Autosomal modeling getting closer to archaeological facts by doubling effective mutation rate

Interesting try at autosomal DNA nuclear clock-o-logy. Not quite it yet but interesting nevertheless because it approximates much better what seems to be the reality, based on archaeological data, than previous attempts.

Stephan Schiffels & Richard Durbin, Inferring human population size and separation history from multiple genome sequences. Pre-published at bioRxiv, 2014. Freely accessible → LINK [doi:http://dx.doi.org/10.1101/005348]

Abstract

The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model their ancestral relationship under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20-30 thousand years ago and to population separations has been limited. Here we present a new method that overcomes these shortcomings. The Multiple Sequentially Markovian Coalescent (MSMC) analyses the observed pattern of mutations in multiple individuals, focusing on the first coalescence between any two individuals. Results from applying MSMC to genome sequences from nine populations across the world suggest that the genetic separation of non-African ancestors from African Yoruban ancestors started long before 50,000 years ago, and give information about human population history as recently as 2,000 years ago, including the bottleneck in the peopling of the Americas, and separations within Africa, East Asia and Europe.

Based on Figure 4c:

Figure 4: Genetic Separation between population pairs
(...) (c) Comparison of the African/Non-African split with simulations of clean splits. We simulated three scenarios, at split times 50kya, 100kya and 150kya. The comparison demonstrates that the history of relative cross coalescence rate between African and Non-African ancestors is incompatible with a clean split model, and suggests it progressively decreased from beyond 150kya to approximately 50kya. (...)

This comparison reveals that no clean split can explain the inferred progressive decline of relative cross coalescence rate. In particular, the early beginning of the drop would be consistent with an initial formation of distinct populations prior to 150kya, while the late end of the decline would be consistent with a final split around 50kya. This suggests a long period of partial divergence with ongoing genetic exchange between Yoruban and Non-African ancestors that began beyond 150kya, with population structure within Africa, and lasted for over 100,000 years, with a median point around 60-80kya at which time there was still substantial genetic exchange, with half the coalescences between populations and half within (see Discussion). We also observe that the rate of genetic divergence is not uniform but can be roughly divided into two phases. First, up until about 100kya, the two populations separated more slowly, while after 100kya genetic exchange dropped faster. We note that the fact that the relative cross coalescence rate has not reached one even around 200kya (Figure 4c) may possibly be due to later admixture from archaic populations such as Neanderthals into the ancestors of CEU after their split from YRI [29].

Follows their population size estimates:

Figure 3: Population Size Inference from whole genome sequences
(a) Population size estimates from four haplotypes (two phased individuals) from each of 9 populations. The dashed line was generated from a reduced data set of only the Native American components of the MXL genomes. Estimates from two haplotypes for CEU and YRI are shown for comparison as dotted lines. (...)

A serious problem I have with this graph is that the gradual bottleneck affecting Eurasian-plus populations does not begin to recover within this simulation before c. 40 Ka. That doesn't seem good enough because by that time the Asian population must have expanded at least moderately, as they had colonized all the continent and even Australasia by that date. 

This means that there is a lot of refining still to be done to the methodology, because there should be signal of expansion in Asia much earlier than 40 Ka and not more and more apparent decrease of the population size, what is totally inconsistent with the ongoing colonization of a whole continent. 

I could try to double again the rates to get a more consistent Asian expansion age of c. 80 Ka but that should push the Eurasian-plus bottleneck to a much earlier date, 600 Ka ago, what is simply nonsensical. So the only possible conclusion is that the algorithm is far from realistic and still needs a lot of work.

Non-Bantu East Africans belong to the proto-Eurasian cluster:

Our results suggest that Maasai ancestors were well mixing with Non-African ancestors until about 80kya, much later than the YRI [Yoruba]/Non-African separation. This is consistent with a model where Maasai ancestors and Non-African ancestors formed sister groups, which together separated from West African ancestors and stayed well mixing until much closer to the actual out-of-Africa migration.

South Asians exchanged a lot with West Eurasians before Neolithic:

.... the GIH [Gujarati emigrants to Texas] ancestors remained in close contact with CEU [NW European emigrants to Utah] ancestors until about 10kya, but received some historic admixture component from East Asian populations, part of which is old enough to have occurred before the split of MXL.

Figure 4: Genetic Separation between population pairs
(...) (d) Schematic representation of population separations. Timings of splits, population separations, gene flow and bottlenecks are schematically shown along a logarithmic axis of time. (...)

Overall their population tree makes good sense, except for the apparently too recent dates for nearly all the events and very especially for the intra-Eurasian split. There are no doubt confounding factors acting here. Probably if MXL (Native American component) were excluded, the West-East split could be moved backwards in time.

They heavily rely on the MXL Native American element to calibrate the clock, what makes sense on the surface. But  the fact that Native American origins are themselves a mix of West/South Eurasian and East Asian origins may be tricking them. In the tree, MXL derives from East Asians and it actually should be, we know for a fact, intermediate between East Asia and West/South Eurasia, something that is not reflected at all and that is almost certainly altering the picture.

But, as said above, there are more corners, some quite prominent, to be polished in all the modeling process until a future version of it can be acknowledged as a reliable "clock" (emphasis on reliable, because some people put way too much faith on these rough approximations, what is clearly an error).

On mutation rates:

Our results are scaled to real times using a mutation rate of 1.25×10-8 per nucleotide per generation, as proposed recently [16] and supported by several direct mutation studies [14-16]. Using a value of 2.5×10-8 as was common previously [44, 45] would halve the times. This would bring the midpoint of the out-of-Africa separation to an uncomfortably recent 30-40kya, but more concerningly it would bring the separation of Native American ancestors (MXL) from East-Asian populations to 5-10kya, inconsistent with the paleontological record [25, 26].

In short: using the usual scholastic mutation rates would have been nonsensical. Doubling them was common sense needed to achieve minimal coherence with observed reality (how many times have I said that?) It is obviously not enough but it was something needed in any case.