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Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations.

ABSTRACT: Neanderthal ancestry remains across modern Eurasian genomes and introgressed sequences influence diverse phenotypes. Here, we demonstrate that introgressed sequences reintroduced thousands of ancestral alleles that were lost in Eurasian populations before introgression. Our simulations and variant effect predictions argue that these reintroduced alleles (RAs) are more likely to be tolerated by modern humans than are introgressed Neanderthal-derived alleles (NDAs) due to their distinct evolutionary histories. Consistent with this, we show enrichment for RAs and depletion for NDAs on introgressed haplotypes with expression quantitative trait loci (eQTL) and phenotype associations. Analysis of available cross-population eQTLs and massively parallel reporter assay data show that RAs commonly influence gene expression independent of linked NDAs. We further validate these independent effects for one RA in vitro. Finally, we demonstrate that NDAs are depleted for regulatory activity compared to RAs, while RAs have activity levels similar to non-introgressed variants. In summary, our study reveals that Neanderthal introgression reintroduced thousands of lost ancestral variants with gene regulatory activity and that these RAs were more tolerated than NDAs. Thus, RAs and their distinct evolutionary histories must be considered when evaluating the effects of introgression.

SUBMITTER: Rinker DC

PROVIDER: S-EPMC7529911 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations.

Rinker David C DC Simonti Corinne N CN McArthur Evonne E Shaw Douglas D Hodges Emily E Capra John A JA

Nature ecology & evolution 20200727 10

Neanderthal ancestry remains across modern Eurasian genomes and introgressed sequences influence diverse phenotypes. Here, we demonstrate that introgressed sequences reintroduced thousands of ancestral alleles that were lost in Eurasian populations before introgression. Our simulations and variant effect predictions argue that these reintroduced alleles (RAs) are more likely to be tolerated by modern humans than are introgressed Neanderthal-derived alleles (NDAs) due to their distinct evolutiona ...[more]

PMID: 32719451

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Project description:BackgroundNeanderthal introgressed DNA has been linked to different normal and disease traits including immunity and metabolism-two important functions that are altered in liver cancer. However, there is limited understanding of the relationship between Neanderthal introgression and liver cancer risk. The aim of this study was to investigate the relationship between Neanderthal introgression and liver cancer risk.MethodsUsing germline and somatic DNA and tumor RNA from liver cancer patients from The Cancer Genome Atlas, along with ancestry-match germline DNA from unaffected individuals from the 1000 Genomes Resource, and allele specific expression data from normal liver tissue from The Genotype-Tissue Expression project we investigated whether Neanderthal introgression impacts cancer etiology. Using a previously generated set of Neanderthal alleles, we identified Neanderthal introgressed haplotypes. We then tested whether somatic mutations are enriched or depleted on Neanderthal introgressed haplotypes compared to modern haplotypes. We also computationally assessed whether somatic mutations have a functional effect or show evidence of regulating expression of Neanderthal haplotypes. Finally, we compared patterns of Neanderthal introgression in liver cancer patients and the general population.ResultsWe find Neanderthal introgressed haplotypes exhibit an excess of somatic mutations compared to modern haplotypes. Variant Effect Predictor analysis revealed that most of the somatic mutations on these Neanderthal introgressed haplotypes are not functional. We did observe expression differences of Neanderthal alleles between tumor and normal for four genes that also showed a pattern of enrichment of somatic mutations on Neanderthal haplotypes. However, gene expression was similar between liver cancer patients with modern ancestry and liver cancer patients with Neanderthal ancestry at these genes. Provocatively, when analyzing all genes, we find evidence of Neanderthal introgression regulating expression in tumor from liver cancer patients in two genes, ARK1C4 and OAS1. Finally, we find that most genes do not show a difference in the proportion of Neanderthal introgression between liver cancer patients and the general population.ConclusionOur results suggest that Neanderthal introgression provides opportunity for somatic mutations to accumulate, and that some Neanderthal introgression may impact liver cancer risk.

Project description:Ancient human migrations led to the settlement of population groups in varied environmental contexts worldwide. The extent to which adaptation to local environments has shaped human genetic diversity is a longstanding question in human evolution. Recent studies have suggested that introgression of archaic alleles in the genome of modern humans may have contributed to adaptation to environmental pressures such as pathogen exposure. Functional genomic studies have demonstrated that variation in gene expression across individuals and in response to environmental perturbations is a main mechanism underlying complex trait variation. We considered gene expression response to in vitro treatments as a molecular phenotype to identify genes and regulatory variants that may have played an important role in adaptations to local environments. We investigated if Neanderthal introgression in the human genome may contribute to the transcriptional response to environmental perturbations. To this end we used eQTLs for genes differentially expressed in a panel of 52 cellular environments, resulting from 5 cell types and 26 treatments, including hormones, vitamins, drugs, and environmental contaminants. We found that SNPs with introgressed Neanderthal alleles (N-SNPs) disrupt binding of transcription factors important for environmental responses, including ionizing radiation and hypoxia, and for glucose metabolism. We identified an enrichment for N-SNPs among eQTLs for genes differentially expressed in response to 8 treatments, including glucocorticoids, caffeine, and vitamin D. Using Massively Parallel Reporter Assays (MPRA) data, we validated the regulatory function of 21 introgressed Neanderthal variants in the human genome, corresponding to 8 eQTLs regulating 15 genes that respond to environmental perturbations. These findings expand the set of environments where archaic introgression may have contributed to adaptations to local environments in modern humans and provide experimental validation for the regulatory function of introgressed variants.

Dataset Information

Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations.

Publications

Neanderthal introgression reintroduced functional ancestral alleles lost in Eurasian populations.

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