Determinants of phase variation rate and the fitness implications of differing rates for bacterial pathogens and commensals

Phase variation (PV) of surface molecules and other phenotypes is a major adaptive strategy of pathogenic and commensal bacteria. Phase variants are produced at high frequencies and in a reversible manner by hypermutation or hypervariable methylation in specific regions of the genome. The major mechanisms of PV involve site-specific recombination, homologous recombination, simple sequence DNA repeat tracts or epigenetic modification by the dam methylase. PV rates of some of these mechanisms are subject to the influence of genome maintenance pathways such as DNA replication, recombination and repair while others are independent of these pathways. For each of these mechanisms, the rate of generation of phase variants is controlled by intrinsic and dispensable factors. These factors can impart environmental regulation on switching rates while many factors are subject to heterogeneity both within isolates of a species and between species. A major gap in our understanding is whether these environmental and epidemiological variations in PV rate have a major impact on fitness. Experimental approaches to studying the biological relevance of differing PV rates are being developed, and a recent intriguing finding is of a co-ordination of switching rates in the phase variable P-pili of uropathogenic bacteria.