Current Biology
Volume 4, Issue 1, 1 January 1994, Pages 24-33
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Review
Adaptive evolution of highly mutable loci in pathogenic bacteria

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Abstract

Bacteria have specific loci that are highly mutable. We argue that the coexistence within bacterial genomes of such ‘contingency’ genes with high mutation rates, and ‘housekeeping’ genes with low mutation rates, is the result of adaptive evolution, and facilitates the efficient exploration of phenotypic solutions to unpredictable aspects of the host environment while minimizing deleterious effects on fitness.

Introduction

All organisms are faced with the perpetual challenge of maintaining their fitness in diverse and changing environments. To meet this challenge, populations of organisms must possess mechanisms and strategies for responding to changes in their environment. These include phenotypic acclimation, by which an individual organism modifies some aspect of its behaviour, morphology or metabolism in response to environmental change, and genetic adaptation, whereby the genetic composition of a population may change as a result of natural selection.

Natural selection has produced a range of genetic mechanisms that facilitate acclimation to a wide variety of external stimuli. In bacteria, these range from feed-back mechanisms, such as catabolite repression of transcription, to sophisticated ‘two-component’ sensory systems, in which a signal from the external environment is transduced through histidine protein kinases [1], ultimately regulating gene expression. These and similar mechanisms enable bacteria to modulate the activity of their genes in response to particular external conditions, thereby maintaining their fitness in changing environments. Indeed, the strong phylogenetic conservation of these mechanisms is testimony to their general and continuing utility; specific responses presumably reflect the probability of bacteria encountering particular environmental situations.

Provided that environmental factors (such as nutrients, temperature, osmolarity or acidity) remain within certain limits, then changes in the external environment may be accommodated by coordinated regulation of gene expression. Given, however, the diversity and unpredictability of environmental changes, these stereotypic responses are unlikely to contribute more than a limited subset of the phenotypic states necessary for long-term evolutionary success. Confronted with a persisting unfavourable environment in which classical regulation of gene expression cannot provide an adequate response, a population of bacteria may face extinction unless it can adapt genetically by natural selection.

Pathogenic bacteria face especially stringent tests of their adaptive potential, due to the characteristic diversity and polymorphic nature of their hosts’ immune responses. This is because, typically, bacterial infections occur within a matter of hours, during which time pathogenic organisms are transmitted between genetically distinct hosts, colonize epithelia and disseminate through a host to produce invasive disease. The capacity of bacteria to negotiate the differing environments in the host, including both intracellular and extracellular locations, is remarkable, especially as infections usually involve the clonal expansion of a single strain of the pathogen [2], [3]. This conflict between the ‘pathogenic personality’ [4] of bacteria and the antagonistic response of the host provides a driving force for, and is shaped by, co-evolutionary processes that have been described by colourful metaphors such as gene-for-gene arms races [5], [6], [7] and the Red Queen hypothesis [8].

Given their relatively large population sizes and short generation times, pathogenic bacteria would seem to have considerable advantages over their hosts in adaptability and evolutionary flexibility. These apparent advantages to the pathogen may be offset by the immune systems that enable the host to generate an extensive repertoire of immunologically competent cells [9], [10]. Such immunity represents a phenotypic response, in the sense that it is not inherited, but the ability to respond in this manner has a genetic basis that is presumably the result of evolutionary adaptation by natural selection. Bacteria may similarly adapt genetically in ways that affect not only their ability to respond phenotypically to environmental variations, but also their propensity to undergo further genetic adaptation.

Biologists have long been fascinated by the evolution of those aspects of an organism's physiology, biochemistry and reproductive biology that affect its rates of genetic recombination and mutation, and hence determine the amount of heritable variation that is available for genetic adaptation by natural selection. For example, it has been argued that sexual reproduction provides important strategic advantages for hosts because of its role in generating the heritable variation that genetic adaptation requires. Indeed, it has been suggested that the selective pressures imposed by pathogenic microbes may have been responsible for the evolutionary origins and maintenance of sexual reproduction [10], [11], [12], [13], [14].

In this article, we shall review evidence indicating that pathogenic bacteria have evolved mechanisms for increasing the frequency of random variations in those genes that are involved in critical interactions with their hosts. Having elevated mutation rates in a specific subset of genes may be highly advantageous, allowing certain phenotypic traits to respond rapidly, by natural selection, to unpredictable changes in the environment, while also ensuring the conservation of essential functions encoded by other genes. This hypothesis accords well with the co-existence in many pathogenic bacteria of highly mutable loci (‘contingency’ genes) and loci with much lower mutation rates (’housekeeping’ genes).

Section snippets

Phenotypic variation generated by highly mutable genes

Phenotypic variation within populations can be generated by alterations to the sequence or conformation of DNA. Such genetic changes can result from inter-genomic events, such as recombination, or intra-genomic events, such as mutations. The contribution of intergenomic mechanisms (reviewed in [15], [16], [17], [18]) to the generation of phenotypic diversity in clonal populations during an acute infection is minimal, and will not be considered further here. Instead, we shall focus on

Contingency behaviour in a host-adapted pathogen

The pathogenic bacterium Haemophilus influenzae, a major cause of meningitis, uses the intragenomic mechanisms of slipped-strand mispairing and homologous recombination, which are rec-independent and rec-dependent, respectively, to generate high-frequency changes in the expression of genes encoding fimbrial, lipopolysaccharide and capsular polysaccharide cell-surface determinants (Figure 1), which are important to its commensal and virulence behaviour. These mechanisms may be widely used by

On randomness and stress

The generation of phenotypic variations of the kind described above is a powerful strategy for responding to changes in the host environment, with its repertoire of genetic polymorphisms and immune mechanisms. Using just a few loci, a population of bacteria within a single host, derived from a single infecting clone, can generate substantial random variation which is potentially useful for adapting, through natural selection, to a constantly changing host environment. This genetic and

Optimal mutation rates

In several population genetic models, the optimal mutation rate has been defined as that which maximizes a population's long-term geometric mean fitness in a fluctuating environment [51], [52], [53], [54]. In particular, the optimal mutation rate must balance the genetic loads caused by deleterious mutations when the environment is constant, and by substitution of a favoured allele when the environment changes. This optimum may also be affected if there is some direct fitness cost associated

Summary

We conclude by restating our thesis as a general hypothesis: mutation rates vary among sites in a genome, and this variation is adaptive because it promotes evolutionary flexibility in the face of environmental change, without necessarily increasing the overall load of deleterious mutations. In particular, we expect mutation rates to be higher in genes whose products interact with the environment in unpredictable ways. Such unpredictability implies that the relevant aspects of the environment

Acknowledgements

E.R.M. wishes to acknowledge scientists of the Molecular Infectious Diseases Group whose work has stimulated and formed the basis of parts of this review. This research is supported by programme grants from the Medical Research Council and Wellcome Trust. P.B.R is an AFRC Research Fellow. M.A.N. is a Wellcome Trust Senior Research Fellow and an E.P. Abraham Junior Research Fellow at Keble College, Oxford. R.E.L. is supported by the U.S. National Science Foundation (BIR- 9120006 and DEB-9249916)

E. Richard Moxon (corresponding author), Molecular Infectious Diseases Group, Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, UK.

Paul B. Rainey, Department of Plant Sciences, University of Oxford, Oxford OX1 3RB, UK.

Martin A. Nowak, Department of Zoology, University of Oxford, Oxford OX1 3PS, UK.

Richard E. Lenski, Center for Microbial Ecology, Michigan State University, East Lansing MI 48824, USA.

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