High-altitude adaptation in humans: from genomics to integrative physiology

Abstract

About 1.2 to 33% of high-altitude populations suffer from Monge’s disease or chronic mountain sickness (CMS). Number of factors such as age, sex, and population of origin (older, male, Andean) contribute to the percentage reported from a variety of samples. It is estimated that there are around 83 million people who live at altitudes > 2500 m worldwide and are at risk for CMS. In this review, we focus on a human “experiment in nature” in various high-altitude locations in the world—namely, Andean, Tibetan, and Ethiopian populations that have lived under chronic hypoxia conditions for thousands of years. We discuss the adaptive as well as mal-adaptive changes at the genomic and physiological levels. Although different genes seem to be involved in adaptation in the three populations, we can observe convergence at genetic and signaling, as well as physiological levels. What is important is that we and others have shown that lessons learned from the genes mined at high altitude can be helpful in better understanding and treating diseases that occur at sea level. We discuss two such examples: EDNRB and SENP1 and their role in cardiac tolerance and in the polycythemic response, respectively.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. 1.

    Semenza GL (2000) HIF-1 and human disease: one highly involved factor. Genes Dev 14:1983–1991

    CAS  PubMed  Google Scholar 

  2. 2.

    Semenza GL (2014) Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu Rev Pathol 9:47–71

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Nathaniel TI, Williams-Hernandez A, Hunter AL, Liddy C, Peffley DM, Umesiri FE, Imeh-Nathaniel A (2015) Tissue hypoxia during ischemic stroke: adaptive clues from hypoxia-tolerant animal models. Brain Res Bull 114:1–12

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Drew KL, Harris MB, LaManna JC, Smith MA, Zhu XW, Ma YL (2004) Hypoxia tolerance in mammalian heterotherms. J Exp Biol 207:3155–3162

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Haddad GG (2006) Tolerance to low O2: lessons from invertebrate genetic models. Exp Physiol 91:277–282

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Boutilier RG (2001) Mechanisms of cell survival in hypoxia and hypothermia. J Exp Biol 204:3171–3181

    CAS  PubMed  Google Scholar 

  7. 7.

    Larson J, Drew KL, Folkow LP, Milton SL, Park TJ (2014) No oxygen? No problem! Intrinsic brain tolerance to hypoxia in vertebrates. J Exp Biol 217:1024–1039

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Beall CM (2006) Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia. Integr Comp Biol 46:18–24

    PubMed  Article  Google Scholar 

  9. 9.

    Villafuerte FC, Corante N (2016) Chronic mountain sickness: clinical aspects, etiology, management, and treatment. High Altitude Med Biol 17:61–69

    Article  Google Scholar 

  10. 10.

    Bao H, Wang D, Zhao X, Wu Y, Yin G, Meng L, Wang F, Ma L, Hackett P, Ge RL (2017) Cerebral edema in chronic mountain sickness: a new finding. Sci Rep 7:43224

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    Richalet JP, Rivera M, Bouchet P, Chirinos E, Onnen I, Petitjean O, Bienvenu A, Lasne F, Moutereau S, Leon-Velarde F (2005) Acetazolamide—a treatment for chronic mountain sickness. Am J Respir Crit Care Med 172:1427–1433

    PubMed  Article  Google Scholar 

  12. 12.

    Sahota IS, Panwar NS (2013) Prevalence of chronic mountain sickness in high altitude districts of Himachal Pradesh. Indian J Occup Environ Med 17:94–100

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Monge C, Leonvelarde F, Arregui A (1989) Increasing prevalence of excessive erythrocytosis with age among healthy high-altitude miners. N Engl J Med 321:1271–1271

    CAS  PubMed  Google Scholar 

  14. 14.

    Leon-Velarde F, Maggiorini M, Reeves JT, Aldashev A, Asmus I, Bernardi L, Ge RL, Hackett P, Kobayashi T, Moore LG et al (2005) Consensus statement on chronic and subacute high altitude diseases. High Alt Med Biol 6:147–157

    PubMed  Article  Google Scholar 

  15. 15.

