Splicing accuracy varies across human introns, tissues and age
Creators
- 1. Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, London, UK.; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815
- 2. Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, London, UK
- 3. Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, London, UK; Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815; Department of Medical and Molecular Genetics, School of Basic and Medical Biosciences, King's College London, London, UK
- 4. Department of Genetics and Genomic Medicine Research & Teaching, UCL GOS Institute of Child Health, London, UK; Department of Neurodegenerative Disease, Queen Square Institute of Neurology, UCL, London, UK
- 5. Departamento de Ingeniería de la Información y las Comunicaciones, Universidad de Murcia, Spain
- 6. Lieber Institute for Brain Development, Baltimore, MD, USA , 21205
Description
Alternative splicing impacts most multi-exonic human genes. Inaccuracies during this process may have an important role in ageing and disease. Here, we investigated mis-splicing using RNA-sequencing data from ~14K control samples and 42 human body sites, focusing on split reads partially mapping to known transcripts in annotation. We show that mis-splicing occurs at different rates across introns and tissues and that these splicing inaccuracies are primarily affected by the abundance of core components of the spliceosome assembly and its regulators. Using publicly available data on short-hairpin RNA knockdowns of these spliceosomal components, we found support for the importance of RNA-binding proteins in mis-splicing. We also demonstrated that age is positively correlated with mis-splicing, and it affects genes implicated in neurodegenerative diseases. This in-depth characterisation of mis-splicing can have important implications for our understanding of the role of splicing inaccuracies in human disease and the interpretation of long-read RNA-sequencing data.
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Additional details
Related works
- Is derived from
- Software: 10.5281/zenodo.7717150 (DOI)