July 13, 2011

Human population history from single human genomes (Li & Durbin 2011)

I will update this blog entry when I read the paper. In the meantime, see Nature News and New Scientist.

UPDATE I

From the supplementary material (p. 8):
The TMRCA estimated by the PSMC model is in the units of mutation per site. To rescale TMRCA in the units of years, we need to know the mutation rate per site per year, which can be estimated by using closely related species. Table S1 implies that in primates, the mutation rate is broadly around 10−9 per site per year, the rate we used in rescaling the PSMC estimate (we assumed a 2.5 × 10−8 mutation rate per site per generation and a 25-year generation time, which is translated to a 1.0 × 10−9 mutation rate per site per year).

However, recent direct measurement using whole genome sequences in pedigrees suggest that in the individuals examined the mutation rate per site per generation approaches 10−8 (Roach et al.,2010; 1000 Genomes Project Consortium, 2010), twice smaller than the rate we use. Nonetheless,what matters for population genetic based methods such as PSMC is the time average. A comparatively small fraction of higher mutation rates could change this average significantly. We therefore feel that although direct measurements are clearly valuable, there are not enough yet to change the mutation rates used in population genetic based analyses.
The mutation rate was an issue in another recent paper, which used a similar 2.36x10-8 rate as the one here, and not the much lower rate from a couple of 1000 Genomes family trios.

As I said in that post (and more recently), we clearly have a lot to learn about autosomal mutation rates yet, and hopefully we will both get a better estimate of the rate from more trios of the 1000 Genomes project, as well as establish possible population variation in that rate.

UPDATE II (Divergence of Europeans and East Asians):

From the supplementary material (p. 13):
On the other hand, several studies using nuclear DNA placed the East Asian-European divergence around 17–25kya (Keinan et al., 2007; Garrigan et al., 2007; Gutenkunst et al., 2009). Our PSMC estimate from the combined Venter and YH X chromosomes is also very recent (Figure S7d). This leads to the apparent inconsistency with the fossil evidence that anatomically modern human have spread across the continent by at least 40kya. One of the possible explanations is that during the Last Glacial Maximum at about 20kya, the non-African populations retreated southward (Forster, 2004), and gene flows may have occurred between the different populations again. Under this hypothesis, the recent gene flow between YRI.X and KOR.X would be reasonable, although autosomal data from more populations are needed to further confirm the existence of the recent gene flow.
Gravel et al. suggested that there may have been "ghost populations" intermediate between Europeans and East Asians that suppress their divergence times; the explanation of Li & Durbin is different, but of the same kind.

An easy reconciliation of the archaeological divergence times with the genetic evidence, would, of course, be immediately effected if the "slow" family-derived rate is adopted: this would double West/East Eurasian split time to about 40kya, but would also push back the split of West Africans from Eurasians to the dawn of anatomical modernity to more than 200kya, and, the African hunter-gatherers (not examined here) well into multiregional evolution time depths.

UPDATE III (Jul 14): (A chicken and egg problem)

The authors use a 2.5 × 10−8 mutation rate per site per generation and a 25-year generation time in the paper, citing Nachman and Crowell (2000).

Nachman and Crowell estimate this rate with a Chimpanze-Human divergence at 5 million years and an ancestral population size of 10,000. However, since their generation length is 20 years, their 5 million years become 6.25 million in 25-year generation terms; the authors of the current paper (Table S1) put the human-chimp divergence at 7 million years.

What is most interesting, is that the current paper estimates ancestral population sizes by fixing the mutation rate; whereas Nachman and Crowell (2000) estimated the mutation rate by making different assumptions about ancestral population size. For example, their rate of 2.5x10-8 assumes an ancestral population size of 10,000 whereas for an ancestral population size of 100,000, this becomes 1.5x10-8.
In other words, it's a chicken and egg problem: the mutation rate has been calibrated on assumptions about ancestral population size in the earlier paper; ancestral population size is estimated by using the mutation rate in the current one.

I really do think that the way forward is to get a better estimate of the mutation rate from actual parents and children, because I see no obvious way to go around the above-mentioned problem.


