Comparative genomics analysis of E. coli and S.flexneri revealed that horizontal gene transfer, gene loss, and IS element-mediated chromosomal rearrangements play important roles in the evolution of these pathogens. Strain differences are not exclusively restricted to large islands, but also occur in a considerable number of smaller gene clusters coding for integrative functions such as nutrient utilization or surface modification. There is no doubt that the large PAIs are of major importance in conferring a virulent phenotype; however, the smaller clusters are of additional benefit in the course of an infection. Comparison of the available complete genome sequences revealed the genetic diversity underlying the pheno-typic diversity of this species. Gene acquisition and loss is extensive, providing different lineages with distinct metabolic, pathogenic, and other capabilities.

No clear distinction can be drawn between pathogenic and commensal E. coli strains, particularly in regard to extraintestinal disease. As colonizing sites outside the gut are unlikely to provide any selective advantage in terms of transmissibility, it is clear that any so-called "extraintestinal virulence factors" are likely to have evolved to enhance survival in the gut and/or transmission between hosts, and therefore will be shared with at least some commensal strains. In addition, geno-mic islands are seldom fixed, as first thought, and bear the potential for ongoing rearrangements, deletions, and insertions. Accessory DNA elements especially, such as IS elements and transposons, play a pivotal role during genome plasticity and evolution in Shigella and E. coli. It is becoming more and more evident that genome evolution in these bacteria cannot be described by a simple "backbone and flexible gene pool" model, but also by "palimpsest' where parts of the genome have seen repeated insertions and deletions.

There is still considerable interest in sequencing additional E. coli and other Shigella genomes. The existing data raise important questions about the levels and mechanisms generating and maintaining genome variability within and between

E. coli and Shigella populations that will require substantial genome-scale sequence information to resolve. Furthermore, knowledge of all proteins expressed in a given bacterial pathogen will provide the entire repertoire of surface proteins that are potential vaccine candidates. Genome comparison between closely related pathogenic and nonpathogenic variants will reveal factors involved in pathogenicity, and furthermore it is anticipated that factors that may direct host specificity of, e.g., human and animal ExPEC isolates could be identified by pathogenomics.

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