2026-04-13T13:30:55Zhttps://recercat.cat/oai/request
oai:recercat.cat:10230/457422025-12-12T02:36:47Zcom_2072_6col_2072_452952
RECERCAT author Baeza Centurión, Pablo, 1989- author Miñana Gómez, Belén author Valcárcel, J. (Juan) author Lehner, Ben, 1978- 2020-11-12T11:43:40Z2020-11-12T11:43:40Z2020 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. © 2020, Baeza-Centurion et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited. http://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess Genetics Genomics Human Mutations primarily alter the inclusion of alternatively spliced exons info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion