RNAi-dependent epimutation induces broad antifungal resistance in Mucor circinelloides

To elucidate the role of epimutation in antifungal resistance of Mucor, epimutations were isolated that confer resistance to 5-fluoroorotic acid (5-FOA). We identified epimutant strains that exhibit resistance to 5-FOA without mutations in either of the 5-FOA target genes, pyrF or pyrG. Using sRNA sequencing, we demonstrate that these epimutants harbor sRNA against either pyrF or pyrG, and further show that this sRNA is lost after reversion to drug sensitivity. 10 samples were sequenced, including 2 pyrF epimutants and 1 pyrG epimutant before and after passaging. Before passaging, samples were URA-; after passaging they reverted to the wildtype phenotype and became URA+. The remaining 4 sequences are derived from the mutant parent strain and the wildtype background for the two pyrF and the single pyrG sequenced strain.