High-altitude adaptation in humans

High-altitude adaptation in humans is an instance of evolutionary modification in certain human populations, including those of Tibet in Asia, the Andes of the Americas, and Ethiopia in Africa, who have acquired the ability to survive at altitudes above 2,500 meters (8,200 ft).^[1] This adaptation means irreversible, long-term physiological responses to high-altitude environments associated with heritable behavioral and genetic changes. While the rest of the human population would suffer serious health consequences at high altitudes, the indigenous inhabitants of these regions thrive in the highest parts of the world. These humans have undergone extensive physiological and genetic changes, particularly in the regulatory systems of oxygen respiration and blood circulation when compared to the general lowland population.^[2][3]

Around 81.6 million humans (approximately 1.1% of the world's human population) live permanently at altitudes above 2,500 meters (8,200 ft),^[4] which would seem to put these populations at risk for chronic mountain sickness (CMS).^[1] However, the high-altitude populations in South America, East Africa, and South Asia have lived there for millennia without apparent complications.^[5] This special adaptation is now recognized as an example of natural selection in action.^[6] The adaptation of the Tibetans is the fastest known example of human evolution, as it is estimated to have occurred between 1,000 BCE^[7][8][9] to 7,000 BCE.^[10][11]

Origin and basis

Himalayas, on the southern rim of the Tibetan Plateau

Humans are generally adapted to lowland environments where oxygen is abundant.^[12] At altitudes above 2,500 meters (8,200 ft), such humans experience altitude sickness, which is a type of hypoxia, a clinical syndrome of severe lack of oxygen. Some humans develop the illness beginning at above 1,500 meters (5,000 ft).^[13] Symptoms include fatigue, dizziness, breathlessness, headaches, insomnia, malaise, nausea, vomiting, body pain, loss of appetite, ear-ringing, blistering and purpling of the hands and feet, and dilated blood vessels.^[14][15][16]

The sickness is compounded by related symptoms such as cerebral oedema (swelling of brain) and pulmonary oedema (fluid accumulation in lungs) .^[17][18] Over a span of multiple days, individuals experiencing the effects of high-altitude hypoxia demonstrate raised respiratory activity and elevated metabolic conditions which persist during periods of rest. Subsequently, afflicted people will experience slowly declining heart rate. Hypoxia is a primary contributor to fatalities within mountaineering groups, making it a significant risk factor within high-altitude related challenges.^[19][20] In women, pregnancy can be severely affected, such as development of preeclampsia, which causes premature labor, low birth weight of babies, and often complicates with profuse bleeding, seizures, or death of the mother.^[2][21]

An estimated 81.6 million humans live at an elevation higher than 2,500 meters (8,200 ft) above sea level, of which 21.7 million reside in Ethiopia, 12.5 million in China, 11.7 million in Colombia, 7.8 million in Peru, and 6.2 million in Bolivia.^[4] Certain natives of Tibet, Ethiopia, and the Andes have been living at these high altitudes for generations and are resistant to hypoxia as a consequence of genetic adaptation.^[5][14] It is estimated that at 4,000 meters (13,000 ft) altitude, every lungful of air has approximately 60% of the oxygen molecules found in a lungful of air at sea level.^[22] Highlanders are thus constantly exposed to a low oxygen environment, yet they live without any debilitating problems.^[23]

One of the best-documented effects of high altitude on non-adapted women is a progressive reduction in birth weight. By contrast, the women of long-resident, high-altitude populations are known to give birth to heavier-weight infants than women of the lowland. This is particularly true among Tibetan babies, whose average birth weight is 294–650g (~470) g heavier than the surrounding Chinese population, and their blood-oxygen level is considerably higher.^[24]

Scientific investigation of high-altitude adaptation was initiated by A. Roberto Frisancho of the University of Michigan in the late 1960s among the Quechua people of Peru.^[25][26] Paul T. Baker of Penn State University’s Department of Anthropology also conducted a considerable amount of research into human adaptation to high altitudes, and mentored students who continued this research.^[27] One of these students, anthropologist Cynthia Beall of Case Western Reserve University, began conducting decades-long research on high altitude adaptation among the Tibetans in the early 1980s.^[28]

Physiological basis

Among the different native highlander populations, the underlying physiological responses to adaptation differ. For example, among four quantitative features, such as resting ventilation, hypoxic ventilatory response, oxygen saturation, and hemoglobin concentration, the levels of variations are significantly different between the Tibetans and the Aymaras.^[29] Methylation also influences oxygenation.^[30]

