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Impacts of Neanderthal-Introgressed Sequences on the Landscape of Human Gene Expression
Open accessAbstract
Regulatory variation influencing gene expression is a key contributor to phenotypic diversity, both within and between species. Unfortunately, RNA degrades too rapidly to be recovered from fossil remains, limiting functional genomic insights about our extinct hominin relatives. Many Neanderthal sequences survive in modern humans due to ancient hybridization, providing an opportunity to assess their contributions to transcriptional variation and to test hypotheses about regulatory evolution. We developed a flexible Bayesian statistical approach to quantify allele-specific expression (ASE) in complex RNA-seq datasets. We identified widespread expression differences between Neanderthal and modern human alleles, indicating pervasive cis-regulatory impacts of introgression. Brain regions and testes exhibited significant downregulation of Neanderthal alleles relative to other tissues, consistent with natural selection influencing the tissue-specific regulatory landscape. Our study demonstrates that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have measurable impacts on gene expression that contribute to variation in modern human phenotypes.
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“Second, Neanderthal ancestry is depleted in regions of the genome with annotated molecular functions (e.g., genes and gene regulatory elements), and this depletion is strongest in annotated brain and testis regulatory regions27–29.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [28]
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“The depletion in cognitive traits suggests that the previously observed strong depletion for Neanderthal alleles in regulatory regions active in the brain may be due to effects on brain-related complex traits5,28,29.”
From Quantifying the contribution of Neanderthal introgression to the heritability of complex traits (2021) · cites this paper as [28]
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“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 [10]
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“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 [10]
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Metadata
- Authors
- McCoy, R. C., Wakefield, J., & Akey, J. M.
- Affiliations
- University of Washington (US)
- Corresponding author
- Akey, Joshua M.
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 168
- Issue
- 5
- Pages
- 916-927.e12
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC6219754
- OpenAlex
- W2594204182
- Cited by
- 200
- References
- 92
- Citations by year
- 2026: 17 · 2025: 10 · 2024: 22 · 2023: 23 · 2022: 15 · 2021: 27 · 2020: 37 · 2019: 26 · 2018: 16 · 2017: 7
- FWCI
- 94.65
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH/NHGRI (5T32HG000035-22)
- NIH (R01GM110068)
- Common Fund of the Office of the Director of the NIH
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- NCI\SAIC-Frederick
- Disease Research Interchange (10XS170)
- Roswell Park Cancer Institute (10XS171)
- Science Care (X10S172, HHSN268201000029C)
- The Broad Institute
- Van Andel Institute (10ST1035)
- SAIC-F (HHSN261200800001E)
- University of Miami (DA006227, DA033684, N01MH000028, MH090941, MH101814, MH090951, MH090937, MH101820, MH101825, MH090936, MH101819, MH090948, MH101782, MH101810, MH101822)
- 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 › Molecular Biology › Genomics and Phylogenetic Studies
- Keywords
- Neanderthal introgression, allele-specific expression, cis-regulatory variation, human gene expression, ancient hybridization, regulatory evolution, natural selection
- MeSH terms
- Animals, Brain, Gene Expression Regulation, Humans, Male, Organ Specificity, Testis, Gene Expression, Evolution, Molecular, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Neanderthals
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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