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：
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
项目类别：
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

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

展开

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）：相似基因型引起的表型的变异性是医学遗传学的主要挑战。即使是同一突变的紧密相关的载体通常具有截然不同的表型。促成这种变异性的分子和遗传机制知之甚少。我们确定了16p11.2区域中的拷贝数变体（CNV），该变体占ASD的百分之一。在整个基因组中，CNV与基因表达水平有关，这被认为是致病性的机理。因此，在血液中显示了16p11.2基因组缺失/重复与该地区整个基因的较低/较高表达相关。然而，这种重大破坏> 25个基因的外观不完整，并且表达式很大。我们最近发现了一种广泛的表观遗传机制，该机制对基因表达及其变异性产生了重大影响。这种机制，单等一的表达或杂合性的表观遗传丧失（ELOH）会影响超过四分之一的人类常染色体基因，包括16p11.2区域中的几个基因。我们假设ELOH对分子的贡献显着，因此对表型变异的贡献不足。拷贝数变化与ELOH的相互作用是一个完全未知的领域，并且了解基因组拷贝数如何影响ELOH可能会导致机械洞察ELOH调节的机理洞察力，以及在神经发育过程中对基因进行基因的表达和表型变异的来源。该项目的目的是建立一个实验平台，以了解影响基因表达（ELOH）的表观遗传机制与神经发育CNV背景下的遗传拷贝数变化之间的相互作用。我们将结合两个主要实验室的专业知识和独特的试剂，以开始解决这个基因调节的基本问题。