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Splicing accuracy varies across human introns, tissues and age

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...

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Autores principales: García-Ruiz, S, Zhang, D, Gustavsson, E K, Rocamora-Perez, G, Grant-Peters, M, Fairbrother-Browne, A, Reynolds, R H, Brenton, J W, Gil-Martínez, A L, Chen, Z, Rio, D C, Botia, J A, Guelfi, S, Collado-Torres, L, Ryten, M
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cold Spring Harbor Laboratory 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081249/
https://www.ncbi.nlm.nih.gov/pubmed/37034741
http://dx.doi.org/10.1101/2023.03.29.534370
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author García-Ruiz, S
Zhang, D
Gustavsson, E K
Rocamora-Perez, G
Grant-Peters, M
Fairbrother-Browne, A
Reynolds, R H
Brenton, J W
Gil-Martínez, A L
Chen, Z
Rio, D C
Botia, J A
Guelfi, S
Collado-Torres, L
Ryten, M
author_facet García-Ruiz, S
Zhang, D
Gustavsson, E K
Rocamora-Perez, G
Grant-Peters, M
Fairbrother-Browne, A
Reynolds, R H
Brenton, J W
Gil-Martínez, A L
Chen, Z
Rio, D C
Botia, J A
Guelfi, S
Collado-Torres, L
Ryten, M
author_sort García-Ruiz, S
collection PubMed
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 numerous spliceosomal components and related regulators, 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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spelling pubmed-100812492023-04-08 Splicing accuracy varies across human introns, tissues and age García-Ruiz, S Zhang, D Gustavsson, E K Rocamora-Perez, G Grant-Peters, M Fairbrother-Browne, A Reynolds, R H Brenton, J W Gil-Martínez, A L Chen, Z Rio, D C Botia, J A Guelfi, S Collado-Torres, L Ryten, M bioRxiv Article 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 numerous spliceosomal components and related regulators, 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. Cold Spring Harbor Laboratory 2023-03-30 /pmc/articles/PMC10081249/ /pubmed/37034741 http://dx.doi.org/10.1101/2023.03.29.534370 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
spellingShingle Article
García-Ruiz, S
Zhang, D
Gustavsson, E K
Rocamora-Perez, G
Grant-Peters, M
Fairbrother-Browne, A
Reynolds, R H
Brenton, J W
Gil-Martínez, A L
Chen, Z
Rio, D C
Botia, J A
Guelfi, S
Collado-Torres, L
Ryten, M
Splicing accuracy varies across human introns, tissues and age
title Splicing accuracy varies across human introns, tissues and age
title_full Splicing accuracy varies across human introns, tissues and age
title_fullStr Splicing accuracy varies across human introns, tissues and age
title_full_unstemmed Splicing accuracy varies across human introns, tissues and age
title_short Splicing accuracy varies across human introns, tissues and age
title_sort splicing accuracy varies across human introns, tissues and age
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10081249/
https://www.ncbi.nlm.nih.gov/pubmed/37034741
http://dx.doi.org/10.1101/2023.03.29.534370
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