    Penaloza D, Arias-Stella J (2007) The heart and pulmonary circulation at high altitudes—healthy highlanders and chronic mountain sickness. Circulation 115:1132–1146

    PubMed  Article  Google Scholar 

  16. 16.

    Aldenderfer M (2011) Peopling the Tibetan plateau: insights from archaeology. High Alt Med Biol 12:141–147

    PubMed  Article  Google Scholar 

  17. 17.

    Simonson TS (2015) Altitude adaptation: a glimpse through various lenses. High Altitude Med Biol 16:125–137

    CAS  Article  Google Scholar 

  18. 18.

    Zhao M, Kong QP, Wang HW, Peng MS, Xie XD, Wang WZ, Jiayang DJG, Cai MC, Zhao SN et al (2009) Mitochondrial genome evidence reveals successful late Paleolithic settlement on the Tibetan plateau. Proc Natl Acad Sci U S A 106:21230–21235

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Abir M (1992) The Oromo of Ethiopia—a history 1570-1860 - Hassen, M. Int J Middle East Stud 24: 344–346

  20. 20.

    Rademaker K, Hodgins G, Moore K, Zarrillo S, Miller C, Bromley GR, Leach P, Reid DA, Alvarez WY, Sandweiss DH (2014) Paleoindian settlement of the high-altitude Peruvian Andes. Science 346:466–469

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Beall CM (2004) Andean, Tibetan and Ethiopian patterns of human adaptation to high-altitude hypoxia. Integr Comp Biol 44:522–522

    Google Scholar 

  22. 22.

    Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, Strohl KP (2002) An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci U S A 99:17215–17218

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  23. 23.

    Bigham A, Bauchet M, Pinto D, Mao XY, Akey JM, Mei R, Scherer SW, Julian CG, Wilson MJ, Herraez DL et al (2010) Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLoS Genet 6:e1001116

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  24. 24.

    Beall CM (2014) Adaptation to high altitude: phenotypes and genotypes. Annu Rev Anthropol 43(43):251–272

    Article  Google Scholar 

  25. 25.

    Beall CM (2007) Two routes to functional adaptation: Tibetan and Andean high-altitude natives. Proc Natl Acad Sci U S A 104:8655–8660

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  26. 26.

    Ronen R, Zhou D, Bafna V, Haddad GG (2014) The genetic basis of chronic mountain sickness. Physiology 29:403–412

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Monge CC, Whittembury J (1976) Chronic mountain sickness. Johns Hopkins Med J 139:87–89

    PubMed  Google Scholar 

  28. 28.

    Dainiak N, Spielvogel H, Sorba S, Cudkowicz L (1989) Erythropoietin and the polycythemia of high-altitude dwellers. Mol Biol Erythropoiesis 271:17–21

    CAS  Article  Google Scholar 

  29. 29.

    Mejia OM, Prchal JT, Leon-Velarde F, Hurtado A, Stockton DW (2005) Genetic association analysis of chronic mountain sickness in an Andean high-altitude population. Haematologica 90:13–18

    CAS  PubMed  Google Scholar 

  30. 30.

    Monge C, Arregui CA, Leonvelarde F (1992) Pathophysiology and epidemiology of chronic mountain sickness. Int J Sports Med 13:S79–S81

    Article  Google Scholar 

  31. 31.

    Moore LG (2001) Human genetic adaptation to high altitude. High Altitude Med Biol 2:257–279

    CAS  Article  Google Scholar 

  32. 32.

    Monge C, Lozano R, Whittembury J (1965) Effect of blood-letting on chronic mountain sickness. Nature 207:770

    CAS  PubMed  Article  Google Scholar 

  33. 33.

    Naeije R (2010) Physiological adaptation of the cardiovascular system to high altitude. Prog Cardiovasc Dis 52:456–466

    PubMed  Article  Google Scholar 

  34. 34.

    Naeije R, Vanderpool R (2013) Pulmonary hypertension and chronic mountain sickness. High Alt Med Biol 14:117–125

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Wright AD, Birmingham Medical Research Expeditionary S (2006) Medicine at high altitude. Clin Med 6:604–608

    Article  Google Scholar 

  36. 36.

    Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, Xu X, Jiang H, Vinckenbosch N, Korneliussen TS et al (2010) Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:75–78

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Bigham AW, Lee FS (2014) Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev 28:2189–2204

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Udpa N, Ronen R, Zhou D, Liang JB, Stobdan T, Appenzeller O, Yin Y, Du YP, Guo LX, Cao R et al (2014) Whole genome sequencing of Ethiopian highlanders reveals conserved hypoxia tolerance genes. Genome Biol 15:R36

    PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Zhou D, Udpa N, Ronen R, Stobdan T, Liang J, Appenzeller O, Zhao HW, Yin Y, Du Y, Guo L et al (2013) Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders. Am J Hum Genet 93:452–462

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Bigham AW, Mao X, Mei R, 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 4:79–90

    CAS  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Eichstaedt CA, Antao T, Pagani L, Cardona A, Kivisild T, Mormina M (2014) The Andean adaptive toolkit to counteract high altitude maladaptation: genome-wide and phenotypic analysis of the Collas. PLoS One 9:e93314

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  42. 42.

    Valverde G, Zhou H, Lippold S, de Filippo C, Tang K, Lopez Herraez D, Li J, Stoneking M (2015) A novel candidate region for genetic adaptation to high altitude in Andean populations. PLoS One 10:e0125444

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    Lorenzo FR, Huff C, Myllymaki M, Olenchock B, Swierczek S, Tashi T, Gordeuk V, Wuren T, Ri-Li G, McClain DA et al (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46:951–956

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  44. 44.

    Wang BB, Zhang YB, Zhang F, Lin HB, Wang XM, Wan N, Ye ZQ, Weng HY, Zhang LL, Li X et al (2011) On the origin of Tibetans and their genetic basis in adapting high-altitude environments. PLoS One 6:e17002

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Wang GD, Fan RX, Zhai WW, Liu F, Wang L, Zhong L, Wu H, Yang HC, Wu SF, Zhu CL et al (2014) Genetic convergence in the adaptation of dogs and humans to the high-altitude environment of the Tibetan plateau. Genome Biol Evol 6:2122–2128

    PubMed  PubMed Central  Article  Google Scholar 

  46. 46.

    Wuren T, Simonson TS, Qin G, Xing JC, Huff CD, Witherspoon DJ, Jorde LB, Ge RL (2014) Shared and unique signals of high-altitude adaptation in geographically distinct Tibetan populations. PLoS One 9:e88252

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    Xu SH, Li SL, Yang YJ, Tan JZ, Lou HY, Jin WF, Yang L, Pan XD, Wang JC, Shen YP et al (2011) A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol Biol Evol 28:1003–1011

    PubMed  Article  CAS  Google Scholar 

  48. 48.

    Jeong C, Ozga AT, Witonsky DB, Malmstrom H, Edlund H, Hofman CA, Hagan RW, Jakobsson M, Lewis CM, Aldenderfer MS et al (2016) Long-term genetic stability and a high-altitude East Asian origin for the peoples of the high valleys of the Himalayan arc. Proc Natl Acad Sci U S A 113:7485–7490

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Ji FY, Sharpley MS, Derbeneva O, Alves LS, Qian P, Wang YL, Chalkia D, Lvova M, Xu JC, Yao W et al (2012) Mitochondrial DNA variant associated with Leber hereditary optic neuropathy and high-altitude Tibetans. Proc Natl Acad Sci U S A 109:7391–7396

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Chen Y, Jiang CH, Luo YJ, Liu FY, Gao YQ (2016) Interaction of CARD14, SENP1 and VEGFA polymorphisms on susceptibility to high altitude polycythemia in the Han Chinese population at the Qinghai-Tibetan plateau. Blood Cells Molecules and Diseases 57:13–22

    CAS  Article  Google Scholar 

  51. 51.

