1932

Abstract

Population genomic studies of humans and other animals at high altitude have generated many hypotheses about the genes and pathways that may have contributed to hypoxia adaptation. Future advances require experimental tests of such hypotheses to identify causal mechanisms. Studies to date illustrate the challenge of moving from lists of candidate genes to the identification of phenotypic targets of selection, as it can be difficult to determine whether observed genotype–phenotype associations reflect causal effects or secondary consequences of changes in other traits that are linked via homeostatic regulation. Recent work on high-altitude models such as deer mice has revealed both plastic and evolved changes in respiratory, cardiovascular, and metabolic traits that contribute to aerobic performance capacity in hypoxia, and analyses of tissue-specific transcriptomes have identified changes in regulatory networks that mediate adaptive changes in physiological phenotype. Here we synthesize recent results and discuss lessons learned from studies of high-altitude adaptation that lie at the intersection of genomics and physiology.

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2021-02-15
2024-06-23
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Literature Cited

  1. 1. 
    Beall CM, Cavalleri GL, Deng L, Elston RC, Gao Y et al. 2010. Natural selection on EPAS1 (HIF2α) associated with low hemoglobin concentration in Tibetan highlanders. PNAS 107:2511459–64
    [Google Scholar]
  2. 2. 
    Bigham A, Bauchet M, Pinto D, Mao X, Akey JM et al. 2010. Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data. PLOS Genet 6:9e1001116
    [Google Scholar]
  3. 3. 
    Simonson TS, Yang Y, Huff CD, Yun H, Qin G et al. 2010. Genetic evidence for high-altitude adaptation in Tibet. Science 329:598772–75
    [Google Scholar]
  4. 4. 
    Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZXP et al. 2010. Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329:598775–78
    [Google Scholar]
  5. 5. 
    Peng Y, Yang Z, Zhang H, Cui C, Qi X et al. 2011. Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas. Mol. Biol. Evol. 28:21075–81
    [Google Scholar]
  6. 6. 
    Xu S, Li S, Yang Y, Tan J, Lou H et al. 2011. A genome-wide search for signals of high-altitude adaptation in Tibetans. Mol. Biol. Evol. 28:21003–11
    [Google Scholar]
  7. 7. 
    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 8:12e1003110
    [Google Scholar]
  8. 8. 
    Scheinfeldt LB, Soi S, Thompson S, Ranciaro T, Woldemeskel D et al. 2012. Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 13:1R1
    [Google Scholar]
  9. 9. 
    Huerta-Sánchez E, Degiorgio M, Pagani L, Tarekegn A, Ekong R et al. 2013. Genetic signatures reveal high-altitude adaptation in a set of Ethiopian populations. Mol. Biol. Evol. 30:81877–88
    [Google Scholar]
  10. 10. 
    Xiang K, Ouzhuluobu, Peng Y, Yang Z, Zhang X et al. 2013. Identification of a Tibetan-specific mutation in the hypoxic gene EGLN1 and its contribution to high-altitude adaptation. Mol. Biol. Evol. 30:81889–98
    [Google Scholar]
  11. 11. 
    Crawford JE, Amaru R, Song J, Julian CG, Racimo F et al. 2017. Natural selection on genes related to cardiovascular health in high-altitude adapted Andeans. Am. J. Hum. Genet. 101:5752–67
    [Google Scholar]
  12. 12. 
    Eichstaedt CA, Pagani L, Antao T, Inchley CE, Cardona A et al. 2017. Evidence of early-stage selection on EPAS1 and GPR126 genes in Andean high altitude populations. Sci. Rep. 7:13042
    [Google Scholar]
  13. 13. 
    Hu H, Petousi N, Glusman G, Yu Y, Bohlender R et al. 2017. Evolutionary history of Tibetans inferred from whole-genome sequencing. PLOS Genet 13:4e1006675
    [Google Scholar]
  14. 14. 
    Yang J, Jin Z-B, Chen J, Huang X-F, Li X-M et al. 2017. Genetic signatures of high-altitude adaptation in Tibetans. PNAS 114:164189–94
    [Google Scholar]
  15. 15. 
    Kaelin WG, Ratcliffe PJ. 2008. Oxygen sensing by metazoans: the central role of the HIF hydroxylase pathway. Mol. Cell 30:4393–402
    [Google Scholar]
  16. 16. 
    Lendahl U, Lee KL, Yang H, Poellinger L 2009. Generating specificity and diversity in the transcriptional response to hypoxia. Nat. Rev. Genet. 10:12821–32
    [Google Scholar]
  17. 17. 
    Greer SN, Metcalf JL, Wang Y, Ohh M 2012. The updated biology of hypoxia-inducible factor. EMBO J 31:112448–60
    [Google Scholar]
  18. 18. 
    Semenza GL. 2012. Hypoxia-inducible factors in physiology and medicine. Cell 148:3399–408
    [Google Scholar]
  19. 19. 
    Semenza GL. 2014. Oxygen sensing, hypoxia-inducible factors, and disease pathophysiology. Annu. Rev. Pathol. Mech. Dis. 9:47–71
    [Google Scholar]
  20. 20. 
    Samanta D, Prabhakar NR, Semenza GL 2017. Systems biology of oxygen homeostasis. Wiley Interdiscip. Rev. Syst. Biol. Med. 9:4e1382
    [Google Scholar]
  21. 21. 
