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Genetic control of the transcriptomic response of monocytes to bacterial and viral stimuli assessed by RNA-seq in Africans and Europeans

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 receptors pathways (TLR1/2, TLR4 and TLR7/8) and influenza virus - and mapped expression quantitative trait loci (eQTL). We identify multiple cis- and trans-eQTL that contribute to the marked differences in immune responses detected within and between populations, including a TLR1 master regulator that decreases expression of pro-inflammatory genes in Europeans only. We show that regulatory variants have been privileged targets of natural selection, uncovering evolutionarily advantageous mechanisms, such as attenuated inflammation. Finally, we demonstrate that admixture with Neandertals introduced regulatory variants into European genomes, affecting preferentially responses to viral challenges, and identify archaic haplotypes that contributed to population genetic adaptation.

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID Description Technology Samples
EGAD00001002714 Illumina HiSeq 2000 970
EGAD00010001131 Illumina HumanOmni5-Quad and exome sequencing 200
Publications Citations
Genetic Adaptation and Neandertal Admixture Shaped the Immune System of Human Populations.
Cell 167: 2016 643-656.e17
225
Exploring the genetic basis of human population differences in DNA methylation and their causal impact on immune gene regulation.
Genome Biol 19: 2018 222
59
Defining the genetic and evolutionary architecture of alternative splicing in response to infection.
Nat Commun 10: 2019 1671
34
ARTDeco: automatic readthrough transcription detection.
BMC Bioinformatics 21: 2020 214
15
Population variation in miRNAs and isomiRs and their impact on human immunity to infection.
Genome Biol 21: 2020 187
10
HERV-Derived Ervpb1 Is Conserved in Simiiformes, Exhibiting Expression in Hematopoietic Cell Lineages Including Macrophages.
Int J Mol Sci 22: 2021 4504
0
A compendium of uniformly processed human gene expression and splicing quantitative trait loci.
Nat Genet 53: 2021 1290-1299
149
Single-Cell and Bulk RNA-Sequencing Reveal Differences in Monocyte Susceptibility to Influenza A Virus Infection Between Africans and Europeans.
Front Immunol 12: 2021 768189
9
Immune-response 3'UTR alternative polyadenylation quantitative trait loci contribute to variation in human complex traits and diseases.
Nat Commun 14: 2023 8347
0
Long-read sequencing for 29 immune cell subsets reveals disease-linked isoforms.
Nat Commun 15: 2024 4285
0