Network Architecture and Mutational Sensitivity of the C. elegans Metabolome

Lindsay M. Johnson, Luke M. Chandler, Sarah K. Davies, Charles F. Baer

A fundamental issue in evolutionary systems biology is understanding the relationship between the topological architecture of a biological network, such as a metabolic network, and the evolution of the network. The rate at which an element in a metabolic network accumulates genetic variation via new mutations depends on both the size of the mutational target it presents and its robustness to mutational perturbation. Quantifying the relationship between topological properties of network elements and the mutability of those elements will facilitate understanding the variation in and evolution of networks at the level of populations and higher taxa. We report an investigation into the relationship between two topological properties of 29 metabolites in the C. elegans metabolic network and the sensitivity of those metabolites to the cumulative effects of spontaneous mutation. The correlations between measures of network centrality and mutability are not statistically significant, but several trends point toward a weak positive association between network centrality and mutational sensitivity. There is a small but significant negative association between the mutational correlation of a pair of metabolites (r M ) and the shortest path length between those metabolites. Positive association between the centrality of a metabolite and its mutational heritability is consistent with centrally-positioned metabolites presenting a larger mutational target than peripheral ones, and is inconsistent with centrality conferring mutational robustness, at least in toto. The weakness of the correlation between r M and the shortest path length between pairs of metabolites suggests that network locality is an important but not overwhelming factor governing mutational pleiotropy. These findings provide necessary background against which the effects of other evolutionary forces, most importantly natural selection, can be interpreted.