    Bigham AW, Lee FS. 2014. Human high-altitude adaptation: forward genetics meets the HIF pathway. Genes Dev 28:202189–204
    [Google Scholar]
  22. 22. 
    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. 95:4394–407
    [Google Scholar]
  23. 23. 
    Petousi N, Robbins PA. 2014. Human adaptation to the hypoxia of high altitude: the Tibetan paradigm from the pregenomic to the postgenomic era. J. Appl. Physiol. 116:7875–84
    [Google Scholar]
  24. 24. 
    Simonson TS. 2015. Altitude adaptation: a glimpse through various lenses. High Alt. Med. Biol. 16:2125–37
    [Google Scholar]
  25. 25. 
    Azad P, Stobdan T, Zhou D, Hartley I, Akbari A et al. 2017. High-altitude adaptation in humans: from genomics to integrative physiology. J. Mol. Med. 95:121269–82
    [Google Scholar]
  26. 26. 
    O'Brien KA, Simonson TS, Murray AJ 2019. Metabolic adaptation to high altitude. Curr. Opin. Endocr. Metab. Res. 11:33–41
    [Google Scholar]
  27. 27. 
    Witt KE, Huerta-Sánchez E. 2019. Convergent evolution in human and domesticate adaptation to high-altitude environments. Philos. Trans. R. Soc. B Biol. Sci. 374:177720180235
    [Google Scholar]
  28. 28. 
    Zhang W, Fan Z, Han E, Hou R, Zhang L et al. 2014. Hypoxia adaptations in the grey wolf (Canis lupus chanco) from Qinghai-Tibet Plateau. PLOS Genet 10:7e1004466
    [Google Scholar]
  29. 29. 
    Liu XX, Zhang Y, Li Y, Pan J, Wang D et al. 2019. EPAS1 gain-of-function mutation contributes to high-altitude adaptation in Tibetan horses. Mol. Biol. Evol. 36:112591–603
    [Google Scholar]
  30. 30. 
    Schweizer RM, Velotta JP, Ivy CM, Jones MR, Muir SM et al. 2019. Physiological and genomic evidence that selection on the transcription factor Epas1 has altered cardiovascular function in high-altitude deer mice. PLOS Genet 15:11e1008420
    [Google Scholar]
  31. 31. 
    Scott GR, Egginton S, Richards JG, Milsom WK 2009. Evolution of muscle phenotype for extreme high altitude flight in the bar-headed goose. Proc. R. Soc. B Biol. Sci. 276:16733645–53
    [Google Scholar]
  32. 32. 
    Cheviron ZA, Bachman GC, Connaty AD, McClelland GB, Storz JF 2012. Regulatory changes contribute to the adaptive enhancement of thermogenic capacity in high-altitude deer mice. PNAS 109:228635–40
    [Google Scholar]
  33. 33. 
    Schippers M-P, Ramirez O, Arana M, Pinedo-Bernal P, McClelland GB 2012. Increase in carbohydrate utilization in high-altitude Andean mice. Curr. Biol. 22:242350–54
    [Google Scholar]
  34. 34. 
    Cheviron ZA, Connaty AD, McClelland GB, Storz JF 2014. Functional genomics of adaptation to hypoxic cold-stress in high-altitude deer mice: transcriptomic plasticity and thermogenic performance. Evolution 68:148–62
    [Google Scholar]
  35. 35. 
    Ge R-L, Simonson TS, Gordeuk V, Prchal JT, McClain DA 2015. Metabolic aspects of high-altitude adaptation in Tibetans. Exp. Physiol. 100:111247–55
    [Google Scholar]
  36. 36. 
    Lui MA, Mahalingam S, Patel P, Connaty AD, Ivy CM et al. 2015. High-altitude ancestry and hypoxia acclimation have distinct effects on exercise capacity and muscle phenotype in deer mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 308:9R779–91
    [Google Scholar]
  37. 37. 
    Scott GR, Elogio TS, Lui MA, Storz JF, Cheviron ZA 2015. Adaptive modifications of muscle phenotype in high-altitude deer mice are associated with evolved changes in gene regulation. Mol. Biol. Evol. 32:81962–76
    [Google Scholar]
  38. 38. 
    Murray AJ. 2016. Energy metabolism and the high-altitude environment. Exp. Physiol. 101:123–27
    [Google Scholar]
  39. 39. 
    Horscroft JA, Kotwica AO, Laner V, West JA, Hennis PJ et al. 2017. Metabolic basis to Sherpa altitude adaptation. PNAS 114:246382–87
    [Google Scholar]
  40. 40. 
    Lau DS, Connaty AD, Mahalingam S, Wall N, Cheviron ZA et al. 2017. Acclimation to hypoxia increases carbohydrate use during exercise in high-altitude deer mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 312:R400–11
    [Google Scholar]
  41. 41. 
    Mahalingam S, McClelland GB, Scott GR 2017. Evolved changes in the intracellular distribution and physiology of muscle mitochondria in high-altitude native deer mice. J. Physiol. 595:144785–801
    [Google Scholar]
  42. 42. 
    Nikel KE, Shanishchara NK, Ivy CM, Dawson NJ, Scott GR 2018. Effects of hypoxia at different life stages on locomotory muscle phenotype in deer mice native to high altitudes. Comp. Biochem. Physiol. B Biochem. Mol. Biol. 224:98–104
    [Google Scholar]
  43. 43. 
