SEGMENTAL ANEUSOMY BETWEEN BLOCKS OF DUPLICATED DNA

人类遗传学领域的主要目标之一是确定人类基因型和表型之间的关系。我们对基因变异的大部分评估都集中在小规模的单核苷酸事件上。然而，我们对疾病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很大贡献。尽管它很重要，但还没有对这种形式的基因变异进行系统的研究。这项提议的长期目标是调查这种大规模变化的模式和性质。我们的方法将针对基因组中包含高度同源重复序列的区域，因此基因组获得和丢失的可能性增加。这项提议是一项合作努力，汇集了基因组结构、阵列比较基因组杂交技术和智力低下方面的专业知识。这项建议的具体目标是(1)识别和验证人类基因组中所有的染色体内重复区域，(2)开发一组被重复序列包围的大插入克隆，将其放置在CGH微阵列平台上用于全基因组筛查，(3)评估正常个体和特发性智力低下儿童的拷贝数变异，以及(4)验证这些大型结构“多态”的程度、频率和遗传模式。这个项目旨在解决两个基本问题：人类基因组中复制介导的结构多态的性质和频率是什么？在智力低下和先天性出生缺陷的儿童中是否存在过多的从头事件？

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?