STRUCTURAL VARIATION IN NEUROLOGICAL DISEASE

在过去的二十年中，基因组重排通常是神经系统疾病的基础突变类型已经变得很明显。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综合征），但也适用于迟发性成人神经系统疾病，如Charcot-Marie-Tooth病。此外，基因组重排往往是复杂性状和散发性疾病（如帕金森病、阿尔茨海默病和其他神经退行性疾病）的基础。与先前的解释相反，对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的要复杂得多。复杂性可以发生在单个基因座上，并给出复杂基因组重排（CGR）的特定模式，如在全基因组阵列CGH上观察到的;如复制-正常-复制（DUP-NML-DUP）或嵌入复制内的三重（DUP-TRP-DUP）。此外，复杂性可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体断裂现象，以及在整个基因组中明显随机分布的多个从头拷贝数变体（CNV）的不寻常的实验观察模式。阐明能够产生这种复杂性的机制是一个新兴领域。我们建议进一步表征已发现与神经系统疾病相关的CGR。具体来说，我们将研究：1）CGR，其由以下组成：i）DUP-NML-DUP模式和ii）嵌入基因组的重复片段内的反向三重片段的模式（DUP-TRP/INV-DUP）;这些是新观察到的CGR类型，其中一个提出的机制在我们以前的申请中阐明; 2）复发性三重化的机制; 3）阐明CGR的潜在分子特征和断裂点连接，其伴随着长的基因组不存在杂合性（AOH），并导致基因组（CGR）和遗传（AOH）改变; 4）β-Alu重排及其在基因组不稳定性和疾病中的作用和5）我们将尝试分离对似乎随机分布在整个基因组中的多个从头CNV现象重要的基因。现在，我们已经可以利用实验方法来实现这些具体目标。这些研究主要需要能够进行全基因组变异测定的基因组方法，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。预计这些研究将表征这些新型重排，并进一步深入了解驱动基因和基因组进化的基本分子突变机制，这些机制可能导致无数神经系统疾病。

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.