Hypoxic ventilatory response

Last updated

Hypoxic ventilatory response (HVR) is the increase in ventilation induced by hypoxia that allows the body to take in and transport lower concentrations of oxygen at higher rates. It is initially elevated in lowlanders who travel to high altitude, but reduces significantly over time as people acclimatize. [1] [2] In biological anthropology, HVR also refers to human adaptation to environmental stresses resulting from high altitude. [3]

Contents

In mammals, HVR invokes several physiological mechanisms. It is a direct result of the decrease in partial pressure of oxygen in arterial blood, and leads to increased ventilation. The body has different ways of coping with acute hypoxia. Mammals that rely on pulmonary ventilation will increase their ventilation to account for the lack of oxygen reaching the tissues. [2] Mammals will also experience decreases in aerobic metabolism and oxygen demand, along with increases in ATP production.

The physiological mechanisms differ in effect and in course of time. HVR is time dependent and can be divided into two phases: the first (0–5 minutes) of ventilation increase, and the second (5–20 minutes) of slow decline. [4]

The initial increase in ventilation from HVR is initiated by the carotid bodies, which are bilaterally located at the port of brain circulation. [2] Carotid bodies contain oxygen-sensitive cells that become more active in response to hypoxia. They send input to the brainstem which is then processed by respiratory centers. Other mechanisms include hypoxia-inducible factors, particularly HIF1. [2] Hormonal changes have also been associated with HVR, particularly those that affect the functioning of the carotid bodies. [5]

As HVR is a response to decreased oxygen availability, [1] it shares the same environmental triggers as hypoxia. Such precursors include travelling to high altitude locations [6] and living in an environment with high levels of carbon monoxide. [7] Combined with climate, HVR can affect fitness and hydration. [2] Especially for lowlanders who traverse past 6000 meters in altitude, the limit of prolonged human exposure to hypoxia, HVR may result in hyperventilation and ultimately the deterioration of the body. Oxygen consumption is reduced to a maximum of 1 liter per minute. [8]

Travelers acclimatized to high altitudes exhibit high levels of HVR, as it provides advantages such as increased oxygen intake, enhanced physical and mental performance, and lower susceptibility to illnesses associated with high altitude. [1] Adaptations in populations living at high altitudes range from cultural to genetic, and vary among populations. For example, Tibetans living at high altitudes have a more sensitive hypoxic ventilatory response than do Andean peoples living at similar altitudes, [5] [9] even though both populations exhibit greater aerobic capacity compared to lowlanders. [10] The cause of this difference is most likely genetic, although developmental factors may also contribute. [10]

Physiology

Acute hypoxic ventilatory response

Acute response (AR)

The first stage of the hypoxic ventilatory response consists of the initial reaction to a hypoxic environment leading up to the peak known as short-term potentiation (STP). [11] The process is induced by a decrease in oxygen partial pressure in blood. Type I glomus cells of carotid bodies detect the change in oxygen levels and release neurotransmitters towards the carotid sinus nerve, which in turn stimulates the brain, ultimately resulting in increased ventilation. [2] The period of increased ventilation varies among different individuals but typically lasts under ten minutes. [12]

Short-term potentiation (STP)

STP is the increase in ventilation after the acute hypoxic response and the eventual return of ventilation to its equilibrium after carotid sinus nerve stimulation, which causes a slowing in heart rate. This mechanism usually lasts between one and two minutes. [13] STP is most apparent in tidal volume or the amplitude of phrenic neural output.

Short-term depression (STD)

STD is a temporary jump in respiratory frequency at the beginning of carotid chemo afferent stimulation or a temporary drop in respiratory frequency at the end of chemo afferent stimulation. This mechanism lasts from a span of several seconds to a few minutes. [14] STP has only been found in the respiratory frequency of phrenic nerve stimulation, which produces contraction of the diaphragm.