UPDATE IV (Jul 14): (Possible population structure)

From the paper:
All populations showed increased Ne between 60 and 200 kyr ago, about the time of origin of anatomically modern humans17. An alternative to an increase in actual population size during this time would be that there was population structure involving separation and admixture11,16 (Supplementary Fig 5).

In the supplement, the authors consider a split into two or three sub-populations at 250ky followed by admixture at 60ky. In such a scenario, the pattern of growth between 200ky and 60ky can be explained without any actual growth taking place: the apparent growth is due to the admixture event between different types of humans.

I would also add the difference between the apparent severity of the Eurasian bottleneck after 60ky (compared to Africans) may also be due to the continuation of admixture in Africa which keeps the apparent effective size high, whereas Eurasians now begin to move outside Africa, and no longer have the opportunity to mix with archaic Africans.

UPDATE V (Jul 14): It is extremely unfortunate that this type of research was not carried out on Native Americans, Native Australians, and African hunter-gatherers. All of these would provide useful insight:
  1. Native Americans, because they would be somewhat immune to "late" gene flow with Africans that is hypothesized to have affected even East Asians
  2. Native Australians of Papuans, because of their substantial hypothesized "Denisovan" admixture which ought to register as an episode of "higher effective population size" prior to the admixture event
  3. African hunter-gatherers, because they, more than anyone else, would push the limits of inference to the past.


Nature (2011) doi:10.1038/nature10231

Inference of human population history from individual whole-genome sequences

Heng Li & Richard Durbin

The history of human population size is important for understanding human evolution. Various studies1, 2, 3, 4, 5 have found evidence for a founder event (bottleneck) in East Asian and European populations, associated with the human dispersal out-of-Africa event around 60 thousand years (kyr) ago. However, these studies have had to assume simplified demographic models with few parameters, and they do not provide a precise date for the start and stop times of the bottleneck. Here, with fewer assumptions on population size changes, we present a more detailed history of human population sizes between approximately ten thousand and a million years ago, using the pairwise sequentially Markovian coalescent model applied to the complete diploid genome sequences of a Chinese male (YH)6, a Korean male (SJK)7, three European individuals (J. C. Venter8, NA12891 and NA12878 (ref. 9)) and two Yoruba males (NA18507 (ref. 10) and NA19239). We infer that European and Chinese populations had very similar population-size histories before 10–20 kyr ago. Both populations experienced a severe bottleneck 10–60 kyr ago, whereas African populations experienced a milder bottleneck from which they recovered earlier. All three populations have an elevated effective population size between 60 and 250 kyr ago, possibly due to population substructure11. We also infer that the differentiation of genetically modern humans may have started as early as 100–120 kyr ago12, but considerable genetic exchanges may still have occurred until 20–40 kyr ago.

Link

8 comments:

terryt said...

"We also infer that the differentiation of genetically modern humans may have started as early as 100–120 kyr ago12, but considerable genetic exchanges may still have occurred until 20–40 kyr ago".

And is still going on. Anyway haplogroup evidence shows that the surviving haplogroups have been zooming fairly widely around the earth.

"All three populations have an elevated effective population size between 60 and 250 kyr ago, possibly due to population substructure11".

Quite likely. But that makes just marginally relevant the comment:

"the human dispersal out-of-Africa event around 60 thousand years (kyr) ago".

The 'dispersal' is far more complicated than just a single population emerging from Africa at any single time, let alone specifically '60 thousand years (kyr) ago'.

"An easy reconciliation of the archaeological divergence times with the genetic evidence, would, of course, be immediately effected if the 'slow' family-derived rate is adopted: this would double West/East Eurasian split time to about 40kya, but would also push back the split of West Africans from Eurasians to the dawn of anatomical modernity to more than 200kya, and, the African hunter-gatherers (not examined here) well into multiregional evolution time depths".

That might be the case though, although the time need not necessarily be 'doubled', just 'longer'.

Annie Mouse said...

"gene flows may have occurred between the different populations again"

I suspect this to be the flow of population along the snowline following big game. Connecting Europe with East Asia.

Andrew Oh-Willeke said...

