BACKGROUND The 15q13.3 microdeletion is associated with several neuropsychiatric disorders, including autism and schizophrenia. Previous association and functional studies have investigated the potential role of several genes within the deletion in neuronal dysfunction, but the molecular effects of the deletion as a whole remain largely unknown. METHODS Induced pluripotent stem cells, from 3 patients with the 15q13.3 microdeletion and 3 control subjects, were generated and converted into induced neurons. We analyzed the effects of the 15q13.3 microdeletion on genome-wide gene expression, DNA methylation, chromatin accessibility, and sensitivity to cisplatin-induced DNA damage. Furthermore, we measured gene expression changes in induced neurons with CRISPR (clustered regularly interspaced short palindromic repeats) knockouts of individual 15q13.3 microdeletion genes. RESULTS In both induced pluripotent stem cells and induced neurons, gene copy number change within the 15q13.3 microdeletion was accompanied by significantly decreased gene expression and no compensatory changes in DNA methylation or chromatin accessibility, supporting the model that haploinsufficiency of genes within the deleted region drives the disorder. Furthermore, we observed global effects of the microdeletion on the transcriptome and epigenome, with disruptions in several neuropsychiatric disorder-associated pathways and gene families, including Wnt signaling, ribosome function, DNA binding, and clustered protocadherins. Individual gene knockouts mirrored many of the observed changes in an overlapping fashion between knockouts. CONCLUSIONS Our multiomics analysis of the 15q13.3 microdeletion revealed downstream effects in pathways previously associated with neuropsychiatric disorders and indications of interactions between genes within the deletion. This molecular systems analysis can be applied to other chromosomal aberrations to further our etiological understanding of neuropsychiatric disorders.

中文翻译：

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15q13.3微缺失对人类诱导神经元转录组和表观基因组的网络效应

背景 15q13.3 微缺失与几种神经精神疾病有关，包括自闭症和精神分裂症。先前的关联和功能研究已经调查了几个基因在神经元功能障碍中缺失中的潜在作用，但作为一个整体的缺失的分子效应仍然很大程度上未知。方法 3 名 15q13.3 微缺失患者和 3 名对照受试者的诱导多能干细胞被生成并转化为诱导神经元。我们分析了 15q13.3 微缺失对全基因组基因表达、DNA 甲基化、染色质可及性和顺铂诱导的 DNA 损伤敏感性的影响。此外，我们测量了单个 15q13 基因敲除后诱导神经元中的基因表达变化。3个微缺失基因。结果 在诱导多能干细胞和诱导神经元中，15q13.3 微缺失内的基因拷贝数变化伴随着基因表达的显着降低，并且 DNA 甲基化或染色质可及性没有补偿性变化，支持缺失区域内基因单倍体不足的模型驱动混乱。此外，我们观察到微缺失对转录组和表观基因组的整体影响，包括 Wnt 信号传导、核糖体功能、DNA 结合和聚集的原钙粘蛋白在内的几个神经精神疾病相关通路和基因家族的中断。单个基因敲除反映了敲除之间以重叠方式观察到的许多变化。结论 我们对 15q13 的多组学分析。3 微缺失揭示了先前与神经精神疾病相关的通路中的下游效应以及缺失内基因之间相互作用的迹象。这种分子系统分析可以应用于其他染色体畸变，以进一步了解我们对神经精神疾病的病因学认识。