Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
Natural mismatch repair mutations mediate phenotypic diversity and drug resistance in Cryptococcus deuterogattii
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DOI：
10.7554/elife.28802
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发表时间：
2017-09-26
期刊：
影响因子：
7.7
通讯作者：
Heitman, Joseph
中科院分区：
文献类型：
--
作者：
Billmyre, R. Blake;Clancey, Shelly Applen;Heitman, Joseph
病原微生物面临着维持基因组稳定性的压力和适应不断增加的外部压力的需要之间的进化冲突。细菌通常会以较高的突变率作出反应，但几乎没有证据表明自然界中存在稳定的真核超变因子。全基因组测序的人类真菌病原体隐球菌deuterogattii确定了爆发谱系的特点是在错配修复组件MSH2的无义突变。这种缺陷导致典型基因的突变率适度增加，以及含有均聚物运行的基因的较大增加。这允许用编码均聚物运行的基因容易地失活，包括FRR 1，其编码免疫抑制性抗真菌药物FK 506和雷帕霉素的靶标。我们的研究确定了一个分布在两大洲的真核超变基因谱系，并表明致病性真核微生物可能会经历与细菌病原体相似的突变率选择压力，特别是在长期的克隆生长或扩展到新的环境中时。
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.