Genomic variation of human microRNAs and its association with functional features

TL;DR

This study explores how genetic variation in human microRNAs affects their function and regulation, revealing population-specific patterns and compensatory changes.

Contribution

The paper introduces a population-based conservation metric for miRNAs and identifies compensatory variant pairs that preserve regulatory function.

Findings

Conserved miRNAs are associated with higher expression, broader target regulation, and essential biological pathways.

miRNA variants form compensatory pairs with target site variants, preserving base-pairing and suggesting co-evolution.

Population-specific miRNA variation patterns are linked to regulatory stability and pathogenic variant mitigation.

Abstract

Current methods for annotating microRNAs (miRNAs) often rely on phylogenetic conservation or expression data, with less attention paid to the impact of human genetic variation. This limits our understanding of how variation shapes miRNA function and regulatory dynamics across populations. In this study, we systematically annotated genomic variants within human miRNAs and investigated their relationship to functional features and evolutionary constraint. To facilitate this, we developed a population-based conservation metric that integrates allele frequency and positional coverage across miRNA loci. We show that miRNA conservation effectively links to functional roles, as evidenced by associations with higher expression levels, broader target gene regulation, and enrichment in essential biological pathways. Conserved miRNAs also preferentially target genes with fewer alternative polyadenylation sites, indicating more stable and consistent regulatory interactions. This trend is also reflected in miRNAs with both 5p and 3p arms, where the more conserved arm typically regulates more targets, especially when conservation differences between arms are pronounced. Moreover, we find that miRNA genomic variants display population-specific patterns, often co-occurring with target site variants to form compensatory pairs that preserve base-pairing. These events suggest co-evolution and several involve pathogenic variants, indicating that some deleterious regulatory disruptions in target genes may be mitigated through compensatory changes in miRNAs that restore binding.

The online version contains supplementary material available at 10.1007/s00018-025-05936-x.

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