Prof. Geraldine ButlerAssociate Professor of Genetics
Virulence characteristics of pathogenic yeasts.
Genomic analysis of Candida parapsilosis
The main work in my lab for the past few years was funded by Science Foundation Ireland. This focuses on an analysis of virulence in Candida parapsilosis, a major cause of infection in premature neonates. C. parapsilosis forms biofilms on indwelling medical devices. We carried out the first genome sequence survey of this organism, and identified almost 4,000 genes. We showed that the mating type loci in C. parapsilosis are defective, and we are now studying the evolution of mating in several Candida species. This work led to the sequencing of the entire C. parapsilosis genome by the Wellcome Trust Sanger Institute (see here). We also designed and manufactured the first genome-based microarrays from this species. Early versions of the arrays were used to determine the transcriptional response of C. parapsilosis to the quorum-sensing agent farnesol, and to determine the transcriptional profile of biofilm cells. The current arrays are based on the entire genome. We have identified one regulator of biofilm formation (Bcr1), and we used whole-genome arrays to investigate the role of the hypoxic response in biofilm development. We also developed the first methods for making gene knockouts in this species. Recently we have begun to use the Illumina/Solexa next generation DNA sequencing facility available at the Conway Institute to improve the annotation of the C. parapsilosis genome, and to characterise transcriptional networks.
Molecular evolution and comparative genomics of Candida species
Our group, together with international collaborators including Dr Christina Cuomo of the Broad Institute, have co-ordinated a community-based analysis of 6 new genomes of Candida and related species, sequenced by the Broad Institute of Harvard and MIT (see here) and by the Wellcome Trust Sanger Institute. This led to an importnat paper published in Nature in 2009 (Butler et al. Nature, 459 :657-662). We carried out the first whole-genome based supertree analysis to determine the phylogenetic relationship of 42 fungal species, and have identified examples of Horizontal Gene Transfer. We also carried out a detailed analysis of the evolution of mating and meiosis in Candida.
C. albicans is one of the major causes of fungal infection, particularly in immunocompromised hosts. We have isolated and characterised the CaACE2 from C. albicans, which encodes a homologue of both Ace2p and Swi5p from S. cerevisiae. Disrupting CaACE2 results in a cell separation defect, and also greatly reduces virulence in animal models. We have used microarrays to identify the targets of CaACE2 , and we have recently shown that that this transcription factor plays a role in regulating the response of Candida to growth in hypoxic (low oxygen) conditions. We have now identified other regulators of the hypoxic response, and are investigating the role of specific oxygen sensors.
We use the Agilent EArray system to design microarrays from the Candida albicans (Assembly 21), Candida glabrata and Candida parapsilosis genomes. We are willing to share the designs with any interested parties.
We recently developed a genome browser tool (Candida Gene Order Browser) that is available here. This is a an interactive tool that enables analysis of all of the sequenced Candida genomes. It computes and displays synteny (gene order) and orthology assignments.