Diploids in the Cryptococcus neoformans Serotype A Population Homozygous for the α Mating Type Originate via Unisexual Mating

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Abstract
The ubiquitous environmental human pathogen Cryptococcus neoformans is traditionally considered a haploid fungus with a bipolar mating system. In nature, the α mating type is overwhelmingly predominant over a. How genetic diversity is generated and maintained by this heterothallic fungus in a largely unisexual α population is unclear. Recently it was discovered that C. neoformans can undergo same-sex mating under laboratory conditions generating both diploid intermediates and haploid recombinant progeny. Same-sex mating (α-α) also occurs in nature as evidenced by the existence of natural diploid αADα hybrids that arose by fusion between two α cells of different serotypes (A and D). How significantly this novel sexual style contributes to genetic diversity of the Cryptococcus population was unknown. In this study, ∼500 natural C. neoformans isolates were tested for ploidy and close to 8% were found to be diploid by fluorescence flow cytometry analysis. The majority of these diploids were serotype A isolates with two copies of the α MAT locus allele. Among those, several are intra-varietal allodiploid hybrids produced by fusion of two genetically distinct α cells through same-sex mating. The majority, however, are autodiploids that harbor two seemingly identical copies of the genome and arose via either endoreplication or clonal mating. The diploids identified were isolated from different geographic locations and varied genotypically and phenotypically, indicating independent non-clonal origins. The present study demonstrates that unisexual mating produces diploid isolates of C. neoformans in nature, giving rise to populations of hybrids and mixed ploidy. Our findings underscore the importance of same-sex mating in shaping the current population structure of this important human pathogenic fungus, with implications for mechanisms of selfing and inbreeding in other microbial pathogens. Although sex typically involves partners of opposite mating type (sexuality), it can also occur with just one mating type and even single individuals (parthenogenesis, homothallism). However, from a population perspective, sexual reproduction occurs by either outcrossing or inbreeding regardless of the partners' sexuality. Here the impact of sex was studied for Cryptococcus neoformans, a pathogen that causes fungal meningitis. While sex in the laboratory is known to occur via opposite-sex-mating, the population is largely unisexual (α) in nature. Recently, an unusual α-α unisexual mating process involving only mating type α was discovered in the lab, but the impact of unisexual mating in nature was unknown. The global survey of this typically haploid organism reveals ∼8% diploids in the population produced by unisexual α-α mating. Some diploids result from fusion of two genetically distinct parents while other diploids arise via sibling mating or genome duplication. Although hybrid fitness is well-documented, how sex between identical isolates benefits the population is a conundrum. The diploid state may confer growth advantages or serve as a capacitor for evolution, allowing mutations to arise that would be deleterious on their own in the haploid, and then releasing these in novel combinations by meiosis and sporulation.