title: Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.
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.
authors: 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.
authors: Hélène
authors: H
authors: Quach
authors: 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.
authors: Maxime
authors: M
authors: Rotival
authors: 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.
authors: Julien
authors: J
authors: Pothlichet
authors: 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.
authors: Yong-Hwee Eddie
authors: YE
authors: Loh
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany.
authors: Michael
authors: M
authors: Dannemann
authors: 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.
authors: Nora
authors: N
authors: Zidane
authors: 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.
authors: Guillaume
authors: G
authors: Laval
authors: 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.
authors: Etienne
authors: E
authors: Patin
authors: 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.
authors: Christine
authors: C
authors: Harmant
authors: 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.
authors: Marie
authors: M
authors: Lopez
authors: 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.
authors: Matthieu
authors: M
authors: Deschamps
authors: Molecular Genetics of RNA Viruses Unit, Institut Pasteur, Paris 75015, France.
authors: Nadia
authors: N
authors: Naffakh
authors: Dendritic Cell Immunobiology Unit, Institut Pasteur, Paris 75015, France.
authors: Darragh
authors: D
authors: Duffy
authors: Center for Vaccinology, Ghent University and University Hospital, Ghent 9000, Belgium.
authors: Anja
authors: A
authors: Coen
authors: Center for Vaccinology, Ghent University and University Hospital, Ghent 9000, Belgium.
authors: Geert
authors: G
authors: Leroux-Roels
authors: Center for Vaccinology, Ghent University and University Hospital, Ghent 9000, Belgium.
authors: Frederic
authors: F
authors: Clément
authors: Centre National de Génotypage, CEA, Evry 91000, France.
authors: Anne
authors: A
authors: Boland
authors: Centre National de Génotypage, CEA, Evry 91000, France.
authors: Jean-François
authors: JF
authors: Deleuze
authors: Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig 04103, Germany.
authors: Janet
authors: J
authors: Kelso
authors: Dendritic Cell Immunobiology Unit, Institut Pasteur, Paris 75015, France; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080, USA.
authors: Matthew L
authors: ML
authors: Albert
authors: 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.
authors: Lluis
authors: L
authors: Quintana-Murci
mesh_terms: D000222:Adaptation, Physiological / Q000235:genetics* / Q000276:immunology*; D056704:Adaptive Immunity / Q000235:genetics; D000483:Alleles; D000818:Animals; D001424:Bacterial Infections / Q000235:genetics / Q000276:immunology; D001483:Base Sequence; D005075:Biological Evolution; D044383:Black People / Q000235:genetics; D005786:Gene Expression Regulation; D014644:Genetic Variation; D006801:Humans; D007107:Immune System; D059125:Neanderthals / Q000235:genetics* / Q000276:immunology*; D040641:Quantitative Trait Loci; D012313:RNA / Q000235:genetics; D012641:Selection, Genetic; D017423:Sequence Analysis, RNA; D051193:Toll-Like Receptors / Q000235:genetics; D014158:Transcription, Genetic; D014777:Virus Diseases / Q000235:genetics / Q000276:immunology; D044465:White People / Q000235:genetics
chemical_list: D051193:Toll-Like Receptors; D012313:RNA
keywords: Neandertal admixture; eQTL mapping; evolution; immune response; monocytes; natural selection; population genetics; transcriptional responses