Tibetans

A Sherpa family

In the early 20th century, researchers observed the impressive physical abilities of Tibetans during Himalayan climbing expeditions. They considered the possibility that these abilities resulted from an evolutionary genetic adaptation to high-altitude conditions.^[31] The Tibetan plateau has an average elevation of 4,000 meters (13,000 ft) above sea level and covers more than 2.5 million km²; it is the highest and largest plateau in the world. In 1990, it was estimated that 4,594,188 Tibetans live on the plateau, with 53% living at an altitude over 3,500 meters (11,500 ft). Fairly large numbers (approximately 600,000) live at an altitude exceeding 4,500 meters (14,800 ft) in the Chantong-Qingnan area.^[32]

Tibetans who have been living in the Chantong-Qingnan area for 3,000 years do not exhibit the same elevated hemoglobin concentrations to cope with oxygen deficiency that are observed in other populations who have moved temporarily or permanently to high altitudes. Instead, the Tibetans inhale more air with each breath and breathe more rapidly than either sea-level populations or Andeans. Tibetans have better oxygenation at birth, enlarged lung volumes throughout life, and a higher capacity for exercise. They show a sustained increase in cerebral blood flow, lower hemoglobin concentration, and less susceptibility to chronic mountain sickness than other populations due to their longer history of high-altitude habitation.^[33][34]

With the proper physical preparation, individuals can develop short-term tolerance to high-altitude conditions. However, these biological changes are temporary and will reverse upon returning to lower elevations.^[35] Moreover, while lowland people typically experience increased breathing for only a few days after entering high altitudes, Tibetans maintain this rapid breathing and elevated lung capacity throughout their lifetime.^[36] This enables them to inhale large amounts of air per unit of time to compensate for low oxygen levels. Additionally, Tibetans typically have significantly higher levels of nitric oxide in their blood, often double that of lowlanders. This likely contributes to enhanced blood circulation by promoting vasodilation.^[37]

Furthermore, their hemoglobin level is not significantly different (average 15.6 g/dl in males and 14.2 g/dl in females)^[38] from those of humans living at low altitude. This is evidenced by mountaineers experiencing an increase of over 2 g/dl in hemoglobin levels within two weeks at the Mt. Everest base camp.^[39] Consequently, Tibetans demonstrate the capacity to mitigate the effects of hypoxia and mountain sickness throughout their lives. Even when ascending extraordinarily high peaks such as Mount Everest, they exhibit consistent oxygen uptake, heightened ventilation, augmented hypoxic ventilatory responses, expanded lung volumes, increased diffusing capacities, stable body weight, and improved sleep quality compared to lowland populations.^[40]

Andeans

In contrast to the Tibetans, Andean highlanders show different patterns of hemoglobin adaptation. Their hemoglobin concentration is higher than those of the lowlander population, which also happens to lowlanders who move to high altitudes. When they spend some weeks in the lowlands, their hemoglobin drops to the same levels as lowland humans. However, in contrast to lowland humans, they have increased oxygen levels in their hemoglobin; that is, more oxygen per blood volume. This confers an ability to carry more oxygen in each red blood cell, meaning a more effective transport of oxygen throughout their bodies.^[36] This enables Andeans to overcome hypoxia and normally reproduce without risk of death for the mother or baby. They have developmentally-acquired enlarged residual lung volume and an associated increase in alveolar area, which are supplemented with increased tissue thickness and moderate increase in red blood cells. Though Andean highlander children show delayed body growth, change in lung volume is accelerated.^[41]

Quechua woman with llamas

Among the Quechua people of the Altiplano, there is a significant variation in NOS3 (the gene encoding endothelial nitric oxide synthase, eNOS), which is associated with higher levels of nitric oxide at high altitude.^[42] Nuñoa children of Quechua ancestry exhibit higher blood-oxygen content (91.3) and lower heart rate (84.8) than their peers of different ethnicities, who have an average of 89.9 blood-oxygen and 88–91 heart rate.^[43] Quechua women have comparatively enlarged lung volume for increased respiration.^[44]

Aymara ceremony

Blood profile comparisons show that among the Andeans, Aymaran highlanders are better adapted to highlands than the Quechuas.^[45][46] Among the Bolivian Aymara people, the resting ventilation and hypoxic ventilatory response were quite low (roughly 1.5 times lower) compared to those of the Tibetans. The intrapopulation genetic variation was relatively smaller among the Aymara people.^[47][48] Moreover, when compared to Tibetans, blood hemoglobin levels at high altitudes among Aymaran is notably higher, with an average of 19.2 g/dl for males and 17.8 g/dl for females.^[38]

Ethiopians

The people of the Ethiopian highlands also live at extremely high altitudes, around 3,000 meters (9,800 ft) to 3,500 meters (11,500 ft). Highland Ethiopians exhibit elevated hemoglobin levels, like Andeans and lowlander humans at high altitudes, but do not exhibit the Andeans’ increase in oxygen content of hemoglobin.^[49] Among healthy individuals, the average hemoglobin concentrations are 15.9 and 15.0 g/dl for males and females, respectively (which is lower than normal, similar to the Tibetans), and an average oxygen saturation of hemoglobin is 95.3% (which is higher than average, like the Andeans).^[50] Additionally, Ethiopian highlanders do not exhibit any significant change in blood circulation of the brain, which has been observed among the Peruvian highlanders and attributed to their frequent altitude-related illnesses.^[51] Yet, similar to the Andeans and Tibetans, the Ethiopian highlanders are immune to the extreme dangers posed by high-altitude environment, and their pattern of adaptation is unique from that of other highland people.^[22]

