Genome-wide Analyses of Recombination and the Genetic Architecture of Virulence Traits in Cryptococcus

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2020

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Abstract

Fungi of the basidiomycete genus Cryptococcus cause disease in an estimated quarter of a million people, annually. Cryptococcus neoformans and Cryptococcus deneoformans are the two most prevalent disease causing species within the Cryptococcus clade, with isolates of these species exhibiting considerable variation in their pathogenicity, ranging from benign to highly virulent. A wide variety of traits, such as thermal tolerance, melanin production, and an extracellular capsule contribute to virulence, yet our understanding of the genetic architecture of such traits is limited. In the studies reported here, I describe the first genome-wide analyses of recombination in C. neoformans and C. deneoformans and provide the first high-resolution genetic mapping studies of virulence traits in these important fungal pathogens.

In studying recombination, I considered both the nuclear and mitochondrial genomes, and estimated recombination rates for both opposite- and same-sex matings. With respect to recombination of the nuclear genome, I found that progeny from opposite-sex mating have more crossovers on average than those from same-sex mating. These analyses also suggest differences in recombination rate between C. neoformans and C. deneoformans. Similarly, analyses of mitochondrial inheritance and recombination point to differences between offspring from opposite- and same-sex matings, though with much lower overall rates of recombination as compared to the nuclear genome.

To dissect the genetic architecture of complex virulence traits, I employed quantitative trait locus (QTL) mapping. A unique aspect of these QTL studies was the application of functional data analysis methods that exploit time-series data and multiple experimental conditions. I mapped QTL for thermal tolerance, melanization, capsule size, salt tolerance, and antifungal drug susceptibility in C. deneoformans. For several QTL, I was able to identify candidate causal variants that underlie these loci. Two major effect QTL for amphotericin B resistance map to SSK1 and SSK2; regulators of the high osmolarity glycerol (HOG) pathway that governs responses to osmotic stress. Epistatic interactions between SSK1 and SSK2 were also shown to govern fludioxonil sensitivity. A third major effect, pleiotropic QTL was mapped to the gene, RIC8, a regulator of cAMP-PKA signaling. RIC8 variation is predicted to contribute to differences in thermal tolerance, melanin production, and capsule size.

In combination, the studies reported here advance our understanding of the mechanisms that generate and maintain variation in Cryptococcus and implicate genetic variants in key stress-responsive signaling pathways as a major contributor to phenotypic variation between lineages of Cryptococcus.

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Roth, Cullen Jon Navarre (2020). Genome-wide Analyses of Recombination and the Genetic Architecture of Virulence Traits in Cryptococcus. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/20886.

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