Rampant transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of a human fungal pathogen
Rampant transposition following RNAi loss causes hypermutation and antifungal drug resistance in clinical isolates of a human fungal pathogen
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DOI：
10.1101/2021.08.11.455996
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发表时间：
2021-08
期刊：
影响因子：
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通讯作者：
Shelby J. Priest;V. Yadav;Cullen Roth;Tim A. Dahlmann;U. Kück;Paul M. Magwene;J. Heitman
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文献类型：
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作者：
Shelby J. Priest;V. Yadav;Cullen Roth;Tim A. Dahlmann;U. Kück;Paul M. Magwene;J. Heitman
微生物通过随机获得增强适应性的突变来生存和竞争。虽然增加的突变率在多细胞生物中通常是有害的，但超突变对于经历强烈选择压力的微生物可能是有益的。由新型隐球菌引起的感染造成了约15%的艾滋病相关死亡，并与高死亡率相关，这归因于抗真菌药物的缺乏和耐药性。我们发现了两个超变子C。其中Cnl1转座子插入是耐药性的原因。全基因组测序显示，这两个hypermutator基因组在RNAi组件ZNF 3和数百个Cnl1元件中含有无义突变，这些元件在每条染色体上组织成大量的亚端粒阵列。QTL定位确定了一个显着的基因座与超突变，包括znf3。CRISPR介导的znf3无义突变编辑消除了超突变并恢复了siRNA的产生。总之，这些分离株中的超突变和耐药性是由RNAi损失和Cnl1元件的显著负担引起的。
Microorganisms survive and compete by stochastically acquiring mutations that enhance fitness. Although increased mutation rates are often deleterious in multicellular organisms, hypermutation can be beneficial for microbes experiencing strong selective pressures. Infections caused by Cryptococcus neoformans are responsible for ∼15% of AIDS-related deaths and associated with high mortality rates, attributable to a dearth of antifungal drugs and drug resistance. We identified two hypermutator C. neoformans clinical isolates in which Cnl1 transposon insertions were responsible for drug resistance. Whole-genome sequencing revealed both hypermutator genomes harbor a nonsense mutation in the RNAi component ZNF3 and hundreds of Cnl1 elements organized into massive subtelomeric arrays on every chromosome. QTL mapping identified a significant locus associated with hypermutation that included znf3. CRISPR-mediated editing of the znf3 nonsense mutation abolished hypermutation and restored siRNA production. In sum, hypermutation and drug resistance in these isolates results from RNAi loss and a significant burden of Cnl1 elements.