Cell tropism predicts long-term nucleotide substitution rates of mammalian RNA viruses.
Cell tropism predicts long-term nucleotide substitution rates of mammalian RNA viruses.
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DOI：
10.1371/journal.ppat.1003838
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发表时间：
2014-01
期刊：
影响因子：
6.7
通讯作者：
Duffy S
中科院分区：
文献类型：
--
作者：
Hicks AL;Duffy S
RNA病毒进化的高速率通常归因于容易出错的RNA依赖的RNA聚合酶的复制。然而，这些长期核苷酸替代率跨越三个数量级，与突变率或选择压力没有很好的相关性。这种替换率的差异可能是由于病毒生态或固有基因组特性的差异造成的。我们生成了哺乳动物RNA病毒的核苷酸替换率估计，并汇编了可比的公布速率，产生了来自51个不同物种的118个结构基因的替换率，以及来自28个物种的40个非结构基因的替换率的数据集。通过ANCOVA分析，我们评估了这些比率与四个生态因素的关系：靶细胞、传播途径、宿主范围、感染持续时间；以及三个基因组属性：基因组长度、基因组意义、基因组分割。在这七个因素中，我们发现靶细胞是病毒替代率的唯一显著预测因素，上皮细胞或神经元的趋向性(P<；0.0001)是最显著的预测因素。此外，单尾t检验表明，主要感染上皮细胞的病毒比嗜神经性病毒进化得更快(结构基因和非结构基因分别为P<；0.0001和P<；0.001)。这些结果提供了强有力的证据，证明进化最快的哺乳动物RNA病毒以最高的周转率感染细胞：高度增殖的上皮细胞。估计的病毒生成时间表明，感染上皮性的病毒比具有不同细胞取向的病毒复制更快。我们的结果表明，细胞嗜性是病毒进化的关键因素。RNA病毒是进化最快的人类病原体，这使得它们的治疗和控制变得困难。与DNA病毒相比，RNA病毒的复制保真度要低得多，这可以解释为什么RNA病毒的进化速度明显快于大多数DNA病毒。然而，不同RNA病毒的进化速率存在巨大差异，这不能用突变率的差异来解释。在这里，我们介绍了哺乳动物RNA病毒进化速率的调查，并对这些速率与病毒基因组结构和生态的不同特性进行了全面的比较。我们发现，细胞嗜性是哺乳动物RNA病毒进化的长期速率的最重要预测因素。例如，以上皮细胞为目标的病毒比以神经元为目标的病毒进化得要快得多。我们的结果为为什么感染呼吸道和胃肠道上皮的病毒很难控制提供了机械性的洞察。
The high rates of RNA virus evolution are generally attributed to replication with error-prone RNA-dependent RNA polymerases. However, these long-term nucleotide substitution rates span three orders of magnitude and do not correlate well with mutation rates or selection pressures. This substitution rate variation may be explained by differences in virus ecology or intrinsic genomic properties. We generated nucleotide substitution rate estimates for mammalian RNA viruses and compiled comparable published rates, yielding a dataset of 118 substitution rates of structural genes from 51 different species, as well as 40 rates of non-structural genes from 28 species. Through ANCOVA analyses, we evaluated the relationships between these rates and four ecological factors: target cell, transmission route, host range, infection duration; and three genomic properties: genome length, genome sense, genome segmentation. Of these seven factors, we found target cells to be the only significant predictors of viral substitution rates, with tropisms for epithelial cells or neurons (P<0.0001) as the most significant predictors. Further, one-tailed t-tests showed that viruses primarily infecting epithelial cells evolve significantly faster than neurotropic viruses (P<0.0001 and P<0.001 for the structural genes and non-structural genes, respectively). These results provide strong evidence that the fastest evolving mammalian RNA viruses infect cells with the highest turnover rates: the highly proliferative epithelial cells. Estimated viral generation times suggest that epithelial-infecting viruses replicate more quickly than viruses with different cell tropisms. Our results indicate that cell tropism is a key factor in viral evolvability. RNA viruses are the fastest evolving human pathogens, making their treatment and control difficult. Compared to DNA viruses, RNA viruses replicate with much lower fidelity, which can explain why RNA viruses evolve significantly faster than most DNA viruses. However, there is tremendous variation among the evolutionary rates of different RNA viruses, which is not explained by variation in mutation rates. Here we present a survey of mammalian RNA virus rates of evolution, and a comprehensive comparison of these rates to different properties of virus genomic architecture and ecology. We found that cell tropism is the most significant predictor of long-term rates of mammalian RNA virus evolution. For instance, viruses targeting epithelial cells evolve significantly faster than viruses that target neurons. Our results provide mechanistic insight into why viruses that infect respiratory and gastrointestinal epithelia have been difficult to control.
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