How widespread is Denisovan ancestry today?

Last month, David Reich and colleagues Reich:Denisova:2011 reported on estimates of Denisovan ancestry for island and mainland Asian populations. Their most memorable conclusion was that they could find no substantial sign of Denisovan ancestry anywhere on the Asian mainland, or indeed on any island that had ever been connected by land to Asia.

The distribution was stark, as illustrated by the map from the paper:

I wrote about the paper when it was released ("Denisovan DNA in the islands, and an Australian genome"), noting:

Notice the apparent lack of Denisovan ancestry in anyone who lives anywhere that was once connected by land with mainland Asia. I say "apparent" deliberately: Abi-Rached and colleagues reported last month on the widespread distribution of Denisovan HLA types among today's Asian populations, and those may well be products of Denisovan genes that were later selected. I've already identified a handful of other loci that seem to reflect Denisovan ancestry in mainland Asian people. According to the comparisons by Reich and colleagues, such loci must be exceptions.

Abi-Rached and colleagues Abi-Rached:2011 had argued that HLA alleles found in the Denisovan genome are presently common in some parts of Asia, and likely reflect local adaptive introgression. Substantial introgression of a small number of genes would not be enough to create a strong genome-wide appearance of Denisovan ancestry. Still, it was a little odd that the first genes anybody looked closely at would provide strong evidence of introgression.

Now, Pontus Skoglund and Mattias Jakobsson Skoglund:Jakobsson:2011 say that Denisovan ancestry is widespread across China and Southeast Asia.

That conclusion contradicts Reich and colleagues, so why do the studies come to such different results?

Skoglund and Jakobsson suggest that they have succeeded in finding introgression where others failed because their model accounts for ascertainment bias in the available datasets. SNP data come from genotyping chips, which have been designed using known polymorphisms. Five years ago, we knew much more about polymorphisms in Europe than other parts of the world, and so the HGDP, and HapMap to a lesser extent, do a good job of sampling rare alleles in Europe but miss many rare alleles in Africa and other populations. This is the ascertainment bias.

Some of the most obvious signs of introgression today are cases where rare alleles are shared with an archaic genome. If ascertainment bias causes you to miss the rare alleles, you'll miss the introgression.

But that explanation isn't really sufficient to explain the differences between these papers. For one thing, Reich and colleagues Reich:Denisova:2011 also worked hard to account for ascertainment biases in their SNP samples. For another, whole genome comparisons between East Asian samples and the Denisova genome have not yielded evidence of Denisovan ancestry, even though whole genomes have no ascertainment bias. The number of whole genomes so far compared is very small, and so the statistical ability to detect introgression is lower, but Skoglund and Jakobsson actually replicate that null result in their current paper.

Probably most important, it's not clear that Skoglund and Jakobsson's result can actually be explained by rare alleles. Here is Figure 1e from their paper:

Figure 1e from Skoglund and Jakobsson (2011). Original caption: Interpolated spatial distribution of the frequency of Denisova alleles at SNPs where Denisova is different from chimpanzee and Neandertal. Sample localities are indicated with rectangles.

This map represents a clever comparison. It is a heat map of the mean local frequency of the subset of alleles that are present in Denisova but absent from chimpanzees and Neandertals. These are presumptively derived alleles relative to the chimpanzee. The SNPs here are all known to vary in human populations, because they are all included in the HGDP sample. So the map does not represent all the Denisova derived mutations in humans today, only a particular subset that is especially likely to be informative.

Given that the sites have been picked in a special way, we need to examine carefully how strong the pattern really is. Notice the scale of the heat map. The difference between the orange area in south China, from the green area in north China, is around 0.001, or a tenth of a percent in mean frequency. The actual values are reported in the online supplement, in Table S3. An exception of Yizu in south China who have around 0.006 more than their neighbors. The Yizu sample includes only 10 individuals (9 males, 1 female). The paper does not report the number of SNPs included in this comparison, but it must be a very small set relative to the total, because only a small fraction of human SNPs are known to be derived in Denisova and ancestral in Neandertals.

With this very small difference in frequencies, I would not rule out the hypothesis that the zone of high Denisova derived frequencies in south China is caused entirely by frequency enrichment of a small number of loci. A handful of genes like the HLA loci observed by Abi-Rached and colleagues might be enough to create this very slight elevation in the average. Hence, the best case is that the data here simply provide greater sensitivity to small amounts of introgression. The worst case is that the pattern may be dominated by the Yizu sample, which is really too small to carry this kind of load.

The strongest evidence presented in the paper is a comparison of north and south East Asian regions directly. Although the comparison of south China against other regions of the world (Africa, Europe) does not yield significant evidence of Denisovan similarity in this paper, south China differs from north China in essentially the same way that the Oceanian people do from other regions. And the Oceanian populations (here, Papua New Guinea and Bougainville) differ from other regions because of their Denisovan ancestry. So Skoglund and Jakobsson infer that the north/south comparison reflects Denisovan ancestry as well.

I think this comparison is sound, and the question is, how much introgression would this pattern require? The paper answers that question in this way:

Quantitative estimation of the precise fraction of Denisova-related ancestry in Southeast Asian populations based on genotype data are unfortunately sensitive to ascertainment bias and genetic drift, and such estimates will require genome sequence data that are currently unavailable. However, both the PCA results (Fig. 1B) and the approximately six times lower absolute values of the D statistic in tests between Northeast Asians and Southeast Asians compared with tests between Northeast Asians and Oceanians (Table S4) indicate a relatively low fraction of Denisova-related ancestry. Thus, the fraction is likely to be smaller than both the ~5% fraction of Denisova-related ancestry present in Oceanians and the ~2.5% fraction of Neandertal ancestry present in non-Africans (23, 24), perhaps around 1%.

One percent is an amount that whole genome comparisons at present do not rule out, and I think it's a reasonable guess. I would not have thought we could rule out a one percent contribution from other, non-Denisovan archaic people, for example.

We aren't very far from a more definitive answer of this question, as the data continue to accumulate every day. What I find interesting is the way that models can generate these 1% differences in ancestry proportions, depending on sampling and the pattern of migration assumed to have happened in the past. Two estimates that differ by less than a percent are not really different. This paper provides the suggestion of a more widespread Denisovan legacy, and I accept that as a possibility.

I should mention: less than one percent of a half billion people is still a very large number, added to five percent of the indigenous population of New Guinea and Australia, and smaller fractions of other island populations. The total amount of Denisovan legacy present in living people probably exceeds the population of Earth at the time the Denisovans lived.