Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation
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Abstract
Archaic admixture is increasingly recognized as an important source of diversity in modern humans, and Neanderthal haplotypes cover 1%-3% of the genome of present-day Eurasians. Recent work has shown that archaic introgression has contributed to human phenotypic diversity, mostly through the regulation of gene expression. Yet the mechanisms through which archaic variants alter gene expression and the forces driving the introgression landscape at regulatory regions remain elusive. Here, we explored the impact of archaic introgression on transcriptional and post-transcriptional regulation. We focused on promoters and enhancers across 127 different tissues as well as on microRNA (miRNA)-mediated regulation. Although miRNAs themselves harbor few archaic variants, we found that some of these variants may have a strong impact on miRNA-mediated gene regulation. Enhancers were by far the regulatory elements most affected by archaic introgression: up to one-third of the tissues we tested presented significant enrichments. Specifically, we found strong enrichments of archaic variants in adipose-related tissues and primary T cells, even after accounting for various genomic and evolutionary confounders such as recombination rate and background selection. Interestingly, we identified signatures of adaptive introgression at enhancers of some key regulators of adipogenesis, raising the interesting hypothesis of a possible adaptation of early Eurasians to colder climates. Collectively, this study sheds new light on the mechanisms through which archaic admixture has impacted gene regulation in Eurasians and, more generally, increases our understanding of the contribution of Neanderthals to the regulation of acquired immunity and adipose homeostasis in modern humans.
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These findings fully recapitulate previously reported observations in Europeans.
“Interestingly, these findings fully recapitulate previously reported observations in Europeans [11, 12].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
Archaic alleles are thought to drive phenotypic differences by altering gene pre- and post-transcriptional regulatory processes.
“Here, archaic alleles are thought to drive phenotypic differences by altering gene pre- and post-transcriptional regulatory processes [11].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
Enhancers are among the top targeted elements of archaic hominin introgression.
“Enhancers, in particular, are amongst the top targeted elements of archaic hominin introgression [10, 11].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
Studies conducted primarily on Neanderthal introgressed DNA have suggested a non-negligible contribution to gene expression variation in modern humans, with repeated examples of Neanderthal archaic variants falling within regulatory elements or the seed region of mature micro-RNAs predicted to affect transcriptional and post-transcriptional regulatory processes.
“Indeed, studies conducted primarily on Neanderthal introgressed DNA have suggested a non-negligible contribution to gene expression variation in modern humans [10, 11, 22], with repeated examples of Neanderthal archaic variants falling within regulatory elements or the seed region of mature micro-RNAs predicted to affect transcriptional and post-transcriptional regulatory processes [11, 62].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
Admixture with Neanderthals might have similar consequences even across distantly related human populations.
“In addition, admixture with Neanderthals might have similar consequences even across distantly related human populations, with Neanderthal aSNPs strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans, replicating previously reported observations [11, 12].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
Neanderthal aSNPs are strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans.
“with Neanderthal aSNPs strongly enriched within elements active within blood & immune T cells and mesenchymal cells both in Papuans and Europeans, replicating previously reported observations [11, 12].”
From Denisovan introgression has shaped the immune system of present-day Papuans (2022) · cites this paper as [11]
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Selection against archaic hominin genetic variation in regulatory regionsPreprint
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Denisovan introgression has shaped the immune system of present-day PapuansPreprint
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A regulatory variant impacting TBX1 expression contributes to basicranial morphology in Homo sapiens
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Underrepresented Populations at the Archaic Introgression Frontier
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Book Review: Neanderthal Language: Demystifying the Linguistic Powers of Our Extinct Cousins
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We shall meet again - Genomics of historical admixture in the seaPreprint
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Book review: Neanderthal Language: Demystifying the Linguistic Powers of Our Extinct CousinsPreprint
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- Authors
- Silvert, M., Quintana-Murci, L., & Rotival, M.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- Corresponding author
- Rotival, Maxime
- ORCID
- Rotival, Maxime
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2019-06
- Volume
- 104
- Issue
- 6
- Pages
- 1241-1250
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC6557732
- OpenAlex
- W2911559590
- Cited by
- 58
- References
- 61
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 11 · 2023: 11 · 2022: 10 · 2021: 9 · 2020: 9 · 2019: 2
- FWCI
- 34.36
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by-nc-sa)
- Funders
- Agence Nationale pour le Développement de la Recherche en Santé
- Topics
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- Neanderthal introgression, archaic admixture, enhancers, promoter, microRNA regulation, post-transcriptional regulation, transcriptional regulation, adaptive introgression, adipogenesis, adipose tissue, T cells, adaptive immunity, cold adaptation, Eurasian populations
- MeSH terms
- Adaptation, Physiological, Adipose Tissue, Animals, Humans, Recombination, Genetic, RNA Processing, Post-Transcriptional, Selection, Genetic, T-Lymphocytes, Transcription, Genetic, Genome, Human, Gene Expression Regulation, Developmental, Evolution, Molecular, Polymorphism, Single Nucleotide, Genomics, MicroRNAs, Adipogenesis, Neanderthals
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