Cited by 257Evolution and Genetic DynamicsGenetic Associations and EpidemiologyForensic and Genetic Research

Genomic Signatures of Selective Pressures and Introgression from Archaic Hominins at Human Innate Immunity Genes

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Deschamps, Matthieu, Laval, Guillaume, Fagny, Maud, Itan, Yuval, Abel, Laurent, Casanova, Jean-Laurent, Patin, Etienne, Quintana-Murci, Lluis·2016·The American Journal of Human Genetics

Abstract

Human genes governing innate immunity provide a valuable tool for the study of the selective pressure imposed by microorganisms on host genomes. A comprehensive, genome-wide study of how selective constraints and adaptations have driven the evolution of innate immunity genes is missing. Using full-genome sequence variation from the 1000 Genomes Project, we first show that innate immunity genes have globally evolved under stronger purifying selection than the remainder of protein-coding genes. We identify a gene set under the strongest selective constraints, mutations in which are likely to predispose individuals to life-threatening disease, as illustrated by STAT1 and TRAF3. We then evaluate the occurrence of local adaptation and detect 57 high-scoring signals of positive selection at innate immunity genes, variation in which has been associated with susceptibility to common infectious or autoimmune diseases. Furthermore, we show that most adaptations targeting coding variation have occurred in the last 6,000-13,000 years, the period at which populations shifted from hunting and gathering to farming. Finally, we show that innate immunity genes present higher Neandertal introgression than the remainder of the coding genome. Notably, among the genes presenting the highest Neandertal ancestry, we find the TLR6-TLR1-TLR10 cluster, which also contains functional adaptive variation in Europeans. This study identifies highly constrained genes that fulfill essential, non-redundant functions in host survival and reveals others that are more permissive to change-containing variation acquired from archaic hominins or adaptive variants in specific populations-improving our understanding of the relative biological importance of innate immunity pathways in natural conditions.

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Crossref · 10.1016/j.ajhg.2015.11.014

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  • Neanderthal variants within immune genes and immune-related CREs have been associated with differential responses to viral infections among present-day Europeans.

    “Neanderthal variants within immune genes and immune-related cis-regulatory elements (CREs) have been associated with differential responses to viral infections among present-day Europeans [21, 22].”
  • Some archaic alleles have been shown to confer an adaptive advantage for modern humans.

    “Some archaic alleles have been shown to confer an adaptive advantage for modern humans”

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Authors
Deschamps, M., Laval, G., Fagny, M., Itan, Y., Abel, L., Casanova, J.-L., Patin, E., & Quintana-Murci, L.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Rockefeller University (US)
  • Inserm (FR)
  • Hôpital Necker-Enfants Malades (FR)
Venue
The American Journal of Human Genetics
Publisher
Elsevier BV
Published
2016-01
Volume
98
Issue
1
Pages
5-21
ISSN
0002-9297 (ISSN-L)
OpenAlex
W2225153589
Cited by
257
References
100
Citations by year
2026: 17 · 2025: 15 · 2024: 24 · 2023: 18 · 2022: 28 · 2021: 24 · 2020: 23 · 2019: 27 · 2018: 26 · 2017: 33 · 2016: 22
FWCI
29.05
Type
journal article
Language
en
Open access
Locations
  • The American Journal of Human Genetics (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • HAL (submittedVersion)
Funders
  • Institut national de la recherche scientifique
  • Agence Nationale de la Recherche (ANR-14-CE14-0007, ANR-14-CE14-0008, ANR-12-BSV7-0012, ANR-10-LABX-0062)
  • Centre National de la Recherche Scientifique
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
  • 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
innate immunity genes, purifying selection, positive selection, archaic humans, adaptive evolution, STAT1, TRAF3, local adaptation, disease susceptibility, transition to agriculture, host-pathogen coevolution
MeSH terms
Adaptation, Physiological, Animals, Humans, Immunity, Innate, Selection, Genetic, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Neanderthals

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