ReviewPlaying Dr Jekyll and Mr Hyde: combined mechanisms of phase variation in bacteria
Introduction
“If he be Mr Hyde, I shall be Mr Seek!”, (RL Stevenson, The Strange Case of Dr Jekyll and Mr Hyde).
Genetic and functional studies, along with recent data from comparative genomics, demonstrate that microorganisms have evolved different strategies to respond and adapt to their environments. Like other organisms, bacteria use classical sensor–effector regulatory circuits to modulate gene expression in response to external stimuli. However, predetermined gene regulation systems are clearly inadequate for the survival of pathogens and symbionts that have to face unpredictable environmental challenges, owing to polymorphism and the immune systems of their hosts. These organisms have opted for an alternative, multicellular-like adaptive strategy based on the production of genetic diversity followed by selection and clonal expansion of the fittest individuals.
Examination of the genomes of pathogenic bacterial species reveals the existence of multiple mechanisms that allow continuous evolution through the deletion, duplication and lateral acquisition of genetic material (1., 2., 3•., 4., 5., 6.; see also the review by DA Rowe-Magnus and D Mazel in this issue, pp 565–569). In addition to this overall genome plasticity, subpopulations of pathogens and commensals exhibit accelerated rates of spontaneous mutations that may facilitate their rapid adaptation to new environmental conditions. Recent in vivo studies, however, demonstrate that such a mutator phenotype may cause long-term disadvantages, owing to indiscriminate and irreversible accumulation of potentially deleterious mutations ([7•]; see also the review by M Radman and F Taddei in this issue, pp 582–585).
To alleviate this problem, bacteria have evolved the ability to produce reversible and high-frequency genetic changes in specific genomic loci, termed ‘contingency’ loci, without increasing the overall mutability of the rest of the genome 8., 9.. The best-documented of these loci are involved in the biosynthesis of surface-exposed antigenic structures, such as outer lipopolysaccharides (LPSs) and lipoproteins, pili, flagella and other secreted proteins that also play a crucial role in the interactions between the bacteria and their host, by modulating their tissue tropism or their ability to use locally available nutrients. Therefore, varying the expression of these structures allows bacteria to counteract the host immune defences as well as to colonise new ecological niches.
Reversible alteration of gene expression in these different loci is mediated by a variety of molecular mechanisms that modify the sequence and/or the structure of DNA 8., 9., 10., 11., 12•.. Some of these mechanisms primarily function as binary switches to turn individual genes ‘on’ or ‘off’, whereas others are used to express multiphasic phenotypes by promoting complex and combinatorial DNA sequence rearrangements. The genomes of bacteria that use these different mechanisms often contain large multigene families that serve as templates for the production of high levels of genetic diversity.
This review discusses recent advances in the understanding of the molecular mechanisms of phase variation and their biological significance, attempting to outline the differences in these mechanisms as well as several aspects that may be viewed as ‘variations on a theme’.
Section snippets
Turning genes ‘on’ or ‘off’ by universal slipped-strand mispairing mechanisms
Phase variation in many bacterial species is mediated by frequent and reversible changes in the lengths of short DNA sequence repeats (termed microsatellites) that are associated with a subset of specific genes 8., 13.. The gain or loss of repeat units in these homo- or heteropolymeric tracts is thought to involve a mechanism of slipped-strand mispairing (SSM) that can occur during chromosomal replication (Fig. 1a) or in the course of a variety of DNA repair and recombination processes that
Site-specific DNA rearrangements
The genomes of many bacterial species exhibit an unexpected potential to undergo homologous recombination-dependent and -independent DNA rearrangements, owing to the presence of multiple repetitive DNA sequences including a variety of transposable elements 1., 2., 3•.. Some of these recombination events may occur spontaneously with respect to time and space and contribute to the overall genetic diversity of a population, whereas others are targeted to specific genomic loci and provide an
DNA shuffling by gene conversion and allele replacement
Unidirectional gene conversion is the result of DNA recombination reactions that lead to complete or partial replacement of one expressed recipient gene with variable DNA segments from a silent copy located in a different part of the genome. Recombination is unidirectional and apparently non-reciprocal, ensuring that the DNA sequence of the donor locus remains unaltered. By reshuffling DNA information from large reservoirs of variable donor sequences, each containing multiple exchangeable
Regulation and control of phase variation: when and at what rate?
Because of their role in adapting bacteria to unpredictable environmental fluctuations, phase-variation mechanisms are often described as essentially stochastic processes that generate random combinations of phenotypes without anticipating whether or not these will be beneficial. However, this does not rule out the possibility that the rate at which genetic diversity is generated may be influenced by external factors, such as stress conditions or cell density. Altering phase-variation
Old and new phase-variable phenotypes: not just surface antigens
Whole-genome-sequence analyses have largely confirmed the importance of varying surface-exposed antigens for allowing bacterial commensals and pathogens to evade the immune system of their host and to adapt to ever-changing environments. However, these analyses, together with several genetic studies, have shown that not all phase-variable genes are associated with cell-surface functions, thereby unveiling new facets of bacterial adaptive strategies.
An increasing number of novel contingency loci
Conclusions
Many questions about the molecular and genetic mechanisms of bacterial phase variation remain unsolved. An emerging view is that they represent fascinating examples of convergent evolution, in which existing mechanisms allowing local modification of the structure and sequence of DNA have been adapted to produce high levels of reversible genetic diversity in strategic regions of the genome. As a consequence, a single mechanism can be used to mediate phase variation in a variety of functions and,
Update
The complete genome sequence of a virulent isolate of Streptococcus pneumoniae recently reported by Tettelin et al. [104•] supports and extends the view that this important pathogen has evolved a range of mechanisms to undergo adaptive genetic changes [3•]. Up to 5% of the genome is composed of insertion sequences belonging to different families, compared with 0–3% in other bacteria. Together with previously identified dispersed DNA sequences termed the ‘RUP’ and ‘BOX’ elements, this high
Acknowledgements
I thank D Yogev for communicating data prior to publication. Also, M Deghorain, S Kotsonis and R Rezsöhazy for critical reading of the manuscript, and S Burteau for technical assistance. The author is a postdoctoral researcher at the Fonds National pour la Recherche Scientifique.
References and recommended reading
Papers of particular interest, published within the annual period of review,have been highlighted as:
• of special interest
•• of outstanding interest
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