    Scott GR, Guo KH, Dawson NJ 2018. The mitochondrial basis for adaptive variation in aerobic performance in high-altitude deer mice. Integr. Comp. Biol. 58:3506–18
    [Google Scholar]
  44. 44. 
    Mahalingam S, Cheviron ZA, Storz JF, McClelland GB, Scott GR 2020. Chronic cold exposure induces mitochondrial plasticity in deer mice native to high altitudes. J. Physiol. 598235411–26
    [Google Scholar]
  45. 45. 
    Storz JF, Runck AM, Sabatino SJ, Kelly JK, Ferrand N et al. 2009. Evolutionary and functional insights into the mechanism underlying high-altitude adaptation of deer mouse hemoglobin. PNAS 106:3414450–55
    [Google Scholar]
  46. 46. 
    Storz JF, Runck AM, Moriyama H, Weber RE, Fago A 2010. Genetic differences in hemoglobin function between highland and lowland deer mice. J. Exp. Biol. 213:152565–74
    [Google Scholar]
  47. 47. 
    Natarajan C, Inoguchi N, Weber RE, Fago A, Moriyama H, Storz JF 2013. Epistasis among adaptive mutations in deer mouse hemoglobin. Science 340:61381324–27
    [Google Scholar]
  48. 48. 
    Projecto-Garcia J, Natarajan C, Moriyama H, Weber RE, Fago A et al. 2013. Repeated elevational transitions in hemoglobin function during the evolution of Andean hummingbirds. PNAS 110:5120669–74
    [Google Scholar]
  49. 49. 
    Galen SC, Natarajan C, Moriyama H, Weber RE, Fago A et al. 2015. Contribution of a mutational hotspot to adaptive changes in hemoglobin function in high-altitude Andean house wrens. PNAS 112:4513958–63
    [Google Scholar]
  50. 50. 
    Natarajan C, Hoffmann FG, Lanier HC, Wolf CJ, Cheviron ZA et al. 2015. Intraspecific polymorphism, interspecific divergence, and the origins of function-altering mutations in deer mouse hemoglobin. Mol. Biol. Evol. 32:4978–97
    [Google Scholar]
  51. 51. 
    Natarajan C, Projecto-Garcia J, Moriyama H, Weber RE, Muñoz-Fuentes V et al. 2015. Convergent evolution of hemoglobin function in high-altitude Andean waterfowl involves limited parallelism at the molecular sequence level. PLOS Genet 11:12e1005681
    [Google Scholar]
  52. 52. 
    Tufts DM, Natarajan C, Revsbech IG, Projecto-Garcia J, Hoffmann FG et al. 2015. Epistasis constrains mutational pathways of hemoglobin adaptation in high-altitude pikas. Mol. Biol. Evol. 32:2287–98
    [Google Scholar]
  53. 53. 
    Jensen B, Storz JF, Fago A 2016. Bohr effect and temperature sensitivity of hemoglobins from highland and lowland deer mice. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 195:10–14
    [Google Scholar]
  54. 54. 
    Natarajan C, Hoffmann FG, Weber RE, Fago A, Witt CC, Storz JF 2016. Predictable convergence in hemoglobin function has unpredictable molecular underpinnings. Science 354:6310336–40
    [Google Scholar]
  55. 55. 
    Storz JF. 2016. Hemoglobin-oxygen affinity in high-altitude vertebrates: Is there evidence for an adaptive trend. J. Exp. Biol. 219:203190–203
    [Google Scholar]
  56. 56. 
    Jendroszek A, Malte H, Overgaard CB, Beedholm K, Natarajan C et al. 2018. Allosteric mechanisms underlying the adaptive increase in hemoglobin-oxygen affinity of the bar-headed goose. J. Exp. Biol. 221:jeb.185470
    [Google Scholar]
  57. 57. 
    Natarajan C, Jendroszek A, Kumar A, Weber RE, Tame JRH et al. 2018. Molecular basis of hemoglobin adaptation in the high-flying bar-headed goose. PLOS Genet 14:4e1007331
    [Google Scholar]
  58. 58. 
    Zhu X, Guan Y, Signore AV, Natarajan C, DuBay SG et al. 2018. Divergent and parallel routes of biochemical adaptation in high-altitude passerine birds from the Qinghai-Tibet Plateau. PNAS 115:81865–70
    [Google Scholar]
  59. 59. 
    Signore AV, Yang Y-Z, Yang Q-Y, Qin G, Moriyama H et al. 2019. Adaptive changes in hemoglobin function in high-altitude Tibetan canids were derived via gene conversion and introgression. Mol. Biol. Evol. 36:102227–37
    [Google Scholar]
  60. 60. 
    Signore AV, Storz JF. 2020. Biochemical pedomorphosis and genetic assimilation in the hypoxia adaptation of Tibetan antelope. Sci. Adv. 6:25eabb5447
    [Google Scholar]
  61. 61. 
    Bennett AF, Huey RB. 1990. Studying the evolution of physiological performance. Oxford Surv. Evol. Biol. 7:251–84
    [Google Scholar]
  62. 62. 
    Storz JF, Bridgham JT, Kelly SA, Garland TJr 2015. Genetic approaches in comparative and evolutionary physiology. Am. J. Physiol. Regul. Integr. Comp. Physiol. 309:3R197–R214
    [Google Scholar]
  63. 63. 
