Growth on human serum albumin drives large genomic inversion in Porphyromonas gingivalis

Insertion sequence transposable elements can bring about breakage and rejoining of chromosomal DNA in inverted orientations. Genomic inversions are a type of chromosomal rearrangement that significantly influence gene expression, yet our understanding of what conditions and processes drive these rearrangements remains unclear. Importantly, these inversions are typically reversible and therefore dynamic. Using long reads to evaluate genome structure, this study revealed that populations of some strains of the oral anaerobe Porphyromonas gingivali s have two distinct genome arrangements, and the large 1.5 Mbp inversion resulting from these rearrangements is controlled by matching ISPg2 transposase elements. Strains that can rearrange their genomes undergo early autolysis when grown on human serum albumin (HSA) as a substrate, yet the strains lacking the matching ISPg2 elements do not. Intriguingly, a subset of cells within the population survives after lysis, and the inverted sub-population orientation becomes dominant. We propose that P. gingivalis maintains different genotypic subpopulations with varying phenotypes within its population as a bet-hedging strategy, where some of the cells will continue to persist after most of the cells lyse, thereby improving overall survival. The findings presented here provide further confirmation of striking differences between P. gingivalis strains and new insights into the impact of genome rearrangement on P. gingivalis physiology by using HSA as a biologically relevant substrate for growth. IMPORTANCE In bacteria, some regions of chromosomal DNA (called insertion sequence transposable elements) can exchange with each other and cause large sections of a genome to flip around in the opposite direction. This study identified a dynamic 1.5 Mbp chromosomal inversion in Porphyromonas gingivalis mediated by ISPg2 elements. Triggered by growth on human serum albumin, this rearrangement modulates autolysis while allowing a resilient subpopulation to dominate. Our findings highlight a bet-hedging strategy as a vital mechanism for P. gingivalis persistence, offering new insights into how genomic plasticity drives survival in biologically relevant growth conditions.