Empirical complexities in the genetic foundations of lethal mutagenesis.
Empirical complexities in the genetic foundations of lethal mutagenesis.
复制标题
DOI：
10.1534/genetics.113.154195
复制
发表时间：
2013-10
期刊：
影响因子：
3.3
通讯作者：
Molineux IJ
中科院分区：
文献类型：
--
作者：
Bull JJ;Joyce P;Gladstone E;Molineux IJ
根据群体遗传学理论，提高大群体的突变率会逐渐降低平均适应度。如果适应度下降足够大，种群将在一个被称为致死突变的过程中灭绝。致死性诱变已在病毒学文献中被认可为一种有前途的病毒治疗方法，并且几项体外研究已经用高剂量的诱变药物迫使病毒灭绝。然而，只有一项实证研究测试了致命突变背后的遗传模型，而且该理论甚至在定性水平上都失败了。在这里，我们提供了一个新的水平的致命突变的分析，开发和评估模型，专门为经验系统，可用于测试的理论。我们首先量化一个关键参数的估计偏差，并考虑是否该偏差的基础上，先前观察到的理论和实验之间缺乏一致性。然后，我们考虑一个看似理想的协议，避免这种偏见的病毒体诱变，但发现它是由其他问题的阻碍。最后，结果表明，仅仅解释从双链基因组测定突变的困难。我们的分析揭示了测试理论时意想不到的复杂性。然而，该理论先前未能预测实验结果似乎是由于该理论忽视了进化机制（例如，有益的突变），而不是来自经验设置和模型假设之间的不匹配。这种解释引起了一种幽灵，即幼稚的致命诱变尝试可能会增加适应，而不是阻碍它。
From population genetics theory, elevating the mutation rate of a large population should progressively reduce average fitness. If the fitness decline is large enough, the population will go extinct in a process known as lethal mutagenesis. Lethal mutagenesis has been endorsed in the virology literature as a promising approach to viral treatment, and several in vitro studies have forced viral extinction with high doses of mutagenic drugs. Yet only one empirical study has tested the genetic models underlying lethal mutagenesis, and the theory failed on even a qualitative level. Here we provide a new level of analysis of lethal mutagenesis by developing and evaluating models specifically tailored to empirical systems that may be used to test the theory. We first quantify a bias in the estimation of a critical parameter and consider whether that bias underlies the previously observed lack of concordance between theory and experiment. We then consider a seemingly ideal protocol that avoids this bias—mutagenesis of virions—but find that it is hampered by other problems. Finally, results that reveal difficulties in the mere interpretation of mutations assayed from double-strand genomes are derived. Our analyses expose unanticipated complexities in testing the theory. Nevertheless, the previous failure of the theory to predict experimental outcomes appears to reside in evolutionary mechanisms neglected by the theory (e.g., beneficial mutations) rather than from a mismatch between the empirical setup and model assumptions. This interpretation raises the specter that naive attempts at lethal mutagenesis may augment adaptation rather than retard it.
登录
查看更多内容
DOI：
10.1016/0020-711x(93)90693-9
发表时间：
1993-10-01
期刊：
INTERNATIONAL JOURNAL OF BIOCHEMISTRY
影响因子：
--
作者：
RAUKO, P;NOVOTNY, L;BALAZOVA, E
通讯作者：
BALAZOVA, E
影响因子：
3.8
作者：
Lalic, J.;Elena, S. F.
通讯作者：
Elena, S. F.
影响因子：
56.9
作者：
Lind, Peter A.;Berg, Otto G.;Andersson, Dan I.
通讯作者：
Andersson, Dan I.
DOI：
10.1098/rspb.1999.0936
发表时间：
1999-12-07
影响因子：
4.7
作者：
Johnson, T
通讯作者：
Johnson, T
影响因子：
4.5
作者：
Domingo-Calap P;Cuevas JM;Sanjuán R
通讯作者：
Sanjuán R