Hawks Refutes African Population Structure Theory

John Hawks, an American anthropologist whose research focus includes Neanderthals, has made a post at his blog strongly refuting the just released paper by Eriksson and Manica at PNAS.  Their paper argued for an African population structure model of Neanderthal contributions to the modern human genome that I discussed yesterday, as opposed to a more recent interspecies mating model.

[T]he idea of Neandertal ancestry has been challenged by several papers that haven't performed any new empirical comparisons at all. . . .We have an unparalleled ability to explore the genomes of humans and Neandertals, and we should believe a computer model with no empirical data?

I've been assessing the Neandertal similarity of 1000 Genomes Project samples here on my blog (e.g., "Which population in the 1000 Genomes Project samples has the most Neandertal similarity?"). This is ongoing research here in my group, but we've been making it open because it tells us immediately that some hypotheses about Neandertal similarity must be wrong. 

For example, our comparisons quickly refute the hypothesis that Neandertal similarity comes only from ancient population structure in Africa. That hypothesis predicts much more heterogeneity within Africans in Neandertal similarity than exists today. We've shown that the heterogeneity in Africans is basically the same as within Europeans or Asians, and that the variance among African populations so far is quite small. Those are very simple observations, which are consistent with what Yang and colleagues [2] concluded on the basis of the frequency spectrum of Neandertal alleles in large samples of living people. Even though many Neandertal-shared SNP alleles came from incomplete lineage sorting, the signature of excess Neandertal sharing outside Africa must come mostly from recent introgression. In Ewen Callaway's article about this research, David Reich dismissed the new paper by Eriksson and Manica as "obsolete". I agree. The paper describes a model without carrying out any new empirical comparisons, and so has fallen behind where the science has gone. . .

Earlier this year, the genome of Ötzi the Tyrolean Iceman was reported by Andreas Keller and colleagues [4]. Aaron Sams and I downloaded the data and have been carrying out several different kinds of comparisons. . . . The European and Asian samples are substantially greater than either African sample (here, Luhya and Yoruba ...). If we took as a baseline that Europeans have an average of 3.5 percent Neandertal, Ötzi would have around 5.5 percent (...the actual percentage would be highly model-dependent). He has substantially greater sharing with Neandertals than any other recent person we have ever examined. . . . I can share the abstract of the conference paper I'll be presenting in September at the meeting of the European Society of Human Evolution in Bordeaux:

Evaluating recent evolution, migration and Neandertal ancestry in the Tyrolean Iceman

Paleogenetic evidence from Neandertals, the Neolithic and other eras has the potential to transform our knowledge of human population dynamics. Previous work has established the level of contribution of Neandertals to living human populations. Here, I consider data from the Tyrolean Iceman. The genome of this Neolithic-era individual shows a substantially higher degree of Neandertal ancestry than living Europeans. This comparison suggests that early Upper Paleolithic Europeans may have mixed with Neandertals to a greater degree than other modern human populations. I also use this genome to evaluate the pattern of selection in post-Neolithic Europeans. In large part, the evidence of selection from living people’s genetic data is confirmed by this specimen, but in some cases selection may be disproved by the Iceman’s genotypes. Neolithic-living human comparisons provide information about migration and diffusion of genes into Europe. I compare these data to the situation within Neandertals, and the transition of Neandertals to Upper Paleolithic populations – three demographic transitions in Europe that generated strong genetic disequilibria in successive populations.

References

1. Eriksson A, and Manica A. 2012. Effect of ancient population structure on the degree of polymorphism shared between modern human populations and ancient hominins. Proceedings of the National Academy of Sciences.
2. Yang MA, Malaspinas A-S, Durand EY, and Slatkin M. 2012. Ancient structure in Africa unlikely to explain Neanderthal and non-African genetic similarity. Molecular biology and evolution.
3. Green RE, Krause J, Briggs AW, Maricic T, Stenzel U, Kircher M, Patterson N, Li H, Zhai W, Fritz MH, et al. 2010. A Draft Sequence of the Neandertal Genome. Science [Internet] 328:710–722. Available from: http://dx.doi.org/10.1126/science.1188021
4. Keller A, Graefen A, Ball M, Matzas M, Boisguerin V, Maixner F, Leidinger P, Backes C, Khairat R, Forster M, et al. 2012. New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing. Nature communications 3:698.

