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7.5.2010 Mutation in key gene allows Tibetans to thrive at high altitude

By Cian O'Luanaigh

A gene that controls red blood cell production evolved quickly to enable Tibetans to tolerate high altitudes, a study suggests. The finding could lead researchers to new genes controlling oxygen metabolism in the body.

An international team of researchers compared the DNA of 50 Tibetans with that of 40 Han Chinese and found 34 mutations that have become more common in Tibetans in the 2,750 years since the populations split. More than half of these changes are related to oxygen metabolism.

The researchers looked at specific genes responsible for high-altitude adaptation in Tibetans. "By identifying genes with mutations that are very common in Tibetans, but very rare in lowland populations we can identify genes that have been under natural selection in the Tibetan population," said Professor Rasmus Nielsen of the University of California Berkeley, who took part in the study. "We found a list of 20 genes showing evidence for selection in Tibet - but one stood out: EPAS1."

The gene, which codes for a protein involved in responding to falling oxygen levels and is associated with improved athletic performance in endurance athletes, seems to be the key to Tibetan adaptation to life at high altitude. A mutation in the gene that is thought to affect red blood cell production was present in only 9% of the Han population, but was found in 87% of the Tibetan population.

"It is the fastest change in the frequency of a mutation described in humans," said Professor Nielsen.

There is 40% less oxygen in the air on the 4,000m high Tibetan plateau than at sea level. Under these conditions, people accustomed to living below 2,000m – including most Han Chinese – cannot get enough oxygen to their tissues, and experience altitude sickness. They get headaches, tire easily, and have lower birth rates and higher child mortality than high-altitude populations.

Tibetans have none of these problems, despite having lower oxygen saturation in their tissues and a lower red blood cell count than the Han Chinese.

Around the world, populations have adapted to life at high altitude in different ways. One adaptation involves making more red blood cells, which transport oxygen to the body's tissues. Indigenous people in the Peruvian Andes have higher red blood cell counts than their countrymen living at sea level, for example.

But Tibetans have evolved a different method. "Tibetans have the highest expression levels for EPAS1 in the world," said co-author Dr Jian Wang of the Beijing Genomics Institute in Schenzhen, China, a research facility that collected the data. "For Western people, after two to three weeks at altitude, the red blood cell count starts to increase. But Tibetans and Sherpas keep the same levels," he said.

"I just summitted Everest a few weeks ago," added Dr Wang. He said the Sherpas and Tibetans were much stronger than the Westerners or lowland Chinese on the climb. "Their tissue oxygen concentration is almost the same as Westerners and Chinese but they are strong," he said "and their red blood cell count is not that high compared to people in Peru."

"The remarkable thing about Tibetans is that they can function well in high altitudes without having to produce so much haemoglobin," said Prof Nielsen. "The entire mechanism is not well-understood – but is seems that the gene responsible is EPAS1."

Nielsen said the gene is involved in regulating aerobic and anaerobic metabolism in the body (cell respiration with and without oxygen). "It may be that the [mutated gene] helps balance anaerobic versus aerobic metabolism in a way that is more optimal for the low-oxygen environment of the Tibetan plateau," he said.

Writing in Science, where the results are published today, the authors say: "EPAS1 may therefore represent the strongest instance of natural selection documented in a human population, and variation at this gene appears to have had important consequences for human survival and/or reproduction in the Tibetan region."

Dr Wang said future research will focus on comparing the levels of EPAS1 expression in the placentas of Tibetan and Han Chinese women.