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题名	基因组中功能模块的种间（人和小鼠）差异比较及其进化模式的初步分析
作者	杨若林
学位类别	博士
答辩日期	2008-06
授予单位	中国科学院研究生院
授予地点	北京
导师	宿兵
关键词	ISA 功能模块 分子进化 物种间差异
其他题名	Interspecies (human and mouse) divergence and patterns of gene evolution of modules in the genome
学位专业	动物学
中文摘要	物种间的表型差异，一直是遗传学家和进化生物学家最感兴趣的问题之一。到目前为止，人们已经发现了许多的因素对物种间的表型差异产生影响。例如，大到整个基因组结构上的变化，小到单个基因的编码区或者调控区出现的结构或序列上的差异，以及基因的不同选择性剪切方式，新基因的形成，甚至是物种间表观遗传学的差异等，所有这些因素都可能对物种间的表型分化产生重要的贡献。传统的研究方法中包括了对物种间直系同源基因的序列以及它们的表达谱差异进行比较，然后从序列变化较大，或者表达谱差异显著的一些候选基因中，找寻物种间表型差异的蛛丝马迹。 在本论文中，作者以人和小鼠作为比较对象，对物种间差异这一问题再次进行了探讨。不过，我们采取了一种新的研究思路。我们的方法既不是直接对物种间的同源序列进行比较，也不是首先鉴定出表达差异显著的基因，而是先鉴定出各物种的组织相关功能模块，然后再在模块的水平上对物种间的差异进行比较。 作者根据ISA（迭代式信号算法）的基本原理，自编了一套程序，分别在人和小鼠相同的29种组织（细胞系）中鉴定到了67和69个非冗余的组织相关功能模块。首先，本文对所有鉴定到的模块，在物种间进行了全局比较。结果显示：人和小鼠的功能模块在基因的组成上发生了巨大的变化。在两个物种所有模块的两两比较中，只有两对模块的相似性接近了50％；接着，我们将所有模块中的基因关联到表达该模块的各种组织（细胞系）上，以组织（细胞系）为单位，对两个物种相同组织（细胞系）关联的基因进行了比较，结果再次显示了物种间相同的组织在其所关联的基因组成上仍然差异巨大；为了进一步了解这种差异，本文最后对所有的模块进行了功能富集性分析，通过将模块中富集的功能项关联到该模块对应的组织（细胞系），以组织（细胞系）为单位，对两个物种相同组织（细胞系）关联的功能项进行了比较。结果显示：在该比较方式下显示出的物种间差异并没有上面两种比较方法显示的差异那么大，即在本次结果中，我们经常能发现物种间相同的组织（细胞系）往往包含了一些相同（类似）的生物过程和分子功能类群。以上这些现象可能暗示了：功能类群在不同物种的进化过程中，虽然其基因的组成经常会出现大的变化，然而这些变化并不会对模块的功能产生大的改变，即模块内含物（基因）的快速变化与模块整体功能的稳定性之间达到了某种调和。 此外，本文还对基因在模块上下文的进化模式进行了初步的探讨。我们的研究结果显示：基因的进化速率与该基因所处的模块背景之间存在着弱的负相关。即如果某一基因参与的模块在更多的组织中表达，并且这些模块包含了更多的其它基因，那么这一基因的进化速率往往就会相对较慢。尽管有文献对基因的进化速率与该基因所处网络的拓扑属性之间进行过相关研究，然而本文的不同之处在于：先前的研究都是基于一个静态的网络结构，而我们的分析更加侧重于从一个动态的角度来捕捉分子水平的进化与其周围环境（即与该基因具有相互作用的其它基因）之间的关系。 总之，本文通过在功能模块的水平对物种间（以人和小鼠为例）进行的比较研究，为我们了解物种间的差异提供了进一步的证据；同时，本文在模块上下文中对基因的进化模式进行的研究工作，也丰富了我们对于分子进化模式的认识。
英文摘要	Phenotypic divergence among species, one of the most interesting biological aspects, has fascinated and puzzled biologists. To date, a series of factors have been discovered which contributed to interspecific divergence, ranging from genome-scale structural variation to difference of coding or regulatory regions of a single gene，from distinct alternative splicing form, origination of new genes to epigenetic difference between species, all of which are likely involved in building and shaping the traits of a species. In previous studies, candidate genes were screened out by detecting sequence divergence and expression variation of orthologous genes among species to explain the phenotype diversity. In this study, the interspecific divergence (human and mouse) was compared in the context of module organization in the genome. The tissue-related modules were identified first for each species, and then the interspecific divergence was assessed in a module context. A set of script was coded according to the principle of ISA (iterative signature algorithm). With the use of the script, 67 and 69 tissue (cell lines)-related modules were identified for 29 common tissues (cell lines) in human and mouse, respectively. The interspecific divergence was compared in three ways. Firstly，all the modules between species were compared in a global fashion. The results showed that the content of modules changed drastically between species. For example, in all the pair-wised comparisons of modules between species, only two pairs showed a similarity near 50%. Secondly, genes of modules were firstly assigned to tissues (cell lines) expressing the modules. Then the interspecific divergence was assessed between every pair of common tissues (cell lines). The results revealed that the genes in the corresponding tissues (cell lines) between species also varied dramatically as shown in the content analysis of modules. To further dissect the observed difference, we conducted GO function enrichment tests for all the modules. Interestingly, the between-species difference is not as large as indicated in the module content analysis.. Collectively, we proposed that although the gene contents in modules evolved rapidly among species, the function of modules were relatively conservative in order to keep a balance between module functionality and its content. Meanwhile, the patterns of gene evolution was also exploited in a module context. The results suggested that the evolution rate of genes are negatively correlated with the constraint of modules. The more tissues in which the modules express and the more genes the modules have, the lower are the evolutionary rates of genes. Compared with the previous studies focusing on establishing the relationship between evolutionary rates of genes and the topological structures of biological networks, this study was conducted by exploring the dynamic changes of networks, which are more informative in understanding the molecular mechanism of module evolution. In summary, we demonstrated that understanding the between-species divergence of modules in the genome is informative for dissecting phenotypic evolution. Furthermore, our preliminary data sheds more light on the molecular patterns of module evolution in the genome.
语种	中文
公开日期	2013-04-24
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/7405]
专题	昆明动物研究所_比较基因组学
推荐引用方式 GB/T 7714	杨若林. 基因组中功能模块的种间（人和小鼠）差异比较及其进化模式的初步分析[D]. 北京. 中国科学院研究生院. 2008.

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