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Environmental Factor, March 2012

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NIH pioneer discovers genes linked to high altitude tolerance

By Jeffrey Stumpf

Sarah Tishkoff, Ph.D.

Tishkoff spoke at NIEHS during a meeting of the National Advisory Environmental Health Sciences Council . She is a Penn Integrates Knowledge professor with appointments in the Perelman School of Medicine and the biology department at the University of Pennsylvania. (Photo courtesy of Steve McCaw)

With the wide range of ecosystems that humans populate, it is possible that populations in extreme climates may have adapted to harsh conditions through evolution.

A new study in Genome Biology is the latest manuscript to identify genetic adaptations prevalent in populations living in high altitudes. Led by a recipient of a 2009 NIH Pioneer Award funded by NIEHS, Sarah Tishkoff, Ph.D., the research team describes mutations in genes involved in adaptation to low oxygen levels, including CBARA1, VAV3, ARNT2, and THRB, three of which have not been previously implicated in genome-wide high altitude studies.

Tishkoff, a professor at the University of Pennsylvania, and her colleagues teamed up with professors in the department of biology of Addis Ababa University to conduct genome-wide association studies (GWAS) comparing populations that live in contrasting regions in Ethiopia.

Living with less oxygen

Tolerance to high altitude conditions had previously been researched using populations living in Tibet and the Andes. These mountain-dwelling people contained mutations in genes that are associated with hemoglobin levels, the proteins that bind oxygen in the blood. Increases in hemoglobin would be favorable for living in hypoxic, or low oxygen, conditions.

In some people, especially pregnant women, hypoxia can cause sickness and sometimes death. Like the Tibetans and Andeans, the Amhara people living in the Ethiopian highlands experience fewer complications due to the altitude. Tishkoff’s group discovered genes in the Amharas that were different from the genes found in the Tibetans and Andeans, but still involved in tolerance to hypoxic conditions. Thus, populations may have adapted to the same conditions through independent mutations — a process called convergent evolution.

A search for candidate genes

Evolutionary biologists, such as Tishkoff, are taking advantage of the recently available opportunity to cost-effectively sequence multiple human genomes. However, knowing entire DNA sequences from different populations does not tell the entire story. Because of variability among people, Tishkoff noted that finding important mutations that change evolutionary processes requires drastic differences to measure.

“The easiest way for us to [find genetic variants that play a role in functional adaptation] is to look at situations where there's been very strong selective pressure — a disease with a really high mortality rate or here at high altitude where there are hypoxic conditions,” Tishkoff was quoted as saying in a University of Pennsylvania press release about the study. “This kind of situation makes a dramatic difference in terms of who passes on their genes, so it gives us more power to find the genetic signatures left behind.”

Choosing the road less traveled

The concept of extracting blood samples from populations in the Ethiopian highlands seems relatively straightforward. However, the lack of infrastructure, limited resources, and even impassable roads made conducting science in these remote locations a major challenge.

“What we planned as a two-month trip turned into a five-month trip,” Tishkoff recalled during a talk at NIEHS this past September (see story). “There are a lot of challenges to doing this kind of research in Africa.”

With members of her lab, Tishkoff travelled with all the necessary supplies in a mobile lab. The lack of electricity in some villages required that they power their centrifuge using a generator or car battery.

To maintain high ethical standards, the studies required multiple rounds of ethical reviews, institutional review board consent at the university level, and consent from the communities and individuals (see related story).

Despite the difficulties, Tishkoff maintains that studies in Africa are especially powerful resources, not only to learn medically important genetic information about the understudied African populations, but also to understand human evolution.

“Because of the high levels of genetic, cultural, and climatic diversity in Africa, there has likely been local adaptation within populations from different regions practicing diverse lifestyles,” Tishkoff said in an interview published in Human Biology. “Therefore, the possibility of geographically restricted rare, as well as common, functional variants requires the inclusion of a broad range of geographically and ethnically diverse African populations in human genetic studies.”


Scheinfeldt LB, Soi S, Thompson S, Ranciaro A, Meskel DW, Beggs W, Lambert C, Jarvis JP, Abate D, Belay G, Tishkoff SA. 2012. Genetic adaptation to high altitude in the Ethiopian highlands. Genome Biol 13(1):R1 [Online 20 January 2012].

Tishkoff S. 2011. Interview with Sarah Tishkoff: perspectives for genetic research in African populations. Interview by Giovanni Destro-Bisol. Hum Biol 83(5):637-644.

(Jeffrey Stumpf, Ph.D., is a postdoctoral fellow in the NIEHS Laboratory of Molecular Genetics Mitochondrial DNA Replication Group.)

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