How Neanderthals Impacted Our Health

By Kevin Fundora

Reconstruction of a male and female Neanderthal.
(ScienceSource, S. Entressangle & E. Daynes)

Do you sunburn easily or suffer from allergies? Are you wondering why some people have severe symptoms from COVID-19 while others do just fine? The reason why may be from genes we inherited from another species of human, the Neanderthals. These ancient cousins of ours lived in Europe and Asia for thousands of years and became well-adapted to handle the cold and dark Ice Age environments, as well as many local infectious diseases. Meanwhile, we modern humans faced the blistering sun and tropical diseases of Africa. When we ventured out to populate the rest of the planet, we needed to quickly adapt to an unfamiliar world and interbreeding with Neanderthals introduced new genes that could have aided in our adaptation.1

While interbreeding only left us with a small amount of Neanderthal DNA, the majority is found in genes relating to skin and the immune system, which makes sense given the changes in ultraviolet B (UVB) radiation and new infectious diseases we encountered in Europe and Asia.2 These new genes might have helped us survive outside of Africa, but not all turned out to be beneficial. Some led to weaknesses or overreactions in our skin and immune systems.1 Plus, not all modern humans inherited the Neanderthal version of these genes. Therefore, it is important that we discuss how these Neanderthal genes both positively and negatively affect our health.

Skin

FIGURE 1: Map showing human migrations superimposed over the Neanderthal geographic range and the skin genes each population inherited from Neanderthals. Created by KF with Biorender.

Our skin is the primary defense mechanism against DNA-damaging UVB radiation. We evolved dark skin rich in melanin pigment to block the intense UVB rays of Africa and later acquired lighter skin as we migrated into Europe and Asia. Evolution of lighter skin was to balance the reduced sunlight of these regions and our increased demand for vitamin D, which requires UVB for its synthesis.3 Our Neanderthal cousins also probably had light skin thanks to similar evolutionary pressures and their genes might contribute to how some of us look today.1,2

East Asians inherited two skin genes from Neanderthals: POU2F3 and HYAL2 (FIG. 1A). POU2F3 encodes a transcription factor found in the outer skin layer and controls skin cell growth and development.4 HYAL2 encodes an enzyme that breaks down the material between our skin cells and helps in their response to UVB.5 Compared to the modern human version, the Neanderthal version of these two genes is found in up to two-thirds of East Asians, a typical pattern seen with beneficial genes.4,5

Neanderthals passed on one main skin gene to Europeans, BNC2 (FIG. 1B), that encodes a skin cell transcription factor associated with lighter skin color, sunburn, and freckles.2,3 A large portion of Europeans (70%) have the Neanderthal version4 and, interestingly, BNC2 has some of the highest amount of Neanderthal DNA in our genome.6

Thanks to ancient migrations back into Africa, many sub-Saharan Africans inherited several Neanderthal genes including two, DDB1 and IL22RA1 (FIG. 1C), involved in skin function and UVB response.7 DDB1 encodes a protein involved in repairing UV-damaged DNA8, while IL22RA1 encodes the receptor for the immune signaling molecule interleukin-22 (IL-22) that is involved in UVB-induced skin inflammation.9

Immune System

The unfamiliar diseases of Europe and Asia probably posed a formidable challenge to modern humans leaving Africa. Neanderthals likely had significant immunity against these diseases built up over thousands of years. Our interbreeding with Neanderthals introduced genes that may have helped us overcome these diseases and succeed in populating this new environment. Fast forwarding to today, some of these Neanderthal immune genes cause negative effects due to our modern lifestyle and changes in disease exposure.1

Most of the immune genes we inherited from Neanderthals relate to the innate immune system, our first line of defense against pathogens like bacteria and viruses. Almost half the people living in Europe and Asia have a Neanderthal version of the TLR10-TLR1-TLR6 gene cluster, a set of genes encoding cell surface toll-like receptors (TLRs) that recognize parts of invading bacteria, fungi, and parasites. People with this version have higher levels of TLR10, TLR1, and TLR6 on their white blood cells, but the effect of their higher expression is not known. Additionally, this Neanderthal gene cluster is associated with increased risk of allergies and lower levels of antibodies against Helicobacter pylori, a bacterium that causes stomach inflammation and ulcers.10

FIGURE 2: Simplified interferon (IFN) signaling pathway. IFN binds an IFN receptor (A) and activates STAT (B), which translocates into the nucleus to help activate transcription of IFN-related genes such as OAS (C) that help degrade viral RNA.11-13 Created by KF with Biorender.

Neanderthal genes have also been found in the interferon (IFN) signaling pathway, an important system that protects us from viruses (FIG. 2). Many sub-Saharan Africans inherited the Neanderthal version of IFNLR1 (FIG. 2A), a receptor that recognizes type III IFNs responsible for defending against respiratory and gastrointestinal viruses.7,11 About half of Papuans, the indigenous people of New Guinea in the Pacific, inherited the Neanderthal version of STAT2 (FIG. 2B), a member of the IFN signaling pathway.12 A quarter to a half of Europeans and Asians inherited the OAS gene cluster (FIG. 2C) from Neanderthals, which triggers destruction of genetic material from invading viruses.13 One of these Neanderthal genes produces a shorter form of OAS2 associated with severe tick-borne encephalitis (TBE), a viral infection native to Europe and Central Asia that causes inflammation of the brain and its membranes.14

FIGURE 3: The six genes located in the COVID-19 risk segment of chromosome 3 and their immune-related functions: (1) LZTFL1, (2) FYCO1, (3) SLC6A20, (4) CXCR6, (5) CCR9, and (6) XCR1.16 Created by KF with Biorender.

