While multiple instances of admixture between archaic and modern humans have now been documented, the biological consequences of these admixture events on modern humans are not fully understood. We analyzed about 80,000 introgressed Neanderthal alleles across 107 distinct phenotypes measured in up to 495,000 people of European ancestry in the UK Biobank dataset, taking advantage of more than 6,000 single nucleotide polymorphisms (SNPs) that we specifically added to the UK Biobank array prior to genotyping to study the impact of these Neanderthal alleles. We discovered 1158 independent associations of introgressed Neanderthal alleles with 75 phenotypes. We developed novel and rigorous methodology to assess whether Neanderthal ancestry is over- or underrepresented in modulating phenotypes compared to random genetic variation, appropriately controlling for the frequencies and allelic age distribution of such variants. We find that the contribution of Neanderthal alleles to phenotypic variation is significantly depleted in the great majority of the phenotypes examined consistent with the observation that in general, natural selection has acted to remove Neanderthal mutations since introgression. We find that Neanderthal alleles were significantly overrepresented in their contribution to a handful of traits including male balding, chronotype, wheat intake, lung capacity, and eye-related phenotypes, but we do not replicate previous associations of Neanderthal alleles to some complex traits such as depression. Notably, we document directional selection in favor of Neanderthal-derived mutations that affect a number of traits including propensity for baldness, later age of female puberty, high lung capacity, number of children, alertness in the morning, and neuroticism. We also detect evidence of natural selection against Neanderthal alleles that today have the effect of increasing educational attainment, which may seem paradoxical but perhaps reflects the fact such alleles also have evidence of reducing the total number of children a person has; thus, our data may be suggesting that Neanderthals had a life history strategy that involved more investment in each child than was the case for early modern humans. All these traits have been under selection during the approximately fifty thousand years of non-African history since introgression from Neanderthals and the start of the Upper Paleolithic-when evidence of symbolic behavior and innovation becomes widespread in the archaeological record-highlighting aspects of modern human biology that have been under selection compared to our ancestors whose genomes may not yet have had adequate time to adapt to behavioral modernity.
A prehistoric branch of our human evolutionary tree, Neanderthals began to disappear around 40,000 years ago as modern humans showed up on the scene. Genomic analyses have revealed that all present-day non-African populations inherit 1-4% of their genetic ancestry from a population related to the Neanderthals. Given the high divergence of Neanderthals and modern humans at the time of admixture, we hypothesize that admixture with Neanderthals may have had a major impact on human biology. Previous analyses of the locations of Neanderthal segments within the genomes of non-African individuals indicate that some of the Neanderthal variants were adaptively beneficial while the bulk of Neanderthal variants were deleterious in the modern human genetic background. While multiple instances of admixture between archaic and modern humans have now been documented, another area of interest is regions of the genome in which derived mutations are at high-frequency in modern humans, and ancestral in Neanderthals. These Fixed Derived alleles (FDs) are mutations that rise to high frequency in modern humans since the split from archaic humans, and may give us clues to the biology that cause modern humans to differ from our closest relatives. We analyzed about 120 FDs across 107 distinct phenotypes measured in up to 495,000 people of European ancestry in the UK Biobank dataset, taking advantage of more than 745 single nucleotide polymorphisms (SNPs) that we specifically added to the UK Biobank array prior to genotyping to study the impact of these fixed derived alleles. We discovered 102 independent associations of fixed derived alleles with 37 phenotypes such as standing height, bone heel density, and thyroid related diseases. We developed novel methodology to assess whether fixed derived alleles are over- or underrepresented in modulating phenotypes compared to random genetic variation, appropriately controlling for the frequencies and linkage-disequilibrium patterns of such variants. We find that the contribution of Fixed derived alleles to phenotypic variation is neutral in the great majority of the phenotypes, however it is significantly depleted in traits including whole body fat mass, trunk fat mass, heel bone mineral density, and heel quantitative ultrasound index. In addition, we find that FDs have a consistent directional effect on townsend deprivation index at recruitment.