8,000-year-old mutation key to human life at high altitudes

August 17, 2014
Tibetan locals living at 4,300m. Credit: Tsewang Tashi, M.D.

In an environment where others struggle to survive, Tibetans thrive in the thin air on the Tibetan Plateau, with an average elevation of 14,800 feet. A study led by University of Utah scientists is the first to find a genetic cause for the adaptation – a single DNA base pair change that dates back 8,000 years – and demonstrate how it contributes to the Tibetans' ability to live in low oxygen conditions. The study appears online in the journal Nature Genetics on Aug. 17, 2014.

"These findings help us understand the unique aspects of Tibetan adaptation to high altitudes, and to better understand human evolution," said Josef Prchal, M.D., senior author and University of Utah professor of internal medicine.

The story behind the discovery is equally about cultural diplomacy as it is scientific advancement. Prchal traveled several times to Asia to meet with Chinese officials, and representatives of exiled Tibetans in India, to obtain permissions to recruit subjects for the study. But he quickly learned that without the trust of Tibetans, his efforts were futile. Wary of foreigners, they refused to donate blood for his research.

After returning to the U.S., Prchal couldn't believe his luck upon discovering that a native Tibetan, Tsewang Tashi, M.D., had just joined the Huntsman Cancer Institute at the University of Utah as a clinical fellow. When Prchal asked for his help, Tashi quickly agreed. "I realized the implications of his work not only for science as a whole but also for understanding what it means to be Tibetan," said Tashi. In another stroke of luck, Prchal received a long-awaited letter of support from the Dalai Lama. The two factors were instrumental in engaging the Tibetans' trust: more than 90, both from the U.S. and abroad, volunteered for the study.

Josef Prchal, M.D., (at computer) enrolls Tibetans into the study in this image. Credit: Tsewang Tashi, M.D.

First author Felipe Lorenzo, Ph.D., spent years combing through the Tibetans' DNA, and unlocking secrets from a "GC-rich" region that is notoriously difficult to penetrate. His hard work was worth it, for the Tibetans' DNA had a fascinating tale to tell. About 8,000 years ago, the gene EGLN1 changed by a single DNA base pair. Today, a relatively short time later on the scale of human history, 88% of Tibetans have the , and it is virtually absent from closely related lowland Asians. The findings indicate the genetic variation endows its carriers with an advantage.

Prchal, collaborated with experts throughout the world, to determine what that advantage is. In those without the adaptation, low oxygen causes their blood to become thick with oxygen-carrying red blood cells - an attempt to feed starved tissues - which can cause long-term complications such as heart failure. The researchers found that the newly identified genetic variation protects Tibetans by decreasing the over-response to low oxygen.

These discoveries are but one chapter in a much larger story. The genetic adaptation likely causes other changes to the body that have yet to be understood. Plus, it is one of many as of yet unidentified genetic changes that collectively support life at high altitudes.

Prchal says the implications of the research extend beyond human evolution. Because oxygen plays a central role in human physiology and disease, a deep understanding of how high altitude adaptations work may lead to novel treatments for various diseases, including cancer. "There is much more that needs to be done, and this is just the beginning," he said.

University of Utah scientists Felipe Lorenzo, Ph.D., Josef Prchal, M.D., Tsewang Tashi, M.D. Credit: Tsewang Tashi, M.D.

At the beginning of the project, while in Asia, Prchal was amazed at how Tashi was able to establish a common ground with Tibetans. He helped them realize they had something unique to contribute. "When I tell my fellow Tibetans, 'Unlike other people, Tibetans can adapt better to living at high altitude,' they usually respond by a little initial surprise quickly followed by agreement," Tashi explained.

"Its as if I made them realize something new, which only then became obvious."

Explore further: The genetic origins of high-altitude adaptations in Tibetans

More information: "A genetic mechanism for Tibetan high-altitude adaptation" will be published online on Aug. 17, 2014, in Nature Genetics: dx.doi.org/10.1038/ng.3067

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1 / 5 (4) Aug 17, 2014
This report links ecological variation from a nutrient-dependent base pair change to changes in the microRNA/messenger RNA balance and amino acid substitutions that differentiate the cell types of species from microbes to man via stabilization of biophysically-constrained thermodynamic cycles of protein biosynthesis and degradation, which enables organism-level thermoregulation. It reveals how much pseudoscientific nonsense is incorporated into the claim that an 8,000 year-old mutation somehow led to the ecological adaptation manifested in this modern human population.

For comparison, a base pair change and single amino acid substitution in another modern human population in what is now central China linked nutrient-dependent pheromone-controlled ecological adaptations in the mouse-to-human model of cell type differentiation manifested in hair, teeth, sweat glands, and mammary tissue. That population supposedly arose in ~30K years. How did the Tibetans mutate and evolve in 8K years?
5 / 5 (3) Aug 17, 2014
Keep going scammer James V Kohl. Your SEO profile is slowly changing, and it won't stop until you stop spamming this board:

1 / 5 (3) Aug 18, 2014
Articles like this tout the pseudoscientific nonsense that is typically found in reports that mutations are the key to something important, other than to understanding diseases and disorders. For comparison, we have everything that is neuroscientifically known. See for examples:

1) "Comparative approaches in evolutionary psychology: molecular neuroscience meets the mind" Link opens pdf nel.edu/pdf_w/23s4/NEL231002R11_Panksepp_.pdf "

Claims regarding evolved, uniquely human, psychological constructs should be constrained by the rigorous evidentiary standards that are routine in other sciences."

2) The article won the same award as our 2001 Review: "Human pheromones: integrating neuroendocrinology and ethology" http://www.nel.ed...view.htm

Has anyone seen any evidence that evolutionary theorists will ever constrain their claims by placing them into the context of "... the rigorous evidentiary standards that are routine in other sciences."

Who's the spammer here
5 / 5 (2) Aug 18, 2014
@JKV I don't really understand what you have written, but you question how Tibetans evolve a mutation in just 8K years. I think that you have misunderstood the statement. It claims that the mutation arose 8K years ago, not that it took 8K years for the mutation to occur. Mutations occur when our highly unstable genome is rearranged during gamete formation. It happens in a single individual, then spreads through the population due to the advantage it confers, it does not slowly develop over time, although other (further) mutations may well complement or add to its effect.

One question I have though, is, how did the researchers pinpoint the mutation as having arisen 8K years ago? Do they have access to ca 9K yo corpses who do not exhibit the mutation?

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