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.
摘要：
RNA剪接在大脑中非常普遍，并且与神经精神疾病有很强的联系；然而，细胞类型特异性剪接和转录本亚型多样性在人脑发育过程中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数测序,在组织和单细胞分辨率下,对发育中的人类新皮质生发区和皮质板区的全长转录组进行了深度分析.我们确定了214,516种不同的亚型，其中72.6%是新颖的(以前在Gencode版本33中没有注释)，并揭示了由RNA结合蛋白调节的转录物同工型多样性在定义发育中的新皮质中的细胞身份方面的重要贡献。我们利用这种全面的以同工型为中心的基因注释来重新确定数千个罕见的从头风险变异的优先级，并阐明神经精神疾病的遗传风险机制。
