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

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 rese...

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Autores principales: Billmyre, R Blake, Clancey, Shelly Applen, Heitman, Joseph
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614558/
https://www.ncbi.nlm.nih.gov/pubmed/28948913
http://dx.doi.org/10.7554/eLife.28802
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author Billmyre, R Blake
Clancey, Shelly Applen
Heitman, Joseph
author_facet Billmyre, R Blake
Clancey, Shelly Applen
Heitman, Joseph
author_sort Billmyre, R Blake
collection PubMed
description 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.
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spelling pubmed-56145582017-09-28 Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii Billmyre, R Blake Clancey, Shelly Applen Heitman, Joseph eLife Microbiology and Infectious Disease 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. eLife Sciences Publications, Ltd 2017-09-26 /pmc/articles/PMC5614558/ /pubmed/28948913 http://dx.doi.org/10.7554/eLife.28802 Text en © 2017, Billmyre et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Microbiology and Infectious Disease
Billmyre, R Blake
Clancey, Shelly Applen
Heitman, Joseph
Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title_full Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title_fullStr Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title_full_unstemmed Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title_short Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
title_sort natural mismatch repair mutations mediate phenotypic diversity and drug resistance in cryptococcus deuterogattii
topic Microbiology and Infectious Disease
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5614558/
https://www.ncbi.nlm.nih.gov/pubmed/28948913
http://dx.doi.org/10.7554/eLife.28802
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