Analysis of Cis-acting Regulatory Motifs Involved in Alternative Splicing

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dc.contributor.advisor Steffen Heber, Committee Chair en_US
dc.contributor.advisor Zhao-Bang Zeng, Committee Co-Chair en_US
dc.contributor.advisor David Bird, Committee Member en_US
dc.contributor.advisor Hao Zhang, Committee Member en_US Zhao, Sihui en_US 2010-04-02T19:12:41Z 2010-04-02T19:12:41Z 2009-04-15 en_US
dc.identifier.other etd-03232009-225516 en_US
dc.description.abstract Alternative splicing is an important posttranscriptional process in eukaryotes. It dramatically expands the proteome and contributes essentially to the regulation of gene expression. Cis-acting regulatory motifs play a pivotal role in the regulation of alternative splicing. Many human diseases involved with aberrant (alternative) splicing are caused by mutations of splicing regulatory motifs. However, due to the short, degenerate and context-dependent nature, the prediction of cis-acting splicing motifs is a very challenging task. In this dissertation, we focus on discovery of splicing signals from sequences. This may help to reveal the integrated splicing code and to understand the regulation of gene expression in the resolution of exon level. In chapter one, we review the up-to-date research development in alternative splicing and its regulation, as well as the experimental and computational approaches in genome-wide alternative splicing analysis. We describe a large-scale data analysis experiment to discover AS motifs in chapter two. We applied a computational framework to re-analyze a dataset containing about 3,000 cassette exons and skipping rates for regulatory motifs. The alternative spliced events were clustered by their expression profiles to find co-regulated genes. Rather than using a fixed cutoff as cluster boundary, we used systematic sampling to sample sequence clusters and eliminated redundant motifs predicted from overlapping clusters. We conclude that these predicted motifs may be promising candidates responsible for AS regulation by comparison to known motifs and by positional bias. In chapter three, we describe a new approach to discover short and degenerate AS motifs. We implemented a two-step approach incorporating skipping rates in motif discovery. In the simulation study, we show that this approach is especially suitable to discover short and highly degenerate motifs. Analysis of cassette exons in Central Nervous System tissues produced 15 motifs which are associated with the variation of skipping rates. We discover that Nova and hnRNP A1 binding sites are involved with AS regulation, as well as about ten novel motifs. Moreover, co-operation between predicted motifs are also revealed. In chapter four, we give the present status of SPRED, a database of cis-acting regulatory splicing elements. The motifs in SPRED are compiled from literature. They are all experimentally validated. The web interface is publically accessible and accompanied with query and similarity search tools. The goal of SPRED is to provide a comprehensive motif dictionary to facilitate the research in AS and its regulation. Finally, we give the conclusions in chapter five. We also give the perspective for future study and briefly review the potential challenge. en_US
dc.rights I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dis sertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to NC State University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. en_US
dc.subject alternative splicing en_US
dc.subject motif discovery en_US
dc.title Analysis of Cis-acting Regulatory Motifs Involved in Alternative Splicing en_US PhD en_US dissertation en_US Bioinformatics en_US Statistics en_US

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