Human Genetics

, Volume 131, Issue 4, pp 527–533

Genetic determinants of Tibetan high-altitude adaptation

  • Tatum S. Simonson
  • Donald A. McClain
  • Lynn B. Jorde
  • Josef T. Prchal
Review Paper

Abstract

Some highland populations have genetic adaptations that enable their successful existence in a hypoxic environment. Tibetans are protected against many of the harmful responses exhibited by non-adapted populations upon exposure to severe hypoxia, including elevated hemoglobin concentration (i.e., polycythemia). Recent studies have highlighted several genes subject to natural selection in native high-altitude Tibetans. Three of these genes, EPAS1, EGLN1 and PPARA, regulate or are regulated by hypoxia inducible factor, a principal controller of erythropoiesis and other organismal functions. Uncovering the molecular basis of hypoxic adaptation should have implications for understanding hematological and other adaptations involved in hypoxia tolerance. Because the hypoxia response involves a variety of cardiovascular, pulmonary and metabolic functions, this knowledge would improve our understanding of disease mechanisms and could ultimately be translated into targeted therapies for oxygen deprivation, cardiopulmonary and cerebral pathologies, and metabolic disorders such as diabetes and obesity.

References

  1. Aggarwal S, Negi S, Jha P, Singh PK, Stobdan T, Pasha MAQ, Ghosh S, Agrawal A, Consortium IGV, Prasher B, Mukerji M (2010) EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda. Proc Natl Acad Sci 107(44):18961–18966PubMedCrossRefGoogle Scholar
  2. Aldenderfer M (2011) Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol 12(2):141–147PubMedCrossRefGoogle Scholar
  3. Beall CM (2000) Tibetan and Andean patterns of adaptation to high-altitude hypoxia. Hum Biol 72(1):201–228PubMedGoogle Scholar
  4. Beall CM (2007) Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci USA 104(Suppl 1):8655–8660PubMedCrossRefGoogle Scholar
  5. Beall CM (2011) Genetic Changes in Tibet. High Alt Med Biol 12(2):101–102PubMedCrossRefGoogle Scholar
  6. Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, Decker MJ, Vargas E, Villena M, Soria R, Alarcon AM, Gonzales C (1998) Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106(3):385–400PubMedCrossRefGoogle Scholar
  7. Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y, Knight J, Li C, Li JC, Liang Y, McCormack M, Montgomery HE, Pan H, Robbins PA, Shianna KV, Tam SC, Tsering N, Veeramah KR, Wang W, Wangdui P, Weale ME, Xu Y, Xu Z, Yang L, Zaman MJ, Zeng C, Zhang L, Zhang X, Zhaxi P, Zheng YT (2010) Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. Proc Natl Acad Sci 107(25):11459–11464PubMedCrossRefGoogle Scholar
  8. Bigham AW, Mao X, Brutsaert T, Wilson MJ, Julian CG, Parra EJ, Akey JM, Moore LG, Shriver MD (2009) Identifying positive selection candidate loci for high-altitude adaptation in Andean populations. Hum Genomics 4(2):79–90PubMedGoogle Scholar
  9. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, López Herráez D, Brutsaert T, Parra EJ, Moore LG, Shriver MD (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6(9):e1001116PubMedCrossRefGoogle Scholar
  10. Brantingham PJ, Rhode D, Madsen DB (2010) Archaeology augments Tibet’s genetic history. Science 329(5998):1467PubMedCrossRefGoogle Scholar
  11. Chen H, Patterson N, Reich D (2010) Population differentiation as a test for selective sweeps. Genome Res 20(3):393–402PubMedCrossRefGoogle Scholar
  12. Cockerham CC, Weir BS (1984) Covariances of relatives stemming from a population undergoing mixed self and random mating. Biometrics 40(1):157–164PubMedCrossRefGoogle Scholar
  13. Denko NC (2008) Hypoxia, HIF1 and glucose metabolism in the solid tumour. Nat Rev Cancer 8(9):705–713PubMedCrossRefGoogle Scholar
  14. Encyclopedia Britannica Online (2011) Tibetan language. http://www.britannica.com/EBchecked/topic/594982/Tibetan-language