Genetic basis

The underlying molecular evolution of high-altitude adaptation has been explored in recent years.^[23] Depending on geographical and environmental pressures, high-altitude adaptation involves different genetic patterns, some of which have evolved not long ago. For example, Tibetan adaptations became prevalent in the past 3,000 years, an example of rapid recent human evolution. At the turn of the 21st century, it was reported that the genetic makeup of the respiratory components of the Tibetan and the Ethiopian populations were significantly different.^[29]

Tibetans

Substantial evidence from Tibetan highlanders suggests that variation in hemoglobin and blood-oxygen levels are adaptive as Darwinian fitness. It has been documented that Tibetan women with a high likelihood of possessing one to two alleles for high blood-oxygen content (which is rare in other women) had more surviving children; the higher the oxygen capacity, the lower the infant mortality.^[52] In 2010, for the first time, the genes responsible for the unique adaptive traits were identified following genome sequencing of 50 Tibetans and 40 Han Chinese from Beijing. Initially, the strongest signal of natural selection was a transcription factor involved in response to hypoxia, called endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1). It was found that one single-nucleotide polymorphism (SNP) at EPAS1 shows a 78% frequency difference between Tibetan and mainland Chinese samples, representing the fastest genetic change observed in any human gene to date. Hence, Tibetan adaptation to high altitude is recognized as one of the fastest processes of phenotypically observable evolution in humans,^[53] which is estimated to have occurred a few thousand years ago, when the Tibetans split from the mainland Chinese population. The time of genetic divergence has been variously estimated as 2,750 (original estimate),^[9] 4,725,^[11] 8,000,^[54] or 9,000^[10] years ago.

Mutations in EPAS1 occur at a higher frequency in Tibetans than their Han neighbors and correlates with decreased hemoglobin concentrations among the Tibetans. This is known as the hallmark of their adaptation to hypoxia. Simultaneously, two genes, egl nine homolog 1 (EGLN1), which inhibits hemoglobin production under high oxygen concentration, and peroxisome proliferator-activated receptor alpha (PPARA), were also identified to be positively selected for decreased hemoglobin levels in the Tibetans.^[55]

Similarly, the Sherpas, known for their Himalayan hardiness, exhibit similar patterns in the EPAS1 gene, which is further evidence that the gene is under selection pressure for adaptation to the high-altitude life of Tibetans.^[56] A study in 2014 indicates that the mutant EPAS1 gene could have been inherited from archaic hominins, the Denisovans.^[57] EPAS1 and EGLN1 are believed to be important genes for unique adaptive traits when compared with those of the Chinese and Japanese.^[58] Comparative genome analysis in 2014 revealed that the Tibetans inherited an equal mixture of genomes from the Nepalese Sherpas and Hans, and that they acquired adaptive genes from the Sherpa lineage. Further, the population split was estimated to occur around 20,000 to 40,000 years ago, a range supported by archaeological, mitochondria DNA, and Y chromosome evidence for an initial colonization of the Tibetan plateau around 30,000 years ago.^[59]

The genes EPAS1, EGLN1, and PPARA function in concert with another gene named hypoxia inducible factors (HIF), which is in turn a principal regulator of red blood cell production (erythropoiesis) in response to oxygen metabolism.^[60][61][62] The genes are associated not only with decreased hemoglobin levels, but also with regulating metabolism. EPAS1 is significantly associated with increased lactate concentration, a product of anaerobic glycolysis, and PPARA is correlated with decrease in the activity of fatty acid oxidation.^[63] EGLN1 codes for an enzyme, prolyl hydroxylase 2 (PHD2), involved in erythropoiesis.

Among the Tibetans, a mutation in EGLN1 (specifically at position 12, where cytosine is replaced with guanine; and at 380, where G is replaced with C) results in mutant PHD2 (aspartic acid at position 4 becomes glutamine, and cysteine at 127 becomes serine) and this mutation inhibits erythropoiesis. This mutation is estimated to have occurred approximately 8,000 years ago.^[64] Further, the Tibetans are enriched for genes in the disease class of human reproduction (such as genes from the DAZ, BPY2, CDY, and HLA-DQ and HLA-DR gene clusters) and biological process categories of response to DNA damage stimulus and DNA repair (such as RAD51, RAD52, and MRE11A), which are related to the adaptive traits of high infant birth weight and darker skin tone and are most likely due to recent local adaptation.^[65]