 From John Hawks weblog (italics in original, emphasis in bold faced body text mine).
Does a lack of heterogeneity in modern Africa populations prove that much?
While I agree with the conclusion reached by John Hawks.  He somewhat overstates the relevance of the fact that the African population structure model calls heterogeneity within Africans in Neanderthal similarity than is seen in modern populations, at least within the data that his group has used in its analysis.

An African population structure model of Neanderthal genome similarity requires considerable heterogeneity within Africans in the Out of Africa era about 100,000 years ago.  But, the African population structure model does not require that this heterogeneity continue to the present.

The genetic evidence in Africa strong supports a model in which the population ancestral to the Yoruba of West Africa, i.e. the proto-Niger-Congo language family speakers, underwent a massive population expansion long after the Out of Africa era and through a combination of dilution and replacement of prior populations became (probably sometime in the last 20,000 years, and possibly considerably more recently) the dominant source of genetic ancestry in West Africa, and later, during Bantu expansion (sometime within the last 3000 years), for which the Luhya, an East African Bantu population is typical, in the rest of sub-Saharan African.  Yet, despite the fact that these two populations are a very narrow subset of even the African genetic diversity that is present today because they derive mostly from a population that expanded much more recently than the out of Africa era, even the variation in Neanderthal genome similarity within these relatively homogeneous African populations is still greater than the variation in Neanderthal genome similarity found among the entire gene pool of Europeans and Asians combined.

There are exceptions to rule that most Africans derive a large part of their genetic ancestry from the proto-Niger-Congo population.  The proto-Niger-Congo populations did not predominantly replace the linguistically non-Niger-Congo language family speakers of Africa in North Africa, the Sahel or East Africa, nor did they erase the genetic traces of relict populations like the Khoisan, the Hazda, and the Pygmies (even though the Pygmies now speak Bantu languages and their pre-Bantu languages are dead and were never committed to writing).  But, no individuals from any of these groups were included in the analysis done by Hawks' group that are discussed in posts at his blog.
But, even these cases don't necessarily capture Out of Africa levels of genetic diversity and population structure in Africa.  There is linguistic evidence (the shared presence of click languages), and genetic evidence, to support the claim that the existing relict pre-Bantu population of the Southern Africa (the Khoisan) has origins shared with relict East African hunter-gatherer populations like the Hazda, possibly long Africa the Out of Africa era.  North African and East African populations show evidence of "recent" (i.e. within the last twenty-thousand years or so, and to a considerable extent, much more recent) introgression of back migrating populations from the Near East into Africa.  The African component of North Africa and East Africa is generally speaking East African in character.  Madagascar's Indonesian genetic component probably arrived in Africa within the last 1,500 to 3,000 years and Madagascar's African component looks a lot like the East African Bantu Luhya population.  There are no pre-Bantu ancient DNA samples from anywhere in Africa and there is precious little Mesolithic modern human skeletal evidence to analyze in Africa outside of East Africa (something partially due to poor conditions for preservation of these kinds of remains).

In short, there is every reason to believe that a small number of population genetically more successful founding populations in Africa, most of which have antecedents either somewhere ion East Africa, or among the proto-Niger-Congo speakers whose ancestral place of origin prior to their expansion is sketchy, are the ancestors of virtual all modern Africans. 

All of these populations may be traceable to someplace that is geographically quite close to the probable ancestral home of the population that is ancestral to all non-Africans.  They may have lived perhaps a few hundred miles away over territory that was passable to early modern human hunter-gatherers, instead of a few thousand miles away across geographic barriers that would have been nearly impossible for early modern human hunter-gatherers, a scenario that was not inconsistent with the available evidence not so long ago.

It is very plausible that these more successful African populations brought about the extinction of, or dilution beyond recognition of, most of other genetic populations that existed in the Out of Africa era when they expanded much later on.  In the process, these expanding populations likely destroyed much of the genetic heterogeneity within Africans that existed in the Out of Africa era.

The African populations that are included in the analysis posted done by Hawks' group might be compared to using a Han Chinese population and a linguistically Chinese speaking modern Taiwanese population as a stand in for all of Asia.  This is clearly a good place to start, because in each case this accurately captures of the genetics of the modal population of the continent in question.  But, it is not a good place to look if you are interested in estimating how much genetic diversity there was on that continent in the Mesolithic.

Hawks' conclusion is very likely correct anyway.

