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Vargold: The Wolf-Time. Digital Vision Cards 1: Vladimir Kush 4 months ago. Mesmerized by sirens. Fantasy paths 4 months ago. Republic of Replicants. Five Leagues from the Borderlands - Part 1 5 months ago. Crawdads and Dragons. Berman and Hadany Page 3 Mating Stress-induced recombination also provides a solution to the third step of parasex by positioning mating partners in close proximity Fig. Reciprocal recombination would NIH-PA Author Manuscript produce two sister cells of opposite mating type, which would be physically adjacent to one another.

If mating did not occur immediately, the two types of cells would then continue to divide near one another, providing a large population of mating partners in close proximity to one another. In the lab, this type of reciprocal recombination would give rise to a colony with two half-sectors, one of each mating type Fig.

Presumably, in vivo, a reciprocal recombination involving MTL would give rise to a population of cells of opposite mating types that would be in close proximity to one another.

To mate, cells produce conjugation tubes that grow towards one another and fuse to form tetraploid zygotes. Interestingly, mating between opaque cells occurs preferentially on nutrient-poor medium [28].

While tetraploid clinical isolates have not been reported, the inability to detect them is a negative result that may simply reflect the few studies that monitored cell ploidy.

Another possibility is that tetraploid zygotes may be unstable and thus short-lived, and might undergo concerted chromosome loss rapidly, perhaps driven to do so by the same stress conditions that promoted increased switching to the opaque form. Consistent with this, tetraploids are less virulent in a systemic murine model of candidiasis [29]. Concerted chromosome loss NIH-PA Author Manuscript Finally, in the lab, tetraploid zygotes undergo concerted chromosome loss at high frequency when exposed to stress conditions such as poor carbon source availability [25].

This yields a high proportion of progeny with new combinations of homologs, frequent whole chromosome aneuploidies as well as a subset of strains that undergo short-range recombination events [13].

We suggest that parasexual progeny have the potential to reenter the parasexual cycle by switching to the opaque state and mating with neighboring cells [20]. Thus, while we do not know if the parasexual cycle occurs in vivo, it appears that most of the requisite steps would ensue with increased frequency when cells are under stress.

Parasex and adaptation If parasex does occur, then does it contribute to adaptation by generating more diverse progeny? Theory predicts that meiotic sex and recombination facilitate adaptation by NIH-PA Author Manuscript generating new combinations of genotypes [30]. Stress-induced sex and recombination are expected to facilitate adaptation even further [31], especially in cases of complex adaptation in which multiple mutations that are deleterious when present independently yet are advantageous when present in specific combinations [32].

What about parasex? Parasex has the potential to facilitate outcrossing—the mating of unrelated individuals, which may occur between different strains that infect the same host [33].

However, outcrossing is expected to be quite rare because a single strain is usually dominant in a given individual and the scenario above suggests that most parasex would involve inbreeding between siblings. Clinical isolates of C. Inbreeding between heterozygous individuals can generate diverse progeny that have significant levels of homozygosity at different combinations of loci.

This parallels the predicted ability of rare conventional sex to reveal variation in mostly clonal organisms [35]. Berman and Hadany Page 4 Importantly, parasex is expected to generate more dramatic diversity than meiotic sex Fig.

First, concerted chromosome loss often results in complete homozygosis of one or more chromosomes, which has the potential to reveal large numbers of recessive traits in new NIH-PA Author Manuscript combinations [9]. Accordingly, loss of heterozygosity LOH of specific transcription factors that regulate drug efflux has given rise to antifungal drug resistance in both in vivo and in vitro [].

This has the potential to reveal much higher levels of copy number variation than seen with conventional mating and meiosis [9].

Thus, when inbreeding is the only option, parasex could offer an advantage in comparison with conventional sex. Consider, for example, the effects of sex and parasex on the diversity of offspring at a single locus see Figure 3. Conventional sex with inbreeding would have a small effect if the locus is heterozygous Bb , by producing 3 possible genotypes: BB, Bb, and bb. Furthermore, if parasexual progeny re-mate with one another, they could generate new ratios of alleles in the second-generation tetraploid zygotes as well.

NIH-PA Author Manuscript Of course, as the numbers of loci that are considered increase, the potential variation that parasex can produce increases further, more than the potential variation produced by sex. Of note, variations in chromosome number have been found in clinical isolates as well as in laboratory strains, and they are dramatically overrepresented in drug-resistant isolates [40]. In this case, it is extra copies of two specific genes on a single chromosome one involved in ergosterol biosynthesis ERG11 and a transcriptional activator of efflux pump genes TAC1 on chromosome 5 that confer increased antifungal drug resistance [3].

