Neanderthals and anatomically modern humans overlapped geographically for a period of over 30,000 years following human migration out of Africa. During this period, Neanderthals and humans interbred, as evidenced by Neanderthal portions of the genome carried by non-African individuals today. A key observation is that the proportion of Neanderthal ancestry is ~12–20% higher in East Asian individuals relative to European individuals. Here, we explore various demographic models that could explain this observation. These include distinguishing between a single admixture event and multiple Neanderthal contributions to either population, and the hypothesis that reduced Neanderthal ancestry in modern Europeans resulted from more recent admixture with a ghost population that lacked a Neanderthal ancestry component (the ‘dilution’ hypothesis). To summarize the asymmetric pattern of Neanderthal allele frequencies, we compiled the joint fragment frequency spectrum of European and East Asian Neanderthal fragments and compared it with both analytical theory and data simulated under various models of admixture. Using maximum-likelihood and machine learning, we found that a simple model of a single admixture did not fit the empirical data, and instead favour a model of multiple episodes of gene flow into both European and East Asian populations. These findings indicate a longer-term, more complex interaction between humans and Neanderthals than was previously appreciated.
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No novel datasets were generated or analysed during the current study.
Green, R. E. et al. A draft sequence of the Neandertal genome. Science 328, 710–722 (2010).
Prüfer, K. et al. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358, 655–658 (2017).
Sankararaman, S., Patterson, N., Li, H., Pääbo, S. & Reich, D. The date of interbreeding between Neandertals and modern humans. PLoS Genet. 8, e1002947 (2012).
Meyer, M. et al. A high-coverage genome sequence from an archaic Denisovan individual. Science 338, 222–226 (2012).
Wall, J. D. et al. Higher levels of Neanderthal ancestry in East Asians than in Europeans. Genetics 194, 199–209 (2013).
Karmin, M. et al. A recent bottleneck of Y chromosome diversity coincides with a global change in culture. Genome Res. 25, 459–466 (2015).
Poznik, G. D. et al. Punctuated bursts in human male demography inferred from 1,244 worldwide Y-chromosome sequences. Nat. Genet. 48, 593–599 (2016).
Skoglund, P. & Mathieson, I. Ancient genomics of modern humans: the first decade. Annu. Rev. Genom. Hum. Genet. 19, 381–404 (2018).
Fu, Q. et al. An early modern human from Romania with a recent Neanderthal ancestor. Nature 524, 216–219 (2015).
Sankararaman, S. et al. The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507, 354–357 (2014).
Lazaridis, I. et al. Genomic insights into the origin of farming in the ancient Near East. Nature 536, 419–424 (2016).
Vernot, B. & Akey, J. M. Complex history of admixture between modern humans and Neandertals. Am. J. Hum. Genet. 96, 448–453 (2015).
Vernot, B. et al. Excavating Neandertal and Denisovan DNA from the genomes of Melanesian individuals. Science 352, 235–239 (2016).
Harris, K. & Nielsen, R. The genetic cost of Neanderthal introgression. Genetics 203, 881–891 (2016).
Kim, B. Y. & Lohmueller, K. E. Selection and reduced population size cannot explain higher amounts of Neandertal ancestry in East Asian than in European human populations. Am. J. Hum. Genet. 96, 454–461 (2015).
Juric, I., Aeschbacher, S. & Coop, G. The strength of selection against Neanderthal introgression. PLoS Genet. 12, e1006340 (2016).
Lazaridis, I. et al. Ancient human genomes suggest three ancestral populations for present-day Europeans. Nature 513, 409–413 (2014).
Petr, M., Pääbo, S., Kelso, J. & Vernot, B. The limits of long-term selection against Neandertal introgression. Preprint at https://www.biorxiv.org/content/early/2018/07/04/362566 (2018).
Steinrücken, M., Spence, J. P., Kamm, J. A., Wieczorek, E. & Song, Y. S. Model-based detection and analysis of introgressed Neanderthal ancestry in modern humans. Mol. Ecol. 27, 3873–3888 (2018).
