Thoughts on: The date of interbreeding between Neandertals and modern humans.

The following are my (Graham Coop, @graham_coop) brief thoughts on Sriram Sankararaman et al.’s arXived article: “The date of interbreeding between Neandertals and modern humans.”. You can read the authors’ guest post here, along with comments by Sriram and others.

Overall it’s a great article, so I thought I’d spend sometime talking about the interpretation of the results. Please feel free to comment, our main reason for doing these posts is to facilitate early discussion of preprints.

The authors analysis relies on measuring the correlation along the genome between alleles that may have been inherited from the putative admixture event [so called admixture. The idea being that if there was in fact no admixture and these alleles have just been inherited from the common ancestral population (>300kya) then these correlations should be very weak, as there has been plenty of time for recombination to break down the correlation between these markers. If there has been a single admixture event, the rate at which the correlation decays with the genetic distance between the markers is proportional to this admixture time [i.e. slower decay for a more recent event, as there is less time for recombination]. These ideas for testing for admixture have been around in the literature for sometime [e.g. Machado et al], its the application and genome-wide application that is novel.

As you can tell from the title and abstract of the paper, the authors find pretty robust evidence that this curve is decaying slower than we’d expect if there had been no gene flow, and estimate this “admixture time” to be 37k-86k years ago. However, as the authors are careful to note in their discussion, this is not a definitive answer to whether modern humans and Neandertals interbred, nor is this number a definite time of admixture. Obviously the biological implications of the admixture result will get a lot of discussion, so I thought I’d instead spend a moment on these caveats. [This post has run long, so I'll only get to the 1st point in this post and perhaps return to write another post on this later].

Okay so did Neandertals actually mate with humans?

The difficulty [as briefly discussed by the authors] is that we cannot know for sure from this analysis that the time estimated is the time of gene flow from Neandertals, and not some [now extinct] population that is somewhat closer to Neandertals than any modern humans.

Consider the figure below. We would like to say that the cartoon history on the left is true, where gene flow has happened directly from Neandertals into some subset of humans. The difficulty is that the same decay curve could be generated by the scenario on the right, where gene flow has occurred from some other population that shares more of its population history with Neandertals than any current day human population does.

Why is this? Well allele frequency change that occurred in the red branch [e.g. due to genetic drift] means that the frequencies in population X and Neandertals are correlated. This means that when we ask questions about correlations along the genome between alleles shared between Neanderthals and humans, we are also asking questions about correlations along the genome between population X and modern humans. So under scenario B I think the rate of decay of the correlation calculated in the paper is a function only of the admixture time of population X with Europeans, and so there may have been no direct admixture from Neandertals into Eurasians*.

First thing is first, that doesn’t diminish how interesting the result is. If interpretation of the decay as a signal of admixture is correct, then it still means that Eurasians interbred with some ancient human population, which was closer to Neandertals than other modern humans. That seems pretty awesome, regardless of whether that population is Neanderthals or some yet undetermined group.

At this point you are likely saying: well we know that Neandertals existed as a [somewhat] separate population/species who are these population X you keep talking about and where are their remains? Population X could easily be a subset of what we call Neandertals, in which case you’ve been reading this all for no reason [if you only want to know if we interbred with Neandertals]. However, my view is that in the next decade of ancient human population history things are going to get really interesting. We have already seen this from the Denisovian papers [1,2], and the work of ancient admixture in Africa (e.g. Hammer et al. 2011, Lachance et al. 2012). We will likely discover a bunch of cryptic somewhat distinct ancient populations, that we’ve previously [rightly] grouped into a relatively small number of labels based on their morphology and timing in the fossil record. We are not going to have names for many of these groups, but with large amounts of genomic data [ancient and modern] we are going to find all sorts of population structure. The question then becomes not an issue of naming these populations, but understanding the divergence and population genetic relationship among them.

There’s a huge range of (likely more plausible) scenarios that are hybrids between A and B that I think would still give the same difficulties with interpretations. For example, ongoing low levels of gene flow from population X into the Ancestral “population” of modern humans, consistent with us calling population X modern humans [see Figure below, **]. But all of the scenarios likely involve some thing pretty interesting happening in the past 100,000 years, with some form of contact between Eurasians and a somewhat diverged population.

As I say, the authors to their credit take the time in the discussion to point out this caveat. I thought some clarification of why this is the case would be helpful. The tools to address this problem more thoroughly are under development by some of the authors on this paper [Patterson et al 2012] and others [Lawson et al.]. So these tools along with more sequencing of ancient remains will help clarify all of this. It is an exciting time for human population genomics!