Thus, some aneuploidies clearly have the potential to be adaptive under specific stress conditions, as they affect copy number at multiple loci. Accordingly, the parasexual cycle, even if it occurs only between siblings, would be expected to generate genetic diversity that has the potential to be beneficial. Importantly, C. Indeed, some aneuploidies that confer increased drug resistance do not have obvious fitness costs when cells are grown in the absence of the drug [2].

Furthermore, it has been suggested that parasex avoids the production of antigenic ascospores, thereby possibly avoiding increased stimulation of an immune response [9]. Examples include stress-induced mutagenesis [44], fitness-associated recombination [21, 45, 46], condition- dependent sexual reproduction [] and revelation of phenotypic variation — through capacitors that buffer the effect of genetic variation in times of well being, and possibly reveal it in times of stress [50, 51], such as the heat shock protein HSP90 in the fruit fly Drosophila melanogaster [52].

We suggest that stress-induced parasex may function as a capacitor of adaptation, revealing variation that accumulated during many generations of clonal reproduction. Thus, even if it occurs only rarely and only under stress conditions, it would provide new diversity, some of which would be better capable of surviving the stress condition than their parents, thereby providing an adaptive advantage to the organism.

Berman and Hadany Page 5 In this context, it is tempting to speculate about the forces driving the evolution of the parasexual cycle: is it maintained because it increases the ability of cells to evolve in response to their environment or, alternatively, is it a meager remnant of a complete sexual NIH-PA Author Manuscript cycle that is deteriorating? We propose that parasex contributes to C. As such, it may be a case of evolution of evolvability [44, 53].

One problem when considering the evolution of parasex is its high cost, even in comparison with conventional sex. That is, in addition to the probability that the shuffling of genotypes will disrupt existing advantageous gene combinations [30], parasex between siblings produces offspring that have high levels of whole chromosome homozygosity and that are frequently aneuploid [13], which are genome changes that usually result in a reduced growth rate reviewed in [41, 42].

However, in the context of high stress, this cost may not be as significant: if the stress is severe enough to inhibit mitotic growth, then asexual reproduction would be a dead end. The potential for parasex to reveal variation at high levels, possibly even higher than conventional sex, suggests that parasex may be an effective strategy for the rapid generation of phenotypically diverse progeny, some of which confer better adaptation to the stress.

Pathogens in general have relatively low chances of meeting unrelated individuals as potential mates, as they are restricted to individuals co- infecting the same host, and the host is usually colonized by a single strain [54]. Thus, parasex may provide a better solution than conventional sex to the challenge of generating the variation necessary for survival when the available mating partners are limited to siblings.

Concluding remarks Most organisms must have mechanisms to survive stress and for many eukaryotes meiosis generates diversity under stress conditions [47, 49]. We propose that parasex in C. Under such conditions, the genetic diversity produced by parasex might be crucial for survival.

This advantage may apply to other organisms as well. For example, a parasexual cycle in Candida tropicalis shares some regulatory features, but differs in phenotypic details from the C. In addition, other fungi e.

Finally, other fungal commensals and pathogens that are assumed to be asexual may undergo parasex as a mechanism to generate diversity in response to stress. We suggest that the use of different stress conditions may facilitate the detection of rare mating events in these organisms, as well as in C.

Berman and Hadany Page 6 Acknowledgments We apologize to our colleagues whose publications we were not able to quote directly because of space limitations. Glossary Aneuploidy an imbalance in chromosome number. Diploids organisms with two copies of each chromosome carrying one chromosome in three copies trisomics or one chromosome in only one copy monosomics are often less fit under standard lab conditions but can have a selective advantage under some stress conditions.

Biofilms groups of cells that adhere to a surface and to each other to form a layered structure that often includes an extracellular matrix produced by the cells that promotes adherence. Loss of homozygosis of alleles due to either recombination or whole heterozygosity chromosome loss. Whole chromosome LOH arises through chromosome loss followed by reduplication of the remaining chromosome.

Parasex a non-conventional life cycle involving alternation of generations. Polyploidy an increase in the number of complete sets of chromosomes. Most organisms alternate between diploidy two copies of each chromosome and haploidy one copy of each chromosome. References 1. Cowen LE, et al. Evolution of drug resistance in experimental populations of Candida albicans. J Bacteriol. Selmecki AM, et al. Acquisition of aneuploidy provides increased fitness during the evolution of antifungal drug resistance.

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