STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE

神经系统疾病的结构变异

• 批准号: 10530664
• 负责人: JAMES R. LUPSKI
• 金额: $ 71.52万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10530664
• 关键词: Adult; Alzheimer' s Disease; Automobile Driving; Behavior Disorders; Biological Assay; Characteristics; Charcot-Marie-Tooth Disease; Chromosomal Rearrangement; Complex; Copy Number Polymorphism; DNA Sequence Rearrangement; Diagnostic; Disease; Evaluation; Evolution; Gene Dosage; Gene Rearrangement; Genes; Genetic; Genome; Genomic Instability; Genomic Segment; Genomic approach; Genomics; Heterozygote; Human; Individual; Intellectual functioning disability; Malignant Neoplasms; Maps; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Parkinson Disease; Pattern; Potocki-Lupski syndrome; Precision Medicine Initiative; Process; Recurrence; Role; SNP array; Schizophrenia; Stretching; Variant; autism spectrum disorder; chromothripsis; comparative genomic hybridization; exome sequencing; gene correction; genome sequencing; genome-wide; insight; malformation; nervous system disorder; novel; trait; whole genome

During the previous two decades it has become apparent that genomic rearrangements are often the type of mutation that underlies neurological disease. This is so not only for neurodevelopmental disorders such as intellectual disability (ID) and different recognizable patterns of human malformation (e.g., Potocki-Lupski syndrome), but also for late-onset adult neurological disorders such as Charcot-Marie-Tooth disease. Moreover, genomic rearrangement can often underlie complex traits and sporadic diseases such as Parkinson’s, Alzheimer’s disease and other neurodegenerative processes. Contrary to prior interpretations, experimental evaluation of disease associated genomic rearrangements has often documented that they can be much more complex than anticipated. Complexities can occur at individual loci and give specific patterns for complex genomic rearrangements (CGR) as observed on genome-wide array CGH; such as duplication-normal-duplication (DUP-NML-DUP), or a triplication embedded within duplications (DUP-TRP-DUP). Furthermore, complexities can occur on a genomic level leading to complex chromosomal rearrangements (CCR) and the phenomena of chromothripsis observed both in cancer and neurodevelopmental disorders, as well as an unusual experimentally observed pattern of multiple de novo copy number variants (CNVs) spread apparently randomly throughout the genome. The elucidation of mechanisms that can generate such complexities is an emerging field. We propose to further characterize CGR that have been found in association with neurological disease. Specifically, we will investigate: 1) CGRs that consists of: i) a DUP-NML-DUP pattern and ii) a pattern of a triplicated segment in inverse orientation embedded within a duplicated segment of the genome (DUP-TRP/INV-DUP); these are newly observed types of CGR with one proposed mechanism elucidated in our previous application; 2) The mechanism for recurrent triplications; 3) Elucidate the underlying molecular characteristics and breakpoint junctions of CGR that are accompanied by long genomic stretches of absence of heterozygosity (AOH), and resulting in both genomic (CGR) and genetic (AOH) alterations; 4) Alu-Alu rearrangements and their role in genomic instability and disease and 5) We will attempt to isolate a gene important to the phenomena of multiple de novo CNV seemingly randomly distributed throughout the genome. The experimental approaches to be utilized to accomplish each one of these specific aims are now within our reach. These studies predominately require genomic approaches that enable genomewide assays of variation such as array comparative genomic hybridization, genomewide SNP chips, whole exome sequencing (WES), whole genome sequencing (WGS), and other mapping and molecular approaches for the delineation of specific breakpoint junctions. It is anticipated these studies will characterize these novel types of rearrangements and lend further insight into basic molecular mutational mechanisms driving gene and genome evolution and that can cause the myriad of neurological diseases.

在过去的二十年中，显然是基因组重排通常是神经系统疾病的突变类型。这不仅对于诸如智力障碍（ID）和人类畸形（例如Potocki-Lupski综合征）等神经发育障碍以及不同的可识别模式，而且对于较晚的成人神经系统疾病，例如Charcot-Marie-Marie-Marie-Marie-Tooth疾病。此外，基因组重排通常是复杂的特征和零星疾病的基础，例如帕金森氏病，阿尔茨海默氏病和其他神经退行性过程。与先前的解释相反，对疾病相关的基因组重排的实验评估通常证明它们可能比预期的要复杂得多。复杂性可以在单个基因座发生，并为整个基因组阵列CGH上观察到的复杂基因组重排（CGR）提供特定的模式。例如重复 - 纳式解读剂（DUP-NML-DUP），或重复嵌入重复（DUP-TRP-DUP）中的一式字母。此外，复杂性可能在基因组水平上发生，导致复杂的染色体重排（CCR）和在癌症和神经发育障碍中观察到的染色体的现象，以及在整个基因组中均随机传播的多个DE Novo拷贝数（CNVS）的多个Novo Novo拷贝数（CNVS）的异常实验模式。可以产生这种复杂性的机制的阐明是一个新兴领域。我们建议进一步表征与神经系统疾病相关的CGR。具体而言，我们将研究：1）由：i）DUP-NML-DUP模式组成的CGR和II）嵌入基因组重复段（DUP-TRP/INV-DUP）中的反向方向中的三分之一段的模式；这些是新观察到的类型的CGR类型，其在我们以前的应用中阐明了一种提议的机制； 2）复发性一式三份的机制； 3）阐明了CGR的潜在分子特征和断点连接，伴随着长长的基因组缺乏杂合性（AOH），并导致基因组（CGR）和遗传（AOH）改变； 4）ALU-ALU重排及其在基因组不稳定性和疾病中的作用，5）我们将尝试将一个重要的基因分离出对多个从头CNV现象的重要性，看似随机分布在整个基因组中。现在，用于实现这些特定目标的每一种实验方法现在都在我们的范围内。这些研究主要采用基因组方法，以使诸如阵列比较基因组杂交，全基因组SNP芯片，整个外显子组测序（WES），全基因组测序（WGS）以及其他映射和分子方法的基因组测定法，例如阵列比较基因组杂交，全基因组测序（WES），全基因组测序（WES）。预计这些研究将表征这些新型的重排类型，并进一步了解驱动基因和基因组进化的基本分子突变机制，并可能导致无数的神经系统疾病。