    Hayes JP, O'Connor CS. 1999. Natural selection on thermogenic capacity of high-altitude deer mice. Evolution 53:41280–87
    [Google Scholar]
  64. 64. 
    Gilbert-Kawai ET, Milledge JS, Grocott MPW, Martin DS 2014. King of the mountains: Tibetan and Sherpa physiological adaptations for life at high altitude. Physiology 29:6388–402
    [Google Scholar]
  65. 65. 
    McClelland GB, Scott GR. 2019. Evolved mechanisms of aerobic performance and hypoxia resistance in high-altitude natives. Annu. Rev. Physiol. 81:561–83
    [Google Scholar]
  66. 66. 
    Storz JF, Cheviron ZA, McClelland GB, Scott GR 2019. Evolution of physiological performance capacities and environmental adaptation: insights from high-elevation deer mice (Peromyscus maniculatus). J. Mammal. 100:3910–22
    [Google Scholar]
  67. 67. 
    Taylor CR, Weibel ER, Weber JM, Vock R, Hoppeler H et al. 1996. Design of the oxygen and substrate pathways. 1. Model and strategy to test symmorphosis in a network structure. J. Exp. Biol. 199:81643–49
    [Google Scholar]
  68. 68. 
    Brutsaert TD. 2008. Do high-altitude natives have enhanced exercise performance at altitude. Appl. Physiol. Nutr. Metab. 33:3582–92
    [Google Scholar]
  69. 69. 
    Gonzalez NC, Kuwahira I. 2018. Systemic oxygen transport with rest, exercise, and hypoxia: a comparison of humans, rats, and mice. Compr. Physiol. 8:41537–73
    [Google Scholar]
  70. 70. 
    West JB. 2006. Human responses to extreme altitudes. Integr. Comp. Biol. 46:125–34
    [Google Scholar]
  71. 71. 
    Simonson TS, Wei G, Wagner HE, Wuren T, Qin G et al. 2015. Low haemoglobin concentration in Tibetan males is associated with greater high-altitude exercise capacity. J. Physiol. 593:143207–18
    [Google Scholar]
  72. 72. 
    Brutsaert TD, Kiyamu M, Revollendo GE, Isherwood JL, Lee FS et al. 2019. Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude. PNAS 116:4824006–11
    [Google Scholar]
  73. 73. 
    Stembridge M, Williams AM, Gasho C, Dawkins TG, Drane A et al. 2019. The overlooked significance of plasma volume for successful adaptation to high altitude in Sherpa and Andean natives. PNAS 116:3316177–79
    [Google Scholar]
  74. 74. 
    Tate KB, Ivy CM, Velotta JP, Storz JF, McClelland GB et al. 2017. Circulatory mechanisms underlying adaptive increases in thermogenic capacity in high-altitude deer mice. J. Exp. Biol. 220:3616–20
    [Google Scholar]
  75. 75. 
    Tate KB, Wearing OH, Ivy CM, Cheviron ZA, Storz JF et al. 2020. Coordinated changes across the O2 transport pathway underlie adaptive increases in thermogenic capacity in high-altitude deer mice. Proc. R. Soc. B 287:20192750
    [Google Scholar]
  76. 76. 
    Velotta JP, Jones J, Wolf CJ, Cheviron ZA 2016. Transcriptomic plasticity in brown adipose tissue contributes to an enhanced capacity for nonshivering thermogenesis in deer mice. Mol. Ecol. 25:122870–86
    [Google Scholar]
  77. 77. 
    Velotta JP, Robertson CE, Schweizer RM, McClelland GB, Cheviron ZA 2020. Adaptive shifts in gene regulation underlie a developmental delay in thermogenesis in high-altitude deer mice. Mol. Biol. Evol. 37:2309–21
    [Google Scholar]
  78. 78. 
    Bigham AW, Julian CG, Wilson MJ, Vargas E, Browne VA et al. 2014. Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude. Physiol. Genom. 46:18687–97
    [Google Scholar]
  79. 79. 
    Jeong C, Witonsky DB, Basnyat B, Neupane M, Beall CM et al. 2018. Detecting past and ongoing natural selection among ethnically Tibetan women at high altitude in Nepal. PLOS Genet 14:9e1007650
    [Google Scholar]
  80. 80. 
    Hawkes LA, Balachandran S, Batbayar N, Butler PJ, Frappell BP et al. 2011. The trans-Himalayan flights of bar-headed geese (Anser indicus). PNAS 108:239516–19
    [Google Scholar]
  81. 81. 
    Hawkes LA, Balachandran S, Batbayar N, Butler PJ, Chua B et al. 2013. The paradox of extreme high-altitude migration in bar-headed geese Anser indicus. Proc. R. Soc. B 280:175020122114
    [Google Scholar]
  82. 82. 
    Bishop CM, Spivey RJ, Hawkes LA, Batbayar N, Chua B et al. 2015. The roller coaster flight strategy of bar-headed geese conserves energy during Himalayan migrations. Science 347:6219250–54
    [Google Scholar]
  83. 83. 
    Storz JF, Quiroga-Carmona M, Opazo JC, Bowen T, Farson M et al. 2020. Discovery of the world's highest dwelling mammal. PNAS 117:3118169–71
    [Google Scholar]
  84. 84. 
    van Tienderen PH. 1991. Evolution of generalists and specialists in spatially heterogeneous environments. Evolution 45:61317–31
    [Google Scholar]
  85. 85. 
