June 17, 2011

Strong introgression of non-Sapiens antigens in 'Eurasian' modern humans (but not in Africa)

HLA-A11
HLA-A11: the legacy of H. erectus in ourselves
Please read the updates below because some of the claims may not be sustainable (however others are plausible).

Prof. Peter Parham (Stanford University, USA) has found that some of the most common immunologic alleles among non-African modern humans have been adopted from other species of Homo living in Eurasia upon the migration out of Africa. 

This would be a typical case of introgression, a process in which, by means of lesser admixture highly adaptive alleles from another population are adopted. The logic here is that Neanderthals and other Eurasian hominins would be much better adapted to Eurasian-specific diseases, while our species would initially be  adapted to African-specific diseases instead. 

According to New Scientist:
One allele, HLA-C*0702, is common in modern Europeans and Asians but never seen in Africans; Parham found it in the Neanderthal genome, suggesting it made its way into H. sapiens of non-African descent through interbreeding. HLA-A*11 had a similar story: it is mostly found in Asians and never in Africans, and Parham found it in the Denisovan genome, again suggesting its source was interbreeding outside of Africa.
Also:
Half of European HLA-A alleles come from other hominins, says Parham, and that figure rises to 72 per cent for people in China, and over 90 per cent for those in Papua New Guinea.

The dominance of Denisovan alleles in Eastern Eurasia is coincident with my theory of these Denisovan specimens being hybrids of H. erectus and Neanderthals and acting actually as a proxy for H. erectus, with whom some of our ancestors would have hybridized in SE Asia, where this hominin is known to have existed until very late dates compatible with our arrival to the region.

Besides HLA, only Melanesians show some clear (albeit very minor) Denisovan admixture, but in the realm of antigens, the legacy of H. erectus has been clearly stronger. 

References:

News found thanks to Neanderfollia[cat].

See also in this blog:


Update: John Hawks, who has also been studying HLA, has objections to the conclusion that these alleles come from Denisovans or Neanderthals. For what I could gather he has two objections:
  • Age estimates, which are high risk slippery terrain.
  • Insufficient resolution of the genetics of the archaic hominin genomes. 


Important Update (Jun 18): the "Neanderthal" allele probably Sapiens, the "Denisovan" one may stand:

Hawks (same post, updated or did I miss it in first read?) directs us to a database of allele frequencies through the World, which would seem a most useful reference site. There we get clear evidence that the "Neanderthal" allele HLA*C:0702 probably migrated with our ancestors from Africa and needs no introgression explanation at all. The allele is frequent enough in many African populations peaking among the Baka Pygmies with 15%.

More complicated is the case of the allegedly Denisovan (Erectus) alleles HLA*A11. A look at the database is very clear: no native African population (south of the Sahara) has it at all except the creole ones of Cape Verde and Sao Tome (where it has without doubt recent European origin) and, crucially, a sample from Kampala, Uganda, where it reaches 4.3%.

This sample one is the only one that could suggest an African origin for this set of haplotypes. It could be argued however that as some genetic back-flow from Asia exists in the area, this case is explained by genetic back-flow. However the apportion is rather high, almost as high as Moroccan Berbers, Italians or Macedonians. Even the largest possible Asian source (Omanis: 11.4%) does not seem to be large enough to justify this island of HLA*A11 in Kampala.

Additionally the Nilotic Nandi of nearby Kenya are reported to have 0% of the controversial alleles. It is really hard to explain how this island of HLA*A11 arose in Kampala. But on the other hand, the fact that it is such an isolated finding is equally suspicious: if the allele (essentially HLA*A11:01) was so old in Africa, we should expect it to be found at least a very low frequencies in other populations.

Fine that malaria or other tropical diseases may have played a contrary selective role, as Hawks argues, but still the allele could, should, have survived in populations not affected by this disease. Also Uganda is not less Malaria-prone than Kenya (or most other nearby countries). So this explanation is not satisfactory.

A very localized founder effect of Asian origin (or a reporting error maybe) would seem to be at the origin of this anomaly. Also no African presence of variants 02, 03 or 04 has ever been reported.

