Epigenetic loss of heterozygosity in a recurrent neurodevelopmental CNV region

描述（由申请人提供）：相似基因型导致的表型变异性是医学遗传学的主要挑战。即使是具有相同突变的密切相关的携带者也往往具有截然不同的表型。导致这种变异的分子和遗传机制知之甚少。我们在16p11.2区域发现了一个拷贝数变异体（CNV），占ASD的1%。在整个基因组中，CNV与基因表达水平相关，这被认为是致病的机制。因此，血液中16p11.2基因组缺失/重复显示与该区域基因的较低/较高表达相关。然而，这种>25个基因的主要破坏的表达是不完全的，并且表达是极其可变的。我们最近发现了一个广泛的表观遗传机制，对基因表达及其变异性有重大影响。这种机制，单等位基因表达或表观遗传杂合性丢失（eLOH），影响超过四分之一的人类常染色体基因，包括16p11.2区域的几个基因。我们假设eLOH对分子变异和表型变异有重要的贡献，但未被充分认识。拷贝数变异与eLOH的相互作用是一个完全未知的领域，了解基因组拷贝数如何影响eLOH可能会导致对eLOH调控的机制性认识，以及表达和表型变异的来源，这些变异可能会在神经发育过程中放大或缩小经历eLOH的基因。本项目的目的是建立一个实验平台，了解影响基因表达的表观遗传机制（eLOH）和遗传拷贝数变异的背景下，神经发育CNV之间的相互作用。我们将联合收割机结合两个领先实验室的专业知识和独特试剂，以开始解决基因调控的这一基本问题。

DESCRIPTION (provided by applicant): Variability of phenotypes resulting from similar genotypes is a major challenge in medical genetics. Even closely related carriers of the same mutation often have drastically distinct phenotypes. Molecular and genetic mechanisms contributing to such variability are poorly understood. We identified a copy number variant (CNV) in 16p11.2 region which accounts for one percent of ASDs. Across the genome, CNVs are associated with gene expression level, which is thought to be the mechanism of pathogenicity. Accordingly, the 16p11.2 genomic deletion/duplication was shown in blood to be correlated with lower/higher expression across the genes in the region. However, the penetrance for this major disruption of >25 genes is incomplete and the expression is extremely variable. We recently uncovered a widespread epigenetic mechanism that has major impact on gene expression and its variability. This mechanism, monoallelic expression or epigenetic loss of heterozygosity (eLOH), affects more than a quarter of human autosomal genes, including several genes in the 16p11.2 region. We hypothesize that eLOH has a significant yet underappreciated contribution to molecular and thus phenotypic variation. The interaction of copy number variation with eLOH is a completely uncharted territory and understanding how genomic copy number influences eLOH could lead to mechanistic insight into the regulation of eLOH as well as a source of expression and phenotypic variability that might be magnified or diminished for genes undergoing eLOH during neurodevelopment. The purpose of this project is to establish an experimental platform for understanding the interaction between an epigenetic mechanism affecting gene expression (eLOH) and genetic copy number variation in the context of a neurodevelopmental CNV. We will combine expertise and unique reagents of two leading laboratories in order to start addressing this fundamental question of gene regulation.