Humans are remarkably close-knit, genetically: of the genetic information that can differ from person to person, less than 10% of this variation is specific to any particular population, while the remaining 90% of differences are seen throughout all human populations []! Yet, people have migrated to populate diverse and extreme environments worldwide, including hot, humid rainforests, arid deserts, and parched, freezing tundra. How humans are able to survive and reproduce under so many different conditions is a mystery scientists are just beginning to understand. New research offers tantalizing clues as to how populations living in the highlands of Tibet, Ethiopia, and the Andes are able to cope with atmospheric oxygen pressures as low as 60% of that at sea level [].

Dangers of living at high-altitude

When people from populations that have lived at sea level for thousands of years go to altitudes above 2,500 meters, they experience hypoxia—a severe lack of oxygen. For several days, people hyperventilate and burn extra energy even while resting. Their ability to extract oxygen from the blood decreases, diminishing their capacity for physical exertion []. The concentration of hemoglobin, which carries oxygen in red blood cells (Figure 1), gradually increases in order to provide more oxygen to the tissues []. If sea-level people remain at high-altitudes for years, with old age this “thickening of the blood” leads to mountain sickness: fatigue, dizziness, breathlessness, headaches, insomnia, pain, ear-ringing, purpling of the hands and feet, and dilated veins []. In extreme cases hypoxia and mountain sickness lead to death []. Pregnant women, who breathe for two, experience a special danger []. Oxygen-restriction for the unborn baby typically results in growth-restriction and the release of distress signals that induce high blood pressure in the mother []. High blood pressure during pregnancy is called preeclampsia, and results in premature labor, small birth-weight babies, and often hemorrhaging, seizures, and death for the mother. Strikingly, high-altitude peoples of Tibet, Ethiopia, and the Andes have been living at altitudes of 2,500 to 4,000 meters for millennia and are protected from these conditions [].

Figure 1. Red blood cells containing hemoglobin molecules travel in the bloodstream. These hemoglobin molecules bind oxygen obtained from the lungs and carry this oxygen through the blood to the tissues. (Credit:

How do high altitude populations avoid hypoxia?

Andeans, who have been living at high-altitudes for no more than 11,000 years, exhibit the same elevated hemoglobin concentrations that low-landers exhibit at high elevations. However, they also have increased oxygen-saturation of their hemoglobin []. Essentially, Andeans have more oxygen per blood volume than other people []. This enables them to avoid hypoxia and reproduce without high danger of death for the mother or baby. Yet elevated hemoglobin levels still leave them at risk for mountain sickness with old age [].

Tibetans, who have been living at high-altitudes for just 3,000 years, don’t exhibit the elevated hemoglobin concentrations of Andeans and sea-level populations at high-altitudes (Figure 2) []. Instead, Tibetans breathe more air with each breath and breathe more rapidly than either sea-level populations or Andeans []. Unlike people from sea level who only experience hyperventilation for a few days after entering high altitudes, Tibetans retain this rapid breathing and elevated lung-capacity throughout their lifetime []. This enables them to breathe larger amounts of air per unit of time to compensate for low oxygen levels. In addition, Tibetans have high levels of nitric oxide in their blood []. Nitric oxide dilates blood vessels, allowing them to move larger volumes of blood through their body in the same amount of time. Together with increased breathing, this allows Tibetans to move sufficient oxygen to their tissues without increasing hemoglobin concentration []. Thus, they avoid both the dangers of hypoxia in pregnancy and mountain sickness with old age [].

Figure 2. Tibetans at 4,000 meters have lower concentrations of hemoglobin, shown in grams per deciliter (gm/dL), than Andeans at 4,000 meters since they have evolved alternative adaptations to cope with hypoxia. (Credit: [], Figure 3)

The Amhara of Ethiopia also live at extremely high altitudes, around 3,000-3,500 meters, but how they manage it physiologically remains a mystery []. They exhibit elevated hemoglobin levels, like Andeans and low-lander peoples at high altitudes, but do not exhibit the Andean’s increase in oxygen-saturation of hemoglobin []. Yet, similar to the Andeans and Tibetans, the Amhara of Ethiopia are protected from the extreme dangers posed by pregnancy at high-altitudes, which means they must rely on a different, unknown mechanism for getting enough oxygen in these conditions [].

How have these adaptations arisen?

