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题名	大脑表达 miRNA 在大脑进化中的作用及其遗传机制初步研究
作者	黄琳
学位类别	硕士
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	miRNA
其他题名	Evolutionary study of brain expressed miRNAs and their target genes
学位专业	细胞生物学
中文摘要	人类区别于其它动物的最本质特征是其拥有其他动物所无法比拟的大脑容量及高 级的认知能力。即使与其近亲－非人灵长类相比，人也拥有比非人灵长类大好几倍的脑 容量和更为发达的认知能力。现在一般认为，人类大脑的形成是适应性选择(达尔文正 选择)的结果。但是到目前为止，对人类起源过程中大脑容量增大及认知能力提高的遗 传学机制却知之甚少。以前的研究表明，几个与大脑发育相关的蛋白质编码基因在人类 起源中受到了正向选择。同时，也有证据表明人类大脑的进化也可能是基因表达调控变 化的结果。因此寻找人与非人灵长类大脑表达基因的调控差异或许能够进一步为人与非 人灵长类为何有如此巨大的差异提供分子生物学水平上的解释。 MicroRNA(miRNA)是一类在转录后水平调控基因表达的不编码蛋白质的小 RNA(长度20－24个碱基)。通过调控靶基因的表达，miRNA参与了众多的生理过程。而 很多大脑表达的miRNA的表达量在大脑发育过程中呈显著的变化，这表明miRNA参与 了大脑的发育调控。由此可知，miRNA对其靶基因调控效率的改变很可能引起大脑发育 调控的改变。 本文通过寻找大脑表达的保守microRNA 及对其靶基因的预测，同时用比较基因组 学的方法发现：有很多microRNA 的靶基因3’UTR 的靶位点中存在人类特异突变位点。 我们推测这些人类特异突变位点可能改变microRNA 对其靶基因的表达调控效应，而调 控效应的改变可能在进化过程中对认知能力的提高发挥重要作用。利用体外报告基因系 统，我们发现有几个预测的靶基因是对应miRNA 的真实靶基因。其中，miR-127 的靶 基因（SEMA3F）3’UTR 的靶位点中所含的一个人类特有的突变增强了miR-127 对 SEMA3F 的调控效率。将该位点突变回复为黑猩猩的位点使得miR-127 对SEMA3F 的 调控效率降低到黑猩猩的水平。这表明miR-127 对SEMA3F 的调控效率的改变确实是 由该人类特异突变位点引起的。我们提供了人类特异突变位点能够引起miR-127 对SEMA3F 的调控效率的改变的体外证据，但是体内的调控模式是否如此尚需进一步的工 作。 总之，本文通过体外试验表明，miRNA靶基因3’UTR的序列变异具有功能效应，它 有可能是人类中枢神经系统在起源和演化中发挥关键作用的重要遗传机制之一。
英文摘要	Human beings are unique when compared with species because of their enlarged brain and highly developed cognitive ability. It is known that even compared with our closely-related relatives, the non-human primates, we have much larger brain size and more sophisticated cognitive skills. It has become a common wisdom that the large brain of humans is the consequence of adaptive evolution, i.e. positive Darwinian selection. But until now, little is known about the genetic mechanism why we have enlarged brain and highly developed cognition. Previous studies have shown that several genes related to brain development have undergone positive selection during human origin. Other studies pointed out that the evolution of human brain may also have something to do with the change in the regulation of gene expression. Therefore, searching for genes differentially regulated between human and non-human primate may shed more light on this issue. MicroRNAs(miRNAs) are a class of noncoding RNAs that can post-transcriptionally regulate the expression of protein coding genes in metazoans. By regulating the expression of their target genes, miRNAs participate in various physiology courses. It has been reported that the expression of many brain expressed miRNAs fluctuates during brain development. This implies that miRNAs play an important role in brain development, and changes of the interactions between miRNAs and their target genes may have effects on brain development. In this study, we focus on miRNAs preferentially expressed in brain and conserved among mammalian species. Through target gene prediction and comparative sequence analysis in representative mammalian species, we identified that several predicted target genes have human specific mutations in the target sites located in their 3’UTR segments. We speculate that these human specific mutation sites may change the efficiency of regulation between miRNAs and their target genes. And this change may contribute to the evolution of human brain. Using in vitro reporter gene system, we found that several predicted target genes were real targets of the corresponding miRNAs. Among them, one of the miR-127 target genes, SEMA3F, contains a human specific mutation in the target site which reinforces the interaction between miR-127 and SEMA3F. Mutation of this human specific site backwards to that of chimpanzee reduces the interaction between miR-127 and SEMA3F to the level of chimpanzee. This result demonstrates that in vitro, the human specific mutation can alter the interaction between miR-127 and SEMA3F. But more experiments are needed to confirm whether it also works in vivo. In conclusion, through in vitro reporter gene system, we found that sequence variations in the 3’UTR segment of miRNA target gene may have functional consequence. And it might be one of the important genetic mechanisms which are pivotal for the origin and evolution of human brain.
语种	中文
公开日期	2010-10-13
内容类型	学位论文
源URL	[http://159.226.149.42:8088/handle/152453/6074]
专题	昆明动物研究所_比较基因组学
推荐引用方式 GB/T 7714	黄琳. 大脑表达 miRNA 在大脑进化中的作用及其遗传机制初步研究[D]. 北京. 中国科学院研究生院. 2008.

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