Amplification-mutagenesis: Evidence that "directed" adaptive mutation and general hypermutability result from growth with a selected gene amplification
Amplification-mutagenesis: Evidence that "directed" adaptive mutation and general hypermutability result from growth with a selected gene amplification
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DOI：
10.1073/pnas.032680899
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发表时间：
2002-02-19
影响因子：
11.1
通讯作者：
Roth, JR
中科院分区：
文献类型：
--
作者：
Hendrickson, H;Slechta, ES;Roth, JR
当大肠杆菌的特定 lac 突变体在乳糖存在下挨饿时，非生长细胞似乎会优先将突变引导至允许生长的位点（适应性突变）。这一观察结果表明，生长限制会刺激变异。这里提供的证据表明，这种行为实际上是由标准达尔文过程引起的，其中自然选择分三个连续步骤进行。首先，生长限制有利于亚群的生长，同时突变体/acgene的扩增；接下来，它有利于扩增阵列中具有 lac(+) 回复等位基因的细胞。最后，它有利于突变体拷贝的丢失，直到稳定的单倍体 lac(+) 回复体出现并在菌落中过度生长。通过增加 lac 拷贝数，选择增强了每个发育克隆内回复的可能性。这一系列事件似乎将突变引导到有用的位点。一般诱变是扩增生长（SOS 诱导）的副作用。携带 lac 的 F' 质粒通过刺激基因复制和扩增来发挥作用。选择性应激对突变率或靶标特异性没有直接影响，但有利于一系列细胞类型在乳糖上的生长逐渐改善。事件的顺序——扩增、突变、分离——可能有助于解释一些癌症的起源和选择下新基因的进化。
When a particular lac mutant of Escherichia coli starves in the presence of lactose, nongrowing cells appear to direct mutations preferentially to sites that allow growth (adaptive mutation). This observation suggested that growth limitation stimulates mutability. Evidence is provided here that this behavior is actually caused by a standard Darwinian process in which natural selection acts in three sequential steps. First, growth limitation favors growth of a subpopulation with an amplification of the mutant/acgene; next, it favors cells with a lac(+) revertant allele within the amplified array. Finally, it favors loss of mutant copies until a stable haploid lac(+) revertant arises and overgrows the colony. By increasing the lac copy number, selection enhances the likelihood of reversion within each developing clone. This sequence of events appears to direct mutations to useful sites. General mutagenesis is a side-effect of growth with an amplification (SOS induction). The F' plasmid, which carries lac, contributes by stimulating gene duplication and amplification. Selective stress has no direct effect on mutation rate or target specificity, but acts to favor a succession of cell types with progressively improved growth on lactose. The sequence of events-amplification, mutation,segregation-may help to explain both the origins of some cancers and the evolution of new genes under selection.