Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations

TLDR

Humans differ in outcomes after exposure to life‑threatening pathogens, yet the extent of population differences in immune responses and their genetic and evolutionary determinants remain undefined. The study aimed to characterize the transcriptional response of primary monocytes from Africans and Europeans to bacterial and viral stimuli and map expression quantitative trait loci. Using RNA sequencing, the authors profiled monocyte responses to TLR1/2, TLR4, TLR7/8 ligands and influenza virus, then identified cis‑ and trans‑eQTLs. They identified numerous cis‑eQTLs underlying population‑specific immune responses, a trans‑eQTL hotspot at TLR1 that reduces pro‑inflammatory gene expression in Europeans, and showed that Neandertal admixture introduced regulatory variants that preferentially affect viral responses, highlighting evolutionarily important determinants of host immune variability.

Abstract

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.