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

Abstract

SummaryHumans 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.

Milieu intérieur: Defining the boundaries of a healthy immune response for improved vaccination strategies

“…This genetic variant may be highly relevant for explaining differences among ethnic populations as work from our group previously showed that this specific genetic regulation is more prevalent in Europeans as compared to Africans. 20 Therefore, this approach may explain not only immune response heterogeneity present in Europeans, but perhaps some of the variability observed between individuals from different racial and ethnic backgrounds populations. Additional studies will continue to further explore how these differences may be regulated at the agonist and ligand level and in more diverse immune phenotypes.…”

Evolutionary and Medical Consequences of Archaic Introgression into Modern Human Genomes

“…In contrast, individuals carrying archaic alleles show down-regulation of OAS1 and OAS3 in esophagus mucosa and spleen, and individuals carrying archaic alleles show down-regulation of OAS2 in fibroblasts and OAS3 in fibroblasts as well as three brain regions (hippocampus, putamen, and caudate nucleus) . Other examples of local adaptation influencing the levels of expression include expression of gene ERAP2, involved in susceptibility to Crohn's disease; CCR1, limiting leukocyte recruitment and preventing inflammatory responses; HLA-DQA1, associated with susceptibility to celiac disease; and TLR1, associated with markedly lower levels of inflammatory response gene expression Quach et al, 2016). Apparently, introgression from Neanderthals also contributed to the diversification of transcriptional responses to infection in human populations.…”

“…Genes involved in the variation of skin pigmentation and hair morphology (BNC2, MC1R) also show the signature of positive selection as the result of adaptation to diverse habitats with different degree of insolation (Dannemann & Kelso, 2017;Ding et al, 2014;Frost et al, 2017). Advantageous immune variants introduced into the modern human population from archaic genomes have substantially contributed in the present-day diversity of immune genes (Mendez et al, 2012;Mendez et al, 2013;Nédélec et al, 2016;Quach et al, 2016;Racimo et al, 2015). Since innate immunity genes have evolved under stronger purifying selection than the rest of the genome , this enrichment of introgressed alleles suggests the presence of strong positive selection at the immune system.…”

“…The introgressed genetic segments in European genomes contain regulatory variants with effects on steady-state expression and responses to TLR7/8 stimulation and influenza virus (Quach et al, 2016;Quach & Quintana-Murci, 2017). Furthermore, the archaic variants of several eQTLs have been reported as potential candidates for adaptive introgression conferring better adaptation through the regulation of gene expression.…”

“…This gene exhibits strong allele-specific expression favoring the Neanderthal allele in brain tissues, but allele-specific expression favoring the modern human allele in non-brain tissues (McCoy et al, 2017). There are also a number of examples of local adaptation driven by regulatory variants resulting in population differences in immune responses Nédélec et al, 2016;Quach et al, 2016). Despite the evidence that functional archaic alleles (non-synonymous and associated with expression) have decreased in frequency over the past 8,500 years, four loci were identified where the archaic alleles associated with differential expression show large increases in frequency over time.…”