Institute for Genetics, University of Cologne, Köln, Germany.
PLoS Genet. 2012 Jun;8(6):e1002783. doi: 10.1371/journal.pgen.1002783. Epub 2012 Jun 28.
For a quantitative understanding of the process of adaptation, we need to understand its "raw material," that is, the frequency and fitness effects of beneficial mutations. At present, most empirical evidence suggests an exponential distribution of fitness effects of beneficial mutations, as predicted for Gumbel-domain distributions by extreme value theory. Here, we study the distribution of mutation effects on cefotaxime (Ctx) resistance and fitness of 48 unique beneficial mutations in the bacterial enzyme TEM-1 β-lactamase, which were obtained by screening the products of random mutagenesis for increased Ctx resistance. Our contributions are threefold. First, based on the frequency of unique mutations among more than 300 sequenced isolates and correcting for mutation bias, we conservatively estimate that the total number of first-step mutations that increase Ctx resistance in this enzyme is 87 [95% CI 75-189], or 3.4% of all 2,583 possible base-pair substitutions. Of the 48 mutations, 10 are synonymous and the majority of the 38 non-synonymous mutations occur in the pocket surrounding the catalytic site. Second, we estimate the effects of the mutations on Ctx resistance by determining survival at various Ctx concentrations, and we derive their fitness effects by modeling reproduction and survival as a branching process. Third, we find that the distribution of both measures follows a Fréchet-type distribution characterized by a broad tail of a few exceptionally fit mutants. Such distributions have fundamental evolutionary implications, including an increased predictability of evolution, and may provide a partial explanation for recent observations of striking parallel evolution of antibiotic resistance.
为了定量理解适应的过程，我们需要了解其“原材料”，即有益突变的频率和适应度效应。目前，大多数经验证据表明有益突变的适应度效应呈指数分布，这与极值理论预测的 Gumbel 域分布相符。在这里，我们研究了在细菌酶 TEM-1 β-内酰胺酶中 48 个独特有益突变的头孢噻肟（Ctx）抗性和适应度的突变效应分布，这些突变是通过筛选随机诱变产物获得的，以提高 Ctx 抗性。我们的贡献有三点。首先，基于 300 多个测序分离物中独特突变的频率，并校正突变偏差，我们保守估计该酶中增加 Ctx 抗性的第一步突变总数为 87（95%CI75-189），或 2,583 个可能的碱基替换中的 3.4%。在这 48 个突变中，有 10 个是同义突变，而 38 个非同义突变中的大多数发生在催化位点周围的口袋中。其次，我们通过确定在不同 Ctx 浓度下的存活率来估计突变对 Ctx 抗性的影响，并通过将繁殖和生存建模为分支过程来推导它们的适应度效应。第三，我们发现这两种度量的分布都遵循一种 Fréchet 型分布，其特征是少数几个适应度特别高的突变体具有广泛的长尾。这种分布具有基本的进化意义，包括进化的可预测性增加，并且可能为最近观察到的抗生素抗性惊人的平行进化提供部分解释。
