Chromosomal Flip-Flop

A study describes how phenotypic switching in Staphylococcus aureus is caused by a reversible large-scale genomic inversion.

Clonal bacterial populations often display various phenotypes. This diversity is most obviously identifiable as colony variation. Many different bacterial genera display ‘small colony variants’ (SCVs), the occurrence of which is generally attributable to deficiencies in various metabolic pathways.

Cui et al have characterised an STV strain of Staphylococcus aureus which reverts to a normal colony variant (NCV) at a frequency of 1-3 in a 1000. Interestingly the NCV progeny revert back to SCV in 1-10% of cases. This frequent bi-directional reversion was stably maintained at these ratios; homogeneous colony populations could never be isolated.

The small colony variant displayed some important phenotypic differences to the NCV. As well as slow growth and less pigmentation, it was susceptible to β-lactam antibiotics whilst the NCV was not. The authors identified over a hundred genes were differentially expressed between the two variants, and that their susceptibilities to many chemicals were different.

Diagram showing reversible genomic inversion forms caused by homologous recombination at inverted repeat regions (break points. BPs)

When Cui et al. sequenced the genomes of the two variants, they discovered that nearly half of the genome (1.26 Mb of 2.87 Mb) was differenttly aligned. This ‘X-shaped’ chromosome inversion occurred between two oppositely oriented pathogenicity islands, symmetrically opposite each other on the chromosome with respect to the replication axis. Each pathogenicity island contained two copies of an identical 3,638bp long sequence. It appears that homologous recombination can occur at these sites and generate the genomic inversion. This is in agreement with experiments in which the authors altered levels of the key recombination regulatory protein RecA; finding that they could increase the rate of reversion with higher recA expression.

The chromosomal flip-flopping therefore regulates the maintenance of two different S. aureus phenotypic variants. The two forms have different advantages and disadvantages. The original SCV strain isolated from a patient suffering persistent reinfection of a surgical site. It appears that the SCV may facilitate immune evasion, whilst the NCV has higher antibiotic resistance. Maintaining a balance between the two variants within the S. aureus population therefore functions as an evolutionarily useful bet-hedging strategy.

This type of flexible genome organisation serving as a self-organising regulatory mechanism for the maintenance of a bi-stable heterogeneous cell population may well be a more wide-spread bacterial evolutionary strategy.

Cui L, Neoh HM, Iwamoto A, & Hiramatsu K (2012). Coordinated phenotype switching with large-scale chromosome flip-flop inversion observed in bacteria. Proceedings of the National Academy of Sciences of the United States of America, 109 (25) PMID: 22645353

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