A new study titled “miRNA gene mutations commonly disrupt the proper functioning of miRNA genes” by researchers from IBCH PAS, Magdalena Machowska, Natalia Szostak, Adrian Tire, Wladyslaw Wegorek, Malwina Suszynska, Arkadiusz Kajdasz, Paulina Galka-Marciniak, Anna Philips, and Piotr Kozlowski has been published in Science Advances. It is the seventeenth and final paper, concluding the NCN MAESTRO grant led by Prof. Piotr Kozłowski, which focused on analyzing mutations in miRNA genes.

The discovery of the genetic code greatly facilitates the prediction of the consequences of mutations in protein-coding genes. However, the vast majority (~99%) of genetic variants in the human genome occur outside protein-coding sequences, in various “noncoding” regions, including miRNA genes, and there is still no “code” to predict their consequences.

In this study, researchers from IBCH PAS analyzed the consequences of mutations in miRNA genes by comparing hundreds of mutations they previously identified in cancer genomes (Martyna Urbanek-Trzeciak et al. eBioMedicine 2020) with corresponding miRNA-seq data. In this way, they showed that most mutations in miRNA genes are deleterious, severely impairing their function; therefore, if they are found in disease-associated miRNA genes, they are likely to be pathogenic. The study demonstrated that mutations may affect (i) miRNA levels, (ii) the 5p/3p miRNA strand balance, (iii) the precision of DROSHA/DICER1 cleavage (isomiR profiles), and (iv) the efficiency of target silencing. It was also shown that the observed effects of mutations depend heavily on their impact on the miRNA precursor structure. The number of miRNA gene mutations analysed in this study, and the number of mutations with identified deleterious effects, exceeded those in other functional studies by orders of magnitude.

The study offers a strong foundation for better understanding and predicting the consequences of mutations found in miRNA genes.

Link to the article: https://www.science.org/doi/10.1126/sciadv.aea6079