Acquisition of Aneuploidy Provides Increased Fitness during the Evolution of Antifungal Drug Resistance

Abstract

The evolution of drug resistance is an important process that affects clinical outcomes. Resistance to fluconazole, the most widely used antifungal, is often associated with acquired aneuploidy. Here we provide a longitudinal study of the prevalence and dynamics of gross chromosomal rearrangements, including aneuploidy, in the presence and absence of fluconazole during a well-controlled in vitro evolution experiment using Candida albicans, the most prevalent human fungal pathogen. While no aneuploidy was detected in any of the no-drug control populations, in all fluconazole-treated populations analyzed an isochromosome 5L [i(5L)] appeared soon after drug exposure. This isochromosome was associated with increased fitness in the presence of drug and, over time, became fixed in independent populations. In two separate cases, larger supernumerary chromosomes composed of i(5L) attached to an intact chromosome or chromosome fragment formed during exposure to the drug. Other aneuploidies, particularly trisomies of the smaller chromosomes (Chr3–7), appeared throughout the evolution experiment, and the accumulation of multiple aneuploid chromosomes per cell coincided with the highest resistance to fluconazole. Unlike the case in many other organisms, some isolates carrying i(5L) exhibited improved fitness in the presence, as well as in the absence, of fluconazole. The early appearance of aneuploidy is consistent with a model in which C. albicans becomes more permissive of chromosome rearrangements and segregation defects in the presence of fluconazole.

The Rho1 GTPase-activating Protein CgBem2 Is Required for Survival of Azole Stress in Candida glabrata

“…Intriguingly, ploidy-dependent gene regulation plays an important role in drug susceptibility, and resistance to fluconazole in C. albicans has been associated with increased copy number of azole resistance genes due to acquired aneuploidy (55). However, the enhanced susceptibility of Cgbem2⌬ cells toward fluconazole, despite their polyploidy nature, probably indicates impaired ability to maintain genomic stability due to defective morphogenesis.…”

Role of chromosomal instability in cancer progression

“…In addition, it is thought that chromosomal instability can act as an adaptive mechanism to allow cancer cells to widely sample a range of genotypes and phenotypes during periods of stress. This concept has been clearly demonstrated in single-celled organisms (Rancati et al 2008, Selmecki et al 2009, Pavelka et al 2010, Yona et al 2012, Chang et al 2013, however, demonstrating this in human cells has been more challenging. There is evidence that aneuploid human cells, although generally appearing less fit than their euploid counterparts under 'standard' conditions (Williams et al 2008, Thompson & Compton 2010 display advantages under selective conditions (Rutledge et al 2016) and that aneuploidy of pluripotent stem cells promotes their efficient adaptation to culture conditions (Barbaric et al 2014, Na et al 2014.…”

Adaptive mechanisms in pathogens: universal aneuploidy in Leishmania

“…The common fungal pathogen Candida albicans displays a high level of genomic plasticity, including aneuploidy, affecting one to three of the eight chromosomes, depending on the strain [54]. This is apparently beneficial under selective pressure: for example, aneuploid C. albicans strains under drug pressure have an increased fitness [55]. In addition, the close relative Candida glabrata (n = 14) also has a variable karyotype and generates a novel chromosome in response to antifungal drug pressure [56].…”