COMPLEX GENOMIC REARRANGEMENTS IN NEUROLOGICAL DISEASE

神经系统疾病中的复杂基因组重排

• 批准号: 9114666
• 负责人: JAMES R. LUPSKI
• 金额: $ 55.5万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9114666
• 关键词: Address; Adult; Alzheimer' s Disease; Autistic Disorder; Behavior Disorders; Biological Assay; Characteristics; Charcot-Marie-Tooth Disease; Chromosomal Rearrangement; Chromosomes; Clinical; Complex; Consensus; Copy Number Polymorphism; DNA Sequence Rearrangement; Data; Development; Diagnostic; Disease; Evaluation; Event; Family; Family Study; Frequencies; Gene Dosage; Genes; Genetic; Genome; Genome Stability; Genomic approach; Genomics; Germ Cells; Grant; Haploidy; Health; Heterozygote; Homologous Gene; Human; Human Genome; Individual; Intellectual functioning disability; Laboratory Study; Length; Malignant Neoplasms; Maps; Mediating; Mental Retardation; Modeling; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Neurodevelopmental Disorder; Neurologic; Neuropathy; PMP22 gene; Parents; Parkinson Disease; Patients; Pattern; Pelizaeus-Merzbacher Disease; Phenotype; Population; Process; Public Health; Recurrence; Resolution; SNP array; Schizophrenia; Sequence Analysis; Sister Chromatid; Somatic Cell; Stretching; Structure; Syndrome; Testing; Variant; chromothripsis; comparative genomic hybridization; disease phenotype; dosage; exome sequencing; genome sequencing; genome-wide; infancy; insight; malformation; nervous system disorder; novel; trait; whole genome

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.

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神经系统疾病的突变类型。这不仅对于神经发育障碍，例如智力障碍（ID）和人类畸形的不同可识别模式（例如Potocki-Lupski综合征），而且对于晚期成人神经系统疾病，例如Charcot-Marie-Marie-Marie-Marie-Tooth病。此外，基因组重排通常是复杂性状和零星疾病的基础，例如帕金森氏症，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，并为复杂的基因组重排（CGR）提供特定模式，例如重复 - 正常 - 复制（DUP-NML-DUP），或重复（DUP-TRP-DUP）中嵌入的一式固定。此外，复杂性可能在基因组水平上发生，从而导致复杂的染色体重排，并且在癌症和神经发育障碍中观察到的染色体术的现象，以及多个从头拷贝数变体（CNV）的异常模式，在整个基因组中都显着随机分布。可以产生这种复杂性的机制的阐明是一个真正起步阶段的领域。 我们建议进一步表征与神经疾病有关的复杂基因组重排（CGR）。具体而言，我们将研究并尝试阐明：1）由嵌入基因组重复段（DUP-trp/Invup）中的反向取向中的三式段段组成的CGR；在我们以前的应用中阐明了一种新观察到的CGR类型； 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裂点连接，这些特征伴随着长长的基因组缺失的杂合性（AOH）（AOH），并导致基因组（CGR）和遗传（AOH）的变化，以及4），我们将试图孤立在多个DE​​ Novo CNV的现象中，我们将尝试分离出一个随机分配的基因。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。它主要需要基因组方法，以促进基因组范围的测定法，例如阵列比较基因组杂交，全基因组SNP芯片，外显子组测序，整个基因组测序以及其他特定断裂点连接划分的绘制的映射和分子方法。预计这些AIS的完成将表征这些新型的重排类型，并进一步了解可能导致无数神经疾病的基本分子突变机制。