Ventilatory response to sustained hypoxia

A continued presence in a hypoxic environment of more than 24 hours leads to a steady flow of ventilation. [11] This contingency in the environment causes hypocapnia which decreases ventilation. [15]

Chronic hypoxic ventilatory response

Chronic hypoxia results in further physiological changes due to the transcription factor hypoxia-inducible factor (HIF). HIF is a dimer composed of the HIF-1α and HIF-1β subunit. HIF-1α is normally unable to bind with HIF-1β. However, lower oxygen partial pressure induces post-transcriptional modification of HIF-1α, allowing HIF-1α to dimerize with HIF-1β to form HIF-1. HIF-1 induces many physiological changes that help the body adapt to the lower availability of oxygen including angiogenesis, increased erythropoietin production, and promoting anaerobic metabolism. [2]

Neurology

The nervous system plays a key role in the hypoxic ventilatory response. The process is triggered by the peripheral nervous system's detection of a low blood oxygen level. In particular, the neurotransmitter glutamate has been shown to have a direct correlation to a rise in ventilation. A study conducted in dogs investigated how their cardiovascular systems respond to various levels of oxygen before and after being given MK-801, which is a glutamate antagonist. With the MK-801, there was a noticeable decrease in both heart rate and breaths per minute under hypoxia. According to the study, the fact that the HVR was lessened when glutamate was inhibited demonstrates that glutamate is essential to the response. [16]

High altitude adaptation

This image depicts the three high altitude areas where studied populations have adapted to their environment: (From left to right) Andean Altiplano, Simian Plateau, and Tibetan Plateau. World Map of HVR adaptation in high altitude populations.jpg
This image depicts the three high altitude areas where studied populations have adapted to their environment: (From left to right) Andean Altiplano, Simian Plateau, and Tibetan Plateau.

Populations residing in altitudes above 2,500 meters have adapted to their hypoxic environments. [18] Chronic HVR is set of adaptations found among most human populations historically native to high-altitude regions, including the Tibetan Plateau, the Andean Altiplano, and the Simian Plateau. [17] Up to 140 million people in total reside in such areas, although not all possess these adaptations. [19] Populations that have permanently settled in high altitude locations show virtually no reaction to acute hypoxia. Natives of the Andes and the Himalayas have been shown to develop adaptation to hypoxia from birth to neonatal years in the form of larger lungs and greater gas exchange surface area. [20] This response can be attributed to genetic factors, but the development of the resistance to acute hypoxia is highly affected by when the individual is exposed to high altitude; [20] while genetic factors play an indefinite role in a person's HVR, because long term migrants do not show reduction in their reactions of high altitude even after living in high altitudes in long term, the discrepancy suggests that reaction to HVR is the combination of environmental exposure and genetic factors. [18]

Anthropology

Populations

Andeans

Cusco, Peru, which has an altitude of 11,000 ft Cuzco-Pano edit.jpg
Cusco, Peru, which has an altitude of 11,000 ft

The Andean peoples are one of three central populations of study that have a decreased HVR. These populations notably inhabit areas in and around the Andes mountain range, which has an average altitude of 13,000 feet (4,000 m). [21] HVR has been studied in inhabitants of Cusco, Peru, which lies at 11,000 feet (3,400 m). [21] Living in such high altitudes has led to cultural adaptations, including the consumption of coca tea. Coca tea is an extract made by boiling the leaves of the coca plant in water and contains the stimulant Cocaine. For millennia, Andeans have used coca tea as a treatment for acute altitude sickness, [22] and to this day it is still given to those travelling to the high altitude regions of Peru, though, its effectiveness has been disputed. [23] In a 2010 study published in the Journal of Travel Medicine, the consumption of coca tea was actually associated with an increase in the incidence of altitude sickness experienced by travelers visiting the city of Cusco, Peru. [23]

It has been found that the ventilatory response is substantially less pronounced in the Andean populations than in the Tibetans, with the HVR response of Tibetans roughly double that of Andeans at an altitude of around 4,000 metres (13,000 ft). [24] The altitude adaptations also appear to be less permanent than those seen in the Tibetan populations, as the Andeans have a much higher prevalence of Chronic Mountain Sickness (CMS), where the body develops a harmful reaction to low oxygen levels over many years. [25]

Tibetans

Mount Everest, the highest peak of the Himalayas. Everest North Face toward Base Camp Tibet Luca Galuzzi 2006.jpg
Mount Everest, the highest peak of the Himalayas.

