Effect of tissue tropism on RNA viral evolutionary rates: three family-level anal

描述（由申请人提供）： RNA病毒的变异和进化速度比其他所有人类病原体都要快。然而，RNA病毒并不都以同样快的速度进化。区分进化更快的RNA病毒很重要，因为它们更有可能产生耐药性变体或逃避疫苗诱导的免疫反应。已知RNA病毒的整个家族比其他家族更容易进化，但我们对是什么导致单个病毒比同一家族中密切相关的病毒进化得更快知之甚少。我们将测试组织向性是否是影响进化速度的因素之一。具体来说，我们正在测试肠道病毒（感染胃肠道的病毒）内的基因是否比感染同一宿主其他组织的相关病毒进化得更快。长期的核苷酸替换率将从三个重要的RNA病毒家族的成员中计算，这些家族在GenBank中有大量的序列：杯状病毒科，包括这个国家食源性疾病的主要原因，小核糖核酸病毒科，包括脊髓灰质炎病毒，呼肠孤病毒科，包括轮状病毒，全球婴儿腹泻的最常见原因。我们将对比相同基因在主要肠道病毒和主要非肠道病毒中的进化速率，这将使我们能够在病毒之间进行苹果对苹果的比较。我们使用的BEAST软件采用贝叶斯系统发育结合方法来计算进化速率。这种估计的准确性在不同的时间尺度上变化，并且我们的一些分析的合并时间在一个数量级上变化（即，有些数据在70年内合并，有些在700年内合并）。由于许多肠道病毒数据集比非肠道病毒数据集合并得更快，因此将进行额外的控制，以确保我们的结果不会因合并时间而产生偏倚。我们的工作有可能开辟研究肠道组织嗜性是否会导致RNA病毒进化速度更快的途径，并突出广泛使用的软件程序的弱点。

DESCRIPTION (provided by applicant): RNA viruses mutate and evolve more quickly than all other human pathogens. However, RNA viruses do not all evolve at the same fast rate. It is important to distinguish the faster evolving RNA viruses because they are more likely to create drug-resistant variants or evade vaccine-induced immune responses. Whole families of RNA viruses are known to be more evolvable than others, but we know very little about what causes individual viruses to evolve more rapidly than closely related viruses in the same family. We will test whether tissue tropism could be one of the factors affecting evolutionary rates. Specifically, we are testing if genes within enteric viruses, those that infect the gastro-intestinal tract, evolve more quickly than related viruses that infect other tissues in the same hosts. Long-term nucleotide substitution rates will be calculated from members of three important RNA virus families that have large numbers of sequences in GenBank: Caliciviridae, which include the leading cause of foodborne illness in this country, Picornaviridae, which include poliovirus, and Reoviridae, which include rotavirus, the most common cause of infant diarrhea worldwide. We will contrast the rates of evolution of the same gene in primarily enteric and primarily non-enteric viruses, which will allow us an apples-to-apples comparison between viruses. The BEAST software we use takes a Bayesian phylogenetic coalescent approach to calculating evolutionary rates. The accuracy of such estimates changes over different timescales, and the time to the coalescent of some of our analyses varies over an order of magnitude (i.e., some data coalesce in 70 years, others in 700 years). Since many of the enteric virus data sets coalesce more quickly than the non-enteric virus data sets, additional controls will be conducted to ensure our results are not biased by coalescent time. Our work has the potential to open up avenues of research into whether enteric tissue tropism mechanistically leads to faster rates of RNA viral evolution, and to highlight weaknesses in a widely used software program.