DGAP: Developmental Genome Anatomy Project

大约每2000名新生儿中就有1名具有明显的平衡 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的严重先天性异常。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，这些罕见的个体为功能性的 人类基因组的注释和揭示机制在人类发展中的运作，这将是困难的或不可能确定与不太复杂的系统。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鉴定基因和保守基因，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破坏或失调。在观察到涉及所有染色体的cfe novo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，我们确定了一些 在DGAP研究对象中发现了这样的基因。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 来识别这些关键基因。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）。分子鉴定和分析 候选基因和其他保守序列元件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。

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.