, 2000); in one population, a neutral mutation identified in an e

, 2000); in one population, a neutral mutation identified in an earlier adaptive mutant was not

found in a later isolated adaptive mutant, clearly suggesting the presence of clonal interference in the fluconazole-exposed population (Cowen et al., 2000). The argument for the presence of clonal interference in C. albicans populations evolving in the presence of antifungal drug was unambiguously determined by our recent work using an adaptive evolution method called visualizing evolution in real-time (VERT) to help track the population dynamics in an evolving population (Huang et al., 2011). VERT involves the use of a set of different fluorescently marked isogenic strains as the initial population in adaptive evolution. The occurrence of an adaptive event (the occurrence and expansion of an adaptive mutant) in the population can be visually observed by the expansion TGF-beta inhibitor of the fluorescently marked subpopulation containing the adaptive mutant. Thus, if the population dynamics follows the clonal replacement model, the first expanding subpopulation will take over the entire population. However, if clonal interference is present in the evolving populations, then the subpopulations will expand and contract as different adaptive

clones compete for expansion. Figure 2 shows an example of the VERT data for C. albicans evolving in the presence of stepwise increases of fluconazole in a chemostat Selleck ABT 263 system (Huang et al., 2011). The use of VERT also allowed us to estimate the frequency

at which adaptive mutants arise in the population. We found that the frequency of adaptive events increased in the presence of the drug. Interestingly, the frequency of adaptive events appears to be independent of drug concentration, at least within the Selleckchem Cobimetinib drug concentration used in our study (Fig. 2b and c); approximately 9 and 10 adaptive events were observed in the populations exposed to lower and higher (two times higher) concentrations of fluconazole, respectively. Is clonal interference also present during the emergence of drug resistance in C. albicans in vivo? Transcriptional analysis of several target genes in a series of 17 isolates from an AIDS patient showed sequential stacking of resistance mechanisms in isolates obtained throughout the course of treatment (White, 1997), suggesting the population structure in vivo during the course of treatment may be governed by the clonal replacement model. However, this may not always be the case. A series of nine clinical isolates of C. albicans isolated from a bone marrow transplant patient, who underwent a series of antifungal drug treatment (Marr et al., 1997), were analysed for LOH at predicted alleles and gross chromosomal rearrangements (Coste et al., 2006; Selmecki et al., 2008). Results from these analyses clearly showed a heterogeneous population where multiple resistance alleles coexist, demonstrating that clonal interference also occurs in vivo.

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