    Sultan SE, Spencer HG. 2002. Metapopulation structure favors plasticity over local adaptation. Am. Nat. 160:2271–83
    [Google Scholar]
  86. 86. 
    Brutsaert T. 2016. Why are high altitude natives so strong at high altitude? Nature versus nurture: genetic factors versus growth and development. Hypoxia: Translation in Progress RC Roach, PD Wagner, PH Hackett 101–12 New York: Springer
    [Google Scholar]
  87. 87. 
    Storz JF, Scott GR, Cheviron ZA 2010. Phenotypic plasticity and genetic adaptation to high-altitude hypoxia in vertebrates. J. Exp. Biol. 213:244125–36
    [Google Scholar]
  88. 88. 
    Scott GR. 2011. Elevated performance: the unique physiology of birds that fly at high altitudes. J. Exp. Biol. 214:152455–62
    [Google Scholar]
  89. 89. 
    Ivy CM, Scott GR. 2015. Control of breathing and the circulation in high-altitude mammals and birds. Comp. Biochem. Physiol. A 186:66–74
    [Google Scholar]
  90. 90. 
    Scott GR, Hawkes LA, Frappell PB, Butler PJ, Bishop CM, Milsom WK 2015. How bar-headed geese fly over the Himalayas. Physiology 30:2107–15
    [Google Scholar]
  91. 91. 
    Storz JF, Scott GR. 2019. Life ascending: mechanism and process in physiological adaptation to high-altitude hypoxia. Annu. Rev. Evol. Ecol. Syst. 50:503–26
    [Google Scholar]
  92. 92. 
    McClelland GB. 2004. Fat to the fire: the regulation of lipid oxidation with exercise and environmental stress. Comp. Biochem. Physiol. B 139:3443–60
    [Google Scholar]
  93. 93. 
    McClelland GB, Lyons SA, Robertson CE 2017. Fuel use in mammals: conserved patterns and evolved strategies for aerobic locomotion and thermogenesis. Integr. Comp. Biol. 57:2231–39
    [Google Scholar]
  94. 94. 
    Monge C, León-Velarde F. 1991. Physiological adaptation to high-altitude: oxygen transport in mammals and birds. Physiol. Rev. 71:41135–72
    [Google Scholar]
  95. 95. 
    Gonzalez NC, Clancy RL, Wagner PD 1993. Determinants of maximal oxygen-uptake in rats acclimated to simulated altitude. J. Appl. Physiol. 75:41608–14
    [Google Scholar]
  96. 96. 
    Wagner PD. 1996. A theoretical analysis of factors determining VO2MAX at sea level and altitude. Respir. Physiol. 106:3329–43
    [Google Scholar]
  97. 97. 
    Ou LC, Salceda S, Schuster SJ, Dunnack LM, Brink-Johnsen T et al. 1998. Polycythemic responses to hypoxia: molecular and genetic mechanisms of chronic mountain sickness. J. Appl. Physiol. 84:41242–51
    [Google Scholar]
  98. 98. 
    Henderson KK, Wagner H, Favret F, Britton SL, Koch LG et al. 2002. Determinants of maximal O2 uptake in rats selectively bred for endurance running capacity. J. Appl. Physiol. 93:41265–74
    [Google Scholar]
  99. 99. 
    Gonzalez NC, Kirkton SD, Howlett RA, Britton SL, Koch LG et al. 2006. Continued divergence in VO2max of rats artificially selected for running endurance is mediated by greater convective blood O2 delivery. J. Appl. Physiol. 101:51288–96
    [Google Scholar]
  100. 100. 
    Scott GR, Milsom WK. 2006. Flying high: a theoretical analysis of the factors limiting exercise performance in birds at altitude. Respir. Physiol. Neurobiol. 154:1–2284–301
    [Google Scholar]
  101. 101. 
    Kirkton SD, Howlett RA, Gonzalez NC, Giuliano PG, Britton SL et al. 2009. Continued artificial selection for running endurance in rats is associated with improved lung function. J. Appl. Physiol. 106:61810–18
    [Google Scholar]
  102. 102. 
    Sears MW, Hayes JP, O'Connor CS, Geluso K, Sedinger JS 2006. Individual variation in thermogenic capacity affects above-ground activity of high-altitude Deer Mice. Funct. Ecol. 20:197–104
    [Google Scholar]
  103. 103. 
    Cheviron ZA, Bachman GC, Storz JF 2013. Contributions of phenotypic plasticity to differences in thermogenic performance between highland and lowland deer mice. J. Exp. Biol. 216:71160–66
    [Google Scholar]
  104. 104. 
    Van Sant MJ, Hammond KA 2008. Contribution of shivering and nonshivering thermogenesis to thermogenic capacity for the deer mouse (Peromyscus maniculatus). Physiol. Biochem. Zool. 81:5605–11
    [Google Scholar]
  105. 105. 
    Hevener AL, He W, Barak Y, Le J, Bandyopadhyay G et al. 2003. Muscle-specific Pparg deletion causes insulin resistance. Nat. Med. 9:121491–97
    [Google Scholar]
  106. 106. 
