The within‐host evolutionary dynamics of tuberculosis (TB) remain unclear, and underlying biological characteristics render standard population genetic approaches based upon the Wright‐Fisher model largely inappropriate. In addition, the compact genome combined with an absence of recombination is expected to result in strong purifying selection effects. Thus, it is imperative to establish a biologically relevant evolutionary framework incorporating these factors in order to enable an accurate study of this important human pathogen. Further, such a model is critical for inferring fundamental evolutionary parameters related to patient treatment, including mutation rates and the severity of infection bottlenecks. We here implement such a model and infer the underlying evolutionary parameters governing within‐patient evolutionary dynamics. Results demonstrate that the progeny skew associated with the clonal nature of TB severely reduces genetic diversity and that the neglect of this parameter in previous studies has led to significant mis‐inference of mutation rates. As such, our results suggest an underlying de novo mutation rate that is considerably faster than previously inferred, and a progeny distribution differing significantly from Wright‐Fisher assumptions. This inference represents a more appropriate evolutionary null model, against which the periodic effects of positive selection, associated with drug‐resistance for example, may be better assessed.

中文翻译：

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评估纯化选择和后代偏斜在决定宿主内结核分枝杆菌进化中的贡献

结核病 (TB) 的宿主内进化动力学仍不清楚，潜在的生物学特征使得基于 Wright-Fisher 模型的标准种群遗传方法在很大程度上不合适。此外，紧凑的基因组与不存在重组相结合，预计会产生强大的纯化选择效应。因此，必须建立一个结合这些因素的生物学相关进化框架，以便能够准确研究这种重要的人类病原体。此外，这样的模型对于推断与患者治疗相关的基本进化参数至关重要，包括突变率和感染瓶颈的严重程度。我们在这里实现了这样一个模型，并推断出控制患者内部进化动力学的潜在进化参数。结果表明，与 TB 的克隆性质相关的后代偏斜严重降低了遗传多样性，并且在先前的研究中忽略了该参数导致了对突变率的严重错误推断。因此，我们的结果表明潜在的从头突变率比先前推断的要快得多，并且后代分布与 Wright-Fisher 假设显着不同。这一推论代表了一个更合适的进化无效模型，可以更好地评估与耐药性相关的正选择的周期性影响。我们的结果表明潜在的从头突变率比以前推断的要快得多，并且后代分布与 Wright-Fisher 假设显着不同。这一推论代表了一个更合适的进化无效模型，可以更好地评估与耐药性相关的正选择的周期性影响。我们的结果表明潜在的从头突变率比以前推断的要快得多，并且后代分布与 Wright-Fisher 假设显着不同。这一推论代表了一个更合适的进化无效模型，可以更好地评估与耐药性相关的正选择的周期性影响。