Where did these amazing abilities to thrive at high altitudes come from? Importantly, the physiological mechanisms responsible are heritable—passed down from one generation to the next. People from sea-level populations born and raised at extreme altitudes do increase hemoglobin levels, but remain at risk for mountain sickness and preeclampsia during pregnancy []. Subtle genetic adaptations enable people to live healthily at high altitudes. Why did this come to be? As described above, the costs of childbirth at high-altitudes—often death for the mother or baby—were so extreme that random genetic mutations that helped to prevent these complications were much more likely to be passed on to the next generation []. Over generations these changes that are advantageous become more common in the population as more people with the altered genes live and reproduce successfully. This represents strong, positive, evolutionary selection. In each of the high-altitude populations, the selection was strong enough to have changed the physiology of the population over just a few hundred generations.

Researchers have begun to identify genetic adaptations using statistical methods to detect evidence of positive selection. Amazingly, many of the genes detected in Tibetans, Andeans, and Amhara are members of a network of interacting genes called the Hypoxia-Inducible Factor (HIF) oxygen signaling pathway []. In other words, it is already known that these genes are activated in conditions of hypoxia, such as aerobic exercise.

For example, changes to the gene EPAS1, which controls hemoglobin production, are being positively selected in Tibetans []. These mutations in EPAS1, at higher frequency in Tibetans than their Han neighbors, correlate with decreased hemoglobin concentrations amongst Tibetans []. Since low hemoglobin concentration at high altitude is the hallmark of Tibetan adaptation to hypoxia, these mutations are likely important genetic adaptations to high-altitude []. Another gene, EGLN1, which decreases hemoglobin production when oxygen is plentiful, also shows genetic patterns of variation consistent with selection in [js1] [EB2] both Tibetans and Andeans []. Other genes under selection are unique to just Tibetan, Andean, or Amhara populations []. Genes under selection in the Amhara have roles in the response to lung injury, hemoglobin production in the unborn baby, and the function of mitochondria – the oxygen-consuming energy producers of the cell []. While scientists cannot yet pinpoint how the Amhara have adapted to high-altitude, these genes provide fascinating hints to further explore []. Furthermore, people from the highlands of Ethiopia and Kenya are some of the best long-distance runners in the world—understanding evolutionary adaptations to high-altitude hypoxia may suggest new avenues for improving aerobic performance []!

Human adaptation to diverse environments remains one of the great mysteries of human evolution. As a species, humans share extraordinary flexibility, using culture to cope with harsh conditions. Yet, populations also employ unique biological adaptations to novel environments. The highlanders of Ethiopia, Tibet, and the Andes demonstrate that even when presented with the same conditions, human populations may adapt in unique ways []. Moreover, if the selection is powerful, populations adapt in just a few thousand years []! Biological and cultural flexibility confer extraordinary powers for humans to live and reproduce around the world.

Elizabeth Brown is a graduate student in the Human Evolutionary Biology program of the Graduate School of Arts and Sciences at Harvard University.


1. University of Washington. “Genome-wide Insights Into Patterns Of The World’s Human Population Structures.” ScienceDaily, 14 May 2009. Web. 17 Jun. 2012. <>

2. Mayell, Hillary. “Three High-Altitude Peoples, Three Adaptations to Thin Air,” National Geographic News. 2004 <>

3. Beall, Cynthia. “Two routes to functional adaptation: Tibetan and Andean high-altitude natives” PNAS, 104:suppl1. 2007.

4. Storz. “Genes for High Altitudes” Science, Perspectives, 329. 2010.

5. Lerner, Evan. “Penn Researchers Help Solve Questions About Ethiopians’ High-Altitude Adaptations,” Penn News. 2012. <>

6. Sanders, Robert. “Tibetans adapted to high altitude in less than 3,000 years,” UC Berkeley News Center. 2010. <>

7. Khan, Razib. “Why Tibetans breathe so easy high up,” Discover Magazine. 2010. <>

8. Fisher, Max. “Why Kenyans Make Such Great Runners: A Story of Genes and Cultures,” The Atlantic Monthly. 2012. <>

2 thoughts on “High-Altitude-Hypoxia: Many solutions to one problem

  1. Suggest modifications of the circulatory and respiratory systems that might help people that live for many years at high altitude

  2. “Furthermore, people from the highlands of Ethiopia and Kenya are some of the best long-distance runners in the world—understanding evolutionary adaptations to high-altitude hypoxia may suggest new avenues for improving aerobic performance”…….. I do not agree with this conclusion. Because the great runners from Ethiopia are not from the highlands of Amhara, rather they are from other part of the country. So I suggest studies should also focus on comparing those parts of the country with the Amhara highlanders (which are already in study).

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