If you live in the lowlands, you may have experienced the huffing and puffing that typically accompany a trip to higher altitudes. That’s because oxygen levels go down as one goes up. Travelling to Denver from sea level means a 17% decrease in available oxygen. Our bodies compensate for even this small change with faster breathing and a higher heart rate — at least until we acclimate to the thinner atmosphere. And a loftier vacation spot (for example, La Paz, Bolivia at 11,942 feet) could bring on serious altitude sickness with insomnia, nausea, and swelling — but not for everyone. Tibetan highlanders have no trouble living at 13,000 feet year in year out, and many Nepalese Sherpas (who are ethnically Tibetan) climb parts of Mount Everest without the supplementary oxygen most people require. How do they do it? New research makes it clear that Tibetan highlanders haven’t just acclimated to their mountain home; they’ve evolved unique physiological mechanisms for dealing with low oxygen levels.
Where's the evolution?
This interview with Dr. Emilia Huerta-Sanchez explains how scientists found the genetic basis for high altitude adaptation in populations of Tibetan highlanders. This video is produced by the National Evolutionary Synthesis Center (NESCent) and UCMP.
The evolutionary adaptations that allow Tibetans to function at high altitudes are very different from the acclimatization process that most of us go through when we spend time in those places. When lowlanders visit Denver, La Paz, or Lhasa, for example, their bodies begin to produce more red blood cells — the purveyors of oxygen in the body. These extra cells seem to help transport available oxygen around the body — and may eventually compensate for decreased oxygen levels, allowing breathing and heart rate to return to normal. This is an example of phenotypic plasticity, shifts in an organism’s body, physiology, or behavior that are dependent upon the environment it occupies, not upon a genetic change. The switch to producing more red blood cells that occurs when a lowlander visits Lhasa does not reflect a new mutation, but rather the body’s response to a new environment. Because they don’t reflect a shift in the genetic makeup of a population, such changes, which occur within the lifespan of a single individual, are not adaptations in an evolutionary sense.
The Tibetan highlander population, on the other hand, has, over the course of thousands of years, evolved adaptations that allow individuals to thrive in a low oxygen environment. Paradoxically, one of these adaptations is almost exactly the opposite of a lowlander’s response to high altitude: Tibetans have gene versions that cause them to produce fewer red blood cells. How is that helpful? It turns out that extra red blood cells make blood thicker — more like honey than water — and after a certain point, this cell-laden blood can actually get so thick that it doesn’t pass through capillaries efficiently to oxygenate cells. Having blood with too many red blood cells can be particularly problematic during pregnancy since it is linked to slow fetal growth and high rates of fetal mortality. One study found that Han Chinese people (lowland relatives of Tibetans whose bodies respond to high altitudes by producing more red blood cells) living in the Tibetan highlands were three times as likely to suffer pre- or post-natal infant death than were ethnic Tibetans! In the long run, producing extra red blood cells may do more harm than good.
The basis for the Tibetans’ adaptation is not a change in a gene that produces hemoglobin or any one of the other proteins that make up red blood cells. Instead, the key change seems to be in a stretch of DNA (called EPAS1), which codes for a regulatory protein. This protein senses oxygen and helps control the process of producing red blood cells. The change in EPAS1 seems to make Tibetans less likely to overproduce red blood cells at extreme altitudes and, hence, probably helps them to avoid altitude sickness and deliver oxygen more effectively to developing fetuses. Other unique traits of Tibetans (a higher breathing rate and blood vessels which expand to allow better oxygen transport) likely also contribute to their altitude aptitude.
This interview with Cynthia Beall is from a 2009 meeting at the National Evolutionary Synthesis Center. Interviews with other scientists from that meeting, a lecture by Dr. Beall and additional classroom resources are available at the NESCent website.
Scientists recently narrowed in on this explanation through a series of studies that all pointed to EPAS1 as a key player in Tibetans’ altitude adaptation. One group of biologists compared the genomes of ethnic Tibetans to the genomes of Han Chinese individuals, as well as to the genomes of distantly related Danes. The basic reasoning was that if a particular gene version is found at high frequency in Tibetans and low frequency in their close and distant relatives, that gene version probably rose to high frequency in the Tibetan population recently through the action of natural selection. The most extreme differences in gene version frequency the scientists observed were in the EPAS1 gene. Another group of scientists observed similar gene frequency differences between Tibetans and Han Chinese in and around the EPAS1 gene. This group of researchers also found that the genetic variants of EPAS1 that were most common in Tibetans were linked to lower levels of hemoglobin, which indicates lower red blood cell counts. All of those observations made a lot of sense in light of what was already known about the function of EPAS1 and fit with previous observations of Tibetans’ low red blood cell counts at high altitudes, their resistance to altitude sickness, and their relatively high fertility at high altitudes. All the different lines of evidence point to the same explanation: the EPAS1 gene and the region around it seems to have been a target of selection as Tibetans moved to higher altitudes and faced the challenges of a low-oxygen environment.