Andeans

The patterns of genetic adaptation among the Andeans are largely distinct from those of the Tibetans, with both populations showing evidence of positive natural selection in different genes or gene regions. For genes in the HIF pathway, EGLN1 is the only instance where evidence of positive selection is observed in both Tibetans and Andeans.^[66] Even then, the pattern of variation for this gene differs between the two populations.^[6] Furthermore, there are no significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration among the Andeans, which is characteristic of the Tibetans.^[67]

The Andean pattern of adaptation is characterized by selection in a number of genes involved in cardiovascular development and function (such as BRINP3, EDNRA, NOS2A).^[68][69] This suggests that selection in Andeans, instead of targeting the HIF pathway like in the Tibetans, focused on adaptations of the cardiovascular system to combat chronic disease at high altitude. Analysis of ancient Andean genomes, some dating back 7,000 years, discovered selection in DST, a gene involved in cardiovascular function.^[70] The whole genome sequences of 20 Andeans (half of them having chronic mountain sickness) revealed that two genes, SENP1 (an erythropoiesis regulator) and ANP32D (an oncogene) play vital roles in their weak adaptation to hypoxia.^[71]

Ethiopians

The adaptive mechanism of Ethiopian highlanders differs from those of the Tibetans and Andeans due to the fact that their migration to the highland was relatively early. For example, the Amhara have inhabited altitudes above 2,500 meters (8,200 ft) for at least 5,000 years and altitudes around 2,000 meters (6,600 ft) to 2,400 meters (7,900 ft) for more than 70,000 years.^[72] Genomic analysis of two ethnic groups, Amhara and Oromo, has revealed that gene variations associated with hemoglobin difference among Tibetans or other variants at the exact gene location do not influence the adaptation in Ethiopians.^[73] Several candidate genes have been identified as possible explanations for the adaptation of Ethiopians, including CBARA1, VAV3, ARNT2 and THRB. Two of these genes (THRB and ARNT2) are known to play a role in the HIF-1 pathway, a pathway implicated in previous work reported in Tibetan and Andean studies. This supports the hypothesis that adaptation to high altitude arose independently among different highlander populations as a result of convergent evolution.^[74]

See also

• Altitude
• Effects of high altitude on humans (including acclimatisation)
• High-altitude adaptation
• High-altitude football controversy
• Tibetan Plateau

