{Reference Type}: Journal Article
{Title}: Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
{Author}: Patowary A;Zhang P;Jops C;Vuong CK;Ge X;Hou K;Kim M;Gong N;Margolis M;Vo D;Wang X;Liu C;Pasaniuc B;Li JJ;Gandal MJ;de la Torre-Ubieta L;
{Journal}: Science
{Volume}: 384
{Issue}: 6698
{Year}: 2024 May 24
{Factor}: 63.714
{DOI}: 10.1126/science.adh7688
{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.