Molecular Neurogenetics Unit and Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Am J Hum Genet. 2014 Jun 5;94(6):870-83. doi: 10.1016/j.ajhg.2014.05.004.
Reciprocal copy-number variation (CNV) of a 593 kb region of 16p11.2 is a common genetic cause of autism spectrum disorder (ASD), yet it is not completely penetrant and can manifest in a wide array of phenotypes. To explore its molecular consequences, we performed RNA sequencing of cerebral cortex from mouse models with CNV of the syntenic 7qF3 region and lymphoblast lines from 34 members of 7 multiplex ASD-affected families harboring the 16p11.2 CNV. Expression of all genes in the CNV region correlated well with their DNA copy number, with no evidence of dosage compensation. We observed effects on gene expression outside the CNV region, including apparent positional effects in cis and in trans at genomic segments with evidence of physical interaction in Hi-C chromosome conformation data. One of the most significant positional effects was telomeric to the 16p11.2 CNV and includes the previously described "distal" 16p11.2 microdeletion. Overall, 16p11.2 CNV was associated with altered expression of genes and networks that converge on multiple hypotheses of ASD pathogenesis, including synaptic function (e.g., NRXN1, NRXN3), chromatin modification (e.g., CHD8, EHMT1, MECP2), transcriptional regulation (e.g., TCF4, SATB2), and intellectual disability (e.g., FMR1, CEP290). However, there were differences between tissues and species, with the strongest effects being consistently within the CNV region itself. Our analyses suggest that through a combination of indirect regulatory effects and direct effects on nuclear architecture, alteration of 16p11.2 genes disrupts expression networks that involve other genes and pathways known to contribute to ASD, suggesting an overlap in mechanisms of pathogenesis.
16p11.2 区 593kb 大小的同源序列拷贝数变异是自闭症谱系障碍（ASD）的常见遗传病因，但它的表现并不完全具有外显性，并且可表现出广泛的表型。为了探索其分子后果，我们对具有同源 7qF3 区拷贝数变异的小鼠模型的大脑皮层和携带 16p11.2 区拷贝数变异的 34 名 7 重 ASD 患者家系的淋巴母细胞系进行了 RNA 测序。该拷贝数变异区内所有基因的表达与其 DNA 拷贝数相关性良好，没有剂量补偿的证据。我们观察到了该拷贝数变异区外的基因表达效应，包括顺式和反式的位置效应，在 Hi-C 染色体构象数据中存在物理相互作用的基因组片段。最显著的位置效应之一位于 16p11.2 区拷贝数变异的远端，包含先前描述的“远端”16p11.2 微缺失。总体而言，16p11.2 区拷贝数变异与多个 ASD 发病机制假说相关基因和网络的表达改变有关，包括突触功能（如 NRXN1、NRXN3）、染色质修饰（如 CHD8、EHMT1、MECP2）、转录调控（如 TCF4、SATB2）和智力障碍（如 FMR1、CEP290）。然而，组织和物种之间存在差异，最强的效应始终存在于拷贝数变异区内。我们的分析表明，通过间接调控效应和对核结构的直接影响的组合，16p11.2 基因的改变破坏了涉及其他基因和已知与 ASD 相关的途径的表达网络，这表明发病机制的机制存在重叠。