Some genetic studies estimate that the Tibetans split from the Han Chinese population and began migrating to the highlands less than 3000 years ago — and that all this adaptation to living tens of thousands of feet above sea level has occurred in just a hundred or so generations. If that estimate is accurate, this would represent the fastest example of human evolution yet documented.
Although Tibetans’ altitude adaptation may be unusually rapid, it is not unique. As humans moved out of Africa and diverged into populations that reside in very different environments — from the heights of the Andes to the bitter cold of Siberia to the tiny islands of the Pacific — these groups experienced natural selection which favored traits well-suited to their conditions and weeded out others. Scientists have studied adaptations that allow Europeans and many Africans to digest lactose, that help Eskimos keep warm, and that allow Europeans to synthesize vitamin D. So the next time you are huffing and puffing up a mountain (or not), drinking a glass of milk (or not), or bundling up in a parka (or not), take a moment to reflect on the unique evolutionary history that has shaped who you are today.
News update, August 2014
Since we last reported on Tibetan highlanders’ fascinating adaptations to their extreme altitude, scientists have been hard at work trying to figure out exactly how the EPAS1 gene works and evolved. Now, new research reveals its unexpected origins: the EPAS1 gene variant traces its ancestry to newly discovered relatives of early humans—the Denisovans, who lived at the same time that early humans and Neanderthals did. The Tibetans’ EPAS1 gene version and the section of DNA surrounding it are different from the gene versions found in any other extant human population, but are remarkably similar to an ancient gene version recovered from a more than 40,000 year old bone in the Denisova cave of Siberia. The best explanation for this surprising observation is that Denisovans and the ancestors of modern Tibetans interbred, introducing EPAS1 and other genetic sequences to that human population. Once Tibetans began living at high altitudes, individuals carrying the unusual gene were favored, and it quickly spread through the population, making life on the high plateau just a little easier.
As the technology that allows us to study ancient DNA continues to improve, we can expect more fascinating discoveries like this one on the horizon. Through analysis of ancient DNA, we’ve recently discovered that humans and Neanderthals interbred, that most human populations still harbor little bits of Neanderthal DNA, and that a gene contributing to diabetes in Mexicans and Latin Americans came to human populations via this route. In fact, just 4 years ago, the Denisovans themselves were discovered through analysis of ancient DNA. Stay tuned to find out what ancient DNA will next reveal about human history!
News update, August 2022
Since our last update, scientists have continued to investigate EPAS1 and its relationship to Denisovans, relatives of early humans that lived alongside our ancestors and Neanderthals. Last year, a team of biologists announced the results of an investigation into the timing of the interbreeding through which Denisovans passed to the ancestors of modern Tibetans the version of EPAS1 that is so helpful to them today. The team used a model that let them experiment with different timings for the population mixture and different strengths of natural selection on EPAS1, checking see how these factors might affect the distribution of Denisovan DNA sequences near EPAS1 in Tibetans today. The scenario that most closely matched the DNA patterns actually observed in modern Tibetans was an interbreeding event with East Asian Denisovans around 50,000 years ago. However, the model also suggested that the new EPAS1 gene version was not especially beneficial for modern humans until tens of thousands of years later. The high-altitude gene version didn’t seem to be favored in humans until around 9000 years ago, which is perhaps when the ancestors of modern Tibetans moved to high altitudes. Scientists are still trying to sort out how this all lines up with the archaeological evidence of human habitation on the Tibetan plateau, but it is exciting to see how DNA can reveal so much about human evolutionary history that once seemed unknowable.
- Beall, C. M. Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., . . . Zhang, Y. T. (2010). Natural selection on EPAS1 (HIF2a) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences USA 107: 11459-11464. Read it »
- Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E. . . .Wang, J. (2010). Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329: 75-78. Read it »
- A quick summary of the research from Inside NOVA
- A thorough review of the new research from The New York Times
- An overview of different human adaptations to living at high altitudes from National Geographic News
Understanding Evolution resources:
- In your own words, explain what an evolutionary adaptation is. Give one example of an adaptation not described in the article above.
