Fitness Effects of Natural Genetic Variation on the Ras Signalling Network in Caenorhabditis elegans

Abstract

Natural genetic variation within populations is an important determinant of susceptibilities to complex diseases like cancer. Cryptic genetic variation refers to a particular type of genetic variation that remains silent unless perturbed by a genetic or environmental change. Understanding the role of this 'hidden' genetic variation in signalling networks can provide insights into how individuals of differing genetic backgrounds might respond to perturbations that cause disease. The well-characterized Ras signalling network is ideal for such studies as it is conserved in nature and regulates a multitude of biological processes that include cellular differentiation, proliferation and survival. I developed a novel approach for studying the effects of cryptic alleles on signalling pathways, which I applied to determine if cryptic genetic variation, influencing the Ras signalling pathway, was a ubiquitous property found in natural populations of C. elegans. This approach utilized mutant alleles to expose cryptic genetic variation in different genetic backgrounds, which were then systematically screened for variations in response to RNAi treatments targeting the Ras signalling network. A population-level fitness phenotype, based on population feeding behaviour, was used to quantify the effects of mutant alleles and RNAi knockdowns. The mechanistic basis of this dynamic phenotype was further explored using an in silico model that I constructed. My findings indicate that cryptic genetic variation is a ubiquitous feature of the Ras signalling network in the six natural isolate backgrounds examined. Specific genes that mediate response variation to elevated Ras signalling in these natural isolates were also identified and found to consist of a mixture of common and unique components from Ras, Notch and Wnt pathways.

Date of Award	31 Dec 2014
Original language	English
Awarding Institution	The University of Manchester
Supervisor	Chris Knight (Supervisor) & Gino Poulin (Supervisor)