* I think I’m right in saying that the intercept of the curve with zero is the only thing that changes between Fig 1A and Fig 1B.

** Note that in the case shown in Figure 2, I think Sriram et al are mostly dating the red arrow, not any of the earlier arrows. This is because they condition their subset of alleles to represent introgression into European and to be at low frequency in Africa. We would likely not be able to date the deeper admixture arrow into the ancestor on Eurasian/Africa using the authors approach, as [I think] it relies on having a relatively non-admixed population to use as a control.

Our paper: The date of interbreeding between Neandertals and modern humans

This post is by Sriram Sankararaman, Nick Patterson, Heng Li, Svante Pääbo, and David Reich on their paper The date of interbreeding between Neandertals and modern humans arXived here

The relationship between modern humans and archaic hominins such as Neandertals has been the subject of intense debate. The sequencing of a Neandertal genome, a couple of years back (Green et al, Science 2010), showed that Neandertals are more closely related to non-African genomes than African genomes. One possible model consistent with this observation is one involving gene flow from Neandertals to modern non-Africans after the divergence of African and non-African populations. Another model that can explain these observations is one in which the population ancestral to modern humans and Neandertals is structured e.g. imagine that the population ancestral to Neandertals and modern humans consists of three groups, A,B and C, where A,B and C represent the ancestors of modern Africans, non-Africans and Neandertals respectively. The extra proximity of Neandertals to non-Africans over Africans could occur if A and B, and B and C exchanged genes with each other followed by C diverging to form Neandertals, and A and B not completely hybridizing before their divergence to form Africans and non-Africans.

The Neandertal (Green et al, Science 2010) and the Denisova genome (Reich et al, Nature 2010) papers considered the possibility of both models — either scenario was shown to produce the skew in the observed D-statistics (a measure of the excess sharing of alleles across groups) that led to Neandertals appearing closer to non-Africans than Africans. Indeed, a recent paper by Eriksson and Manica (Eriksson and Manica, PNAS 2012) used an Approximate Bayesian Computation framework with D-statistics as the summary statistics and arrived at similar conclusions.

A paper from Monty Slatkin’s group (Yang et al, MBE 2012) attempted to differentiate the two scenarios by using the site frequency spectrum. Yang et al considered the site frequency spectrum in Europeans conditioned on observing a derived allele in Neandertal and an ancestral allele in Africans (termed the doubly-conditioned frequency spectrum, dcfs). They used theory and simulations to show that an ancient structure model produces a linear dcfs. On the other hand, they showed that recent gene flow can produce an excess of rare variants which matches the observed dcfs. Interestingly, they also observed that bottlenecks post gene flow had the effect of making the dcfs linear suggesting that gene flow from Neandertals could not have preceded strong bottlenecks in the non-African populations.

A different idea that we explored was to ask if patterns of linkage disequilibrium (LD) might discriminate the two scenarios. If we could pick out haplotypes that came into modern humans from Neandertal, recombination is expected to break these haplotypes down at a fixed rate every generation (assuming neutrality). Haplotypes that came in 1000 generations ago (under recent gene flow) should be expected to be 10 times longer on average than haplotypes that came in 10000 generations ago (under ancient structure). And if we could measure LD precisely enough, we could even date these ancient events. To date such ancient events, we had to address two technical challenges : i) measures of LD can be sensitive to demographic events, ii) for events that occurred 1000s of generations ago, we need to measure LD at size scales at which genetic maps can be quite noisy and this noise can bias estimates of dates.

Theory indicates that the expected LD (measured by Lewontin’s D), across SNPs that arose on the Nenadertal lineage and introgressed, decays exponentially with genetic distance at a rate given by the time of gene flow and is robust to demographic events. This result does not hold in practice due to imperfect ascertainment of these SNPs. We did simulations to show that this decay of LD does provide accurate estimates and can differentiate gene flow and ancient structure. We also came up with a model to assess errors in genetic maps which we then used to obtain a corrected date.

Our results support the recent gene flow scenario with a likely date of gene flow into the ancestors of modern Europeans 37000-86000 years BP although this does not exclude the possibility of ancient structure. A broader methodological question we are exploring is whether LD-based analyses might be generally applicable as a tool for dating other ancient gene flow events.

Sriram Sankararaman, Nick Patterson, Heng Li, Svante Pääbo, and David Reich