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

Yohann Nédélec¹, Joaquín Sanz¹, Golshid Baharian¹, Zachary A Szpiech², Alain Pacis¹, Anne Dumaine³, Jean-Christophe Grenier³, Andrew Freiman⁴, Aaron J Sams⁵, Steven Hebert³, Ariane Pagé Sabourin³, Francesca Luca⁶, Ran Blekhman⁷, Ryan D Hernandez⁸, Roger Pique-Regi⁶, Jenny Tung⁹, Vania Yotova³, Luis B Barreiro¹⁰

Affiliations

¹ 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.
² Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
⁴ Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA.
⁵ Department of Biological Statistics & Computational Biology, Cornell University, Ithaca, NY 14850, USA.
⁶ 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.
⁷ Department of Genetics, Cell Biology, and Development and Department of Ecology, University of Minnesota, Twin Cities, MN 55108, USA.
⁸ 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.
⁹ Departments of Evolutionary Anthropology and Biology and Duke Population Research Institute, Duke University, Durham, NC 27708, USA.
¹⁰ 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.

PMID: 27768889
DOI: 10.1016/j.cell.2016.09.025

Free article

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

Yohann Nédélec et al. Cell. 2016.

Free article

. 2016 Oct 20;167(3):657-669.e21.

doi: 10.1016/j.cell.2016.09.025.

Authors

Affiliations

¹ 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.
² Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA.
³ Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T1C5, Canada.
⁴ Department of Obstetrics and Gynecology, Wayne State University, Detroit, MI 48202, USA.
⁵ Department of Biological Statistics & Computational Biology, Cornell University, Ithaca, NY 14850, USA.
⁶ 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.
⁷ Department of Genetics, Cell Biology, and Development and Department of Ecology, University of Minnesota, Twin Cities, MN 55108, USA.
⁸ 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.
⁹ Departments of Evolutionary Anthropology and Biology and Duke Population Research Institute, Duke University, Durham, NC 27708, USA.
¹⁰ 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.

PMID: 27768889
DOI: 10.1016/j.cell.2016.09.025

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.

Keywords: Neanderthal introgression; bacterial infection; eQTL; immune responses; macrophages; natural selection; population variation.

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

Affiliations

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

Authors

Affiliations

Abstract

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Molecular Biology Databases