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Massive Neandertal & Denisovan Introgression
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Update: John Hawks’ lab is working in the same area, and he disagrees with the specific results presented here. Always reminds you to be careful about sexy results presented at conference! (someone should do a study!)

So claimed Peter Parham at a Royal Society meeting last week, Human evolution, migration and history revealed by genetics, immunity and infection. You can actually listen to the talk by pulling down the mp3 file. To get the part about human evolution and introgression, jump to 24 minutes in.

Here is the general sketch: It looks like ~50 percent of the HLA Class I alleles in Europeans derive from Neandertals, ~70-80 percent of HLA Class I alleles in East Asians derive from Denisovans, and that and ~90-95 percent of HLA Class I alleles in Papuans derive from Denisovans. If you recall, ~2.5% of the total genome content of non-Africans seems to be Neandertal, while ~5% of the total genome content of Papuans seems to be Denisovan. The total genome content proportions are rough estimates, there may be some wiggle room in there. But you can see that the HLA allele admixture estimates from these ancient Eurasian lineages is greater by an order of magnitude. Why?

Parham is at pains to point out that there is a major distinction in the nature of the genealogies of alleles which have generally been buffeted by neutral dynamics, and those which have been subject to selection. The HLA region is among the most polymorphic in the human genome, and that is due to the fact that balancing selection maintains diversity (likely a great deal of this through negative frequency dependence over the long term). Presumably this is the target of selection when one conceives of the Red Queen’s Hypothesis in terms of pathogen-host immune system coevolution.

In the presentation it is clear that something seemed off in some of the HLA haplotypes which these researchers had analyzed. They “looked” as if they were introgressed. There has been evidence of this before on other genes. But, with the draft sequences of ancient Neandertals and the Denisovan, scholars could check to see if inferences of admixture between archaic and neo-African lineages were borne out by matching them against the actual sequenced ancient DNA. In some cases they did. In others instances the inferences were wrong (or, the archaic introgression was from a lineage which hasn’t been sequenced yet). In this case Parham reports that his researchers found that the alleles found at high frequency in eastern Eurasia and Oceania seem to derive from the same lineage as that of the Denisovan. Intriguingly, he also adds that the Europeans are about ~50 percent admixed at the HLA Class I locus. If I heard Parham correctly, there are two major points in relation to human evolutionary history:

- East Asians have the Denisovan allele, when they don’t have Denisovan ancestry

- They don’t have the Neandertal alleles, when they do have Neandertal ancestry

- The Papuans are nearly fixed for the Denisovan allele, and lack the Neandertal one

This is why the term “introgression” is key. We’re not talking simple admixture. Rather, admixture followed by selection, whether negative selection which purges introduced alleles, or positive selection which increases the allele’s frequency. We already saw a recent possible case of introgression with a dystrophin allele. This is much more exciting, as the HLA alleles have clear functional relevance, and are known to be targets of natural selection. If adaptation occurs via introgression, this would be one of the key candidate regions a priori. Additionally, the deviation from expectation as inferred by admixture estimates is so great that you have to wonder if selection is responsible for the difference at such a functionally relevant locus. In the East Asian case if these results hold (and I hear Parhman correctly that East Asians carry the Denisovan variant) you see a case where admixture was at such a low level that it’s not detectable, but natural selection preserved a signature of the admixture by amplifying the frequency of an introgressed allele.

In the summation of his presentation Parhman makes a lot of good points about how useful the variation of the Neandertals and Denisovans probably was for the neo-Africans. First, if they went through a bottleneck they may have lacked a large complement of HLA alleles. Because of the need for diversity at this locus to combat pathogens admixture may have been like an injection of mutations which were already preselected for a high degree of utility. Secondarily, Eurasian hominins were probably well adapted to local Eurasian pathogens. The fast that East Asians have much more detectable Neandertal ancestry (~2.5%) than Denisovan (~0.0%), but the Denisovan HLA Class I allele is much more prominent in these populations, indicates that Neandertal and Deninsovan variants were adaptive for different pathogens endemic to their regions of Eurasia!

Finally, a special shout out to Greg Cochran and John Hawks. They’ve been talking to me about introgression as a concept relevant to human evolution since 2005, so a lot of these findings are pretty unsurprising.

(Republished from Discover/GNXP by permission of author or representative)
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  1. “natural selection preserved a signature of admixture by amplifying the introgressed allele” I like the sound of that!

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  2. Two questions:

    First, do we know or can we guess who the Denisovians are? H. erectus?

    Second, does this shift the balances towards Wolpert’s theory of regional evolution?

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  3. Any idea if the alleles in question are tested by 23andme? Or if there is a way to determine HLA haplotype there?

