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Splicing accuracy varies across human introns, tissues, age and disease

Author

Listed:
  • S. García-Ruiz

    (UK Dementia Research Institute, University of Cambridge
    University of Cambridge
    UCL GOS Institute of Child Health
    University College London)

  • D. Zhang

    (UCL GOS Institute of Child Health)

  • E. K. Gustavsson

    (UK Dementia Research Institute, University of Cambridge
    UCL GOS Institute of Child Health
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • G. Rocamora-Perez

    (UCL GOS Institute of Child Health)

  • M. Grant-Peters

    (UK Dementia Research Institute, University of Cambridge
    University of Cambridge
    UCL GOS Institute of Child Health
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • A. Fairbrother-Browne

    (UK Dementia Research Institute, University of Cambridge
    University of Cambridge
    UCL GOS Institute of Child Health
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • R. H. Reynolds

    (UCL GOS Institute of Child Health)

  • J. W. Brenton

    (UK Dementia Research Institute, University of Cambridge
    University of Cambridge
    UCL GOS Institute of Child Health
    Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network)

  • A. L. Gil-Martínez

    (UCL)

  • Z. Chen

    (UCL GOS Institute of Child Health
    UCL
    The Francis Crick Institute)

  • D. C. Rio

    (Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network
    University of California
    University of California)

  • J. A. Botia

    (Universidad de Murcia)

  • S. Guelfi

    (UCL)

  • L. Collado-Torres

    (Lieber Institute for Brain Development
    Johns Hopkins Bloomberg School of Public Health)

  • M. Ryten

    (UK Dementia Research Institute, University of Cambridge
    University of Cambridge
    UCL GOS Institute of Child Health
    University College London)

Abstract

Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigate splicing accuracy using RNA-sequencing data from >14k control samples and 40 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that splicing inaccuracies occur at different rates across introns and tissues and are affected by the abundance of core components of the spliceosome assembly and its regulators. We find that age is positively correlated with a global decline in splicing fidelity, mostly affecting genes implicated in neurodegenerative diseases. We find support for the latter by observing a genome-wide increase in splicing inaccuracies in samples affected with Alzheimer’s disease as compared to neurologically normal individuals. In this work, we provide an in-depth characterisation of splicing accuracy, with implications for our understanding of the role of inaccuracies in ageing and neurodegenerative disorders.

Suggested Citation

  • S. García-Ruiz & D. Zhang & E. K. Gustavsson & G. Rocamora-Perez & M. Grant-Peters & A. Fairbrother-Browne & R. H. Reynolds & J. W. Brenton & A. L. Gil-Martínez & Z. Chen & D. C. Rio & J. A. Botia & S, 2025. "Splicing accuracy varies across human introns, tissues, age and disease," Nature Communications, Nature, vol. 16(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-024-55607-x
    DOI: 10.1038/s41467-024-55607-x
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    1. Eric L. Nostrand & Peter Freese & Gabriel A. Pratt & Xiaofeng Wang & Xintao Wei & Rui Xiao & Steven M. Blue & Jia-Yu Chen & Neal A. L. Cody & Daniel Dominguez & Sara Olson & Balaji Sundararaman & Liju, 2020. "A large-scale binding and functional map of human RNA-binding proteins," Nature, Nature, vol. 583(7818), pages 711-719, July.
    2. Ho, Daniel & Imai, Kosuke & King, Gary & Stuart, Elizabeth A., 2011. "MatchIt: Nonparametric Preprocessing for Parametric Causal Inference," Journal of Statistical Software, Foundation for Open Access Statistics, vol. 42(i08).
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