Analysis of Cis-acting Regulatory Motifs Involved in Alternative Splicing

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Title: Analysis of Cis-acting Regulatory Motifs Involved in Alternative Splicing
Author: Zhao, Sihui
Advisors: Steffen Heber, Committee Chair
Zhao-Bang Zeng, Committee Co-Chair
David Bird, Committee Member
Hao Zhang, Committee Member
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.
Date: 2009-04-15
Degree: PhD
Discipline: Bioinformatics

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