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（由申请人提供）：2000年的新生儿大约有1个明显平衡的重排，从头易位的风险为6.1％，而对先天性异常严重异常的从头逆转的风险为9.4％。这些异常可能包括孤立的缺陷，从唇裂/pa/pain，腹壁缺陷，肢体缺陷，心脏异常或智力低下，或者可以作为临床上可识别的综合征的一部分发生。因此，这些罕见的人为人类基因组的功能注释提供了独特的资源，并揭示了人类发展中可行的机制，这些机制将很难或不可能用较不复杂的系统识别。发展基因组解剖项目（DGAP）的目的是通过在具有发育异常的受试者中利用平衡的染色体重排来追求人类的功能基因组学，以鉴定基因和保守对破坏或失调的发育至关重要的序列。在观察到涉及所有染色体的CFE Novo结构异常与先天异常有关，人们据推测，大量此类染色体断裂直接破坏对特定分子途径至关重要的基因。在资金的第一阶段，我们在DGAP研究对象中确定了许多此类基因。在其他情况下，破坏机制并不能直接打破基因，而是改变其调节。在这种DGAP的重新提取应用中，我们建议继续研究具有多个先天性异常和显然平衡的染色体重排的个体，目的是促进基因发现，调节性元素的描述以及对无知功能的保守序列的含义。均衡的染色体重排将作为识别这些关键基因的路标。已经建立了整个医学遗传学界的细胞遗传学家与临床遗传学家之间的合作，以收集具有多种发育缺陷和平衡染色体重排的患者样本。通过鱼类图研究对染色体断点的分析用于识别包含相关候选序列的单个基因组克隆，并且可以使用在线DGAP数据库（项目1）。分子鉴定和分析候选基因和其他保守序列元素以及受影响个体的突变研究是随后研究的重点（项目2）。确定候选基因的模型生物的开发和表征将在人类疾病中建立致病性（项目3）。行政和临床遗传学核心支持这项研究。 DGAP构成了临床遗传学，细胞遗传学，分子生物学和发育遗传学的多样性和多机构研究，以照亮人类发展过程中涉及基本途径的基因。相关性：发展基因组解剖项目研究一组由医疗保健系统服务的患者：由于染色体重排而导致先天性异常的患者。我们的使命是发现这些染色体重排破坏人类发展中重要性的基因，这些基因难以通过更传统的人类遗传策略来识别，从而开始研究它们引起的疾病。