2026-04-17T06:32:32Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/457422025-12-12T02:36:47Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Baeza Centurión, Pablo, 1989- author Miñana Gómez, Belén author Valcárcel, J. (Juan) author Lehner, Ben, 1978- author 2020-11-12T11:43:40Z 2020-11-12T11:43:40Z 2020 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. We thank Yamile Márquez and Manuel Irimia for identifying PSMD14 exon 11 as a constitutive exon whose inclusion levels are conserved across many vertebrate species. Work in B.L.’s is supported by a European Research Council (ERC) Consolidator grant (616434), the Spanish Ministry of Economy and Competitiveness (BFU2017-89488-P and SEV-2012-0208), the AXA Research Fund, the Bettencourt Schueller Foundation, Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, SGR-831), the EMBL Partnership, and the CERCA Program/Generalitat de Catalunya. P.B.-C. was funded in part by a Severo Ochoa PhD fellowship. Work in J.V.’s laboratory is supported by Fundación Botín, Banco de Santander through its Santander Universities Global Division, ERC AdvG 670146, AGAUR, Spanish Ministry of Economy and Competitiveness (BFU 2014-005153, BFU 2017 89308-P, and SEV-2012-0208), the EMBL Partnership, and the CERCA program/Generalitat de Catalunya. Genetics Genomics Human Mutations primarily alter the inclusion of alternatively spliced exons