Nonrecurrent rearrangements, genome architecture and neurodegenerative disease.

非复发性重排、基因组结构和神经退行性疾病。

• 批准号: 7650633
• 负责人: JAMES R. LUPSKI
• 金额: $ 53.73万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7650633
• 关键词: 17p; Address; Affect; Alzheimer' s Disease; Architecture; Autistic Disorder; Base Sequence; Behavior Disorders; Benign; Bioinformatics; Biological Assay; Charcot-Marie-Tooth Disease; Chromosomes; Code; Complex; Copy Number Polymorphism; DNA Sequence; DNA Sequence Rearrangement; Diagnostic; Disease; Event; Gene Dosage; Genes; Genetic Recombination; Genome; Genomics; Homologous Gene; Inherited; Ligation; Maps; Mental Retardation; Mutation; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neuropathy; Parents; Parkinson' s Dementia; Patients; Positioning Attribute; Predisposition; Public Health; Recurrence; Resolution; Schizophrenia; Structure; Syndrome; Technology; Therapeutic; X Chromosome; autosome; clinical application; clinical phenotype; cohort; comparative genomic hybridization; insight; nervous system disorder; trait

It has become apparent during the last 15 years that many neurological disease traits are not the result of coding region mutations within genes, but instead manifest because of alterations of the genome. Diseases due to genomic rearrangements have been referred to as genomic disorders. In the post-genomic era, with widespread clinical application of high-resolution genome analyses by comparative genome hybridization (aCGH) and other array technologies, submicroscopic rearrangements are increasingly being recognized as a cause of neurologic disease. Genomic rearrangements can be recurrent with fixed positions for genomic breakpoints or nonrecurrent varying in size and with different breakpoints, but sharing a Smallest Region of Overlap (SRO) of a specific genomic interval among unrelated patients. We hypothesize that nonrecurrent rearrangements may occur by mechanisms that are distinct from well-established recombination mechanisms and our PRELIMINARY STUDIES strongly support this hypothesis. Furthermore, we suggest that some nonrecurrent rearrangements may result because of specific genomic architectural features causing susceptibility to such rearrangements. We will investigate these hypotheses experimentally by: 1) mapping breakpoints of duplication rearrangements, 2) bioinformatic analyses of the genomic region undergoing rearrangement, and 3) determining the products of recombination through direct DNA sequencing. Non recurrent duplication of 17p associated with Potocki-Lupski Syndrome (PTLS). and non recurrent PMP22 rearrangements associated with CMT1A or HNPP neuropathy will be studied in detail. In this manner we will identify the substrates for recombination, gain insights into genome architecture and regions involved, and potentially infer mechanism. Three specific aims are proposed: (1) Determine the sizes and breakpoint junctions of duplications of the proximal short arm of chromosome 17 associated with the Potocki-Lupski syndrome; (2) Carefully examine trios of patients with Potocki-Lupski syndrome who have nonrecurrent duplications to determine parent of origin, and structure of the parental chromosome on which the de novo duplication occurred; and (3) From a large cohort of patients with neuropathy who are screened for the recurrent CMT1A duplication and HNPP deletion by multiplex ligation- dependent probe amplification (MLPA) identify those that DO NOT have the usual recurrent CMT1A duplication or HNPP deletion and examine the structure of such nonrecurrent rearrangements by aCGH and determine the sequence at the breakpoint junctions. Our findings will have widespread diagnostic and therapeutic implications for these and other neurodegenerative diseases that can result from gene copy number variation (CNV).

在过去的15年中，许多神经系统疾病特征不是基因内编码区域突变的结果，而是由于基因组的改变而表现出来。由于基因组重排引起的疾病已被称为基因组疾病。在基因组后时代，通过比较基因组杂交（ACGH）和其他阵列技术对高分辨率基因组分析的广泛临床应用，越来越多地被认为是造成神经系统疾病的原因。基因组重排可以复发具有基因组断点的固定位置，也可以在大小和不同的断点变化，但在无关患者中共享特定基因组间隔的重叠（SRO）最小的区域。我们假设这是非爆发的 重排可能是通过与建立良好的重组机制不同的机制进行的，我们的初步研究强烈支持这一假设。此外，我们建议可能由于特定的基因组建筑特征而导致一些非急流重排，从而导致对此类重排的敏感性。我们将通过以下方式在实验中研究这些假设，以下方法：1）映射重新排列的重新分组的断点，2）对进行重排的基因组区域的生物信息学分析，以及3）通过直接DNA测序来确定重组的产物。与波基 - 卢普斯基综合征（PTLS）相关的17p的非复发重复。将详细研究与CMT1A或HNPP神经病相关的非复发性PMP22重排。这样我们将 确定重组的底物，对所涉及的基因组结构和区域的见解，并有可能推断机制。提出了三个具体目的：（1）确定与Potocki-Lupski综合征相关的17染色体近端短臂重复的大小和断点连接； （2）仔细检查了具有非急性重复的Potocki-Lupski综合征患者的三重奏，以确定起源的父母和从头重复发生的亲本染色体的结构； （3）来自大量神经病患者的群体，这些患者被筛查，这些患者被筛查，以复发性CMT1A重复和HNPP删除，并通过多重连接依赖性探针扩增（MLPA）筛选那些没有常规的CMT1A doplication and Hnpp Pointer and Breakerrent Rebrent and rebrient ander的序列，并确定那些不常见的CMT1A的结构。 连接。我们的发现将对这些基因拷贝数（CNV）可能导致的这些神经退行性疾病具有广泛的诊断和治疗意义。