Division of Developmental Medicine, Boston Children's Hospital, Boston, MA 02115, USA; Division of Genetics and Genomics, Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pediatrics, Harvard Medical School, Boston, MA 02115, USA.
Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Am J Hum Genet. 2024 Aug 8;111(8):1544-1558. doi: 10.1016/j.ajhg.2024.07.002. Epub 2024 Jul 29.
Recurrent copy-number variation represents one of the most well-established genetic drivers in neurodevelopmental disorders, including autism spectrum disorder. Duplication of 15q11-q13 (dup15q) is a well-described neurodevelopmental syndrome that increases the risk of autism more than 40-fold. However, the effects of this duplication on gene expression and chromatin accessibility in specific cell types in the human brain remain unknown. To identify the cell-type-specific transcriptional and epigenetic effects of dup15q in the human frontal cortex, we conducted single-nucleus RNA sequencing and multi-omic sequencing on dup15q-affected individuals (n = 6) as well as individuals with non-dup15q autism (n = 7) and neurotypical control individuals (n = 7). Cell-type-specific differential expression analysis identified significantly regulated genes, critical biological pathways, and differentially accessible genomic regions. Although there was overall increased gene expression across the duplicated genomic region, cellular identity represented an important factor mediating gene-expression changes. As compared to other cell types, neuronal subtypes showed greater upregulation of gene expression across a critical region within the duplication. Genes that fell within the duplicated region and had high baseline expression in control individuals showed only modest changes in dup15q, regardless of cell type. Of note, dup15q and autism had largely distinct signatures of chromatin accessibility but shared the majority of transcriptional regulatory motifs, suggesting convergent biological pathways. However, the transcriptional binding-factor motifs implicated in each condition implicated distinct biological mechanisms: neuronal JUN and FOS networks in autism vs. an inflammatory transcriptional network in dup15q microglia. This work provides a cell-type-specific analysis of how dup15q changes gene expression and chromatin accessibility in the human brain, and it finds evidence of marked cell-type-specific effects of this genetic driver. These findings have implications for guiding therapeutic development in dup15q syndrome, as well as understanding the functional effects of copy-number variants more broadly in neurodevelopmental disorders.
反复出现的拷贝数变异是神经发育障碍（包括自闭症谱系障碍）最确定的遗传驱动因素之一。15q11-q13 重复（dup15q）是一种描述明确的神经发育综合征，会使自闭症的风险增加 40 多倍。然而，这种重复在人类大脑特定细胞类型中的基因表达和染色质可及性的影响仍然未知。为了确定 dup15q 在人类额叶皮层中的特定细胞类型的转录和表观遗传效应，我们对受 dup15q 影响的个体（n=6）以及非 dup15q 自闭症个体（n=7）和神经典型对照个体（n=7）进行了单核 RNA 测序和多组学测序。特定细胞类型的差异表达分析确定了显著调节的基因、关键生物学途径和差异可及的基因组区域。尽管整个重复基因组区域的基因表达总体上增加，但细胞身份是介导基因表达变化的重要因素。与其他细胞类型相比，神经元亚型在重复区域内的关键区域表现出更高的基因表达上调。在对照个体中，位于重复区域内且基线表达较高的基因，无论细胞类型如何，在 dup15q 中仅显示出适度的变化。值得注意的是，dup15q 和自闭症在染色质可及性方面具有截然不同的特征，但共享大多数转录调控基序，表明存在趋同的生物学途径。然而，每种情况下涉及的转录结合因子基序暗示了不同的生物学机制：自闭症中的神经元 JUN 和 FOS 网络与 dup15q 小胶质细胞中的炎症转录网络。这项工作提供了 dup15q 如何改变人类大脑中基因表达和染色质可及性的特定细胞类型分析，并发现了这种遗传驱动因素对基因表达和染色质可及性具有显著的细胞类型特异性影响的证据。这些发现对于指导 dup15q 综合征的治疗发展以及更广泛地理解神经发育障碍中的拷贝数变异的功能影响具有重要意义。
