As modern-day humans began to emerge from Africa, the divergent characteristics of archaic groups, which were precursors to other archaic human groups, namely Neanderthals and Denisovans, began to overlap spatially and temporally. Modern DNA sequencing has unearthed several regions of the modern human genome that show evidence of introgression from a small number of meetings between human and archaic ancestors (i.e, Neanderthals).
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What are neanderthals and what is their impact on the modern-day human genome?
Modern-day humans migrated from Africa over 60,000 years ago and interbred with Neanderthals and other archaic human groups such as Denisovans. Consequently, genomes of populations outside Africa show evidence of archaic ancestry. Increasingly a growing number of non-European cohorts with genotype and phenotype data have expanded the annotation of genetic variants to a larger set of ancestries, particularly non-European ancestries. Previously, studies have been restricted largely to European population-specific cohorts – with limits to annotations due to the large difference in Neandertal DNA between Europeans and Asians.
The Neanderthals are an archaic Hominin group. Modern non-African populations derive ~ 2% of their ancestry from this group, with a higher proportion of archaic common ancestry observed in some Oceanians (~5%). Moreover, <0.5% of the genomes of East Asians are derived from Denisovans.
How did Neanderthal DNA persist?
A phenomenon called archaic introgression is considered to be a relevant factor in modern medicine as alleles introduced previously along the evolutionary time frame continue to impact modern-day populations, despite the extinction of the archaic hominin lineages such as Neanderthals.
Some of this archaic DNA is thought to have evolved under negative selection, whereas at least 40% of the Neanderthal genome can be reconstructed from the Neanderthal ancestry from people today. Some of this has been suggested to have been targeted by positive selection.
Despite the presence of Neanderthal variants in present-day populations, variants are at low frequencies which necessitate large cohorts of genotype and phenotype data to study their effect. Using these cohorts comment studies have shown that Neanderthal DNA influences disease traits such as immunity and neurological traits. However, this DNA has been shown to affect non-disease phenotypes such as skin morphology, skin, and hair-related phenotypes, or behavioral phenotypes.
Other effects seen include impacts on sleeping patterns, mood, and addiction. These latter traits have been observed most prominently in European cohorts as these have been studied more prevalently.
How does Neanderthal DNA affect health and disease?
In an analysis of 40 disease genome-wide association study (GWAS) cohorts of ~212,000 individuals derived from the Biobank Japan Project, it was found that Neanderthal DNA could be associated with autoimmune diseases, type 2 diabetes, and prostate cancer.
Several of these disease associations were linked to a specific population of Neanderthal DNA (population-specific variants) which suggests the importance of sampling phenotype from diverse cohorts to determine the effects of Neanderthal DNA on modern-day phenotypes such as health.
In a study conducted in 2014 researchers examined the genetic variants in 846 and 176 people of non-African and sub-Saharan Africa origin, respectively, and a high-quality genome sequence of a 50,000-year-old Neanderthal. If a gene variant appeared in some non-Africans and the Neanderthal but was absent from the sub-Saharan African population, then a gene variant could be sourced to the Neanderthal.
The team found that some regions of modern non-African human genomes were rich in Neanderthal DNA; this DNA was posited to be helpful for human survival. Other regions were considered to be ‘deserts’ with less Neanderthal ancestry than the average observed. These deserts suggest that the introduction of some Neanderthal mutations represented a source of harm and so were later removed by natural selection.
These areas of reduced Neanderthal ancestry were found to cluster in two distinct regions of the genome: those most active in the testes and genes on the X chromosome. This patterning of inheritance has been linked in animals to a phenomenon termed hybrid infertility; the offspring of a male from one of the species and the female from another display limited or no fertility. These findings suggest a biological incompatibility between the two species i.e. an interbreeding challenge. Fast forward to present-day human populations which are temporarily separated by as many as 100,000 years (i.e., Europeans and West Africans), this incompatibility no longer exists, with no evidence of greater risk of male infertility.
Neanderthal DNA and COVID
In a GWAS study involving 1980 patients with COVID-19 with severe disease, defined as respiratory failure, European researchers demonstrated that a gene cluster located on chromosome 3 could be posited as a genetic susceptibility locus. Importantly, the Neanderthal DNA strand is found on chromosome 3.
Differences between Neanderthal and modern human alleles
In a study conducted in 2017, researchers used gene expression in modern humans to understand how gene flow from Neanderthals affects human gene expression. The group used genomes of >400 diseased individuals across 52 different body parts and looked for instances of heterozygous genes (one of which was inherited from a Neanderthal). Results demonstrated that differences in human and Neanderthal gene expression occurred in 25% of the areas tested, with differences having potential effects in traits ranging from height to the likelihood of contracting lupus.
Moreover, there were differences in how strongly human and Neanderthal genes were expressed in different body parts, with weak expression of Neanderthal genes occurring in the brain and testes of the people surveyed. This could be attributed to unequal evolution, as humans continued to evolve away from Neanderthal ancestry, these anatomical sites are likely to have evolved faster, resulting in greater divergence from the Neanderthal ancestor. This subsequently results in a decreased probability of expression by cells of those organs.
Long-lasting effects of Neanderthal DNA on human health
Neanderthal ancestry has been proven to persist in modern-day humans, with concomitant effects on health. By combining knowledge of evolutionary events how long the human lineages and the outputs of genomic studies, an explanatory framework for disease risk and health can be formed. These studies can reveal a set of genetic variants associated with increased risk of certain diseases and can be used as measures of selection to propose an evolutionary explanation for the relative difference in incidents of diseases between populations.
By looking at Neanderthal DNA, it can help understand not just why we get sick, but how. For example, the protective effect against prostate cancer is thought to have arisen with higher frequency in non-African populations due to selection on the nearby variants associated with skin pigmentation.
To discover traits associated with loci and understand the effect of a range of environmental exposures and evolutionary histories on the genetic make-up, diverse human populations will need to be studied.
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- Severe Covid-19 GWAS Group, Ellinghaus D, Degenhardt F, Bujanda L, et al. (2020) Genomewide Association Study of Severe Covid-19 with Respiratory Failure. N Engl J Med. doi: 10.1056/NEJMoa2020283.
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- Sankararaman S, Mallick S, Patterson N, et al. (2016) The Combined Landscape of Denisovan and Neanderthal Ancestry in Present-Day Humans. Curr Biol. doi: 10.1016/j.cub.2016.03.037.