Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms
Ashok Patowary, Pan Zhang, Connor Jops, Celine K. Vuong, Xinzhou Ge, Kangcheng Hou, Minsoo Kim, Naihua N. Gong, Michael Margolis, Daniel Vo, Xusheng Wang, Chunyu Liu, Bogdan Paşaniuc, Jingyi Jessica Li, Michael J. Gandal, Luis de la Torre-Ubieta
Abstract
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.