Archaic DNA Segments

Divergence Of Human Populations

The divergence of human populations follows a complex timeline shaped by migration, adaptation, and genetic isolation. The first major split occurred between Neanderthals and Denisovans from the lineage leading to modern humans, estimated at ~600,000–700,000 years ago[1]. This separation led to Neanderthals evolving in Europe and West Asia, while Denisovans adapted to environments further east in Asia[2]. New studies from high-coverage Denisovan genomes suggest that they carried significant substructure, hinting at multiple distinct Denisovan populations[3]. Meanwhile, early modern human ancestors continued evolving in Africa, with significant population substructure emerging before the Out of Africa migration. One of the deepest known divergences within Homo sapiens is between Pygmies (Rainforest Hunter-Gatherers) and Khoisan hunter-gatherers, estimated at ~200,000–300,000 years ago, preceding the split between all other modern human populations[4]. This suggests that significant genetic diversity existed within Africa long before humans expanded into Eurasia.

The Out of Africa migration (~50,000–70,000 years ago) led to the expansion of a subset of modern humans across Eurasia, where they encountered Neanderthals and Denisovans, resulting in interbreeding events that introduced archaic DNA into non-African populations[5]. More recent paleogenomic reconstructions suggest that interbreeding between modern humans and archaic hominins was more widespread than previously thought, affecting population dynamics in both Eurasia and Africa[6]. In contrast, African populations retained a deeper genetic structure, with multiple ancient lineages persisting, particularly among Khoisan and Central African Pygmies, whose ancestors represent some of the most ancient human populations[7]. This divergence pattern underscores the deep-rooted genetic complexity within Africa before modern humans dispersed across the globe.

 

Citations:

 

  1. Prüfer et al. (2014): “The complete genome sequence of a Neanderthal from the Altai Mountains” – Discusses the Neanderthal-Denisovan divergence timeline.

  2. Slon et al. (2018): “The genome of the offspring of a Neanderthal mother and a Denisovan father” – Provides genetic evidence of interbreeding and divergence times between Neanderthals and Denisovans.

  3. Zhang et al. (2021): “Denisovan DNA from Late Pleistocene sediments in North China” – Suggests Denisovan population structure and multiple migration waves.

  4. Schlebusch et al. (2017): “Southern African ancient genomes estimate modern human divergence to 350,000 to 260,000 years ago” – Discusses the early divergence of Khoisan and other African populations.

  5. Posth et al. (2017): “Deeply divergent archaic mitochondrial genome provides lower time boundary for African gene flow into Neanderthals” – Discusses early African population structure and archaic interactions.

  6. Villanea et al. (2022): “Archaic introgression shaped modern human genetic variation” – Highlights recent advances in paleogenomics and archaic admixture in Africa and Eurasia.

  7. Lipson et al. (2020): “Ancient West African foragers in the context of African population history” – Covers ancient African genetic diversity and the role of Pygmy and Khoisan populations.

Archaic Ancestry Analysis

Included in your report will be a breakdown of your archaic ancestry, detailing which percentage of your genome descends from Neanderthals and Denisovans. Globally, most modern populations outside of Africa have trace percentages of archaic DNA. The amount estimated varies per study due to several factors that make it challenging to ascertain. Neanderthal percentages generally range from under 1% to between 2% and 3%, while Denisovan percentages range from 0% to around 5%.

These stem from multiple introgression events, first with Neanderthals and later with Denisovans, which occurred after humans entered Eurasia. African populations have been found to have trace amounts of Neanderthal DNA as well, most likely from historical migrations of Eurasians back into parts of Africa[5]. Genetic segments associated with Denisovans were initially thought to only be present in Papuans and Aboriginal Australians, but subsequent studies indicate these are present at trace amounts throughout Eurasia.

Several studies, such as those from Sankararaman et al. (2014) and Vernot & Akey (2014), identified 10,000–20,000 archaic SNPs, but not all of these are covered by genotyping arrays from providers like AncestryDNA and 23andMe. We have analyzed prior studies indicating SNPs in modern humans linked to Neanderthals and Denisovans and determined which ones are most likely to be present in raw DNA data files from mainstream DNA providers. Since results from mainstream providers analyze fewer DNA segments than whole genome sequencing, the number of SNPs attributable to archaic hominins in these files is significantly lower than the total numbers determined by academic studies.