    Zhang YB, Li X, Zhang F, Wang DM, Yu J (2012) A preliminary study of copy number variation in Tibetans. PLoS One 7:e41768

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Alkorta-Aranburu G, Beall CM, Witonsky DB, Gebremedhin A, Pritchard JK, Di Rienzo A (2012) The genetic architecture of adaptations to high altitude in Ethiopia. PLoS Genet 8:e1003110

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Huerta-Sanchez E, Degiorgio M, Pagani L, Tarekegn A, Ekong R, Antao T, Cardona A, Montgomery HE, Cavalleri GL, Robbins PA et al (2013) Genetic signatures reveal high-altitude adaptation in a set of Ethiopian populations. Mol Biol Evol 30:1877–1888

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G et al (2012) Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 13:R1

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    Tekola-Ayele F, Adeyemo A, Chen GJ, Hailu E, Aseffa A, Davey G, Newport MJ, Rotimi CN (2015) Novel genomic signals of recent selection in an Ethiopian population. Eur J Hum Genet 23:1085–1092

    CAS  PubMed  Article  Google Scholar 

  56. 56.

    Peng Y, Yang ZH, Zhang H, Cui CY, Qi XB, Luo XJ, Tao XA, Wu TY, Ouzhuluobu B et al (2011) Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol Biol Evol 28:1075–1081

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    Song D, Li LS, Arsenault PR, Tan Q, Bigham AW, Heaton-Johnson KJ, Master SR, Lee FS (2014) Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J Biol Chem 289(21):14656–14665

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Azad P, Zhao HW, Cabrales PJ, Ronen R, Zhou D, Poulsen O, Appenzeller O, Hsiao YH, Bafna V, Haddad GG (2016) Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge’s disease. J Exp Med 213:2729–2744

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Stobdan T, Zhou D, Ao-Ieong E, Ortiz D, Ronen R, Hartley I, Gan Z, McCulloch AD, Bafna V, Cabrales P et al (2015) Endothelin receptor B, a candidate gene from human studies at high altitude, improves cardiac tolerance to hypoxia in genetically engineered heterozygote mice. Proc Natl Acad Sci U S A 112:10425–10430

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Xu XH, Huang XW, Qun L, Li YN, Wang Y, Liu C, Ma YY, Liu QM, Sun K, Qian F et al (2014) Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. Sci Rep 4:7465

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Yang DY, Peng Y, Ouzhuluobu B, Cui CY, Bianba WLB, Xiang K, He YX, Zhang H et al (2016) HMOX2 functions as a modifier gene for high-altitude adaptation in Tibetans. Hum Mutat 37:216–223

    CAS  PubMed  Article  Google Scholar 

  62. 62.

    Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J, Kasperaviciute D, Bhosle SG, Mueller M, Geschka S, Rison S, Kojonazarov B, Morrell NW, Neidhardt I, Surmeli NB, Aitman TJ, Stasch JP, Behrends S, Marletta MA (2014) Alpha 1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circ-Cardiovasc Gene 7(6):920–U505

    CAS  Article  Google Scholar 

  63. 63.

    Cao L, Tan L, Jiang T, Zhu XC, Yu JT (2015) Induced pluripotent stem cells for disease modeling and drug discovery in neurodegenerative diseases. Mol Neurobiol 52:244–255

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Hossain MK, Dayem AA, Han J, Saha SK, Yang GM, Choi HY, Cho SG (2016) Recent advances in disease modeling and drug discovery for diabetes mellitus using induced pluripotent stem cells. Int J Mol Sci 17:256

    Article  CAS  Google Scholar 

  65. 65.

    Ooi L, Sidhu K, Poljak A, Sutherland G, O'Connor MD, Sachdev P, Munch G (2013) Induced pluripotent stem cells as tools for disease modelling and drug discovery in Alzheimer’s disease. J Neural Transm 120:103–111

    PubMed  Article  Google Scholar 

  66. 66.

    Sterneckert JL, Reinhardt P, Scholer HR (2014) Investigating human disease using stem cell models. Nat Rev Genet 15:625–639

    CAS  PubMed  Article  Google Scholar 

  67. 67.

    Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, Decker MJ, Vargas E, Villena M, Soria R et al (1998) Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am J Phys Anthropol 106:385–400

    CAS  PubMed  Article  Google Scholar 

  68. 68.

    Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, Strohl KP (2002) An Ethiopian pattern of human adaptation to high-altitude hypoxia. Proc Natl Acad Sci U S A 99:17215–17218

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, Bai Z, Lorenzo FR, Xing J, Jorde LB et al (2010) Genetic evidence for high-altitude adaptation in Tibet. Science 329:72–75

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Xiang K, Ouzhuluobu PY, Yang Z, Zhang X, Cui C, Zhang H, Li M, Zhang Y, Bianba et al (2013) Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Mol Biol Evol 30:1889–1898

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Yang J, Jin ZB, Chen J, Huang XF, Li XM, Liang YB, Mao JY, Chen X, Zheng Z, Bakshi A et al (2017) Genetic signatures of high-altitude adaptation in Tibetans. Proc Natl Acad Sci U S A 114:4189–4194

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Appenzeller O, Minko T, Qualls C, Pozharov V, Gamboa J, Gamboa A, Wang Y (2006) Gene expression, autonomic function and chronic hypoxia: lessons from the Andes. Clin Auton Res 16:217–222

    PubMed  Article  Google Scholar 

  73. 73.

    Leon-Velarde F, Mejia O (2008) Gene expression in chronic high altitude diseases. High Alt Med Biol 9:130–139

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Gonzales GF, Chaupis D (2014) Higher androgen bioactivity is associated with excessive erythrocytosis and chronic mountain sickness in Andean highlanders: a review. Andrologia. https://doi.org/10.1111/and.12359

  75. 75.

    Foll M, Gaggiotti OE, Daub JT, Vatsiou A, Excoffier L (2014) Widespread signals of convergent adaptation to high altitude in Asia and America. Am J Hum Genet 95:394–407

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  76. 76.

    Ezkurdia I, Juan D, Rodriguez JM, Frankish A, Diekhans M, Harrow J, Vazquez J, Valencia A, Tress ML (2014) Multiple evidence strands suggest that there may be as few as 19 000 human protein-coding genes. Hum Mol Genet 23:5866–5878

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Ghezzi P, Brines M (2004) Erythropoietin as an antiapoptotic, tissue-protective cytokine. Cell Death Differ 11:S37–S44

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Senger DR (2010) Vascular endothelial growth factor: much more than an angiogenesis factor. Mol Biol Cell 21:377–379

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  79. 79.

    Achaz G (2009) Frequency Spectrum Neutrality Tests: one for all and all for one. Genetics 183:249–258

    PubMed  PubMed Central  Article  Google Scholar 

  80. 80.

    Semenza GL (2000) HIF-1: mediator of physiological and pathophysiological responses to hypoxia. J Appl Physiol 88:1474–1480

    CAS  PubMed  Google Scholar 

  81. 81.

    Haase VH (2010) Hypoxic regulation of erythropoiesis and iron metabolism. Am J Physiol-Renal Physiol 299:F1–F13

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Semenza GL (2009) Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis. Blood 114:2015–2019

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Rankin EB, Biju MP, Liu QD, Unger TL, Rha J, Johnson RS, Simon MC, Keith B, Haase VH (2007) Hypoxia-inducible factor-2 (HIF-2) regulates hepatic erythropoietin in vivo. J Clin Investig 117:1068–1077

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Cheng J, Kang X, Zhang S, Yeh ET (2007) SUMO-specific protease 1 is essential for stabilization of HIF1alpha during hypoxia. Cell 131:584–595

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Hattangadi SM, Wong P, Zhang LB, Flygare J, Lodish HF (2011) From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications. Blood 118:6258–6268

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  86. 86.

    Schechter AN (2008) Hemoglobin research and the origins of molecular medicine. Blood 112:3927–3938

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  87. 87.

    Giani FC, Fiorini C, Wakabayashi A, Ludwig LS, Salem RM, Jobaliya CD, Regan SN, Ulirsch JC, Liang G, Steinberg-Shemer O et al (2016) Targeted application of human genetic variation can improve red blood cell production from stem cells. Cell Stem Cell 18:73–78

    CAS  PubMed  Article  Google Scholar 

  88. 88.

