DGAP: Developmental Genome Anatomy Project

DGAP：发育基因组解剖项目

• 批准号: 8854505
• 负责人: Cynthia Casson Morton
• 金额: $ 175.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8854505
• 关键词: Affect; Anatomy; Animal Model; Balanced Chromosomal Translocation; Biological; Biological Assay; Biology; Candidate Disease Gene; Cell Line; Chromosomal Breaks; Chromosomal Rearrangement; Chromosome abnormality; Chromosomes; Clinical; Communication; Communities; Complex; Computational Biology; Congenital Abnormality; Congenital Disorders; Congenital Heart Defects; Conserved Sequence; Cytogenetics; Data; Databases; Defect; Development; Developmental Biology; Developmental Gene; Diagnostic; Disease; Dominant-Negative Mutation; Equilibrium; Etiology; Evaluation; Feedback; Female; Genes; Genetic; Genetic Engineering; Genome; Genomics; Genotype; Goals; Healthcare Systems; Human; Human Biology; Human Development; Human Genetics; Human Genome; Human Genome Project; Individual; Infant; Institution; Investigation; Investments; Limb structure; Link; Location; Medical Genetics; Medicine; Mental Retardation; Methods; Mission; Modeling; Molecular; Molecular Biology; Mutation; Newborn Infant; Nuclear; Pathway interactions; Peripheral; Phase; Phenotype; Regulation; Regulatory Element; Reporting; Research; Research Personnel; Resources; Risk; Role; Structural defect; Syndrome; System; Testing; Translations; United States National Institutes of Health; Validation; Variant; Work; Zebrafish; abdominal wall; base; cleft lip and palate; clinical phenotype; comparative; congenital anomaly; cost effective; functional genomics; gene discovery; high throughput screening; human DNA sequencing; human morbidity; induced pluripotent stem cell; innovation; insight; next generation sequencing; precision medicine; programs; public health relevance; rare variant; trait; variant of unknown significance

 DESCRIPTION (provided by applicant): Approximately 1 in 2000 newborns has an apparently balanced chromosome rearrangement, with 6.1% and 9.4% risks for a serious congenital anomaly from a de novo translocation and inversion, respectively. These anomalies include isolated defects ranging from cleft lip/palate, abdominal wall defects, limb defects, cardiac abnormalities or mental retardation, or they can occur as part of clinically recognizable syndromes. Consequently, these rare individuals offer a unique resource for functional annotation of the human genome and for revealing mechanisms operative in human development that would be difficult or impossible to identify with less complex systems. The goal of the Developmental Genome Anatomy Project (DGAP) is to pursue functional genomics in humans by capitalizing on balanced chromosomal rearrangements in subjects with developmental abnormalities to identify genes and conserved sequences critical to development that are disrupted or dysregulated. Following the observation that de novo structural abnormalities involving all chromosomes have been reported in association with congenital anomalies, it has been speculated that a significant number of such chromosomal breaks directly disrupt or dysregulate genes critical to specific molecular pathways. So far, we have identified over 150 such genes in DGAP subjects. In other cases, the mechanism of disruption does not directly break the gene but rather alters its regulation. In this renewal application of DGAP, we propose to continue our study of individuals with multiple congenital anomalies and apparently balanced chromosomal rearrangements with the aim of furthering gene discovery, delineation of regulatory elements and implication of conserved sequences of unknown function. Balanced chromosomal rearrangements will serve as the signposts to identify these critical genes. In addition we will extend our efforts in structural variation to explore the role of crypti rearrangements in human morbidities as well as annotating the genome for rearrangements without phenotypic consequences.

 描述（由申请人提供）：大约 2000 名新生儿中就有 1 名具有明显平衡的染色体重排，从头易位和倒位导致严重先天性异常的风险分别为 6.1% 和 9.4%。这些异常包括孤立的缺陷，包括唇裂/腭裂、腹壁缺陷、肢体缺陷、心脏异常或智力迟钝，或者它们可能作为临床可识别综合征的一部分出现。因此，这些稀有个体为人类基因组的功能注释和揭示人类发育中起作用的机制提供了独特的资源，而用不太复杂的系统很难或不可能识别这些机制。发育基因组解剖学计划 (DGAP) 的目标是通过利用发育异常受试者的平衡染色体重排来识别对发育至关重要的被破坏或失调的基因和保守序列，从而研究人类的功能基因组学。据报道，涉及所有染色体的从头结构异常与先天性异常有关，据观察，据推测，大量此类染色体断裂直接破坏或失调对特定分子途径至关重要的基因。到目前为止，我们已经在 DGAP 受试者中鉴定出 150 多个此类基因。在其他情况下，破坏机制并不直接破坏基因，而是改变其调控。在 DGAP 的更新应用中，我们建议继续对具有多种先天性异常和明显平衡的染色体重排的个体进行研究，目的是进一步发现基因、描述调控元件以及未知功能的保守序列的含义。平衡的染色体重排将作为识别这些关键基因的路标。此外，我们将扩大结构变异方面的努力，探索隐秘重排在人类发病中的作用，并注释基因组重排而不会产生表型后果。