One of the most fascinating aspects of the human genome is what it reveals about our enigmatic extinct siblings, the Neanderthals. Two bioRxiv preprints (Harris and Nielsen, and Juric et al.) out just this week have given us new insights into the effects of Neanderthal admixture on ancient Homo sapiens populations, with implications for the phylogenetic relationships between the two hominins. Even though these are still provisional findings, I think they’re significant enough to warrant discussion in an evolution forum, and I’m delighted to write my first post here about them.
In case you’re not up to date on the latest Neanderthal research, a bit of background is in order. The latest estimates indicate that Neanderthals and humans likely shared a last common ancestor sometime between 550-765 kya. From the sequencing of Neanderthal mitochondrial and nuclear genomes, we’ve learned that as modern humans spread out of Africa there was subsequent hybridization between human and Neanderthal groups in Europe and Asia resulting in varying degrees (~2-4%) of Neanderthal ancestry among contemporary non-African populations. We have also learned that Neanderthal populations were quite small, maintaining an effective population size of just ~1,000 for about 400,000 years (see reference list at the end of this post for citations and further reading).
How did admixture with Neanderthals affect human populations? Some of the alleles from Neanderthal populations appear to provide an adaptive advantage to non-Africans, particularly those for hair and skin color. However, these are only a tiny fraction of Neanderthal-derived alleles. There are large, conserved swathes of the human genome where Neanderthal ancestry appears to be depleted, implying that there is selection against the majority of Neanderthal-derived functional alleles. But what does this selection mean for our evolutionary history? Was it due to hybrid incompatibility between the Neanderthals and humans? Or were those alleles also deleterious in Neanderthals?
In “The genetic cost of Neanderthal introgression”, Kelley Harris and Rasmus Nielsen tested the potential fitness effects of Neanderthal alleles in human genomes. Measures of relative fitness in simulations of Neanderthals’ and humans’ inferred demographic histories under a variety of evolutionary scenarios were consistent with a hypothesis that Neanderthals harbored a large number of weakly deleterious alleles due to genetic drift in their extremely small effective population size, and that introgresson of Neanderthal alleles into larger, human populations resulted in selection effects strong enough to account for the depletion of Neanderthal alleles throughout the human genome. The authors suggest that it is therefore unnecessary to invoke hybrid incompatibility to explain the selection against Neanderthal alleles. Furthermore, they hypothesize that the introgression of these alleles may have affected the mutational load of non-Africans as much as the out-of-Africa bottleneck is hypothesized to have done.
In “The strength of selection against Neanderthal introgression,” Ivan Juric, Simon Aeschbacher, and Graham Coop also explored the question of how Neanderthal admixture affected human populations. They fit a model to patterns of Neanderthal ancestry to estimate the effects of selection against Neanderthal alleles, and found—as Harris and Nielsen had– that the patterns of Neanderthal ancestry in contemporary humans are best explained by weak purifying selection. Juric et al. also inferred that this selection was tied to population size; although effectively neutral in small Neanderthal populations, these alleles were weakly deleterious and therefore subjected to purifying selection in the larger human populations. Furthermore, they hypothesize that stronger purifying selection on the X chromosome as well as sex-biased matings between Neanderthal males and human females could account for the reduced level of Neanderthal-derived ancestry seen on that chromosome. (This sex-biased admixture could potentially also explain the lack of Neanderthal-derived mitochondrial genomes in human populations).
It is remarkable that both groups working independently, using complementary methods, reached such similar conclusions. Both emphasize that selection against deleterious alleles, rather than hybrid incompatibilities, most likely accounts for patterns of Neanderthal ancestry in modern human populations. Even though each allele’s effect would have been small, cumulatively they must have been quite significant, and thus early human and Neanderthal hybrids likely experienced significant reductions in fitness because of this introgression. Juric et al. and Harris and Kelley estimate an average F1 individual would carry somewhere between an astonishing 40 to 94% reduction in fitness compared to modern humans.
What’s particularly fascinating to me is that both research groups also found that the patterns of Neanderthal ancestry in contemporary human populations were not explained by hybrid incompatibility. The implication of this result, of course, is that it weakens the argument that humans and Neanderthals were separate species. I have no doubt that many people will take this question as far from settled, however! Another question that really interests me is whether the large number of deleterious alleles present in Neanderthal populations contributed to some extent to their extinction. However, Juric et al. caution that a direct cause and effect relationship will be difficult to identify, in no small part because of genetic adaptations, soft selection and epistatic effects, but also because of Neanderthal cultural adaptations (which will not appear in the genome) that might have offset such disadvantages. It may fall to archaeologists and paleontologists, therefore, to solve this particular question.
These new findings add to a growing body of knowledge derived from the application of next generation sequencing methods to ancient DNA research, which I think far exceeds the expectations of most of us working in the field a decade ago. Of course, these two papers are still at the preprint stage, which means they haven’t yet been peer-reviewed, and therefore their conclusions remain provisional. However, I do think that their findings merit discussion while the review process is ongoing. The fact that both research groups reached such similar results using different approaches really strengthens my confidence in their interpretations. It’s an exciting time to be studying human evolution!
Many thanks to Graham Coop for helpful comments and answers to my questions.
References and further reading
The two preprints discussed in this post:
Harris K and Nielsen R. The genetic cost of Neanderthal introgression. bioRxiv doi: http://dx.doi.org/10.1101/030387
Juric I, Aeschbacher S, Coop G. The strength of selection againt Neanderthal introgression. bioRxiv doi: http://dx.doi.org/10.1101/030148
Green RE et al. 2010. A draft sequence of the Neandertal Genome. Science 328(5979): 710-722.
Kim BY and Lohmueller KE. 2015. Selection and reduced population size cannot explain higher amounts of Neandertal ancestry in East Asian than in European human populations. American Journal of Human Genetics 96 (3): 454-461.
Meyer M. et al. 2012. A high coverage genome sequence from an archaic Denisovan individual. Science 338 (6014): 222-226.
Noonan JP, Coop G, Kudaravalli S, Smith D, Krause J, Alessi J, Chen F, Platt D, Pääbo S, Pritchard JK, Rubin EM. 2006. Sequencing and analysis of Neanderthal genomic DNA. Science 314 (5802): 1113-1118.
Pruefer K. et al. 2014. The complete genome sequence of a Neanderthal from the Altai mountains. Nature 505 (7481): 43-49.
Racimo F, Sankararaman S, Nielsen R, Huerta-Sanchez E. 2015. Evidence for archaic adaptive introgression in humans. Nature Reviews Genetics 16(6):359-371.
Reich D. et al. 2010. Genetic history of an archaic hominin group from Denisova Cave in Siberia. Nature 468(7327): 1053-1060.
Sankararaman S, Patterson N, Li H, Pääbo S, Reich D. 2012. The date of interbreeding between Neandertals and modern humans. PLoS Genetics 8(10):e1002947.
Sankararaman S, Mallick S, Dannemann M, Pruefer K, Kelso J, Pääbo S, Patterson N, Reich D. 2014. The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507 (7492): 354-357
Vernot B and Akey JM. 2014. Resurrecting surviving Neandertal lineages from modern human genomes. Science 343(6174):1017-1021.
Vernot B and Akey JM. 2015. Complex history of admixture between modern humans and Neandertals. American Journal of Human Genetics 96(3): 448-453.
Wall JD, Yang MA, Jay F, Kim SK, Durand EY, Stevison LS, Gignoux C, Woerner A, Hammer MF, Slatkin M. 2013. Higher levels of Neanderthal ancestry in East Asians than in Europeans. Genetics 194(1):199-209.