Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.
The standard model is that 500-750,000 years ago the ancestors of African (modern) stem humans and Neandersovans diverged, and that’s that before the recent admixture and assimilation. But it’s pretty clear there were contacts between stem lineage and Neandersovans before the recent expansion of the African lineage. Neanderthals acquired lots of neat genes from our lineage, and we probably acquired stuff from them too.
(note that I think there were old modern lineages that disappeared)
Modern humans appeared in Europe by at least 45,000 years ago but the extent of their interactions with Neanderthals, who disappeared by about 40,000 years ago, and their relationship to the broader expansion of modern humans outside Africa are poorly understood. Here we present genome-wide data from three individuals dated to between 45,930 and 42,580 years ago from Bacho Kiro Cave, Bulgaria. They are the earliest Late Pleistocene modern humans known to have been recovered in Europe so far, and were found in association with an Initial Upper Palaeolithic artefact assemblage. Unlike two previously studied individuals of similar ages from Romania and Siberia who did not contribute detectably to later populations, these individuals are more closely related to present-day and ancient populations in East Asia and the Americas than to later west Eurasian populations. This indicates that they belonged to a modern human migration into Europe that was not previously known from the genetic record, and provides evidence that there was at least some continuity between the earliest modern humans in Europe and later people in Eurasia. Moreover, we find that all three individuals had Neanderthal ancestors a few generations back in their family history, confirming that the first European modern humans mixed with Neanderthals and suggesting that such mixing could have been common.
There are two primary points of interest:
More evidence of ubiquitous ‘admixture’ between Neanderthals and ‘modern humans’ who may have been in contact with them.
These earliest European modern humans in Southeast Europe seem to be more closely related to (possibly ancestral to?) people in East Asia than modern Europeans.
On the first point, twenty years ago there were some paleoanthropologists who were arguing there was no admixture between Neanderthals and modern humans. That is, no fertile offspring. To not pussyfoot around it, Neanderthals were barely acknowledged as human in the early years of this century by many scholars. This is evident in Richard Klein’s The Dawn of Human Culture, written in 2002. With hindsight much of this is ridiculous. It really didn’t make any sense that the Neanderthal and modern human lineage were not inter-fertile when you dug into the literature on mammalian hybridization. There just wasn’t that much time for them to be totally incompatible.
In 2010 when it was found that Neanderthal ancestry seems to be found in non-Africans, we updated many of our priors. I think it is clear on some level Neanderthal humanization is driven by the fact of Neanderthal admixture. Nevertheless, there was a plausible case this admixture was rare. Perhaps a single Neanderthal tribe was mixed into expanding modern humans? Perhaps a single Neanderthal? These were ideas that were mooted.
With what we know now I’m not sure this is tenable. There are two primary issues. First, there is variation in Neanderthal ancestry among non-African populations which does not seem to be due to African admixture. East Asians have more Neanderthal admixture (~25% more last I checked) than Europeans who have more than West Asians. South Asian Neanderthal admixture is proportional to their distance from East Asians. The less West Eurasian the South Asian, the more Neanderthal.
There are a few ways to understand this. A simple explanation is that there was a secondary admixture event that impacted people migrating to eastern Eurasia. Another hypothesis is that natural selection reduced the Neanderthal fraction over time, but East Eurasians were less impacted by this due to small effective population size. Then, there is the idea that a non-African population, “Basal Eurasians”, that did not have much Neanderthal admixture later mixed into West Asians and Europeans, reducing the original Neanderthal fraction.
Because of the small fractions and the paucity of ancient DNA more than 10,000 years old, there are still arguments around this. These results increase the probability that there were multiple Neanderthal admixture events. At least in my way of thinking.
The authors found that the Neanderthal fraction seems to have decreased from a higher level relatively early on. Rather than a gradual decrease, the authors found suggestions of strong effective selection in the first few generations. Though there is still room for the Basal Eurasian model, I’m not sure it’s quite as necessary now. Along with Oase, and the existence of a Neanderthal-Denisovan hybrid from Denisova cave, the likelihood of frequent admixture between ancient hominin lineages seems pretty high.
I believe the primary issue at this point is that the admixture event seems to be dated to a narrow time period, before the extinction of Neanderthals, but not too ancient (before 60,000 years ago), and the Neanderthal ancestry is quite similar. Perhaps there isn’t the power to detect multiple secondary admixtures at “around the same time.” From the perspective of today, 45,000 v. 50,000 years ago is “around the same time.” But the reality is 5,000 years is a long time.
