Background splicing as a predictor of aberrant splicing in genetic disease

Alexieva, D, Long, Y, Sarkar, R, Dhayan, H, Bruet, E, Winston, R, Vorechovsky, I, Castellano, L and Dibb, N J (2022) Background splicing as a predictor of aberrant splicing in genetic disease. RNA Biology, 19 (1). pp. 256-265. ISSN 1547-6286

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Mutations of splice sites, auxiliary splicing elements and the splicing machinery cause a wide range of genetic disease. Here we report that many of the complex effects of splicing mutations can be predicted from background splicing information, with emphasis on BRCA1, BRCA2 and DMD. Background splicing arises from very low level splicing between rarely used background splice sites and from low-level exon skipping between intron splice sites. We show how this information can be downloaded from the Snaptron database of spliced RNA, which we then compared with databases of human splice site mutations. We report that inactivating mutations of intron splice sites typically caused the non-mutated partner splice site to splice to a known background splice site in over 90% of cases and to the strongest background splice site in the large majority of cases. Consequently, background splicing information can usefully predict the effects of splice site mutations, which include cryptic splice activation and single or multiple exon skipping. In addition, de novo splice sites and splice sites involved in pseudoexon formation, recursive splicing and aberrant splicing in cancer show a 90% match to background splice sites, so establishing that the enhancement of background splicing causes a wide range of splicing aberrations. We also discuss how background splicing information can identify cryptic splice sites that might be usefully targeted by antisense oligonucleotides (ASOs) and how it might indicate possible multiple exon skipping side effects of ASOs designed to induce single exon skipping.

Item Type: Article
Keywords: Cryptic splice site, background splicing, cancer, exon skipping, pseudoexons, recursive splicing, Alternative Splicing, Computational Biology, Databases, Genetic, Exons, Gene Expression Profiling, Gene Expression Regulation, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Humans, Introns, Mutation, RNA Splice Sites, RNA Splicing
Schools and Departments: School of Life Sciences > Biochemistry
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 29 Apr 2022 16:08
Last Modified: 29 Apr 2022 16:15

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