Extinct Humans Passed High-Altitude Gene to Tibetans

Tibetan people can survive on the roof of the world—one of the most inhospitable places that anybody calls home—thanks to a version of a gene that they inherited from a group of extinct humans called Denisovans, who were only discovered four years ago thanks to 41,000-year-old DNA recovered from a couple of bones that would fit in your palm.  If any sentence can encapsulate why the study of human evolution has never been more exciting, it’s that one.

In 2010, Rasmus Nielsen from the University of California, Berkeley found that Tibetan people have a mutation in a gene called EPAS1, which helps them handle low levels of oxygen. Thanks to this mutation, they can cope with air that has 40 percent less oxygen than what most of us inhale, and they can live on a 4,000-metre-high plateau where most of us would fare poorly. To date, this is still “strongest instance of natural selection documented in a human population”—the EPAS1 mutation is found in 87 percent of Tibetans and just 9 percent of Han Chinese, even though the two groups have been separated for less than 3,000 years.

But when the team sequenced EPAS1 in 40 more Tibetans and 40 Han Chinese, they noticed that the Tibetan version is incredibly different to those in other people. It was so different that it couldn’t have gradually arisen in the Tibetan lineage. Instead, it looked like it was inherited from a different group of people.

By searching other complete genomes, the team finally found the source: the Denisovans! The Tibetan EPAS1 is almost identical to the Denisovan version. It’s now a Tibetan speciality, but it was a Denisovan innovation.

This discovery is all the more astonishing because we still have absolutely no idea what the Denisovans looked like. The only fossils that we have are a finger bone, a toe, and two teeth. Just by sequencing DNA from these fragments, scientists divined the existence of this previously unknown group of humans, deciphered their entire genome, and showed how their genes live on in modern people. Denisovan DNA makes up 5 to 7 percent of the genomes of people from the Pacific islands of Melanesia. Much tinier proportions live on in East Asians. And now, we know that some very useful Denisovan DNA lives on in Tibetans.

Svante Paabo, who sequenced the Denisovan genome, is delighted. “It’s very satisfying to see that gene flow from Denisovans, an extinct group of archaic humans which we discovered only four years ago, is now found to have had important consequences for people living today,” he says.

“It was a complete surprise,” says Nielsen. “It took years after the Denisovan genome was published for us to even try this, because we thought it was so far-fetched.”

The discovery also adds to a growing picture of human evolution—one involving a lot of cross-breeding. Humans evolved in Africa, and everyone outside that continent descends from a relatively small group of pioneers who left it at some point in our prehistory. These trailblazers were adapted to life on the tropical savannah. As they migrated, they experienced all the varied challenges that the world has to offer, such as extreme temperatures and new diseases.

At the time, the world was already populated by other groups of humans, like Neanderthals and Denisovans. As the African immigrants met up with these groups, they had sex. And through these liaisons, their genomes became infused with DNA from people who had long adapted to these new continents. “It’s a new way of thinking of human evolution—a network of exchange of genes between many lineages,” says Nielsen.

Nielsen suspects that modern humans had sex with Denisovans in Asia, somewhere between 30,000 and 40,000 years ago. They inherited the Denisovan version of EPAS1, which lingered in the populations at very low frequencies. The carriers fared better at higher altitudes, and their descendants colonised the Tibetan plateau. This explains why the team found the Denisovan EPAS1 in the vast majority of Tibetans, but also in a couple of Han Chinese people living outside of Tibet.

Denisova_TibetOther scientists have shown that sex with Neanderthals could also have imported useful genes into our genome, including those involved in skin, hair, and the immune system. “What we’re learning from ancient genomes is that while each of them may have contributed only a little to our ancestry, those genetic streams were full of tiny golden nuggets of useful genes,” says anthropologist John Hawks, who emailed me just before visiting Denisova Cave where the Denisovan fossils were found.

“What is a bit surprising is that Denisova is not at high altitude,” says Hawks. It’s in the Altai mountains of Siberia, but it’s not that high up. If Denisovans had the high-altitude version of EPAS1, this could imply that they also spread through the more mountainous parts of China and South Asia. “This gives a route by which Denisovans might have gotten into Southeast Asia where we know modern humans picked up their genes on the way to Australia,” says Hawks.

Nielsen adds that the Denisovans weren’t necessarily adapted to high altitudes. Their version of EPAS1 could have helped them in other ways, and coincidentally allowed the Tibetans to colonise the roof of the world.

