Thursday, July 22, 2010


Unraveling the Genetics of High Altitude Adaptations in Tibetans

In an unusual confluence of events three studies on the genetics of high-altitude adaptations among Tibetans have recently been published. They all target alleles associated with genes in the hypoxia-inducible factor (HIF) oxygen signaling pathway that have been subject to strong and recent positive selection in Tibetan highlanders. One gene in particular EPAS1 maintains low hemoglobin levels in the face of low oxygen concentrations at high altitude. During acclimatization to high altitudes individuals from lower altitudes increase their production of red blood cells and hemoglobin to compensate for the lower atmospheric pressure which inhibits the absorption of oxygen into the blood stream. This however has a number of deleterious effects associated with high altitude sickness.

In a collaborative effort that included scientists from the China, Europe and the U.S., Yi et al. (2010) identified more than 30 genes with alleles that have become more prevalent in Tibetans than Han Chinese. More than half of these are related to how the body uses oxygen. One allele seen in 90% of the Tibetans studied was seen in only 10% of Chinese, indicating that it underwent extremely severe positive selection in the 3,000 years since the Tibetan and Han Chinese populations split. It is found near EPAS1 and codes for a protein involved in sensing oxygen levels and perhaps balancing aerobic and anaerobic metabolism. The mutation may be in a transcription factor that regulates the activity of EPAS1.

Other strongly selected variants were near the genes for the fetal and adult versions of the globin genes, which produce the structural proteins of hemoglobin. Two other genes showing a dramatic shift in frequency have been linked to anemia, while several other genes have been linked to diseases, including schizophrenia and epilepsy, possibly caused by low oxygen levels in the womb. The full story can be found at Science Daily.

In another study Simonson et al. (2010) identified 10 unique oxygen-processing genes associated with HIF that help Tibetans live at higher altitudes. The Tibetans have genetic adaptations to prevent polycythemia (a process in which the body produces too many red blood cells in response to oxygen deprivation), as well as other health abnormalities such as swelling of the lungs and brain (edema) and hypertension of the lung vessels leading to eventual respiratory failure. Even at elevations of 14,000 feet above sea level or higher, where the atmosphere contains much less oxygen than at sea level, most Tibetans do not overproduce red blood cells and do not develop lung or brain complications. The full story can be found at Science Daily.

The third paper is by Beall et al. (2010). This study by scientists from China, England, Ireland, and the United States pinpoints a genetic variant of the EPAS1 gene linked to low hemoglobin in the blood -- that helps explain how Tibetans cope with low-oxygen conditions. The study sheds light on how Tibetans, who have lived at extreme elevation for more than 10,000 years, have evolved to differ from their low-altitude ancestors The full story can be found at Science Daily.

Storz offers a technical review of all three articles in the same issue of Science that carries the Yi et al. (2010) and Simonson et al. (2010) articles. Unfortunately the full review is not available to non-subscribers to the journal.

All these studies are looking at the same set of genetic factors from slightly different perspectives. They attest to the fact that we have entered into a new phase of teasing apart the genetic mechanisms behind human adaptation. China in collaboration with other nations is playing a leading role in these investigations

Literature Cited:

Beall, C., G. Cavalleri, et al. (2010) Natural selection on EPAS1 (HIF2%u03B1) associated with low hemoglobin concentration in Tibetan highlanders. Proceedings of the National Academy of Sciences 107, 11459-11464.

Simonson, T. et al. (2010) Genetic Evidence for High-Altitude Adaptation in Tibet. Science, 329, 72–75.

Storz, J.F. (2010) Genes for High Altitudes Science 329 (5987), 40-41.

Yi, X. et al. (2010) Sequencing of 50 Human Exomes Reveals Adaptation to High Altitude. Science 329, 75 - 78.

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