    Amin RH, Mathews ST, Camp HS, Ding L, Leff T 2010. Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance. Am. J. Physiol. Endocrinol. Metab. 298:1E28–E37
    [Google Scholar]
  107. 107. 
    Storz JF. 2019. Hemoglobin: Insights into Protein Structure, Function, and Evolution Oxford, UK: Oxford Univ. Press
    [Google Scholar]
  108. 108. 
    Grether GF. 2005. Environmental change, phenotypic plasticity, and genetic compensation. Am. Nat. 166:4E115–23
    [Google Scholar]
  109. 109. 
    Velotta JP, Cheviron ZA. 2018. Remodeling ancestral phenotypic plasticity in local adaptation: a new framework to explore the role of genetic compensation in the evolution of homeostasis. Integr. Comp. Biol. 58:61098–110
    [Google Scholar]
  110. 110. 
    Storz JF. 2010. Genes for high altitudes. Science 329:598740–41
    [Google Scholar]
  111. 111. 
    van Patot MCT, Gassmann M 2011. Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α. High Alt. Med. Biol. 12:2157–67
    [Google Scholar]
  112. 112. 
    Yoon D, Ponka P, Prchal JT 2011. Hypoxia. 5. Hypoxia and hematopoiesis. Am. J. Physiol. Cell Physiol. 300:6C1215–22
    [Google Scholar]
  113. 113. 
    Tashi T, Song J, Prchal JT 2019. Congenital and evolutionary modulations of hypoxia sensing and their erythroid phenotype. Curr. Opin. Physiol. 7:27–32
    [Google Scholar]
  114. 114. 
    Beall CM, Reichsman AB. 1984. Hemoglobin levels in a Himalayan high-altitude population. Am. J. Phys. Anthropol. 63:3301–6
    [Google Scholar]
  115. 115. 
    Winslow RM, Chapman KW, Gibson CC, Samaja M, Monge CC et al. 1989. Different hematologic responses to hypoxia in Sherpas and Quechua Indians. J. Appl. Physiol. 66:41561–69
    [Google Scholar]
  116. 116. 
    Beall CM, Brittenham GM, Strohl KP, Williams-Blangero S, Goldstein MC et al. 1998. Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara. Am. J. Phys. Anthropol. 106:3385–400
    [Google Scholar]
  117. 117. 
    Wu TY, Wang X, Wei C, Cheng H, Wang X et al. 2005. Hemoglobin levels in Qinghai-Tibet: different effects of gender for Tibetans vs. Han. J. Appl. Physiol. 98:2598–604
    [Google Scholar]
  118. 118. 
    Beall CM. 2007. Two routes to functional adaptation: Tibetan and Andean high-altitude natives. PNAS 104:8655–60
    [Google Scholar]
  119. 119. 
    Peng Y, Cui C, He Y, Ouzhuluobu, Zhang H et al. 2017. Down-regulation of EPAS1 transcription and genetic adaptation of Tibetans to high-altitude hypoxia. Mol. Biol. Evol. 34:4818–30
    [Google Scholar]
  120. 120. 
    Persson SGB, Bergsten G. 1975. Circulatory effects of splenectomy in horse. 4. Effect on blood-flow and blood lactate at rest and during exercise. Zentralbl. Vet. Reihe A 22:10801–7
    [Google Scholar]
  121. 121. 
    Fedde MR, Wood SC. 1993. Rheological characteristics of horse blood—significance during exercise. Respir. Physiol. 94:3323–35
    [Google Scholar]
  122. 122. 
    Wu EY, Ramanathan M, Hsia CCW 1996. Role of hematocrit in the recruitment of pulmonary diffusing capacity: comparison of human and dog. J. Appl. Physiol. 80:31014–20
    [Google Scholar]
  123. 123. 
    Dane DM, Hsia CCQ, Wu EY, Hogg RT, Hogg DC et al. 2006. Splenectomy impairs diffusive oxygen transport in the lung of dogs. J. Appl. Physiol. 101:1289–97
    [Google Scholar]
  124. 124. 
    Hsia CCW, Johnson RLJr., Dane DM, Wu EY, Estrera AS et al. 2007. The canine spleen in oxygen transport: gas exchange and hemodynamic responses to splenectomy. J. Appl. Physiol. 103:51496–505
    [Google Scholar]
  125. 125. 
    Evans DL, Rose RJ. 1988. Cardiovascular and respiratory responses to submaximal exercise training in the thoroughbred horse. Pflugers Arch 411:3316–21
    [Google Scholar]
  126. 126. 
    Bοning D, Maassen N, Pries A 2011. The hematocrit paradox—How does blood doping really work. Int. J. Sports Med. 32:4242–46
    [Google Scholar]
  127. 127. 
    Crowell JW, Smith EE. 1967. Determinant of optimal hematocrit. J. Appl. Physiol. 22:3501–4
    [Google Scholar]
  128. 128. 
    Fan F-C, Chen RYZ, Schuessler GB, Chien S 1980. Effects of hematocrit variations on regional hemodynamics and oxygen-transport in the dog. Am. J. Physiol. 238:4H545–52
    [Google Scholar]
  129. 129. 
    Gaehtgens P, Kreutz F, Albrecht KH 1979. Optimal hematocrit for canine skeletal muscle during rhythmic isotonic exercise. Eur. J. Appl. Physiol. Occup. Physiol. 41:127–39
    [Google Scholar]
  130. 130. 
