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

Author

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  • Philippe Julien

    (EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF))

  • Belén Miñana

    (Universitat Pompeu Fabra (UPF)
    Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology)

  • Pablo Baeza-Centurion

    (EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF))

  • Juan Valcárcel

    (Universitat Pompeu Fabra (UPF)
    Gene Regulation, Stem Cells and Cancer Program, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

  • Ben Lehner

    (EMBL/CRG Systems Biology Research Unit, Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology
    Universitat Pompeu Fabra (UPF)
    Institució Catalana de Recerca i Estudis Avançats (ICREA))

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.

Suggested Citation

  • Philippe Julien & Belén Miñana & Pablo Baeza-Centurion & Juan Valcárcel & Ben Lehner, 2016. "The complete local genotype–phenotype landscape for the alternative splicing of a human exon," Nature Communications, Nature, vol. 7(1), pages 1-8, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11558
    DOI: 10.1038/ncomms11558
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    Cited by:

    1. Mariela Cortés-López & Laura Schulz & Mihaela Enculescu & Claudia Paret & Bea Spiekermann & Mathieu Quesnel-Vallières & Manuel Torres-Diz & Sebastian Unic & Anke Busch & Anna Orekhova & Monika Kuban &, 2022. "High-throughput mutagenesis identifies mutations and RNA-binding proteins controlling CD19 splicing and CART-19 therapy resistance," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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