title: Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens.
abstract: Individuals from different populations vary considerably in their susceptibility to immune-related diseases. To understand how genetic variation and natural selection contribute to these differences, we tested for the effects of African versus European ancestry on the transcriptional response of primary macrophages to live bacterial pathogens. A total of 9.3% of macrophage-expressed genes show ancestry-associated differences in the gene regulatory response to infection, and African ancestry specifically predicts a stronger inflammatory response and reduced intracellular bacterial growth. A large proportion of these differences are under genetic control: for 804 genes, more than 75% of ancestry effects on the immune response can be explained by a single cis- or trans-acting expression quantitative trait locus (eQTL). Finally, we show that genetic effects on the immune response are strongly enriched for recent, population-specific signatures of adaptation. Together, our results demonstrate how historical selective events continue to shape human phenotypic diversity today, including for traits that are key to controlling infection.
authors: Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Yohann
authors: Y
authors: Nédélec
authors: Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Joaquín
authors: J
authors: Sanz
authors: Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Golshid
authors: G
authors: Baharian
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Zachary A
authors: ZA
authors: Szpiech
authors: Department of Biochemistry, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Alain
authors: A
authors: Pacis
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Anne
authors: A
authors: Dumaine
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Jean-Christophe
authors: JC
authors: Grenier
authors: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA.
authors: Andrew
authors: A
authors: Freiman
authors: Department of Biological Statistics & Computational Biology, Cornell University, Ithaca, NY 14850, USA.
authors: Aaron J
authors: AJ
authors: Sams
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Steven
authors: S
authors: Hebert
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Ariane
authors: A
authors: Pagé Sabourin
authors: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48202, USA.
authors: Francesca
authors: F
authors: Luca
authors: Department of Genetics, Cell Biology, and Development and Department of Ecology, University of Minnesota, Twin Cities, MN 55108, USA.
authors: Ran
authors: R
authors: Blekhman
authors: Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA; Institute for Human Genetics and Quantitative Biosciences Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
authors: Ryan D
authors: RD
authors: Hernandez
authors: Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48202, USA.
authors: Roger
authors: R
authors: Pique-Regi
authors: Departments of Evolutionary Anthropology and Biology and Duke Population Research Institute, Duke University, Durham, NC 27708, USA.
authors: Jenny
authors: J
authors: Tung
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
authors: Vania
authors: V
authors: Yotova
authors: Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada; Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T1J4, Canada. Electronic address: luis.barreiro@umontreal.ca.
authors: Luis B
authors: LB
authors: Barreiro
keywords: Neanderthal introgression; bacterial infection; eQTL; immune responses; macrophages; natural selection; population variation