Molecular Dissection of the 22q11.2 Deletion Syndrome

22q11.2 缺失综合征的分子解剖

• 批准号: 10473894
• 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/10473894
• 关键词: 22q; 22q11; 22q11.2; Affect; African; African American; African American population; 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; 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.

项目摘要/摘要 许多人类疾病是由涉及不稳定基因组区域的反复DNA重排引起的。他们 通过区域特异性低拷贝重复序列(LCR)的存在而变得容易，并且是非等位基因的结果 这些相似基因组片段之间的同源重组(Nahr)。22q11.2区域 经历了大量的生殖系重排。因此，它被归类为 人类基因组的不稳定区域。最常见的是22q11.2缺失综合征(22q11DS 微缺失障碍。它与表型和神经精神病理学有关，两者都广泛存在。 变量。在大多数受影响的个体中，缺失是从头开始的，是由四个人介导的Nahr的结果 22q11中22号染色体特有的低拷贝重复序列(LCRA、-B、-C和-D)。它们的大小和存在的 许多序列几乎相同的片段使这些染色体特异的LCR作为底物 纳尔。许多基因组疾病，包括22q11DS是Nahr的结果。LCR22非常 由于它们的结构特点，很难可靠地绘制和排序。目前，一个准确的参考 该区域的序列不存在。此外，他们对短读测序的顽固性使得水平 它们在普通人群中的多态和变异性尚不清楚。然而，光学测绘 Bionano基因组公司的Sassir技术克服了这一困难。因此，22q11.2成为一个测试用例 用于通过光学测绘来划定LCR。我们的初步光学测绘数据显示 LCRA和LCRD内复制的160KB模块的数量，包括副本数量和方向差异。 此外，在LCRD中发现了一种常见的倒位多态。我们的初步数据表明 这种多态倒置在非裔美国人(AA)中不太普遍，这可能最终解释了相对的 我们基于CHOP的22q11DS队列中AAs缺乏。我们建议使用创新的Bionano光学测绘 技术检测22q11 LCR多态在普通人群中的频率并探索 它们在促进重新安排方面发挥了作用。LCRD倒置在几种不同类型中的患病率 人口(1000基因组计划中的CEU、非洲人和非裔美国人；当地白人和AA 22q11DS三联体)将被确定。将在中检查与22q11DS相关的包含LCR22的区域 这些相同的种群决定了它们的结构和变异。最后，我们建议对断点进行分析 由Bionano光学地图指导的一些典型和非典型的22q11.2缺失和复制 22q11DS和复制三重奏中的先驱。通过利用Long Single提供的更高的灵敏度 在纳米通道阵列上的分子光学映射，这一提议将阐明先前未映射的结构 以及更详细的LCR22及其周围区域的变异。此处生成的数据和地图将 提供访问许多其他难以绘制和测序基因组区域和其他基因组疾病的途径。