The Tibetan people are an ethnic group native to Tibet that live throughout the Tibetan Plateau. They live at altitudes up to 15,000 feet (4,600 m), [26] and are thus of extreme interest to researchers investigating HVR in high altitude populations. One of these populations are the Sherpa people, a group of Tibetans who are sought after for their knowledge of and skill with navigating through the Himalayas. Historically, Sherpas have been contracted to guide expeditions up Mount Everest, but the practice has since declined in light of exploitation of the Sherpa guides. The energy and ease at which the Sherpa ascend and descend mountains is due to their ability to use oxygen more efficiently. [27] This ability to excel at mountaineering has shifted their culture around it. Tourism has become a driving force for the financial income of the Sherpa people. The Sherpa are able to make much more money [28] acting as travel guides due to their local knowledge, and climbing ability.

Genetic evidence suggests that the Tibetan peoples diverged from the larger Han Chinese population any time around 1,000 B.C.E. [29] [30] [31] to 7,000 B.C.E. [32] [33] Given the significant mutations to the EPAS1 gene that contribute to the Tibetan resistance to altitude sickness, this suggests that the extreme evolutionary pressure on the Tibetan peoples has produced one of the fastest natural selection effects seen in a human population. [34] The adaptations of Tibetans to their hypoxic ventilatory response interact with other adaptations to promote successful reproduction. For example, Tibetans have evolved a greater oxygen saturation during infancy, leading to a lower rate of child mortality than experienced by non-adapted populations at altitude. [35]

Amhara

Simien Mountains 14,900 ft Semien Mountains 13.jpg
Simien Mountains 14,900 ft

The Amhara people are the occupants of the central and northern Highlands of Ethiopia in the Amhara Region, where the elevation ranges consistently between 1500 m (4,921 ft) to 4550 m (14,928 ft). For over 5,000 years humans have been living near the Simien Mountains at altitudes above 3,000m and over that time they genetically adapted to the hypoxic conditions of high altitude. [36] [37]

Related Research Articles

<span class="mw-page-title-main">Hypoxia (medicine)</span> Medical condition of lack of oxygen in the tissues

Hypoxia is a condition in which the body or a region of the body is deprived of adequate oxygen supply at the tissue level. Hypoxia may be classified as either generalized, affecting the whole body, or local, affecting a region of the body. Although hypoxia is often a pathological condition, variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise.

<span class="mw-page-title-main">Altitude sickness</span> Medical condition due to rapid exposure to low oxygen at high altitude

Altitude sickness, the mildest form being acute mountain sickness (AMS), is a harmful effect of high altitude, caused by rapid exposure to low amounts of oxygen at high elevation. People can respond to high altitude in different ways. Symptoms may include headaches, vomiting, tiredness, confusion, trouble sleeping, and dizziness. Acute mountain sickness can progress to high-altitude pulmonary edema (HAPE) with associated shortness of breath or high-altitude cerebral edema (HACE) with associated confusion. Chronic mountain sickness may occur after long-term exposure to high altitude.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Altitude training</span> Athletic training at high elevations

Altitude training is the practice by some endurance athletes of training for several weeks at high altitude, preferably over 2,400 metres (8,000 ft) above sea level, though more commonly at intermediate altitudes due to the shortage of suitable high-altitude locations. At intermediate altitudes, the air still contains approximately 20.9% oxygen, but the barometric pressure and thus the partial pressure of oxygen is reduced.

<span class="mw-page-title-main">Glomus cell</span>

Glomus cells are the cell type mainly located in the carotid bodies and aortic bodies. Glomus type I cells are peripheral chemoreceptors which sense the oxygen, carbon dioxide and pH levels of the blood. When there is a decrease in the blood's pH, a decrease in oxygen (pO2), or an increase in carbon dioxide (pCO2), the carotid bodies and the aortic bodies signal the dorsal respiratory group in the medulla oblongata to increase the volume and rate of breathing. The glomus cells have a high metabolic rate and good blood perfusion and thus are sensitive to changes in arterial blood gas tension. Glomus type II cells are sustentacular cells having a similar supportive function to glial cells.

Hypoxic pulmonary vasoconstriction (HPV), also known as the Euler-Liljestrand mechanism, is a physiological phenomenon in which small pulmonary arteries constrict in the presence of alveolar hypoxia. By redirecting blood flow from poorly-ventilated lung regions to well-ventilated lung regions, HPV is thought to be the primary mechanism underlying ventilation/perfusion matching.

