Bioinformatics study of mammalian MRNA polydenylation

Messenger RNA polyadenylation is one of the key post-transcriptional events in mammalian cells, which have influences on many aspects of mRNA metabolism. Several human diseases have been shown to associate with abnormal polyadenylation, highlighting the importance of this process. The availability of the complete sequence of human and mouse genomes, together with their gene expression data provides valuable resources to study mRNA polyadenylation on a system level. This dissertation addresses the following issues of mammalian mRNA polyadenylation through bioinformatics approaches: (1) the extensive documentation of several key aspects of polyadenylation sites in humans and mice on a genomic level; (2) the evaluation of whether polyadenylation is an evolutionarily conserved cellular process between human and mouse ortholog genes; (3) the tissue-specificity of the regulation of alternative polyadenylation in humans and mice; (4) the development of a novel approach to use SAGE data to study polyadenylation. A database is built to comprehensively document mappings of poly(A) sites in humans and mice genome-wide. About 54% of human genes and 32% of mouse genes are shown that can undergo alternative polyadenylation. Conservation studies show that polyadenylation configurations are highly conserved in humans and mice. In addition, Gene Ontology studies identified certain functional groups of genes associated with different types of polyadenylation configurations. Furthermore, tissue-specific usage of alternative poly(A) sites is observed. Microarray data analysis and sequence analysis identified certain trans-acting factors and cis-regulatory elements that might be responsible for such regulation of alternative polyadenylation. Finally, a novel approach to use SAGE data to study alternative polyadenylation is developed and demonstrated. The results presented provide important insights into the mechanism of mRNA polyadenylation and a genomic view of the regulation of gene expression by alternative polyadenylation in mammals