Before performing any estimation of ancestry, we phase genotypes using Hidden Markov Models with statistical phasing to reduce errors and improve detection of archaic DNA segments. Target genomes are compared to reference panels of SNPs to determine which genomic regions are attributable to archaic DNA.

Neanderthal introgression in humans is overwhelmingly related to the genetic cluster of Neanderthals most closely related to the Vindija Neanderthal sample. Only around 1% of the Neanderthal DNA in humans is related to the Altai Neanderthal[6].Vindija Neanderthal from Croatia represents the primary source of Neanderthal introgression into our ancestry. [7][8] [10] The Altai Neanderthal lineage from Denisova Cave in Siberia, appears to have contributed significantly less to modern human genomes. [9]

Denisovan introgression in humans has not been uniform and has been found to belong to three separate divisions labeled D0, D1, and D2[1]. These groups represent different waves of Denisovan introgression into modern human populations.

D0 is primarily found in East Asians and Siberians, with trace levels in Native Americans, and is related to the Altai Denisovan genome[1].
D1 is found in Papuans and Australian Aboriginal groups[2][3].
D2 is the most divergent Denisovan lineage, found in Southeast Asians, including Indonesians, Filipinos, and some South Asian populations, but not in East Asians[4].
These findings demonstrate that Denisovan ancestry is not uniform, but instead consists of multiple introgression events from genetically distinct Denisovan groups into different modern human populations.

D0 is present in trace amounts in West Eurasia through later population migrations and admixture. Mallick et al. (2016) and Sankararaman et al. (2016) reported that West Eurasians have minimal Denisovan ancestry (<0.02%), likely originating from ancient East Asian admixture rather than direct Denisovan introgression. Browning et al. (2018) found Denisovan introgression in East Asians but only minor traces in Europeans, suggesting D0 as the primary source.

References:
[1] Browning, S. R., Browning, B. L., Zhou, Y., Tucci, S., & Akey, J. M. (2018). Analysis of human sequence data reveals two pulses of Denisovan admixture. Cell, 173(1), 53-61.e9. DOI: 10.1016/j.cell.2018.02.031
[2] Jacobs, G. S., Hudjashov, G., Saag, L., Kusuma, P., Darusallam, C. C., Lawson, D. J., et al. (2019). Multiple deeply divergent Denisovan ancestries in Papuans. Cell, 177(4), 1010-1021.e32. DOI: 10.1016/j.cell.2019.02.035
[3] Reich, D., Patterson, N., Kircher, M., Delfin, F., Nandineni, M. R., Pugach, I., et al. (2011). Denisova admixture and the first modern human dispersals into Southeast Asia and Oceania. The American Journal of Human Genetics, 89(4), 516-528. DOI: 10.1016/j.ajhg.2011.09.005
[4] Sankararaman, S., Mallick, S., Dannemann, M., Prüfer, K., Kelso, J., Pääbo, S., et al. (2016). The combined landscape of Denisovan and Neanderthal ancestry in present-day humans. Cell, 166(3), 611-623. DOI: 10.1016/j.cell.2016.06.024
[5] Chen, L., Wolf, A. B., Fu, W., Li, L., Akey, J. M. (2020). Identifying and interpreting apparent Neanderthal ancestry in African individuals. Cell, 180(4), 677-687.e16. DOI: 10.1016/j.cell.2020.01.012
[6] Prüfer, K., Racimo, F., Patterson, N., Jay, F., Sankararaman, S., Sawyer, S., et al. (2014). The complete genome sequence of a Neanderthal from the Altai Mountains. Nature, 505(7481), 43-49. DOI: 10.1038/nature12886
[7] Williams, S. R. (2019). The Neanderthal and Denisovan Genomes. *Wiley Interdisciplinary Reviews: Anthropology*, 6(3), 157–178. [DOI: 10.1002/9781118768853.ch6](https://onlinelibrary.wiley.com/doi/abs/10.1002/9781118768853.ch6)
[8] Villanea, F. A., Huerta-Sanchez, E., & Fox, P. K. (2020). ABO genetic variation in Neanderthals and Denisovans. *bioRxiv*. [DOI: 10.1101/2020.07.27.223628](https://www.biorxiv.org/content/10.1101/2020.07.27.223628.abstract)
[9] Taskent, O., Lin, Y. L., Patramanis, I., & Pavlidis, P. (2020). Analysis of haplotypic variation and deletion polymorphisms point to multiple archaic introgression events, including from Altai Neanderthal lineage. *Genetics*, 215(2), 497–512. [DOI: Not available](https://academic.oup.com/genetics/article-abstract/215/2/497/5930453)
[10] Prüfer, K., De Filippo, C., Grote, S., Mafessoni, F., Korlević, P., et al. (2017). A high-coverage Neanderthal genome from Vindija Cave in Croatia. *Science*, 358(6363), 655-658. [DOI: 10.1126/science.aao1887](https://www.science.org/doi/abs/10.1126/science.aao1887)

