RT Journal Article
SR Electronic
T1 Isoform transcriptome of developing human brain provides new insights into autism risk variants
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.06.27.175489
DO 10.1101/2020.06.27.175489
A1 Kevin Chau
A1 Pan Zhang
A1 Jorge Urresti
A1 Megha Amar
A1 Akula Bala Pramod
A1 Amy Thomas
A1 Roser Corominas
A1 Guan Ning Lin
A1 Lilia M. Iakoucheva
YR 2020
UL http://biorxiv.org/content/early/2020/06/27/2020.06.27.175489.abstract
AB Alternative splicing plays important role in brain development, however its global contribution to human neurodevelopmental diseases (NDD) has not been fully investigated. Here, we examined the relationships between splicing isoforms expression in the brain and de novo loss-of-function mutations identified in the patients with NDDs. We constructed isoform transcriptome of the developing human brain, and observed differentially expressed isoforms and isoform co-expression modules undetectable by the gene-level analyses. These isoforms were enriched in loss-of-function mutations and microexons, co-expressed with a unique set of partners, and had higher prenatal expression. We experimentally tested the impact of splice site mutations in five NDD risk genes, including SCN2A, DYRK1A and BTRC, and demonstrated exon skipping. Furthermore, our results suggest that the splice site mutation in BTRC reduces translational efficiency, likely impacting Wnt signaling through impaired degradation of β-catenin. We propose that functional effect of mutations associated with human diseases should be investigated at isoform-rather than gene-level resolution.HighlightsDifferential isoform expression analysis of human brain transcriptome reveals neurodevelopmental processes and pathways undetectable by differential gene expression analyses.Splicing isoforms impacted by neurodevelopmental disease (NDD) risk mutations exhibit higher prenatal expression, are enriched in microexons and involved in neuronal-related functions.Isoform co-expression network analysis identifies modules with splicing and synaptic functions that are enriched in NDD mutations.Splice site mutations impacting NDD risk genes cause exon skipping and produce novel isoforms with altered biological properties.Functional impact of mutations should be investigated at isoform-rather than gene-level resolutionCompeting Interest StatementThe authors have declared no competing interest.