  15. Formenti F, Constantin-Teodosiu D, Emmanuel Y, Cheeseman J, Dorrington KL, Edwards LM, Humphreys SM, Lappin TRJ, McMullin MF, McNamara CJ, Mills W, Murphy JA, O’Connor DF, Percy MJ, Ratcliffe PJ, Smith TG, Treacy M, Frayn KN, Greenhaff PL, Karpe F, Clarke K, Robbins PA (2010) Regulation of human metabolism by hypoxia-inducible factor. Proc Natl Acad Sci 107(28):12722–12727PubMedCrossRefGoogle Scholar
  16. Furlow PW, Percy MJ, Sutherland S, Bierl C, McMullin MF, Master SR, Lappin TRJ, Lee FS (2009) Erythrocytosis-associated HIF-2α mutations demonstrate a critical role for residues C-terminal to the hydroxyl acceptor proline. J Biol Chem 284(14):9050–9058PubMedCrossRefGoogle Scholar
  17. Hackett PH, Roach RC (2001) High-Altitude Illness. N Engl J Med 345(2):107–114PubMedCrossRefGoogle Scholar
  18. HapMap Consortium (2007) A second generation human haplotype map of over 3.1 million SNPs. Nature 449(7164):851–861CrossRefGoogle Scholar
  19. Hirota K, Semenza GL (2006) Regulation of angiogenesis by hypoxia-inducible factor 1. Crit Rev Oncol Hematol 59(1):15–26PubMedCrossRefGoogle Scholar
  20. Holsinger KE, Weir BS (2009) Genetics in geographically structured populations: defining, estimating and interpreting FST. Nat Rev Genet 10(9):639–650PubMedCrossRefGoogle Scholar
  21. Huff C, Harpending H, Rogers A (2010) Detecting positive selection from genome scans of linkage disequilibrium. BMC Genomics 11(1):8PubMedCrossRefGoogle Scholar
  22. Kaelin WGJ, Ratcliffe PJ (2008) Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol Cell 30(4):393–402PubMedCrossRefGoogle Scholar
  23. Lee FS (2008) Genetic causes of erythrocytosis and the oxygen-sensing pathway. Blood Rev 22(6):321–332PubMedCrossRefGoogle Scholar
  24. Li JZ, Absher DM, Tang H, Southwick AM, Casto AM, Ramachandran S, Cann HM, Barsh GS, Feldman M, Cavalli-Sforza LL, Myers RM (2008) Worldwide human relationships inferred from genome-wide patterns of variation. Science 319(5866):1100–1104PubMedCrossRefGoogle Scholar
  25. Lorenzo F, Swierczek S, Huff C, Prchal JT (2011) The Tibetan PHD2 polymorphism Asp4Glu is associated with hypersensitivity of erythroid progenitors to EPO and upregulation of HIF-1 regulated genes hexokinase (HK1) and glucose transporter 1 (SLC2A/GLUT1). Abstract submitted to 2011 meeting of the American Society of HematologyGoogle Scholar
  26. MacInnis MJ, Rupert JL (2011) ’ome on the Range: altitude adaptation, positive selection, and himalayan genomics. High Alt Med Biol 12(2):133–139PubMedCrossRefGoogle Scholar
  27. MacInnis MJ, Koehle MS, Rupert JL (2010) Evidence for a genetic basis for altitude illness: 2010 update. High Alt Med Biol 11(4):349–368PubMedCrossRefGoogle Scholar
  28. Majmundar AJ, Wong WJ, Simon MC (2010) Hypoxia-inducible factors and the response to hypoxic stress. Mol Cell 40(2):294–309PubMedCrossRefGoogle Scholar
  29. Monge CC, Whittembury J (1976) Chronic mountain sickness. Johns Hopkins Med J 139(SUPPL):187–189Google Scholar
  30. Moore LG (2001) Human genetic adaptation to high altitude. High Alt Med Biol 2(2):257–279PubMedCrossRefGoogle Scholar
  31. Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, Tao X, Wu T, Ouzhuluobu, Basang, Ciwangsangbu, Danzengduojie, Chen H, Shi H, Su B (2011) Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol 28(2):1075–1081Google Scholar
  32. Prchal JT (2010) Clinical manifestations and classification of erythrocyte disorders. In: Kaushansky N, Beutler E, Seligsohn U, Litchman MA, Kipps TJ, Prchal JT (eds) Williams Hematology, Vol 8. McGraw-Hill, New York, pp 455–462Google Scholar
  33. Qin Z, Yang Y, Kang L, Yan S, Cho K, Cai X, Lu Y, Zheng H, Zhu D, Fei D, Li S, Jin L, Li H (2010) A mitochondrial revelation of early human migrations to the Tibetan Plateau before and after the last glacial maximum. Am J Phys Anthropol 143(4):555–569PubMedCrossRefGoogle Scholar
  34. Rupert J (2010) Will blood tell? Three recent articles demonstrate genetic selection in Tibetans. High Alt Med Biol 11(4):307–308PubMedCrossRefGoogle Scholar
  35. Rupert JL, Koehle MS (2006) Evidence for a genetic basis for altitude-related illness. High Alt Med Biol 7(2):150–167PubMedCrossRefGoogle Scholar
