The importance of within-species diversity in determining the evolutionary potential of a population to evolve drug resistance or tolerance is not well understood, including in eukaryotic pathogens. To examine the influence of genetic background, we evolved replicates of 20 different clinical isolates of Candida albicans, a human fungal pathogen, in fluconazole, the commonly used antifungal drug. The isolates hailed from the major C. albicans clades and had different initial levels of drug resistance and tolerance to the drug. The majority of replicates rapidly increased in fitness in the evolutionary environment, with the degree of improvement inversely correlated with parental strain fitness in the drug. Improvement was largely restricted to up to the evolutionary level of drug: only 4% of the evolved replicates increased resistance (MIC) above the evolutionary level of drug. Prevalent changes were altered levels of drug tolerance (slow growth of a subpopulation of cells at drug concentrations above the MIC) and increased diversity of genome size. The prevalence and predominant direction of these changes differed in a strain-specific manner, but neither correlated directly with parental fitness or improvement in fitness. Rather, low parental strain fitness was correlated with high levels of heterogeneity in fitness, tolerance, and genome size among evolved replicates. Thus, parental strain background is an important determinant in mean improvement to the evolutionary environment as well as the diversity of evolved phenotypes, and the range of possible responses of a pathogen to an antimicrobial drug cannot be captured by in-depth study of a single strain background.

中文翻译：

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白色念珠菌的遗传背景影响氟康唑进化过程中药物反应的均值和异质性以及基因组稳定性。

种内多样性在确定种群发展抗药性或耐受性的进化潜力中的重要性尚未得到很好的理解，包括在真核病原体中。为了检查遗传背景的影响，我们在氟康唑（一种常用的抗真菌药物）中进化出了20种不同临床分离株的副本，该分离株是人的真菌病原体白色念珠菌。分离株来自主要的白色念珠菌进化枝具有不同的初始耐药水平和对药物的耐受性。多数复制品在进化环境中的适应性迅速增加，而改善程度与药物中亲本菌株的适应性成反比。改善主要限于药物的进化水平：只有4％的进化复制品会在药物进化水平之上增加耐药性（MIC）。普遍的变化是药物耐受性水平的改变（在高于MIC的药物浓度下，细胞亚群的缓慢生长）和基因组大小多样性的增加。这些变化的流行和主要方向以菌株特异性的方式有所不同，但都与父母的健康状况或健康状况的改善没有直接关系。而是 低亲本菌株适应性与进化重复物中适应性，耐受性和基因组大小的高水平异质性相关。因此，亲本菌株的背景是对进化环境的平均改善以及进化表型多样性的重要决定因素，并且通过对单个菌株的深入研究无法确定病原体对抗菌药物的可能反应范围。背景。