Hypoxia-inducible factors (HIFs) are transcription factors that respond to decreases in available oxygen in the cellular environment, or hypoxia. They also respond to instances of pseudohypoxia, such as thiamine deficiency. Both hypoxia and pseudohypoxia leads to impairment of adenosine triphosphate (ATP) production by the mitochondria.

<span class="mw-page-title-main">Hypoxemia</span> Abnormally low level of oxygen in the blood

Hypoxemia is an abnormally low level of oxygen in the blood. More specifically, it is oxygen deficiency in arterial blood. Hypoxemia has many causes, and often causes hypoxia as the blood is not supplying enough oxygen to the tissues of the body.

Chronic mountain sickness (CMS) is a disease in which the proportion of blood volume that is occupied by red blood cells increases (polycythaemia) and there is an abnormally low level of oxygen in the blood (hypoxemia). CMS typically develops after extended time living at high altitude. It is most common amongst native populations of high altitude nations. The most frequent symptoms of CMS are headache, dizziness, tinnitus, breathlessness, palpitations, sleep disturbance, fatigue, loss of appetite, confusion, cyanosis, and dilation of veins.

Peripheral chemoreceptors are so named because they are sensory extensions of the peripheral nervous system into blood vessels where they detect changes in chemical concentrations. As transducers of patterns of variability in the surrounding environment, carotid and aortic bodies count as chemosensors in a similar way as taste buds and photoreceptors. However, because carotid and aortic bodies detect variation within the body's internal organs, they are considered interoceptors. Taste buds, olfactory bulbs, photoreceptors, and other receptors associated with the five traditional sensory modalities, by contrast, are exteroceptors in that they respond to stimuli outside the body. The body also contains proprioceptors, which respond to the amount of stretch within the organ, usually muscle, that they occupy.

<span class="mw-page-title-main">Effects of high altitude on humans</span> Environmental effects on physiology and mental health

The effects of high altitude on humans are mostly the consequences of reduced partial pressure of oxygen in the atmosphere. The medical problems that are direct consequence of high altitude are caused by the low inspired partial pressure of oxygen, which is caused by the reduced atmospheric pressure, and the constant gas fraction of oxygen in atmospheric air over the range in which humans can survive. The other major effect of altitude is due to lower ambient temperature.

<span class="mw-page-title-main">HIF1A</span> Protein-coding gene in the species Homo sapiens

Hypoxia-inducible factor 1-alpha, also known as HIF-1-alpha, is a subunit of a heterodimeric transcription factor hypoxia-inducible factor 1 (HIF-1) that is encoded by the HIF1A gene. The Nobel Prize in Physiology or Medicine 2019 was awarded for the discovery of HIF.

Fabiola León-Velarde Servetto is a Peruvian physiologist who has devoted her research to the biology and physiology of high altitude adaptation. Born in Lima, Peru. She is the daughter of Carlos Leon-Velarde Gamarra and Juana Servetto Marti from Uruguay, and granddaughter of Angelica Gamarra. Under the mentorship of high altitude physiologist Carlos Monge Cassinelli, she obtained a BSc. in Biology (1979), an MSc (1981) and DSc (1986) in physiology at Cayetano Heredia University in Lima, Perú.

<span class="mw-page-title-main">EPAS1</span> Protein-coding gene in the species Homo sapiens

Endothelial PAS domain-containing protein 1 is a protein that is encoded by the EPAS1 gene in mammals. It is a type of hypoxia-inducible factor, a group of transcription factors involved in the physiological response to oxygen concentration. The gene is active under hypoxic conditions. It is also important in the development of the heart, and for maintaining the catecholamine balance required for protection of the heart. Mutation often leads to neuroendocrine tumors.

A hypoxicator is a medical device intended to provide a stimulus for the adaptation of an individual's cardiovascular system by means of breathing reduced oxygen hypoxic air and triggering mechanisms of compensation. The aim of intermittent hypoxic training or hypoxic therapy conducted with such a device is to obtain benefits in physical performance and wellbeing through improved oxygen metabolism.

<span class="mw-page-title-main">Organisms at high altitude</span> Organisms capable of living at high altitudes

Organisms can live at high altitude, either on land, in water, or while flying. Decreased oxygen availability and decreased temperature make life at such altitudes challenging, though many species have been successfully adapted via considerable physiological changes. As opposed to short-term acclimatisation, high-altitude adaptation means irreversible, evolved physiological responses to high-altitude environments, associated with heritable behavioural and genetic changes. Among vertebrates, only few mammals and certain birds are known to have completely adapted to high-altitude environments.

