Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii.

R Blake Billmyre,Joseph Heitman,Shelly Applen Clancey

doi:10.7554/elife.28802

Abstract

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.

Highlights

IntroductionAll organisms must strike a balance between allowing enough random mutations for selection to act upon, and the fact that most of these mutations are likely to be deleterious and must be purged from the population
Mutation is the raw material of evolution
We identified a candidate potential large effect mutation shared by these three diminished virulence isolates that resulted in a predicted non-functional Msh[2]

Summary

Introduction

All organisms must strike a balance between allowing enough random mutations for selection to act upon, and the fact that most of these mutations are likely to be deleterious and must be purged from the population. This is true for pathogenic microbes that take part in Red Queen conflicts with their hosts and require a continuous supply of mutations to maintain competitive fitness. In this case, increased pressure may exist to maintain an elevated mutation rate to increase the rate of adaptation.

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Results

Conclusion