What Neanderthals tells us about modern humans

In Who We Are and How We Got Here: Ancient DNA and the New Science of the Human Past David Reich spends a fair amount of time on Neanderthal admixture into modern human lineages. Reich details exactly the process of how his team arrived to analyze the data that Svante Paabo’s group had produced, and how they replicated some peculiar patterns. In short, eventually, they concluded that modern humans outside of Africa have Neanderthal ancestry, because the Neanderthal genome that Paabo’s group had recovered happened to be subtly, but distinctively, closer to all non-Africans than to Africans. At the time, the group reported that Neanderthal ancestry was relatively evenly spread across non-African populations, which lead them to suggest that it was likely a singular admixture event early on during the expansion phase of modern humans.

Nearly a decade things have changed. There is a consistent pattern of West Eurasians having less Neanderthal ancestry than East Eurasians. That is, Europeans have lower Neanderthal ancestry fractions than Chinese (South Asians are in between, in direct proportion to their West Eurasian ancestral quantum). There have been a variety of arguments and explanations for why this might be, which fall into two classes:

  1. Neanderthal ancestry was purged more efficiently from West Eurasians due to larger effective population sizes (selection is stronger in large populations).
  2. There may have been multiple admixture events into modern humans, or, gene-flow into West Eurasians diluting their Neanderthal ancestry.

But what if all these arguments are mostly wrong? That’s what a new preprint seems to suggest: The limits of long-term selection against Neandertal introgression:

Several studies have suggested that introgressed Neandertal DNA was subjected to negative selection in modern humans due to deleterious alleles that had accumulated in the Neandertals after they split from the modern human lineage. A striking observation in support of this is an apparent monotonic decline in Neandertal ancestry observed in modern humans in Europe over the past 45 thousand years. Here we show that this apparent decline is an artifact caused by gene flow between West Eurasians and Africans, which is not taken into account by statistics previously used to estimate Neandertal ancestry. When applying a more robust statistic that takes advantage of two high-coverage Neandertal genomes, we find no evidence for a change in Neandertal ancestry in Western Europe over the past 45 thousand years. We use whole-genome simulations of selection and introgression to investigate a wide range of model parameters, and find that negative selection is not expected to cause a significant long- term decline in genome-wide Neandertal ancestry. Nevertheless, these models recapitulate previously observed signals of selection against Neandertal alleles, in particular a depletion of Neandertal ancestry in conserved genomic regions that are likely to be of functional importance. Thus, we find that negative selection against Neandertal ancestry has not played as strong a role in recent human evolution as had previously been assumed.

The basic argument in the preprint is that the model assumed for the ancestry of West Eurasians and Africans was wrong. Wrong assumptions can lead to wrong inferences. Using two Neanderthal genomes which are from different populations, one of whom directly contributed to the Neanderthal ancestry in modern humans, a new statistic which was insensitive to model assumptions about modern human phylogeny was computed.

The older statistic held that West Eurasians and Africans were distinct clades which had not had gene flow in ~50,000 years. Using simulations the authors argue that the best fit to the statistics that they do see, the earlier flawed one, and the current more robust one, is a situation where a population of West Eurasian origin mixed with Africans starting about ~20,000 years ago.

This explains why there was a consistent decline in Neanderthal ancestry: the earlier statistic’s model assumption got worse and worse over time, and so began to underestimate Neanderthal ancestry more and more. There was continuous gene flow into Africa over the past 20,000 years.

Not everything that came before is wrong. It could still be that there are multiple admixtures. And, the authors do agree that some selection for Neanderthal alleles has occurred. It’s just that it’s not the primary reason for the decline of Neanderthal ancestry in West Eurasians.

As for the other explanation, that Neanderthal-less Basal Eurasian ancestry diluted the European hunter-gatherer fractions, the authors seem very skeptical of that. One point the authors make is that though an early European farmer was estimated to have ~40% Basal Eurasian, its Neanderthal estimate is still quite high. Iosif Lazaridis points out that this is an old estimate, and the Reich group now puts it closer to ~25%. Additionally, another recent preprint put the fraction closer to ~10%. With such low values, it is possible that Basal Eurasians may have had low Neanderthal fractions, but that that was a marginal effect on the aggregate West Eurasian ancestry quantum from Neanderthals.

I think the bigger thing to consider is that our understanding of the relationships of modern humans is roughly right, but there are lots of nuanced details we’re missing or misunderstanding. Ancient DNA from South Africa, for example, shows that modern Bushmen all seem to have exotic ancestry compared to samples from 2,000 years ago. But what about samples from 20,000 years ago?

