8,000-Year-Old Mutation Key to Human Life at High AltitudesAug 15, 2014
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. Senior author Josef Prchal, M.D., professor of internal medicine, native Tibetan and author Tsewang Tashi, M.D., and first author Felipe Lorenzo, M.D., Ph.D., describe their work published online in the journal Nature Genetics. on August 17.
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Interviewer: Tibetans thrive in the high mountains of the Tibetan Plateau, conditions that most others just can't survive in. My guest, Dr. Josef Prchal, a professor in internal medicine at the University of Utah, led a study; identifying an 8000-year-old variation in the DNA sequence of Tibetans that help explain their amazing adaptation.
Today, I'm also joined by first author of the study, Dr. Felipe Lorenzo, and Dr. Tsewang Tashi, who is also an author on the paper and a native Tibetan. Dr. Prchal, Tibetans and lowlanders like us adapt very differently to high altitude conditions, what are the differences that you're interested in?
Dr. Prchal: The obvious difference is that if lowlanders go to very high altitude, they may die, but if you stay there for a long time, there are some chronic consequences which are not suitable for reproduction and for thriving in this high altitude. There are many and some of them we will not fully understand, but one of them is, what we call, pulmonary hypertension; that the pressure on the lungs is so high that it interferes with the circulation and you get, eventually, heart failure.
The other well-known adaptation is the level of oxygen tightly controls how many red cells we make. It means if we don't have enough oxygen, we make more red cells. So if you go to high altitude where the oxygen pressure is lower we make too many red cells. That's called polycythemia. That means the blood gets too thick and it's not very suitable for them, but it has been known that most of the Tibetans have a normal level of hemoglobin in very high altitude and this is something which gave us tools to study this.
And we selected then the Tibetans who had high hemoglobin and low hemoglobin, and that allows us to look at the genetic differences in these two populations. And with a graduate student here from department of genetics, Tatum Simonson, we selected these two population, did, at that time, the state of our genetic studies and we were able to look at the fingerprint of the genes of interest. We selected about 300 genes and 10 of them had clearly selected, that means they achieve much higher frequence in Tibetans, in those who were adapted well to high altitude.
And these adaptation mutations then must have some beneficial effect and so that was the first lead. And at two of the genes, which are selected, had something to do with how the body responds to oxygen, so one of them, a gene called PHD2 is a negative regulator of master regulators of response to hypoxia which is called HIF.
Interviewer: And what does the gene do?
Dr. Prchal: It decreases the over-response to very low oxygen. So sometimes our physiological responses may be detrimental. And so by modulating the intensity of the response, I think that was one of the benefits.
Interviewer: Dr. Lorenzo, you've been on the trail of this gene for a long time. It must have been satisfying to find it at last.
Dr. Lorenzo: It's really a challenge actually. Sequencing that region of a gene we just recently reach took me like six to nine months of trial and error. Finally, when we get it, it was just like you win a lottery and it's something to move on.
Interviewer: So when you saw it, you knew that was the one.
Dr. Lorenzo: Yes, because it's reproducible, it's there, it's common in our sample, and not common in the controls, so there's a story to tell.
Interviewer: So if the variation was selected for it, it must be important.
Dr. Prchal: If a gene happens to be beneficial in a given environment, with each generation the prevalence of these genes will increase. And so, again, if the Dr. Lorenzo's mutation of variant is find of 85% of Tibetans, it must be beneficial.
Interviewer: Dr. Tashi, you're a native Tibetan, it sounds like you guys went through great lengths to gain acceptance by the Tibetan community.
Dr. Tashi: So I join here in 2012 in University of Utah and one day Dr. Prchal approached me while I was in clinic and he was very excited that I was a Tibetan and I was kind of surprised.
Interviewer: Who's this guy?
Dr. Tashi: Initially, it seemed to me that he just wanted some blood and I said, "Well, that's easy. I can get some friends and get some blood."
Interviewer: Were you one of the ones sequenced in this study?
Dr. Tashi: Oh, of course, yes.
Dr. Prchal: He is.
Dr. Lorenzo: One of the first ones.
Dr. Tashi: And later on as the study progressed, I realized the significance of the whole study and this is a new potential, a very groundbreaking discovery, in a sense, and the importance that it would have, not only for the science as a whole. But being a Tibetan and also something uniquely Tibetan that's potentially the result of this, then we decided, okay, we should go and get involved more Tibetan. Actually, we went there twice and they don't really like to give blood because when you hear blood, it's kind of "Wow."
Interviewer: Yeah. But once you were able to explain it to them, and probably the fact that you are a Tibetan yourself and you're willing to undergo this, that helped them to accept it?
Dr. Tashi: Yeah, that was one of the major helping point.
Dr. Lorenzo: This is why Tsewang is a key for the success of this study because Dr. Prchal and I went actually to the community. It took us six to nine months talking to them and we got two samples.
Dr. Tashi: It's really difficult.
Dr. Prchal: We were well received.
Dr. Tashi: When it came to collecting blood, they just backed out. So it's really a key to get them into the study, and it really did go well.
Interviewer: And in the end, how many took part, the Tibetans?
Dr. Tashi: For here, locally, we have 26 or 28 and then I brought it 60 plus.
Dr. Prchal: Well, began probably more than 200 samples.
Dr. Lorenzo: More than 200 in China.
Dr. Prchal: Yeah, more than 200 samples.
Interviewer: It's important for you to get letters of support from high leaders in the Tibetan community, including the Dalai Lama.
Dr. Prchal: The Dalai Lama was contacted by a principle physician called Dr. Dorjee, who easily organized all these Tibetan health care in exile community and that only happen through Dr. Tashi. And Dr. Dorjee has contacted Dalai Lama, explained to him what we try to do, and Dalai Lama felt a better of the Tibetan adaptation would be helpful to Tibetan community, but also to humanity at large. And I think that Dalai Lama is very ethical man and when it comes to ethic issues, I think it's very important to him.
Interviewer: What are the implications of this work?
Dr. Prchal: There are many human disorders which are regulated by oxygen; not only the pulmonary or lung diseases, brain edema, but also cancer. So we think that delineation of this Tibetan adaptation and deeper understanding of this can eventually lead to better understanding of common human diseases.
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