Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-rea...

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Published inScience (American Association for the Advancement of Science) Vol. 384; no. 6698; p. eadh7688
Main Authors Patowary, Ashok, Zhang, Pan, Jops, Connor, Vuong, Celine K., Ge, Xinzhou, Hou, Kangcheng, Kim, Minsoo, Gong, Naihua, Margolis, Michael, Vo, Daniel, Wang, Xusheng, Liu, Chunyu, Pasaniuc, Bogdan, Li, Jingyi Jessica, Gandal, Michael J., de la Torre-Ubieta, Luis
Format Journal Article
LanguageEnglish
Published United States The American Association for the Advancement of Science 24.05.2024
Subjects
Alternative Splicing
Autism
Autism Spectrum Disorders
Brain
Cellular structure
Cerebral cortex
Clustering
Disorders
Exons
Gene expression
Gene sequencing
Genetic diversity
Genetic Predisposition to Disease
Genetic variance
Humans
Intellectual disabilities
Isoforms
Mental disorders
Mental Disorders - genetics
Molecular modelling
Molecular Sequence Annotation
Neocortex
Neocortex - embryology
Neocortex - metabolism
Neurodevelopmental disorders
Neurogenesis
Neurogenesis - genetics
Protein Isoforms - genetics
Protein Isoforms - metabolism
Protein structure
Proteins
Proteomes
Ribonucleic acid
RNA
RNA Splicing
RNA-binding protein
RNA-Binding Proteins - genetics
RNA-Binding Proteins - metabolism
Single-Cell Analysis
Therapeutic applications
Transcriptome
Transcriptomes
Transcriptomics
Transcripts (Written Records)
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Summary:RNA splicing is highly prevalent in the brain and has strong links to neuropsychiatric disorders; yet, the role of cell type–specific splicing and transcript-isoform diversity during human brain development has not been systematically investigated. In this work, we leveraged single-molecule long-read sequencing to deeply profile the full-length transcriptome of the germinal zone and cortical plate regions of the developing human neocortex at tissue and single-cell resolution. We identified 214,516 distinct isoforms, of which 72.6% were novel (not previously annotated in Gencode version 33), and uncovered a substantial contribution of transcript-isoform diversity—regulated by RNA binding proteins—in defining cellular identity in the developing neocortex. We leveraged this comprehensive isoform-centric gene annotation to reprioritize thousands of rare de novo risk variants and elucidate genetic risk mechanisms for neuropsychiatric disorders.
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Author contributions: A.P., M.J.G., and L.d.l.T.-U. conceived and designed the study. C.K.V. and L.d.l.T.-U. collected and processed the tissue specimens and dissected the samples for processing. A.P. and L.d.l.T.-U. generated the library for scIso-Seq. A.P. processed the single-cell raw data and performed the validation experiments. C.J. and A.P. analyzed bulk tissue Iso-Seq data; C.J. and M.J.G. analyzed bulk tissue isoform switching; P.Z., X.W., and C.L. performed the proteomic analysis; N.G. performed the APA analysis; C.K.V. performed the RBP-associated analysis; C.K.V., L.d.l.T.-U., and M.J.G. conducted network analyses; A.P., C.J., and M.M. performed scIso-Seq analysis; and M.K., D.V., and A.P. performed single-cell isoform-switch analysis. X.G. and J.J.L. performed single-cell DTU analysis; A.P. and L.d.l.T.-U. analyzed the DTU results; and M.J.G., L.d.l.T.-U., P.Z., K.H., C.J., A.P., and B.P. performed the disease enrichment analysis. A.P., C.K.V., M.J.G., and L.d.l.T.-U. interpreted the data. A.P., C.K.V., P.Z., M.J.G., and L.d.l.T.-U. wrote the manuscript.
These authors contributed equally to this work.
ISSN:0036-8075
1095-9203
1095-9203
DOI:10.1126/science.adh7688