SEGMENTAL ANEUOSOMY BETWEEN BLOCKS OF DUPLICATED DNA

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。人类遗传学领域的主要目标之一是定义人类基因型和表型之间的关系。我们对基因型变异的评估大多集中在小规模的单核苷酸事件上。然而，我们对疾病的分子基础的理解已经开始揭示，包括微复制和微缺失在内的大规模差异对儿童疾病、疾病易感性和人群中的正常变异有显著影响。尽管它的重要性，一直没有系统的研究，这种形式的基因型变异。这项建议的长期目标是调查这种大规模变化的模式和性质。我们的方法将针对含有高度同源重复序列的基因组区域，因此具有增加的基因组获得和丢失的可能性。这项提案是一项合作努力，汇集了基因组结构、阵列比较基因组杂交技术和智力迟钝方面的专门知识。该建议的具体目的是（1）鉴定和验证人类基因组内所有染色体内重复区域，（2）开发一组由重复序列包围的大插入克隆，以放置在CGH微阵列平台上进行全基因组筛选，（3）评估正常个体和特发性智力低下儿童中的拷贝数变异，以及（4）验证这些大的结构“多态性”的频率和遗传模式。该项目旨在解决两个基本问题：人类基因组内重复介导的结构多态性的性质和频率是什么？在智力迟钝和先天性出生缺陷的儿童中是否有过多的新生事件？

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the major goals of the field of human genetics is to define the relationship between human genotype and phenotype. Much of our assessment of genotypic variation has been focused on small scale, single nucleotide events. Our understanding of the molecular basis of disease, however, has begun to reveal that large-scale differences including micro duplications and micro deletions contribute significantly to childhood disease, disease susceptibility and normal variation in the population. Despite its importance, there has been no systematic study of this form of genotypic variation. The long-term objective of this proposal is to investigate the pattern and nature of this large-scale variation. Our approach will be directed to regions of the genome that contain highly homologous duplicated sequence and therefore have an increased probability of genomic gain and loss. This proposal is a collaborative effort that brings together expertise in genome structure, array comparative genomic hybridization technology and mental retardation. The specific aims of this proposal are (1) to identify and validate all intrachromosomally duplicated regions within the human genome, (2) to develop a set of large-insert clones bracketed by duplicated sequence to be placed on a CGH microarray platform for genome-wide screening, (3) to assess copy number variation within both normal individuals and children with idiopathic mental retardation and (4) to validate the extent, frequency and inheritance pattern of these large structural "polymorphisms". This project aims to address two fundamental questions; what is the nature and frequency of duplication-mediated structural polymorphisms within the human genome? Are there an excess of de novo events among children with mental retardation and congenital birth defects?