Disease-related miRNA mutations are associated with mature miRNA secondary structure changes

MicroRNAs (miRNAs) are ubiquitous short RNAs regulating gene expression in many organisms, including humans. How the secondary structure (SS) of a mature miRNA affects its regulatory function remains an open question. Here, we investigate this question through computational SS predictions of miRNA point mutants. We explore the mutational neighborhoods of miRNAs with association to human diseases, including cancer. We focus on possible SS changes independent of target-site complementarity by leaving the seed region unchanged. We formulate metrics of the SS differences between such mutants and their wild types (WTs) and test whether disease-associated mutations tend to differ from others in terms of these metrics by comparing our results with the miRNASNP-v3 database. We find that disease-related mutants tend to have a higher probability of being fully unfolded than their WT; this and other SS-related measures are statistically significant at the database level. This is confirmed when we restrict the analysis to the better-validated miRNAs encoded by genes that appear in the manually curated MiRGeneDB database. With the same approach, we identify a subset of individual miRNAs for which SS changes are most likely to be related to disease. These are hsa-miR-1269b, hsa-miR-4537, hsa-miR-4477b, hsa-miR-4641, and hsa-miR-6821-3p; when focusing on the higher-confidence MiRGeneDB miRNAs, we find that hsa-miR-485-5p and hsa-miR-1908-3p are the ones for which SS changes are most likely to be linked to disease. In addition, we show that there are pairs of known miRNA WTs differing only by disease-related point mutations outside the seed region that exhibit very different SS. These pairs include hsa-miR-1269a-hsa-miR-1269b and hsa-miR-3689a-3p-hsa-miR-3689b-3p.