Fish are exposed to large oxygen fluctuations in their aquatic environment since the inherent properties of water can result in marked spatial and temporal differences in the concentration of oxygen. Fish respond to hypoxia with varied behavioral, physiological, and cellular responses to maintain homeostasis and organism function in an oxygen-depleted environment. The biggest challenge fish face when exposed to low oxygen conditions is maintaining metabolic energy balance, as 95% of the oxygen consumed by fish is used for ATP production releasing the chemical energy of nutrients through the mitochondrial electron transport chain. Therefore, hypoxia survival requires a coordinated response to secure more oxygen from the depleted environment and counteract the metabolic consequences of decreased ATP production at the mitochondria.

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. 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.

Cynthia Beall is an American physical anthropologist at the Case Western Reserve University, Cleveland, Ohio. Four decades of her research on people living in extremely high mountains became the frontier in understanding human evolution and high-altitude adaptation. Her groundbreaking works among the Andean, Tibetan and East African highlanders are the basis of our knowledge on adaptation to hypoxic condition and how it influences the evolutionary selection in modern humans. She is currently the Distinguished University Professor, and member of the U.S. National Academy of Sciences and the American Philosophical Society.

<span class="mw-page-title-main">Intermittent hypoxia</span>

Intermittent hypoxia (also known as episodic hypoxia) is an intervention in which a person or animal undergoes alternating periods of normoxia and hypoxia. Normoxia is defined as exposure to oxygen levels normally found in Earth's atmosphere (~21% O2) and hypoxia as any oxygen levels lower than those of normoxia. Normally, exposure to hypoxia is negatively associated to physiological changes to the body, such as altitude sickness. However, when used in moderation, intermittent hypoxia may be used clinically as a means to alleviate various pathological conditions.

