Did sex with Neanderthals and Denisovans shape our immune systems? The jury’s still out

By Ed Yong | August 25, 2011 2:00 pm

The Neanderthals may be extinct, but they live on inside us. Last year, two landmark studies from Svante Paabo and David Reich showed that everyone outside of Africa can trace 1-4 percent of their genomes to Neanderthal ancestors. On top of that, people from the Pacific Islands of Melanesia owe 5-7 percent of their genomes to another group of extinct humans – the Denisovans, known only from a finger bone and a tooth. These ancient groups stand among our ancestors, their legacy embedded in our DNA.

Paabo and Reich’s studies clearly showed that early modern humans must have bred with other ancient groups as they left Africa and swept around the world. But while they proved that Neanderthal and Denisovan genes are still around, they said little about what these genes are doing. Are they random stowaways or did they bestow important adaptations?

When I spoke to Reich about this earlier this year, he was starting to sift through the data. “To a first approximation, they are random,” he said. “It’s possible that modern humans could have used the Neanderthal or Denisovan material to adapt to their environment, but we don’t have evidence for that.” However, palaeontologist Chris Stringer offered an intriguing suggestion: “If Denisovans were in South-East Asia long-term, they would have evolved immunities and defences to some of the diseases there, like different forms of malaria. That’s something modern humans could have picked up that would’ve been useful.”

He might have been right. Laurent Abi-Rached from Stanford University has just published a new study suggesting that our immune system owes a debt to our ancestors’ trysts with Neanderthals and Denisovans.

Abi-Rached looked at a set of three diverse immune system genes called HLA-A, HLA-B and HLA-C. These help our cells recognise and respond to a wide variety of invasive threats like viruses and bacteria. And because we such threats are legion, the HLA genes are exceptionally diverse. For each of the three, there are thousands of different versions, or alleles.

Abi-Rached thinks that we inherited several of these alleles from Denisovans, for they are far more common in Asia and Melanesia than in other parts of the world such as Africa. For example, a version of HLA-A known as A*11 is found in 50-60 percent of people in China and Papua New Guinea, but it is supposedly absent in Africans. Abi-Rached thinks that these variants entered the human genome after our ancestors bred with Denisovans somewhere in ancient Asia. These incoming genes provided an advantage in those areas, probably against local infections, and they gradually became more common.

Neanderthals also made their mark. Again, some of the HLA versions carried by the three individuals whose genomes have been sequenced are still around today. They are common in Europe and Asia, and absent in Africa. All in all, Abi-Rached thinks that Europeans gained over half of their HLA-A variants from having sex with other groups of ancient humans. Asians gained over 70 percent of their HLA-A variants in this way, and Papua New Guineans 95 percent.

It is a big claim, but David Reich is not convinced. “It is well known that present-day frequencies of genetic variants provide a very poor clue to the geographic place where those variants arose,” he says. John Hawks from the University of Wisconsin makes a similar point. For example, he notes that A*11, which Abi-Rached describes as “absent from Africa” is actually found in the region, albeit very rarely. “This is difficult to interpret,” he writes on his blog. “If it has any tiny disadvantage against malaria, for instance, its rarity in Africa is easily explained as a function of recent evolution, while its presence almost everywhere outside Africa would be no surprise even if there were never any interbreeding.”

Hawks argues that the presence of variants like A*11 in Denisovans and modern Asians could be coincidence. Both of them could have inherited A*11 from a common ancestor, a possibility that Abi-Rached discounted. Hawks argues that all of the major HLA alleles are much older than the origins of modern humans, or than the split between Neanderthals and Denisovans. To truly show that Asians inherited A*11 from Denisovans, Abi-Rached would need to show that there are changes in the allele that are common to these groups, but are absent elsewhere in the world.

There are other inconsistencies in the paper. Abi-Rached says that humans picked up a version of HLA-B called B*73 from Denisovans, somewhere in western Asia. But Reich failed to find any evidence of Denisovan genes in people outside of southeast Asia and Melanesia. Paabo notes that the allele could have come from Neanderthals, who were certainly around in Western Asia.

Despite these misgivings, both Paabo and Reich are excited to see other scientists expand upon their work. Paabo says, “I think it is really great that they have used the two genomes to look at new and exciting things. This is of course exactly why we sequenced the genomes.” Regardless of whether Abi-Rached is right about the immune system genes, his study is a sign that groups around the world are starting to interrogate the genes of our ancient relatives for clues about our own evolution. And that is certainly a step in the right direction.

Reference: Abi-Rached, Jobin, Kulkami, McWhinnie, Dalva, Gragert, Babrzadeh, Gharizadeh, Luo, Plummer, Kimani, Carrington, Middleton, Rajalingam, Beksac, Marsh, Maiers, Guethlein, Tavoularis, Little, Green, Norman & Parham. 2011. The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans. Science http://dx.doi.org/10.1126/science.1209202

Image (source)

More on ancient DNA:

Comments (14)

  1. great write up! my main question: if 2.5% of the genome in eurasians is neanderthal, what’s the likelihood that there are some major loci which were adaptive? seems pretty good likelihood IMO.

  2. zackoz

    It’s thought, isn’t it, that Neanderthals and homo sapiens diverged several hundred thousand years ago, so even after that period they were able to interbreed.