Of course, we must always await for further data and research, but on the grounds of what we have now, I would say that:
  • Claim 1: HLA*C0702 is a Neanderthal introgressed allele. Busted!
  • Claim 2: HLA*A11 (several alleles) is a Denisovan (Erectus probably) introgressed allele. Plausible (but watch that Kampala island in Africa). 

Update (Aug 26):

The reference paper is:


Laurent Abi-Rached et al., The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans. Science, 2011. Pay per view

The supplementary material however is freely available

22 comments:

  1. Maju,

    My theory from last year:
    Denisovans = Home Erectus

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  2. My theory is that Denisovans are hybrids of H. erectus and Neanderthals with mtDNA from H. erectus but nuclear gene pool that is roughly 50-50. That's why they appear much closer to Neanderthals by autosomal genetics than by mtDNA.

    Hence I think that the "Denisovan" admixture found in Melanesians (and at very slight and blurry levels maybe also in SE Asians) should represent admixture with H. erectus but only at half the percentage detected by using Denisovans as proxy. The rest is just redundant Neanderthal admixture.

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  3. "(and at very slight and blurry levels maybe also in SE Asians"

    They don't seem to have more "denisovan" admixture than the French (according to the last paper).
    Maybe that population was H. erectus instead of denisovan (the specimen was found in Siberia).

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  4. When I looked at Reich 2011 first of all, I wrote in small type as a note:

    "In the same table S8.2 French, Han and Cambodians (and only them) also appear to show some admixture with Denisovans, though maybe a third or fourth of that of Melanesians".

    The text of the paper does not even consider that but the raw data in the supplemental material does suggest that indeed. It is however such a small trend that is not unmistakable and that's why I understand that the authors preferred to let it stay.

    But I did get that impression from table S8.2, which is the core of the study. And now we have other indications in the same line (HLA introgression).

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  5. I'm not sure if your point was to include the French, which I think it's correct. But Sardinians, Mongols or Karitiana did not show that "Denisovan" admixture in any case.

    It's a very slight thing, if Melanesians have 2.4% "erectus" (i.e. half of the "Denisovan", my best estimate), French, Cambodians and Han would only have 0.6% to 0.8%. It's little but it's still something.

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  6. "I'm not sure if your point was to include the French, which I think it's correct. But Sardinians, Mongols or Karitiana did not show that "Denisovan" admixture in any case. "

    Yes, that was my point. That doesn't have too much logic: how can the French have more or less the same admixture as an SE Asian, but not the Sardinians, Mongols nor other populations closely related with them? Does this mean the French are half SE Asian? I think it's much like the case as with the Karitiana and his/her low neandertal admixture.

    I read from the same paper that the most likely explanation for this "denisovan" ancestry in non-melanesians may have other reasons. For example, if neandertals and denisovans are related, it's expected that the populations carrying neandertal admixture may also show some denisovan admixture, even if that's not due to direct admixture. That's what I understood.

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  7. Even in the case of denisovan admixture in the French: how can we explain the presence of supposedly denisovan HLAs in all Europe, if most of them don't carry denisovan DNA? How can this be possible? Maybe genetic tests aren't powerful enough to detect this?

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  8. It does not have much logic indeed and seems to demand greater research before we can jump to any conclusions. The only common element among those with a bit of admixture and those showing none is that the first are larger more cosmopolitan peoples, while the latter are smaller more isolated ones. But that does not explain much, right?

    What it shows in any case is that the Erectus/Denisovan admixture episode did not just end up in the Melanesian cul-de-sac but that, in a quite more diluted form, also shows up among other Eurasians. Enough to justify the seeding of Erectus/Denisovan HLA alleles, which were then propped up by adaptive selection.

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  9. "What it shows in any case is that the Erectus/Denisovan admixture episode did not just end up in the Melanesian cul-de-sac but that, in a quite more diluted form, also shows up among other Eurasians. Enough to justify the seeding of Erectus/Denisovan HLA alleles, which were then propped up by adaptive selection."

