Splicing accuracy varies across human introns, tissues, age and disease
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.
Authors
- Zhongbo Chen (ORCID: https://orcid.org/0000-0001-6668-7202)
- G Rocamora-Perez
- Jonathan Brenton (ORCID: https://orcid.org/0000-0002-2381-8484)
- Juan A. Botía (ORCID: https://orcid.org/0000-0002-6992-598X)
- Sonia García-Ruiz (ORCID: https://orcid.org/0000-0003-4913-5312)
- Donald C. Rio
- Regina Hertfelder Reynolds (ORCID: https://orcid.org/0000-0001-6470-7919)
- Mina Ryten (ORCID: https://orcid.org/0000-0001-9520-6957)
- Ana Luisa Gil-Martínez (ORCID: https://orcid.org/0000-0001-8455-5676)
- Sebastian Guelfi (ORCID: https://orcid.org/0000-0002-0256-2686)
- Aine Fairbrother-Browne (ORCID: https://orcid.org/0000-0002-7196-1410)
- Melissa Grant‐Peters (ORCID: https://orcid.org/0000-0003-0585-0971)
- Emil Karl Gustavsson (ORCID: https://orcid.org/0000-0003-0541-7537)
- Leonardo Collado‐Torres (ORCID: https://orcid.org/0000-0003-2140-308X)
- David Zhang (ORCID: https://orcid.org/0000-0002-5027-5286)
Institutions
- QB3 (US)
- Johns Hopkins University (US)
- University of Cambridge (GB)
- Great Ormond Street Hospital (GB)
- The Francis Crick Institute (GB)
- Cambridge School (PT)
- UK Dementia Research Institute (GB)
- Institute of Child Health (IN)
- Lieber Institute for Brain Development (US)
- National Hospital for Neurology and Neurosurgery (GB)
- Research Network (United States) (US)
- University College London (GB)
- Universidad de Murcia (ES)
- University of California, Berkeley (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-01-27
- DOI
- https://doi.org/10.1038/s41467-024-55607-x
- Citations
- 14
- Primary Topic
- RNA Research and Splicing
- Type
- article
- Field-Weighted Citation Impact
- 9.67
Funders
- Michael J. Fox Foundation for Parkinson's Research
- BrightFocus Foundation
- National Institutes of Health
- Directorate for Biological Sciences
- Medical Research Council
- Biotechnology and Biological Sciences Research Council