DGAP: Developmental Genome Anatomy Project

DGAP：发育基因组解剖项目

• 批准号: 7631543
• 负责人: Cynthia Casson Morton
• 金额: $ 172.17万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7631543
• 关键词: DGAP; Developmental; Genome; Anatomy; Project

DESCRIPTION (provided by applicant): Approximately 1 in 2000 newborns has an apparently balanced rearrangement, with a 6.1% risk from a de novo translocation and a 9.4% risk from a de novo inversion for a serious congenital anomaly. These anomalies can 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 cfe 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. In the first period of funding we identified a number of such genes in DGAP research subjects. In others, the mechanism of disruption does not directly break the gene but rather alters its regulation. In this resubmission 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. Collaborations between cytogeneticists and clinical geneticists across the medical genetics community have been established to collect patient samples with a variety of developmental defects and balanced chromosomal rearrangements. Analysis of chromosomal breakpoints through FISH mapping studies is used to identify single genomic clones containing relevant candidate sequences, and an online DGAP database is available (Project 1). Molecular identification and analysis of candidate genes and other conserved sequence elements, as well as mutation studies in affected individuals is the focus of subsequent studies (Project 2). Development and characterization of model organisms for the candidate genes identified will establish pathogenicity in the human disorders (Project 3). Administrative and Clinical Genetics Cores support the research endeavor. DGAP constitutes multi-laboratory and multi-institutional research encompassing the disciplines of clinical genetics, cytogenetics, molecular biology and developmental genetics to illuminate genes involved in fundamental pathways during human development. RELEVANCE: The Developmental Genome Anatomy Project studies a group of patients underserved by the health care system: those with congenital abnormalities due to chromosome rearrangements. Our mission is to discover genes of importance in human development that are disrupted by these chromosomal rearrangements, genes that are difficult to identify by more traditional human genetic strategies, thereby opening investigation of the disorders that they cause.

描述（由申请方提供）：大约1/2000的新生儿具有明显的平衡重排，其中6.1%的风险来自新生易位，9.4%的风险来自新生倒位，导致严重的先天性异常。这些异常可以包括孤立的缺陷，从唇腭裂，腹壁缺陷，肢体缺陷，心脏异常或智力迟钝，或者它们可以作为临床可识别的综合征的一部分发生。因此，这些罕见的个体为人类基因组的功能注释和揭示人类发育中的机制提供了独特的资源，这些机制很难或不可能用不太复杂的系统来识别。发育基因组解剖学项目（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鉴定对发育至关重要的基因和保守序列，从而在人类中进行功能基因组学研究。在观察到涉及所有染色体的cfe新生结构异常与先天性异常相关后，人们推测大量的染色体断裂直接破坏或失调了对特定分子途径至关重要的基因。在第一阶段的资助中，我们在DGAP研究对象中发现了一些这样的基因。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的重新提交申请中，我们建议继续研究具有多种先天性异常和明显平衡的染色体重排的个体，目的是进一步发现基因，描绘调控元件和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。已经建立了医学遗传学界的细胞遗传学家和临床遗传学家之间的合作，以收集具有各种发育缺陷和平衡染色体重排的患者样本。通过FISH作图研究分析染色体断裂点用于鉴定含有相关候选序列的单个基因组克隆，并且可获得在线DGAP数据库（项目1）。候选基因和其他保守序列元件的分子鉴定和分析，以及受影响个体的突变研究是后续研究的重点（项目2）。开发和鉴定候选基因的模式生物将确定人类疾病的致病性（项目3）。行政和临床遗传学核心支持研究奋进。DGAP包括多实验室和多机构研究，涵盖临床遗传学，细胞遗传学，分子生物学和发育遗传学等学科，以阐明人类发育过程中参与基本途径的基因。相关性：发育基因组解剖学项目研究了一组医疗保健系统服务不足的患者：那些由于染色体重排而患有先天性异常的患者。我们的使命是发现在人类发育中重要的基因，这些基因被这些染色体重排破坏，这些基因很难通过更传统的人类遗传策略识别，从而开启对它们引起的疾病的调查。