Phasevariable

Phasevariable refers to mechanisms by which genes or regulons can switch between discrete expression states, producing phenotypic diversity within a clonal population. Classic phase variation involves reversible on/off switching of gene expression, often mediated by changes in simple sequence repeats that alter promoter or coding sequences via slipped-strand mispairing. A related mechanism uses invertible DNA elements or site-specific recombination to invert promoters, thereby changing transcription without altering the gene itself.

An additional, epigenetic form of phase variation is driven by phase-variable DNA methyltransferases. These enzymes periodically switch expression state, creating a regulatory phasevarion—a phase-variable regulon—through DNA methylation, which globally modulates transcription of many genes. In this case, the switching changes the methylation pattern and downstream gene expression without changing the underlying DNA sequence of the regulated genes.

Phase-variable systems are widespread in bacterial pathogens, where they contribute to immune evasion, colonization, and persistence. Neisseria meningitidis, Neisseria gonorrhoeae, and Haemophilus influenzae exhibit phase-variable surface structures such as Opa proteins, pili, lipooligosaccharide, and capsules; Campylobacter jejuni and Helicobacter pylori also use phase variation to diversify surface antigens.

Switching frequencies vary by mechanism and organism, typically ranging from about 10^-3 to 10^-5 per generation for repeat-mediated switches, and can be higher for some methyltransferase-driven systems. The presence of phase-variable traits complicates vaccine design, diagnostic assays, and experimental reproducibility.

See also: antigenic variation, phasevarion, DNA methyltransferase, slipped-strand mispairing, invertible promoter.