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Computational Analysis of Synthetic Gene/reaction Lethality In E. coli

Alireza Zomorrodi, Patrick F. Suthers, and Costas D. Maranas. Chemical Engineering Department, Penn State University, The Pennsylvania State University, University Park, PA 16802

Essential genes are defined as genes whose deletion is lethal. By analogy, synthetic lethals refer to pairs of non-essential genes whose simultaneous deletion is lethal (i.e., no biomass formation). One can extend the concept of synthetic lethality by considering gene groups of increasing size where only the simultaneous elimination of all genes is lethal but individual deletion are not. We developed an optimization based framework using a bilevel representation to exhaustively identify multi-gene (and by extension reaction) lethals for genome-scale models. Specifically, this framework was applied to the iAF1260 model of E. coli leading to the exhaustive identification of all double, triple and some higher-order synthetic lethals. Graphical representations of these synthetic lethals reveal a variety of motifs ranging from hub-like to highly connected sub-graphs. These results provide a birds-eye view of the redundant mechanisms available for redirecting metabolism and reveal complex patterns of gene utilization and interdependence. By analyzing the functional classifications of the genes involved (such as carbohydrate or nucleotide metabolism) we uncovered trends in connectivity within and between classifications.