Models of Pre-mRNA Splicing Under Intron and Exon Definition
Kayla McCue, Massachusetts Institute of Technology
Between transcription from the DNA sequence and translation into protein, messenger RNA must undergo several processing steps. One of the most important is the removal of introns by the spliceosome, an incredibly complex and dynamic macromolecular machine. The spliceosome, unlike much of the cell's machinery, assembles dynamically on each pre-mRNA to perform its function and then dissociates once the intron is spliced. A key part of this process is the correct definition of pairs of splice sites, which can be accomplished in two modes. The first, called intron definition, is when the splice sites are initially paired across the intron, defining the intronic bases to be spliced out. The alternative, called exon definition, is when the splice sites are initially paired across the exon, defining the bases to remain in, followed by rearrangement of the splicing machinery to pair across introns, the orientation that is required for catalysis. The mode has consequences for the phenotypes of splicing mutations and likely for the speed and accuracy of splicing as well. It is unknown exactly what factors determine the usage of one mode of spliceosome assembly over the other, although intron and exon lengths are thought to play an important role. Considering this, many organisms have gene structures that are consistent with the use of one mode of definition or the other (e.g., yeast genes favor intron definition and most human genes favor exon definition), but some use a mixture of the two. One such organism, Drosophila melanogaster, also has the advantage of being a well-studied organism with a great deal of publicly available data. We have developed stochastic context-free grammar models of splicing under both intron and exon definition to address questions about how splicing mode affects splicing accuracy and other properties.
Abstract Author(s): Kayla McCue, Chris Burge