    Schuler B, Arras M, Keller S, Rettich A, Lundby C et al. 2010. Optimal hematocrit for maximal exercise performance in acute and chronic erythropoietin-treated mice. PNAS 107:1419–23
    [Google Scholar]
  131. 131. 
    Villafuerte FC, Cárdenas R, Monge-C C 2004. Optimal hemoglobin concentration and high altitude: a theoretical approach for Andean men at rest. J. Appl. Physiol. 96:51581–88
    [Google Scholar]
  132. 132. 
    Gonzalez NC, Erwig LP, Painter CJ3rd, Clancy RL, Wagner PD 1994. Effect of hematocrit on systemic O2 transport in hypoxic and normoxic exercise in rats. J. Appl. Physiol. 77:31341–48
    [Google Scholar]
  133. 133. 
    Fedde MR, Koehler JA, Wood SC, Gonzalez NC 1996. Blood viscosity in chronically hypoxic rats: an effect independent of packed cell volume. Respir. Physiol. 104:145–52
    [Google Scholar]
  134. 134. 
    Calbet JAL, Rådegran G, Boushel R, Søndergaard H, Saltin B, Wagner PD 2002. Effect of blood haemoglobin concentration on O2,max and cardiovascular function in lowlanders acclimatised to 5260 m. J. Physiol. 545:2715–28
    [Google Scholar]
  135. 135. 
    Vargas E, Spielvogel H. 2006. Chronic mountain sickness, optimal hemoglobin, and heart disease. High Alt. Med. Biol. 7:2138–49
    [Google Scholar]
  136. 136. 
    Donnelly S. 2003. Why is erythropoietin made in the kidney? The kidney functions as a ‘critmeter’ to regulate the hematocrit. Hypoxia: Through the Lifecycle RC Roach, PD Wagner, PH Hackett 73–87 New York: Springer
    [Google Scholar]
  137. 137. 
    Storz JF, Cheviron ZA. 2016. Functional genomic insights into regulatory mechanisms of high-altitude adaptation. Adv. Exp. Med. Biol. 903:113–28
    [Google Scholar]
  138. 138. 
    Cho JI, Basnyat B, Jeong C, Di Rienzo A, Childs G et al. 2017. Ethnically Tibetan women in Nepal with low hemoglobin concentration have better reproductive outcomes. Evol. Med. Public Health 2017:182–96
    [Google Scholar]
  139. 139. 
    Gonzales GF, Steenland K, Tapia V 2009. Maternal hemoglobin level and fetal outcome at low and high altitudes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 297:5R1477–85
    [Google Scholar]
  140. 140. 
    Moore LG, Zamudio S, Zhuang J, Sun S, Droma T 2001. Oxygen transport in Tibetan women during pregnancy at 3,658 m. Am. J. Phys. Anthropol. 114:142–53
    [Google Scholar]
  141. 141. 
    Julian CG, Wilson MJ, Lopez M, Yamashiro H, Tellez W et al. 2009. Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth. Am. J. Physiol. Regul. Integr. Comp. Physiol. 296:5R1564–75
    [Google Scholar]
  142. 142. 
    Browne VA, Julian CG, Toledo-Jaldin L, Cioffi-Ragan D, Vargas E, Moore LG 2015. Uterine artery blood flow, fetal hypoxia and fetal growth. Philos. Trans. R. Soc. B 370:166320140068
    [Google Scholar]
  143. 143. 
    Ivy CM, Scott GR. 2017. Control of breathing and ventilatory acclimatization to hypoxia in deer mice native to high altitudes. Acta Physiol 221:4266–82
    [Google Scholar]
  144. 144. 
    Gonzalez NC, Clancy RL, Moue Y, Richalet J-P 1998. Increasing maximal heart rate increases maximal O2 uptake in rats acclimatized to simulated altitude. J. Appl. Physiol. 84:1164–68
    [Google Scholar]
  145. 145. 
    Sylvester JT, Shimoda LA, Aaronson PI, Ward JPT 2012. Hypoxic pulmonary vasoconstriction. Physiol. Rev. 92:1367–520
    [Google Scholar]
  146. 146. 
    Dempsey JA, Morgan BJ. 2015. Humans in hypoxia: A conspiracy of maladaptation?. ! Physiology 30:4304–16
    [Google Scholar]
  147. 147. 
    Durmowicz AG, Hofmeister S, Kadyraliev TK, Aldashev AA, Stenmark KR 1993. Functional and structural adaptation of the yak pulmonary circulation to residence at high-altitude. J. Appl. Physiol. 74:52276–85
    [Google Scholar]
  148. 148. 
    Groves BM, Droma T, Sutton JR, McCullough RG, McCullough RE et al. 1993. Minimal hypoxic pulmonary hypertension in normal Tibetans at 3,658 m. J. Appl. Physiol. 74:1312–18
    [Google Scholar]
  149. 149. 
    Ge R-L, Kubo K, Kobayashi T, Sekiguchi M, Honda T 1998. Blunted hypoxic pulmonary vasoconstrictive response in the rodent Ochotona curzoniae (pika) at high altitude. Am. J. Physiol. 274:5H1792–99
    [Google Scholar]
  150. 150. 
    Sakai A, Matsumoto T, Saitoh M, Matsuzaki T, Koizumi T et al. 2003. Cardiopulmonary hemodynamics of blue-sheep, Pseudois nayaur, as high-altitude adapted mammals. Jpn. J. Physiol. 53:5377–84
    [Google Scholar]
  151. 151. 