Our immune response to the ongoing COVID-19 pandemic could be due to Neanderthals as well. We are all well-aware of COVID-19 and heard how the novel SARS-CoV-2 virus can lead to loss of smell, fever, and serious complications like respiratory failure. When the pandemic ravaged Europe earlier this year, doctors discovered a segment of chromosome 3 that is the strongest genetic risk factor for severe COVID-19 and almost doubles your chances of hospitalization.15 The segment contains six genes relating to ACE2 (the receptor SARS-CoV-2 uses to enter cells), lung inflammation, and viral infection (FIG. 3).16 Recent studies revealed the segment was inherited from Neanderthals. While less than 20% of Europeans have the segment, about half of South Asians carry it with the highest levels seen among Bangladeshis. Among countless other factors, such high levels of the segment in the population could explain why Bangladeshis in the UK have about two times higher risk of death from COVID-19.15

What Now?

Overall, Neanderthals impacted how our skin responds to UVB and immune system reacts to viruses, especially relevant to COVID-19. Their genes also influenced our lighter skin color and increased our risk of allergies. Nevertheless, most of these impacts are just genetic associations with only a few being investigated further to observe for their functional effects. This knowledge gap between relevant genes and their effects on health and disease is often the case as the human body is complex. Despite this uncertainty, we are still learning more and more every day about how the Neanderthal genetic legacy living on inside us may explain why we are the way we are.


References

1. Dolgova, O., & Lao, O. (2018). Evolutionary and medical consequences of archaic introgression into modern human genomes. Genes, 9(7). https://doi.org/10.3390/genes9070358.

2. Dannemann, M., & Kelso, J. (2017). The Contribution of Neanderthals to Phenotypic Variation in Modern Humans. American Journal of Human Genetics, 101(4), 578–589. https://doi.org/10.1016/j.ajhg.2017.09.010.

3. Jacobs, L. C., Wollstein, A., Lao, O., Hofman, A., Klaver, C. C., Uitterlinden, A. G., Nijsten, T., Kayser, M., & Liu, F. (2013). Comprehensive candidate gene study highlights UGT1A and BNC2 as new genes determining continuous skin color variation in Europeans. Human Genetics, 132(2), 147–158. https://doi.org/10.1007/s00439-012-1232-9.

4. Vernot, B., & Akey, J. M. (2014). Resurrecting surviving Neandertal lineages from modern human genomes. Science, 343(6174), 1017–1021. https://doi.org/10.5061/dryad.5tll0.www.sciencemag.org/content/343/6174/1014/suppl/DCl.

5. Ding, Q., Hu, Y., Xu, S., Wang, J., & Jin, L. (2014). Neanderthal introgression at chromosome 3p21.31 was under positive natural selection in east asians. Molecular Biology and Evolution, 31(3), 683–695. https://doi.org/10.1093/molbev/mst260.

6. Sankararaman, S., Mallick, S., Dannemann, M., Prüfer, 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. https://doi.org/10.1038/nature12961.

7. 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. https://doi.org/10.1016/j.cell.2020.01.012.

8. Iovine, B., Iannella, M. L., & Bevilacqua, M. A. (2011). Damage-specific DNA binding protein 1 (DDB1): A protein with a wide range of functions. International Journal of Biochemistry and Cell Biology, 43(12), 1664–1667. https://doi.org/10.1016/j.biocel.2011.09.001.

9. Kim, Y., Lee, J., Kim, J., Choi, C. W., Hwang, Y. Il, Kang, J. S., & Lee, W. J. (2017). The pathogenic role of interleukin-22 and its receptor during UVB-induced skin inflammation. PLoS ONE, 12(5), 1–15. https://doi.org/10.1371/journal.pone.0178567.

10. 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, 98(1), 22–33. https://doi.org/10.1016/j.ajhg.2015.11.015.

11. Kotenko, S. V., & Durbin, J. E. (2017). Contribution of type III interferons to antiviral immunity: Location, location, location. Journal of Biological Chemistry, 292(18), 7295–7303. https://doi.org/10.1074/jbc.R117.777102.

12. Mendez, F. L., Watkins, J. C., & Hammer, M. F. (2012). A haplotype at STAT2 introgressed from neanderthals and serves as a candidate of positive selection in Papua New Guinea. American Journal of Human Genetics, 91(2), 265–274. https://doi.org/10.1016/j.ajhg.2012.06.015.

13. Mendez, F. L., Watkins, J. C., & Hammer, M. F. (2013). Neandertal origin of genetic variation at the cluster of OAS immunity genes. Molecular Biology and Evolution, 30(4), 798–801. https://doi.org/10.1093/molbev/mst004.

14. Barkhash, A. V., Babenko, V. N., Kobzev, V. F., Romaschenko, A. G., & Voevoda, M. I. (2010). Polymorphism of 2′-5′-Oligoadenylate Synthetase (OAS) Genes, Associated with Predisposition to Severe Forms of Tick-Borne Encephalitis, in Human Populations of North Eurasia. Molecular Biology, 44(6), 875–882. https://doi.org/10.1134/S002689331006004X.

15. Zeberg, H., & Pääbo, S. (2020). The major genetic risk factor for severe COVID-19 is inherited from Neanderthals. Nature, 587(7835), 610–612. https://doi.org/10.1038/s41586-020-2818-3. 16. Tello, C. (n.d.) Can This Neanderthal Gene Predispose You to Severe COVID-19 Infections?. SelfDecode. https://selfdecode.com/blog/article/rs11385942-coronavirus-234/.

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