Compensating the Fitness Costs of Synonymous Mutations.
Compensating the Fitness Costs of Synonymous Mutations.
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DOI：
10.1093/molbev/msw028
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发表时间：
2016-06
影响因子：
10.7
通讯作者：
Andersson DI
中科院分区：
文献类型：
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作者：
Knöppel A;Näsvall J;Andersson DI
同义突变不会改变多肽的序列，但仍可能影响适应度。我们研究了肠沙门氏菌rpsT基因（编码核糖体蛋白S20）的四种同义突变是如何降低适应性（即生长速度）的，以及这种成本可以通过遗传补偿的机制。同义突变体的生长速率降低与rpsT转录物和S20蛋白水平降低相关。在适应性进化实验中，这些适应性损伤可以通过突变来补偿，这些突变可以通过增加基因剂量（由于重复）、增加rpsT基因的转录（由于rpoD突变或rpsT突变）或增加rpsT转录物的翻译（由于rpsT突变）来引起S20的上调。我们认为，同义突变体中S20水平的降低导致30S亚基缺乏S20的缺陷亚群的产生，从而减少蛋白质合成和细菌生长，而代偿性突变恢复S20水平和功能核糖体的数量。我们的研究结果表明，特定的同义突变如何导致适应度大幅降低，许多不同类型的基因内和基因外补偿性突变可以有效地恢复适应度。此外，本研究强调，同义位点也可能处于强选择之下，这可能对使用dN/dS比率作为选择的标志具有启示意义。
Synonymous mutations do not change the sequence of the polypeptide but they may still influence fitness. We investigated in Salmonella enterica how four synonymous mutations in the rpsT gene (encoding ribosomal protein S20) reduce fitness (i.e., growth rate) and the mechanisms by which this cost can be genetically compensated. The reduced growth rates of the synonymous mutants were correlated with reduced levels of the rpsT transcript and S20 protein. In an adaptive evolution experiment, these fitness impairments could be compensated by mutations that either caused up-regulation of S20 through increased gene dosage (due to duplications), increased transcription of the rpsT gene (due to an rpoD mutation or mutations in rpsT), or increased translation from the rpsT transcript (due to rpsT mutations). We suggest that the reduced levels of S20 in the synonymous mutants result in production of a defective subpopulation of 30S subunits lacking S20 that reduce protein synthesis and bacterial growth and that the compensatory mutations restore S20 levels and the number of functional ribosomes. Our results demonstrate how specific synonymous mutations can cause substantial fitness reductions and that many different types of intra- and extragenic compensatory mutations can efficiently restore fitness. Furthermore, this study highlights that also synonymous sites can be under strong selection, which may have implications for the use of dN/dS ratios as signature for selection.