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Explore the mutational trajectories shaping fungal adaptation
Secondary Supervisor(s): Dr Megan McDonald
University of Registration: University of Birmingham
BBSRC Research Themes: Understanding the Rules of Life (Microbiology, Systems Biology)
Project Outline
The rapid emergence of fungal diseases is a global threat to animal, plant and our ecosystem, while fungal infections affect billions of people, including >1.5 million global deaths each year. Within a fifteen-year period (1995-2010), fungi have caused species extinction of 39 animal and four plant species [1], and there are only three classes of antifungal drugs available in the clinic in the past four decades. Inevitably, multidrug resistance has become an urgent problem for the agricultural industries and human medicine. Additionally, with climate change, extreme weathers also facilitate the interactions between fungal pathogens and their host (and/or environment), and many environmental fungi now can overcome growth temperature barriers (12–30°C) to affect human [2]. The development of stress (thermo-) tolerance phenotypes likely results from the high genome plasticity in fungal genome, while aneuploidy, an unbalanced genomic state with gain or loss of chromosomes, is prevalent in wild and clinical fungal isolates. Whether and how aneuploidy contributes to the selection processes to adaptive traits in fungi remains elusive.
This project aims to investigate the mutational trajectories across the adaptation history in the context of aneuploidy and to identify the key genetic and non-genetic determinants enabling antifungal resistance.
Objective and Methods:
We will use both the model organism Saccharomyces cerevisiae and multiple fungal pathogens (mainly Candida species), together with animal, cell line infection models to investigate the mutational cues for adaptive phenotypes.
Objective 1: Investigate the fungal genomic plasticity at the host-fungal interface.
As fungi possess a high level of genome plasticity, we will identify the types of genomic alterations (mutations/CNV/ploidy variations) when fungal pathogens encounter the host and environmental stress in a temporal manner. Importantly, the mutual relationship between each type of genomic abnormalities will be investigated. For example, whether ploidy variations “buffer” or promote DNA damage responses? Both genomics and cell biological methods will be used to reveal the mutational evolution in the adaptive process.
Objective 2: Explore the mutational cues in response to genetic variation in fungi.
While genome-phenome gap is the main obstacle allowing us to combat antifungal drug resistance, we will use experimental evolution approaches to monitor the relationship between mutational complexity and phenotypic outcomes (e.g., tolerance and fitness) based on our recent observations of “genome instability burst”.
Together, this project will leverage both genomics, proteomics, biochemistry and cell biological approaches to understand the molecular evolution of fungal diseases from the interactions of hosts, fungal pathogens and their microenvironment.
References
1. Fisher, M., Henk, D., Briggs, C. et al. Emerging fungal threats to animal, plant and ecosystem health. Nature 484, 186–194 (2012). https://doi.org/10.1038/nature10947.
2. Case NT, Berman J. et al. The future of fungi: threats and opportunities. G3 (Bethesda). 2022 Nov 4;12(11) https://doi.org/10.1093/g3journal/jkac224.