Full-length isoform transcriptome of the developing human brain provides further insights into autism.

Alternative splicing plays an important role in brain development, but its global contribution to human neurodevelopmental diseases (NDDs) requires further investigation. Here we examine the relationships between splicing isoform expression in the brain and de novo loss-of-function mutations from in...

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Autores: Chau, Kevin K., Zhang, Pan, Urresti, Jorge, Amar, Megha, Pramod, Akula Bala, Chen, Jiaye, Thomas, Amy, Corominas Castiñeira, Roser, Lin, Guan Ning, Iakoucheva, Lilia M.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2021
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/183886
Acceso en línea:https://hdl.handle.net/2445/183886
Access Level:acceso abierto
Palabra clave:Autisme
Isoenzims
Autism
Isoenzymes
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spelling Full-length isoform transcriptome of the developing human brain provides further insights into autism.Chau, Kevin K.Zhang, PanUrresti, JorgeAmar, MeghaPramod, Akula BalaChen, JiayeThomas, AmyCorominas Castiñeira, RoserLin, Guan NingIakoucheva, Lilia M.AutismeIsoenzimsAutismIsoenzymesAlternative splicing plays an important role in brain development, but its global contribution to human neurodevelopmental diseases (NDDs) requires further investigation. Here we examine the relationships between splicing isoform expression in the brain and de novo loss-of-function mutations from individuals with NDDs. We analyze the full-length isoform transcriptome of the developing human brain and observe differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. These isoforms are enriched in loss-of-function mutations and microexons, are co-expressed with a unique set of partners, and have higher prenatal expression. We experimentally test the effect of splice-site mutations and demonstrate exon skipping in five NDD risk genes, including SCN2A, DYRK1A, and BTRC. Our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely affecting Wnt signaling through impaired degradation of β-catenin. We propose that functional effects of mutations should be investigated at the isoform- rather than gene-level resolution.Elsevier2021info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/183886Articles publicats en revistes (Genètica, Microbiologia i Estadística)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1016/j.celrep.2021.109631Cell Reports, 2021, vol. 36, num. 109631, p. 1-13https://doi.org/10.1016/j.celrep.2021.109631cc-by (c) Chau, Kevin K. et al., 2021https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1838862026-05-27T06:46:51Z
dc.title.none.fl_str_mv Full-length isoform transcriptome of the developing human brain provides further insights into autism.
title Full-length isoform transcriptome of the developing human brain provides further insights into autism.
spellingShingle Full-length isoform transcriptome of the developing human brain provides further insights into autism.
Chau, Kevin K.
Autisme
Isoenzims
Autism
Isoenzymes
title_short Full-length isoform transcriptome of the developing human brain provides further insights into autism.
title_full Full-length isoform transcriptome of the developing human brain provides further insights into autism.
title_fullStr Full-length isoform transcriptome of the developing human brain provides further insights into autism.
title_full_unstemmed Full-length isoform transcriptome of the developing human brain provides further insights into autism.
title_sort Full-length isoform transcriptome of the developing human brain provides further insights into autism.
dc.creator.none.fl_str_mv Chau, Kevin K.
Zhang, Pan
Urresti, Jorge
Amar, Megha
Pramod, Akula Bala
Chen, Jiaye
Thomas, Amy
Corominas Castiñeira, Roser
Lin, Guan Ning
Iakoucheva, Lilia M.
author Chau, Kevin K.
author_facet Chau, Kevin K.
Zhang, Pan
Urresti, Jorge
Amar, Megha
Pramod, Akula Bala
Chen, Jiaye
Thomas, Amy
Corominas Castiñeira, Roser
Lin, Guan Ning
Iakoucheva, Lilia M.
author_role author
author2 Zhang, Pan
Urresti, Jorge
Amar, Megha
Pramod, Akula Bala
Chen, Jiaye
Thomas, Amy
Corominas Castiñeira, Roser
Lin, Guan Ning
Iakoucheva, Lilia M.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Autisme
Isoenzims
Autism
Isoenzymes
topic Autisme
Isoenzims
Autism
Isoenzymes
description Alternative splicing plays an important role in brain development, but its global contribution to human neurodevelopmental diseases (NDDs) requires further investigation. Here we examine the relationships between splicing isoform expression in the brain and de novo loss-of-function mutations from individuals with NDDs. We analyze the full-length isoform transcriptome of the developing human brain and observe differentially expressed isoforms and isoform co-expression modules undetectable by gene-level analyses. These isoforms are enriched in loss-of-function mutations and microexons, are co-expressed with a unique set of partners, and have higher prenatal expression. We experimentally test the effect of splice-site mutations and demonstrate exon skipping in five NDD risk genes, including SCN2A, DYRK1A, and BTRC. Our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely affecting Wnt signaling through impaired degradation of β-catenin. We propose that functional effects of mutations should be investigated at the isoform- rather than gene-level resolution.
publishDate 2021
dc.date.none.fl_str_mv 2021
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/183886
url https://hdl.handle.net/2445/183886
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.celrep.2021.109631
Cell Reports, 2021, vol. 36, num. 109631, p. 1-13
https://doi.org/10.1016/j.celrep.2021.109631
dc.rights.none.fl_str_mv cc-by (c) Chau, Kevin K. et al., 2021
https://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by (c) Chau, Kevin K. et al., 2021
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Elsevier
publisher.none.fl_str_mv Elsevier
dc.source.none.fl_str_mv Articles publicats en revistes (Genètica, Microbiologia i Estadística)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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