Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms

Ashok Patowary(University of California, Los Angeles), Pan Zhang(University of California, Los Angeles), Connor Jops(Children's Hospital of Philadelphia), Celine K. Vuong(University of California, Los Angeles), Xinzhou Ge(University of California, Los Angeles), Kangcheng Hou(University of California, Los Angeles), Minsoo Kim(University of California, Los Angeles), Naihua N. Gong(University of Pennsylvania), Michael Margolis(University of California, Los Angeles), Daniel Vo(Children's Hospital of Philadelphia), Xusheng Wang(St. Jude Children's Research Hospital), Chunyu Liu(Central South University), Bogdan Paşaniuc(University of California, Los Angeles), Jingyi Jessica Li(University of California, Los Angeles), Michael J. Gandal(Children's Hospital of Philadelphia), Luis de la Torre-Ubieta(University of California, Los Angeles)
Science
May 23, 2024
10.1126/science.adh7688
Cited by 70Open Access
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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.

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