Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations
Hélène Quach11, Maxime Rotival11, Julien Pothlichet11,12, Yong-Hwee Eddie Loh11, Michael Dannemann, Nora Zidane, Guillaume Laval, Etienne Patin, Christine Harmant, Marie Lopez, Matthieu Deschamps, Nadia Naffakh, Darragh Duffy, Anja Coen, Geert Leroux-Roels, Frederic Clément, Anne Boland, Jean-François Deleuze, Janet Kelso, Matthew L. Albert, Lluis Quintana-Murci13,correspondencePress enter key for correspondence informationemailPress enter key to Email the author
11Co-first author
12Present address: DIACCURATE, Institut Pasteur, PARIS 75015, France
13Lead Contact
Open Access
Open access funded by European Research Council
Article Info
Publication History
Published: October 20, 2016 Accepted: September 15, 2016 Received in revised form: July 14, 2016
Received: April 12, 2016
User License
Creative Commons Attribution – NonCommercial – NoDerivs (CC BY-NC-ND 4.0)
Highlights
• Human populations differ in their transcriptional responses to immune challenges
• Cis- and trans-eQTLs contribute to population differences in immune responses
• Immune-responsive regulatory variants have participated in human adaptation
• Neandertals introduced variants affecting immune responses into European genomes
Summary
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.
Keywords: population genetics, immune response, eQTL mapping, transcriptional responses, monocytes, evolution, natural selection, Neandertal admixture
Received: April 12, 2016; Received in revised form: July 14, 2016; Accepted: September 15, 2016; Published: October 20, 2016
© 2016 The Author(s). Published by Elsevier Inc.
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