Ronen, R., Udpa, N., Halperin, E. & Bafna, V. Learning natural selection from the site frequency spectrum. Genetics 195, 181–193 (2013).
Schrider, D. R. & Kern, A. D. S/HIC: robust identification of soft and hard sweeps using machine learning. PLoS Genet. 12, e1005928 (2016).
Sheehan, S. & Song, Y. S. Deep learning for population genetic inference. PLoS Comput. Biol. 12, e1004845 (2016).
Schrider, D. R. & Kern, A. D. Supervised machine learning for population genetics: a new paradigm. Trends Genet. 34, 301–312 (2018).
Bengio, Y. et al. in Large-Scale Kernel Machines (eds Bottou, L., Chapelle, O., DeCoste, D. & Weston, J.) 321–360 (MIT Press, Cambridge, 2007).
Kamm, J. A., Terhorst, J., Durbin, R. & Song, Y. S. Efficiently inferring the demographic history of many populations with allele count data. Preprint at https://www.biorxiv.org/content/early/2018/03/23/287268 (2018).
Do, R. et al. No evidence that selection has been less effective at removing deleterious mutations in Europeans than in Africans. Nat. Genet. 47, 126–131 (2015).
Simons, Y. B., Turchin, M. C., Pritchard, J. K. & Sella, G. The deleterious mutation load is insensitive to recent population history. Nat. Genet. 46, 220–224 (2014).
Browning, S. R., Browning, B. L., Zhou, Y., Tucci, S. & Akey, J. M. Analysis of human sequence data reveals two pulses of archaic Denisovan admixture. Cell 173, 53–61 (2018).
Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).
Mafessoni, F. & Prüfer, K. Better support for a small effective population size of Neandertals and a long shared history of Neandertals and Denisovans. Proc. Natl Acad. Sci. USA 114, E10256–E10257 (2017).
Rogers, A. R., Bohlender, R. J. & Huff, C. D. Early history of Neanderthals and Denisovans. Proc. Natl Acad. Sci. USA 114, 9859–9863 (2017).
Rogers, A. R., Bohlender, R. J. & Huff, C. D. Reply to Mafessoni and Prüfer: Inferences with and without singleton site patterns. Proc. Natl Acad. Sci. USA 114, E10258–E10260 (2017).
Jouganous, J., Long, W., Ragsdale, A. P. & Gravel, S. Inferring the joint demographic history of multiple populations: beyond the diffusion approximation. Genetics 206, 1549–1567 (2017).
Kelleher, J., Etheridge, A. M. & McVean, G. Efficient coalescent simulation and genealogical analysis for large sample sizes. PLoS Comput. Biol. 12, 1–22 (2016).
Hinch, A. G. et al. The landscape of recombination in African Americans. Nature 476, 170–175 (2011).
We are grateful to S. Mathieson and J. Spence for several useful discussions about neural network architecture and appropriate methods for training neural networks. We also thank J. Spence and M. Steinrücken for extensive discussions on errors in fragment calling. I. Mathieson, S. Mathieson and J. Spence provided invaluable feedback on an early draft of this manuscript that helped improve its clarity. K. Harris provided invaluable discussions during the conception and work of this manuscript. We are grateful to M. Petr and B. Vernot for sharing processed simulation data with us, and for discussions about the impact of selection on Neanderthal ancestry. J.G.S. and F.A.V. were supported by NIH grant R35 GM124745. This research was supported in part by the National Science Foundation through major research instrumentation grant number 1625061 for the Owl’s Nest high-performance cluster at Temple University.
The authors declare no competing interests.
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Villanea, F.A., Schraiber, J.G. Multiple episodes of interbreeding between Neanderthal and modern humans. Nat Ecol Evol 3, 39–44 (2019). https://doi.org/10.1038/s41559-018-0735-8
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