References

1. Azad P, Stobdan T, Zhou D, Hartley I, Akbari A, Bafna V, Haddad GG (December 2017). "High-altitude adaptation in humans: from genomics to integrative physiology". Journal of Molecular Medicine. 95 (12): 1269–1282. doi:10.1007/s00109-017-1584-7. PMC 8936998. PMID 28951950. S2CID 24949046.
2. Frisancho AR (1993). Human Adaptation and Accommodation. University of Michigan Press. pp. 175–301. ISBN 978-0472095117.
3. Hillary Mayell (24 February 2004). "Three High-Altitude Peoples, Three Adaptations to Thin Air". National Geographic News. National Geographic Society. Archived from the original on March 30, 2021. Retrieved 1 September 2013.
4. Tremblay JC, Ainslie PN (May 2021). "Global and country-level estimates of human population at high altitude". Proceedings of the National Academy of Sciences of the United States of America. 118 (18): e2102463118. Bibcode:2021PNAS..11802463T. doi:10.1073/pnas.2102463118. PMC 8106311. PMID 33903258.
5. Moore LG (1983). "Human genetic adaptation to high altitude". High Altitude Medicine & Biology. 2 (2): 257–279. doi:10.1089/152702901750265341. PMID 11443005.
6. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, et al. (September 2010). "Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data". PLOS Genetics. 6 (9): e1001116. doi:10.1371/journal.pgen.1001116. PMC 2936536. PMID 20838600.
7. Sanders R (1 July 2010). "Tibetans adapted to high altitude in less than 3,000 years". News Centre, UC Berkeley. UC Regents. Retrieved 2013-07-08.
8. Hsu J (1 July 2010). "Tibetans Underwent Fastest Evolution Seen in Humans". Live Science. TechMediaNetwork.com. Retrieved 2013-07-08.
9. Yi X, Liang Y, Huerta-Sanchez E, Jin X, Cuo ZX, Pool JE, et al. (July 2010). "Sequencing of 50 human exomes reveals adaptation to high altitude". Science. 329 (5987): 75–78. Bibcode:2010Sci...329...75Y. doi:10.1126/science.1190371. PMC 3711608. PMID 20595611.
10. Hu H, Petousi N, Glusman G, Yu Y, Bohlender R, Tashi T, et al. (April 2017). Tishkoff SA (ed.). "Evolutionary history of Tibetans inferred from whole-genome sequencing". PLOS Genetics. 13 (4): e1006675. doi:10.1371/journal.pgen.1006675. PMC 5407610. PMID 28448578.
11. Yang J, Jin ZB, Chen J, Huang XF, Li XM, Liang YB, et al. (April 2017). "Genetic signatures of high-altitude adaptation in Tibetans". Proceedings of the National Academy of Sciences of the United States of America. 114 (16): 4189–4194. Bibcode:2017PNAS..114.4189Y. doi:10.1073/pnas.1617042114. PMC 5402460. PMID 28373541.
12. Moore LG, Regensteine JG (1983). "Adaptation to High Altitude". Annual Review of Anthropology. 12: 285–304. doi:10.1146/annurev.an.12.100183.001441.
13. Brundrett G (March 2002). "Sickness at high altitude: a literature review". The Journal of the Royal Society for the Promotion of Health. 122 (1): 14–20. doi:10.1177/146642400212200109. PMID 11989137. S2CID 30489799.
14. Penaloza D, Arias-Stella J (March 2007). "The heart and pulmonary circulation at high altitudes: healthy highlanders and chronic mountain sickness". Circulation. 115 (9): 1132–1146. doi:10.1161/CIRCULATIONAHA.106.624544. PMID 17339571.
15. León-Velarde F, Villafuerte FC, Richalet JP (2010). "Chronic mountain sickness and the heart". Progress in Cardiovascular Diseases. 52 (6): 540–549. doi:10.1016/j.pcad.2010.02.012. PMID 20417348.
16. Wheatley K, Creed M, Mellor A (March 2011). "Haematological changes at altitude". Journal of the Royal Army Medical Corps. 157 (1): 38–42. doi:10.1136/jramc-157-01-07. PMID 21465909. S2CID 12821635.
17. Paralikar SJ (May 2012). "High altitude pulmonary edema-clinical features, pathophysiology, prevention and treatment". Indian Journal of Occupational and Environmental Medicine. 16 (2): 59–62. doi:10.4103/0019-5278.107066. PMC 3617508. PMID 23580834.
18. Eide RP, Asplund CA (2012). "Altitude illness: update on prevention and treatment". Current Sports Medicine Reports. 11 (3): 124–130. doi:10.1249/JSR.0b013e3182563e7a. PMID 22580489. S2CID 46056757.
19. Huey RB, Eguskitza X, Dillon M (2001). "Mountaineering in thin air". Hypoxia. Advances in Experimental Medicine and Biology. Vol. 502. pp. 225–236. doi:10.1007/978-1-4757-3401-0_15. ISBN 978-1-4419-3374-4. PMID 11950141.
20. Firth PG, Zheng H, Windsor JS, Sutherland AI, Imray CH, Moore GW, et al. (December 2008). "Mortality on Mount Everest, 1921-2006: descriptive study". BMJ. 337: a2654. doi:10.1136/bmj.a2654. PMC 2602730. PMID 19074222.
