The complete local genotype-phenotype landscape for the alternative splicing of a human exon

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  • dc.contributor.author Julien, Philippeca
  • dc.contributor.author Miñana Gómez, Belénca
  • dc.contributor.author Baeza Centurión, Pablo, 1989-ca
  • dc.contributor.author Valcárcel, J. (Juan)ca
  • dc.contributor.author Lehner, Ben, 1978-ca
  • dc.date.accessioned 2016-06-01T13:54:53Z
  • dc.date.available 2016-06-01T13:54:53Z
  • dc.date.issued 2016
  • dc.description.abstract The properties of genotype-phenotype landscapes are crucial for understanding evolution but are not characterized for most traits. Here, we present a >95% complete local landscape for a defined molecular function-the alternative splicing of a human exon (FAS/CD95 exon 6, involved in the control of apoptosis). The landscape provides important mechanistic insights, revealing that regulatory information is dispersed throughout nearly every nucleotide in an exon, that the exon is more robust to the effects of mutations than its immediate neighbours in genotype space, and that high mutation sensitivity (evolvability) will drive the rapid divergence of alternative splicing between species unless it is constrained by selection. Moreover, the extensive epistasis in the landscape predicts that exonic regulatory sequences may diverge between species even when exon inclusion levels are functionally important and conserved by selection.ca
  • dc.description.sponsorship Work in B.L.’s lab was supported by the European Research Council (Consolidator grant IR-DC, 616434), the Spanish Ministry of Economy and Competitiveness (MICINN, BFU2011-26206), the AXA Research Fund, FP7 Project 4DCellFate (277899), Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR) and the EMBL-CRG Systems Biology Program. Work in J.V.’s lab was supported by Fundación Botín, by Banco de Santander through its Santander Universities Global Division and by Consolider RNAREG, MICINN and AGAUR. P.J. was supported by an EMBO long-term fellowship.
  • dc.format.mimetype application/pdfca
  • dc.identifier.citation Julien P, Miñana B, Baeza-Centurion P, Valcárcel J, Lehner B. The complete local genotype-phenotype landscape for the alternative splicing of a human exon. Nature communications. 2016; 7: 11558. DOI 10.1038/ncomms11558ca
  • dc.identifier.doi http://dx.doi.org/10.1038/ncomms11558
  • dc.identifier.issn 2041-1723
  • dc.identifier.uri http://hdl.handle.net/10230/26794
  • dc.language.iso engca
  • dc.publisher Nature Publishing Groupca
  • dc.relation.ispartof Nature communications. 2016; 7: 11558
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2011-26206
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/277899
  • dc.rights © Nature Publishing Group. http://www.nature.com/ncomms/2016/160510/ncomms11558/pdf/ncomms11558.pdf/nThis work is licensed under a Creative Commons Attribution 4.0 International Licenseca
  • dc.rights.accessRights info:eu-repo/semantics/openAccessca
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/ca
  • dc.subject.other Exonsca
  • dc.title The complete local genotype-phenotype landscape for the alternative splicing of a human exonca
  • dc.type info:eu-repo/semantics/articleca
  • dc.type.version info:eu-repo/semantics/publishedVersionca

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