Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

Science 329 (5987): 72-75

Copyright © 2010 by the American Association for the Advancement of Science

Genetic Evidence for High-Altitude Adaptation in Tibet

Tatum S. Simonson,1 Yingzhong Yang,2,* Chad D. Huff,1 Haixia Yun,2,* Ga Qin,2,* David J. Witherspoon,1 Zhenzhong Bai,2,* Felipe R. Lorenzo,3 Jinchuan Xing,1 Lynn B. Jorde,1,{dagger} Josef T. Prchal,1,3,{dagger} RiLi Ge2,*,{dagger}

Abstract: Tibetans have lived at very high altitudes for thousands of years, and they have a distinctive suite of physiological traits that enable them to tolerate environmental hypoxia. These phenotypes are clearly the result of adaptation to this environment, but their genetic basis remains unknown. We report genome-wide scans that reveal positive selection in several regions that contain genes whose products are likely involved in high-altitude adaptation. Positively selected haplotypes of EGLN1 and PPARA were significantly associated with the decreased hemoglobin phenotype that is unique to this highland population. Identification of these genes provides support for previously hypothesized mechanisms of high-altitude adaptation and illuminates the complexity of hypoxia-response pathways in humans.

1 Eccles Institute of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
2 Research Center for High-Altitude Medicine, Qinghai University Medical School, Xining, Qinghai 810001, People’s Republic of China.
3 Division of Hematology and Department of Pathology (ARUP), University of Utah School of Medicine and VAH, Salt Lake City, UT 84112, USA.

* The Research Center for High-Altitude Medicine initiated the research project and was primarily responsible for phenotyping and DNA collection.

{dagger} To whom correspondence should be addressed. E-mail: lbj{at} (L.B.J); josef.prchal{at} (J.T.P.); geriligao{at} (R.L.G.)