  36. Sabeti PC, Varilly P, Fry B, Lohmueller J, Hostetter E, Cotsapas C, Xie X, Byrne EH, McCarroll SA, Gaudet R, Schaffner SF, Lander ES (2007) Genome-wide detection and characterization of positive selection in human populations. Nature 449(7164):913–918PubMedCrossRefGoogle Scholar
  37. Scheinfeldt L, Tishkoff S (2010) Living the high life: high-altitude adaptation. Genome Biol 11(9):133PubMedCrossRefGoogle Scholar
  38. Semenza GL (1999) Perspectives on oxygen sensing. Cell 98(3):281–284PubMedCrossRefGoogle Scholar
  39. Semenza GL (2009) Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood 114(10):2015–2019PubMedCrossRefGoogle Scholar
  40. Semenza GL (2010) Vascular responses to hypoxia and ischemia. Arterioscler Thromb Vasc Biol 30(4):648–652PubMedCrossRefGoogle Scholar
  41. Semenza GL (2011) Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning. Biochim Biophys Acta (BBA): Mol Cell Res 1813(7):1263–1268CrossRefGoogle Scholar
  42. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB, Prchal JT, Ge R (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329(5987):72–75PubMedCrossRefGoogle Scholar
  43. Storz JF, Scott GR, Cheviron ZA (2010) Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J Exp Biol 213(24):4125–4136PubMedCrossRefGoogle Scholar
  44. Tissot van Patot MC, Gassmann M (2011) Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. High Alt Med Biol 12(2):157–167CrossRefGoogle Scholar
  45. Vargas PE, Spielvogel H (2006) Chronic mountain sickness, optimal hemoglobin, and heart disease. High Alt Med Biol 7(2):138–149PubMedCrossRefGoogle Scholar
  46. Voight BF, Kudaravalli S, Wen X, Pritchard JK (2006) A map of recent positive selection in the human genome. PLoS Biol 4(3):e72PubMedCrossRefGoogle Scholar
  47. Wang B, Zhang Y-B, Zhang F, Lin H, Wang X, Wan N, Ye Z, Weng H, Zhang L, Li X, Yan J, Wang P, Wu T, Cheng L, Wang J, Wang D-M, Ma X, Yu J (2011) On the origin of Tibetans and their genetic basis in adapting high-altitude environments. PLoS One 6(2):e17002PubMedCrossRefGoogle Scholar
  48. Wills C (2011) Rapid recent human evolution and the accumulation of balanced genetic polymorphisms. High Alt Med Biol 12(2):149–155PubMedCrossRefGoogle Scholar
  49. Wu T, Wang X, Wei C, Cheng H, Wang X, Li Y, Ge D, Zhao H, Young P, Li G, Wang Z (2005) Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs Han. J Appl Physiol 98(2):598–604PubMedCrossRefGoogle Scholar
  50. Xu S, Li S, Yang Y, Tan J, Lou H, Jin W, Yang L, Pan X, Wang J, Shen Y, Wu B, Wang H, Jin L (2011) A genome-wide search for signals of high altitude adaptation in Tibetans. Mol Biol Evol 28(2):1003–1011PubMedCrossRefGoogle Scholar
  51. Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS, 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 (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329(5987):75–78Google Scholar
  52. Yoon D, Pastore YD, Divoky V, Liu E, Mlodnicka AE, Rainey K, Ponka P, Semenza GL, Schumacher A, Prchal JT (2006) Hypoxia-inducible factor-1 deficiency results in dysregulated erythropoiesis signaling and iron homeostasis in mouse development. J Biol Chem 281(35):25703–25711PubMedCrossRefGoogle Scholar
  53. Zhao M, Kong Q-P, Wang H-W, Peng M-S, Xie X-D, Wang W-Z, Jiayang, Duan J-G, Cai M-C, Zhao S-N, Cidanpingcuo, Tu Y-Q, Wu S-F, Yao Y-G, Bandelt H-J, Zhang Y-P (2009) Mitochondrial genome evidence reveals successful late paleolithic settlement on the Tibetan Plateau. Proc Natl Acad Sci 106(50):21230–21235Google Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Tatum S. Simonson
    • 1
  • Donald A. McClain
    • 2
  • Lynn B. Jorde
    • 1
  • Josef T. Prchal
    • 3
  1. 1.Eccles Institute of Human GeneticsUniversity of Utah School of MedicineSalt Lake CityUSA
  2. 2.Endocrinology, Metabolism and DiabetesUniversity of Utah School of MedicineSalt Lake CityUSA
  3. 3.Hematology and Pathology (ARUP)University of Utah School of MedicineSalt Lake CityUSA

Personalised recommendations