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

Maxime Rotival (1) , Katherine J. Siddle (2, 3) , Martin Silvert (1, 4) , Julien Pothlichet (1) , Hélène Quach (1) , Lluis Quintana-Murci (1, 5)

1 Génétique Evolutive Humaine - Human Evolutionary Genetics
2 BROAD INSTITUTE - Broad Institute of MIT and Harvard
3 OEB - Department of Organismic and Evolutionary Biology [Cambridge]
4 ED515 - Ecole Doctorale Complexité du Vivant
5 Collège de France - Chaire Génomique humaine et évolution

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.

Mots clés: miRNAs; Isoforms; Population; miR-QTLs; Immunity

Domaines: Génétique humaine

Maxime Rotival, Katherine J. Siddle, Martin Silvert, Julien Pothlichet, Hélène Quach, et al.. Population variation in miRNAs and isomiRs and their impact on human immunity to infection. Genome Biology, 2020, 21 (1), pp.187. ⟨10.1186/s13059-020-02098-w⟩. ⟨pasteur-03169760⟩