Extrachromosomal DNA as a mediator of rapid, transient genetic adaptation in fungal pathogens

Fungal infections are stubbornly resistant to eradication by host defences and drug treatments. We hypothesise that transient genetic adaptation mediated by extrachromosomal circular DNA (eccDNA) is a major contributor to this fungal resilience. eccDNAs mediate drug resistance in many cancers and could do so in fungal infections, but almost nothing is known about eccDNA biology in fungal pathogens. eccDNA-mediated adaptation would render fungal infections difficult to treat, yet the genetic changes mediating survival would be heterogeneous and unstable, disappearing when cells are cultured for laboratory analysis. We will study eccDNA biology in fungal pathogens, determining how eccDNA species form and spread, and how these impact the resilience of fungal pathogen populations. We have found that pathogenic fungi produce swathes of random eccDNAs encompassing protein coding genes, providing a rich pool of genetic heterogeneity for selection under environmental stress. Furthermore, we find that model yeast can gain resistance to environmental challenges by controlling eccDNA segregation. Our ambitious research programme will comprehensively characterise eccDNA biology in highly diverged pathogenic fungi, combining laboratory models and clinical samples to understand how eccDNAs contribute to fungal resilience. Through this work we aim to reveal new targets and strategies to control fungal infections.