Parasex Generates Phenotypic Diversity de Novo and Impacts Drug Resistance and Virulence in Candida albicans

Abstract

is a diploid fungus that is a frequent cause of mucosal and systemic infections in humans. This species exhibits an unusual parasexual cycle in which mating produces tetraploid cells that undergo a nonmeiotic program of concerted chromosome loss to return to a diploid or aneuploid state. In this work, we used a multipronged approach to examine the capacity of parasex to generate diversity in First, we compared the phenotypic properties of 32 genotyped progeny and observed wide-ranging differences in fitness, filamentation, biofilm formation, and virulence. Strikingly, one parasexual isolate displayed increased virulence relative to parental strains using a model of infection, establishing that parasex has the potential to enhance pathogenic traits. Next, we examined parasexual progeny derived from homothallic, same-sex mating events, and reveal that parasex can generate diversity from identical parental strains. Finally, we generated pools of parasexual progeny and examined resistance of these pools to environmental stresses. Parasexual progeny were generally less fit than control strains across most test conditions, but showed an increased ability to grow in the presence of the antifungal drug fluconazole (FL). FL-resistant progeny were aneuploid isolates, often being diploid strains trisomic for both Chr3 and Chr6. Passaging of these aneuploid strains frequently led to loss of the supernumerary chromosomes and a concomitant decrease in drug resistance. These experiments establish that parasex generates extensive phenotypic diversity, and that this process has important consequences for both virulence and drug resistance in populations.

Metabolism‐induced oxidative stress and DNA damage selectively trigger genome instability in polyploid fungal cells

“…Both polyploid and aneuploid forms facilitate karyotypic variation, tumor progression, and the emergence of drug resistance. Polyploid C. albicans cells similarly exhibit increased genome instability, and the resulting karyotypic diversity can promote adaptation and resistance to antifungal drugs (Bennett & Johnson, ; Harrison et al , ; Hirakawa et al , ).…”

“…Both polyploid and aneuploid forms facilitate karyotypic variation, tumor progression, and the emergence of drug resistance. Polyploid C. albicans cells similarly exhibit increased genome instability, and the resulting karyotypic diversity can promote adaptation and resistance to antifungal drugs (Bennett & Johnson, 2003;Harrison et al, 2014;Hirakawa et al, 2017). While links between ploidy and genome instability are well recognized both in yeast and in mammalian cells (Storchova & Kuffer, 2008), those between ploidy and metabolism are considerably more complex.…”

Aneuploidy in yeast: Segregation error or adaptation mechanism?

“…These cells either reproduce asexually as tetraploids or revert to diploid or near diploid haplotype, through a concentrated chromosome loss event (Bennett & Johnson, ). This parasexual cycle frequently generates a vast variety of aneuploid offspring (Hickman, Paulson, Dudley, & Berman, ) with more variation in phenotype than euploid strains (Hirakawa et al, ). Although these aneuploidies were detrimental under normal conditions, in some cases, they assisted in increasing virulence and resistance to fluconazole, with an extra Chr III or Chr VI being most common (Forche, Magee, Selmecki, Berman, & May, ).…”

“…These cells either reproduce asexually as tetraploids or revert to diploid or near diploid haplotype, through a concentrated chromosome loss event (Bennett & Johnson, 2003). This parasexual cycle frequently generates a vast variety of aneuploid offspring (Hickman, Paulson, Dudley, & Berman, 2015) with more variation in phenotype than euploid strains (Hirakawa et al, 2017 Box 1 Aneuploidy in response to different types of stress Temperature When exposed to high temperatures (39°C), three replicate S. cerevisiae populations showed aneuploidy of Chr III after 450 generations (Yona et al, 2012). However, by 1,000 generations, all populations lost their extra copy of Chr III, instead retaining increased expression of 17 genes within a region of Chr III ( Figure 2).…”

“…For instance, several experimental evolution studies using yeast (Chen, Bradford, Seidel, & Li, ; Gorter et al, ; Pavelka et al, ; Selmecki et al, ; Selmecki, Dulmage, Cowen, Anderson, & Berman, ; Yona et al, ) and other pathogenic fungi such as Candida albicans (Selmecki, Forche, & Berman, ) and Cryptococcus neoformans (Gerstein et al, ) suggest that aneuploidy can confer increased stress and drug resistance. This is likely due to the variation in gene dosage caused by the loss or gain of chromosomes causing higher phenotypic diversity or pathogenic potential in aneuploid microbial populations (Bader et al, ; Beach et al, ; Gerstein et al, ; Hirakawa, Chyou, Huang, Slan, & Bennett, ; Hu et al, ; Ni et al, ).…”