Role of Long-Range Chromatin Interactions in Genetic Disease

长程染色质相互作用在遗传性疾病中的作用

• 批准号: 8511702
• 负责人: ANDREW R HOFFMAN
• 金额: $ 34.04万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511702
• 关键词: 22q11; Affect; Biological Assay; Candidate Disease Gene; Cardiac; Cataloging; Catalogs; Cell Line; Cells; Chromatin; Chromosomal Rearrangement; Chromosome Mapping; Chromosomes; Chromosomes, Human, Pair 8; Complex; DNA; Development; Disease; Fluorescent in Situ Hybridization; Genes; Genetic; Genetic Risk; Genome; Genomics; Hereditary Disease; Human; Human Genome Project; Individual; Knockout Mice; Learning; Lesion; Malignant Neoplasms; Medical Genetics; Methodology; Molecular; Molecular Conformation; Patients; Phenotype; Publishing; RNA; Resolution; Role; Sampling; Schizophrenia; Syndrome; Testing; Variant; Work; cancer genetics; combinatorial; gene interaction; genetic risk factor; high risk; novel

DESCRIPTION (provided by applicant): A central paradigm of medical genetics is that the phenotype of a deletion syndrome results from the disruption of the deleted genes themselves. In direct contradistinction to this dogma, we propose that genetic diseases can be caused or modified by changes in physical, long-range interactions that normally occur between loci that are now deleted and genes that are far from the deleted region when plotted on a linear genetic map. In contrast to focusing on singe deletion-candidate gene interaction, though, we propose that a network of co- regulated genes physically co-localizes, and that phenotypic variation results from the combinatorial disruption of different spokes of this chromatin hub in different individuals. Since deletion syndromes are often characterized by multiple phenotypes, we will test our hypothesis on the most common genomic deletion disorder, deletion of human 22q11 (del22q11), which is characterized by remarkable phenotypic variation. del22q11 may be the most common genetic risk factor for schizophrenia. We have identified a hub of 13 genes on 8 chromosomes that physically interacts with 22q11. We will study DNA and RNA samples from fully phenotyped patients who harbor the deletion, as well as cell lines from normal and affected patients. 1) Using the Associated Chromosome Trap assay, our recently published novel methodology for discovering long-range chromatin interactions, we will identify all genes that physically interact with the commonly deleted region of 22q11. 2) We will confirm that these interactions occur in healthy individuals using fluorescent in situ hybridization and the high-resolution molecular assay chromosome conformation capture. 3) We can then use this catalog of associated genes to examine their potential roles in disease manifestation. 4) We will use knock-out mice to confirm the role of the genes in this hub in cardiac development and disease. This proposal is high-risk because we aim to focus on the physical network itself, rather than the high-yield disease-causing genes that compose those networks. The impact of this hypothesis will extend beyond genetic syndromes to chromosomal rearrangements in cancers, and it will uncover and explain genetic risks for complex diseases.

描述（由申请人提供）：医学遗传学的中心范式是缺失综合征的表型是由缺失基因本身的破坏引起的。与这一教条形成直接对比的是，我们提出，遗传疾病可以通过物理、远程相互作用的变化引起或改变，这种相互作用通常发生在现在被删除的基因座和绘制在线性遗传图谱上的远离删除区域的基因之间。然而，与关注单一缺失-候选基因相互作用相反，我们提出共同调控的基因网络在物理上共定位，并且表型变异是由不同个体中该染色质中心的不同辐条的组合破坏造成的。由于缺失综合征通常以多种表型为特征，因此我们将测试我们对最常见的基因组缺失疾病的假设，即人类 22q11 缺失 (del22q11)，其特征是显着的表型变异。 del22q11 可能是精神分裂症最常见的遗传风险因素。我们已经确定了 8 条染色体上 13 个基因的中心，这些基因与 22q11 发生物理相互作用。我们将研究来自具有缺失的完全表型患者的 DNA 和 RNA 样本，以及来自正常和受影响患者的细胞系。 1) 使用关联染色体陷阱测定（我们最近发表的用于发现长程染色质相互作用的新方法），我们将识别与 22q11 常见删除区域发生物理相互作用的所有基因。 2) 我们将使用荧光原位杂交和高分辨率分子分析染色体构象捕获来确认这些相互作用发生在健康个体中。 3）然后我们可以使用相关基因的目录来检查它们在疾病表现中的潜在作用。 4）我们将使用基因敲除小鼠来确认该中心的基因在心脏发育和疾病中的作用。这个提议是高风险的，因为我们的目标是关注物理网络本身，而不是组成这些网络的高产致病基因。这一假说的影响将超越遗传综合症，扩展到癌症中的染色体重排，并将揭示和解释复杂疾病的遗传风险。