The Population-Specific Impact of Neandertal Introgression on Human Disease

Abstract

Since the discovery of admixture between modern humans and Neandertals, multiple studies investigated the effect of Neandertal-derived DNA on human disease and non-disease phenotypes. These studies have linked Neandertal ancestry to skin and hair related phenotypes, immunity, neurological and behavioral traits. However, these inferences have so far been limited to cohorts with participants of European ancestry. Here, I analyze summary statistics from 40 disease GWAS cohorts of ∼212,000 individuals provided by the Biobank Japan Project for phenotypic effects of Neandertal DNA. I show that Neandertal DNA is associated with autoimmune diseases, prostate cancer and type 2 diabetes. Many of these disease associations are linked to population-specific Neandertal DNA, highlighting the importance of studying a wider range of ancestries to characterize the phenotypic legacy of Neandertals in people today.

The impact of evolutionary processes in shaping the genetics of complex traits in East Asia and Europe: a specific contribution from Denisovan and Neanderthal introgression

“…Neanderthal and Denisovan admixture have been previously associated with the diversity of innate immunity genes in modern humans 20,65,66 . Neanderthal introgression was previously linked to immunological phenotypes, rheumatoid arthritis 27 and chronic hepatitis B 67 , and Graves' disease 27 in EUR and EAS. Denisovan introgression was linked to several immune processes, e.g., antiviral immune response, HIV-1 DNA integration, and cytokine signaling 66 .…”

“…Among novel phenotypes related to introgressed variants, pancreatic, and breast cancers were associated with two Denisovan-introgressed variants (rs12615584 and rs12143332, respectively). Previously, Neanderthal introgressed haplotypes were associated with prostate cancer 27 . These convergent findings support that some molecular mechanisms linked to cancer susceptibility are shared between archaic humans and modern populations.…”

“…Introgression from Neanderthals and Denisovans, the only archaic humans sequenced to date, also contributes to the genetic pool of modern populations 18,19 and consequently to the human phenotypic spectrum 20,21 . Signatures of introgression in several traits, (e.g., hair and skin traits and immunity [21][22][23][24][25] , neoplasms and metabolic traits [25][26][27] , and male sterility 23,28 ) were identified from Neanderthals and Denisovans. The genomic segments of anatomically modern humans inherited from the admixture events with extinct human species are hypothesized to have contributed to the adaptation processes of worldwide populations that occurred during the colonization of landmasses [23][24][25]28,29 .…”

Quantitative Human Paleogenetics: What can Ancient DNA Tell us About Complex Trait Evolution?

“…Additionally, comparisons between the combined phenotypic effects of Neandertal variants and frequency-matched non-archaic variants have revealed that Neanderthal DNA is over-proportionally associated with neurological and behavioural phenotypes, as well as viral immune responses and type 2 diabetes ( Quach et al, 2016 ; Simonti et al, 2016 ; Dannemann and Kelso, 2017 ; Dannemann, 2021 ). These groups of phenotypes may be linked to environmental factors, such as ultraviolet light exposure, pathogen prevalence and climate, that substantially differed between Africa and Eurasia.…”

“…Furthermore, the majority of tested cohorts used for such studies are of European ancestry, which limits analyses to archaic variants present in these populations. This is particularly notable since Neandertal phenotype associations in European and Asian populations have been shown to contain population-specific archaic variants ( Dannemann, 2021 ). It has also been shown that negative selection, soon after admixture, has played an important role in removing some of the missing segments of archaic DNA ( Harris and Nielsen, 2016 ; Juric et al, 2016 ; Petr et al, 2019 ).…”