Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

• 成果类型: Article
• 署名作者: 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
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of Pennsylvania; University of Pennsylvania; University of Pennsylvania; Pennsylvania Medicine; Childrens Hospital of Philadelphia; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of Tennessee System; University of Tennessee Health Science Center; St Jude Children's Research Hospital; State University of New York (SUNY) System; SUNY Upstate Medical University; Central South University; Central South University; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-13653
• DOI: 10.1126/science.adh7688
• 发表日期: 2024-05-24
• 关键词: messenger-rna; brain-development; gene-expression; radial glia; cell; landscape; transcriptome; neurogenesis; DISCOVERY; SEQUENCES

摘要

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.