The Broad Ecological Range of Salmonella enterica Serotype Typhimurium Is Associated With Genomic Diversification

ABSTRACT Salmonella Typhimurium is a versatile foodborne pathogen with a broad ecological range, making it an ideal model to better understand pathogen adaptations that allow them to infect multiple hosts and persist across environments. Here, we analysed 595 genomes of S. Typhimurium representing three food animal sources (bovine, swine, and poultry) and one non‐food animal source (wild birds). We found that S. Typhimurium from food animal sources generally had a more open pangenome and harboured more antimicrobial resistance genes (ARGs). Notably, swine isolates exhibited the most open pangenome and the highest prevalence of ARGs, patterns that were associated with a greater presence of mobile genetic elements, particularly plasmids. Despite similar core genome sizes, S. Typhimurium from different sources displayed distinct patterns of positive selection in the core genome that varied in frequency and targeted functional categories. In contrast, although accessory genome sizes varied substantially across sources, the frequency of positive selection remained similar. Using machine learning, we identified source‐predictive genetic variants, many of which are associated with stress‐response functions. These findings suggest that gain and loss of accessory genes and positive selection acting on core genes support differential adaptation in S. Typhimurium, potentially contributing to its broad ecological range.