tions in the rifampicin resistance-determining regions (Siu et al., 2011); rather, they have mutations in a different part of the gene that affects resistance. These variants are rare, so they do not make a large contribution to overall resistance levels, and they may exact a fitness cost that does not occur with the common mutations. However, some studies have found that rare mutations with fitness costs can subsequently be overcome by compensatory mutations (Pym et al., 2002; Comas et al., 2011).

Genes associated with mutations conferring resistance or a growth or fitness advantage in the presence of a drug are likely to be under strong evolutionary positive selection. To explore this process, Murray and her colleagues sequenced multiple strains of M.tb. from around the world, half of which were drug-resistant and half of which were drug-sensitive. Strains that had acquired stepwise resistance to individual drugs over time were oversampled. Using a newly developed technique for detecting selection in the M.tb. genome, the researchers identified a set of genes that are involved in the evolution of resistance. Many of these genes have functions that remain unknown, but most with known functions encode cell wall components or are known to be involved in the cell wall’s permeability. Some of these mutants may confer low-level resistance, some may be compensatory mutations correcting for a fitness loss from an earlier drug-resistance mutation, and some may be correcting for metabolic changes. “We don’t know,” said Murray. “It opens up a new avenue for research into drug resistance. It also opens up the idea that what we have considered a very black-andwhite, simple process—that organisms acquire drug-resistance mutations and then either are or are not resistant—is a simplification of what actually is going on. There are probably many steps to the acquisition of resistance, and much more to be learned.”

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