The Department of Microbiology and Plant Pathology's weekly Plant Pathology 250 seminar series is presented this week by Robert Todd from Creighton University.

Seminar Title: "Expandable and reversible copy number amplifications drive rapid adaptation to antifungal drugs in Candida albicans”

Abstract: Copy number variation (CNV) is a major source of genomic diversity in bacteria, fungi, and human cancer cells and can drive rapid adaptive evolution via altered gene dosage and mutational target size. In the primary human fungal pathogen, Candida albicans, CNVs amplify genes that are both necessary and sufficient to confer antifungal drug resistance. However, the mechanism and dynamics of CNV formation in response to antifungal drug treatment is not known. Here, we describe the rapid and recurrent acquisition of novel, high copy number CNVs during adaptation to azole antifungal drugs. TheseCNVs amplify over 12 copies per genome of large chromosomal regions (164 kb to >1 MB) and decrease sensitivity to multiple azole antifungal drugs. Real-time, single-cell karyotype analysis indicates that these CNVs arise via a dicentric chromosome intermediate and successive breakage-fusion-bridge cycles that are repaired using two, distinct, long inverted repeat sequences. This leads to rapid and amplifiable CNV formation during antifungal drug selection. Removal from antifungal drug can lead to a dramatic loss of the CNV and reversion to the progenitor genotype and drug susceptibility phenotype. Together, these findings support a novel mechanism for the rapid acquisition of antifungal drug resistance and provide new genomic evidence for the phenotypic heterogeneity and antifungal drug tolerance frequently observed in clinical settings.

Seminar Host: Dr. Jason Stajich; jason.stajich@ucr.edu