Biosciences Research Seminar - Chromatin regulation and the adaptation of Saccharomycotina yeast to virulence

The genomics revolution has propelled us into an unprecedented era of discovery in the field of evolutionary genetics. We now have the access to sequencing data that allows us to generate specific hypotheses about the genetic basis for evolutionarily interesting traits and phenotypic adaptation. By testing such hypotheses in the lab, we can begin to gain a comprehensive molecular understanding of how life evolved.

Using such an approach, our research aims to understand the role of chromatin regulation in the evolution of pathogenicity within closely related yeast species from the Saccharomycotina phylum. We employed comparative genomics across 23 yeast species and have identified significant genetic divergence of the histone acetylation machinery. Furthermore, we employed CodeML within the PAML phylogenetic package to test for heterogeneity in selective pressure between Saccharomycotina yeast, and have identified 42 genes related to chromatin regulation, close to 65% of the genes analysed, which are predicted to be under positive selection. Interestingly, many of these genes are thought to influence histone acetylation pathways.

To validate these predictions, we focused on the pathogenic species Candida glabrata. Phylogenetic analysis suggests that this species evolved pathogenicity independently of other Candida species, and as such, represents a good evolutionary model system. Our genomic analysis predicted positive selection has acted on the C. glabrata chromatin-related genes cg_HAT1, cg_SPP1 and cg_AHC1. Phenotypic analyses support this prediction, as deletion of each of these loci leads to changes in virulence related phenotypes such as biofilm formation, anti-fungal resistance, stress tolerance and in vivo virulence using the Galleria mellonella model of fungal infection. RNAseq data identifies the genetic pathways that are disrupted by these mutations, which may account for their phenotypic consequences. Furthermore, we have shown that treatment of C. glabrata with small molecule inhibitors of histone deacetylases negatively impacts measures of virulence within this pathogen, supporting a growing awareness of the utility of these drugs to combat fungal disease.