21. Moore LG, Shriver M, Bemis L, Hickler B, Wilson M, Brutsaert T, et al. (April 2004). "Maternal adaptation to high-altitude pregnancy: an experiment of nature--a review". Placenta. 25 (Suppl A): S60 – S71. doi:10.1016/j.placenta.2004.01.008. PMID 15033310.
22. Hornbein T, Schoene R (2001). High Altitude: An Exploration of Human Adaptation (Lung Biology in Health and Disease Volume 161). Marcel Dekker, New York, USA. pp. 42–874. ISBN 978-0824746049.
23. Muehlenbein, MP (2010). Human Evolutionary Biology. Cambridge University Press, Cambridge, UK. pp. 170–191. ISBN 978-0521879484.
24. Niermeyer S, Yang P, Zhuang J, Moore LG (November 1995). "Arterial oxygen saturation in Tibetan and Han infants born in Lhasa, Tibet". The New England Journal of Medicine. 333 (19): 1248–1252. doi:10.1056/NEJM199511093331903. PMID 7566001.
25. Frisancho AR (September 1969). "Human growth and pulmonary function of a high altitude Peruvian Quechua population". Human Biology. 41 (3): 365–379. JSTOR 41435777. PMID 5372293.
26. Leonard WR (2009). "Contributions of A. Roberto Frisancho to human population biology: an introduction". American Journal of Human Biology. 21 (5): 599–605. doi:10.1002/ajhb.20916. PMID 19367580. S2CID 41568762.
27. "Paul Baker". www.nasonline.org. Retrieved 2018-10-16.
28. Beall CM (2013). "Human adaptability studies at high altitude: research designs and major concepts during fifty years of discovery". American Journal of Human Biology. 25 (2): 141–147. doi:10.1002/ajhb.22355. PMID 23349118. S2CID 42661256.
29. Beall CM (February 2000). "Tibetan and Andean patterns of adaptation to high-altitude hypoxia". Human Biology. 72 (1): 201–228. PMID 10721618.
30. Kreier, Freda (22 December 2020). "High-altitude living has changed more than just the genes of some Peruvians". Science. doi:10.1126/science.abg2903. S2CID 234398150.
31. Wu T, Kayser B (2006). "High altitude adaptation in Tibetans". High Altitude Medicine & Biology. 7 (3): 193–208. doi:10.1089/ham.2006.7.193. PMID 16978132.
32. Wu T (2001). "The Qinghai-Tibetan plateau: how high do Tibetans live?". High Altitude Medicine & Biology. 2 (4): 489–499. doi:10.1089/152702901753397054. PMID 11809089.
33. Moore LG, Niermeyer S, Zamudio S (1998). "Human adaptation to high altitude: regional and life-cycle perspectives". American Journal of Physical Anthropology. 107 (Suppl 27): 25–64. doi:10.1002/(SICI)1096-8644(1998)107:27+<25::AID-AJPA3>3.0.CO;2-L. PMID 9881522.
34. Moore LG (2001). "Human genetic adaptation to high altitude". High Altitude Medicine & Biology. 2 (2): 257–279. doi:10.1089/152702901750265341. PMID 11443005.
35. Muza SR, Beidleman BA, Fulco CS (2010). "Altitude preexposure recommendations for inducing acclimatization". High Altitude Medicine & Biology. 11 (2): 87–92. doi:10.1089/ham.2010.1006. PMID 20586592.
36. Beall CM (May 2007). "Two routes to functional adaptation: Tibetan and Andean high-altitude natives". Proceedings of the National Academy of Sciences of the United States of America. 104 (Suppl 1): 8655–8660. Bibcode:2007PNAS..104.8655B. doi:10.1073/pnas.0701985104. PMC 1876443. PMID 17494744.
37. Beall CM, Laskowski D, Erzurum SC (April 2012). "Nitric oxide in adaptation to altitude". Free Radical Biology & Medicine. 52 (7): 1123–1134. doi:10.1016/j.freeradbiomed.2011.12.028. PMC 3295887. PMID 22300645.
38. Beall CM, Brittenham GM, Strohl KP, Blangero J, Williams-Blangero S, Goldstein MC, et al. (July 1998). "Hemoglobin concentration of high-altitude Tibetans and Bolivian Aymara". American Journal of Physical Anthropology. 106 (3): 385–400. doi:10.1002/(SICI)1096-8644(199807)106:3<385::AID-AJPA10>3.0.CO;2-X. PMID 9696153. S2CID 5692192.
39. Windsor JS, Rodway GW (March 2007). "Heights and haematology: the story of haemoglobin at altitude". Postgraduate Medical Journal. 83 (977): 148–151. doi:10.1136/pgmj.2006.049734. PMC 2599997. PMID 17344565.
40. Wu T, Li S, Ward MP (2005). "Tibetans at extreme altitude". Wilderness & Environmental Medicine. 16 (1): 47–54. doi:10.1580/pr04-04.1. PMID 15813148.
41. Frisancho AR (2013). "Developmental functional adaptation to high altitude: review". American Journal of Human Biology. 25 (2): 151–168. doi:10.1002/ajhb.22367. hdl:2027.42/96751. PMID 24065360. S2CID 33055072.
42. Wang P, Ha AY, Kidd KK, Koehle MS, Rupert JL (2010). "A variant of the endothelial nitric oxide synthase gene (NOS3) associated with AMS susceptibility is less common in the Quechua, a high altitude Native population". High Altitude Medicine & Biology. 11 (1): 27–30. doi:10.1089/ham.2009.1054. PMID 20367485.
