Friday, 20 January 2012

Introgression of archaic haplotype at OAS1 in Melanesians (Mendez et al. 2012)

It seems that Michael Hammer was good on his promise that in 2012 "This year, we should be able to confirm what we found and go way beyond that."  In a new paper, conclusive evidence is presented about introgression of an archaic sequence into Melanesian populations. The argument is as follows:

  • Melanesians are more diverse in that region than Africans.
  • The common ancestor of the "archaic" and "African" haplotypes lived >3 million years ago.
  • The "archaic" haplotype matches the ancient DNA from the Denisova hominin.
  • Balancing selection (which can sometimes maintain extremely old polymorphism) is not reasonable in this case, because it would need to maintain both "archaic" and "African" haplotypes for a long time, but then (inexplicably) would continue to operate in Melanesia and cease to operate everywhere else.

Notice that once again, this is based on resequencing a small region of the genome. This is why I am all the more confident in my prediction that the advent of full genome sequencing will uncover more archaic admixture in humans. It may not always be able to use all the above listed criteria to confirm this admixture (since we do not and cannot have ancient DNA from all the archaic hominins that once roamed the planet), but all the remaining ones will suffice to make a very good case for introgression.

What I find particularly interesting, is that Mendez et al. re-iterate a few times that genomewide averages admit to different explanations:

Full genome comparisons of the Neandertal and Denisova draft genomes with modern human sequences have revealed different amounts of shared ancestry between each of these archaic forms and anatomically modern human (AMH) populations from different geographic regions. For example, a higher proportion of SNPs was shared between non-African and Neandertal, and between Melanesian and the Denisova genomes, than between either Neandertal or Denisova and extant African genomes (Green et al. 2010; Reich et al. 2010). An intriguing possibility is that these patterns result from introgression of archaic genes into AMH populations in Eurasia. However, this SNP sharing pattern could also be explained by ancestral population structure in Africa (i.e., without the need to posit introgression). For example, if non-Africans and the ancestors of Neandertals descend from the same deme in a subdivided African population, and this structure persisted with low levels of gene flow among African residents until the ancestors of non-Africans migrated into Eurasia, then we would expect more SNP sharing between non-Africans and Neandertals (Durand et al. 2011). 
While genome-wide comparisons detect more sequence agreement between non-African and Neandertal genomes, and between Melanesian and Denisova genomes, the specific loci exhibiting these signals have not yet been identified. Furthermore, current analyses do not elucidate the relative roles of recent introgression versus long-term population structure in Africa in explaining these patterns.

The current paper does a good job at showing how in one particular region archaic introgression into Melanesians is indeed the best explanation for the evidence. But, the fact that the authors seem to re-iterate the possibility of African population structure and repeatedly caution against using patterns of genomewide sharing between modern and archaic humans is a strong hint that there are more things to come on the topic.

We should remember that the widely-circulated estimates of Neandertal->Eurasian introgression are based on genomewide averages. It is true that Reich et al. (2010) identified 13 regions of potential Neandertal introgression, which together make up a very small portion of the human genome. So, the jury is out on whether African population structure or Neandertal introgression is responsible for most of the genomewide pattern.

What you can be sure of is that many scientists are busy lining up full genomes from different human populations as we speak, and finding plenty of regions where haplotypes of extremely old divergence times co-exist in our species. We will probably learn more about such efforts during 2012.

Mol Biol Evol (2012)doi: 10.1093/molbev/msr301

Global genetic variation at OAS1 provides evidence of archaic admixture in Melanesian populations

Fernando L. Mendez, Joseph C. Watkins and Michael F. Hammer

Recent analysis of DNA extracted from two Eurasian forms of archaic human show that more genetic variants are shared with humans currently living in Eurasia than with anatomically modern humans in sub-Saharan Africa. While these genome-wide average measures of genetic similarity are consistent with the hypothesis of archaic admixture in Eurasia, analyses of individual loci exhibiting the signal of archaic introgression are needed to test alternative hypotheses and investigate the admixture process. Here, we provide a detailed sequence analysis of the innate immune gene, OAS1, a locus with a divergent Melanesian haplotype that is very similar to the Denisova sequence from the Altai region of Siberia. We re-sequenced a 7 kb region encompassing the OAS1 gene in 88 individuals from 6 Old World populations (San, Biaka, Mandenka, French Basque, Han Chinese, and Papua New Guineans) and discovered previously unknown and ancient genetic variation. The 5' region of this gene has unusual patterns of diversity, including 1) higher levels of nucleotide diversity in Papuans than in sub-Saharan Africans, 2) very deep ancestry with an estimated time to the most recent common ancestor of >3 million years, and 3) a basal branching pattern with Papuan individuals on either side of the rooted network. A global geographic survey of >1500 individuals showed that the divergent Papuan haplotype is nearly restricted to populations from eastern Indonesia and Melanesia. Polymorphic sites within this haplotype are shared with the draft Denisova genome over a span of ∼90 kb and are associated with an extended block of linkage disequilibrium, supporting the hypothesis that this haplotype introgressed from an archaic source that likely lived in Eurasia.