1. Genetics and Genomics

Mutations primarily alter the inclusion of alternatively spliced exons

  1. Pablo Baeza-Centurion
  2. Belen Minana
  3. Juan Valcarcel  Is a corresponding author
  4. Ben Lehner  Is a corresponding author
  1. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Spain
https://doi.org/10.7554/eLife.59959
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  1. Pablo Baeza-Centurion
  2. Belen Minana
  3. Juan Valcarcel
  4. Ben Lehner
(2020)
Mutations primarily alter the inclusion of alternatively spliced exons
eLife 9:e59959.
https://doi.org/10.7554/eLife.59959
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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.

Data availability

Raw sequencing data have been submitted to GEO with accession number GSE151942. All scripts used in this study are available at https://github.com/lehner-lab/Constitutive_Exons.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Pablo Baeza-Centurion

    Systems Biology, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    Competing interests
    No competing interests declared.

  2. Belen Minana

    Gene Regulation, Stem cells and Cancer, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    Competing interests
    No competing interests declared.

  3. Juan Valcarcel

    Systems Biology, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    For correspondence
    juan.valcarcel@crg.eu
    Competing interests
    Juan Valcarcel, Reviewing editor, eLife.

  4. Ben Lehner

    Systems Biology, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Barcelona, Spain
    For correspondence
    ben.lehner@crg.eu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8817-1124

Funding

ERC (ERC 616434)

  • Ben Lehner

ERC (ERC 670146)

  • Belen Minana

Ministerio de Economía y Competitividad (BFU2017-89488-P)

  • Ben Lehner

Ministerio de Economía y Competitividad (BFU 2017 89308-P)

  • Juan Valcarcel

Banco Santander (Fundación Botín)

  • Juan Valcarcel

Fondation Bettencourt Schueller (Liliane Bettencourt Prize for Life Sciences)

  • Ben Lehner

Ministerio de Economía y Competitividad (Severo Ochoa PhD fellowship)

  • Pablo Baeza-Centurion

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Chris P Ponting, University of Edinburgh, United Kingdom

Publication history

  1. Received: June 12, 2020
  2. Accepted: October 27, 2020
  3. Accepted Manuscript published: October 28, 2020 (version 1)
  4. Version of Record published: November 18, 2020 (version 2)

Copyright

© 2020, Baeza-Centurion et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Pablo Baeza-Centurion
  2. Belen Minana
  3. Juan Valcarcel
  4. Ben Lehner
(2020)
Mutations primarily alter the inclusion of alternatively spliced exons
eLife 9:e59959.
https://doi.org/10.7554/eLife.59959

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