Genetic Ancestry and Natural Selection Drive Population Differences in Immune Responses to Pathogens
Yohann Nédélec11, Joaquín Sanz11, Golshid Baharian11, 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. Barreiro12, Email the author
Published: October 20, 2016 Accepted: September 15, 2016 Received in revised form: July 28, 2016
Received: April 13, 2016
• Thousands of genes show population differences in transcriptional response to infection
• African ancestry is associated with a stronger inflammatory response
• Population differences in immune response are often genetically controlled
• Natural selection contributed to ancestry-associated differences in gene regulation
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: natural selection, immune responses, population variation, macrophages, Neanderthal introgression, eQTL, bacterial infection
Received: April 13, 2016; Received in revised form: July 28, 2016; Accepted: September 15, 2016; Published: October 20, 2016
© 2016 Elsevier Inc. Published by Elsevier Inc. All rights reserved.
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