人与其他高等真核生物基因组isochore和超级保守序列研究
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摘要
随着基因组测序技术的蓬勃发展,越来越多的全基因组序列完成测序。这带给我们一个前所未有的机会,使我们可以在序列水平上研究基因组结构特征,可以对多个物种进行全基因组水平上的比较研究。已有的研究工作揭示了基因组结构的许多基本特征。本论文主要致力于人与其他高等真核生物基因组的isochore结构和超级保守序列的研究。
论文第一部分介绍了生命科学研究的新动态和生物信息学相关知识。简要介绍了Z曲线理论和方法,以及在基因组研究中的应用。
论文第二部分主要致力于人与其他高等真核生物基因组isochore结构的研究。着眼于人类基因组isochore边界的生物学意义,使用最新开发的基于Z曲线理论的基因组序列分段算法,在单核苷酸精度的水平上重新定位了人类基因组56个isochore的边界,共得到79个独立的边界。通过与其他的生物学特征相比较,我们发现isochore边界与很多有生物学意义的生物学元件的边界重合,如:重复元件(repeat),GpG岛分布,保守序列等。另外isochore边界附近的序列组成高度保守。通过和已被实验证实的MHC序列中的复制开关点附近的序列相比较,有理由推断这79个isochore边界都有可能是人类基因组中的复制开关位点。结果表明,isochore的边界可能发挥着重要的功能,并且为理解人类基因组的结构提供新的方向。论文还分析了六个基因组(人,鼠,牛,斑马鱼,脂鲤,杨树)的isochore结构,发现温血脊椎动物,冷血脊椎动物,和植物基因组中都具有isochore结构,并且分析了isochore结构特征的异同。发现植物基因组中内含子(外显子)的平均G+C含量与它们所在的isochore的G+C含量的关系,明显不同于脊椎动物。
论文第三部分是围绕植物基因组中超级保守序列的问题展开的。我们选择了模式生物拟南芥,水稻和杨树基因组。研究发现了拟南芥和水稻两个基因组间的33个独立的超级保守序列片段。论文详细分析了这些超级保守序列的长度,数量,序列特征,它们的基因功能,以及和其它物种之间的序列相似程度等诸多问题。
With the development of the sequencing technology, the whole genomic sequences of numerous organisms have become publicly available. It gave us an unprecedented opportunity to analyze the features of genome organizations at sequence level and to study differences among organisms by comparing the whole genomic sequences. Previous research works have revealed many basic features of the genome organizational structures. In this thesis, the isochore structures and ultraconserved sequences of human and other eukaryotic genomes were analyzed.
The human genome is composed of large sequence segments with fairly homogeneous GC content, namely isochores, which have been linked to many important functions. Biological implications of most isochore boundaries, however, remain elusive, partly due to the difficulty in determining these boundaries at high resolution. Using the segmentation algorithm based on the quadratic divergence, we re-determined all 79 boundaries of previously identified human isochores at single-nucleotide resolution, and then compared the boundary coordinates with other genome features. We found that 55.7% of isochore boundaries coincide with termini of repeat elements; 45.6% of isochore boundaries coincide with termini of highly conserved sequences based on alignment of 17 vertebrate genomes, i.e., the highly conserved genome sequence switches to a less or non-conserved one at the isochore boundary; some isochore boundaries coincide with abrupt change of CpG island distribution (note that one boundary can associate with more than one genome feature). In addition, sequences around isochore boundaries are highly conserved. These results suggest possible key roles of the isochore boundaries and may further our understanding of the human genome organization. By the analysis of the whole genomes of human, mouse, cow, zebrafish, tetraodon and poplar, we have found that all the genomes are composed of isochores. They share some common characters, but in some aspects they differ from each other. The features of isochores in the poplar genome are obviously different from others.
The discovery of the ultraconserved elements in the human genome has caused wide attentions. The ultraconserved elements in insect genomes have also been studied. But the instance of the ultraconserved sequences in the plant genomes remains untouched. In this thesis we found 33 independent ultraconserved segments which are absolutely conserved between A. thaliana and rice genomes. Many problems about these ultraconserved sequences have been analyzed, such as lengths of the ultraconserved sequences, the total number of them, the sequence features, the genetic functions, and the sequence similarities with other plant genomes.
