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

Maxime Rotival, Katherine J Siddle, Martin Silvert, Julien Pothlichet, Hélène Quach, View ORCID ProfileLluis Quintana-Murci
doi: https://doi.org/10.1101/2020.01.31.928580
Maxime Rotival
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, France
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  • For correspondence: maxime.rotival@pasteur.fr quintana@pasteur.fr
Katherine J Siddle
Broad Institute of MIT and Harvard, Cambridge, MA, USADepartment of Organismic and Evolutionary Biology, Harvard University, Cambridge, MA 02138, USA
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Martin Silvert
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, FranceSorbonne Universités, École Doctorale Complexité du Vivant, 75005 Paris, France
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Julien Pothlichet
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, FranceDIACCURATE, Institut Pasteur, 75015 Paris, France
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Hélène Quach
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, FranceUMR7206, Muséum National d’Histoire Naturelle, CNRS, Université Paris Diderot, 75016 Paris, France
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Lluis Quintana-Murci
Human Evolutionary Genetics Unit, Institut Pasteur, CNRS UMR 2000, 75015 Paris, FranceChair Human Genomics and Evolution, Collège de France, 75005 Paris, France
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  • ORCID record for Lluis Quintana-Murci
  • For correspondence: maxime.rotival@pasteur.fr quintana@pasteur.fr
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ABSTRACT

MicroRNAs (miRNAs) are key epigenetic regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized. Here, we generated 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, however, 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 G×E 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. Yet, on average, miR-QTLs explain ~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. 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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted January 31, 2020.
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Population variation of miRNAs and isomiRs and their impact on human immunity to infection
Maxime Rotival, Katherine J Siddle, Martin Silvert, Julien Pothlichet, Hélène Quach, Lluis Quintana-Murci
bioRxiv 2020.01.31.928580; doi: https://doi.org/10.1101/2020.01.31.928580
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Population variation of miRNAs and isomiRs and their impact on human immunity to infection
Maxime Rotival, Katherine J Siddle, Martin Silvert, Julien Pothlichet, Hélène Quach, Lluis Quintana-Murci
bioRxiv 2020.01.31.928580; doi: https://doi.org/10.1101/2020.01.31.928580

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