DGAP: Developmental Genome Anatomy Project

说明书(申请人摘要)：发展的目标 基因组解剖计划(DGAP)是为了识别人类关键基因 被平衡的染色体干扰或失调的发育 患有多种先天畸形的人类的重排。约1英寸 2000名新生儿有明显的平衡重排，风险为6.1% 因为严重的先天畸形。这些异常可能包括孤立的缺陷 从腭裂/唇裂，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的一部分发生 可辨认的综合症。特别相关的是，从头开始 涉及所有染色体的结构异常已在 与先天畸形有关；据推测， 大量这样的染色体断裂直接扰乱或失调 对特定分子途径至关重要的基因。我们建议研究个人 有多种先天畸形和明显的染色体平衡 重排，目的是使用平衡的染色体重排作为 识别这些关键基因的路标。DGAP的潜力将是 通过快速进化的基因组资源，包括完整的 人类DNA序列和人类基因组的有序鱼类BAC图谱。 细胞遗传学家和临床遗传学家之间建立的合作 已经建立了整个医学遗传学社区来收集患者 具有多种发育缺陷和染色体平衡的样本 重新安排。染色体断裂点的FISH定位分析 研究将用于鉴定包含相关基因的单个基因组克隆 正在创建一个在线DGAP数据库(项目1)。 候选基因的分子鉴定和分析，以及突变 对受影响个体的研究将是后续研究的重点。 (项目2)。鉴定评估组织或颞叶的表达模式 接下来将是特异性，以及分离肌肉分枝杆菌和D。 黑猩猩(项目3)。最终，转基因动物将被用于研究 感兴趣的特定克隆，以更充分地阐明它们在发育中的作用 (项目3)。DGAP构成了一个多实验室、多机构的 将临床遗传学学科结合在一起的研究努力， 细胞遗传学、分子生物学和发育遗传学阐明基因 参与人类发展的基本途径。

DESCRIPTION (Applicant's Abstract): The goal of the Developmental Genome Anatomy Project (DGAP) is to identify genes critical in human development that are disrupted or dysregulated by balanced chromosomal rearrangements in humans with multiple congenital anomalies. Approximately 1 in 2000 newborns has an apparently balanced rearrangement, with a 6.1 percent risk for a serious congenital anomaly. These anomalies can include isolated defects ranging from cleft palate/lip, abdominal wall defects, limb defects, cardiac abnormalities or mental retardation, or they can occur as part of clinically recognizable syndromes. Of particular relevance is the fact that de 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. We propose to study individuals with multiple congenital anomalies and apparently balanced chromosomal rearrangements, with the aim of using balanced chromosomal rearrangements as signposts to identify these critical genes. The potential of DGAP will be greatly enhanced by rapidly evolving genomic resources including the complete human DNA sequence and an ordered FISH BAC map of the human genome. Collaborations established 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 will be used to identify single genomic clones containing relevant candidate sequences, and an online DGAP database is being created (Project 1). Molecular identification and analysis of candidate genes, as well as mutation studies in affected individuals will be the focus of subsequent studies (Project 2). Identification of expression patterns assessing tissue or temporal specificity will follow, as well as isolation of homologs in M. musculus and D. melanogaster (Project 3). Ultimately, transgenic animals will be used to study specific clones of interest to elucidate more fully their role in development (Project 3). DGAP constitutes a multi-laboratory and multi-institutional research endeavor which brings together the disciplines of clinical genetics, cytogenetics, molecular biology and developmental genetics to illuminate genes involved in fundamental pathways during human development.