We have the best temporal transect from Ice Age Europe, and in this region, there are many population turnovers and admixtures. It seems implausible that Europe is entirely exceptional. The West Eurasian gene flow event dated to ~20,000 years ago is curiously coincidental with the beginning of the recession of the Last Glacial Maximum. To get a better understanding of the relationships of Pleistocene people looking at paleoclimate data is probably useful. The ancient DNA will come online at some point…and unless you think ahead, we’re going to be surprised.

12 thoughts on “What Neanderthals tells us about modern humans

  1. Very groundbreaking paper if it bears out, couple of things I’m not sure about and would be interested to see anyone else’s take on:

    1) Yang and Fu’s paper on Tianyuan Man suggested – “Present-day Asian individuals carry ancestry from both Neanderthals and Denisovans. We find that the Tianyuan individual carried about as much Neanderthal DNA as other Upper Paleolithic Eurasians (4%–5%), which is more than that in present-day Eurasians (1%–2%; Figures S3A and S3B; Table S4C) and is consistent with the hypothesis that purifying selection acting since introgression has reduced the amount of Neanderthal DNA in present-day genomes”.

    This suggests that using the indirect statistic would also be affecting recent East Eurasians relative to ancient East Eurasians, just to a lesser degree than is the case in West Eurasia. So seems like there must be a hierarchy to which the indirect statistic affects samples both by time and by distance from Africa (Middle East>Europe>East Asia).

    This all seems consistent with some gene flow of some sort between East Eurasians and late Upper Paleolithic to Mesolithic Europeans (Loschbour, etc.) relative to Upper Paleolithic Europeans (the Vestonice Clade and others), which has also been reported.

    2) Hard to tell the actual estimates of ancestry from West Eurasians->Africans in the model over last 20kya. They state “0.0001 migrants per generation, beginning 20 k” assume roughly 20 years per generation, 1000 generations, then does that lead to something like 0.1% total ancestry or am I looking at this the wrong way?

  2. I’m reading it now and it’s too much to digest. That’s why I liked your bullet point list of 10 things to know about human ancestry blog post you did a while back (that Nathan edited for you.) Like Carl and Ed’s book, it’s a lot of info to take in so an end of chapter summary is nice or it becomes too difficult to know what to focus on.

  3. If it helps anyone, the direct f4 ratio from the paper, is not really too hard to understand and it’s really well explained in the paper, but assuming I’ve understood it, I’ll try and do it in an even more compressed way:

    Direct ratio = Stat B / Stat A where

    Stat A: f4(Altai,Chimp;Vindija,African) measures the excess to which Altai is phylogenetically closer to Vindija relative to African, using Chimp as neutral outgroup.

    Could be Z=200, could be Z=1.4. Of course, it’s gonna be by some very large value since the ‘thals were a pretty tight clade.

    Stat B: f4(Altai,Chimp;Eurasian,African) measures the excess to which Altai is phylogenetically closer to Eurasian relative to African, using Chimp as neutral outgroup.

    Now, say Stat A: 200, and Stat B: 5. Simple f4 ratio: B/A = 5/200= 2.5%.

    So pretty simple. (Of course the overall percentage could be inflated or deflated respectively by either Neanderthal or super archaic into African; but this won’t matter for comparing the f4 ratio results of Eurasians to each other).

    Let’s compare the indirect ratio, as Indirect ratio = Stat D / Stat C

    Stat C: f4(West African,Chimp;East African,Neanderthal) measures the offset measures the excess to which East African is phylogenetically closer to Eurasian relative to African, using Chimp as neutral outgroup. Let’s say it’s Z=200, again for the sake of consistently

    Stat D: f4(West African,Chimp;Eurasian,Neanderthal) measures the offset measures the excess to which West African is phylogenetically closer to Eurasian relative to African, using Chimp as neutral outgroup.

    Now let’s say D= 195 and C=200. f4 ratio: D/C = 195/200 = 0.975 = 97.5%.

    That is, Eurasians would be 97.5% modern human, in this model. Ergo what is left is 2.5% Neanderthal. (It’s indirect because it actually seeks to estimate the Homo Sap. in Eurasians, and then what is left is ‘thal).

    But as they say, the stat D may be different between different Eurasians because of subtle gene flow between different Eurasians and African.

    That’s not an issue for the direct stat.

