Sequential gene loss promotes expansion of monophasic Salmonella Typhimurium ST34.
Understanding the genetic factors facilitating emergence of infectious diseases is critical, however, mechanisms underlying expansion of pathogenic bacterial variants remain unclear. Here we performed a large-scale genomic analysis of 44,597 Salmonella Typhimurium genomes and observe that sequential gene loss in monophasic Salmonella Typhimurium (mSTM) ST34 explains its clonal expansion as an increasingly prevalent zoonotic lineage. Functional and in vivo competition experiments show that a frameshift mutation in dinB, a polymerase for translesion DNA synthesis, leads to transcriptional changes affecting flagellin gene expression and subsequent loss of the flagellin-encoding fljB, altering the requirements for gut infection. Temporal evolutionary modelling supports a role for gene loss events in a specific chronological order for mSTM ST34 expansion. Our findings reveal a stepwise pathoadaptation model underpinning clonal global spread, providing mechanistic insights relevant to forecasting future pandemics.