    Yes, this makes more sense, but still, I can't understand how can be possible for people to have (a lot of) denisovan-derived genes without having any detectable denisovan ancestry.

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  10. It is perfectly possible: the inter-individual differences in the human (H. sapiens) genome amount up to 15-20 million bases (<1% of 2.9 billion). This is the part that was measured when comparing with Neanderthals and "Denisovans".

    The 0.7% of my estimation of H. erectus (Denisovan/2) admixture in these peoples would therefore amount to roughly 150,000 bases. And this produced such a faint signal that the authors preferred to ignore it in the text (I'm quite persuaded that they were aware but overly cautious about this).

    The other peoples that show no signal may still have maybe as much as 50,000 or at least a few thousand base pairs that are coincident with Denisovan and not Neanderthal but that is like the proverbial needle in the haystack: you don't really see it unless you get yourself to search for it meticulously... and even then.

    In any case there would be enough coincidental base pairs to code not one but many such alleles.

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  11. "In any case there would be enough coincidental base pairs to code not one but many such alleles."

    Thanks, now I can understand, althought I'm still confused, because I've read (Gene expression) that Parham apparently said ALL east asian and denisovan 70-90% of HLA genes come from denisovans, while 50% of the HLA-I genes in Europeans come from neandertals. This doesn't make too much sense according to the % of archaic admixture.

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  12. However I am not sure how linkage disequilibrium (i.e. the fact that fractions of the genome tend to be inherited in blocs, which only get fragmented after many generations) could play here.

    The second admixture event (with H. erectus) surely took place after the first divisions of the proto-Eurasian population had occurred but before the gates of genetic flow between the continental sub-regions were really closed (mostly by demographic pressure alone), which I think happened c. 50 Ka ago more or less.

    In these circumstances I am not yet sure how the blocks of genes containing Erectus admixture could have been moved around but they may have been more or less randomly "fixated" in some populations and not others. Just food for thought because we don't seem to have enough data to judge this matter, so it can't be but a path to keep open for whenever further research allows to transit or to discard definitively.

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  13. "This doesn't make too much sense according to the % of archaic admixture".

    That's exactly what Parham claims: that there has been a very strong adaptive selection for those alleles, so they have become dominant even if the overall Erectus or Neanderthal admixture is very small, sometimes not even noticeable at all.

    This phenomenon is called introgression and is relatively common among animals: tiny admixture events, typically via a small unstable hybrid population, allow for much more important flow of key genes that have high adaptive value, alleles that are then selected for repeatedly until they become dominant. The rest of the genes, which have no adaptive value usually remain marginal or even vanish (unless they hitchhike).

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  14. "This phenomenon is called introgression and is relatively common among animals: tiny admixture events, typically via a small unstable hybrid population, allow for much more important flow of key genes that have high adaptive value, alleles that are then selected for repeatedly until they become dominant. The rest of the genes, which have no adaptive value usually remain marginal or even vanish (unless they hitchhike)."

    I understand, but what I've read is that the neanderthal alleles have been fixated mostly in the European population, instead of the Asian/PNG population. I don't see how can this be due to selective pressures, moreover, it seems most of these alleles can be found in Africa as well (according to J.Hawks)

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  15. "The dominance of Denisovan alleles in Eastern Eurasia is coincident with my theory of these Denisovan specimens being hybrids of H. erectus and Neanderthals and acting actually as a proxy for H. erectus"

    There is a much more parsimonious solution, but I know you are bitterly opposed to it.

    "My theory from last year:
    Denisovans = Home Erectus"

    I would expect SE Asia H. erectus to vary from Denisovans as much, or more, than Neanderthals and Denisovans from each other.

    "The only common element among those with a bit of admixture and those showing none is that the first are larger more cosmopolitan peoples, while the latter are smaller more isolated ones. But that does not explain much, right?"

    It could explain a lot: if the Denisova-admixed population had become widespread before the later expansion of the population lacking such admixture.

