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

基本信息

批准号：
8922061
负责人：
Alexander Gimelbrant
金额：
$ 20.73万
依托单位：
DANA-FARBER CANCER INST
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-05 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8922061
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 Genomic Segment Genomics Genotype Health 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 Research Risk Role Series Source Tissues Variant Work X Inactivation autism spectrum disorder chromatin immunoprecipitation clinical phenotype deep sequencing disorder prevention epigenetic regulation genome-wide imprint induced pluripotent stem cell insight nerve stem cell neurodevelopment research study risk variant single molecule

项目摘要

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）：由相似基因型引起的表型变异是医学遗传学中的一个主要挑战。即使是具有相同突变的密切相关的携带者也常常具有截然不同的表型。人们对造成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 (CNV)，该区域占 ASD 的百分之一。在整个基因组中，CNV 与基因表达水平相关，这被认为是致病机制。因此，血液中的 16p11.2 基因组缺失/重复与该区域基因的较低/较高表达相关。然而，>25 个基因的这种主要破坏的外显率是不完整的，并且表达变化极大。我们最近发现了一种广泛存在的表观遗传机制，它对基因表达及其变异性具有重大影响。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 区域的多个基因。我们假设 eLOH 对分子变异和表型变异具有显着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 可以从机制上洞察 eLOH 的调节，以及表达和表型变异的来源，这些变异可能会因基因的变化而被放大或减弱。神经发育期间的 eLOH。该项目的目的是建立一个实验平台，用于了解影响基因表达的表观遗传机制 (eLOH) 与神经发育 CNV 背景下的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试剂，以开始解决基因调控的这一基本问题。