EPAS1, the athlete and highland gene
When I started researching this week’s article, I was amazed myself. EPAS1 is a really fascinating protein. So I’ll do my best to try and tell you what is so special about EPAS1. Only so much in advance: it has to do with Tibetans, athletes, oxygen and a long extinct human species. In fact, the only uninteresting thing about EPAS1 is its full name: endothelial PAS domain-containing protein 1. What was breathtaking, in contrast, was the observation that Tibetans almost exclusively carry a certain variant of the EPAS1 gene, which hardly ever occurs in Han Chinese (published in 2010 in science).
In fact, the unequal distribution of these two variants between the two populations, which split only a few thousand years ago, is as high as has ever been observed for any other human gene. So what environmental factor could it be that has made this gene evolve so incredibly fast? There is very good evidence that it is the extraordinary sea level of Tibet. Even Tibets capital Lhasa is located at almost 4000m, an altitude in which a human being during normal breathing absorbs one third less oxygen than at sea level. Most Tibet travelers (whether Europeans, Americans or Han Chinese) respond to this with a full-blown altitude sickness.
When Rasmus Nielsen, a professor in Berkeley, discovered that almost all Tibetans carry a variant of EPAS1 that was not found anywhere else in the world, he got the impression that the Tibetans had inherited this gene from another species. And this was exactly the theory he published in 2014 in Nature, which caused a lot of fuzz. It says that the Tibetans have inherited their variant of the EPAS1 gene from the Denisova people. The Densiova were only described in 2010, when human skeletal parts had been found in the Altai Mountains in southern Siberia. However, their genetic material was so different from both Neanderthals and modern humans that they are now widely accepted as a stand-alone species within the genus Homo. Similar to the Neanderthals, the Denisova people died towards the end of the Paleolithic, but not without first mixing (to a moderate extent) with the modern Homo sapiens that was then on the rise. And with such mixing probably some ancestors of the Chinese and Tibetans (then not yet separate populations) have taken up an about 30,000 base-long piece of Denisova DNA. For those people who then settled on the Tibetan plateau, this piece of DNA proved so beneficial that it solidified in the population, whereas most of the remaining Han Chinese lost it or “diluted it out” in their population.
So how can this section of DNA with the Denisova variant of the EPAS1 gene be such a huge advantage for people who have settled at over 4,000 meters? For a long time, EPAS1 has been known under another name: hypoxia-inducible transcription factor alpha 2 (HIF-2a for short). As the name implies, EPAS1 is a transcription factor expressed in oxygen deficiency. And the genes, which are activated by the EPAS1 transcription factor, work – not surprisingly – largely on the production of blood vessels, red blood cells and, above all, the oxygen-transporting molecule hemoglobin. In chronic altitude sickness, the body responds to the decreased oxygen by producing more hemoglobin. However, the increased hemoglobin makes our blood harder and it becomes a lot tougher for our heart to pump it. In the long term this result in a lot of medical problems.
Residents of extreme highlands in the Andes also have elevated hemoglobin levels; however, they have developed strategies to deal with them. For the Tibetans, however, the height adjustment seems to work differently, because they don’t have elevated hemoglobin levels at all. They probably owe this, at least in part, to their special EPAS1 variant, because it seems to stimulate hemoglobin production to a much lesser extent than it would do to us Europeans in the event of oxygen deficiency.
That the adaptation to extreme altitudes by the EPAS1 gene variants is very old, is shown not only by the presumed origin of the Tibetan variant in the extinct Denisova humans, but also by the occurrence of specific, sea-level-dependent variants of the gene in different animal species. Even cattle, for example, can develop altitude sickness and might die as a result of it, which is a real problem in the American Rocky Mountains. Here it is an unfavorable version of the EPAS1 gene, which was linked in 2015 with the often deadly high altitude edema in cattle. And just a week ago, an article was published discussing various EPAS1 variants in a particular falcon species of the Tibetan plateau.
But not only humans and animals in the mountains need a particularly good oxygen supply system. Athletes also demand a lot from their body in this regard. Indeed, as early as 2005, in a small, underappreciated study, an association between the EPAS1 gene and the energy metabolism of endurance athletes was demonstrated. However, after all the attention the Denisova-Tibetan story had caused, Polish and Australian scientists searched again for unequally distributed EPAS1 variants between successful athletes and not so sporty people. However, a large-scale study on EPAS1 and physical performance does not yet exist. Nevertheless, all we know so far is that EPAS1 is one of those candidates for a starting point, when it comes to the idea of providing genetic enhancement to us, in case we would at some point agree on the genetic manipulation of humans. Such enhancements were recently discussed again, when it came to the question, that with the help of genetic engineering we could or better prepare ourselves for a potential life on Mars. Whether we really want to do that – I think – we should first think and discuss in detail again.