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Letter to the Editor

In our paper, ' 'Adaptive evolution of highlymutable loci in pathogenic bacteria, ' ' l we reviewed the evidence that some bacteria have highly mutable loci that influence the expression ofa subpopulation ofchromosomal genes. We argued that the coexistence of these highly mutable genes with those that have much lower mutation rates is the result of adaptive evolution. High rates ofmutation in such genes facilitate the efficient exploration ofphenotypic solutions to unpredictable aspects of the environment. We also suggested that similarly hyper-mutable genes might be found in other organisms, including the hosts that bacteria parasitise. Concerning this latter comment, we have been gently taken to task in a recent essay by Neil Greenspan ( "Genomic logic, allelic inference and the functional classification of genes").2 The crux of Greenspan's objections is our use of the term 'contingency' to identify genes with high, sequence dependent, rates of mutability. In his essay, Greenspan opts for a definition that is based on the functions ofmolecules encoded by genes, a perfectly reasonable preference, albeit imparting a different meaning. He discussed eucaryotic genes that apparently do not have higher than usual mutation rates, but which interact with numerous different microbes, and considers that it would be ". . . preferable to consider the C3 alleles to be contingency genes, at least with respect to their functions in host defense." We think it is unreasonable for Greenspan to charge us with inadequacies of a scheme ofgene classification that, ipso facto, we did not use in the first place! We accept his conclusion that "... the extent of sequence variation in a gene does not logically determine the class of function," but not with his assertion that this is what our paper was proposing. Indeed, based on our subsequent discussions conducted by e-mail, there appear to be few, if any, fundamental differences in our views. Rather, our views are complementary and we would be disappointed if mere semantics (differences in definition) were to undermine our respective efforts to understand how organisms evolve mechanisms for processing information in the environment and respond to its myriad challenges. Greenspan questions the legitimacy and utility of classifying genes into those with high and low mutation rates. A gene may evolve higher rates ofmutation or change its primary function and, therefore, this will lead to an imperfect correspondence between function and mutability. This is certainly true, but what we emphasised in our paper is that, at any particular point in time, there can be a very strong, although imperfect, association between function and mutability. That this association has predictive power was subsequently demonstrated when the hypothesis was put to the test through the availability ofwhole genome sequences of pathogenic bacteria. The results provide strong support for the utility of sequence motifs (tandem DNA repeats) , as a method of identifying novel bacterial genes involved in host-microbial interactions, examples being genes for lipopolysaccharide and flagellin biosynthesis, haemoglobin-binding genes and outer membrane proteins.3,4 The high mutation rates associated with repetitive DNA are one, but of course not the only, determinant of an organism's capacity for variation, one that has implications for adap tation ofmicrobes because it facilitates "... the efficien t exploration of pheno-