Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens

Yohann Nédélec, Joaquín Sanz, Golshid Baharian, Zachary A. Szpiech, Alain Pacis, Anne Dumaine, Jean Christophe Grenier, Andrew Freiman, Aaron J. Sams, Steven Hebert, Ariane Pagé Sabourin, Francesca Luca, Ran Blekhman, Ryan D. Hernandez, Roger Pique-Regi, Jenny Tung, Vania Yotova, Luis B. Barreiro

Research output: Contribution to journalArticlepeer-review

133 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)657-669.e21
JournalCell
Volume167
Issue number3
DOIs
StatePublished - Oct 20 2016

Bibliographical note

Funding Information:
We thank members of the L.B.B. lab for helpful discussions and comments on the manuscript, Danielle Malo for a gift of the Listeria and Salmonella strains used in this study, and L. Tailleux for advice on the infection experiments. This study was funded by grants to L.B.B. from the Canadian Institutes of Health Research (301538 and 232519), the Human Frontiers Science Program (CDA-00025/2012), and the Canada Research Chairs Program (950-228993). We thank Calcul Québec and Compute Canada for providing access to the supercomputer Briaree from the University of Montreal. Y.N. was supported by a fellowship from the Réseau de Médecine Génétique Appliquée (RMGA); J.S. by a fellowship from the Fonds de recherche du Québec-Nature et technologies (FRQNT), and G.B. and J.S. by a fellowship from the Fonds de recherche du Québec-Santé (FRQS).

Publisher Copyright:
© 2016 Elsevier Inc.

Keywords

  • Neanderthal introgression
  • bacterial infection
  • eQTL
  • immune responses
  • macrophages
  • natural selection
  • population variation

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