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选择性剪接的调控及与疾病关系的研究
中文摘要

选择性剪接是高等真核生物基因表达过程中的一种普遍现象,其调控非常复杂,涉及到多种因素,其中任何一个调控因素出现异常都可能会影响剪接,进而可能导致疾病的产生。本论文主要对选择性剪接的调控及与疾病的关系进行生物信息学的研究,包括如下三部分内容: 第一,分析了5'剪接位点的U1 snRNA结合自由能在选择性5'剪接位点调控中的作用。U1 snRNA识别5'剪接位点是剪接过程的第一步,对于剪接有重要的影响。在大规模的统计分析基础上,我们发现在不同情况下自由能对5'剪接位点选择的作用是不同的,说明在5'剪接位点的选择过程中,存在自由能依赖的调控机制。这种自由能的作用在特定情况下才比较明显,说明还存在着剪接增强子/沉默子依赖等其他选择性5'剪接位点的调控机制。基于这些结果,我们设计了新的选择性5'剪接位点识别算法,提高了选择性剪接位点的识别性能。 第二,研究了剪接增强子、沉默子在组织特异性选择性剪接中的调控作用。我们在6个组织中进行了分析,识别出了选择性外显子及其上下游序列中的剪接增强子、沉默子。通过比较分析,发现这些调控元件的功能与其所处位置间存在依赖性。同时,我们发现选择性外显子上下游序列中的调控元件之间存在关联,这种关联在几乎所有6个正常组织中均可以观察到,说明了它的重要性。我们的研究还发现在除了肝之外的所有5个肿瘤组织中,这种调控元件间的关联性被削弱了,这进一步说明了调控元件间的关联对于剪接的重要性。 第三,发现了多外显子跳跃事件与肿瘤之间可能存在关联。通过分析正常组织和肿瘤组织中的表达情况,我们发现相比于单外显子跳跃事件,多外显子跳跃事件更可能与肿瘤相关联,而这种可能性随跳过外显子数目的增加而增大。保守性的分析进一步验证了这个结果。有启发意义的是,即使比较跳跃序列长度相似的多外显子跳跃事件和单外显子跳跃事件,仍能观察到二者在之前的各方面存在差异,说明多外显子跳跃事件与肿瘤的关联至少部分来源于其在调控机制上的某些固有特性。 关键词:选择性剪接;生物信息学;调控;疾病

英文摘要

Alternative splicing is a wide-spread phenomenon in the expression of higher eukaryotic genes. The regulation of alternative splicing is a complex process involving many regulatory elements. Defects in any regulatory element can possibly induce splicing alterations, which are often observed in human disease. In this dissertation, we studied the regulation of alternative splicing and its relationship with human disease using bioinformatics approaches. The dissertation includes three parts as follows: 1.We analyzed the regulatory role of U1 snRNA binding free energy in the selection of alternative 5' splice sites. The recognition of 5' splice sites by U1 snRNA is the first step of the splicing process, and therefore it is very important in splicing regulation. On the basis of a large-scale statistical analysis, we classified free energies into two groups. Subsequently, based on the classification of free energies, we divided alternative 5' splice sites into three categories. It was observed that free energy plays different roles in the selection of 5' splice sites in different categories, which suggests a free-energy-dependent regulatory mechanism in the regulation of alternative 5' splice sites. The effect of free energy is significant only in some certain situations, implying that there may be some other regulatory mechanisms, such as enhancer/silencer-dependent regulation. Based on these results, we developed a new algorithm for the recognition of alternative 5' splice sites and improved the performance of alternative splice site recognition. 2.We studied the regulatory role of splicing enhancers and silencers in tissue-specific alternative splicing. We analyzed tissue-specific alternative splicing in six tissues which have enough data: brain, testis, muscle, pancreas, eye and liver. Splicing enhancers and silencers located in alternative exons and their flanking sequences were first identified. Based on a comparative analysis, we provided evidences for the dependence of the function of these regulatory elements on their locations. It was also found that there existed some associations between upstream and downstream elements. The associations were observed in almost all the six normal tissues and therefore they may be important for the functions of splicing enhancers and silencers. The importance of the associations between regulatory elements was further demonstrated in the study of tumor tissues, where the associations were found to be weakened. 3.We found that multi-exon skipping (MES) events might be associated with tumors. By evaluating the expression in normal and tumor tissues, we found that compared with single-exon skipping (SES) events, MES events are more likely associated with tumors and the likelihood increases with skipped exon number. Conservation analysis further validated this result. Interestingly, the differences still existed even after comparison of MES and SES events with similar-length skipped regions, which suggests that the association of MES events with tumors originates at least in part from their intrinsic characteristics in regulation. Key words: alternative splicing; bioinformatics; regulation; disease

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