Mathematical Modelling of Bacterial DNA Inversion Dynamics Uncovers an Organized Multi-Locus Response to Phage Predation in Bacteroides fragilis

This bioRxiv preprint investigates how phase variation—reversible DNA inversions that generate phenotypic diversity—shapes bacterial responses to phage predation. Using longitudinal data from a gnotobiotic mouse experiment with B. fragilis NCTC 9343 and phage Barc2635, the authors built a dynamical model across 18 invertible regions to analyze temporal patterns, region-level susceptibility, and combinatorial promoter-state combinations.

The model uncovered a structured phage-susceptibility landscape: loci differed in effective phage-associated sensitivity and occupied distinct parameter regimes. Projecting fitted susceptibility weights onto observed ON-fraction trajectories showed that the temporal response was dominated by a small subset of phase-variable region (PVR) contributors. A two-dimensional contribution-space analysis separated persistent contributors from rare high-impact loci, indicating that susceptibility evolves along constrained temporal paths rather than fluctuating randomly.

Several loci contributed to the modelled susceptibility signal in phase-dependent patterns, with the PVR of polysaccharide F (PSF) providing a persistent contribution. Recurring PSF-centered patterns appeared in combinatorial scoring of pairwise, triple, and quadruple locus sets. The authors note that their results do not identify a physical receptor or establish direct causal infection states, but demonstrate that phage predation is associated with a structured, low-dimensional, multi-locus organization of phase variation.