Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data
Open accessAbstract
High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.
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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 [179]
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Cites
Controlling the False Discovery Rate: A Practical and Powerful Approach to Multiple Testing
Benjamini, Y., & Hochberg, Y. (1995) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1995.tb02031.x · Cited by 109,482 · see citing works
PLINK: a tool set for whole-genome association and population-based linkage analyses.
Purcell, S., Neale, B., Todd-Brown, K., Thomas, L., Ferreira, M. A. R., Bender, D., Maller, J., Sklar, P., de Bakker, P. I. W., Daly, M. J., et al. (2007) · The American Journal of Human Genetics · doi:10.1086/519795 · Cited by 34,089 · see citing works
Jaakkola, P., Mole, D. R., Tian, Y.-M., Wilson, M. I., Gielbert, J., Gaskell, S. J., Kriegsheim, A. V., Hebestreit, H. F., Mukherji, M., Schofield, C. J., et al. (2001) · Science · doi:10.1126/science.1059796 · Cited by 5,535 · see citing works
Self-citationIvan, M., Kondo, K., Yang, H., Kim, W., Valiando, J., Ohh, M., Salic, A., Asara, J. M., Lane, W. S., & Kaelin Jr., W. G. (2001) · Science · doi:10.1126/science.1059817 · Cited by 4,735 · see citing works
Convergent adaptation of human lactase persistence in Africa and Europe
Tishkoff, S. A., Reed, F. A., Ranciaro, A., Voight, B. F., Babbitt, C. C., Silverman, J. S., Powell, K., Mortensen, H. M., Hirbo, J. B., Osman, M., et al. (2007) · Nature Genetics · doi:10.1038/ng1946 · Cited by 1,615 · see citing works
Characterization of the human prolyl 4-hydroxylases that modify the hypoxia-inducible factor
Hirsilä, M., Koivunen, P., Günzler, V., Kivirikko, K. I., & Myllyharju, J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m304982200 · Cited by 794 · see citing works
Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias
Weatherall, D. J. (2001) · Nature Reviews Genetics · doi:10.1038/35066048 · Cited by 692 · see citing works
Genetic evidence for the convergent evolution of light skin in Europeans and East Asians
Norton, H. L., Kittles, R. A., Parra, E., McKeigue, P., Mao, X., Cheng, K., Canfield, V. A., Bradley, D. G., McEvoy, B., & Shriver, M. D. (2006) · Molecular Biology and Evolution · doi:10.1093/molbev/msl203 · Cited by 410 · cited 6× · see citing works
“For example, at a threshold of 0.9 (240,969 SNPs) the gap between Europeans and Indigenous Americans is partially reduced (in fact this axis switches from PC1 to PC2).”
BackgroundInfluentialSelf-citationJulian, C. G., Wilson, M. J., Lopez, M., Yamashiro, H., Tellez, W., Rodriguez, A., Bigham, A. W., Shriver, M. D., Rodriguez, C., Vargas, E., et al. (2009) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.90945.2008 · Cited by 141 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
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
Finding the genomic basis of local adaptation: pitfalls, practical solutions, and future directions
Hoban, S., Kelley, J. L., Lotterhos, K. E., Antolin, M. F., Bradburd, G., Lowry, D. B., Poss, M. L., Reed, L. K., Storfer, A., & Whitlock, M. C. (2016) · The American Naturalist · doi:10.1086/688018 · Cited by 876 · see citing works
“A number of studies have found nonparallel adaptation (Tif fi n and Ross-Ibarra 2014), including drug resistance in malaria (Anderson and Roper 2005; Pearce et al. 2009), high-elevation adaptation in humans (Bigham et al. 2010), and melanism in deer mice (Kingsley et al. 2009).”
