Fig. 4

Proposed model for the effect of a selection bottleneck and random mutations on the population structure of M. tuberculosis clinical isolates. a A rifampicin mono-resistant clinical M. tuberculosis isolate where each cell comprising the population contains an rpoB mutation. Numerous other genetic mutations are present thereby creating a diverse population structure. (b) Following the onset of treatment the genetic mutations in the population may change, and a spontaneous isoniazid resistance causing (for example katG gene or inhA promoter) mutation is selected for and becomes dominant within the population. (c) Selective pressure of treatment results in the emergence of an isoniazid resistant M. tuberculosis population where each cell contains a katG mutation. Numerous other genetic mutations are lost during the selection bottleneck resulting in a loss of genetic diversity. (d) Subsequent replication cycles and population growth results in new genetic mutations arising within the population allowing for new diversification e.g. R1210. Each cell in this MDR population retains the rpoB and katG resistance causing mutations. Key: x denotes an isoniazid resistance causing mutation (katG)