DGAP: Developmental Genome Anatomy Project

描述（由申请人提供）：大约2000名新生儿中有1名具有明显平衡的重排，对于严重的先天性异常，从头易位的风险为6.1%，从头倒置的风险为9.4%。这些异常可以包括孤立的缺陷，如唇腭裂、腹壁缺陷、肢体缺陷、心脏异常或智力低下，或者它们可以作为临床可识别综合征的一部分发生。因此，这些罕见的个体为人类基因组的功能注释和揭示在人类发展中运作的机制提供了独特的资源，这些机制在较不复杂的系统中很难或不可能识别。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识别对发育至关重要的基因和保守序列被破坏或失调，从而追求人类功能基因组学。在观察到涉及所有染色体的先天性结构异常与先天性异常相关后，人们推测，大量这样的染色体断裂直接破坏或失调了对特定分子通路至关重要的基因。在资助的第一个阶段，我们在DGAP研究对象中确定了一些这样的基因。在其他情况下，破坏机制并不直接破坏基因，而是改变其调节。在DGAP的重新申请中，我们建议继续我们对具有多种先天性异常和明显平衡染色体重排的个体的研究，以进一步发现基因，描述调控元件和暗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。医学遗传学界的细胞遗传学家和临床遗传学家之间已经建立了合作，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定位研究对染色体断点进行分析，用于鉴定包含相关候选序列的单基因组克隆，并且可以使用在线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建立人类疾病的致病性（项目3）。行政和临床遗传学核心支持研究工作。DGAP由多实验室和多机构的研究组成，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。相关性：发育基因组解剖计划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。我们的任务是发现在人类发育中被这些染色体重排破坏的重要基因，这些基因很难被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研究。

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.