Regulation 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
Self-citationEvidence 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
The genetics of Mexico recapitulates Native American substructure and affects biomedical traits
Moreno-Estrada, A., Gignoux, C. R., Fernández-López, J. C., Zakharia, F., Sikora, M., Contreras, A. V., Acuña-Alonzo, V., Sandoval, K., Eng, C., Romero-Hidalgo, S., et al. (2014) · Science · doi:10.1126/science.1251688 · Cited by 478 · 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
Humans at high altitude: Hypoxia and fetal growth
Moore, L. G., Charles, S. M., & Julian, C. G. (2011) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2011.04.017 · Cited by 251 · see citing works
Self-citationUterine 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
Self-citationIndirect evolution of hybrid lethality due to linkage with selected locus in Mimulus guttatus
Wright, K. M., Lloyd, D., Lowry, D. B., Macnair, M. R., & Willis, J. H. (2013) · PLoS Biology · doi:10.1371/journal.pbio.1001497 · Cited by 121 · see citing works
Ancestral components of admixed genomes in a Mexican cohort
Johnson, N. A., Coram, M. A., Shriver, M. D., Romieu, I., Barsh, G. S., London, S. J., & Tang, H. (2011) · PLoS Genetics · doi:10.1371/journal.pgen.1002410 · Cited by 114 · 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
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
Self-citationComparing signals of natural selection between three Indigenous North American populations
Reynolds, A. W., Mata-Míguez, J., Miró-Herrans, A., Briggs-Cloud, M., Sylestine, A., Barajas-Olmos, F., Garcia-Ortiz, H., Rzhetskaya, M., Orozco, L., Raff, J. A., et al. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1819467116 · Cited by 67 · see citing works
Ashmore, T., Fernandez, B. O., Branco‐Price, C., West, J. A., Cowburn, A. S., Heather, L. C., Griffin, J. L., Johnson, R. S., Feelisch, M., & Murray, A. J. (2014) · The Journal of Physiology · doi:10.1113/jphysiol.2014.275263 · Cited by 58 · see citing works
A review of inter- and intraspecific variation in the eutherian placenta
Gundling, W. E., & Wildman, D. E. (2015) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2014.0072 · Cited by 58 · see citing works
Zhang, Y., Hu, Y., Wang, X., Jiang, Q., Zhao, H., Wang, J., Ju, Z., Yang, L., Gao, Y., Wei, X., et al. (2020) · Frontiers in Genetics · doi:10.3389/fgene.2019.01404 · Cited by 42 · see citing works
- Authors
- Bigham, A., Bauchet, M., Pinto, D., Mao, X., Akey, J. M., Mei, R., Scherer, S. W., Julian, C. G., Wilson, M. J., López Herráez, D., Brutsaert, T., Parra, E. J., Moore, L. G., & Shriver, M. D.
- Affiliations
- Pennsylvania State University (US)
- Max Planck Institute for Evolutionary Anthropology (DE)
- University of Toronto (CA)
- University of Washington (US)
- Thermo Fisher Scientific (United States) (US)
- University of Colorado Denver (US)
- Syracuse University (US)
- Wake Forest University Health Sciences (US)
- Corresponding author
- Bigham, Abigail
- ORCID
- Venue
- PLoS Genetics
- Publisher
- Public Library of Science (PLoS)
- Published
- 2010-09-09
- Volume
- 6
- Issue
- 9
- Pages
- e1001116
- ISSN
- 1553-7390 (ISSN-L)
- 1553-7404
- PMC
- PMC2936536
- OpenAlex
- W2092574926
- Cited by
- 597
- References
- 9
- Citations by year
- 2026: 22 · 2025: 27 · 2024: 28 · 2023: 39 · 2022: 26 · 2021: 38 · 2020: 32 · 2019: 48 · 2018: 35 · 2017: 41 · 2016: 52 · 2015: 55 · 2014: 42 · 2013: 51 · 2012: 33
- FWCI
- 19.99
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Genetics (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Figshare (submittedVersion, cc-by)
- MPG.PuRe (Max Planck Society) (submittedVersion, cc-by)
- Funders
- National Science Foundation (8919645, 0622337)
- American Heart Association
- Wenner-Gren Foundation
- National Institutes of Health (HLBI 079647, 079647)
- National Heart, Lung, and Blood Institute (HL079647, R01HL079647)
- National Human Genome Research Institute (R01HG002154, HG-002154)
- Fogarty International Center (TW-001188, R03TW007957, R03TW001188)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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, hypoxia, natural selection signatures, Tibetan Plateau, Andean peoples, EGLN1, PHD2, HIF pathway, oxygen sensing, oxygen metabolism, positive selection, candidate genes, genome scan
- MeSH terms
- Adaptation, Physiological, Altitude, Genetics, Population, Geography, Globins, Humans, Phylogeny, Procollagen-Proline Dioxygenase, Renin-Angiotensin System, Selection, Genetic, South America, Genome, Human, Tibet, Polymorphism, Single Nucleotide, Gene Expression Profiling, Databases, Genetic, Hypoxia-Inducible Factor 1, alpha Subunit, DNA Copy Number Variations, Hypoxia-Inducible Factor-Proline Dioxygenases
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