- In your own words, explain what phenotypic plasticity is. Give one example of phenotypic plasticity not described in the article above.
- Review some background information on natural selection. Explain how a mutation that allows normal levels of infant survival at high altitudes would spread through a human population that had just begun living high in the mountains. Make sure to include the concepts of variation, selection, and inheritance in your explanation.
- Imagine that the Tibetan highland population migrates to the lowlands and stays there. What would you expect to happen to the frequency of the altitude adaptations in the EPAS1 gene in that population? Explain your reasoning. Keep in mind that the mutations in EPAS1 that help Tibetans handle high altitudes are found at low frequencies in Han Chinese populations.
- Examine this table from an original journal article on altitude adaptation in Tibetans. It shows data from individuals with different versions of the EPAS1 gene. The different gene versions are called “C” and “G.” Remember that humans have two copies of each gene, so this table shows data for people who carry two copies of these gene versions (CC and GG) and for individuals who carry one of each (CG). Also remember that since red blood cells contain hemoglobin, which carries oxygen in the blood, the last three columns of data on this table are related.
Genotype Tibetan individuals with this genotype in sample (n = 366) Mean hemoglobin concentration Mean red blood cell count Mean oxygen level in blood CC 10 178 5.3 87.5 CG 84 178.9 5.6 86.68 GG 272 167.5 5.2 86.42 * Adapted from Table S4 in Yi et al (2010).
- What is the most common gene version among Tibetans?
- What is the most common genotype among Tibetans?
- Which gene version is most likely to be adaptive for Tibetans living at high altitudes? Which data from the table support this inference and how?
- Advanced: Review the topic of Hardy-Weinberg equilibrium in your textbook. Calculate the allele frequencies for C and G and the expected number of individuals of each genotype in the Tibetan sample.
- Advanced: Review chi-square tests in your textbook. Perform a chi-square test and determine whether or not this locus conforms to Hardy-Weinberg equilibrium in Tibetans.
- Advanced: Does your answer for item e above have any implications for the evolution of the EPAS1 locus among Tibetans? Be sure to reference random or assortative mating, mutation, migration, and natural selection in your response. Does this conflict or cohere with the idea that EPAS1 has been under selection in the Tibetan highland population? Explain your answer.
- Teach about natural selection and adaptation: This board game for grades 9-12 simulates natural selection. It is suitable for an introductory biology class and for more advanced classes where you could go into more detail on important principles such as the role of variation and mutation.
- Teach about another example of human microevolution: This article for grades 9-16 describes how evolution has allowed different human populations to take advantage of the nutritional possibilities of dairying.
- Teach about human genetic variation: In this activity for grades 9-12, students investigate variation in the beta globin gene by identifying base changes that do and do not alter function, and by using several internet-based resources to consider the significance in different environments of the base change associated with sickle cell disease.
- Beall, C. M. Cavalleri, G. L., Deng, L., Elston, R. C., Gao, Y., Knight, J., . . . Zhang, Y. T. (2010). Natural selection on EPAS1 (HIF2a) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences USA 107: 11459-11464.
- Huerta-Sánchez, E., Jin, X., Asan, Bianba, Z., Peter, B. M., Vinckenbosch, N., … Nielsen, R. (2014). Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. Nature. doi:10.1038/nature13408
- Mayell, H. (February 25, 2004). Three high-altitude peoples, three adaptations to thin air. Retrieved October 12, 2010 from National Geographic News.
- Moore, L. G., Young, D., McCullough, R. E., Droma, T., and Zamudio, S. (2001). Tibetan protection from intrauterine grown restriction (IUGR) and reproductive loss at high altitude. American Journal of Human Biology 13: 635-644.
- Storz, J. F. (2010) Genes for high altitudes. Science 329: 40-41.
- Yi, X., Liang, Y., Huerta-Sanchez, E., Jin, X., Cuo, Z. X. P., Pool, J. E. . . .Wang, J. (2010). Sequencing of 50 human exomes reveals adaptation to high altitude. Science 329: 75-78.
- Zhang, X., Witt, K. E., Bañuelos, M. M, Ko, A., Yuan, K., Xu, S., Nielson, R., and Huerta-Sanchez, E. (2021). The history and evolution of the Denisovan-EPAS1 haplotype in Tibetans. Proceedings of the National Academy of Sciences USA. 118: e2020803118.