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复发性DNA重排引起的。他们 通过特异性低拷贝重复序列（LCR）的存在来促进，是非平行的结果 这种寄生基因组段之间的同源重组（NAHR）。 22q11.2区域 经历了大量的种系重排。因此，它已被归类为更多 人类基因组的不稳定区域。 22q11.2删除综合征（22q11ds）是最常见的 微骨骼障碍。它与表型和神经精神病学有关，两者都广泛 多变的。在大多数受影响的个体中，删除是从头开始的，是NAHR介导的结果。 22q11中的Chromosome22特异性低复制重复序列（LCRA，-B，-C和-D）。他们的大小和存在 许多具有近乎相同序列的片段使这些染色体特异性LCR作为底物作为底物 纳尔。包括22Q11D在内的许多基因组疾病是NAHR的结果。 LCR22非常非常 由于其结构特征，难以可靠地映射和顺序。目前，准确的参考 该区域的序列不存在。另外，它们对简短读取测序是顽固的，以使水平 它们的多态性和普通人群的可变性尚不清楚。但是，光学映射 Bionano Genomics的Saphyr技术的区域克服了这一困难。因此，22q11.2成为测试案例 用于通过光学映射的LCR描述。我们的初步光学映射数据表明一个复杂的组织 LCRA和LCRD中重复的160KB模块的重复，包括拷贝数和方向差异。 此外，已经确定了LCRD内的共同反转多态性。我们的初步数据表明 在非洲裔美国人（AAS）中，这种多态性反转不那么普遍，这可能最终解释了相对 我们基于CHOP的22q11ds队列中AAS的赤字。我们建议采用创新的Bionano光学映射 确定一般人群中22q11 LCR多态性频率的技术并探索 他们在促进重排方面扮演的角色。 LCRD反转的流行率几种不同 人口（1000个基因组项目的CEU，非洲和非裔美国人受试者；当地白人和AA 将确定22q11ds Trios）。将检查与22Q11DS相关的含LCR22的区域 这些相同的人群以确定其结构和变化。最后，我们建议分析断点 在一些典型和非典型22q11.2的删除和重复的中，由bionano光学地图引导。 22q11ds和重复三重复的概率。通过利用长单个的提高灵敏度 分子光学映射在纳米渠道阵列上，该提案将阐明先前未塑造的结构 LCR22和周围区域的变化更详细。本文生成的数据和地图将 提供许多其他难以映射和序列基因组区域和其他基因组疾病的访问权限。