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，很明显基因组重排通常是神经系统疾病的突变类型。这不仅适用于神经发育障碍，如智力障碍 (ID) 和不同可识别的人类畸形模式（如波托茨基-卢普斯基综合征），也适用于迟发性成人神经障碍，如夏科-马里-图思病。此外，基因组重排通常可能是复杂性状和散发性疾病的基础，例如帕金森病、阿尔茨海默病和其他神经退行性疾病。与之前的解释相反，疾病相关基因组重排的实验评估经常证明它们可能比预期复杂得多。复杂性可能发生在单个基因座上，并给出在全基因组阵列 CGH 上观察到的复杂基因组重排 (CGR) 的特定模式；例如重复-正常-重复 (DUP-NML-DUP)，或嵌入重复中的三重复制 (DUP-TRP-DUP)。此外，基因组水平上可能发生复杂性，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碎裂现象，以及实验观察到的不寻常的多个从头拷贝数变异（CNV）模式，这些变异明显随机地分布在整个基因组中。阐明产生如此复杂性的机制是一个新兴领域。我们建议进一步表征与神经系统疾病相关的 CGR。具体来说，我们将研究：1) CGR，其组成为：i) DUP-NML-DUP 模式和 ii) 嵌入基因组重复片段中的反向三重片段模式 (DUP-TRP/INV-DUP)；这些是新观察到的 CGR 类型，在我们之前的申请中阐明了一种提议的机制； 2）循环三倍的机制； 3）阐明CGR的潜在分子特征和断点连接，这些特征和断点连接伴随着杂合性缺失（AOH）的长基因组延伸，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) 我们将尝试分离对看似随机分布在整个基因组中的多个从头 CNV 现象重要的基因。用于实现这些具体目标中每一项的实验方法现在已经触手可及。这些研究主要需要能够进行全基因组变异分析的基因组方法，例如阵列比较基因组杂交、全基因组 SNP 芯片、全外显子组测序 (WES)、全基因组测序 (WGS) 以及用于描绘特定断点连接的其他作图和分子方法。预计这些研究将描述这些新型重排的特征，并进一步深入了解驱动基因和基因组进化并可能导致多种神经系统疾病的基本分子突变机制。