Still, the model emerging from multiple lines of evidence including the Ötzi and 1000 Genomes genetic data, is one in which Upper Paleolithic modern humans have more Neanderthal admixture than other Out of Africa populations.   In this model, this excess admixture was then diluted by later episodes of migration into Europe after Neanderthals went extinct.  Thus, the European excess admixture attributable to continued interspecies mating in Europe that continued after admixture with Neanderthals by the ancestors of modern Asian populations is difficult to distinguish in the data, although not invisible if there is enough data and the right methods are used.

How can agree with Hawks' despite thinking that his first and primary argument based on a lack of heterogeneity within Africans? 

The quibbles I outline above with the weight that Hawks' gives to one particular line of evidence that he uses to support the conclusion that African population structure is not the source of differences in genetic similarity to Neanderthals in modern humans does not mean that his bottom line conclusion is wrong.  This piece of evidence standing alone wouldn't prove the point.  But, this piece of evidence doesn't stand alone.  When it is taken together with other evidence, important parts of which he himself played an important part in bringing into being (and the rest of which he is intimately familar with), the total mosaic picture created emphatically supports his conclusion.

Indirect Arachaic Admixture Evidence

For example, one point that he doesn't mention, but that I find convincing, is that studies using the same indirect methods (which I won't describe in detail in this post) that predicted the amount of Neanderthal admixture observed in non-Africans before a direct comparison with ancient Neanderthal DNA was made in 2010, and that also predicted the presence of an excess of ancient admixture in Papuans and Aboriginal Australians before a direct comparison was made between their genomes and ancient Denisovian archaic hominin DNA, has revealed low levels of archaic admixture (perhaps 1-2% or so) in modern Khoisan and Pygmy populations.  These indirect measures imply that this archaic hominin admixture in Africans probably happened sometime in the Upper Paleolithic era (i.e. well after the Out of Africa era).  These indirect traces of archaic hominin admixture in African relict populations don't match either the Neanderthal or the Denisovian ancient DNA samples, so they were probably one or two different species of archaic hominins than either Neanderthals or Denisovians or modern humans. 

This, in turn, suggests that even if there was far more genetic heterogeneity within Africans and population structure in Africa in the Out of Africa era than is today, that it probably didn't follow the kind of North-South cline in Neanderthal genome similarity that could fit the African population structure model.  It also suggests that there is not a huge amount of ancient African population structure not seen in Luhya and Yoruba populations that could be teased out of an analysis of African relict populations that would favor an African population structure model over a Neanderthal admixture in the Out of Africa era model.

This indirect archaic admixture evidence suggests that there isn't a huge amount of undiscovered archaic admixture out there in either non-Africans, or in the predominant African populations that isn't explained by a model that includes only Neanderthal and Denisovian admixture, even though that probably doesn't fully capture every bit of the story of archaic admixture in Africa.  There are no meaningful traces of non-Neanderthal archaic admixture on the side of the Africans that include almsot all Niger-Congo language family speakers (other than Pygmies), Nilo-Saharan language speakers, and Afro-Asiatic language speakers (perhaps 98%+ of all Africans), as opposed to the branch of African populations that includes the Pygmies and Khoisan peoples.  And, the Neanderthal archaic admixture in Africans that do have Neanderthal admixture closely tracks the overall level of Eurasian admixture attributable to backmigration from Eurasia in the last 20,000 years or so in these individuals.

The pattern of specific possibly Neanderthal gene frequency observed in particular populations.

Another couple of important data points that he has observed in his prior posts on Neanderthal DNA patterns in modern Eurasians are that (1) the particular loci of Neanderthal DNA in Asian and European populations don't overlap much, and (2) while most of these loci show a pattern consistent with genes that are neutral from a genetic fitness perspective, that a small number of these genes show clear signs of having their frequency enhanced because they have imparted increased genetic fitness to people who have the genes sometimes after the Out of Africa migration.  These data points strongly favor an interspecies admixture model over an African population structure model.
It would be difficult to get such a clear split in the particular Neanderthal genes inherited by Asians and Europeans respectively from the schism of a small population migrating Out of Africa around 100,000 years ago, and then spliting into distinct subpopulations sometime not more recent than 50,000 years ago, in a model where apparent Neanderthal admixture arose from African population structure derived from a common ancestor of modern humans and Neanderthals at least 350,000 years ago.  If that was the case, the archaic components of the modern human genome in the African subpopulation that migrated out of Africa would have long prior to that point reached fixation in that subpopulation, so the mix of seemingly Neanderthal genes in both Europeans and Asians should have been much more similar, even considering founder effects.