In simulations, we find that estimates of the mean time of admixture are largely robust to details in gene flow models. In contrast, the duration of the gene flow is much more difficult to recover, except under ideal circumstances where gene flow is recent or the exact recombination rate is known. We conclude that gene flow from Neandertals into modern humans could have happened over hundreds of generations. Ancient genomes from the time around the admixture event are thus likely required to resolve the question when, where, and for how long humans and Neandertals interacted.
The second major finding of this paper is that the very first modern humans to settle in Europe are more genetically close to East Asians than to modern Europeans. This is in contrast to the Oase sample from Romania, just to the north, and a few thousand years later, that was no closer to East or West Eurasians. Or, a new 45,000-year-old sample from Czech Republic, which also shows no connection to any modern people.
If you read the first paper, you know that years ago the GoyetQ116-1 sample from Belgium that dates to 35,000 years before the present, and which seems to have some ancestral connection to the later Magdalenian people of Pleistocene Europe, had an East Eurasian affinity. Additionally, earlier mtDNA work showed eastern affinities in some Pleistocene Europeans. The authors above make the connection between these eastern-affinity early Europeans and the “Initial Upper Paleolithic” (IUP), which seems to have expanded across a broad swath of Eurasian, from Europe all the way to western Mongolia.
The implication then is that some of the ancestry of East Eurasians comes from a migration that took a route through Europe, and around the Black Sea littoral. This is a bit more complicated than a pure “southern route”, but it’s not crazy, and has long been proposed.
I think at this point we need to take a step back, and acknowledge that the period between 40 and 60 thousand years ago is important, but we look through the glass darkly. Something happened, as all the ancient Eurasian hominin lineages were absorbed by the “Out of Africa” population (which may not have been expanding out of Africa!), and the phylogenetic relationships of some of these people do not make sense in light of the phylogeography of the present.
It is entirely feasible to me that the ancient non-African or proto-non-African populations had already started to develop some internal structure. The putative Basal Eurasian v. “the rest” is one key bifurcation, but there may already have been divisions between the western and eastern branches of Eurasians in northeast Africa or the Near East. We just don’t know yet. Basically, ancient substructure that is getting “blown up” with rapid radiation.
I don’t have time to blog in detail today so I’ll point you to Ann Gibbon’s story, How Neanderthals lost their Y chromosome. You can find the link to the paper in there. The big issue here is that both mtDNA and Y chromosomes were replaced due to introgression from a population closer to modern humans than the Neandersovans, though basal to any modern humans alive today. This new group may actually be basal to the “basal human” group hypothesized by some scholars (there are suggestions of its existence in autosomal admixture into Neanderthals).
The probability of fixation of a newly introduced allele is the frequency of that allele, so how is it that these paleo-modern variants swept into Neanderthals? Perhaps on one locus, but two? One solution offered is naturals selection. This seems plausible, but the possibility of natural selection on Y and mtDNA lineages has always been a “wild card” that would make us rethink a lot of our phylogeography in general.
Finally, though it looks like the vast majority of modern ancestry outside of Africa is derived from a relatively recent (60,000 years ago) rapid expansion, it is clear that the picture at any given time is more complex than the signal we see today. It seems more and more likely that there was more a continuum between the African and Neandersovan lineages, and I strongly suspect that some of the paleo-modern lineages will at some point be detected in some modern groups once we have ancient DNA (the closer genetic distance and low fraction makes it hard for these segments to be identified in extant modern lineages using standard inference).
The first preprint is an empirical one focused on a new high-coverage Neanderthal genome, which allows for more powerful inferences. To me, the most interesting insight is that Neanderthals seem to have been a highly structured population. This is something we knew from other research, but they used the fact that European Neanderthals seem to have medium-length runs of homozygosity to get a better sense of it. One modern group with lots of medium length runs of homozygosity are Ashkenazi Jews, who went through a very modest bottleneck and were highly endogamous. This suggests that Neanderthal subpopulations did now have much gene flow between them and that their demes were rather viscous.
Additionally, the contribution of Neanderthal ancestry to modern humans seems to come from one particular subpopulation. This reiterates that even if there were multiple admixtures (there were), in non-African humans the vast majority of the Neanderthal admixture comes from a single pulse.
The second paper focuses more on broad population genetic questions and theory. Using an HHM-based framework the author looks at various Neanderthal and Denisovan genomes and infers long-lasting and repeated instances of reciprocal gene flow between the two populations in the Altai. This is entirely expected. But, the author notes that Denisovan ancestry isn’t present in European Neanderthals. This is in keeping with the earlier preprint, which highlighted a strong degree of population structure. Presumably the Altai was a zone of contact between these two Eurasian hominin populations, but it did not serve as a mediator of gene flow due to high structure in both groups, and repeated local extinction (later Altai Neanderthals are very different from earlier Altai Neanderthals).
