Tibetans breathe easy
(appeared in August 2014)

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Genetic bases for Tibetans’ tolerance to high altitudes have been discovered, says S.Ananthanarayanan.

The body has a well oiled mechanism for getting oxygen to all parts, to keep body processes going. And, when oxygen supply is low, the body has ways to adapt, to grab more of the scarce oxygen. But the adaptation has its own cost and long spells can cause disease, even death. In the context, the way the Tibetan population thrives at altitudes with depleted oxygen raises questions that have not been fully answered.

The oxygen that is there in the air, which we breathe into our lungs, reaches our body cells through the red blood corpuscles, a component of our blood. When RBC is in a place where oxygen is rich, like in the lungs, they absorb oxygen, and give up oxygen at places where it is poor and needed, like at the site of body cells. It is hence important to have enough of this component in the blood and how much we have is measured by the levels of haemoglobin (Hb), the operative, iron-rich constituent of the RBC. To have 12-14 grams of Hb per 100 cc of blood is considered OK and lower counts are usually treated with nutrition rich in iron, to help create haemoglobin molecules.

But even with normal Hb levels, the supply of oxygen to the cells can drop when the level of oxygen in the air itself becomes low. The body then needs to adapt, and one way the body reacts is to create more red blood corpuscles, the oxygen transporting agents. But a danger of high levels of Hb in the blood is that this makes the blood get sticky and difficult to move through the body, and this causes the mountain sickness that people feel when they move to high altitude places, where the oxygen supply in the air is low.

There can also be other causes for oxygen levels to fall and Hb to rise, and one of these is habitual smoking. Cigarette smoke is highly depleted in oxygen and smokers’ bodies also need to adapt by raising Hb levels. Nutrition deficiency in smokers is often undetected because a blood test shows healthy Hb counts, although this is only in reaction to the lungs being starved of oxygen, not an indication of vitality! But people in places of high altitude generally have higher Hb levels and when plains people move to very high-altitude places, like Tibet, where the altitude averages at 14,000 feet, their bodies create so much of RBCs that they fall sick and may even die. But in Tibetans, who spend their lives at high altitudes, there seems to be an internal ‘brake’, which keeps the level of RBC and Hb under control.

Dr.Josef T Prchal, from the University of Utah, with colleagues from the same and other institutes in USA, Finland, China and India, report in the journal, Nature Genetics, both that they have worked out the genetic mechanism by which Tibetans are enabled to keep this form of adaptation under control, and also the time frame during which Tibetans acquired this unique genetic trait.

The story starts with earlier work of Prchal’s group, which announced in 2010 that there was a genetic basis for Tibetans’ high altitude tolerance. And soon after, Dr Felipe Lorenzo, also an author of the Nature Genetics paper, was able to identify the specific part of the Tibetan DNA where the adaptation had taken place. And the current study has established that it is in a variation, a tiny variation, of a single gene called EGLN1, that is responsible for a chain of genetically controlled biochemical events that helps Tibetans keep haemoglobin growth in check, even while other genetic factors push for more red blood cells in response to a low oxygen environment. And the genetic feature was clearly of great survival benefit, and very selective, as 99% of Tibetans have this variation, which is almost completely absent in closely related populations that live in lower altitudes.

A note from the University of Utah also describes the human relations part of the research effort, in getting sufficient numbers of Tibetans to volunteer blood samples. “It took several trips to Asia, meeting with Chinese officials and representatives of exiled Tibetans in India, to get the necessary permissions to recruit subjects for the study. But he (Prchal) quickly learned that official documents would not be enough. Wary of foreigners, the Tibetans refused to participate,” says the note. Even the Dalai Lama was approached. “The Dalai Lama felt that a better understanding of the adaptation would be helpful not only to the Tibetan community but also to humanity at large,” Prchal says. And the list of authors of the research paper includes native Tibetan Tsewang Tashi, M.D., clinical fellow at the Huntsman Cancer Institute at the University of Utah.

Age of the adaptation

The way this protective genetic feature arose in Tibetans is by evolutionary selection, of a chance error during DNA replication. When living cells reproduce, they create an extra copy of the DNA molecule, which contains all the genetic information, so that the new cell can have its own DNA. As the DNA molecule is billions of units long, this is complex process and there are generally some errors during the replication. But all such errors are not significant, because DNA has a built-in redundancy, by which the most common errors leave its function unchanged. If the errors are serious, the new cell may not survive, or its progeny may not be successful and the strain with this error would die out. But if the error proved to be an advantage, progeny with the error may do well and proliferate.

In the case of Tibetans too, a chance error like this conferred the capacity to live on at high altitudes and this proved a survival advantage. Progeny which had the advantage then prospered and soon most of the population had the advantage too.

Now the way to estimate when this change in DNA first began is by looking at the other, non-consequential, small genetics changes, which continue in the progeny of individuals who have the change, but these changes do not dominate or spread, as they do not confer a survival advantage. Now, these changes show certain relationships, or association with one another, which decay over generations. It is this rate of decay, in the near environment of the genetic change of interest, that leads, by statistical analysis, to how many generations ago the change of interest may have happened. Prchal and his group considered generations to arise every twenty five years, and worked it out that the genetic trait that helps Tibetans arose eight thousand years ago.

The Dalai Lama was quite right that the analysis, assisted by the cooperation of Tibetan subjects, has progressed our understanding of the science of genetics. The study has also shown us a case of very rapid consolidation of a genetic variation, and invites further studies, of movement of people or the rise of population in Tibet, to validate this way of working things out, or to find refinements.