Monday, June 23, 2014

Inferring human population size and separation history from multipule genome sequences

Stephen Schiffels, Richard Durbin

Nature Genetics
Accepted 30 May 2014; published 22 June 2014;
Nature (Link)
Open Access prepint on BioRXiv (Link)
Author comments on the paper (Link)
[Blog note:  The African populations examined in this paper are: Yoruban (YRI), Maasai (MKK), and Luhya (LWK)(Kenya).  CEU is a population commonly used to represent Europeans.]

The availability of complete human genome sequences from populations across the world has given rise to new population genetic inference methods that explicitly model ancestral relationships under recombination and mutation. So far, application of these methods to evolutionary history more recent than 20,000–30,000 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) analyzes 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 recent as 2,000 years ago, including the bottleneck in the peopling of the Americas and separations within Africa, East Asia and Europe.

Divergence from and Within African Populations
MSMC lets us explicitly study the genetic separation between two populations as a function of time by modeling the relationship of multiple haplotypes, half of which are from one population and half of which are from the other. From analyzing four haplotypes for each pair of populations, we found that all relative cross coalescence rates between any non-African population and the Yoruba were very similar and exhibited a slow, gradual divergence beginning earlier than 200,000 years ago and lasting until about 40,000 years ago (Fig. 4a). This similarity in rates gives additional information beyond estimates of population size and is consistent with all non-African populations diverging as a single population from the Yoruban ancestors.

To understand whether the gradual divergence in relative cross coalescence rate between the YRI and non-African ancestors was due to the inability of MSMC to detect rapid changes (Fig. 2b) or due to true ongoing genetic exchange, we compared its results with simulated clean split scenarios at three different time points in the past (Fig. 4c). This comparison showed that no clean split could explain the inferred progressive divergence in relative cross coalescence rate. In particular, the early beginning of the divergence would be consistent with an initial formation of distinct populations before 150,000 years ago, whereas the late end of the decline would be consistent with a final split around 50,000 years ago. This comparison suggests a long period of partial divergence with ongoing genetic exchange between the Yoruban and non-African ancestors that began beyond 150,000 years ago, with population structure within Africa, and lasted for over 100,000 years. The median point of this divergence was around 60,000–80,000 years ago, at which time there was still substantial genetic exchange, with half the coalescences between populations and half within. We also observed that the rate of genetic divergence was not uniform but could be roughly divided into two phases. First, up until about 100,000 years ago, the two populations separated more slowly, whereas after 100,000 years ago, the rate of genetic exchange decreased faster. We note that the fact that the relative cross coalescence rate did not reach 1, even around 200,000 years ago (Fig. 4c), might be owing to later admixture of archaic populations such as the Neanderthals into the CEU population after its split from the YRI ancestral population [29].

We also saw extended divergence patterns in eight-haplotype analysis between the ancestors of the three African populations (Fig. 4a), with the LWK and YRI ancestral populations being closest and the MKK ancestral population showing a very slow increase in relative cross coalescence rate going back in time with the YRI and LWK ancestral populations. These declines in rate were all more gradual than those shown in Figure 4b between out-of-Africa populations, suggesting that the separations of African populations were also not clean splits but gradual separations, perhaps reflecting complex ancestral structure with admixture. In addition, we saw a different separation history between CEU and MKK ancestral populations compared to the LWK and CEU ancestral populations, which in turn was very similar to our estimates of the YRI-CEU separation. Our results suggest that the Maasai ancestors were mixing extensively with non-African ancestors until about 80,000 years ago, much later than the separation of the YRI and non-African populations. This observation is consistent with a model in which the Maasai ancestors and non-African ancestors formed sister groups, which together separated from West African ancestors and continued to extensively mix until much closer to the time of the actual out-of-Africa migration. Nonzero estimates of relative cross coalescence rate between the MKK and CEU ancestors after 50,000 years ago are probably confounded by more recent admixture from non-African populations back into East African populations, including the Maasai [30, 31].

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