Mark Achtman introduced the term “genetically monomorphic bacteria” (GM bacteria) for some human and plant pathogens. They displayed a great uniformity in terms of their “genetic” properties. This “uniformity” poses a challenge to microbiologists. To address these problems, we used CodonW and IslandViewer 3 as analytical tools and took Escherichia coli, Salmonella, and Shigella strains as a model organisms. We hypothesized that GM bacterium contains a common molecular signature among them. We have found a significant correlation regarding the number of protein‐coding genes, predicted highly expressed genes, and the highest length of gene in this regard. On the other hand, the correspondence analysis of pathogenicity‐related genes identified by IslandViewer 3 displayed a somewhat unique pattern in GM bacteria. The probable pathogenic genes are clustered into two separate groups, which is a hallmark of some pattern. Similar genes of non‐monomorphic pathogenic strain clustered almost similarly, but the clusters are joined together, they are not completely separated. These features, in our considered view, may be considered as codon usages signatures of these bacteria, and E. coli in particular.