TY - JOUR TI - Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii AU - Billmyre, R Blake AU - Clancey, Shelly Applen AU - Heitman, Joseph A2 - Rokas, Antonis VL - 6 PY - 2017 DA - 2017/09/26 SP - e28802 C1 - eLife 2017;6:e28802 DO - 10.7554/eLife.28802 UR - https://doi.org/10.7554/eLife.28802 AB - Pathogenic microbes confront an evolutionary conflict between the pressure to maintain genome stability and the need to adapt to mounting external stresses. Bacteria often respond with elevated mutation rates, but little evidence exists of stable eukaryotic hypermutators in nature. Whole genome resequencing of the human fungal pathogen Cryptococcus deuterogattii identified an outbreak lineage characterized by a nonsense mutation in the mismatch repair component MSH2. This defect results in a moderate mutation rate increase in typical genes, and a larger increase in genes containing homopolymer runs. This allows facile inactivation of genes with coding homopolymer runs including FRR1, which encodes the target of the immunosuppresive antifungal drugs FK506 and rapamycin. Our study identifies a eukaryotic hypermutator lineage spread over two continents and suggests that pathogenic eukaryotic microbes may experience similar selection pressures on mutation rate as bacterial pathogens, particularly during long periods of clonal growth or while expanding into new environments. KW - Cryptococcus deuterogattii KW - hypermutator KW - Cryptococcus gattii KW - homopolymers KW - phenotypic diversity JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -