Ancestral genomic contributions to complex traits in contemporary Europeans

Marnetto, Davide; Pankratov, Vasili; Mondal, Mayukh; Montinaro, Francesco; Pärna, Katri; Vallini, Leonardo; Molinaro, Ludovica; Saag, Lehti; Loog, Liisa; Montagnese, Sara; Costa, Rodolfo; Metspalu, Mait; Eriksson, Anders; Pagani, Luca

doi:10.1016/j.cub.2022.01.046

Cited by 9 publications

(14 citation statements)

References 44 publications

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“…We used CLUES ( Stern et al 2019 ) to estimate changes in the allele frequency of the aSNPs over the last 500 generations and to test whether these changes might have happened under natural selection. CLUES was run as in Marnetto et al . (2022) .…”

Section: Methodsmentioning

confidence: 99%

Long-range regulatory effects of Neandertal DNA in modern humans

et al. 2022

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The admixture between modern humans and Neandertals has resulted in ∼2% of the genomes of present-day non-Africans being composed of Neandertal DNA. Introgressed Neandertal DNA has been demonstrated to significantly affect the transcriptomic landscape in people today and via this molecular mechanism influence phenotype variation as well. However, little is known about how much of that regulatory impact is mediated through long-range regulatory effects that have been shown to explain ∼20% of expression variation. Here we identified 60 transcription factors (TFs) with their top cis-eQTL SNP in GTEx being of Neandertal ancestry and predicted long-range Neandertal DNA-induced regulatory effects by screening for the predicted target genes of those TFs. We show that the TFs form a significantly connected protein-protein interaction network. Among them are JUN and PRDM5, two brain-expressed TFs that have their predicted target genes enriched in regions devoid of Neandertal DNA. Archaic cis-eQTLs for the 60 TFs include multiple candidates for local adaptation, some of which show significant allele frequency increases over the last ∼10,000 years. A large proportion of the cis-eQTL-associated archaic SNPs have additional associations with various immune traits, schizophrenia, blood cell type composition and anthropometric measures. Finally, we demonstrate that our results are consistent with those of Neandertal-DNA-associated empirical trans-eQTLs. Our results suggest that Neandertal DNA significantly influences regulatory networks, that its regulatory reach goes beyond the 40% of genomic sequence that it still covers in present-day non-Africans and that via the investigated mechanism Neandertal DNA influences the phenotypic variation in people today.

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Section: Methodsmentioning

confidence: 99%

Long-range regulatory effects of Neandertal DNA in modern humans

et al. 2022

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“…Until recently, the large sample sizes required to carry out these studies with high statistical precision have not been available. The earliest efforts to study natural selection using ancient DNA data have therefore been limited [4][5][6] , often focusing on candidate loci or single traits [7][8][9][10] . More recent approaches have looked at selection genome-wide but focus on obtaining evidence of selection across the full range of time from the Paleolithic leading to modern Europeans [11][12][13] .…”

Section: Mainmentioning

confidence: 99%

1,000 ancient genomes uncover 10,000 years of natural selection in Europe

Smith

Akbari

et al. 2022

Preprint

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Ancient DNA has revolutionized our understanding of human population history. However, its potential to examine how rapid cultural evolution to new lifestyles may have driven biological adaptation has not been met, largely due to limited sample sizes. We assembled genome-wide data from 1,291 individuals from Europe over 10,000 years, providing a dataset that is large enough to resolve the timing of selection into the Neolithic, Bronze Age, and Historical periods. We identified 25 genetic loci with rapid changes in frequency during these periods, a majority of which were previously undetected. Signals specific to the Neolithic transition are associated with body weight, diet, and lipid metabolism-related phenotypes. They also include immune phenotypes, most notably a locus that confers immunity to Salmonella infection at a time when ancient Salmonella genomes have been shown to adapt to human hosts, thus providing a possible example of human-pathogen co-evolution. In the Bronze Age, selection signals are enriched near genes involved in pigmentation and immune-related traits, including at a key human protein interactor of SARS-CoV-2. Only in the Historical period do the selection candidates we detect largely mirror previously-reported signals, highlighting how the statistical power of previous studies was limited to the last few millennia. The Historical period also has multiple signals associated with vitamin D binding, providing evidence that lactase persistence may have been part of an oligogenic adaptation for efficient calcium uptake and challenging the theory that its adaptive value lies only in facilitating caloric supplementation during times of scarcity. Finally, we detect selection on complex traits in all three periods, including selection favoring variants that reduce body weight in the Neolithic. In the Historical period, we detect selection favoring variants that increase risk for cardiovascular disease plausibly reflecting selection for a more active inflammatory response that would have been adaptive in the face of increased infectious disease exposure. Our results provide an evolutionary rationale for the high prevalence of these deadly diseases in modern societies today and highlight the unique power of ancient DNA in elucidating biological change that accompanied the profound cultural transformations of recent human history.

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“…WHG; Anatolia_N; Yamnaya) that contribute to the genetic makeup of that population. This metric was introduced in our previous work 39 for the analysis of complex traits in EstBB and is ultimately a covariance between allele dosage in a contemporary individual and a given ancestral population, with respect to the contemporary and ancient average frequencies. We regress each complex trait t in the present-day dataset on the covA for each ancestry p so that for each individual i : where the slope β covA(p) quantifies the association between each ancestry p with the trait t .…”

Section: Resultsmentioning

confidence: 99%

Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks

Pankratov,

Mezzavilla,

Aneli

et al. 2023

Preprint

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The genetic structure in Europe was mostly shaped by admixture between the Western Hunter-Gatherer, Anatolian Neolithic and Steppe’s Yamnaya ancestral components. Such structure is regarded as a confounder in GWAS and follow-up studies, and gold-standard methods exist to correct for it. However, it is still poorly understood to which extent these ancestral components contribute to complex trait variation in present-day Europe.In this work we harness the UK Biobank to address this question. By extensive demographic simulations and incorporating previous results obtained using the Estonian Biobank, we carefully evaluate the significance and scope of our findings.Heart rate, platelet count, monocyte percentage and many other traits show stratification similar to height and pigmentation traits, likely targets of selection and divergence across ancestral groups. The consistency of our results across biobanks indicates that these ancestry-specific genetic predispositions act as a source of variability and as potential confounders in Europe as a whole.

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Ancestral genomic contributions to complex traits in contemporary Europeans

Cited by 9 publications

References 44 publications

Long-range regulatory effects of Neandertal DNA in modern humans

Long-range regulatory effects of Neandertal DNA in modern humans

1,000 ancient genomes uncover 10,000 years of natural selection in Europe

Ancestral genetic components are consistently associated with the complex trait landscape in European biobanks

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