, H. W., Burton, G. J., Giussani, D. A., & Moore, L. G. (2016) · The Journal of Physiology · doi:10.1113/jp270995 · Cited by 69 · see citing works
Verma, P., Sharma, A., Sodhi, M., Thakur, K., Kataria, R. S., Niranjan, S. K., Bharti, V. K., Kumar, P., Giri, A., Kalia, S., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-25736-7 · Cited by 63 · see citing works
Mastrogiannaki, M., Matak, P., Delga, S., Deschemin, J.-C., Vaulont, S., & Peyssonnaux, C. (2012) · Blood · doi:10.1182/blood-2011-09-380337 · Cited by 57 · see citing works
Tissot van Patot, M. C., Ebensperger, G., Gassmann, M., & Llanos, A. J. (2012) · High Altitude Medicine & Biology · doi:10.1089/ham.2012.1046 · Cited by 45 · see citing works
Two new mutations in the <i>HIF2A</i> gene associated with erythrocytosis
Percy, M. J., Chung, Y. J., Harrison, C., Mercieca, J., Hoffbrand, A. V., Dinardo, C. L., Santos, P. C. J. L., Fonseca, G. H. H., Gualandro, S. F. M., Pereira, A. C., et al. (2012) · American Journal of Hematology · doi:10.1002/ajh.23123 · Cited by 37 · see citing works
Human Evolution: Genomic Gifts from Archaic Hominins
Vernot, B., & Akey, J. M. (2014) · Current Biology · doi:10.1016/j.cub.2014.07.079 · Cited by 13 · see citing works
Zanoaga, M.-D., Cavinato, T., Latrille, T., Liska, O., Schoeler, T., Papp, B., & Kutalik, Z. (2026) · doi:10.64898/2026.10.16.759432
- Authors
- Beall, C. M., Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., Li, C., Li, J. C., Liang, Y., McCormack, M., Montgomery, H. E., Pan, H., Robbins, P. A., Shianna, K. V., Tam, S. C., Tsering, N., Veeramah, K. R., Wang, W., Wangdui, P., Weale, M. E., Xu, Y., Xu, Z., Yang, L., Zaman, M. J., Zeng, C., Zhang, L., Zhang, X., Zhaxi, P., & Zheng, Y. T.
- Affiliations
- Case Western Reserve University (US)
- Royal College of Surgeons in Ireland (IE)
- Chinese Academy of Sciences (CN)
- National Health Service (GB)
- Yunnan Population and Family Planning Research Institute (CN)
- BGI Group (China) (CN)
- University College London (GB)
- University of Oxford (GB)
- Duke University (US)
- Chinese University of Hong Kong (HK)
- Tibetan Academy of Social Science (CN)
- University of California, Los Angeles (US)
- Guy's Hospital (GB)
- Cleveland Clinic (US)
- Kunming Institute of Zoology (CN)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-06-07
- Volume
- 107
- Issue
- 25
- Pages
- 11459-11464
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2895075
- OpenAlex
- W2062818316
- Cited by
- 845
- References
- 9
- Citations by year
- 2026: 50 · 2025: 54 · 2024: 39 · 2023: 65 · 2022: 34 · 2021: 62 · 2020: 54 · 2019: 53 · 2018: 47 · 2017: 54 · 2016: 56 · 2015: 69 · 2014: 61 · 2013: 54 · 2012: 42
- FWCI
- 26.29
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Lancaster EPrints (Lancaster University) (submittedVersion)
- Figshare (submittedVersion, cc-by-nc-nd)
- Research Portal (King's College London) (submittedVersion)
- Funders
- National Science Foundation
- National Evolutionary Synthesis Center
- Royal Society
- National Natural Science Foundation of China (30890031)
- Chinese Academy of Sciences (KSCX2-YW-R)
- National Institutes of Health
- Beijing Institute of Genomics, Chinese Academy of Sciences
- National Heart, Lung, and Blood Institute
- National Cancer Institute
- National Institute of General Medical Sciences
- National Center for Research Resources
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › High Altitude and Hypoxia
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Physical Performance
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Keywords
- EPAS1, HIF-2α, natural selection, high altitude, Tibetan highlanders, hemoglobin levels, chronic mountain sickness, single nucleotide polymorphisms, linkage disequilibrium, Tibetan Plateau, Han Chinese, erythropoiesis
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Alleles, Altitude, Altitude Sickness, Hypoxia, Hemoglobins, Homozygote, Humans, Selection, Genetic, Genetic Variation, Linkage Disequilibrium, Genome, Human, Tibet, Polymorphism, Single Nucleotide, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins
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