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  4. I wonder if it is statistically possible to take Denisovian/Neanderthal genes and sort them into selectively neutral and selectively influences loci. The proportion of archaic admixture in the former would presumably be closer to the initial admixture level (and necessary somewhat lower than the current total archaic admixture fraction). The ratio of this baseline level of admixture to the selectively influenced loci’s level of introgression would indicate the strength of the natural selection at that loci.

    Given the lack of catastrophic differences in disease vulnerability between modern day Denisovian admixed individuals and modern day Neanderthal admixed individuals, however, I’m a little skeptical of what appear to be such intense selective pressures on the HLA complexes which seem to rival that of malaria resistance genes, for example. Maybe this is because modern food producers aren’t exposed to the same kinds of pathogens that hunter-gather populations were, but I’d be more comfortable that this result was accurate if we could figure out specifically what pathogenic selective pressures are driving the respective allelic variants.

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  5. Couldn’t this point to a possible reason for a postulated lag between the immediate “out-of Africa” into the Near East and the expansion of Human lineages beyond it into the rest of Eurasia (and similar “neutral” Neanderthal-admixture levels in all Eurasians found previously)?

    That is in order to make it necessary for such populations to acquire high levels of HLA variants from archaics from such low general admixture levels, HLA variants found in Africans may have been immediately wholly inadequate to deal with ancient West Eurasian pathogens. Thus a “pause” in the Near East may be explained by a need for Neanderthal admixture and subsequent slowish spread of such alleles in sufficiently diverse populations.
    Neanderthal HLA variants might later be inadequate for East Eurasian pathogens co-evolving with Denisovans, and necessarily be replaced by Denisovan ones, perhaps after a second pause further along the route.

    One difficulty is the lack of major disease vulnerability of Africans in Europe in recent millenia, and of West Eurasians in East Eurasia (and vice-versa).
    But perhaps such pathogens don’t exist anymore either- pathogens adapted to Neanderthals and Denisovans would likely be often highly contagious and deadly when jumping to recently “out-of-Africa” modern Humans (pathogens jumping between closely related species are often specially deadly in the non-pathogen-co-evolving receiving species- like HIV, falciparum leap versus the more indolent malaria parasites?)- demanding specific defense mechanisms only available in co-evolving archaics. But maybe other genetic differences between hosts then prevented the evolution of more chronic (more beneficial to parasite spread) infections in local modern humans.
    (sorry for wild speculation-it’s compulsive)

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  6. #2 Denisovans are another lineage of homo like Neanderthal. So they would be a similar, i.e. another at the same level classification as Neanderthals. Where that should be I believe is still open to question. This is concluded by divergence times estimated from the DNA for humans, Densovans and Neanderthals. Check articles in Nature and Discover and such from about the beginning of this years or so.

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  7. @ohwilleke
    “Maybe this is because modern food producers aren’t exposed to the same kinds of pathogens that hunter-gather populations were”

    During historic times, we have had major epidemics every few hundred years despite some measure of cleanliness and cooking. During paleolithic times, people ate raw or undercooked meat, innards, and brains, came in contact with animal feces on an almost daily basis (think bovine E. coli), drank unfiltered water from questionable sources, and always had unprotected sex. And there are of course huge differences between the animals hunted and eaten (and thus pathogens) between tropical and subtropical/northern regions.

    Still, I am not so sure about the bottleneck argument: I could picture the ooA group(s) as having quite some internal diversity by today’s standards.

    As to the Denisovans, they could have been heidelbergensis-like. There is some indication that heidelbergensis spread eastward around 200,000 years ago.

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  8. Given the mitochondrial DNA showing the Denisovans to be not too distantly related from Neandertals, I think it is unlikely they could be H. erectus. Its possible and even probable Denisovans are descendants of H. heidelbergensis but at this point we don’t have enough evidence to say with any degree of certainty.

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  9. I am reminded of how utterly dominating European genes for disease resistance were over Amerind genes for disease resistance. When long separated groups of human met one group could very easily predominate over the other just by having built up disease resistance that the other group had no exposure to. Even if modern humans had a superior cognitive tool kit they would have had to remain on the fringes of archaic humans until there was enough interbreeding to pick up their disease resistance genetic advantage. As Diogenes above said this could have considerably delayed expansion of one human lineage into another one’s turf.

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  10. Could neanderthal DNA obtained from a very limited number of initial admixtures coalesce under strong selection to cause clusters of deletions/duplications in identical regions shared between parents? I only ask because autism rates have been increasing in countries that have information industries (i.e. selection for nerd-folk) and the disorder has already been linked to CNVs. There’s a discussion on the “Causes of Autism” wiki:

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  11. Is there a list somewhere of which HLA alleles are supposed to have introgressed? I did a google search, but I keep bumping up against the generalities (~50 percent of the HLA Class I alleles in Europeans derive from Neandertals) without any specifics.

    I’m particularly curious about HLA DQ2.5, which seems to have some interesting auto-immune associations.

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