A new preprint reports on the peculiar Y chromosomal patterns that one finds in Neanderthals, Denisovans, and modern humans. Spencer Wells has told me that Y and mtDNA are actually much more informative now that we have an ancient DNA autosomal scaffold. I think that’s right. The strange result from Neanderthals is both their Y and mtDNA lineages seem to form a clade with modern humans, while Denisovans the outgroup, though the whole genomes cluster Denisovans with Neanderthals. This reminds us that we put way too much weight on mtDNA during the molecular ecology heyday of the 2000s.
…Here we present sequences of the first Denisovan Y chromosomes (Denisova 4 and Denisova 8), as well as the Y chromosomes of three late Neandertals (Spy 94a, Mezmaiskaya 2 and El Sidrón 1253). We find that the Denisovan Y chromosomes split around 700 thousand years ago (kya) from a lineage shared by Neandertal and modern human Y chromosomes, which diverged from each other around 370 kya. The phylogenetic relationships of archaic and modern human Y chromosomes therefore differ from population relationships inferred from their autosomal genomes, and mirror the relationships observed on the level of mitochondrial DNA. This provides strong evidence that gene flow from an early lineage related to modern humans resulted in the replacement of both the mitochondrial and Y chromosomal gene pools in late Neandertals. Although unlikely under neutrality, we show that this replacement is plausible if the low effective population size of Neandertals resulted in an increased genetic load in their Y chromosomes and mitochondrial DNA relative to modern humans.
First, the first author gives due credit to the bench scientists who managed to get usable Y chromosomal sequences out of ancient DNA. That’s not a trivial task. Second, confirming both earlier autosomal and mtDNA work, it does seem that the Neanderthal lineage experienced Y and mtDNA turnover during the last 400,000 years, with the donor population being an outgroup to most modern humans, albeit closer to that lineage than the Denisovan clade (the Y evidence suggests it’s an outgroup to all modern humans, but the autosomal work is more difficult to pin down in terms of dating of divergence). Third, the replacement of the Y and mtDNA aren’t random, but a function of fitness differences due to the accumulated burden of deleterious alleles. Using simulations they show that very small differences can give notable selective advantages and result in likely replacement of mutation burdened lineages. Finally, we see a different dynamic with Denisovans.
In fact, the Denisovan Y divergence is suspiciously concordant with the autosomal divergence dates in some models.
Many years ago John Hawks pointed out to me that some of the patterns in human evolution may simply be a consequence of large population sizes for Homo in Africa. When it comes to Neanderthals this seems to be a reasonable way to think about it. The genetic and non-genetic evidence points to huge fluctuations in population size of Neanderthals, so the accumulation of deleterious mutations is plausible, and, impact by more numerous southern Homo lineages seems likely. But what about “Denisovans”? I think this work will be part of a tradition that shows Denisovans exhibit fundamentally different population dynamics as compared to Neanderthals.
While Neanderthals seem to have been a coherent population from the Altai to Europe, undergoing repeated bottlenecks, I think Denisovans were a diverse array of populations that exhibited a wide range in population sizes (this is genetically supported by recent work which shows diverse Denisovan contributions to East, South, and Southeast Asians). Additionally, the region of the Old World that seems to be second to Africa in being suitable ape habitat is Southeast Asia.
Finally, due to the reality that colder climates present better opportunities for DNA preservation, we may obtain some of our best understanding of the genomics of paleo-modern humans outside of Africa from Neanderthals as more and more data accumulates. The non-African populations today seem to be almost exclusively descended from an African or Africa-adjacent expansion that dates to ~50,000 years ago. But archaeology and suggestive genetic clues indicate that there were other African lineages which ventured out 100 to 200 thousand years ago. These did not leave a major impact on today’s populations, but with enough Neanderthal genomes, one might be able to reconstruct these people.
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:
Neanderthal ancestry was purged more efficiently from West Eurasians due to larger effective population sizes (selection is stronger in large populations).
There may have been multiple admixture events into modern humans, or, gene-flow into West Eurasians diluting their Neanderthal ancestry.
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.
The cool thing about the first paper is that it combined UK Biobank data, 100,000+ individuals, with hundreds of thousands of markers, and Neanderthal genomic data. Note that: a paper comparing ancient genomes with over 100,000 individuals and hundreds of thousands of markers. Now that’s 2017!
