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Fine analysis of low copy repeat sequences which cause diseases by chromosomal microdeletion/microduplication and complete identification of content genes within them

精细分析因染色体微缺失/微重复引起疾病的低拷贝重复序列，并完整鉴定其中的内容基因

基本信息

批准号：
13470167
负责人：
MINOSHIMA Shinsei
金额：
$ 8万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2002
项目状态：
已结题

项目摘要

There exist a class of sequences Low Copy Repeats (LCRs) in human genome. LCRs are not ordinary repetitive sequences, but consist of various units such as genes, pseudogenes and their fragments. It is considered that LCRs have been formed by duplication, inversion and deletion of those units together with surrounding sequences during the evolution. LCR-mediated dynamic change of human genome is one of mechanisms for generation of copy number variation (CNV). CNVs occasionally cause diseases such as DiGeorge syndrome and Smith-Magenis syndrome. Responsible regions of those diseases are usually surrounded by LCRs. CNVs are thought to be associated with many other genetic diseases and some of mental diseases, and are being extensively investigated. LCRs are also one of the important factors of sequence gaps in human genome. Thus, CNV and LCRs are important targets of current genome research and its medical application. Here, we analyzed LCRs in Williams syndrome region (WBSCR) on 7q11.23 and 8p23.1 duplication syndrome. All of sequence data of these regions in NCBI build 36 were obtained and manually re-analyzed to construct more precise sequence contigs. Position of various LCR units and genes/pseudogenes in LCR units were identified. Comparative analyses using primate genomes strongly suggested that in both disease regions a core unit sequence existed in a common ancestor genome, and that in various events during evolution the core sequence enveloped surrounding sequences and made them a new class of LCRs. Also, we indicated that a sequence gap within WBSCR (7q11.23) in build 36 is actually not a gap, which was introduced because of co-existence of 2 different alleles with CNVs. The gap has been cleared up by separating these BAC clones into 2 alleles. These results were reported also in the following papers after the term of project: Nature 431:931,2004; BMC Genomics 5:92,2004; Nature 439:331,2006.

人类基因组中存在一类低拷贝重复序列(LCRs)。LCRs不是普通的重复序列，而是由基因、伪基因及其片段等各种单位组成。在进化过程中，LCRs被认为是由这些单位与周围序列的复制、倒置和缺失形成的。LCR介导的人类基因组动态变化是产生拷贝数变异(CNV)的机制之一。CNV有时会引起DiGeorge综合征和Smith-Magenis综合征等疾病。这些疾病的责任区通常被LCR包围。CNV被认为与许多其他遗传疾病和一些精神疾病有关，目前正在进行广泛的研究。LCRs也是人类基因组序列缺失的重要因素之一。因此，CNV和LCRs是当前基因组研究及其医学应用的重要靶点。在这里，我们分析了7q11.23和8p23.1重复综合征上的Williams综合征区域(WBSCR)的LCR。获得NCBI Build 36中所有这些区域的序列数据，并手动重新分析以构建更精确的序列重叠群。确定了不同LCR单位的位置和LCR单位中的基因/假基因。利用灵长类基因组进行的比较分析有力地表明，在这两个病区，一个共同的祖先基因组中存在一个核心单位序列，在进化过程中，在不同的事件中，核心序列包裹着周围的序列，使它们成为一类新的LCR。此外，我们还指出，Build 36中WBSCR(7q11.23)中的序列缺口实际上不是缺口，这是由于两个不同的等位基因与CNV共存而引入的。通过将这些BAC克隆分离成2个等位基因，差距被消除了。在项目结束后的下列论文中也报告了这些结果：自然431：931,2004；BMC基因组学5：92,2004；自然439：331,2006。