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.

项目总结/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 区域特异性低拷贝重复序列（LCR）的存在促进了这些基因的表达， 同源重组（NAHR）是这种旁系同源基因组区段之间的同源重组。22q11.2区域 经历了大量的种系重排。因此，它已被列为一个更 人类基因组的不稳定区域。22q11.2缺失综合征（22 q11 DS）是最常见的 微缺失症它与表型和神经精神病理学有关，这两种病理学都被广泛地 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NAHR介导的结果。 22 q11中22号染色体特异性低拷贝重复序列（LCRA、-B、-C和-D）。他们的规模和存在的 许多具有几乎相同序列的片段使这些染色体特异性LCR成为 NAHR。许多基因组疾病，包括22 q11 DS是NAHR的结果。LCR 22非常适合 由于它们的结构特征，难以可靠地作图和测序。目前，一个准确的参考 该区域的序列不存在。此外，它们对短读段测序是不相容的，使得它们的水平 它们在一般人群中的多态性和变异性尚不清楚。然而， 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 用于通过光学映射进行LCR描绘。我们初步的光学测绘数据显示 LCRA和LCRD内重复的160 kb模块的差异，包括拷贝数和方向差异。 此外，一个共同的倒位多态性LCRD内已被确定。我们的初步数据显示， 这种多态倒位在非洲裔美国人（AAs）中不太普遍，这可能最终解释了相对的 在我们的基于CHOP的22 q11 DS队列中，AA缺失。我们建议采用创新的Bionano光学映射 技术，以确定22 q11 LCR多态性在一般人群中的频率，并探讨 在促进重组中发挥作用。在几个不同的LCRD倒置的患病率 人群（来自1000基因组计划的CEU、非洲人和非裔美国人受试者;当地白色和AA 22 q11 DS trios）将被确定。与22 q11 DS相关的含LCR 22的区域将在 来确定它们的结构和变异。最后，我们建议分析断点 一些典型的和非典型的22q11.2缺失和复制的Bionano光学地图来自 22 q11 DS的先证者和重复三人组。通过利用长时间单脉冲信号提供的更高灵敏度， 在纳米通道阵列上的分子光学映射，该提议将阐明以前未映射的结构 以及LCR 22和周围区域的变化。此处生成的数据和地图将 提供了对许多其他难以绘制和测序的基因组区域和其他基因组病症的访问。