Neanderthal heritage in modern humans

The close encounters we had with our extinct relatives more than 50,000 years ago have left a mark on our genome, which continues to influence how we adapt to the environment, including exposure to certain pathogens.

Sexual encounters between modern humans and Neanderthals left their mark on our genome, through what is known as introgression (introduction of genetic material from one species to another through hybridization). In this case, we are talking about archaic introgression because it is an extinct archaic species

The Neanderthals were a sub-species of hominins similar to modern humans, which inhabited Europe and Asia approximately 400,000 to 300,000 years ago1, until about 40,000 to 28,000 years ago.

The particularities of this sub-species of hominins began to be known from the examination of the fossil record. In studying their morphology, anthropologists classified them as a species different to modern humans, taking into account characteristics of their skull, jaw and skeleton, which were different from those seen in modern humans1.

The “Out-of-Africa” model proposes that modern humans, when leaving Africa and populating other regions of the world, stumbled in their wake with other species of hominins, such as Neanderthals, with whom it is estimated that they may have coexisted  in Europe and Asia over a span of 30,000 years2.

Being such an anatomically similar subspecies to modern humans, it was not strange to assume that, as a result of their coexistence, genetic exchange would occur between them. However, until just over two decades ago it was not accurately known whether this had happened. In 1997, employing techniques developed for the study of ancient DNA, researchers obtained the first genetic sequence of a Neanderthal based on a small region of mitochondrial DNA, which, when compared to that of modern humans, revealed that they were indeed two different species, and that they had separated 500,000 years ago 3..  But later on, with advances in ancient DNA recovery and genetic sequencing techniques, it was possible to obtain the first genome draft of a Neanderthal4 and, subsequently, individual genomes sequences from several Neanderthals5–7.

The close encounters we had with our extinct relatives more than 50,000 years ago have left a mark on our genome, which continues to influence how we adapt to the environment, including exposure to certain pathogens

The study of these Neanderthal genomes has made it possible to know interesting aspects about their biology and population history5–8. But that’s not all: the history of Neanderthals has also allowed us to learn more about our history as modern humans.

Sexual encounters between modern humans and Neanderthals left their mark on our genome, through what is known as introgression (introduction of genetic material from one species to another through hybridization). In this case, we are talking about archaic introgression because it is an extinct archaic species2.9.

Through the comparison between the genomes of modern humans and Neanderthals, it has been discovered that a small part of our genome is of Neanderthal origin: approximately 1.5-2.1% in current non-African populations and 0-0.3% in current African populations 9,11.

It has been theorized that one of the reasons why this percentage is low is related to genetic incompatibility between the two species. In the genome of modern humans there are large regions that have no Neanderthal gene footprint. These regions have very important functions and variants of Neanderthal origin are likely to have been removed through negative selection10.

On the other hand, some of the genetic segments we acquired from the Neanderthals  (and which did remain in our genome) may have helped our ancestors adapt more quickly to the conditions of an environment different from that of the African continent; a phenomenon known as adaptive archaic introgresion9.

So far, some possibly beneficial variants we inherited from Neanderthals have been identified, which are related to: 1) the formation of keratin filaments, which may have  facilitated  the adaptation of skin and hair to new environmental conditions; 2) galactose metabolism; 3) linoleic acid metabolism10; 4) cellular response to ultraviolet-B rays12; and, finally,  5) proteins that interact with RNA viruses, which may have conferred resistance to viral pathogens against which Neanderthals were already “adapted”1 3.

However, there are also other genetic variants inherited from Neanderthals, which could be related to an increased risk of certain diseases, such as lupus, biliary cirrhosis, Crohn’s disease and type 2 diabetes, among others10.

It is important to note that the fact that a variant is assumed to be beneficial, neutral or deleterious, does not depend entirely on genetic variants, but largely on our interaction with the environment

By the middle of this year, in response to the SARS-CoV-2 virus pandemic, a study was conducted analyzing the genomes (8,582,968 SNPs) of 1610 Covid-19 patients with respiratory failure in in Italy and Spain and 2205 negative controls. The study revealed that chromosome 3 has a set of genes that may be associated with an increased risk of respiratory failure during SARS-CoV-2 infection1. Following this finding, researchers Hugo  Zeberg and Svante Pääbo compared the set of variants (haplotype) associated with an increased risk of respiratory failure against the haplotype found in archaic humans to identify whether it had been transferred to modern humans through  archaic introgression. These scientists concluded that the haplotype of increased risk of respiratory failure was transferred to modern humans due to their contact with Neanderthals. Sampling reveals that the frequency of this haplotype is 30% in populations in South Asia, 8% in Europe, 4% in American ‘mestizos’ and 0% in Africa15.

Taken together, these findings allow us to see that there is still much to know about the genetic variation we have inherited through the thousands of years of evolution of our species. It is important to note that the fact that a variant is assumed to be beneficial, neutral or deleterious, does not depend entirely on genetic variants, but largely on our interaction with the environment.

References:

  1. Green, R. E. et al. Analysis of one million base pairs of Neanderthal DNA. Nature 444, 330–336 (2006).
  2. Villanea, F. A. & Schraiber, J. G. Multiple episodes of interbreeding between Neanderthal and modern humans. Nat. Ecol. Evol. 3, 39–44 (2019).
  3. Krings, M., Stone, A., Schmitz, R. W., Krainitzki, H. & Stoneking, M. Neandertal DNA Sequences and the Origin of Modern Humans. Cell 90(1), 19–30 (1997).
  4. Green, R. E. et al. A Draft Sequence of the Neandertal Genome. Science 328, 710–722 (2010).
  5. Prüfer, K. et al. The complete genome sequence of a Neanderthal from the Altai Mountains. Nature 505, 43–49 (2014).
  6. Prüfer, K. et al. A high-coverage Neandertal genome from Vindija Cave in Croatia. Science 358, 655–658 (2017).
  7. Mafessoni, F. et al. A high-coverage Neandertal genome from Chagyrskaya Cave. Proc. Natl. Acad. Sci. 117, 15132–15136 (2020).
  8. Fabre, V., Condemi, S. & Degioanni, A. Genetic Evidence of Geographical Groups among Neanderthals. PLoS ONE 4, e5151 (2009).
  9. Racimo, F., Sankararaman, S., Nielsen, R. & Huerta-Sánchez, E. Evidence for archaic adaptive introgression in humans. Nat. Rev. Genet. 16, 359–371 (2015).
  10. Sankararaman, S. et al. The genomic landscape of Neanderthal ancestry in present-day humans. Nature 507, 354–357 (2014).
  11. 1.Chen, L., Wolf, A. B., Fu, W., Li, L. & Akey, J. M. Identifying and Interpreting Apparent Neanderthal Ancestry in African Individuals. Cell 180, 677-687.e16 (2020).
  12. Ding, Q., Hu, Y., Xu, S., Wang, J. & Jin, L. Neanderthal Introgression at Chromosome 3p21.31 Was Under Positive Natural Selection in East Asians. Mol. Biol. Evol. 31, 683–695 (2014).
  13. Enard, D. & Petrov, D. A. Evidence that RNA Viruses Drove Adaptive Introgression between Neanderthals and Modern Humans. Cell 175, 360-371.e13 (2018).
  14. Ellinghaus, D. et al. Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N. Engl. J. Med. NEJMoa2020283 (2020) doi:10.1056/NEJMoa2020283.
  15. Zeberg, H. & Pääbo, S. The major genetic risk factor for severe COVID-19 is inherited from Neandertals. http://biorxiv.org/lookup/doi/10.1101/2020.07.03.186296 (2020) doi:10.1101/2020.07.03.186296.
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