    Perna F, Gurvich N, Hoya-Arias R, Abdel-Wahab O, Levine RL, Asai T, Voza F, Menendez S, Wang L, Liu F et al (2010) Depletion of L3MBTL1 promotes the erythroid differentiation of human hematopoietic progenitor cells: possible role in 20q-polycythemia vera. Blood 116:2812–2821

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  89. 89.

    Charu R, Stobdan T, Ram RB, Khan AP, Qadar Pasha MA, Norboo T, Afrin F (2006) Susceptibility to high altitude pulmonary oedema: role of ACE and ET-1 polymorphisms. Thorax 61:1011–1012

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Stobdan T, Ali Z, Khan AP, Nejatizadeh A, Ram R, Thinlas T, Mohammad G, Norboo T, Himashree G, Qadar Pasha M (2011) Polymorphisms of renin—angiotensin system genes as a risk factor for high-altitude pulmonary oedema. J Renin-Angiotensin-Aldosterone Syst 12:93–101

    CAS  PubMed  Article  Google Scholar 

  91. 91.

    Stobdan T, Karar J, Pasha MA (2008) High altitude adaptation: genetic perspectives. High Alt Med Biol 9:140–147

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Beall CM, Laskowski D, Strohl KP, Soria R, Villena M, Vargas E, Alarcon AM, Gonzales C, Erzurum SC (2001) Pulmonary nitric oxide in mountain dwellers. Nature 414:411–412

    CAS  PubMed  Article  Google Scholar 

  93. 93.

    Kojonazarov B, Isakova J, Imanov B, Sovkhozova N, Sooronbaev T, Ishizaki T, Aldashev AA (2012) Bosentan reduces pulmonary artery pressure in high altitude residents. High Alt Med Biol 13:217–223

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Plata R, Cornejo A, Arratia C, Anabaya A, Perna A, Dimitrov BD, Remuzzi G, Ruggenenti P, Commission on Global Advancement of Nephrology RSotISoN (2002) Angiotensin-converting-enzyme inhibition therapy in altitude polycythaemia: a prospective randomised trial. Lancet 359:663–666

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Scherrer U, Vollenweider L, Delabays A, Savcic M, Eichenberger U, Kleger GR, Fikrle A, Ballmer PE, Nicod P, Bartsch P (1996) Inhaled nitric oxide for high-altitude pulmonary edema. N Engl J Med 334:624–629

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Lundvall J, Hillman J, Gustafsson D (1982) Beta-adrenergic dilator effects in consecutive vascular sections of skeletal muscle. Am J Physiol 243:H819–H829

    CAS  PubMed  Google Scholar 

  97. 97.

    Wu S, Hao G, Zhang S, Jiang D, Wuren T, Luo J (2016) Cerebral vasoconstriction reactions and plasma levels of ETBR, ET-1, and eNOS in patients with chronic high altitude disease. Mol Med Rep 14:2497–2502

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  98. 98.

    Tykocki NR, Watts SW (2010) The interdependence of endothelin-1 and calcium: a review. Clin Sci (Lond) 119:361–372

    CAS  Article  Google Scholar 

  99. 99.

    Schneider MP, Boesen EI, Pollock DM (2007) Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol 47:731–759

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Chen C, Wang L, Liao Q, Huang Y, Ye H, Chen F, Xu L, Ye M, Duan S (2013) Hypermethylation of EDNRB promoter contributes to the risk of colorectal cancer. Diagn Pathol 8:199

    PubMed  PubMed Central  Google Scholar 

  101. 101.

    Cruz-Munoz W, Jaramillo ML, Man S, Xu P, Banville M, Collins C, Nantel A, Francia G, Morgan SS, Cranmer LD et al (2012) Roles for endothelin receptor B and BCL2A1 in spontaneous CNS metastasis of melanoma. Cancer Res 72:4909–4919

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Zuiverloon TC, Beukers W, van der Keur KA, Munoz JR, Bangma CH, Lingsma HF, Eijkemans MJ, Schouten JP, Zwarthoff EC (2012) A methylation assay for the detection of non-muscle-invasive bladder cancer (NMIBC) recurrences in voided urine. BJU Int 109:941–948

    CAS  PubMed  Article  Google Scholar 

  103. 103.