    The only issue possible for the direct stat is if there is differential gene flow between Eurasian populations with the Altai Neanderthal, e.g. let’s say Natufians had less overall geneflow from Neanderthal, but it was from a different Neanderthal admix event more closely related to Altai, than Neanderthal that contributed to say, Villabruna, and that inflated their f4 stat.

    But fortunately this is both:

    a) unlikely for the populations who are found to have higher Neanderthal ancestry on the direct stat than the indirect stat (they are, uh, not temporally and geographically close to the Altai)

    b) unlikely to give a flat distribution if this were the case

    Then finally as they say that while “(the direct ratio) assumes that any Neandertal population that contributed ancestry to West Eurasians formed a clade with the Vindija Neandertal population … Recent analyses showed that this is the case for all non-African populations studied to date, including the ancient modern humans included in this study”.

    Really, it’s a very simple, short paper.

    Now Iosif Lazaridis’s comment that f4(West_Eurasian, East_Eurasian; African, Chimp) is non-significant is actually the serious objection to all this… but I can’t see any way that the direct stat could seriously be confounded (there’s only one possible confound and everything implies that it does not apply).

    It may be that the problem here is that the source mixing into Africans was a population like Taforalt, marginally closer enough to recent West Eurasians than to ancient Europeans and closer to West Eurasians than East Eurasians to mess with the indirect f4 ratio, but not close enough to West Eurasians to seriously shift the actual f4(recent West_Eurasian, recent East_Eurasian; African, Chimp).

  4. Matt

    Do you mean in your comment on stat C: “the offset measures the excess to which West African is phylogenetically closer to East African relative to Neanderthal”?

  5. “This explains why there was a consistent decline in Neanderthal ancestry: the earlier statistic’s model assumption got worse and worse over time, and so began to underestimate Neanderthal ancestry more and more. There was continuous gene flow into Africa over the past 20,000 years.”

    This would not seem (to my understanding, but of course I could be missing something) to explain the lower neanderthal affinity in Western Eurasians relative to Eastern Eurasians.

    Is it also possible that African gene flow into Western Eurasia (in the reverse direction) played a role—or also did—(in decreasing neanderthal affinity/detected affinity over time)?

  6. “With such low values, it is possible that Basal Eurasians may have had low Neanderthal fractions, but that that was a marginal effect on the aggregate West Eurasian ancestry quantum from Neanderthals.”

    It seems it may also be possible that neolithic Western Eurasians may have varied significantly in their degrees of Basal Eurasian ancestry (perhaps regionally and temporally/over time), and consequently also in their Neanderthal ancestry and possible dilution thereof. It seems Lazaridis may be suggesting this or something similar in his tweet where he says:

    “It would be nice to see estimates of N. ancestry for post-glacial Europeans/Near Easterners (shown as points in Fig. 1B) It is not clear from Fig. 1B that post-glacial West Eurasians all had the same amount of N. ancestry (and hence no dilution from B.E.).”

    A broader sample/analysis of various neolithic/post-glacial European and other Eurasian groups/specimens could likely be helpful (if I understand correctly) in understanding the variation in Basal Eurasian and neanderthal admixture in them (and the extent of the the former’s effect on the latter).

  7. Edit: ” A broader sample/analysis of various neolithic/post-glacial European and other Western Eurasian groups specimens…”

    (particularly Western Eurasian)

  8. “A population of West Eurasian origin mixed with Africans starting about ~20,000 years ago.” Should it not be” A population of African origin mixed with West Eurasians starting about ~20,000 years ago.” I don’t understand the logic. If Neanderthal in Western Eurasia has decreased over time and Africans are responsible for diluting that Neanderthal admixture, why are they suggesting Western Eurasian admixture into Africa?

  9. Edit (very sorry again for the frequent edits; I believe I phrased my first comment unclearly):

    “This would not seem (to my understanding, but of course I could be missing something) to explain the lower neanderthal affinity in Western Eurasians relative to Eastern Eurasians.

    Is it also possible that African gene flow (and/or Basal Eurasian, which itself may or may not have been an African population and thus maybe low in or without neanderthal dna) into Western Eurasia (in the reverse direction) was/may have been the cause, or played a role (in decreasing neanderthal affinity/detected affinity over time)?”

  10. (the following parenthetical was included in my comment above, but did not, for some reason, show in it when it was posted):
    “…that African (and/or Basal Eurasian, which itself may or may not have been an African population perhaps low in or without neanderthal DNA) gene flow into Western Eurasia…?”

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