DGAP: Developmental Genome Anatomy Project

 描述(申请人提供)：在2000名新生儿中，大约有1名具有明显平衡的染色体重排，因新生易位和倒位而导致严重先天性异常的风险分别为6.1%和9.4%。这些异常包括孤立的缺陷，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人类发育中的机制提供了独特的资源，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识别对发育至关重要的基因和保守序列，从而在人类中进行功能基因组学研究。在观察到涉及所有染色体的从头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。到目前为止，我们已经在DGAP受试者中发现了150多个这样的基因。在其他情况下，干扰机制不会直接破坏基因，而是改变了它的调控。在DGAP的这一新的应用中，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。此外，我们将在结构变异方面继续努力，探索隐蔽重排在人类疾病中的作用，以及为没有表型后果的重排注释基因组。

 DESCRIPTION (provided by applicant): Approximately 1 in 2000 newborns has an apparently balanced chromosome rearrangement, with 6.1% and 9.4% risks for a serious congenital anomaly from a de novo translocation and inversion, respectively. These anomalies 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 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. So far, we have identified over 150 such genes in DGAP subjects. In other cases, the mechanism of disruption does not directly break the gene but rather alters its regulation. In this renewal 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. In addition we will extend our efforts in structural variation to explore the role of crypti rearrangements in human morbidities as well as annotating the genome for rearrangements without phenotypic consequences.