    I suppose this isn’t so surprising – I seem to recall reports of evidence that human-ancestors and chimp-ancestors interbred for quite some time after the likely time of their split. Another blow against what Dawkins calls the discontinuous mind.

  3. Charles Sullivan

    Wonderful piece. My only quibble is in the title and in the first sentence where you use the words ‘we’ and ‘us’.

    Since everyone outside of Africa can trace some percentage of their genomes to Neanderthal ancestors, those within Africa cannot, I assume.

    So when you say ‘we’ and ‘us’ do you mean all humans except most sub-Saharan Africans?

    I’ve encountered something similar in pieces (not your pieces) discussing the out-of-Africa theory, where ‘we’ and ‘us’ are used in a way that sounds inclusive (as if it were all of humanity), but obviously it’s not inclusive of those of our species who remained in sub-Saharan Africa

    I just wonder what an African would make of the use of ‘we’ and ‘us’ in these contexts.

  4. @Charles – Good point. I’ve actually corrected this before for the reason you point out but it’s too easy for it to slip in.

    @Razib – I agree. I’d be really surprised if there wasn’t some adaptive function, but I guess the question is whether this paper is strong enough to make the point and clearly the folks I spoke to felt otherwise.

  5. Donna B.

    So much for “purity” eh?

  6. Bob Dole

    @Charles – Is there direct evidence that 0 neanderthal alleles made it into Africa? I was under the impression that the Max Planck team had only established a relative difference between the quantity of admixed alleles in a group containing [a Frenchman, a Papuan, and a Han], vs. [a San and a Yoruban] (two human populations already known to be fascinatingly diverse/divergent *within* Africa). Their method is described at 46:18 in this video: http://www.youtube.com/watch?v=RzT4rojbPJM&t=46m18s

  7. @Bob Dole – Of course, absence of evidence is not evidence of absence. But there is currently no evidence of Neanderthal or Denisovan alleles in Africa. Here’s what David Reich said to me (about Denisovans, but equally applies to Neanderthals; just change Asia/Oceania to Eurasia):

    “We did not detect any evidence of Denisovan genetic material outside of southeast Asia and Oceania. Our failure to detect Denisova genes in western Asia and Africa of course doesn’t mean that Denisova genes do not occur there. However, it does mean that the contribution of Denisova genes to people in these parts of the world is sufficiently small that we did not have statistical power to detect it in a whole genome data set.

  8. Bob Dole

    “about Denisovans, but equally applies to Neanderthals; just change Asia/Oceania to Eurasia”
    – Ed Yong

    I’m pretty sure Denisovans are genetically distinct from Neanderthals. Do we know that Neanderthal DNA is absent in Africa or are we extrapolating data about a continent from two samples?

  9. Thank you for a balanced perspective that is much less sensationalistic than some of the current headlines. There are significant reasons for caution on some of these findings and I appreciate how you have highlighted John Hawks’s critique. I also agree with Bob Dole that there is a danger in putting too much emphasis on “never in Africa” or the “non-Africans.”

    For more analysis and links, see my blog post Denisovans, Neandertals, Immunity, Anthropology, Sex.

  10. Henry Soloway

    The Denisovans are known genetically only because of two fossils, a “pinky” and a molar tooth. From these two troves of DNA the entire genome of the Denisovan has been pieced together. The one problem I have is that on the occlusal surface of the molar is a large amalgam filling. Does this suggest that among the Denisovans was one or more proto-dentists?

  11. Bob Dole

    “…on the occlusal surface of the molar is a large amalgam filling”

    Do you have a link for that?

  12. @Bob Dole

    I wonder if the troll you replied to really has teeth that are diamond :)

    Photo of tooth here. http://news.nationalgeographic.com/news/2010/12/101222-new-human-species-dna-nature-science-evolution-fossil-finger/

    I can’t see a “large amalgam filling” in the photo, I can however see what appear to be Arabic numerals suggesting either a South Asian / Middle Eastern / European origin of the tooth or contamination after discovery. (Joke)

  13. Chris Woollcott

    It’s hard not imagining still other yet-to-be-discovered hominins contributing to regional DNA. This period of Homo evolution is truly fascinating. Surely it’s possible that Africa had a hominin of its own capable of interbreeding with our ancestors there? Plenty of mountains and deserts and space for DRIFT, after all.

    How safe is this speculation that Neanderthals, tho tool makers, seem to have lacked a sense of symbolism? It makes you wonder what they had in spades that we didn’t, or only absorbed aspects of. It also makes you wonder about the nature of the Densovans. Perhaps their sense of symbolism proved paralyzing!

    If some small biological quirk in us spawned “humanness” as we know it, these other hominins certainly had their own neural filters (ie. frames of mind) that helped them coexist as a social species, etc. These adaptive experiments in early hominin consciousness are inspiring to imagine. I guess i’m stating the obvious, but HOW COOL.

  14. skyrask1113

    Interesting next tell me I have antigions in my blood. Just kidding i am o negitive only if i get a o positive liver read about it on this website. Its actually very interesting. But I am curious if it is realated to o negitive people if it is i shall look in to it. I heard that that branch is realated to o negitive. I research o negitive blood to solve how it was formed as a hobby oddly i am only 11. If any one has any knolege on it please contact me by posting a comment.

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