On Detecting Incomplete Soft or Hard Selective Sweeps Using Haplotype Structure.
A. Ferrer-Admetlla, M. Liang, T. Korneliussen, and R. Nielsen (2014)
Mol. Biol. Evol. 31, 1275-1291
   Abstract »    Full Text »    PDF »
Population Variation Revealed High-Altitude Adaptation of Tibetan Mastiffs.
Y. Li, D.-D. Wu, A. R. Boyko, G.-D. Wang, S.-F. Wu, D. M. Irwin, and Y.-P. Zhang (2014)
Mol. Biol. Evol. 31, 1200-1205
   Abstract »    Full Text »    PDF »
Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia.
N. Petousi, Q. P. P. Croft, G. L. Cavalleri, H.-Y. Cheng, F. Formenti, K. Ishida, D. Lunn, M. McCormack, K. V. Shianna, N. P. Talbot, et al. (2014)
J Appl Physiol 116, 893-904
   Abstract »    Full Text »    PDF »
Less is more: blunted responses to hypoxia revealed in sea-level Tibetans.
T. S. Simonson and F. L. Powell (2014)
J Appl Physiol 116, 711-712
   Full Text »    PDF »
Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era.
N. Petousi and P. A. Robbins (2014)
J Appl Physiol 116, 875-884
   Abstract »    Full Text »    PDF »
Acute environmental hypoxia induces LC3 lipidation in a genotype-dependent manner.
E. Masschelein, R. Van Thienen, G. D'Hulst, P. Hespel, M. Thomis, and L. Deldicque (2014)
FASEB J 28, 1022-1034
   Abstract »    Full Text »    PDF »
mtDNA Lineage Expansions in Sherpa Population Suggest Adaptive Evolution in Tibetan Highlands.
L. Kang, H.-X. Zheng, F. Chen, S. Yan, K. Liu, Z. Qin, L. Liu, Z. Zhao, L. Li, X. Wang, et al. (2013)
Mol. Biol. Evol. 30, 2579-2587
   Abstract »    Full Text »    PDF »
Congenital erythrocytosis associated with gain-of-function HIF2A gene mutations and erythropoietin levels in the normal range.
S. Perrotta, D. P. Stiehl, F. Punzo, S. Scianguetta, A. Borriello, D. Bencivenga, M. Casale, B. Nobili, S. Fasoli, A. Balduzzi, et al. (2013)
Haematologica 98, 1624-1632
   Abstract »    Full Text »    PDF »
Robust Identification of Local Adaptation from Allele Frequencies.
T. Gunther and G. Coop (2013)
Genetics 195, 205-220
   Abstract »    Full Text »    PDF »
Erythrocytosis: the HIF pathway in control.
K. Franke, M. Gassmann, and B. Wielockx (2013)
Blood 122, 1122-1128
   Abstract »    Full Text »    PDF »
The gut in iron homeostasis: role of HIF-2 under normal and pathological conditions.
M. Mastrogiannaki, P. Matak, and C. Peyssonnaux (2013)
Blood 122, 885-892
   Abstract »    Full Text »    PDF »
Inferring Selection Intensity and Allele Age from Multilocus Haplotype Structure.
H. Chen and M. Slatkin (2013)
g3 3, 1429-1442
   Abstract »    Full Text »    PDF »
Genetic Signatures Reveal High-Altitude Adaptation in a Set of Ethiopian Populations.
E. Huerta-Sanchez, M. DeGiorgio, L. Pagani, A. Tarekegn, R. Ekong, T. Antao, A. Cardona, H. E. Montgomery, G. L. Cavalleri, P. A. Robbins, et al. (2013)
Mol. Biol. Evol. 30, 1877-1888
   Abstract »    Full Text »    PDF »
Genetic Evidence of Paleolithic Colonization and Neolithic Expansion of Modern Humans on the Tibetan Plateau.
X. Qi, C. Cui, Y. Peng, X. Zhang, Z. Yang, H. Zhong, H. Zhang, K. Xiang, X. Cao, Y. Wang, et al. (2013)
Mol. Biol. Evol. 30, 1761-1778
   Abstract »    Full Text »    PDF »
Identification of a Tibetan-Specific Mutation in the Hypoxic Gene EGLN1 and Its Contribution to High-Altitude Adaptation.
K. Xiang, Ouzhuluobu, Y. Peng, Z. Yang, X. Zhang, C. Cui, H. Zhang, M. Li, Y. Zhang, Bianba, et al. (2013)
Mol. Biol. Evol. 30, 1889-1898
   Abstract »    Full Text »    PDF »
PPAR-{alpha} as a Key Nutritional and Environmental Sensor for Metabolic Adaptation.
A. V. Contreras, N. Torres, and A. R. Tovar (2013)
Adv Nutr 4, 439-452
   Abstract »    Full Text »    PDF »
Bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases.
D. C. Wallace (2013)
Phil Trans R Soc B 368, 20120267
   Abstract »    Full Text »    PDF »
Prolyl Hydroxylase Domain Protein 2 (PHD2) Binds a Pro-Xaa-Leu-Glu Motif, Linking It to the Heat Shock Protein 90 Pathway.
D. Song, L.-S. Li, K. J. Heaton-Johnson, P. R. Arsenault, S. R. Master, and F. S. Lee (2013)
J. Biol. Chem. 288, 9662-9674
   Abstract »    Full Text »    PDF »
Phenotypic plasticity in blood-oxygen transport in highland and lowland deer mice.
D. M. Tufts, I. G. Revsbech, Z. A. Cheviron, R. E. Weber, A. Fago, and J. F. Storz (2013)
J. Exp. Biol. 216, 1167-1173
   Abstract »    Full Text »    PDF »
Detecting Signatures of Selection Through Haplotype Differentiation Among Hierarchically Structured Populations.
M. I. Fariello, S. Boitard, H. Naya, M. SanCristobal, and B. Servin (2013)
Genetics 193, 929-941
   Abstract »    Full Text »    PDF »
H. F. Bunn (2013)
Cold Spring Harb Perspect Med 3, a011619
   Abstract »    Full Text »    PDF »
Cardiovascular and renal effects of chronic exposure to high altitude.
A. Hurtado, E. Escudero, J. Pando, S. Sharma, and R. J. Johnson (2012)
Nephrol. Dial. Transplant. 27, iv11-iv16
   Abstract »    Full Text »    PDF »
Genetic Adaptation of the Hypoxia-Inducible Factor Pathway to Oxygen Pressure among Eurasian Human Populations.
