Investigating the genomic basis of metabolic robustness through in silico flux analysis

We employ a novel implementation of flux balance analysis to investigate the role of genome structure in the maintenance of metabolic robustness. We propose the hypothesis that the genomic organization of a bacterium buffers its metabolome against random gene deletion. To test this hypothesis, we use a novel implementation of producibility analysis to determine the metabolomic impact of gene deletions in the E. coli iJR904 genome-scale metabolic model. From these results, we determine metabolomic fragility, which we compute as the average number of metabolites knocked out across all gene deletions of a given size in a given nutrient media. We apply this analysis for three deletion window sizes (4000, 8000, 16000 bp) across the length of the E. coli genome. We compare these results to those obtained from several null distributions of permuted genomes to assess the impact of E. coli genome organization on its metabolic robustness. Our results strongly suggest that the arrangement of genes on the E. coli genome buffers metabolite producibility against random gene deletion. Our results have interesting implications for the understanding of metabolic network evolution. Future work includes examining our hypothesis for a wider range of deletion sizes and nutrient environments and extending our results to the metabolic networks of other species.