Abstract
BackgroundMicroRNAs (miRNAs) are key regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized.ResultsWe generate 977 miRNA-sequencing profiles from primary monocytes from individuals of African and European ancestry following activation of three TLR pathways (TLR4, TLR1/2, and TLR7/8) or infection with influenza A virus. We find that immune activation leads to important modifications in the miRNA and isomiR repertoire, particularly in response to viral challenges. These changes are much weaker than those observed for protein-coding genes, suggesting stronger selective constraints on the miRNA response to stimulation. This is supported by the limited genetic control of miRNA expression variability (miR-QTLs) and the lower occurrence of gene-environment interactions, in stark contrast with eQTLs that are largely context-dependent. We also detect marked differences in miRNA expression between populations, which are mostly driven by non-genetic factors. On average, miR-QTLs explain approximately 60% of population differences in expression of their cognate miRNAs and, in some cases, evolve adaptively, as shown in Europeans for a miRNA-rich cluster on chromosome 14. Finally, integrating miRNA and mRNA data from the same individuals, we provide evidence that the canonical model of miRNA-driven transcript degradation has a minor impact on miRNA-mRNA correlations, which are, in our setting, mainly driven by co-transcription.ConclusionTogether, our results shed new light onto the factors driving miRNA and isomiR diversity at the population level and constitute a useful resource for evaluating their role in host differences of immunity to infection.
Highlights
MicroRNAs are key regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized
Strong selective constraints limit miRNA expression variability To assess the extent to which miRNA expression variability is under genetic control, we focused on the 598 miRNAs associated to a unique genomic location and searched for genetic variants associated with changes in miRNA abundances within a 1 Mb window around each miRNA
Together, this study shows that genetic and non-genetic factors contribute to marked population differences in miRNA abundance and isomiR ratios
Summary
MicroRNAs (miRNAs) are key regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized. Fueled by the advent of deep sequencing technologies, growing evidence has emerged that mature miRNAs undergo important post-transcriptional modifications [22,23,24,25,26] These include nucleotide substitutions (miRNA editing) [27, 28], 3′ adenylation or urydilation by terminal nucleotidyl transferases [29, 30], shortening of their 3′ end by poly(A)-specific ribonuclease [31], and, more rarely, shifts in their 5′ start sites [24]. Our understanding of the variability of isomiR expression across individuals and populations remains largely incomplete
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