Epigenetic loss of heterozygosity in a recurrent neurodevelopmental CNV region

复发性神经发育 CNV 区域杂合性的表观遗传丧失

• 批准号: 8806270
• 负责人: Alexander Gimelbrant
• 金额: $ 24.83万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-05 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8806270
• 关键词: 16p11.2; Accounting; Address; Affect; Alleles; Biological Models; Blood; Buffers; Cell Communication; Cell Differentiation process; Cells; ChIP-seq; Chromatin; Clinical; Copy Number Polymorphism; Development; Diagnosis; Disease; Dose; Epigenetic Process; Fibroblasts; Gene Dosage; Gene Expression; Gene Expression Regulation; Gene Targeting; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Histone H3; Human; Human Genome; Individual; Laboratories; Lead; Link; Loss of Heterozygosity; Lysine; Maps; Medical Genetics; Messenger RNA; Methodology; Molecular; Molecular Genetics; Mutation; Natural experiment; Neurodevelopmental Disorder; Neurons; Parents; Pathogenicity; Patients; Pattern; Penetrance; Phenotype; Process; Property; Proteins; Reagent; Recurrence; Regulation; Research; Risk; Role; Series; Source; Tissues; Variant; Work; X Inactivation; autism spectrum disorder; chromatin immunoprecipitation; clinical phenotype; deep sequencing; disorder prevention; genome-wide; imprint; insight; nerve stem cell; neurodevelopment; public health relevance; research study; risk variant; single molecule

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.

描述(由申请人提供)：由相似的基因类型引起的表型的可变性是医学遗传学中的一个主要挑战。即使是关系密切的相同突变携带者，通常也有截然不同的表型。造成这种变异的分子和遗传机制还知之甚少。我们在16p11.2区域发现了一个拷贝数变异(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基因组的缺失/复制与该区域基因的低/高表达相关。然而，这种主要的基因突变的外显性是不完整的，表达也是极不稳定的。我们最近发现了一种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，即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对分子和表型变异有重要但被低估的贡献。拷贝数变化与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可能导致对ELoH调控的机械性洞察，以及在神经发育过程中ELoH基因的表达和表型变异可能被放大或减弱的来源。本项目的目的是建立一个实验平台，在神经发育CNV的背景下，了解影响基因表达的表观遗传学机制(ELoH)和遗传拷贝数变化之间的相互作用。我们将结合两个领先实验室的专业知识和独特的试剂，以开始解决这个基因调控的基本问题。