Molecular Dissection of the 22q11.2 Deletion Syndrome

22q11.2 缺失综合征的分子解剖

• 批准号: 10296523
• 负责人: BEVERLY S EMANUEL
• 金额: $ 53.7万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-15 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10296523
• 关键词: 22q; 22q11; 22q11.2; Affect; African; African American; Alleles; Automobile Driving; Characteristics; Child; Childhood; Chromosome 22; Chromosome Deletion; Chromosomes; Complex; Copy Number Polymorphism; DNA; DNA Sequence; Data; DiGeorge Syndrome; Disease; Dissection; Ethnic Origin; Event; Family; Fostering; Frequencies; Gene Rearrangement; General Population; Generations; Genetic Polymorphism; Genetic Recombination; Genetic Structures; Genome; Genomic Segment; Genomics; Goals; Haplotypes; Hospitals; Human Genome; Individual; Lead; Live Birth; Maps; Mediating; Molecular; Optics; Parents; Pathology; Patients; Phenotype; Play; Population; Positioning Attribute; Prevalence; Recurrence; Risk Factors; Role; Site; Structural defect; Structure; Suggestion; Syndrome; Technology; Testing; Variant; Work; base; cat eye syndrome; caucasian American; cohort; homologous recombination; human disease; innovation; insight; microdeletion; nanochannel; neuropsychiatry; novel; novel strategies; offspring; proband; single molecule; structural genomics; whole genome

Project Summary/Abstract Numerous human diseases result from recurrent DNA rearrangements involving unstable genomic regions. They are facilitated by the presence of region-specific low-copy repeats (LCRs) and are the result of nonallelic homologous recombination (NAHR) between such paralogous genomic segments. The 22q11.2 region undergoes a significant number of germline rearrangements. As such, it has been classified as one of the more unstable regions of the human genome. The 22q11.2 deletion syndrome (22q11DS) is the most common microdeletion disorder. It is associated with phenotypic and neuropsychiatric pathology, both of which are widely variable. In most affected individuals, the deletion is de novo and is the result of NAHR mediated by four chromosome22-specific low copy repeats (LCRA, -B, -C and -D) in 22q11. Their size and the presence of numerous segments with near-identical sequence render these chromosome specific LCRs as substrates for NAHR. Numerous genomic disorders, including the 22q11DS are the result of NAHR. LCR22s are extremely difficult to reliably map and sequence because of their structural characteristics. Currently, an accurate reference sequence for the region does not exist. Also, they are recalcitrant to short read sequencing such that the level of their polymorphism and variability in the general population is unknown. However, optical mapping of the region with Bionano Genomics' Saphyr technology overcomes this difficulty. Thus, 22q11.2 becomes a test case for LCR delineation by optical mapping. Our preliminary optical mapping data suggests a complex organization of duplicated 160kb modules within LCRA and LCRD, including copy number and orientation differences. Further, a common inversion polymorphism within LCRD has been identified. Our preliminary data suggests that this polymorphic inversion is less prevalent in African Americans (AAs), which may finally explain the relative deficit of AAs in our CHOP-based 22q11DS cohort. We propose to employ innovative Bionano optical mapping technology to determine the frequency of 22q11 LCR polymorphisms in the general population and explore the role they play in facilitating rearrangements. The prevalence of the LCRD inversion in several different populations (CEU, African, and African American subjects from the 1000 Genomes Project; local white and AA 22q11DS trios) will be determined. The LCR22-containing regions associated with 22q11DS will be examined in these same populations to determine their structure and variation. Finally, we propose to analyze the breakpoints of some typical and atypical 22q11.2 deletions and duplications guided by Bionano optical maps derived from probands in the 22q11DS and duplication trios. By leveraging the increased sensitivity afforded by long single molecule optical mapping on nanochannel arrays, this proposal will elucidate the previously unmapped structure and variation of LCR22s and surrounding regions in greater detail. The data and maps generated herein will provide access to many other difficult to map and sequence genomic regions and other genomic disorders.

项目概要/摘要 许多人类疾病都是由涉及不稳定基因组区域的反复 DNA 重排引起的。他们 区域特异性低拷贝重复序列 (LCR) 的存在促进了这一点，并且是非等位基因的结果 此类旁系同源基因组片段之间的同源重组（NAHR）。 22q11.2区域 经历大量的种系重排。因此，它被列为最重要的之一 人类基因组的不稳定区域。 22q11.2 缺失综合征 (22q11DS) 是最常见的 微缺失障碍。它与表型和神经精神病理学相关，两者都被广泛 多变的。在大多数受影响的个体中，缺失是从头开始的，是 NAHR 由四个介导的结果 22q11 中的 22 号染色体特异性低拷贝重复序列（LCRA、-B、-C 和 -D）。它们的大小和存在 许多具有几乎相同序列的片段使得这些染色体特异性LCR作为底物 NAHR。许多基因组疾病，包括 22q11DS，都是 NAHR 的结果。 LCR22 非常 由于其结构特征，难以可靠地绘制和测序。目前，准确的参考 该区域的序列不存在。此外，它们不愿意接受短读测序，因此水平 它们在一般人群中的多态性和变异性尚不清楚。然而，光学测绘 Bionano Genomics 的 Saphyr 技术克服了这一困难。因此，22q11.2 成为一个测试用例 通过光学映射进行 LCR 描绘。我们的初步光学测绘数据显示了一个复杂的组织 LCRA 和 LCRD 中重复的 160kb 模块，包括拷贝数和方向差异。 此外，LCRD 内常见的倒位多态性已被鉴定。我们的初步数据表明 这种多态性倒置在非裔美国人 (AA) 中不太常见，这可能最终解释了相对 我们基于 CHOP 的 22q11DS 队列中存在 AA 缺陷。我们建议采用创新的 Bionano 光学测绘 技术确定一般人群中 22q11 LCR 多态性的频率并探索 它们在促进重组方面发挥着重要作用。 LCRD 倒置在几个不同的国家中普遍存在 人群（来自千人基因组计划的 CEU、非洲人和非裔美国人受试者；当地白人和 AA 22q11DS 三重奏）将被确定。与 22q11DS 相关的包含 LCR22 的区域将在 这些相同的种群以确定它们的结构和变异。最后我们建议分析一下断点 由 Bionano 光学图引导的一些典型和非典型 22q11.2 缺失和重复 22q11DS 和重复三重奏中的先证者。通过利用长单提供的增加的灵敏度 纳米通道阵列上的分子光学映射，该提案将阐明以前未映射的结构 以及 LCR22 和周围区域的变化的更详细信息。本文生成的数据和地图将 提供对许多其他难以绘制和测序的基因组区域和其他基因组疾病的访问。