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Cell. 2016 Oct 20;167(3):643-656.e17. doi: 10.1016/j.cell.2016.09.024.

Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.

Author information

1
Human Evolutionary Genetics Unit, Institut Pasteur, Paris 75015, France; CNRS, URA3012, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France.
2
Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany.
3
Human Evolutionary Genetics Unit, Institut Pasteur, Paris 75015, France; CNRS, URA3012, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France; Université Pierre et Marie Curie, Cellule Pasteur, Institut Pasteur, Paris 75015, France.
4
Molecular Genetics of RNA Viruses Unit, Institut Pasteur, Paris 75015, France.
5
Dendritic Cell Immunobiology Unit, Institut Pasteur, Paris 75015, France.
6
Center for Vaccinology, Ghent University and University Hospital, Ghent 9000, Belgium.
7
Centre National de Génotypage, CEA, Evry 91000, France.
8
Dendritic Cell Immunobiology Unit, Institut Pasteur, Paris 75015, France; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
9
Human Evolutionary Genetics Unit, Institut Pasteur, Paris 75015, France; CNRS, URA3012, Paris 75015, France; Center of Bioinformatics, Biostatistics and Integrative Biology, Institut Pasteur, Paris 75015, France. Electronic address: quintana@pasteur.fr.

Abstract

Humans differ in the outcome that follows exposure to life-threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. Here, we characterized, using RNA sequencing, the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli-ligands activating Toll-like receptor pathways (TLR1/2, TLR4, and TLR7/8) and influenza virus-and mapped expression quantitative trait loci (eQTLs). We identify numerous cis-eQTLs that contribute to the marked differences in immune responses detected within and between populations and a strong trans-eQTL hotspot at TLR1 that decreases expression of pro-inflammatory genes in Europeans only. We find that immune-responsive regulatory variants are enriched in population-specific signals of natural selection and show that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges. Together, our study uncovers evolutionarily important determinants of differences in host immune responsiveness between human populations.

KEYWORDS:

Neandertal admixture; eQTL mapping; evolution; immune response; monocytes; natural selection; population genetics; transcriptional responses

PMID:
27768888
PMCID:
PMC5075285
DOI:
10.1016/j.cell.2016.09.024
[Indexed for MEDLINE]
Free PMC Article
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