The following lists contain studies that were used during the formulation of our reference panel of Neanderthal and Denisovan associated SNPs.

Denisovan-Associated SNPs:

  1. Koller, D., Wendt, F. R., Pathak, G. A., & De Lillo, A. (2022). Denisovan and Neanderthal archaic introgression differentially impacted the genetics of complex traits in modern populations. BMC Biology. https://link.springer.com/article/10.1186/s12915-022-01449-2
  2. Sankararaman, S., Mallick, S., Patterson, N., & Reich, D. (2016). The combined landscape of Denisovan and Neanderthal ancestry in present-day humans. Current Biology. https://www.cell.com/current-biology/fulltext/S0960-9822(16)30247-0
  3. Qin, P., & Stoneking, M. (2015). Denisovan ancestry in East Eurasian and native American populations. Molecular Biology and Evolution, 32(10), 2665-2674. https://academic.oup.com/mbe/article-abstract/32/10/2665/1210305
  4. Vespasiani, D. M., Jacobs, G. S., Cook, L. E., & Brucato, N. (2022). Denisovan introgression has shaped the immune system of present-day Papuans. PLOS Genetics. https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1010470
  5. Ongaro, L., & Huerta-Sanchez, E. (2024). A history of multiple Denisovan introgression events in modern humans. Nature Genetics. https://www.nature.com/articles/s41588-024-01960-y
  6. Villanea, F. A., & Huerta-Sanchez, E. (2021). ABO genetic variation in Neanderthals and Denisovans. Molecular Biology and Evolution, 38(8), 3373-3383. https://academic.oup.com/mbe/article-abstract/38/8/3373/6248100
  7. Dannemann, M., Andrés, A. M., & Kelso, J. (2016). Introgression of Neandertal- and Denisovan-like haplotypes contributes to adaptive variation in human Toll-like receptors. American Journal of Human Genetics. https://www.cell.com/ajhg/fulltext/S0002-9297(15)00486-3
  8. Yermakovich, D., André, M., & Brucato, N. (2024). Denisovan admixture facilitated environmental adaptation in Papua New Guinean populations. Proceedings of the National Academy of Sciences (PNAS). https://www.pnas.org/doi/abs/10.1073/pnas.2405889121
  9. Lowery, R. K., Uribe, G., Jimenez, E. B., & Weiss, M. A. (2013). Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms. Gene. https://www.sciencedirect.com/science/article/pii/S0378111913007567
  10. Akkuratov, E. E., & Gelfand, M. S. (2018). Neanderthal and Denisovan ancestry in Papuans: A functional study. Journal of Bioinformatics and Computational Biology. https://www.worldscientific.com/doi/abs/10.1142/S0219720018400115

Neanderthal-Associated SNPs:

  1. Simonti, C. N., Capra, J. A., & Vernot, B. (2016). The phenotypic legacy of admixture between modern humans and Neanderthals. Science. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4849557/
  2. Dannemann, M., Prufer, K., & Kelso, J. (2022). The lingering effects of Neanderthal introgression on human complex traits. eLife, 11, e80757. https://elifesciences.org/articles/80757
  3. Gunz, P., Tilot, A. K., Wittfeld, K., et al. (2017). Neanderthal-derived genetic variation shapes modern human cranium and brain. Scientific Reports, 7, 6476. https://www.nature.com/articles/s41598-017-06587-0
  4. Petr, M., Pääbo, S., Kelso, J., & Vernot, B. (2019). A catalog of single nucleotide changes distinguishing modern humans from Neanderthals and Denisovans. Scientific Reports, 9, 8463. https://www.nature.com/articles/s41598-019-44877-x
  5. Zeberg, H., & Pääbo, S. (2022). The contribution of Neanderthal introgression to modern human traits. Nature Genetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9741939/