Discovery of microRNA gene mutations in ALS patient genomes
published: July 21, 2017, recorded: May 2017, views: 773
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MicroRNAs, endogenous small RNAs, have been suggested to play a role in many pathologies, including neurodegeneration. We recently demonstrated that Dicer activity is impaired in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of the human motor neuron system, causing dysregulation of miRNA biogenesis. Accordingly, conditional loss of Dicer allele in mice is sufficient to cause motor neuron disease. Nowadays, we are directly testing the existence of causative mutations in microRNA genes in patients suffering from ALS. To this end, in collaboration with project MinE, we performed in silico capture, which calls specific genomic regions of interest from whole genome sequencing data. Our approach enabled us to capture all known microRNA genes, their protein cofactors and the 3' untranslated region of disease-associated genes. We then performed an extensive bioinformatics analysis to identify gene variants that are associated with disease, and further developed methodologies to weight the impact of the newly-identified mutations in miRNA genes. The analysis of miRNA gene mutations in 4300 ALS patients, by in silico capture, is unprecedented. The data and approaches developed to reveal the centrality of noncoding RNA genetics in human disease will plausibly influence future genetics studies, beyond the specific pathology in focus.
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