L.-d. Ji, Y.-q. Qiu, J. Xu, D. M. Irwin, S.-C. Tam, N. L. S. Tang, and Y.-p. Zhang (2012)
Mol. Biol. Evol. 29, 3359-3370
   Abstract »    Full Text »    PDF »
Common Polymorphisms in Angiogenesis.
M. S. Rogers and R. J. D'Amato (2012)
Cold Spring Harb Perspect Med 2, a006510
   Abstract »    Full Text »    PDF »
Late Pleistocene climate change and the global expansion of anatomically modern humans.
A. Eriksson, L. Betti, A. D. Friend, S. J. Lycett, J. S. Singarayer, N. von Cramon-Taubadel, P. J. Valdes, F. Balloux, and A. Manica (2012)
PNAS 109, 16089-16094
   Abstract »    Full Text »    PDF »
Identification of chicken eNOS gene and differential expression in highland versus lowland chicken breeds.
J. F. Peng, Y. Ling, W. Y. Gou, H. Zhang, and C. X. Wu (2012)
Poultry Science 91, 2275-2281
   Abstract »    Full Text »    PDF »
Adaptive and Maladaptive Cardiorespiratory Responses to Continuous and Intermittent Hypoxia Mediated by Hypoxia-Inducible Factors 1 and 2.
N. R. Prabhakar and G. L. Semenza (2012)
Physiol Rev 92, 967-1003
   Abstract »    Full Text »    PDF »
Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans.
F. Ji, M. S. Sharpley, O. Derbeneva, L. S. Alves, P. Qian, Y. Wang, D. Chalkia, M. Lvova, J. Xu, W. Yao, et al. (2012)
PNAS 109, 7391-7396
   Abstract »    Full Text »    PDF »
A Major Genome Region Underlying Artemisinin Resistance in Malaria.
I. H. Cheeseman, B. A. Miller, S. Nair, S. Nkhoma, A. Tan, J. C. Tan, S. Al Saai, A. P. Phyo, C. L. Moo, K. M. Lwin, et al. (2012)
Science 336, 79-82
   Abstract »    Full Text »    PDF »
Hypoxic Pulmonary Vasoconstriction.
J. T. Sylvester, L. A. Shimoda, P. I. Aaronson, and J. P. T. Ward (2012)
Physiol Rev 92, 367-520
   Abstract »    Full Text »    PDF »
Giant sucking sound: can physiology fill the intellectual void left by the reductionists?.
M. J. Joyner (2011)
J Appl Physiol 111, 335-342
   Abstract »    Full Text »    PDF »
Hypoxia. 5. Hypoxia and hematopoiesis.
D. Yoon, P. Ponka, and J. T. Prchal (2011)
Am J Physiol Cell Physiol 300, C1215-C1222
   Abstract »    Full Text »    PDF »
Matrix Metalloproteinase (MMP)-9 Induced by Wnt Signaling Increases the Proliferation and Migration of Embryonic Neural Stem Cells at Low O2 Levels.
C. A. Ingraham, G. C. Park, H. P. Makarenkova, and K. L. Crossin (2011)
J. Biol. Chem. 286, 17649-17657
   Abstract »    Full Text »    PDF »
Maximum-likelihood estimation of recent shared ancestry (ERSA).
C. D. Huff, D. J. Witherspoon, T. S. Simonson, J. Xing, W. S. Watkins, Y. Zhang, T. M. Tuohy, D. W. Neklason, R. W. Burt, S. L. Guthery, et al. (2011)
Genome Res. 21, 768-774
   Abstract »    Full Text »    PDF »
B-type natriuretic peptide, vascular endothelial growth factor, endothelin-1, and nitric oxide synthase in chronic mountain sickness.
R.-L. Ge, V. Y. Mo, J. L. Januzzi, G. Jin, Y. Yang, S. Han, M. J. Wood, and B. D. Levine (2011)
Am J Physiol Heart Circ Physiol 300, H1427-H1433
   Abstract »    Full Text »    PDF »
Ten questions about systems biology.
M. J. Joyner and B. K. Pedersen (2011)
J. Physiol. 589, 1017-1030
   Abstract »    Full Text »    PDF »
A Genome-Wide Search for Signals of High-Altitude Adaptation in Tibetans.
S. Xu, S. Li, Y. Yang, J. Tan, H. Lou, W. Jin, L. Yang, X. Pan, J. Wang, Y. Shen, et al. (2011)
Mol. Biol. Evol. 28, 1003-1011
   Abstract »    Full Text »    PDF »
Genetic Variations in Tibetan Populations and High-Altitude Adaptation at the Himalayas.
Y. Peng, Z. Yang, H. Zhang, C. Cui, X. Qi, X. Luo, X. Tao, T. Wu, Ouzhuluobu, Basang, et al. (2011)
Mol. Biol. Evol. 28, 1075-1081
   Abstract »    Full Text »    PDF »
Adaptive selection of an incretin gene in Eurasian populations.
C. L. Chang, J. J. Cai, C. Lo, J. Amigo, J.-I. Park, and S. Y. T. Hsu (2011)
Genome Res. 21, 21-32
   Abstract »    Full Text »    PDF »
Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates.
J. F. Storz, G. R. Scott, and Z. A. Cheviron (2010)
J. Exp. Biol. 213, 4125-4136
   Abstract »    Full Text »    PDF »
EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda.
S. Aggarwal, S. Negi, P. Jha, P. K. Singh, T. Stobdan, M. A. Q. Pasha, S. Ghosh, A. Agrawal, Indian Genome Variation Consortium, B. Prasher, et al. (2010)
PNAS 107, 18961-18966
   Abstract »    Full Text »    PDF »
Exome sequencing: the sweet spot before whole genomes.
J. K. Teer and J. C. Mullikin (2010)
Hum. Mol. Genet. 19, R145-R151
   Abstract »    Full Text »    PDF »
Fine-scale population structure and the era of next-generation sequencing.
B. M. Henn, S. Gravel, A. Moreno-Estrada, S. Acevedo-Acevedo, and C. D. Bustamante (2010)
Hum. Mol. Genet. 19, R221-R226
   Abstract »    Full Text »    PDF »
Ancient Atmospheres and the Evolution of Oxygen Sensing Via the Hypoxia-Inducible Factor in Metazoans.
C. T. Taylor and J. C. McElwain (2010)
Physiology 25, 272-279
   Abstract »    Full Text »    PDF »
Genes for High Altitudes.
J. F. Storz (2010)
Science 329, 40-41
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882