43. Huicho L, Pawson IG, León-Velarde F, Rivera-Chira M, Pacheco A, Muro M, Silva J (2001). "Oxygen saturation and heart rate in healthy school children and adolescents living at high altitude". American Journal of Human Biology. 13 (6): 761–770. doi:10.1002/ajhb.1122. PMID 11748815. S2CID 11768057.
44. Kiyamu M, Bigham A, Parra E, León-Velarde F, Rivera-Chira M, Brutsaert TD (August 2012). "Developmental and genetic components explain enhanced pulmonary volumes of female Peruvian Quechua". American Journal of Physical Anthropology. 148 (4): 534–542. doi:10.1002/ajpa.22069. hdl:2027.42/92086. PMID 22552823.
45. Arnaud J, Quilici JC, Rivière G (1981). "High-altitude haematology: Quechua-Aymara comparisons". Annals of Human Biology. 8 (6): 573–578. doi:10.1080/03014468100005421. PMID 7337418.
46. Arnaud J, Gutierrez N, Tellez W, Vergnes H (July 1985). "Haematology and erythrocyte metabolism in man at high altitude: an Aymara-Quechua comparison". American Journal of Physical Anthropology. 67 (3): 279–284. doi:10.1002/ajpa.1330670313. PMID 4061583.
47. Beall CM, Strohl KP, Blangero J, Williams-Blangero S, Almasy LA, Decker MJ, et al. (December 1997). "Ventilation and hypoxic ventilatory response of Tibetan and Aymara high altitude natives". American Journal of Physical Anthropology. 104 (4): 427–447. doi:10.1002/(SICI)1096-8644(199712)104:4<427::AID-AJPA1>3.0.CO;2-P. PMID 9453694. S2CID 158629.
48. Beall CM (2007). "Tibetan and Andean Contrasts in Adaptation to High-Altitutde Hypoxia". Tibetan and Andean contrasts in adaptation to high-altitude hypoxia. Advances in Experimental Medicine and Biology. Vol. 475. pp. 63–74. doi:10.1007/0-306-46825-5_7. ISBN 978-0-306-46367-9. PMID 10849649.
49. Beall CM (February 2006). "Andean, Tibetan, and Ethiopian patterns of adaptation to high-altitude hypoxia". Integrative and Comparative Biology. 46 (1): 18–24. CiteSeerX 10.1.1.595.7464. doi:10.1093/icb/icj004. PMID 21672719.
50. Beall CM, Decker MJ, Brittenham GM, Kushner I, Gebremedhin A, Strohl KP (December 2002). "An Ethiopian pattern of human adaptation to high-altitude hypoxia". Proceedings of the National Academy of Sciences of the United States of America. 99 (26): 17215–17218. Bibcode:2002PNAS...9917215B. doi:10.1073/pnas.252649199. PMC 139295. PMID 12471159.
51. Claydon VE, Gulli G, Slessarev M, Appenzeller O, Zenebe G, Gebremedhin A, Hainsworth R (February 2008). "Cerebrovascular responses to hypoxia and hypocapnia in Ethiopian high altitude dwellers". Stroke. 39 (2): 336–342. doi:10.1161/STROKEAHA.107.491498. PMID 18096845.
52. Beall CM, Song K, Elston RC, Goldstein MC (September 2004). "Higher offspring survival among Tibetan women with high oxygen saturation genotypes residing at 4,000 m". Proceedings of the National Academy of Sciences of the United States of America. 101 (39): 14300–14304. Bibcode:2004PNAS..10114300B. doi:10.1073/pnas.0405949101. PMC 521103. PMID 15353580.
53. Native Village Youth; Education news (May 2011). "Tibetans evolved at fastest pace ever measured". Archived from the original on November 2, 2014. Retrieved 2013-04-15.
54. Lorenzo FR, Huff C, Myllymäki M, Olenchock B, Swierczek S, Tashi T, et al. (September 2014). "A genetic mechanism for Tibetan high-altitude adaptation". Nature Genetics. 46 (9): 951–956. doi:10.1038/ng.3067. PMC 4473257. PMID 25129147.
55. Simonson TS, Yang Y, Huff CD, Yun H, Qin G, Witherspoon DJ, et al. (July 2010). "Genetic evidence for high-altitude adaptation in Tibet". Science. 329 (5987): 72–75. Bibcode:2010Sci...329...72S. doi:10.1126/science.1189406. PMID 20466884. S2CID 45471238.
56. Hanaoka M, Droma Y, Basnyat B, Ito M, Kobayashi N, Katsuyama Y, et al. (2012). "Genetic variants in EPAS1 contribute to adaptation to high-altitude hypoxia in Sherpas". PLOS ONE. 7 (12): e50566. Bibcode:2012PLoSO...750566H. doi:10.1371/journal.pone.0050566. PMC 3515610. PMID 23227185.
57. Huerta-Sánchez E, Jin X, Bianba Z, Peter BM, Vinckenbosch N, Liang Y, et al. (August 2014). "Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA". Nature. 512 (7513): 194–197. Bibcode:2014Natur.512..194H. doi:10.1038/nature13408. PMC 4134395. PMID 25043035.
58. Peng Y, Yang Z, Zhang H, Cui C, Qi X, Luo X, et al. (February 2011). "Genetic variations in Tibetan populations and high-altitude adaptation at the Himalayas". Molecular Biology and Evolution. 28 (2): 1075–1081. doi:10.1093/molbev/msq290. PMID 21030426.
59. Jeong C, Alkorta-Aranburu G, Basnyat B, Neupane M, Witonsky DB, Pritchard JK, et al. (2014). "Admixture facilitates genetic adaptations to high altitude in Tibet". Nature Communications. 5 (3281): 3281. Bibcode:2014NatCo...5.3281J. doi:10.1038/ncomms4281. PMC 4643256. PMID 24513612.
60. MacInnis MJ, Rupert JL (2011). "'ome on the Range: altitude adaptation, positive selection, and Himalayan genomics". High Altitude Medicine & Biology. 12 (2): 133–139. doi:10.1089/ham.2010.1090. PMID 21718161.
61. van Patot MC, Gassmann M (2011). "Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α". High Altitude Medicine & Biology. 12 (2): 157–167. doi:10.1089/ham.2010.1099. PMID 21718164.
62. Simonson TS, McClain DA, Jorde LB, Prchal JT (April 2012). "Genetic determinants of Tibetan high-altitude adaptation". Human Genetics. 131 (4): 527–533. doi:10.1007/s00439-011-1109-3. PMID 22068265. S2CID 17636832.
63. Ge RL, Simonson TS, Cooksey RC, Tanna U, Qin G, Huff CD, et al. (June 2012). "Metabolic insight into mechanisms of high-altitude adaptation in Tibetans". Molecular Genetics and Metabolism. 106 (2): 244–247. doi:10.1016/j.ymgme.2012.03.003. PMC 3437309. PMID 22503288.
64. Lorenzo FR, Huff C, Myllymäki M, Olenchock B, Swierczek S, Tashi T, et al. (September 2014). "A genetic mechanism for Tibetan high-altitude adaptation". Nature Genetics. 46 (9): 951–956. doi:10.1038/ng.3067. PMC 4473257. PMID 25129147.
65. Zhang YB, Li X, Zhang F, Wang DM, Yu J (2012). "A preliminary study of copy number variation in Tibetans". PLOS ONE. 7 (7): e41768. Bibcode:2012PLoSO...741768Z. doi:10.1371/journal.pone.0041768. PMC 3402393. PMID 22844521.
66. Bigham A, Bauchet M, Pinto D, Mao X, Akey JM, Mei R, et al. (September 2010). "Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data". PLOS Genetics. 6 (9): e1001116. doi:10.1371/journal.pgen.1001116. PMC 2936536. PMID 20838600.
67. Bigham AW, Wilson MJ, Julian CG, Kiyamu M, Vargas E, Leon-Velarde F, et al. (2013). "Andean and Tibetan patterns of adaptation to high altitude". American Journal of Human Biology. 25 (2): 190–197. doi:10.1002/ajhb.22358. hdl:2027.42/96682. PMID 23348729. S2CID 1900321.
68. Bigham AW, Mao X, Mei R, Brutsaert T, Wilson MJ, Julian CG, et al. (December 2009). "Identifying positive selection candidate loci for high-altitude adaptation in Andean populations". Human Genomics. 4 (2): 79–90. doi:10.1186/1479-7364-4-2-79. PMC 2857381. PMID 20038496.
69. Crawford JE, Amaru R, Song J, Julian CG, Racimo F, Cheng JY, et al. (November 2017). "Natural Selection on Genes Related to Cardiovascular Health in High-Altitude Adapted Andeans". American Journal of Human Genetics. 101 (5): 752–767. doi:10.1016/j.ajhg.2017.09.023. PMC 5673686. PMID 29100088.
70. Lindo J, Haas R, Hofman C, Apata M, Moraga M, Verdugo RA, et al. (November 2018). "The genetic prehistory of the Andean highlands 7000 years BP though European contact". Science Advances. 4 (11): eaau4921. Bibcode:2018SciA....4.4921L. doi:10.1126/sciadv.aau4921. PMC 6224175. PMID 30417096.
71. Zhou D, Udpa N, Ronen R, Stobdan T, Liang J, Appenzeller O, et al. (September 2013). "Whole-genome sequencing uncovers the genetic basis of chronic mountain sickness in Andean highlanders". American Journal of Human Genetics. 93 (3): 452–462. doi:10.1016/j.ajhg.2013.07.011. PMC 3769925. PMID 23954164.
72. Pleurdeau D (2006). "Human technical behavior in the African Middle Stone Age: The lithic assemblage of Porc-Epic Cave (Dire Dawa, Ethiopia)". African Archaeological Review. 22 (4): 177–197. doi:10.1007/s10437-006-9000-7. S2CID 162259548.
73. 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 Genetics. 8 (12): e1003110. arXiv:1211.3053. doi:10.1371/journal.pgen.1003110. PMC 3516565. PMID 23236293.
74. Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Woldemeskel D, Beggs W, et al. (January 2012). "Genetic adaptation to high altitude in the Ethiopian highlands". Genome Biology. 13 (1): R1. doi:10.1186/gb-2012-13-1-r1. PMC 3334582. PMID 22264333.

External links

• Adapting to High Altitude Archived 2013-01-06 at the Wayback Machine
• High Altitude and Cold: Adaptation to the extremes Archived 2016-03-04 at the Wayback Machine
• Understanding adaptation to high altitude in the Andean region Archived 2016-03-03 at the Wayback Machine
• BBC: Altitude tolerant
• Understanding Evolution: The mysteries of Tibet
• Scientific resources at the Center for Research on Tibet
• Evolutionary Adaptations in High Altitude Tibet Archived 2012-09-27 at the Wayback Machine
• The Challenge of Living at High Altitudes
• Adapting to High Altitude Archived 2013-03-06 at the Wayback Machine