References

  1. 1 2 3 Cymerman, A; Rock, PB. "Medical Problems in High Mountain Environments. A Handbook for Medical Officers" [usurped] . USARIEM-TN94-2. US Army Research Inst. of Environmental Medicine Thermal and Mountain Medicine Division Technical Report. Retrieved 2009-03-05.
  2. 1 2 3 4 5 6 7 Teppema, Luc J., and Albert Dahan. "The ventilatory response to hypoxia in mammals: mechanisms, measurement, and analysis." Archived 18 May 2013 at the Wayback Machine Physiological Reviews 90.2 (2010): 675-754.
  3. ↑ Stanford, Craig, John S. Allen, and Susan C. Anton. Biological Anthropology : The Natural History of Humankind. 2nd ed. Upper Saddle River: Prentice Hall Higher Education, 2008. 151-52.
  4. ↑ Duffin, James (1 October 2007). "Measuring the ventilatory response to hypoxia". The Journal of Physiology. 584 (Pt 1): 285–293. doi:10.1113/jphysiol.2007.138883. ISSN   0022-3751. PMC   2277066 . PMID   17717019.
  5. 1 2 Hornbein, Thomas F., and Robert B. Schoene. High Altitude: An Exploration Of Human Adaptation. n.p., New York: Marcel Dekker, c2001., 2001. OskiCat. Web. 8 Nov. 2016.
  6. ↑ "Altitude Hypoxia Explained." Archived 10 November 2016 at the Wayback Machine Altitude Research Center. Altitude Research Center, n.d. Web. 08 Nov. 2016.
  7. ↑ Karius, Diane R. "Respiratory Adaptations in Health and Disease: Forms of Hypoxia." Forms of Hypoxia. Kansas City University, n.d. Web. 08 Nov. 2016.
  8. ↑ West John B (2006). "Human responses to extreme altitudes". Integrative and Comparative Biology. 46 (1): 25–34. doi: 10.1093/icb/icj005 . PMID   21672720.
  9. ↑ Beall Cynthia M. "Tibetan and Andean patterns of adaptation to high-altitude hypoxia". Human Biology. 2000: 201–228.
  10. 1 2 Hochachka Peter W.; Christian Gunga Hanns; Kirsch Karl (1998). "Our ancestral physiological phenotype: An adaptation for hypoxia tolerance and for endurance performance?". Proceedings of the National Academy of Sciences. 95 (4): 1915–1920. Bibcode:1998PNAS...95.1915H. doi: 10.1073/pnas.95.4.1915 . PMC   19213 . PMID   9465117.
  11. 1 2 Easton, P. A.; Slykerman, L. J.; Anthonisen, N. R. (1 September 1986). "Ventilatory response to sustained hypoxia in normal adults". Journal of Applied Physiology. 61 (3): 906–911. doi:10.1152/jappl.1986.61.3.906. ISSN   8750-7587. PMID   3759775.
  12. ↑ Lipton, Andrew J.; Johnson, Michael A.; Macdonald, Timothy; Lieberman, Michael W.; Gozal, David; Gaston, Benjamin (2001). "S-Nitrosothiols signal the ventilatory response to hypoxia". Nature. 413 (6852): 171–174. Bibcode:2001Natur.413..171L. doi:10.1038/35093117. PMID   11557982. S2CID   9305953.
  13. ↑ Eldridge, Frederic L.; Millhorn, David E. (1 January 2011). Comprehensive Physiology. John Wiley & Sons, Inc. doi:10.1002/cphy.cp030203. ISBN   9780470650714.
  14. ↑ Hayashi, F.; Coles, S. K.; Bach, K. B.; Mitchell, G. S.; McCrimmon, D. R. (1 October 1993). "Time-dependent phrenic nerve responses to carotid afferent activation: intact vs. decerebellate rats". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 265 (4): R811–R819. doi:10.1152/ajpregu.1993.265.4.R811. ISSN   0363-6119. PMID   8238451.
  15. ↑ Severinghaus, J. W.; Bainton, C. R.; Carcelen, A. (1 January 1966). "Respiratory insensitivity to hypoxia in chronically hypoxic man". Respiration Physiology. 1 (3): 308–334. doi:10.1016/0034-5687(66)90049-1. PMID   5968347.
  16. ↑ Ang, R. C.; Hoop, B.; Kazemi, H. (1 April 1992). "Role of glutamate as the central neurotransmitter in the hypoxic ventilatory response". Journal of Applied Physiology. 72 (4): 1480–1487. doi:10.1152/jappl.1992.72.4.1480. ISSN   8750-7587. PMID   1350580.
  17. 1 2 Bigham, Abigail; Bauchet, Marc; Pinto, Dalila; Mao, Xianyun; Akey, Joshua M.; Mei, Rui; Scherer, Stephen W.; Julian, Colleen G.; Wilson, Megan J. (9 September 2010). "Identifying Signatures of Natural Selection in Tibetan and Andean Populations Using Dense Genome Scan Data". PLOS Genet. 6 (9): e1001116. doi: 10.1371/journal.pgen.1001116 . ISSN   1553-7404. PMC   2936536 . PMID   20838600.
  18. 1 2 Beall, Cynthia M. (1 January 2002). "Tibetan and Andean Contrasts in Adaptation to High-Altitude Hypoxia". In Lahiri, Sukhamay; Prabhakar, Naduri R.; II, Robert E. Forster (eds.). Oxygen Sensing. Advances in Experimental Medicine and Biology. Vol. 475. Springer US. pp. 63–74. doi:10.1007/0-306-46825-5_7. ISBN   9780306463679. PMID   10849649.