论文第一部分介绍了生命科学研究的新动态和生物信息学相关知识。简要介绍了Z曲线理论和方法,以及在基因组研究中的应用。
论文第二部分主要致力于人与其他高等真核生物基因组isochore结构的研究。着眼于人类基因组isochore边界的生物学意义,使用最新开发的基于Z曲线理论的基因组序列分段算法,在单核苷酸精度的水平上重新定位了人类基因组56个isochore的边界,共得到79个独立的边界。通过与其他的生物学特征相比较,我们发现isochore边界与很多有生物学意义的生物学元件的边界重合,如:重复元件(repeat),GpG岛分布,保守序列等。另外isochore边界附近的序列组成高度保守。通过和已被实验证实的MHC序列中的复制开关点附近的序列相比较,有理由推断这79个isochore边界都有可能是人类基因组中的复制开关位点。结果表明,isochore的边界可能发挥着重要的功能,并且为理解人类基因组的结构提供新的方向。论文还分析了六个基因组(人,鼠,牛,斑马鱼,脂鲤,杨树)的isochore结构,发现温血脊椎动物,冷血脊椎动物,和植物基因组中都具有isochore结构,并且分析了isochore结构特征的异同。发现植物基因组中内含子(外显子)的平均G+C含量与它们所在的isochore的G+C含量的关系,明显不同于脊椎动物。
论文第三部分是围绕植物基因组中超级保守序列的问题展开的。我们选择了模式生物拟南芥,水稻和杨树基因组。研究发现了拟南芥和水稻两个基因组间的33个独立的超级保守序列片段。论文详细分析了这些超级保守序列的长度,数量,序列特征,它们的基因功能,以及和其它物种之间的序列相似程度等诸多问题。
With the development of the sequencing technology, the whole genomic sequences of numerous organisms have become publicly available. It gave us an unprecedented opportunity to analyze the features of genome organizations at sequence level and to study differences among organisms by comparing the whole genomic sequences. Previous research works have revealed many basic features of the genome organizational structures. In this thesis, the isochore structures and ultraconserved sequences of human and other eukaryotic genomes were analyzed.
The human genome is composed of large sequence segments with fairly homogeneous GC content, namely isochores, which have been linked to many important functions. Biological implications of most isochore boundaries, however, remain elusive, partly due to the difficulty in determining these boundaries at high resolution. Using the segmentation algorithm based on the quadratic divergence, we re-determined all 79 boundaries of previously identified human isochores at single-nucleotide resolution, and then compared the boundary coordinates with other genome features. We found that 55.7% of isochore boundaries coincide with termini of repeat elements; 45.6% of isochore boundaries coincide with termini of highly conserved sequences based on alignment of 17 vertebrate genomes, i.e., the highly conserved genome sequence switches to a less or non-conserved one at the isochore boundary; some isochore boundaries coincide with abrupt change of CpG island distribution (note that one boundary can associate with more than one genome feature). In addition, sequences around isochore boundaries are highly conserved. These results suggest possible key roles of the isochore boundaries and may further our understanding of the human genome organization. By the analysis of the whole genomes of human, mouse, cow, zebrafish, tetraodon and poplar, we have found that all the genomes are composed of isochores. They share some common characters, but in some aspects they differ from each other. The features of isochores in the poplar genome are obviously different from others.
The discovery of the ultraconserved elements in the human genome has caused wide attentions. The ultraconserved elements in insect genomes have also been studied. But the instance of the ultraconserved sequences in the plant genomes remains untouched. In this thesis we found 33 independent ultraconserved segments which are absolutely conserved between A. thaliana and rice genomes. Many problems about these ultraconserved sequences have been analyzed, such as lengths of the ultraconserved sequences, the total number of them, the sequence features, the genetic functions, and the sequence similarities with other plant genomes.
引文
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