Mutations primarily alter the inclusion of alternatively spliced exons

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• dc.contributor.author Baeza Centurión, Pablo, 1989-
• dc.contributor.author Miñana Gómez, Belén
• dc.contributor.author Valcárcel, J. (Juan)
• dc.contributor.author Lehner, Ben, 1978-
• dc.date.accessioned 2020-11-12T11:43:40Z
• dc.date.available 2020-11-12T11:43:40Z
• dc.date.issued 2020
• dc.description.abstract 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.
• dc.description.sponsorship 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.
• dc.format.mimetype application/pdf
• dc.identifier.citation Baeza-Centurion P, Miñana B, Valcarcel J, Lehner B. Mutations primarily alter the inclusion of alternatively spliced exons. Elife. 2020 Oct 28;9:e59959. DOI: 10.7554/eLife.59959
• dc.identifier.doi http://dx.doi.org/10.7554/eLife.59959
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/45742
• dc.language.iso eng
• dc.publisher eLife
• dc.relation.ispartof Elife. 2020 Oct 28;9:e59959
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/616434
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89488-P
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/670146
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/BFU2017-89308-P
• dc.rights © 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.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Genetics
• dc.subject.keyword Genomics
• dc.subject.keyword Human
• dc.title Mutations primarily alter the inclusion of alternatively spliced exons
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion