Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms.
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人类新皮质的发育亚型多样性揭示了神经精神风险机制。
DOI：
10.1101/2023.03.25.534016
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
delaTorre-Ubieta,Luis
中科院分区：
文献类型：
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作者：
Patowary,Ashok;Zhang,Pan;Jops,Connor;Vuong,CelineK;Ge,Xinzhu;Hou,Kangcheng;Kim,Minsoo;Gong,Naihua;Margolis,Michael;Vo,Daniel;Wang,Xusheng;Liu,Chunyu;Pasaniuc,Bogdan;Li,JingyiJessica;Gandal,MichaelJ;delaTorre-Ubieta,Luis
RNA剪接在大脑中非常普遍，与神经精神疾病有很强的联系;然而，在人类大脑发育过程中细胞类型特异性剪接和转录异构体多样性的作用尚未得到系统研究。在这项工作中，我们利用单分子长读测序，以组织和单细胞分辨率深入分析发育中的人类新皮质的生发区和皮质板区域的全长转录组。我们确定了214，516种不同的亚型，其中72.6%是新的（以前没有在Gencode版本33中注释），并揭示了转录本亚型多样性的实质性贡献-由RNA结合蛋白调节-在定义发育中的新皮层细胞身份。我们利用这种全面的以亚型为中心的基因注释来重新优先考虑数千种罕见的新发风险变体，并阐明神经精神疾病的遗传风险机制。
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.