    "ALL east asian and denisovan 70-90% of HLA genes come from denisovans, while 50% of the HLA-I genes in Europeans come from neandertals. This doesn't make too much sense according to the % of archaic admixture".

    As Maju says, selection would probably explain the difference.

    "the neanderthal alleles have been fixated mostly in the European population, instead of the Asian/PNG population. I don't see how can this be due to selective pressures"

    The alleles have retained their regional distribution in spite of apparently major human migrations. This tends to suggest that the migrations did not involve total replacement of preceding populations.

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  16. "I understand, but what I've read is that the neanderthal alleles have been fixated mostly in the European population, instead of the Asian/PNG population. I don't see how can this be due to selective pressures"...

    It's possible that Neanderthal and "Denisovan" alleles do similar functions and also availability must have played a role. If the Neanderthal allele did the trick then there was no need for the "Denisovan" one or vice versa.

    "... moreover, it seems most of these alleles can be found in Africa as well (according to J.Hawks)".

    Did he? In what parts of Africa? I mean: North Africa or Ethiopia would be misleading here.

    I did not understand he said that in his blog entry. But actually it's very difficult to say what's going on as no paper has been actually published. We are talking around very generic figures which have been thrown to the public without the necessary documentation or precission.

    We can't therefore judge with clarity.

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  17. I notice that Hawks directs us to a database for the allegedly "Neanderthal" allele HLA-C:07:02. The fact that Baka Pygmy have 15% (0.150) of this allele pretty much demolishes the theory of Parham for this allele. There are many other populations in Africa with the variant ranging from 0.8% to 11.5%. Essentially "busted".

    However the "Denisovan" HLA*11 issue is still open. My search could not find trace of the various alleles under this category, excepting Natal Tamils (an immigrant population), the admixed populations of Cape Verde and Sao Tome (2-3%) and critically Kampala, Uganda (4.3%). All the rest have exactly 0%.

    The debate now should rage about whether the Ugandan apportion should be considered a back-flow from Eurasia (Cushitic and Nilotic peoples show some Asian admixture) or it is the other way around: Ugandan 4.3% is the (local remnant of) the original source of HLA*11 variants in Papua and Eurasia. This part is pretty much open.

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  18. I've written an update on this matter: I'd say that only the HLA*A11 claim really stands (with some doubts).

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  19. There are other alleles, I suppose, because Parham said the % is much higher, however HLA-C:07:02 don't seem to come from neandertals, so much of this work is crap. Maybe the press manipulated his words?

    As for the Denisovan allele... it could have been lost in most Africans and that's why it seems denisovan. The fact that is shared between the genome of that individual and present day humans doesn't mean the allele originated in denisovans. Just don't know.

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  20. I think it's crazy. If you look at the database you posted, HLA*11 has such a random distribution that can't be true. There are several non-African populations with 0.000 % while in other samples, the same populations have low but a real % of the allele. This is hard to believe, so I think it might be due to some problems with samples or something, and these 0.000 we see in sub-saharans may turn to be false.

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  21. Kampala, Uganda is near the southernmost fringe of ancient Egyptian trade routes. Some ancient historians have suggest that either Punt or Yam, which were kingdoms that were important trade partners with Egypt were in what is now Northern Uganda, and Northern Uganda may have been an important or even primary source of copper for ancient Egyptians.

    If so, the Eurasian component of the Egyptian trade delegations (which would have included people who participated in the maritime Indian Ocean trade at its tail end of the time that this trade route existed) could have been sources for the 4.3%.

    Alternately, the source could be in more recent Chinese or Indian minority populations in Uganda (some members of which might have admixed with local in SE Asia before reaching Africa), which, IIRC, were subsequently expelled in the late 20th century.

    At any rate, the 4.3% looks like an outlier of recent origins to me.

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  22. It does not matter much: no possible source, like Oman or Iran, has more HLA*A11 than Kampala (and considering all the surroundings are 0%, the source should have quite more).

    What may be the case is that there is some sort of error in that Kampala sample because it does not make much sense that nearby populations have just 0% for no obvious reason at all and these 4.3%.

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