Genomic diversification underlies the broad ecological range of Salmonella enterica serotype Typhimurium

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 diverse environments. We analyzed 745 genomes of S. Typhimurium isolated from three food animal sources (bovine, swine, and poultry) and two non-food animal sources (wild birds and the environment). We found that S. Typhimurium from food animal sources generally had a more open pangenome and harbored more antimicrobial resistance genes (ARGs) than non-food animal sources. Notably, swine isolates exhibited the most open pangenome and prevalent ARGs, likely as a result of horizontal gene transfer primarily mediated by plasmids. Despite similar core genome sizes, S. Typhimurium from different sources displayed distinct patterns of positive selection in the core genome that varied in both 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 further identified genetic variants (e.g., virulence factors) highly predictive of sources. These findings suggest that gain and loss of accessory genes and positive selection acting on core genes facilitate differential adaptation in S. Typhimurium, contributing to its broad ecological range.