  19. ↑ Moore, L G; Regensteiner, J G (28 November 2003). "Adaptation to High Altitude". Annual Review of Anthropology. 12 (1): 285–304. doi:10.1146/annurev.an.12.100183.001441.
  20. 1 2 Lahiri, S.; Delaney, R. G.; Brody, J. S.; Simpser, M.; Velasquez, T.; Motoyama, E. K.; Polgar, C. (13 May 1976). "Relative role of environmental and genetic factors in respiratory adaptation to high altitude". Nature. 261 (5556): 133–135. Bibcode:1976Natur.261..133L. doi:10.1038/261133a0. PMID   1272381. S2CID   4297547.
  21. 1 2 "Andes Mountains | mountain system, South America". Encyclopædia Britannica. Retrieved 10 November 2016.
  22. ↑ Rottman, April (9 December 1997). "Erythroxylum: The Coca Plant" . Retrieved 11 November 2016.
  23. 1 2 Salazar, Hugo; Swanson, Jessica; Mozo, Karen; Clinton White, A.; Cabada, Miguel M. (1 July 2012). "Acute Mountain Sickness Impact Among Travelers to Cusco, Peru". Journal of Travel Medicine. 19 (4): 220–225. doi: 10.1111/j.1708-8305.2012.00606.x . ISSN   1708-8305. PMID   22776382.
  24. ↑ Beall, Cynthia M. (15 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. doi: 10.1073/pnas.0701985104 . ISSN   0027-8424. PMC   1876443 . PMID   17494744.
  25. ↑ Xing, Guoqiang; Qualls, Clifford; Huicho, Luis; River-Ch, Maria; Stobdan, Tsering; Slessarev, Marat; Prisman, Eitan; Ito, Soji; Wu, Hong (4 June 2008). "Adaptation and Mal-Adaptation to Ambient Hypoxia; Andean, Ethiopian and Himalayan Patterns". PLOS ONE. 3 (6): e2342. Bibcode:2008PLoSO...3.2342X. doi: 10.1371/journal.pone.0002342 . ISSN   1932-6203. PMC   2396283 . PMID   18523639.
  26. ↑ "Plateau of Tibet | plateau, China". Encyclopædia Britannica. Retrieved 10 November 2016.
  27. ↑ Meera Senthilingam, for (11 November 2015). "Scientists discover why Sherpas are superhuman climbers - CNN.com". CNN. Retrieved 11 November 2016.
  28. ↑ "Guide: What does a Sherpa at Mount Everest do? - CBBC Newsround". 23 April 2014. Retrieved 11 November 2016.
  29. ↑ Sanders R (1 July 2010). "Tibetans adapted to high altitude in less than 3,000 years". News Centre, UC Berkeley. UC Regents. Retrieved 8 July 2013.
  30. ↑ Hsu J (1 July 2010). "Tibetans Underwent Fastest Evolution Seen in Humans". Live Science. TechMediaNetwork.com. Retrieved 8 July 2013.
  31. ↑ Yi, X.; Liang, Y.; Huerta-Sanchez, E.; Jin, X.; Cuo, Z. X. P.; Pool, J. E.; Xu, X.; Jiang, H.; et al. (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.
  32. ↑ Hu, Hao; Petousi, Nayia; Glusman, Gustavo; Yu, Yao; Bohlender, Ryan; Tashi, Tsewang; Downie, Jonathan M.; Roach, Jared C.; Cole, Amy M.; Lorenzo, Felipe R.; Rogers, Alan R. (2017). Tishkoff, Sarah A. (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.
  33. ↑ Yang, Jian; Jin, Zi-Bing; Chen, Jie; Huang, Xiu-Feng; Li, Xiao-Man; Liang, Yuan-Bo; Mao, Jian-Yang; Chen, Xin; Zheng, Zhili; Bakshi, Andrew; Zheng, Dong-Dong (2017). "Genetic signatures of high-altitude adaptation in Tibetans". Proceedings of the National Academy of Sciences. 114 (16): 4189–4194. Bibcode:2017PNAS..114.4189Y. doi: 10.1073/pnas.1617042114 . PMC   5402460 . PMID   28373541.
  34. ↑ Yi, Xin; Liang, Yu; Huerta-Sanchez, Emilia; Jin, Xin; Cuo, Zha Xi Ping; Pool, John E.; Xu, Xun; Jiang, Hui; Vinckenbosch, Nicolas (2 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. ISSN   0036-8075. PMC   3711608 . PMID   20595611.
  35. ↑ Beall, Cynthia M.; Song, Kijoung; Elston, Robert C.; Goldstein, Melvyn C. (28 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. doi: 10.1073/pnas.0405949101 . ISSN   0027-8424. PMC   521103 . PMID   15353580.
  36. ↑ Pleurdeau, David (14 June 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. ISSN   0263-0338. S2CID   162259548.
  37. ↑ Alkorta-Aranburu, Gorka; Beall, Cynthia M.; Witonsky, David B.; Gebremedhin, Amha; Pritchard, Jonathan K.; Rienzo, Anna Di (6 December 2012). "The Genetic Architecture of Adaptations to High Altitude in Ethiopia". PLOS Genet. 8 (12): e1003110. arXiv: 1211.3053 . doi: 10.1371/journal.pgen.1003110 . ISSN   1553-7404. PMC   3516565 . PMID   23236293.

This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.