STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE

摘要 在过去的二十年里，基因组重排通常是一种 导致神经系统疾病的突变。这不仅适用于神经发育障碍，如 智力残疾(ID)和人类畸形的不同可识别模式(例如Potocki-Lupski 综合症)，但也用于迟发性成人神经疾病，如夏科-玛丽-图斯病。 此外，基因组重排往往会导致复杂的特征和零星的疾病，如帕金森氏症， 阿尔茨海默病和其他神经退行性疾病。与先前的解释相反，实验性的 对疾病相关基因组重排的评估通常证明它们可以更多 比预想的要复杂。复杂性可以发生在单个基因座上，并给出复杂的特定模式 全基因组阵列CGH上观察到的基因组重排(CGR)，如复制正常- 复制(DUP-NML-DUP)或嵌入复制中的三重(DUP-Trp-DUP)。此外， 复杂性可能发生在基因组水平上，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质增多现象，以及 不寻常的实验观察到的多拷贝数变异(CNV)传播模式明显 在整个基因组中随机产生。对产生这种复杂性的机制的阐明是一种 新兴领域。我们建议进一步描述已发现的与神经病学相关的CGR 疾病。具体地说，我们将研究：1)CGRS，它包括：i)DUP-NML-DUP模式和ii)a 在基因组的复制片段中嵌入反向的三重片段的图案 (DUP-Trp/INV-DUP)；这些是新观察到的CGR类型，并在 我们以前的应用；2)循环三倍体的机制；3)阐明潜在的分子 伴随着基因组长时间缺失的CGR的特征和断点连接 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和疾病中的作用和5)我们将尝试分离一个基因 重要的是多个从头CNV似乎随机分布在整个基因组的现象。 用于实现这些特定目标中的每一个的实验方法现在都在我们的 伸手。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、整个外显子组测序(WES) 全基因组测序(WGS)，以及其他描绘的作图和分子方法 特定的断点连接。预计这些研究将描述这些新类型的 重排并进一步深入了解驱动基因和基因组的基本分子突变机制 进化，这会导致无数的神经疾病。

ABSTRACT 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, Alzheimer 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.