DGAP: Developmental Genome Anatomy Project

DGAP：发育基因组解剖项目

• 批准号: 8049770
• 负责人: Cynthia Casson Morton
• 金额: $ 170.93万
• 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/8049770
• 关键词: DGAP; Developmental; Genome; Anatomy; Project

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 multiinstitutional research encompassing the disciplines of clinical genetics, cytogenetics, molecular biology and developmental genetics to illuminate genes involved in fundamental pathways during human development.

大约每2000个新生儿中就有一个有明显的平衡 重排，对于严重的先天性畸形，有6.1%的风险来自从头易位，9.4%的风险来自从头倒置。这些异常可以包括孤立的缺陷，包括唇腭裂、腹壁缺陷、肢体缺陷、心脏异常或智力低下，也可以作为临床可识别综合征的一部分发生。因此，这些罕见的个体为功能提供了独特的资源 对人类基因组的注释，以及揭示在人类发育中起作用的机制，这些机制很难或不可能与较不复杂的系统相一致。发育基因组解剖计划(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确定基因和保守的基因，从而在人类中进行功能基因组学研究 对发育至关重要的序列被打乱或失调。在观察到涉及所有染色体的CFE新结构异常与先天性异常有关后，人们推测，相当数量的此类染色体断裂直接扰乱或失调了对特定分子通路至关重要的基因。在第一阶段的资助中，我们确定了一些 在DGAP研究对象中发现了这样的基因。在另一些情况下，干扰机制不会直接破坏基因，而是改变了它的调控。在DGAP的重新提交应用中，我们建议继续我们对患有多种先天性异常和明显平衡的染色体重排的个体的研究，目的是进一步发现基因，描述调控元件，并揭示未知功能的保守序列。平衡的染色体重排将作为 识别这些关键基因的路标。细胞遗传学家和临床遗传学家之间已经建立了跨医学遗传学社区的合作，以收集具有各种发育缺陷和平衡的染色体重排的患者样本。通过FISH作图研究对染色体断裂点进行分析，以确定包含相关候选序列的单个基因组克隆，并建立了一个在线DGAP数据库(项目1)。黄曲霉毒素的分子鉴定与分析 候选基因和其他保守的序列元件以及在受影响个体中的突变研究是后续研究的重点(项目2)。已确定候选基因的模式生物的开发和表征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这项研究努力。DGAP由多个实验室和多个机构组成，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，以阐明参与人类发育基本途径的基因。