Virulence Attributes and Hyphal Growth of C. neoformans Are Quantitative Traits and the MATα Allele Enhances Filamentation

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Abstract
Cryptococcus neoformans is a fungal human pathogen with a bipolar mating system. It undergoes a dimorphic transition from a unicellular yeast to hyphal filamentous growth during mating and monokaryotic fruiting. The traditional sexual cycle that leads to the production of infectious basidiospores involves cells of both α and a mating type. Monokaryotic fruiting is a modified form of sexual reproduction that involves cells of the same mating type, most commonly α, which is the predominant mating type in both the environment and clinical isolates. However, some a isolates can also undergo monokaryotic fruiting. To determine whether mating type and other genetic loci contribute to the differences in fruiting observed between α and a cells, we applied quantitative trait loci (QTL) mapping to an inbred population of F2 progeny. We discovered that variation in hyphal length produced during fruiting is a quantitative trait resulting from the combined effects of multiple genetic loci, including the mating type (MAT) locus. Importantly, the α allele of the MAT locus enhanced hyphal growth compared with the a allele. Other virulence traits, including melanization and growth at 39 °C, also are quantitative traits that share a common QTL with hyphal growth. The Mac1 transcription factor, encoded in this common QTL, regulates copper homeostasis. MAC1 allelic differences contribute to phenotypic variation, and mac1Δ mutants exhibit defects in filamentation, melanin production, and high temperature growth. Further characterization of these QTL regions will reveal additional quantitative trait genes controlling biological processes central to fungal development and pathogenicity. Pathogenic fungi have emerged as a major threat to human health. Because most invasive fungi reside in nature and are acquired by inhalation of infectious spores, understanding spore production may uncover strategies to block these infections. Like animals, the fungus Cryptococcus neoformans typically requires two individuals with opposite mating types/sexes, α and a, for sexual reproduction and spore generation. However, because the α mating type predominates in nature, C. neoformans has evolved an alternative mechanism, “monokaryotic fruiting,” for individual strains, mostly α, to produce spores. To investigate the genetics of this process, Lin and colleagues analyzed fruiting and two other virulence traits, growth at 39 °C and melanin production in an inbred population. By correlating these phenotypes among the population with the inheritance of DNA markers, the authors showed that (1) strains of either mating type are capable of initiation of fruiting, (2) the α mating type enhances hyphal growth during fruiting, (3) all three phenotypes are affected by gene(s) in the same genomic region, and (4) the Mac1 copper transcription factor encoded by this region was confirmed to affect these properties. This is to the authors' knowledge the first study to dissect complex virulence traits in a human fungal pathogen by mapping genomic loci associated with polygenic traits.