Depletion of CpG Dinucleotides in Papillomaviruses and Polyomaviruses: A Role for Divergent Evolutionary Pressures

BackgroundPapillomaviruses and polyomaviruses are small ds-DNA viruses infecting a wide-range of vertebrate hosts. Evidence supporting co-evolution of the virus with the host does not fully explain the evolutionary path of papillomaviruses and polyomaviruses. Studies analyzing CpG dinucleotide frequencies in virus genomes have provided interesting insights on virus evolution. CpG dinucleotide depletion has not been extensively studied among papillomaviruses and polyomaviruses. We sought to analyze the relative abundance of dinucleotides and the relative roles of evolutionary pressures in papillomaviruses and polyomaviruses.MethodsWe studied 127 full-length sequences from papillomaviruses and 56 full-length sequences from polyomaviruses. We analyzed the relative abundance of dinucleotides, effective codon number (ENC), differences in synonymous codon usage. We examined the association, if any, between the extent of CpG dinucleotide depletion and the evolutionary lineage of the infected host. We also investigated the contribution of mutational pressure and translational selection to the evolution of papillomaviruses and polyomaviruses.ResultsAll papillomaviruses and polyomaviruses are CpG depleted. Interestingly, the evolutionary lineage of the infected host determines the extent of CpG depletion among papillomaviruses and polyomaviruses. CpG dinucleotide depletion was more pronounced among papillomaviruses and polyomaviruses infecting human and other mammals as compared to those infecting birds. Our findings demonstrate that CpG depletion among papillomaviruses is linked to mutational pressure; while CpG depletion among polyomaviruses is linked to translational selection. We also present evidence that suggests methylation of CpG dinucleotides may explain, at least in part, the depletion of CpG dinucleotides among papillomaviruses but not polyomaviruses.ConclusionsThe extent of CpG depletion among papillomaviruses and polyomaviruses is linked to the evolutionary lineage of the infected host. Our results highlight the existence of divergent evolutionary pressures leading to CpG dinucleotide depletion among small ds-DNA viruses infecting vertebrate hosts.

研究背景 乳头瘤病毒（Papillomaviruses）与多瘤病毒（Polyomaviruses）均为小型双链DNA（ds-DNA）病毒，可感染广泛的脊椎动物宿主。现有支持病毒与宿主共进化的证据，尚无法完全阐明两类病毒的进化路径。针对病毒基因组中CpG二核苷酸（CpG dinucleotide）频率的相关研究，已为病毒进化提供了颇具价值的见解。但目前针对乳头瘤病毒与多瘤病毒的CpG二核苷酸缺失现象，尚未开展广泛深入的研究。本研究旨在分析两类病毒的二核苷酸相对丰度，以及进化压力在其进化过程中的相对作用。

研究方法 本研究共纳入127条乳头瘤病毒全长序列与56条多瘤病毒全长序列。通过分析二核苷酸相对丰度、有效密码子数（effective codon number, ENC）以及同义密码子使用偏好性差异，探究CpG二核苷酸缺失程度与感染宿主进化谱系之间的关联。同时，本研究还调查了突变压力与翻译选择在两类病毒进化中的贡献。

研究结果 所有乳头瘤病毒与多瘤病毒均存在CpG二核苷酸缺失现象。值得注意的是，感染宿主的进化谱系决定了两类病毒的CpG缺失程度：相较于感染鸟类的毒株，感染人类及其他哺乳类动物的乳头瘤病毒与多瘤病毒，其CpG二核苷酸缺失更为显著。本研究结果表明，乳头瘤病毒的CpG缺失与突变压力相关，而多瘤病毒的CpG缺失则与翻译选择相关。此外，本研究提供的证据显示，CpG二核苷酸的甲基化作用至少可以部分解释乳头瘤病毒的CpG缺失现象，但无法解释多瘤病毒的该现象。

研究结论 乳头瘤病毒与多瘤病毒的CpG缺失程度与感染宿主的进化谱系密切相关。本研究结果揭示，在感染脊椎动物宿主的小型双链DNA病毒中，驱动CpG二核苷酸缺失的进化压力存在分化。