    Velotta JP, Ivy CM, Wolf CJ, Scott GR, Cheviron ZA 2018. Maladaptive phenotypic plasticity in cardiac muscle growth is suppressed in high-altitude deer mice. Evolution 72:122712–27
    [Google Scholar]
  152. 152. 
    Lande R. 2019. Developmental integration and evolution of labile plasticity in a complex quantitative character in a multiperiodic environment. PNAS 116:2311361–69
    [Google Scholar]
  153. 153. 
    Petousi N, Croft QPP, Cavalleri GL, Cheng H-Y, Formenti F et al. 2014. Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia. J. Appl. Physiol. 116:7893–904
    [Google Scholar]
  154. 154. 
    Cheviron ZA, Natarajan C, Projecto-Garcia J, Eddy DK, Jones J et al. 2014. Integrating evolutionary and functional tests of adaptive hypotheses: a case study of altitudinal differentiation in hemoglobin function in an Andean sparrow. Zonotrichia capensis. Mol. Biol. Evol. 31:112948–62
    [Google Scholar]
  155. 155. 
    Lorenzo FR, Huff C, Myllymäki M, Olenchock B, Swierczek S et al. 2014. A genetic mechanism for Tibetan high-altitude adaptation. Nat. Genet. 46:9951–56
    [Google Scholar]
  156. 156. 
    Song D, Li L-S, Arsenault PR, Tan Q, Bigham AW et al. 2014. Defective Tibetan PHD2 binding to p23 links high altitude adaption to altered oxygen sensing. J. Biol. Chem. 289:2114656–65
    [Google Scholar]
  157. 157. 
    Wilkins MR, Aldashev AA, Wharton J, Rhodes CJ, Vandrovcova J et al. 2014. α1-A680T variant in GUCY1A3 as a candidate conferring protection from pulmonary hypertension among Kyrgyz highlanders. Circulation 7:6920–29
    [Google Scholar]
  158. 158. 
    Xu X-H, Huang X-W, Qun L, Li Y-N, Wang Y et al. 2015. Two functional loci in the promoter of EPAS1 gene involved in high-altitude adaptation of Tibetans. Sci. Rep. 4:7465
    [Google Scholar]
  159. 159. 
    Stobdan T, Zhou D, Ao-leong E, Ortiz D, Ronen R, Hartley I 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. PNAS 112:3310425–30
    [Google Scholar]
  160. 160. 
    Azad P, Zhao HW, Cabrales PJ, Ronen R, Zhou D et al. 2016. Senp1 drives hypoxia-induced polycythemia via GATA1 and Bcl-xL in subjects with Monge's disease. J. Exp. Med. 213:122729–44
    [Google Scholar]
  161. 161. 
    Stobdan T, Zhou D, Williams AT, Cabrales P, Haddad GG 2018. Cardiac-specific knockout and pharmacological inhibition of Endothelin receptor type B lead to cardiac resistance to extreme hypoxia. J. Mol. Med. 96:9975–82
    [Google Scholar]
  162. 162. 
    Yang D, Peng Y, Ouzhuluobu, Bianbazhuoma, Cui C et al. 2016. HMOX2 functions as a modifier gene for high-altitude adaptation in Tibetans. Hum. Mutat. 37:2216–23
    [Google Scholar]
  163. 163. 
    Song D, Navalsky BE, Guan W, Ingersoll C, Wang T et al. 2020. Tibetan PHD2, an allele with loss-of-function properties. PNAS 117:2212230–38
    [Google Scholar]
  164. 164. 
    Dawson NJ, Lyons SA, Henry DA, Scott GR 2018. Effects of chronic hypoxia on diaphragm function in deer mice native to high altitude. Acta Physiol 223:1e13030
    [Google Scholar]
  165. 165. 
    Ivy CM, Scott GR. 2018. Evolved changes in breathing and CO2 sensitivity in deer native to high altitudes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 315:5R1027–37
    [Google Scholar]
  166. 166. 
    Robertson CE, Tattersall GJ, McClelland GB 2019. Development of homeothermic endothermy is delayed in high-altitude native deer mice (Peromyscus maniculatus). Proc. R. Soc. B 286:190720190841
    [Google Scholar]
  167. 167. 
    Robertson CE, McClelland GB. 2019. Developmental delay in shivering limits thermogenic capacity in juvenile high-altitude deer mice (Peromyscus maniculatus). J. Exp. Biol. 222:jeb210963
    [Google Scholar]
  168. 168. 
    Scott AL, Pranckevicius NA, Nurse CA, Scott GR 2019. Regulation of catecholamine release from the adrenal medulla is altered in deer mice (Peromyscus maniculatus) native to high altitudes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 317:3R407–17
    [Google Scholar]
  169. 169. 
    Grocott M, Montgomery H, Vercueil A 2007. High-altitude physiology and pathophysiology: implications and relevance for intensive care medicine. Crit. Care 11:1203
    [Google Scholar]
  170. 170. 
    Carey HV, Martin SL, Horwitz BA, Yan L, Bailey SM et al. 2012. Elucidating nature's solutions to heart, lung, and blood diseases and sleep disorders. Circ. Res. 110:7915–21
    [Google Scholar]
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