COMPLEX GENOMIC REARRANGEMENTS IN NEUROLOGICAL DISEASE

描述（由申请人提供）：在过去的二十年中，很明显，基因组重排通常是导致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Potocki- Lupski综合征），也适用于迟发性成人神经障碍，如Charcot-Marie-Tooth病。此外，基因组重排往往是复杂特征和散发性疾病（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，与疾病相关的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，并为复杂的基因组重排（CGR）提供特定的模式，如重复-正常-重复（DUP-NML-DUP），或重复内嵌的三次重复（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和在癌症和神经发育障碍中观察到的染色体分裂现象，以及在整个基因组中明显随机分布的多个新生拷贝数变异（cnv）的不寻常模式。对能够产生如此复杂性的机制的阐明是一个真正处于起步阶段的领域。我们建议进一步表征与神经系统疾病相关的复杂基因组重排（CGR）。具体来说，我们将研究并试图阐明以下机制：1)由反向复制的基因组片段（DUP-TRP/INV-DUP）组成的CGR；一种新观测到的CGR类型，其机制在我们之前的应用中得到了阐明；2)反复发作的机制；3)阐明CGR的潜在分子特征和断点连接点，这些特征伴随着基因组的缺乏杂合性（AOH），并导致基因组（CGR）和遗传（AOH）的改变；4)我们将尝试分离一个对基因组中随机分布的多重新生CNV现象很重要的基因。用于实现这些具体目标的实验方法现在已经触手可及。它主要需要能够进行全基因组变异分析的基因组方法，如阵列比较基因组杂交、全基因组SNP芯片、外显子组测序、全基因组测序以及其他用于描述特定断点连接的作图和分子方法。预计这些ai的完成将表征这些新型重排，并进一步深入了解可能导致无数神经系统疾病的基本分子突变机制。

DESCRIPTION (provided by applicant): 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) 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 and the phenomena of chromothripsis observed both in cancer and neurodevelopmental disorders, as well as an unusual 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 a field that is truly in its infancy. We propose to further characterize complex genomic rearrangements (CGR) that have been found in association with neurological disease. Specifically, we will investigate and attempt to elucidate mechanisms for: 1) A CGR that consists of a triplicated segment in inverse orientation embedded within a duplicated segment of the genome (DUP-TRP/INV-DUP); a newly observed type of CGR with a 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, and 4) 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. It predominately requires genomic approaches that enable genomewide assays of variation such as array comparative genomic hybridization, genomewide SNP chips, exome sequencing, whole genome sequencing, and other mapping and molecular approaches for the delineation of specific breakpoint junctions. It is anticipated that completion of these ais will characterize these novel types of rearrangements and lend further insight into basic molecular mutational mechanisms that can cause myriad of neurological diseases.