TY - JOUR TI - Mutations primarily alter the inclusion of alternatively spliced exons AU - Baeza-Centurion, Pablo AU - Miñana, Belén AU - Valcárcel, Juan AU - Lehner, Ben A2 - Ponting, Chris P A2 - Wittkopp, Patricia J A2 - Barbosa-Morais, Nuno L VL - 9 PY - 2020 DA - 2020/10/28 SP - e59959 C1 - eLife 2020;9:e59959 DO - 10.7554/eLife.59959 UR - https://doi.org/10.7554/eLife.59959 AB - Genetic analyses and systematic mutagenesis have revealed that synonymous, non-synonymous and intronic mutations frequently alter the inclusion levels of alternatively spliced exons, consistent with the concept that altered splicing might be a common mechanism by which mutations cause disease. However, most exons expressed in any cell are highly-included in mature mRNAs. Here, by performing deep mutagenesis of highly-included exons and by analysing the association between genome sequence variation and exon inclusion across the transcriptome, we report that mutations only very rarely alter the inclusion of highly-included exons. This is true for both exonic and intronic mutations as well as for perturbations in trans. Therefore, mutations that affect splicing are not evenly distributed across primary transcripts but are focussed in and around alternatively spliced exons with intermediate inclusion levels. These results provide a resource for prioritising synonymous and other variants as disease-causing mutations. KW - splicing KW - mutations KW - deep mutagenesis KW - genetic prediction JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -