EvolSpliceKinetics · From co-transcriptional splicing kinetics to the evolutionary impact of exon and intron definition

From co-transcriptional splicing kinetics to the evolutionary impact of exon and intron definition

Biological systems often bewilder the observer with their staggering levels of complexity. This complexity creates a vulnerability – each of the cogs in the machine could potentially break, perhaps leading to disease. A prime example of such complexity is a process referred to as splicing, a key step in gene expression. A gene is said to be “expressed” when its DNA sequence is transcribed into an RNA molecule, which then either directly carries out the biological functions of the gene, or serves as a template for the production of a protein. In both cases, most RNAs must first undergo splicing – a processing step, where certain regions of the RNA (“introns”) are removed and the remainder (“exons”) ligated together again. Our genes are pock-marked throughout with scores of tiny sequence signals, which combine in a complex code, allowing the cell to recognize which regions are exons and which are introns. Disruption of either these sequence signals or the proteins that recognize them can lead to malformed RNAs being produced, sometimes with disastrous consequences. Indeed, about a third of disease-causing mutations in humans disrupt splicing. Adding to this complexity, it is now known that often, introns located towards the start of the RNA molecule are spliced out whilst transcription of regions further down is still in progress. This is referred to as “co-transcriptional” splicing, and it opens up completely new ways of thinking about the process. Rather than simply considering the end product of splicing – which regions are removed and which ones remain – one can now turn the spotlight on the dynamics of the process. How do splicing and transcription affect one another, given that they often happen simultaneously? Are all introns removed equally fast? Do the sequence signals that control splicing differ for introns with slow and fast splicing? In this project, I have studied the dynamics of co-transcriptional splicing in the fruit fly Drosophila melanogaster, a species whose genes have widely varying exon-intron structures. I have found the dynamics of splicing to vary dramatically between introns. Moreover, the kinetics of how an RNA is transcribed appear to co-vary with the kinetics of its splicing. In addition, the project led me to interact with scientists from a wide array of backgrounds. I realized how gravely research was often hampered by the fact that young researchers were not sufficiently trained in statistical thinking. Hence, a further goal of the project became to implement interventions to address this challenge.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз