Abstract Mutation rates and fitness costs of deleterious mutations are difficult to measure in vivo but essential for a quantitative understanding of evolution. Using whole genome deep sequencing data from longitudinal samples during untreated HIV-1 infection, we estimated mutation rates and fitness costs in HIV-1 from the dynamics of genetic variation. At approximately neutral sites, mutations accumulate with a rate of 1.2 × 10−5 per site per day, in agreement with the rate measured in cell cultures. We estimated the rate from G to A to be the largest, followed by the other transitions C to T, T to C, and A to G, while transversions are less frequent. At other sites, mutations tend to reduce virus replication. We estimated the fitness cost of mutations at every site in the HIV-1 genome using a model of mutation selection balance. About half of all non-synonymous mutations have large fitness costs (>10 percent), while most synonymous mutations have costs <1 percent. The cost of synonymous mutations is especially low in most of pol where we could not detect measurable costs for the majority of synonymous mutations. In contrast, we find high costs for synonymous mutations in important RNA structures and regulatory regions. The intra-patient fitness cost estimates are consistent across multiple patients, indicating that the deleterious part of the fitness landscape is universal and explains a large fraction of global HIV-1 group M diversity.

中文翻译：

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HIV-1 的体内突变率和适应成本情况


摘要 有害突变的突变率和适应成本很难在体内测量，但对于定量理解进化至关重要。利用未经治疗的 HIV-1 感染期间纵向样本的全基因组深度测序数据，我们根据遗传变异的动态估计了 HIV-1 的突变率和适应成本。在大约中性位点，突变以每个位点每天 1.2 × 10−5 的速率累积，与细胞培养物中测量的速率一致。我们估计从 G 到 A 的速率最大，其次是其他转换 C 到 T、T 到 C 和 A 到 G，而颠换频率较低。在其他位点，突变往往会减少病毒复制。我们使用突变选择平衡模型估计了 HIV-1 基因组中每个位点突变的适应成本。大约一半的非同义突变具有较大的适应成本 (>10%)，而大多数同义突变的成本为 <1%。同义突变的成本在大多数 pol 中特别低，我们无法检测到大多数同义突变的可测量成本。相比之下，我们发现重要 RNA 结构和调控区域的同义突变成本很高。多个患者的患者内部健康成本估计是一致的，这表明健康状况的有害部分是普遍存在的，并解释了全球 HIV-1 M 族多样性的很大一部分。