Laehnemann David, Peña-Miller Rafael, Rosenstiel Philip, Beardmore Robert, Jansen Gunther, Schulenburg Hinrich
Department of Evolutionary Ecology and Genetics, University of Kiel, Germany.
Biosciences, Geoffrey Pope Building, University of Exeter, United KingdomDepartment of Zoology, University of Oxford, United Kingdom.
Genome Biol Evol. 2014 May 20;6(6):1287-301. doi: 10.1093/gbe/evu106.
Evolutionary adaptation can be extremely fast, especially in response to high selection intensities. A prime example is the surge of antibiotic resistance in bacteria. The genomic underpinnings of such rapid changes may provide information on the genetic processes that enhance fast responses and the particular trait functions under selection. Here, we use experimentally evolved Escherichia coli for a detailed dissection of the genomics of rapid antibiotic resistance evolution. Our new analyses demonstrate that amplification of a sequence region containing several known antibiotic resistance genes represents a fast genomic response mechanism under high antibiotic stress, here exerted by drug combination. In particular, higher dosage of such antibiotic combinations coincided with higher copy number of the sequence region. The amplification appears to be evolutionarily costly, because amplification levels rapidly dropped after removal of the drugs. Our results suggest that amplification is a scalable process, as copy number rapidly changes in response to the selective pressure encountered. Moreover, repeated patterns of convergent evolution were found across the experimentally evolved bacterial populations, including those with lower antibiotic selection intensities. Intriguingly, convergent evolution was identified on different organizational levels, ranging from the above sequence amplification, high variant frequencies in specific genes, prevalence of individual nonsynonymous mutations to the unusual repeated occurrence of a particular synonymous mutation in Glycine codons. We conclude that constrained evolutionary trajectories underlie rapid adaptation to antibiotics. Of the identified genomic changes, sequence amplification seems to represent the most potent, albeit costly genomic response mechanism to high antibiotic stress.
进化适应可能极其迅速，尤其是在面对高强度选择时。一个典型例子是细菌中抗生素耐药性的激增。这种快速变化的基因组基础可能提供有关增强快速反应的遗传过程以及选择作用下特定性状功能的信息。在此，我们使用实验进化的大肠杆菌来详细剖析快速抗生素耐药性进化的基因组学。我们的新分析表明，包含几个已知抗生素耐药基因的序列区域的扩增代表了在高抗生素压力下（此处由药物组合施加）的一种快速基因组反应机制。特别是，此类抗生素组合的剂量越高，该序列区域的拷贝数就越高。这种扩增似乎在进化上代价高昂，因为在去除药物后扩增水平迅速下降。我们的结果表明，扩增是一个可扩展的过程，因为拷贝数会随着所遇到的选择压力迅速变化。此外，在实验进化的细菌群体中发现了趋同进化的重复模式，包括那些抗生素选择强度较低的群体。有趣的是，趋同进化在不同的组织水平上被识别出来，从上述序列扩增、特定基因中的高变异频率、个别非同义突变的流行到甘氨酸密码子中特定同义突变的异常重复出现。我们得出结论，受限的进化轨迹是快速适应抗生素的基础。在所识别的基因组变化中，序列扩增似乎代表了对高抗生素压力最有效的（尽管代价高昂）基因组反应机制。
