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

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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.