Differential CpG Island Methylation in Down Syndrome

描述(申请人提供)：唐氏综合症是由21三体(TS21)(21号染色体的一个额外拷贝)引起的。TS21导致广泛的表型，包括智力低下和各种心脏缺陷。TS21是了解非整倍体或异常染色体数目及其引起的大量遗传疾病的主要模型。关于唐氏综合症的病理最广泛接受的假说是众所周知的基因剂量假说。与正常人相比，唐氏综合征患者21号染色体的RNA转录本增加。许多转录本的表达水平远远高于或低于理论上1.5倍的增幅，这表明除了21号染色体的三个副本外，还有其他因素参与调节RNA转录本的水平。表观遗传修饰是转录调控的主要来源。这项拟议研究的广泛和长期目标是了解TS21中发生的任何表观遗传学变化，以此作为染色体拷贝数增加引起的其他疾病的模型。表观遗传变化将通过使用亚硫酸氢盐测序确定CpG岛的甲基化状态来检查。亚硫酸氢盐测序技术的进步将允许产生大量数据，为甲基化变化的全面数据提供机会。将开发数据分析和可视化工具，以准确和完整地了解数据。遗传物质的异常数量是遗传病的主要原因。在唐氏综合症中，额外的21号染色体拷贝会导致21号染色体产生的RNA水平增加，最终导致这种疾病的特征。理解DNA的修饰(它在产生多少RNA方面起着重要作用)是理解这些类型的遗传疾病的重要一步。这项拟议的研究将检查唐氏综合症患者的DNA修饰及其与RNA水平的关系。这项研究的结果将作为遗传物质异常数量引起的其他疾病的模型。

DESCRIPTION (provided by applicant): Down syndrome is caused by trisomy 21 (TS21) (an extra copy of chromosome 21). TS21 leads to a broad spectrum of phenotypes including mental retardation and various heart defects. TS21 is the primary model for understanding aneuploidies or aberrant chromosomal numbers and the numerous genetic disorders they cause. The most widely accepted hypothesis concerning the pathology of Down syndrome is known as the gene dosage hypothesis. Chromosome 21 RNA transcripts are increased in individuals with Down syndrome as compared to the RNA transcripts in normal individuals. Many transcripts are expressed at much higher or lower levels than the theoretical 1.5 fold increase, which indicates that factors other than the three copies of chromosome 21 are involved in regulating the RNA transcript levels. Epigenetic modifications are a major source of transcription control. The broad, long-term objective of the proposed research is to understand any epigenetic changes occurring in TS21 as a model for other disorders caused by increases in chromosomal copy number. Epigenetic changes will be examined by determining the methylation status of CpG islands using bisulfite sequencing. Advances in bisulfite sequencing technology will allow large amounts of data to be generated, providing the opportunity for comprehensive data on methylation changes. Data analysis and visualization tools will be developed to provide an accurate and complete understanding of the data. Abnormal amounts of genetic material are a primary cause of genetic disorders. In Down syndrome, an extra copy of chromosome 21 leads to an increase in the level of RNA generated from chromosome 21 and ultimately the features of the disorder. Understanding modification of the DNA (which plays a significant role in how much RNA is generated) is an important step in understanding these types of genetic disorders. The proposed research will examine DNA modifications and their relationship to RNA levels in Down syndrome. The results of this research will act as a model for other disorders caused by abnormal amounts of genetic material.