Volatility of Mutator Phenotypes at Single Cell Resolution.
Volatility of Mutator Phenotypes at Single Cell Resolution.
复制标题
突变表型在单细胞分辨率下的挥发性。
DOI：
10.1371/journal.pgen.1005151
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发表时间：
2015-04
期刊：
影响因子：
4.5
通讯作者：
Herr AJ
中科院分区：
文献类型：
--
作者：
Kennedy SR;Schultz EM;Chappell TM;Kohrn B;Knowels GM;Herr AJ
突变子表型加速肿瘤转化的进化过程。从历史上看，突变率的测量依赖于对大量细胞群体中靶基因中罕见突变的发生进行评分。在大细胞群体中平均突变率假设新的突变在每次细胞分裂期间以恒定的速率出现。如果突变率不是恒定的，则扩展的增变子群体可能包含具有广泛差异的进化率的亚克隆。在这里，我们报告突变率测量的个别细胞分裂的突变酵母缺乏DNA聚合酶ε校正和碱基错配修复。我们的数据最适合一个模型，在这个模型中，细胞可以假设两个不同的增变子状态之一，突变率相差一个数量级。在易出错的细胞分裂中，突变发生在同一染色体上的频率比预期的更高，通常在DNA中具有相似的预测复制时间，与超变状态的时空维度一致。将突变映射到预测的复制子上显示，突变在复制子的前半部分以及终止区附近富集。总之，我们的研究结果表明，个体基因组复制事件表现出意想不到的波动性，这可能会加深我们对突变驱动的恶性肿瘤演变的理解。突变会促进微生物进化和癌症。具有增加的突变率的细胞被认为具有“突变表型”并且比非突变细胞更快地适应。我们的研究利用了一种新的方法来测量单个细胞分裂的突变率，以表明增变细胞可以采用两种突变率之一，这两种突变率的大小相差十倍。这种增变因子的波动性表明，在同一个增变因子细胞克隆中，突变累积的速率可能差异很大。了解如何调节突变子状态可能会为治疗某些癌症提供一种途径。
Mutator phenotypes accelerate the evolutionary process of neoplastic transformation. Historically, the measurement of mutation rates has relied on scoring the occurrence of rare mutations in target genes in large populations of cells. Averaging mutation rates over large cell populations assumes that new mutations arise at a constant rate during each cell division. If the mutation rate is not constant, an expanding mutator population may contain subclones with widely divergent rates of evolution. Here, we report mutation rate measurements of individual cell divisions of mutator yeast deficient in DNA polymerase ε proofreading and base-base mismatch repair. Our data are best fit by a model in which cells can assume one of two distinct mutator states, with mutation rates that differ by an order of magnitude. In error-prone cell divisions, mutations occurred on the same chromosome more frequently than expected by chance, often in DNA with similar predicted replication timing, consistent with a spatiotemporal dimension to the hypermutator state. Mapping of mutations onto predicted replicons revealed that mutations were enriched in the first half of the replicon as well as near termination zones. Taken together, our findings show that individual genome replication events exhibit an unexpected volatility that may deepen our understanding of the evolution of mutator-driven malignancies. Mutations fuel microbial evolution and cancer. Cells with an increased rate of mutation are said to have a “mutator phenotype” and adapt more rapidly than non-mutator cells. Our study utilizes a novel way of measuring mutation rates of individual cell divisions to show that mutator cells can adopt one of two mutation rates that differ tenfold in magnitude. This mutator volatility suggests that the rates of mutation accumulation may vary widely within the same clone of mutator cells. Understanding how to modulate the mutator state may provide an avenue to treat certain cancers.
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