CpG岛在脊椎动物中的进化研究

KIZ OpenIR > 科研部门 > 比较基因组学（宿兵）

	CpG岛在脊椎动物中的进化研究
	韩冷
学位类型	博士
导师	宿兵 ; 赵中明
	2010
学位授予单位	中国科学院研究生院
学位授予地点	北京
学位专业	遗传学
关键词	Cpg岛甲基化基因组进化疾病
摘要	CpG岛是指一段GC含量高且富含CpG双核苷酸的序列。由于CpG岛通常位于基因的5’端，尤其是基因启动子区域，因而被认为是基因标志。与启动子相关的CpG岛的非正常甲基化（甲基化不足和甲基化过量）可能会改变基因调控并导致其异常表达。这些基因往往参与了多种重要的细胞功能，因此，通常会引起各种各样的疾病，包括癌症。由于CpG岛功能上的重要性，在基因组序列中识别CpG岛具有重要作用。1987年，Gardiner-Garden和Frommer首先根据CpG岛的序列特征确定了CpG岛的识别标准。随后，许多CpG岛的识别算法被开发出来。这些算法可以分为两大类，一类是基于CpG岛序列特征的传统算法，包括Gardiner-Garden和Frommer（1987），Takai和Jones（2002）以及CpGPRoD（2002）；另一类是基于序列统计性质的算法，包括CpGcluster（2006）和CG cluster（2007）。我们总结了这些算法的性质，并对各算法进行了系统地评估。尽管各哺乳动物基因组之间基因数量较为接近，作为基因标志的CpG岛的数量却有很大差异。我们分析比较了人-小鼠同源基因中与启动子相关的CpG岛，发现小鼠基因组中的CpG岛的数量明显低于人基因组中的数量，其CpG岛的性质也较弱。我们以狗基因组为外类群，推算了CpG岛在祖先物种中的状态，并计算了核苷酸的突变模式及方向。我们的结果显示，CpG岛在人和小鼠基因组中都处于逐渐丢失的状态，并且在小鼠基因组中的丢失速率约为人基因组中丢失速率的2到4倍，另外，我们的研究结果也表明CpG岛倾向于从CpG岛的两端向中心区域逐渐丢失。一直以来，狗由于其物种内形态和行为上的巨大差异，引起了广泛关注。狗的基因组测序的完成，为我们研究狗基因组中CpG岛的独特性质提供了条件。相对于人和小鼠基因组而言，狗基因组中有更多的CpG岛，其数量几乎为小鼠基因组中的3倍。我们的研究表明，这一差异主要集中在非编码区（基因间和内含子区域）。令人意外的是，狗基因组中与启动子相关的CpG岛数量要少于人和小鼠。通过对狗-人-小鼠同源基因的比较，我们发现狗基因组中与启动子相关的CpG岛可能比在人和小鼠基因组中丢失的更快。一些遗传因素，包括重组率和染色体组型，可能与狗的这一独特性质相关。为了进一步研究CpG岛在脊椎动物中的进化，我们系统的比较了CpG岛在10个哺乳动物基因组中的分布。我们发现CpG岛的密度与染色体的数量，染色体的大小，重组等基因组性质之间呈显著的相关性。我们同时也发现，CpG岛在染色体上的分布倾向于从中心粒向端粒区域逐渐升高。我们还比较了哺乳动物和其它脊椎动物基因组中CpG岛的分布及性质。我们系统的研究了CpG岛的算法及在脊椎动物中的进化。这些工作不仅仅展示了CpG岛在调控基因方面的功能，也为研究脊椎动物基因组进化及人类疾病基因组的特征提供了参考。
其他摘要	CpG islands (CGIs), clusters of CpG dinucleotides in GC-rich regions, are often located in the 5’ end of genes and considered gene markers. Aberrant methylation (e.g., hypomethylation and hypermethylation) of the promoter-associated CGIs might influence gene expression. These genes affected by aberrant methylation are involved in many basic cellular functions, thus may cause diseases. Because of the functional importance, it is meaningful to identify CGIs from gemoic sequences. In 1987, Gardiner-Garden and Frommer proposed the first criteria for CGIs based on sequence features. Then, multiple algorithms have been develpoed for identifying CGIs in a genome or a sequence. They can be categorized into the traditional algorithms (e.g., Gardiner-Garden and Frommer (1987), Takai and Jones (2002), and CpGPRoD (2002)) or statistical property based algorithms (CpGcluster (2006) and CG cluster (2007)). We reviewed the features of these algorithms and evaluated their performance on identifying functional CGIs. The number of CGIs varies among mammalian genomes that have similar numbers of genes. We investigated the distribution of CGIs in the promoter regions of human-mouse orthologous gene pairs and found that the mouse genome has notably fewer CGIs in the promoter regions and less pronounced CGI characteristics than the human genome does. We further inferred CGI’s ancestral state using the dog genome as a reference and examined the nucleotide substitution pattern and the mutational direction in the conserved regions of human and mouse CGIs. The results revealed many losses of CGIs in both genomes but the loss rate in the mouse lineage is two to four times the rate in the human lineage. We found an intriguing feature of CGI loss, namely that the loss of a CGI usually starts from erosion at both the edges and gradually moves towards the center. The dog has long been a subject of scientific curiosity because its great diversity in both morphological and behavioral traits. The recent release of the domestic dog genome provides us with an ideal opportunity to investigate dog-specific genomic features. Compared with the human and mouse genomes, the dog genome has a remarkably large number of CGIs and high CGI density, which is contributed by its noncoding sequences. Surprisingly, the dog genome has fewer CGIs associated with the promoter regions of genes than the human or the mouse. Further examination of functional features of dog-human-mouse homologous genes suggests that the dog might have undergone a faster erosion rate of promoter-associated CGIs than human or mouse. Some genetic or genomic factors such as local recombination rate and karyotype may be related to the unique dog CGI features. To further understand the evolution of CGIs in the vertebrate genomes, we performed a systematic analysis of CGIs in 10 mammalian genomes. We observed significant correlations between CGI density and genomic features such as number of chromosomes, chromosome size, and recombination rate. We also observed a trend of higher CGI density in telomeric regions. We also compared our observations in mammals to other non-mammal vertebrates. We systematically investigated the algorithms to identify CGIs and the evolution of CGIs among vertebrate genomes. Our work revealed the function of CGIs in gene regulation, and shed light on vertebrate genome evolution as well as the regulation of CGIs in human disease.
语种	中文
文献类型	学位论文
条目标识符	http://ir.kiz.ac.cn/handle/353002/6806
专题	科研部门_比较基因组学（宿兵）
推荐引用方式 GB/T 7714	韩冷. CpG岛在脊椎动物中的进化研究[D]. 北京. 中国科学院研究生院,2010.

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