研究人员利用单分子长读测序技术，以组织和单细胞分辨率深入分析了发育中的人类新皮层的生发区和皮层板区域的全长转录本组。研究人员鉴定出了214516种不同的亚型，其中72.6%是新的亚型（以前未在Gencode 33版中注释过），并发现了转录本亚型多样性在确定发育中的新皮层细胞身份方面的巨大贡献：它受RNA结合蛋白的调控。研究人员利用这种以亚型为中心的全面基因注释，重新确定了数千个罕见新风险变异的优先次序，并阐明了神经精神疾病的遗传风险机制。
据悉，RNA剪接在大脑中非常普遍，与神经精神疾病有密切联系；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。
附：英文原文
Title: Developmental isoform diversity in the human neocortex informs neuropsychiatric risk mechanisms
Author: Ashok Patowary, Pan Zhang, Connor Jops, Celine K. Vuong, Xinzhou Ge, Kangcheng Hou, Minsoo Kim, Naihua Gong, Michael Margolis, Daniel Vo, Xusheng Wang, Chunyu Liu, Bogdan Pasaniuc, Jingyi Jessica Li, Michael J. Gandal, Luis de la Torre-Ubieta
Issue&Volume: 2024-05-24
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.
DOI: adh7688
Source: https://www.science.org/doi/10.1126/science.adh7688