Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

• Published in: Science (American Association for the Advancement of Science) 2024-05, Vol.384 (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: Article
• Language: English
• 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; 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)
• ISSN: 0036-8075; 1095-9203; 1095-9203
• DOI: 10.1126/science.adh7688

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.