Examining the molecular clock hypothesis for the contemporary evolution of the rabies virus
Examining the molecular clock hypothesis for the contemporary evolution of the rabies virus
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DOI：
10.1101/2023.09.04.556169
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发表时间：
2023-09
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通讯作者：
Rowan Durrant;C. Cobbold;K. Brunker;Kathryn Campbell;J. Dushoff;E. A. Ferguson;Gurdeep Jaswant;A. Lugelo;K. Lushasi;Lwitiko Sikana;Katie Hampson
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作者：
Rowan Durrant;C. Cobbold;K. Brunker;Kathryn Campbell;J. Dushoff;E. A. Ferguson;Gurdeep Jaswant;A. Lugelo;K. Lushasi;Lwitiko Sikana;Katie Hampson
分子钟是一种测量病毒进化速率的方法，但关键的假设是，随着时间的推移，突变在基因组上以恒定的速率积累并不总是正确的。虽然建模方法存在，以适应严格的分子钟的偏差，关于速率变化的假设可能无法完全代表潜在的进化过程，并可能影响时钟校准和发散时间估计的准确性。狂犬病病毒（RABV）潜伏期有很大的变化，从几天到一年多不等，在此期间病毒复制可能会减少。这就提出了一个问题，即在每个感染世代的基础上建立RABV模型是否更合适。我们研究如何可变的潜伏期影响根到顶端的分歧下每单位时间和每代突变模型。此外，我们评估如何以及这些模型代表根到尖的分歧，在时间戳RABV序列。我们发现，在低突变率下（每代每个基因组<1个取代），这些模型之间的分歧模式很难区分，而高于此阈值，在一系列采样率下差异变得明显。使用坦桑尼亚的数据集，我们计算出平均替换率为每代每个基因组0.17个替换。在RABV的替代率，每代替代模型是不太可能代表狂犬病的演变实质上不同的分子时钟模型时，检查当代爆发;在足够的代任何分歧积累，极端的潜伏期平均。然而，测量每代的替代率在诸如推断传播树和预测谱系出现等应用中具有潜力。
The molecular clock is a method for measuring the rate of virus evolution but the key assumption that mutations accumulate on the genome at a constant rate over time does not always hold true. While modelling approaches exist to accommodate deviations from a strict molecular clock, assumptions about rate variation may not fully represent the underlying evolutionary processes and can affect the accuracy of clock calibration and divergence time estimates. There is considerable variability in rabies virus (RABV) incubation periods, ranging from days to over a year, during which viral replication may be reduced. This prompts the question of whether modelling RABV on a per infection generation basis might be more appropriate. We investigate how variable incubation periods affect root-to-tip divergence under per-unit time and per-generation models of mutation. Additionally, we assess how well these models represent root-to-tip divergence in time-stamped RABV sequences. We find that at low mutation rates (<1 substitution per genome per generation) divergence patterns between these models are difficult to distinguish, while above this threshold differences become apparent across a range of sampling rates. Using a Tanzanian dataset, we calculate the mean substitution rate to be 0.17 substitutions per genome per generation. At RABV’s substitution rate, the per-generation substitution model is unlikely to represent rabies evolution substantially differently than the molecular clock model when examining contemporary outbreaks; over enough generations for any divergence to accumulate, extreme incubation periods average out. However, measuring substitution rates per-generation holds potential in applications such as inferring transmission trees and predicting lineage emergence.