If I travelled to the Tibetan plateau, my body would try to cope by making more red blood cells, which transport oxygen around my body. But I’d overcompensate and make too many of these cells. My blood would become thick and viscous, leaving me prone to high blood pressure and stroke. Tibetans don’t have this problem. Their EPAS1 stops them from overproducing red blood cells and helps them acclimatise to the altitude without doing themselves harm. But cold climates can also raise blood pressure by constricting blood vessels. So perhaps the Denisovan version of EPAS1 helped them to adapt to extreme cold, rather than a lack of oxygen.

“To give you a definitive answer, I’d need to find a Denisovan and do some physiological experiments,” he says. “And I can’t.”

Reference: Huerta-Sanchez, Jin, Asan, Bianba, Peter, Vinckenbosch, Liang, Yi, He, Somel, Ni, Wang, Ou, Huasang, Luosang, Cuo, Li, Gao, Yin, Wang, Zhang, Xu, Yang, Li, Wang, Wang & Nielsen. 2014. Altitude adaptation in Tibetans caused by introgression of Denisovan-like DNA. http://dx.doi.org/10.1038/nature13408

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There are 25 Comments. Add Yours.

  1. G. P. Wreggitt
    July 2, 2014

    Very interesting. It certainly does make sense. A great article.

  2. Rowan Johnson
    July 2, 2014

    Fascinating new research. Was aware of how interbreeding between Neanderthals & modern humans developed our immune systems; enabling us 2cope with the new bacteria & viruses (& giving rise 2 conditions such as Hodgkins Lymphoma) -and assumed similar was the case in the Denisovans locale. But this shows how much further the melting pot goes & how useful ancient DNA was in adapting 2 environs new. And how relatively quickly, too genes are turned on & off -like the gene for lactose intolerance in modern humanity.

  3. Tom Campbell
    July 2, 2014

    Now to check out the high Andean Peruvians and Chileans. They must have some pretty interesting alleles, too, for high altitude living….

  4. John CARTMELL
    July 3, 2014

    Neanderthals, Denisovans: and how many more are there – and how do we find them? How many (species?) of human were there when Homo sapiens strode out of Africa? This research is utterly fascinating.

    [John, sometimes it comes down to looking at the right fossil. But scientists are also starting to find hints of sequences in modern human genomes which probably came from interbreeding with other extinct groups. That would be REALLY exciting – finding groups of extinct humans without any fossil remains at all! See http://www.nature.com/news/mystery-humans-spiced-up-ancients-sex-lives-1.14196 for a start. – Ed]

  5. Eva
    July 3, 2014

    Cool! Sherpa people in Nepal also handle altitude much better than everyone else (including non-Sherpa Nepalese) and they look quite similar to Tibetan people, so I wonder if they have the same mutation…

  6. Robin
    July 3, 2014

    Like all the best science this is, at its core, a great detective story! I love how much detail can be teased out of tiny fragments – genes, finger bones etc. Very interesting, clear article – thanks.

  7. Daniel Dmello
    July 3, 2014

    Is there a similar genetic explanation for how people living in the Andes mountains cope with low oxygen levels?

  8. razib
    July 3, 2014

    eva, yes.

  9. Jampa tenzin
    July 3, 2014

    @eva, well sherpa people in nepal are descended from tibet, sherpa literally mean easterners in tibetan language.. They eat same food same religion and same culture its something to do with border dispute between nepal and tibet , many tibetan lands went under nepal many centuries ago and they became nepali …

  10. Tim Martin
    July 3, 2014

    Some questions about the wording of the article, and our evolutionary lineage…

    Denisovans and Neanderthals are also “humans,” yes? So is it true to say that humans evolved in Africa? Did Denisovans and Neaderthals come out of Africa as well, or somewhere else (or do we not know)? If they evolved somewhere else, then not only do all of us non-Africans descend from the original group of homo -whatever, but some of us also descend from groups of Neaderthals or Denisovans that trace their lineage back to some other place!

  11. Jason
    July 3, 2014

    Are the Denisovians really extinct if some of there genes lived on in modern man?

    [Yes. In the same way that you would still be dead even if your children (who have half of your genes) were still alive. – Ed]

  12. Josh Udall
    July 3, 2014

    Correction for your first sentence.

    Everyone inherits the GENE called EPAS1. The Tibetan inherited the ALLELE from the Denisovans.

    It should read:

    Tibetan people can survive on the roof of the world—one of the most inhospitable places that anybody calls home—thanks to a version of a gene (i.e. allele) that they inherited from a group of extinct humans called Denisovans, who were only discovered four years ago thanks to 41,000-year-old DNA recovered from a couple of bones that would fit in your palm

    I understand the article was written for a lay audience, but not providing the distinction confuses the average lay person. Unedited, they assume that no else has the EPAS1 gene.

    [Good point. Edited slightly. – Ed]

  13. Andrew Durso
    July 3, 2014

    Ed, I will definitely make my evolutionary biology students read this article. Thanks for the quality coverage. Denisovans are one of the most interesting parts of human evolution if you ask me.

