Lessons from non-canonical splicing

The development of new methods for preparing and sequencing RNA sequencing libraries, as well as new alignment algorithms, have revealed many thousands of previously unknown non-canonical splicing events.Non-canonical splicing events are often tissue-specific and are particularly enriched in the central nervous system, thereby increasing proteome diversity or regulating gene expression.Cryptic exons, microexons and recursive splice sites often require unconventional exon definition mechanisms.Other non-canonical splicing events result from lower or higher splicing efficiency than normal (such as retained introns and exonic introns), changes in the usual order of splicing (circular RNAs and chimeric RNAs) or changes in the consensus sequence (atypical splice sites).Transposable elements are a rich source of newly emerging cryptic exons, which can contribute to the evolution of gene regulatory networks.Mutations that perturb functionally important non-canonical splicing events, or strongly increase the recognition of cryptic splice sites, can cause numerous diseases.Non-canonical splicing mechanisms offer new therapeutic opportunities to treat disease.