Also, even if the African population structure model could explain the mix of fitness neutral derived Neanderthal SNPs in non-Africans, it could not easily explain how genetic fitness enhancing derived Neanderthal SNPs that are present at highly elevated levels in non-Africans managed to stay so rare in other modern humans in different African subpopulations not all that geographically distant from the homeland of the subpopulation of Africans that is ancestral to all non-African modern humans.  Genetic fitness enhancing genes spread like wildfire even between populations with very low levels of gene exchange (e.g., one instance of gene exchange per generation between the two populations).  Moreover, some of the environments where the genetic fitness enhancing genes also found in Neanderthals are common aren't that different from Africa.

Recent Relevant Archaeological Discoveries

My statement that the Out of Africa subpopulation was "not all that geographically distant" from the ancestors of other known African populations is also far less hypothetical than it would have been a couple of years ago.  This year, for the first time, anthropologists have linked archaeological relics from some of the earliest modern humans in the interior of Arabia in the Out of Africa era to contemporaneous modern humans in Sudan and the Nile basin. 
Likewise, considerable progress has been made in the last few years in determining from archaeological evidence:

(1) when modern humans reached Southern India (sometime after Out of Africa and before the Toba volcano exploded about 75,000 years ago),

(2) when and where populations that used characteristically Neanderthal tools were present in South Asia,

(3) that there were very ancient modern human populations in the interior of Arabia as far back as 75,000 years ago who were in cultural continuity with early Levantine modern humans (during a climate phase when the interior of Arabia was wetter there than it is now),

(4) the precise time frame during which the first modern humans arrived in Europe (about 43,000 years ago and spreading to the entire region faster than had previously been assumed), and

(5) more clearly the archaeological demarkations between Neanderthal and modern human sites in Europe during the period when the two hominin species co-existed in Europe - this disfavors the possibility that the two species ever used identical lithic tool sets and material cultures at the same time and is contrary to prior knowledge which would have allowed for that possibility and greater cultural sharing between the two species.

Not So Recent Data Points

This list of data points to support the conclusions being reached by John Hawks' group and others isn't exhaustive and is pretty much limited to evidence available for the first time in the last few years.  For example, we have known for many decades that the earliest modern humans in the Levant co-existed at first with Neanderthals in the same region around 100,000 to 75,000 years ago.  And, we have known for at least a decade the general outlines of the evolutionary tree of modern human genetic diversity that is rooted by every measure in Africa, with Eurasians generally having closer phylogenetic links to genetic markers, such as mtDNA haplogroup L3, that are now most common within Africa in East Africa.  Similarly, we have known for a decade or so, the gist of how East Eurasians, in general, differ genetically from West Eurasians.

Bottom Line: Lots Of Old Models Are Now Ruled Out

The facts have firmed up enough to rule out a lot of models that were previously believed to be consistent with all available evidence in the last decade or so. This has been mostly due to analysis of large and rich DNA sampling from large numbers of people who include representatives of almost all significantly distinct populations in the world, the availability and analysis of a large number of ancient DNA samples, improved paleoclimate data, and recent archaeological relic discoveries.

The bottom line point is that when you piece together multiple, at least somewhat independent, pieces of genetic and archaeological evidence at our disposal, they hang together in the kind of model modern human population history that I spelled out in my post yesterday which includes Neanderthal and Denisovian admixture outside Africa.  In contrast, these puzzle pieces aren't a good fit for an African population structure model even if individual pieces of the evidence could be fit to that model.  Likewise, a model in which the Neolithic revolution in Europe (or pretty much anywhere else) took place predominantly via cultural diffusion has been pretty definitively ruled out.  The story of human prehistory and genetic ancestry isn't seemless and complete.  But, it is much better defined by the available hard evidence than it was when I graduated from college in 1992, for example.

Evidence From Regional Differences In Neanderthal Admixture

The gap in the number of shared Neanderthal derived SNPs between the two African populations, on one hand, and the Asian and European individuals on the other, is about three times as great as the range of variation in the number of shared Neanderthal derived SNPs among Africans, and among the combined Asian and European population, respectively.  There is no overlap at all between the number of SNPs in the two African populations examined and the number of SNPs in the non-African individuals.

The number of shared Neanderthal derived SNPs in Asian individuals and in European individuals does overlap, although the mean number of SNPs in slightly higher in the European individuals for whom data is available from the 1000 Genomes project and the Asian individuals.  Also, the highest number of SNPs in the 1000 Genomes project is found in Europeans, while the lowest number of SNPs in Eurasians in the 1000 Genomes project is found in Asians. 