To find archaic alleles they:
Looked for variants fixed in Yoruba (no Neanderthal), and homozygote or heterozygote in the alternative state in the Altai Neanderthal, which also segregated (varied) in the UK Biobank population. Basically, an allele not found in Africans but found in Neanderthals, and also found in appreciable fractions in the UK Biobank data set.
They then took the SNPs above, and only retained ones confidently embedded in tracts of Neanderthal ancestry. Haplotype was consistent with admixture ~50,000 years ago (the length), and exhibited lower distance to Neanderthal than African genomes.
They did some stuff with tag-SNPs though. Overall they found a lot of the usual suspects. Pigmentation. Chronotype. But this passage jumped out at me:
In fact, for most associations, Neanderthal variants do not seem to contribute more than non-archaic variants. However, there are four phenotypes, all behavioral, to which Neanderthal alleles contribute more phenotypic variation than non-archaic alleles: chronotype, loneliness or isolation, frequency of unenthusiasm or disinterest in the last 2 weeks, and smoking status.
What they are saying is that for a lot of traits Neanderthals don’t really change the direction of the trait in humans, they just add more variants. This seems to be the case in pigmentation. Entirely unsurprising, Neanderthals were around for hundreds of thousands of years. Of course they had a lot of variation amongst themselves.
But the behavioral traits above shifted the modern humans in the aggregate who had the archaic allele somewhat. That is, being Neanderthal derived made a difference.
There have long been speculations about the sociality (or lack thereof) of Neanderthals. It would not be surprising if small population sizes meant that Neanderthals were less gregarious than modern humans, and that their lack of gregariousness did not redound to their benefit when they encountered the last wave of moderns.
Which brings us to the second paper. The big deal here is that it gives us a very high quality ancient genome of a European Neanderthal that lived ~50,000 years ago (the Vindija sample). Before this we had a high quality ancient genome of an Asian Neanderthal that lived ~125,000 years ago (Altai sample). ~75,000 years is a long time. It’s so long that almost all the ancestry of modern non-Africans would have converged to a common population that long ago. Additionally, all the available data indicate that most of the admixture into modern humans from Neanderthals occurred around 50,000 years ago. So this new sample is definitely welcome.
It is not surprising that the Vindijia sample seems to be closer to the Neanderthal admixture population than the Altai sample. First, it is likely geographically closer, since all non-African populations have some Neanderthal ancestry West Asia is probably the top candidate, and southeastern Europe is not that far from West Asia in comparison to Mongolia. Second, it is basically contemporaneous with the Neanderthals who contributed ancestry to modern humans who left Africa. This means that the Neanderthal admixture percentage in non-Africans goes up moderately.
To me this is the most important paragraph:
It has been suggested that Denisovans received gene flow from a human lineage that diverged prior to the common ancestor of modern humans, Neandertals and Denisovans (2). In addition, it has been suggested that the ancestors of the Altai Neandertal received gene flow from early modern humans that may not have affected the ancestors of European Neandertals (13). In agreement with these studies, we find that the Denisovan genome carries fewer derived alleles that are fixed in Africans, and thus tend to be older, than the Altai Neandertal genome while the Altai genome carries more derived alleles that are of lower frequency in Africa, and thus younger, than the Denisovan genome (20). However, the Vindija and Altai genomes do not differ significantly in the sharing of derived alleles with Africans indicating that they may not differ with respect to their putative interactions with early modern humans (Fig. 3A & B). Thus, in contrast to earlier analyses of chromosome 21 data for the European Neandertals (13), analyses of the full genomes suggest that the putative early modern human gene flow into Neandertals occurred prior to the divergence of the populations ancestral to the Vindija and Altai Neandertals ~130-145 thousand years ago (Fig. 2). Coalescent simulations show that a model with only gene flow from a deeply diverged hominin into Denisovan ancestors explains the data better than one with only gene flow from early modern humans into Neandertal ancestors, but that a model involving both gene flows explains the data even better. It is likely that gene flow occurred between many or even most hominin groups in the late Pleistocene and that more such events will be detected as more ancient genomes of high quality become available.
These results seem to support earlier work indicate that Denisovans were admixed with an ancient hominin group which diverged very early on (probably the descendents of East Asia erectus?). And, that Neanderthals received gene flow from a lineage of modern (African?) humans 150,000 or more years ago. Since the latest work suggests that modern humans in some form have existed between from 200,000 to 350,000 years ago, this is entirely plausible.
But, it brings us the take-home message that the emergence of Pleistocene humanity was to a some extent characterized by reticulate gene flow, rather than a bifurcating tree.
Many years ago 