    Merlen C, Farhat N, Luo X, Chatenet D, Tadevosyan A, Villeneuve LR, Gillis MA, Nattel S, Thorin E, Fournier A et al (2013) Intracrine endothelin signaling evokes IP3-dependent increases in nucleoplasmic Ca(2)(+) in adult cardiac myocytes. J Mol Cell Cardiol 62:189–202

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Kuc RE, Maguire JJ, Davenport AP (2006) Quantification of endothelin receptor subtypes in peripheral tissues reveals downregulation of ET(A) receptors in ET(B)-deficient mice. Exp Biol Med (Maywood) 231:741–745

    CAS  Google Scholar 

  105. 105.

    Kedzierski RM, Grayburn PA, Kisanuki YY, Williams CS, Hammer RE, Richardson JA, Schneider MD, Yanagisawa M (2003) Cardiomyocyte-specific endothelin A receptor knockout mice have normal cardiac function and an unaltered hypertrophic response to angiotensin II and isoproterenol. Mol Cell Biol 23:8226–8232

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Dagassan PH, Breu V, Clozel M, Kunzli A, Vogt P, Turina M, Kiowski W, Clozel JP (1996) Up-regulation of endothelin-B receptors in atherosclerotic human coronary arteries. J Cardiovasc Pharmacol 27:147–153

    CAS  PubMed  Article  Google Scholar 

  107. 107.

    Dimitrijevic I, Edvinsson ML, Chen Q, Malmsjo M, Kimblad PO, Edvinsson L (2009) Increased expression of vascular endothelin type B and angiotensin type 1 receptors in patients with ischemic heart disease. BMC Cardiovasc Disord 9:40

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Krejci V, Hiltebrand LB, Erni D, Sigurdsson GH (2003) Endothelin receptor antagonist bosentan improves microcirculatory blood flow in splanchnic organs in septic shock. Crit Care Med 31:203–210

    CAS  PubMed  Article  Google Scholar 

  109. 109.

    Wanecek M, Weitzberg E, Alving K, Rudehill A, Oldner A (2001) Effects of the endothelin receptor antagonist bosentan on cardiac performance during porcine endotoxin shock. Acta Anaesthesiol Scand 45:1262–1270

    CAS  PubMed  Article  Google Scholar 

  110. 110.

    Prchal JT (2015) Genetic selection by high altitude: beware of experiments at ambient conditions. Proc Natl Acad Sci U S A 112:10080–10081

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Mohyeldin A, Garzon-Muvdi T, Quinones-Hinojosa A (2010) Oxygen in stem cell biology: a critical component of the stem cell niche. Cell Stem Cell 7:150–161

    CAS  PubMed  Article  Google Scholar 

  112. 112.

    Spencer JA, Ferraro F, Roussakis E, Klein A, Wu J, Runnels JM, Zaher W, Mortensen LJ, Alt C, Turcotte R et al (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–273

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Suda T, Takubo K, Semenza GL (2011) Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9:298–310

    CAS  PubMed  Article  Google Scholar 

  114. 114.

    Tiwari A, Wong CS, Nekkanti LP, Deane JA, McDonald C, Jenkin G, Kirkland MA (2016) Impact of oxygen levels on human hematopoietic stem and progenitor cell expansion. Stem Cells Dev. https://doi.org/10.1089/scd.2016.0153

  115. 115.

