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

人类基因组中存在着一类低拷贝重复序列。LCR不是普通的重复序列，而是由基因、假基因及其片段等多种单元组成。认为LCR是在进化过程中由这些单元与周围序列的重复、倒位和缺失形成的。LCR介导的人类基因组动态变化是拷贝数变异（CNV）产生的机制之一。CNV偶尔会引起疾病，如DiGeorge综合征和Smith-Magenis综合征。这些疾病的责任区域通常被LCR包围。CNVs被认为与许多其他遗传疾病和一些精神疾病有关，并且正在被广泛研究。LCR也是人类基因组序列缺失的重要因素之一。因此，CNV和LCR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重复综合征的威廉姆斯综合征区（WBSCR）的LCR。获得NCBI build 36中这些区域的所有序列数据并手动重新分析以构建更精确的序列重叠群。鉴定了各种LCR单元和LCR单元中的基因/假基因的位置。使用灵长类动物基因组进行的比较分析强烈表明，在这两个疾病区域中，一个核心单位序列存在于一个共同的祖先基因组中，并且在进化过程中的各种事件中，核心序列包裹周围的序列，使它们成为一类新的LCR。此外，我们指出构建36中WBSCR（7q11.23）内的序列缺口实际上不是缺口，其是由于2个不同等位基因与CNV共存而引入的。通过将这些BAC克隆分离成2个等位基因，消除了差距。这些结果也在项目结束后的下列论文中报道：Nature 431：931，2004; BMC Genomics 5：92，2004; Nature 439：331，2006。

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.