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miRNA gene mutations commonly disrupt the proper functioning of miRNA genes
Magdalena Machowska1,2, Natalia Szostak1, Adrian Tire1
1Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
Abstract:
A growing number of mutations are being identified in the noncoding genome, including microRNA (miRNA) genes; however, little is known about the consequences of these mutations and how harmful they are to the functioning of miRNA genes. To evaluate the effects of miRNA gene mutations, we took advantage of a large collection of somatic mutations identified in miRNA genes in >10,000 The Cancer Genome Atlas cancer samples and compared them with the corresponding miRNA sequencing data. Using different analytical approaches and rigorous statistical criteria, we revealed that a substantial fraction of mutations is deleterious for the proper functioning of miRNA genes affecting the level of mature miRNAs, isomiR profiles (precision of DROSHA/DICER1 cleavage), and/or 5p/3p miRNA strand balance. We also showed that most mutations, especially those identified as deleterious, destabilize the structure of miRNA precursors. The analysis showed that many miRNA gene mutations can damage miRNA genes and, if located in disease-related miRNA genes, may be pathogenic variants.
Insights
Mutations in microRNA (miRNA) genes can harm their function, altering miRNA levels and structures. Many of these genetic changes, especially in disease-related genes, may be pathogenic.
Area of Science:
- Genomics
- Molecular Biology
- Cancer Research
Background:
- Noncoding genome mutations, including in microRNA (miRNA) genes, are increasingly identified.
- The functional consequences and pathogenicity of miRNA gene mutations remain largely unknown.
Purpose of the Study:
- To evaluate the effects of somatic mutations in miRNA genes on miRNA function.
- To assess the impact of these mutations on miRNA levels, processing, and precursor stability.
Main Methods:
- Analysis of >10,000 The Cancer Genome Atlas (TCGA) cancer samples.
- Comparison of somatic mutations in miRNA genes with miRNA sequencing data.
- Application of rigorous statistical criteria to identify deleterious mutations.
Main Results:
- A significant fraction of miRNA gene mutations negatively impacts miRNA function.
- Mutations affect mature miRNA levels, isomiR profiles (DROSHA/DICER1 cleavage precision), and 5p/3p strand balance.
- Most mutations, particularly deleterious ones, destabilize miRNA precursor structures.
Conclusions:
- Many miRNA gene mutations can impair miRNA gene function.
- Deleterious mutations in disease-related miRNA genes may represent pathogenic variants.
- Understanding miRNA mutations is crucial for cancer genomics and genetic disease research.
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