  14. Aseem S Johri
    July 3, 2014

    The author wonders why Denisonvans had high altitude genes, when they themselves weren’t from high altitude area. The reason could be that Denisovans, as we know them, may not be native to Denisova Caves. It is just that we have found few pieces of evidence in those caves. Hypothetically, they could very well be natives of Tibet, where they acquired those traits as a part of natural selection.

  15. chris y
    July 4, 2014

    EPAS1 is presumably a nuclear gene, but given the unexpected Denisovan-like mtDNA found in the 400kya Sima de los Huesos sample that was published recently, you have to wonder when this allele originated, as well as where. Is it possible that it was primitive to early “archaic” Eurasian populations – evolved somewhere like the Ethiopian highlands – and lost in Neanderthals?

  16. Equinox
    July 4, 2014

    @Jason –

    Being fascinated by our Deep Time past, and learning about it all the way back 4.55 billion years, has made me think that we need two different words for “extinct”. Ordovician sea scorpions are “extinct” in that no Ordovician sea scorpions live today, but they are Ancestral to all spiders, so their gggg… grandkids live all around us. That’s very different from, say, pterosaurs like pterodactyl or pteranodon, who have 0 living descendants. I think that “extinct” should apply to “really extinct” creatures like pterosaurs, and that we need a new word for “not alive but with descendants”, a word that we could apply to Vikings, australopithicenes, and Aunt Edna. Maybe “Ancestor” itself would work?

  17. Mark Stockman
    July 4, 2014

    Interesting. In the old Norse legends, the Jotuns (“frost giants”) weren’t really giants, as they could and did interbreed with the presumably human Aesir. They were, however, immensely strong, adapted to life in cold and rugged climates, and far more wise than intelligent (on average). Could the “frost giants” of legend have been Neanderthals? And if so, could the other races mentioned in many cultures’ languages, such as elves and dwarves, have a basis in other extinct hominid groups?

  18. mimi simmons
    July 6, 2014

    really enjoyed and learnt from your debates ,would be nice to get the follow ups ,

  19. Jukka Vuorinen
    July 7, 2014

    “Denisovans and Neanderthals are also “humans,” yes? So is it true to say that humans evolved in Africa? Did Denisovans and Neaderthals come out of Africa as well, or somewhere else (or do we not know)? If they evolved somewhere else, then not only do all of us non-Africans descend from the original group of homo -whatever, but some of us also descend from groups of Neaderthals or Denisovans that trace their lineage back to some other place!”

    @Tim Martin I have understood neanderthals and denisovans were “humans”. There were proto humans in africa millions of years ago, and they migrated to europe and asia on many migration waves. Neanderthals and denisovans moved away from africa before homo sapiens did. And because neanderthals, denisovans, and others lived hundreds of thousands or millions of years separately, they evolved to different species/races.

    So they are all from same homo lineage, which was born in africa. This is how I have understood this, and I haven’t studied this matter deeply (actually no formal education about this matter), so take this as one opinion. If I have understood incorrectly, please correct me. And with sources please. :)

    • Tim Martin
      July 7, 2014

      Thanks, Jukka!

  20. Peter Demou
    July 7, 2014

    Jukka Vuorinen and Tim Martin. You have undertsood it well. Excellent references that explain the evolutionary paths and timescales can be found in books by Brian Fagan “Cro-Magnon”; “Evolution: The Human Story”; Svante Paabo, “Neanderthal Man”; Clive Findlayson, “The Humans Who Went Extinct”. All great reads too.

  21. bruno
    July 8, 2014

    another explanation for the genome in the Denisovans is that the atmosphere could have some pain much less oxygen at that point in time. The Sun cools down every 400 years or so and this causes are magnetosphere to weaken. this allows solar wind to strip the atmosphere of cold oxygen. There are many other possible world events that could have occurred that far back that would have released that much oxygen and the survivors live through it.

  22. Huw Sayer – Business Writer
    July 21, 2014

    @MarkStockam – interesting point about the ice giants possibly being a collective tribal memory of encounters with Neanderthals (although some have suggested polar bears – which look like giant humans standing up). There is probably much more ‘truth’ in many legends than we realise – rather than simply being conjured up from imagination they are a form of collective, if distorted, memory of experiences in life. For many years Troy was considered a legend until it was discovered by an archaeologist who decided to see if it was real.



  23. Hongliang
    August 28, 2014

    its really great peogress.The next setp is that we should get hard evidence from archaeology.

  24. José Antonio Ortiz Reyes
    January 14, 2015

    Did you know if scientists have found a link between the genome of the Denisovans and the ancestors of the Native Americans?

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