Bacterial genetics and strain variation

Paul D. van Helden

MRC Centre for Molecular and Cellular Biology, Department of MedicalBiochemistry, Faculty of Medicine, University of Stellenbosch, PO Box 19063, Tygerberg, 7505, South Africa

A bstract. An entire genome sequence will provide valuable information, but the genome of only one individual will limit interpretation of that information. Knowledge concerning genome variation in both eukaryotic and prokaryotic organisms such as Mycobacterium tuberculosis is likely to yield information of equal value and provide fundamental insights concerning the function of the genome. The variability in the genome between individual strains may be small and well defined, but it may cause large phenotypic changes (e.g. point mutations causing drug resistance). Clinical and epidemiological observations have led to the development of hypotheses, assumptions and models concerning disease dynamics. However, genome variation studied by molecular epidemiology has made new insights possible, which have allowed us to examine prevailing dogmas concerning tuberculosis. Recent results suggest that historical dogmas may well hold true in some communities, but not all. The information gathered from studying strain variation can be used for modelling disease dynamics, prediction of epidemics, policy planning and for monitoring the outcome of new interventions, as well as for gaining insight into the life processes of the organism. However, molecular epidemiology has its own limitations, some of which result from our lack of understanding of genome variation. We need further information in order to understand clonality and evolution of this organism so that our use of molecular tools in epidemiology and drug development may become more relevant and accurate.

1998 Genetics and tuberculosis. Wiley, Chichester (Novartis Foundation Symposium 217) p 178-194

The association of serotype with disease has been used to refine the study of classical epidemiology of infectious disease. Historically, bacterial typing by serotype or phenotype analysis has suggested that bacteria are clonal and that a line of infection can therefore be traced. However, in tuberculosis the tracing of routes of infection by phenotype analysis has not proven to be sensitive or specific and other techniques are therefore required. In this context, genotyping could be theoretically considered the most accurate form of typing of any organism, because it has been shown that strains of bacteria are genomically different, as are individual humans. Although we are likely to gain an enormous amount of knowledge and information from the sequence of any genome, the study of the genome of only one individual will provide only limited information and be restricted in its practical applications. A better understanding of genome variation is likely to yield information of equal value and provide fundamental insights concerning the function of the genome. This applies to both eukaryotic and prokaryotic organisms such as Mycobacterium tuberculosis. The variations in the genome may be small and well defined, but they can cause large phenotypic changes (e.g. point mutations resulting in drug resistance). Thus, genome variations may be responsible for many different phenotypes and families of bacteria which may vary from, for example, highly virulent to attenuated strains. The study of the genome is likely to yield information for both drug development in the longer term and for short-term applications, such as the study of the dynamics of the disease.

Clinical and epidemiological observations using the tools available at the time have led to the development of hypotheses, assumptions and models concerning disease dynamics. However, since tuberculosis patients appear to harbour only one bacterial strain and each strain has a unique genotype, the new branch of science named molecular epidemiology has made new insights possible. This technology has allowed us to examine some of the prevailing dogmas concerning this disease and ask new questions. Results of studies in different communities suggest that these dogmas may well hold true in some communities, particularly developed countries with low incidence of disease, but they may not necessarily be valid in all communities. There is therefore a danger in extrapolating findings from one community and geographical area to another. In addition, limitations in traditional epidemiology have been revealed. The information gathered from studying strain variation in a community can also be used for modelling the disease dynamics, predicting epidemics and for planning policy. This technology can also be used to monitor the results of any new intervention on the dynamics of disease in the community being studied. However, molecular epidemiology is not a panacea, it is still in its infancy and has its own limitations, some of which are due to our lack of understanding of genome variation in the bacillus. We need further information in order to understand the clonality, genome variation, ecology and evolution of this organism and therefore improve our use of molecular tools in epidemiology and drug development. Although the use of antibiotics is clearly important for combating infectious disease at present, real breakthroughs are likely to come from a better understanding of ecology, social behaviour and an appreciation for the interaction between host and pathogen as part of the biosphere (Dubos I960).

In this chapter the overall concept of bacterial variation will be considered in the context of molecular epidemiology and the dynamics of the disease. The measurement of variation will be by genotype analysis using markers detecting polymorphisms.

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