The magnitude of the difference between the Asian and European individuals is about what my back in napkin estimates in yesterday's post suggested, a barely discernable fraction of a percentage point that is less than the standard deviation of the differences within each of the respective populations.

The Ötzi genome as evidence of demic diffusion

Indeed, the Ötzi genome is at least as powerful in establishing the theory that the Neolithic era came to Europe a heavily demic migration model, as it is in establishing that Neanderthal admixture is attributable to interspecies mating rather than African population structure.  In the demic migration model, existing European hunter-gatherer populations provide only a minority contribution to the modern European gene pool, because farming and herding came to Europe mostly through the migration of farmers and herders from elsewhere who moved into Europe after their people became herders and farmers.  This is in contrast to the now largely discredited model, popular in the 1970s, in which existing European hunter-gatherers adopted farming and herding methods, crops, and animals ultimately from Fertile Crescent Neolithic sources, with minimal population replacement or dilution.

Ötzi, in the early Neolithic, in Southern Europe, had a less diluted European hunter-gatherer component to his genome than anyone living today whose whole genome has been sequenced.  The Ötzi genetic data is corroborated by ancient DNA data showing stark genetic differences between ancient DNA from European hunter-gatherers and ancient DNA from early Neolithic individuals (and from both, in turn, relative to modern European populations) in uniparental genetic markers.  It is also corroborated by physical anthropology data that show stark differences apparent in skeletal remain dimensions between European hunter-gathers populations and Neolithic individuals. 

The Upper Paleolithic modern human hunter-gatherers of Europe and the Neolithic migrants who moved into Europe would have looked as different from each other on the Neolithic revolution's frontier as Australian Aborigines looked from the English colonists who later migrated to Australia (and would have been genetically distinct from each other to a similar degree).

Also, I note here, as I did in my previous post, the European hunter-gatherer population at the dawn of the Neolithic revolution in Europe had probably already been infused with significant amounts of migration from outside Europe after the Neanderthals went extinct, particularly during the time period when Europe was repopulated from the South as the glaciers retreated.

Given Ötzi's age and location not so far from the boundary between Europe and parts of Western Asia that were inhabited by modern humans long before they reached Europe, its is reasonable to infer that the Ötzi genome with something on the order of 5.5% Neanderthal admixture probably had less Neanderthal admixture than Cro-Magnons in Northern Europe prior to the Last Glacial Maximum around 20,000 years ago did. 

In light of Ötzi, I am beginning to think that a level of Neanderthal admixture with Cro-Magnons that reached something around 8% (the estimated level of peak admixture in the population that was the source of Denisovian admixture in Melanesian and Aboriginal Australians), is a fairly realistic estimate.  My best guess (and admittedly no more than an educated guess) would be that Ötzi was perhaps half or a quarter Cro-Magnon by descent and probably had a West Asian paternal grandfather given his Y-DNA haplogroup.

This is huge.  By comparison, this is about the same amount of introgressed Neanderthal ancestry in early modern human European hunter-gatherers as the amount of introgressed Turkic genetic ancestry found in modern day Turkey.  (The original Turks who brought their language to Turkey originated someplace a bit to the Northeast of Mongolia and arrived in Turkey in the first millenium of the common era; for at least twenty-five hundred years before that (some would argue much longer than that, although I would disagree), most Anatolians spoke Indo-European languages of one kind or another).

A peak Cro-Magnon level of Neanderthal admixture of 8% would also imply that my back of napkin estimate in yesterday's post materially overestimated the percentage of modern European ancestry that is traceable to Cro-Magnons.  The actual percentage of Cro-Magnon ancestry must have been closer to half of my previous rough estimate, perhaps 4%-5% rather than the 10% that I previously estimated, in the vast majority of European populations, although more in a select minority of European populations with a larger European hunter-gatherer component.

This would also disfavor, for example, a Basque population that not dervive from European hunter-gatherers to a greater extent than most Indo-European linguistic family populations of Europe, because they do not have a particularly elevated level of Neanderthal admixture compared to Indo-European language speaking populations that are more widely assumed to have thoroughly replaced pre-existing hunter-gatherer populations.  Basque genetic roots predominantly in the early Neolithic or copper age, or at the very least, in the Epipaleolithic, are a better fit to this data point.