Even if there is population structure from 200kya to 60 kya, this would have been population structure involving populations that were originally less differentiated than the continental populations today, and there is no a priori reason to think that proto-Africans, proto-Europeans and proto-Asians would have lined up neatly into cleanly divided groups from each other.

The relative unity of Y-DNA and mtDNA origins for Eurasians that seems to have just a couple of roots each in Africa phylogenies also argues against really deep population structure, pre-OoA in Africa.

The spread of rare mutations by continental populations that was recently released, also strongly disfavors any significant cross-continental gene exchange in the Upper Paleolithic or early Neolithic. Very few rare mutations are shared by multiple continental groups compared to what one would expect with even extremely thin levels of gene exchange between them.

Dienekes said...

The relative unity of Y-DNA and mtDNA origins for Eurasians that seems to have just a couple of roots each in Africa phylogenies also argues against really deep population structure, pre-OoA in Africa.

Not sure what you mean by that; the Y chromosomes coalesce to 142ky, so, by definition, are unsuitable for detecting population structure.

Note also, that including African hunter gatherers would almost certainly push the earliest split in the human family tree to the dawn of anatomical modernity, even if no adjustment to the mutation rate used in this paper is needed.

gcochran said...

The paper was submitted in 2009, quite a long time ago in genome-sequencing years.

Pushing the earliest split in the human tree to the dawn of anatomical modernity may be correct, but it certainly has implications that a lot of people will not like.

terryt said...

"I suspect this to be the flow of population along the snowline following big game. Connecting Europe with East Asia".

I think you are absolutely correct. Y-haps R and Q are related and seem to have parted ways in Central Asia along the snowline, R going west and Q going east.

"this would have been population structure involving populations that were originally less differentiated than the continental populations today, and there is no a priori reason to think that proto-Africans, proto-Europeans and proto-Asians would have lined up neatly into cleanly divided groups from each other".

Why do you think that? In H. erectus times there was surely less genetic movement than there has been since 'modern' humans appeared. Therefore it is reasonable to assume greater ancient regional diversity than remained during the Upper Paleolithic.

"The relative unity of Y-DNA and mtDNA origins for Eurasians that seems to have just a couple of roots each in Africa phylogenies also argues against really deep population structure, pre-OoA in Africa".

Not really. By the time Y-hap CT and mtDNA M and N left Africa Y-haps A1a, A1b, A2, A3 and B (and possibly B1 and B2) had appeared, and (according to Maju's old diagram) mtDNAs L0, L1, L2 and L5 had already diversified, some considerably so. And just two of the several L3s made it out so we can presume the others spread round much of Africa as M and N moved out.

"Pushing the earliest split in the human tree to the dawn of anatomical modernity may be correct, but it certainly has implications that a lot of people will not like".

What implications would a lot of people not like?

Andrew Oh-Willeke said...

"The relative unity of Y-DNA and mtDNA origins for Eurasians that seems to have just a couple of roots each in Africa phylogenies also argues against really deep population structure, pre-OoA in Africa".

The point I was trying to make (and misworded a bit) was not the pre-OoA Africa has no population structure at all, but that the proto-Eurasian population in Africa prior to OoA likely had little population structure.

All Eurasians on the Y-side desecend from D (which is a thin offshoot of DE and a thinner offshoot of overall African diversity) or CT (which is a thin offshoot of a common ancestor of B and CT).

All Eurasians on the mtDNA side descend from M or N which in turn descend from a very basal form of L3.

These facts suggest that the Out of Africans did not arise from many parts of the African population structure - probably just one to three, quite possibly just one. So, Eurasian population structure probably wasn't very advance within Africa before AMHs left at OoA.

terryt said...

"These facts suggest that the Out of Africans did not arise from many parts of the African population structure - probably just one to three, quite possibly just one".

Thanks for the clarification. I now agree. However the variation outside Africa now becomes most easily explained as being a product of interbreeding with pre-existing Eurasian populations. A population that contains just two mtDNA lines and at most three, and possibly just one, Y-hap line is unlikely to have enough genetic variation to survive for many generations.