Epigenetic loss of heterozygosity in a recurrent neurodevelopmental CNV region

描述（由申请人提供）：由相似基因型引起的表型变异是医学遗传学的主要挑战。即使是密切相关的相同突变的携带者也经常有截然不同的表型。造成这种变异的分子和遗传机制尚不清楚。我们在占asd 1%的16p11.2区域发现了拷贝数变异（CNV）。在整个基因组中，CNVs与基因表达水平相关，这被认为是致病性的机制。因此，血液中的16p11.2基因组缺失/重复与该区域基因的低/高表达相关。然而，bbb25基因的这种主要破坏的外显子是不完整的，表达是非常可变的。我们最近发现了一个广泛的表观遗传机制，它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缺失（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对分子和表型变异有显著但未被充分认识的贡献。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调控的机制洞察，以及在神经发育过程中经历eLOH的基因可能会放大或减少的表达和表型变异的来源。本项目的目的是建立一个实验平台，了解神经发育CNV背景下影响基因表达（eLOH）的表观遗传机制与遗传拷贝数变异之间的相互作用。我们将结合两个领先实验室的专业知识和独特的试剂，以便开始解决这个基因调控的基本问题。

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.