An insertion into deep history

A couple of weeks ago I noted a new article by Chad Huff and colleagues in PNAS. It wasn’t available yet when I wrote, but I’ve had the chance to study it now.

The paper presents a tremendously clever way of using contemporary genetics to look at different time slices in Pleistocene human evolution. If you can imagine traveling to different parts of the human genome and looking at different times in the past, that’s more or less what they are doing.

We have the genomes of several people now – the paper focuses on Venter’s sequence versus the official HGP draft sequence, but there are others. A whole genome is limited in its utility to look at genetic variation, but it has some very interesting sampling properties. Much of population genetics theory is based on a simple question: what happens if you sample two individuals at random? How similar are they? What will be the distribution of genetic differences between them? How long ago did each of their genes descend from a single common ancestor? Sampling a diploid genome yields precisely the data for which these questions were designed.

Huff and colleagues dredge up a relatively obscure point of theory. Suppose you take a particular kind of rare event – they consider mobile element insertions, including Alu and LINE insertions. Even though these elements make up a large fraction of the human genome, the events that give rise to them are rare, occurring only once in a whole genome every 20 births or more. Now, look around the genome and partition it into two kinds of regions. One kind of region will include the rare events (insertions in this case) and the area immediately flanking them. The other will include everywhere else in the genome. Now, the partitioning creates a bias. The areas that include these rare events will, on average, represent more diverse parts of the genome, with deeper genealogies. This is because the intrinsically rare event is more likely to have happened in the long time span represented by such areas than in the relatively shorter times represented by the remainder of the genome. In fact, the average depth of these areas including the insertions should be precisely double the average depth of the areas that lack them.

In other words, looking at these rare events is sort of like opening the box on Schroedinger’s cat. There’s something that we shouldn’t be able to find out a priori – how old is the genealogy of a part of the genome? By sifting through the genome and picking out all the parts that have these insertions, we know something about them: We know that they represent a time interval double that of the rest of the genome. Our looking at these insertions has collapsed the likelihood function that relates genetic location to age. When we look at the variation around insertions, we can then ignore some of the events that changed the population’s diversity in the last couple of hundred thousand years. And by comparing these sites with the rest of the genome, we have another way to test hypotheses about whether the population was once a lot bigger or smaller than it has been over the last few hundred thousand years.

The analysis shows that the population in that early part of the genealogy – corresponding more or less to dates over 1.2 million years ago – was consistent with an effective population size of 18000 individuals, give or take. As I pointed out in my earlier post, that value itself isn’t surprising – it’s a bit higher than the average genome-wide. The best-fit model, including both areas near insertions and the rest of the genome, was one in which the effective population size actually declined from 18,500 to 8500 individuals at 1.2 million years ago. They explain that the recent value should be depressed by the separation of present human populations – Venter and the human reference sequence both being primarily derived from Europe, they undersample human variation.

Now, it’s easy to see some of the limitations on the analysis. The authors considered only a two-epoch model of population history. That is to say, once upon the time the population was x individuals, then at some time t, the population becomes y individuals. Two epochs of population size, separated by one time. Clearly the actual history of human populations was more complicated than this, but does it matter? Recent history will not greatly influence nucleotide diversity, and in particular the insertions – because they are intrinsically rare – are likely to reflect much more ancient events that have survived any subsequent vicissitudes of population.

But, I suspect that the distribution of insertions with relation to recent selection will make an appreciable difference to the nearby SNP diversity. The geographic distribution of variation will also make some difference, although we won’t know how much until we look at non-European genomes.

Meanwhile, if I were looking to the archaeological record to identify times that made a difference to the human population, 1.2 million years ago would really not register. It certainly would not strike me as a time of substantial reduction of the human population.

The lack of any archaeological referent is typical of such studies – after all, they’re not trying to match numbers from archaeology, they’re trying to establish internally consistent genetic tests of population history. But if these values are real, they must match what we know from the fossil and archaeological record. There is some text in the paper about the small effective size and its relevance to humans as a sign of repeated bottlenecks or other events. As I pointed out earlier, I think 18,000 is pretty significantly large compared to most other estimates of human effective population size. When we get an estimate of human effective size so near those of other apes, we are looking at a value consistent with habitation of a large, certainly continent-wide range by large populations. So now I have to think what the pertinent comparison from the archaeological record should be.

One archaeological comparison is of special interest to me: a real-life comparison that will be immediately relevant. This study should be giving us information about the population ancestral to Neandertals and humans. In that sense, it duplicates the information that we ought to be able to derive from the comparison of human and Neandertal genomes.

Interestingly, the effective size estimates published so far for the human-Neandertal ancestral population are much lower than the 18,500 estimated in this study. Green and colleagues (2006) made a point estimate of 3000 effective individuals at the time of Neandertal-human divergence. That estimate is likely to be supplanted by the Neandertal genome release, because the Green et al. (2006) estimate was influenced by some fraction of contaminating sequence from humans. And the error bars on that estimate are large. But there’s a lot of space between them – we’re talking about at least a sixfold difference.

Something doesn’t add up. The human-Neandertal ancestral population must have contained all these polymorphic insertions that supposedly occurred before 800,000 years ago. The effective size of the population may have been lower, but if so we should look for some explanation for that substantial loss of variation.

UPDATE (2010-02-10): A couple of people have asked about effective population size. Here’s a helpful post that explains why a small effective size may not mean a small population size, and some of the current hypotheses that try to explain the human value.

References:

Green RE, Krause J, Ptak SE, Briggs AW, Ronan MT, Simons JF, Du L, Egholm M, Rothberg JM, Paunovic M, Pääbo S. 2006. Analysis of one million base pairs of Neanderthal DNA. Nature 444:330-336. doi:10.1038/nature05336

Huff CD. Xing J, Rogers AR, Witherspoon D, Jorde LB. 2010. Mobile elements reveal small population size in the ancient ancestors of Homo sapiens. Proc Nat Acad Sci USA (early online) doi:10.1073/pnas.0909000107