Clusters of mutations from transient hypermutability
Clusters of mutations from transient hypermutability
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DOI：
10.1073/pnas.0503009102
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发表时间：
2005-09-06
影响因子：
11.1
通讯作者：
Peddada, S
中科院分区：
文献类型：
--
作者：
Drake, JW;Bebenek, A;Peddada, S
从突变频率和突变的随机分布来看，突变集合通常包含比预期更多的突变，具有多个突变。这种过剩在各种生物体中都可以看到，在体外DNA合成之后也是如此。这种过剩不太可能源于突变体，而是由于维持遗传保真度的众多交易中的一项受到扰动而导致的瞬时高度突变。多个突变有时是聚集的，有时是随机分布的。我们将一些光谱建模为包含大多数具有低突变频率和少数具有高突变频率的群体。在由噬菌体RB69突变DNA聚合酶在体外产生的突变的情况下，具有两个突变的突变大约是10倍的过剩，具有三个突变的突变甚至更多。然而，仅被视为搭便车的人的表型无法检测的突变的频率大约是携带可检测突变的突变体的5倍，这表明它们出现在突变频率更高的亚群中。过量的多重突变可能会对癌症的发生和适应性突变起到关键作用，包括病原体在宿主之间转移时的适应性。在快速变异的核病毒的情况下，病毒群体似乎由突变频率大大低于平均水平的大多数和突变载量巨大的少数组成。
Collections of mutants usually contain more mutants bearing multiple mutations than expected from the mutant frequency and a random distribution of mutations. This excess is seen in a variety of organisms and also after DNA synthesis in vitro. The excess is unlikely to originate in mutator mutants but rather from transient hypermutability resulting from a perturbation of one of the many transactions that maintain genetic fidelity. The multiple mutations are sometimes clustered and sometimes randomly distributed. We model some spectra as populations comprising a majority with a low mutation frequency and a minority with a high mutation frequency. In the case of mutants produced in vitro by a bacteriophage RB69 mutator DNA polymerase, mutants with two mutations are in approximate to 10-fold excess and mutants with three mutations are in even greater excess. However, phenotypically undetectable mutations seen only as hitchhikers with detectable mutations are approximate to 5-fold more frequent than mutants bearing detectable mutations, indicating that they arose in a subpopulation with a higher mutation frequency. Excess multiple mutations may contribute critically to carcinogenesis and to adaptive mutation, including the adaptations of pathogens as they move from host to host. In the case of the rapidly mutating riboviruses, the viral population appears to be composed of a majority with a mutation frequency substantially lower than the average and a minority with a huge mutational load.