%0 Journal Article
%T Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
%A Patowary A
%A Zhang P
%A Jops C
%A Vuong CK
%A Ge X
%A Hou K
%A Kim M
%A Gong N
%A Margolis M
%A Vo D
%A Wang X
%A Liu C
%A Pasaniuc B
%A Li JJ
%A Gandal MJ
%A de la Torre-Ubieta L
%J Science
%V 384
%N 6698
%D 2024 May 24
%M 38781356
%F 63.714
%R 10.1126/science.adh7688
%X 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.