Investigating CpG islands in mammalian genomes

描述(由申请人提供)： CpG岛是位于GC富集区的CpG二核苷酸簇，通常位于基因的5‘端，被认为是哺乳动物基因组中的基因标记。实验表明，启动子CpG岛的甲基化在基因沉默、基因组印记、X染色体失活和癌症发生中起着重要作用。虽然人们已经进行了许多研究来确定CpG岛，估计CpG突变率，并检查疾病基因的甲基化调控，但对CpG岛在哺乳动物基因组中特定基因组区域的分布或CpG岛或启动子相关CpG岛的遗传变异模式知之甚少。此外，哺乳动物基因组中的CpG岛是如何进化的，以及哪种基因倾向于获得或失去CpG岛，我们在很大程度上仍然未知。最近几个哺乳动物基因组的发布，在这些基因组中发现了数百万个单核苷酸多态(SNPs)，以及人类基因组中大规模的甲基化状态数据，为我们提供了一个前所未有的机会来详细研究这些问题。在这个项目中，我们将首先对CpG岛在五种哺乳动物基因组(人、黑猩猩、小鼠、大鼠和狗)及其基因组区域中的分布进行全面的调查。我们将比较看家基因和组织特异性基因中CpG岛的特征，并比较CpG岛在不同类别的基因本体论(GO)中的分布和特征。其次，我们将研究四个基因组(人、黑猩猩、小鼠和狗)中CpG岛的突变模式，每个基因组都有100多万个SNP。第三，我们将研究哺乳动物基因组中CpG岛的进化机制，并推断其对基因功能的影响。一种方法是检查CpG岛每一段的突变模式(例如，CpG？？TPG/CPA)和序列特征。利用HapMap SNPs及其等位基因频率，我们将测试CpG岛可能的自然选择。最后，我们将检验CpG岛缺失与CpG岛甲基化状态之间存在关系的假设。我们的比较基因组学和生物医学信息学分析将提供关于CpG岛在哺乳动物基因组中的分布、CpG岛进化的机制以及CpG岛突变模式与基因功能类别的关系的详细信息，特别是与癌症相关的基因。

DESCRIPTION (provided by applicant): CpG islands, clusters of CpG dinucleotides in GC-rich regions, are often located in the 5' end of genes and are considered gene markers in mammalian genomes. Experiments have shown that methylation of promoter CpG islands plays an important role in gene silencing, genomic imprinting, X-chromosome inactivation, and carcinogenesis. Although many studies have been performed to identify CpG islands, to estimate the CpG mutation rates, and to examine the methylation modulation on disease genes, little is known about the distribution of CpG islands in the specific genomic regions across mammalian genomes or the pattern of genetic variation in CpG islands or in promoter-associated CpG islands. In addition, how CpG islands in mammalian genomes evolved and which kind of genes tend to gain or lose CpG islands remains largely unknown to us. The recent releases of several mammalian genomes, the discovery of millions of single nucleotide polymorphisms (SNPs) in these genomes, and large-scale methylation status data in the human genome provide us with an unprecedented opportunity to examine these issues in details. In this project, we will first perform a comprehensive survey of the distribution of CpG islands in five mammalian genomes (human, chimpanzee, mouse, rat, and dog) and their genomic regions. We will compare the features of CpG islands in the housekeeping genes with those in tissue-specific genes and compare the distribution and features of CpG islands in different categories of Gene Ontology (GO). Second, we will examine mutation patterns in CpG islands in four genomes (human, chimpanzee, mouse, and dog), each of which has more than 1 million SNPs. Third, we will investigate the mechanisms of CpG island evolution in mammalian genomes and to infer its effect on gene function. One approach is to examine the mutation pattern (e.g., CpG??TpG/CpA) and sequence features in each segment of CpG islands. Using the HapMap SNPs with their allele frequencies, we will test the possible natural selection in CpG islands. Finally, we will test the hypothesis that there is a relationship between CpG island loss and methylation status in CpG islands. Our comparative genomics and biomedical informatics analyses will provide a detailed view of the CpG island distribution in mammalian genomes, the mechanisms of CpG island evolution, and the relationship of the mutation pattern in CpG islands with functional categories of genes, especially cancer-related genes.