    Yu L, Ji W, Zhang H, Renda MJ, He Y, Lin S, Cheng EC, Chen H, Krause DS, Min W (2010) SENP1-mediated GATA1 deSUMOylation is critical for definitive erythropoiesis. J Exp Med 207:1183–1195

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Bawa-Khalfe T, Cheng J, Lin SH, Ittmann MM, Yeh ETH (2010) SENP1 induces prostatic intraepithelial neoplasia through multiple mechanisms. J Biol Chem 285:25859–25866

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Shao L, Zhou HJ, Zhang HF, Qin LF, Hwa J, Yun Z, Ji WD, Min W (2015) SENP1-mediated NEMO deSUMOylation in adipocytes limits inflammatory responses and type-1 diabetes progression. Nat Commun 6:8917

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

    Langley B, Sauve A (2013) Sirtuin deacetylases as therapeutic targets in the nervous system. Neurotherapeutics 10:605–620

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Hala D, Huggett DB, Burggren WW (2014) Environmental stressors and the epigenome. Drug Discov Today Technol 12:e3–e8

    CAS  PubMed  Article  Google Scholar 

  120. 120.

    Luo W, Chang R, Zhong J, Pandey A, Semenza GL (2012) Histone demethylase JMJD2C is a coactivator for hypoxia-inducible factor 1 that is required for breast cancer progression. Proc Natl Acad Sci U S A 109:E3367–E3376

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Prickaerts P, Adriaens ME, Beucken TV, Koch E, Dubois L, Dahlmans VE, Gits C, Evelo CT, Chan-Seng-Yue M, Wouters BG et al (2016) Hypoxia increases genome-wide bivalent epigenetic marking by specific gain of H3K27me3. Epigenetics Chromatin 9:46

    PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Salminen A, Kaarniranta K, Kauppinen A (2016) Hypoxia-inducible histone lysine demethylases: impact on the aging process and age-related diseases. Aging Dis 7:180–200

    PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    Ueda J, Ho JC, Lee KL, Kitajima S, Yang H, Sun W, Fukuhara N, Zaiden N, Chan SL, Tachibana M et al (2014) The hypoxia-inducible epigenetic regulators Jmjd1a and G9a provide a mechanistic link between angiogenesis and tumor growth. Mol Cell Biol 34:3702–3720

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Frisancho AR (2009) Developmental adaptation: where we go from here. Am J Hum Biol 21:694–703

    PubMed  Article  Google Scholar 

  125. 125.

    Hartley I, Elkhoury FF, Heon Shin J, Xie B, Gu X, Gao Y, Zhou D, Haddad GG (2013) Long-lasting changes in DNA methylation following short-term hypoxic exposure in primary hippocampal neuronal cultures. PLoS One 8:e77859

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Nanduri J, Makarenko V, Reddy VD, Yuan G, Pawar A, Wang N, Khan SA, Zhang X, Kinsman B, Peng YJ et al (2012) Epigenetic regulation of hypoxic sensing disrupts cardiorespiratory homeostasis. Proc Natl Acad Sci U S A 109:2515–2520

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Nanduri J, Peng YJ, Wang N, Khan SA, Semenza GL, Kumar GK, Prabhakar NR (2017) Epigenetic regulation of redox state mediates persistent cardiorespiratory abnormalities after long-term intermittent hypoxia. J Physiol 595:63–77

    CAS  PubMed  Article  Google Scholar 

Download references

Acknowledgements

Our study is funded by NIH grant 1P01HL098053 and 5P01HD32573 to GGH, VB, and AA who were supported in part by grants from the NSF (DBI-1458557, IIS-1318386) and NIH (1R01GM114362). Dr. Vineet Bafna is a co-founder, has an equity interest, and receives income from Digital Proteomics, LLC. The terms of this arrangement have been reviewed and approved by the University of California, San Diego, in accordance with its conflict of interest policies. DP was not involved in the research presented here. The authors declare no competing financial interests.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Gabriel G Haddad.

Electronic supplementary material

ESM 1

(PDF 134 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Azad, P., Stobdan, T., Zhou, D. et al. High-altitude adaptation in humans: from genomics to integrative physiology. J Mol Med 95, 1269–1282 (2017). https://doi.org/10.1007/s00109-017-1584-7

Download citation

Keywords

  • High-altitude adaptation
  • Chronic mountain sickness
  • Genomics
  • Polycythemic response
  • Cardiovascular response