Population variation in miRNAs and isomiRs and their impact on human immunity to infection

Abstract

Background: 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. Results: We 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 miRNAdriven transcript degradation has a minor impact on miRNA-mRNA correlations, which are, in our setting, mainly driven by co-transcription. Conclusion: Together, 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.

Human pancreatic islet microRNAs implicated in diabetes and related traits by large-scale genetic analysis

“…In our genetic analysis of HPIs, we show that the expression of highly heritable miRNAs is driven primarily by trans -acting genetic effects, whereas the expression of highly heritable mRNAs is driven by a combination of cis- and trans- acting genetic effects. This model is supported by previous studies in rodents that compare the heritability of miRNAs and mRNAs ( 39 , 40 ) and suggests that miRNAs may be under greater selective pressure than mRNAs, as has been postulated by previous studies in humans ( 47 , 54 ). Such selection pressures imply that to map miRNA-eQTLs thoroughly, large sample sizes will be required.…”

Mapping interindividual dynamics of innate immune response at single-cell resolution

“…Dysregulation of this response can affect a wide range of inflammatory and autoimmune diseases and determine the outcome of infection [2][3][4][5][6] . Common genetic variants have been shown to modulate transcriptional responses to various viral and bacterial stimuli, and to contribute to disease onset and progression [7][8][9][10][11] . Most past gene expression-focused studies of this program are based on bulk RNA-sequencing technologies, which do not fully elucidate the continuous dynamics of transcriptional changes during the innate immune response.…”

miR-4482 and miR-3912 aim for 3ʹUTR of ERG mRNA in prostate cancer

“…miR-4482 has been previously reported to have differential expression in several diseases such as pediatric embryonal central nervous system neoplasms [ 34 ], immune thrombocytopenia [ 35 , 36 ], and infections [ 37 ]. Similarly, miR-3912 is differentially expressed in papillary thyroid cancer patients [ 38 ] and pediatric embryonal central nervous system neoplasms [ 34 ].…”