In a recent note, Jensen and Lynch (2020) remarked on the role of “mutational meltdown” as a strategy to restrict the expansion of COVID-19 in human populations. Mutational meltdown is a well-known population genetics process by which a population may become extinct due to the accumulation of deleterious mutations (Lynch and Gabriel 1990). As explained by Jensen and Lynch (2020), a sufficiently large increase of mutation rate may lead to a spiral of decline in fitness that eventually causes the extinction of the population. In a separate body of literature, virologists refer to that process as “lethal mutagenesis” in the context of drug-induced increase in viral mutation rate (Bull et al. 2007). Based on that concept, the development of drug therapies to induce errors during virus replication, either by lowering its RNA polymerase fidelity or by using base analogs, may become a promising strategy to fight viruses (such as SARS-CoV-2). An additional issue related to the above argument is the role of recombination. Muller (1964) emphasized that in species devoid of recombination the accumulation of mutations is higher than in species with sexual reproduction. In the latter case, deleterious mutations can be assembled in the same genome by recombination, facilitating their efficient elimination. In contrast, in the absence of recombination, mutations accumulate without the possibility of reconstructing genomes with a mutation number lower than the minimum present in a given generation. This process, known as Muller’s ratchet, is a consequence of the action of purifying selection, which ultimately leads to a strong reduction in effective population size (Ne); i.e., an increase of genetic drift and a consequent increase in the rate of fixation of combinations of deleterious mutations. Conceptually, Ne refers to the number of individuals that effectively contribute to descendants in the long term which, under selection, can be much smaller than the population census size N. Muller’s ratchet can be considered as part of the more general theory of “background selection,” which predicts the reduction of Ne by the action of purifying selection on linked sites (Charlesworth 2013) and applies to both sexual and asexual species. Santiago and Caballero (2016) showed that the rate of accumulation of deleterious mutations, extended to any degree of recombination, can be predicted from the effective population size theory of selection on linked sites and Kimura (1957) equations for the probability of fixation of mutations. Thus, the mean rate of decline in fitness (W) can be predicted (Fig. 1a) as a function of four factors: the population size (N); the average effect of deleterious mutations (s); the rate of recombination, reflected here by the recombination map length (L) across the genome; and the overall genomic rate of deleterious mutations (U), the latter being proportional to the genome size and to the mutation rate per site. Coronaviruses have two characteristics that allow them to have the largest genomes among RNA viruses: an RNA polymerase with proofreading activity; and a homologous recombination mechanism associated with replication, which is effectively equivalent to sexual reproduction. These features entail a relatively low mutation rate and a high efficiency in eliminating deleterious mutations from the population of viral particles, which opens up the possibility of having large and sophisticated genomes. Although no direct measures of recombination rates are available for SARS-CoV-2, estimates from betacoronavirus mouse hepatitis virus (MHV) (Baric et al. 1995) suggest that, on average, they could be on the order Associate editor: Barbara Mable

中文翻译：

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靶向重组作为对抗冠状病毒疾病的策略的价值

在最近的一份报告中，詹森和林奇（2020 年）评论了“突变崩溃”作为限制 COVID-19 在人群中扩散的策略的作用。突变崩溃是众所周知的种群遗传学过程，通过该过程，由于有害突变的积累，种群可能会灭绝（Lynch 和 Gabriel 1990）。正如 Jensen 和 Lynch (2020) 所解释的那样，突变率足够大的增加可能会导致适应性下降的螺旋式下降，最终导致种群灭绝。在另一篇文献中，病毒学家在药物诱导病毒突变率增加的背景下将该过程称为“致死突变”（Bull 等人，2007 年）。基于这个概念，开发了在病毒复制过程中诱发错误的药物疗法，通过降低其 RNA 聚合酶保真度或使用碱基类似物，可能成为对抗病毒（如 SARS-CoV-2）的有希望的策略。与上述论点相关的另一个问题是重组的作用。Muller (1964) 强调，在没有重组的物种中，突变的积累要高于有性繁殖的物种。在后一种情况下，有害突变可以通过重组在同一基因组中组装，促进它们的有效消除。相比之下，在没有重组的情况下，突变累积而无法重建具有低于给定代中存在的最小值的突变数的基因组。这个过程，被称为穆勒棘轮，是净化选择的结果，最终导致有效种群规模（Ne）的大幅减少；即，遗传漂变的增加和随之而来的有害突变组合固定率的增加。从概念上讲，Ne 指的是长期有效地为后代做出贡献的个体数量，在选择下，它可能比人口普查规模 N 小得多。穆勒棘轮可以被视为更一般的“背景选择理论”的一部分，”它预测 Ne 会通过在链接站点上进行净化选择而减少（Charlesworth 2013），并且适用于有性和无性物种。Santiago 和 Caballero (2016) 表明，有害突变的积累率，扩展到任何程度的重组，可以从链接位点选择的有效种群规模理论和 Kimura (1957) 突变固定概率方程预测。因此，可以将适应度（W）的平均下降率预测为（图 1a）作为四个因素的函数：种群规模（N）；有害突变的平均影响（s）；重组率，这里由整个基因组的重组图谱长度 (L) 反映；以及有害突变的总体基因组率 (U)，后者与基因组大小和每个位点的突变率成正比。冠状病毒具有两个特征，使其拥有 RNA 病毒中最大的基因组：具有校对活性的 RNA 聚合酶；以及与复制相关的同源重组机制，实际上相当于有性繁殖。这些特征需要相对较低的突变率和从病毒颗粒群体中消除有害突变的高效率，这开启了拥有庞大而复杂的基因组的可能性。虽然没有直接测量 SARS-CoV-2 的重组率，但对 β 冠状病毒小鼠肝炎病毒 (MHV) 的估计（Baric 等人，1995 年）表明，平均而言，它们可能在订单上 副主编：Barbara Mable