Background: With more than 300 million potentially infected people every year, and with the expanded habitat of mosquitoes due to climate change, dengue cannot be considered anymore only a tropical disease. The RNA secondary structure is a functional characteristic of RNA viruses, and together with the accumulated high-throughput sequencing data could provide general insights towards understanding virus biology. Here, we profiled the RNA secondary structure of >7500 complete viral genomes from 11 different species of viral hemorrhagic fevers, including dengue serotypes, ebola, and yellow fever. Results: We achieved high prediction scores (AUC up to 0.85 with experimental data), and computed consensus secondary structure profiles using hundreds of structural in silico models. We observed that virulent viruses such as DENV-2 and ebola tend to be less structured than the other viruses. Furthermore, we observed virus-specific correlations between secondary structure and the number of interaction sites with human proteins, reaching a correlation of 0.89 in the case of zika. We demonstrate that the secondary structure and presence of protein-binding domains in the genomes can be used as intrinsic signature to further classify the viruses. We also used structural data to study the geographical distribution of dengue, finding a significant difference between DENV-3 from Asia and South-America, which could imply different evolutionary routes of this subtype. Conclusions: Our massive computational analysis provided novel results regarding the secondary structure and the interaction with human proteins, not only for Dengue serotypes, but also for other viral hemorrhagic fevers. We also provided a new approach to classify viruses according ot their structure, which could be useful for future cassifications. We envision that these approaches can be used by the scientific community to further classify and characterise these complex viruses.

中文翻译：

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登革热血清型和其他病毒性出血热完整基因组的计算机推断结构图

背景：由于每年有3亿多潜在感染者，而且由于气候变化，蚊子的栖息地不断扩大，因此，登革热不再仅被视为一种热带疾病。RNA二级结构是RNA病毒的功能特征，并且与积累的高通量测序数据一起可以为理解病毒生物学提供一般见识。在这里，我们从11种不同的病毒性出血热物种（包括登革热血清型，埃博拉病毒和黄热病）中分析了> 7500个完整病毒基因组的RNA二级结构。结果：我们获得了较高的预测分数（根据实验数据，AUC高达0.85），并使用数百种结构化计算机模型计算了共有的二级结构轮廓。我们观察到，像DENV-2和ebola这样的强毒病毒往往比其他病毒的结构更少。此外，我们观察到二级结构和与人类蛋白质的相互作用位点之间的病毒特异性相关性，在寨卡病毒中，相关性达到0.89。我们证明了二级结构和基因组中蛋白质结合结构域的存在可以用作内在签名，以进一步对病毒进行分类。我们还使用结构数据来研究登革热的地理分布，发现亚洲和南美的DENV-3之间存在显着差异，这可能意味着该亚型的进化途径不同。结论：我们的大量计算分析提供了有关二级结构以及与人类蛋白质相互作用的新颖结果，不仅适用于登革热血清型，还适用于其他病毒性出血热。我们还提供了一种根据病毒的结构对病毒进行分类的新方法，这可能对将来的分类很有用。我们设想，科学界可以使用这些方法对这些复杂的病毒进行进一步的分类和表征。