Conversion of adenosine to inosine in RNA by ADAR enzymes, termed “RNA editing,” is essential for healthy brain development. Editing is dysregulated in neuropsychiatric diseases, but has not yet been investigated at scale at the level of individual neurons. We quantified RNA editing sites in nuclear transcriptomes of 3055 neurons from six cortical regions of a neurotypical female donor, and found 41,930 sites present in at least ten nuclei. Most sites were located within Alu repeats in introns or 3′ UTRs, and approximately 80% were cataloged in public RNA editing databases. We identified 9285 putative novel editing sites, 29% of which were also detectable in unrelated donors. Intersection with results from bulk RNA-seq studies provided cell-type and spatial context for 1730 sites that are differentially edited in schizophrenic brain donors, and 910 such sites in autistic donors. Autism-related genes were also enriched with editing sites predicted to modify RNA structure. Inhibitory neurons showed higher overall transcriptome editing than excitatory neurons, and the highest editing rates were observed in the frontal cortex. We used generalized linear models to identify differentially edited sites and genes between cell types. Twenty nine genes were preferentially edited in excitatory neurons, and 43 genes were edited more heavily in inhibitory neurons, including RBFOX1, its target genes, and genes in the autism-associated Prader–Willi locus (15q11). The abundance of SNORD115/116 genes from locus 15q11 was positively associated with editing activity across the transcriptome. We contend that insufficient editing of autism-related genes in inhibitory neurons may contribute to the specific perturbation of those cells in autism.

中文翻译：

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以单细胞分辨率进行 RNA 编辑的调查将中间神经元与精神分裂症和自闭症联系起来

通过 ADAR 酶将 RNA 中的腺苷转化为肌苷，称为“RNA 编辑”，对于健康的大脑发育至关重要。编辑在神经精神疾病中失调，但尚未在单个神经元水平上进行大规模研究。我们量化了来自神经典型女性供体的六个皮质区域的 3055 个神经元的核转录组中的 RNA 编辑位点，并发现至少 10 个细胞核中存在 41,930 个位点。大多数位点位于内含子或 3' UTR 中的 Alu 重复序列内，大约 80% 被编入公共 RNA 编辑数据库中。我们确定了 9285 个推定的小说编辑位点，其中 29% 在无关的捐赠者中也可检测到。与大量 RNA-seq 研究的结果相交为精神分裂症脑供体中差异编辑的 1730 个位点提供了细胞类型和空间背景，和 910 个这样的站点在自闭症捐赠者中。自闭症相关基因也富含预测修饰 RNA 结构的编辑位点。抑制性神经元显示出比兴奋性神经元更高的整体转录组编辑，并且在额叶皮层中观察到最高的编辑率。我们使用广义线性模型来识别细胞类型之间差异编辑的位点和基因。29 个基因在兴奋性神经元中被优先编辑，43 个基因在抑制性神经元中被更重地编辑，包括 我们使用广义线性模型来识别细胞类型之间差异编辑的位点和基因。29 个基因在兴奋性神经元中被优先编辑，43 个基因在抑制性神经元中被更重地编辑，包括 我们使用广义线性模型来识别细胞类型之间差异编辑的位点和基因。29 个基因在兴奋性神经元中被优先编辑，43 个基因在抑制性神经元中被更重地编辑，包括RBFOX1、其靶基因以及自闭症相关的 Prader–Willi 基因座 (15q11) 中的基因。来自基因座 15q11 的 SNORD115/116 基因的丰度与整个转录组的编辑活动呈正相关。我们认为抑制性神经元中自闭症相关基因的编辑不足可能导致自闭症中这些细胞的特定扰动。