PDF(Pubmed)
Abstract：
Despite a relatively low mutation rate, the large number of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has allowed for substantial genetic change, leading to a multitude of emerging variants. Using a recently determined mutation rate (per site replication), as well as within-host parameter estimates for symptomatic SARS-CoV-2 infection, we apply a stochastic transmission-bottleneck model to describe the survival probability of de novo SARS-CoV-2 mutations as a function of bottleneck size and selection coefficient. For narrow bottlenecks, we find that mutations affecting per-target-cell attachment rate (with phenotypes associated with fusogenicity and ACE2 binding) have similar transmission probabilities to mutations affecting viral load clearance (with phenotypes associated with humoral evasion). We further find that mutations affecting the eclipse rate (with phenotypes associated with reorganization of cellular metabolic processes and synthesis of viral budding precursor material) are highly favoured relative to all other traits examined. We find that mutations leading to reduced removal rates of infected cells (with phenotypes associated with innate immune evasion) have limited transmission advantage relative to mutations leading to humoral evasion. Predicted transmission probabilities, however, for mutations affecting innate immune evasion are more consistent with the range of clinically estimated household transmission probabilities for de novo mutations. This result suggests that although mutations affecting humoral evasion are more easily transmitted when they occur, mutations affecting innate immune evasion may occur more readily. We examine our predictions in the context of a number of previously characterized mutations in circulating strains of SARS-CoV-2. Our work offers both a null model for SARS-CoV-2 mutation rates and predicts which aspects of viral life history are most likely to successfully evolve, despite low mutation rates and repeated transmission bottlenecks.
摘要：
尽管突变率相对较低,大量的严重急性呼吸道综合症冠状病毒2（SARS-CoV-2）感染允许实质性的遗传变化，导致了许多新兴的变体。使用最近确定的突变率（每个位点复制），以及有症状的SARS-CoV-2感染的宿主内参数估计，我们应用随机传输瓶颈模型来描述SARS-CoV-2突变的生存概率，作为瓶颈大小和选择系数的函数。对于狭窄的瓶颈，我们发现,影响每靶细胞附着率的突变(表型与融合性和ACE2结合相关)与影响病毒载量清除的突变(表型与体液逃避相关)具有相似的传播概率.我们进一步发现，相对于所有其他检查的性状，影响日食率的突变（与细胞代谢过程的重组和病毒出芽前体材料的合成相关的表型）受到高度青睐。我们发现，相对于导致体液逃避的突变，导致感染细胞的去除率降低的突变（具有与先天免疫逃避相关的表型）具有有限的传播优势。预测的传输概率，然而,对于影响先天免疫逃避的突变,与临床估计的从头突变的家庭传播概率范围更为一致.这一结果表明，尽管影响体液逃避的突变在发生时更容易传播，影响先天免疫逃避的突变可能更容易发生。我们在SARS-CoV-2循环菌株中许多先前表征的突变的背景下检查了我们的预测。我们的工作提供了SARS-CoV-2突变率的空模型，并预测了病毒生活史的哪些方面最有可能成功进化。尽管突变率低和反复的传播瓶颈。
