Adaptively introgressed Neandertal haplotype at the OAS locus functionally impacts innate immune responses in humans
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Abstract
BACKGROUND: The 2'-5' oligoadenylate synthetase (OAS) locus encodes for three OAS enzymes (OAS1-3) involved in innate immune response. This region harbors high amounts of Neandertal ancestry in non-African populations; yet, strong evidence of positive selection in the OAS region is still lacking. RESULTS: Here we used a broad array of selection tests in concert with neutral coalescent simulations to demonstrate a signal of adaptive introgression at the OAS locus. Furthermore, we characterized the functional consequences of the Neandertal haplotype in the transcriptional regulation of OAS genes at baseline and infected conditions. We found that cells from people with the Neandertal-like haplotype express lower levels of OAS3 upon infection, as well as distinct isoforms of OAS1 and OAS2. CONCLUSIONS: We present evidence that a Neandertal haplotype at the OAS locus was subjected to positive selection in the human population. This haplotype is significantly associated with functional consequences at the level of transcriptional regulation of innate immune responses. Notably, we suggest that the Neandertal-introgressed haplotype likely reintroduced an ancestral splice variant of OAS1 encoding a more active protein, suggesting that adaptive introgression occurred as a means to resurrect adaptive variation that had been lost outside Africa.
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Selected variants can exert their effect by modifying gene expression or by changing the amino acid sequence.
“Selected variants can exert their effect by modifying gene expression or by changing the amino acid sequence [8–12].”
From Functional implications of Neandertal introgression in modern humans (2017) · cites this paper as [12]
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- Authors
- Sams, A. J., Dumaine, A., Nédélec, Y., Yotova, V., Alfieri, C., Tanner, J. E., Messer, P. W., & Barreiro, L. B.
- Affiliations
- Cornell University (US)
- Centre Hospitalier Universitaire Sainte-Justine (CA)
- Venue
- Genome Biology
- Published
- 2016-11-29
- Volume
- 17
- Issue
- 1
- Pages
- 246-246
- ISSN
- 1465-6906 (ISSN-L)
- 1474-760X
- PMC
- PMC5129249
- OpenAlex
- W2952264760
- Cited by
- 140
- References
- 61
- Citations by year
- 2026: 15 · 2025: 10 · 2024: 13 · 2023: 15 · 2022: 19 · 2021: 19 · 2020: 14 · 2019: 13 · 2018: 11 · 2017: 10 · 2016: 1
- FWCI
- 45.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Genome biology (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Institute of Genetics (301538, 232519)
- Human Frontier Science Program (CDA-00025/2012)
- Canada Excellence Research Chairs, Government of Canada (950-228993)
- Topics
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- 2',5'-oligoadenylate synthetase, OAS1, OAS2, OAS3, positive selection, innate immune response, transcriptional regulation, splice variants, non-African populations, adaptive introgression
- MeSH terms
- Animals, Haplotypes, Humans, Immunity, Innate, Infections, Selection, Genetic, 2',5'-Oligoadenylate Synthetase, Genome, Human, Gene Expression Regulation, Enzymologic, Evolution, Molecular, Protein Isoforms, Polymorphism, Single Nucleotide, Neanderthals
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