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所有其他人类病原体都要快。然而，RNA病毒并不都以同样快的速度进化。区分进化较快的RNA病毒很重要，因为它们更有可能产生抗药性变异或逃避疫苗诱导的免疫反应。众所周知，整个RNA病毒家族比其他病毒更具进化能力，但我们对单个病毒比同一家族中关系密切的病毒进化得更快的原因知之甚少。我们将测试组织趋向性是否可能是影响进化速度的因素之一。具体地说，我们正在测试肠道病毒内的基因是否比感染同一宿主中其他组织的相关病毒进化得更快。长期的核苷酸替代率将从GenBank中拥有大量序列的三个重要RNA病毒家族的成员计算得出：Caliciviridae，包括美国食源性疾病的主要原因；PicorNaviridae，包括脊髓灰质炎病毒；以及Reoviridae，包括轮状病毒，全球最常见的婴儿腹泻原因。我们将比较主要是肠道病毒和主要是非肠道病毒中相同基因的进化速度，这将使我们能够在病毒之间进行对等比较。我们使用的Beast软件采用了贝叶斯系统发育合并的方法来计算进化率。这些估计的准确性在不同的时间尺度上发生变化，我们的一些分析合并的时间在一个数量级上也不同(即，一些数据在70年内合并，另一些数据在700年内合并)。由于许多肠道病毒数据集的合并速度比非肠道病毒数据集更快，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差。我们的工作有可能开辟研究途径，研究肠道组织趋向性是否机械地导致RNA病毒进化的更快速度，并突出广泛使用的软件程序中的弱点。 公共卫生相关性： 进化较快的RNA病毒比进化较慢的RNA病毒更难控制和治疗，但我们还没有确定导致病毒进化更快的许多特征。这项研究测试了肠道病毒，即那些感染哺乳动物胃肠道的病毒，如脊髓灰质炎病毒、诺沃克病毒和轮状病毒，是否比感染其他哺乳动物组织的同类病毒进化得更快。如果感染肠道组织导致病毒进化速度更快，病毒学家将知道在开发肠道病毒疫苗和持久抗病毒药物时要更加小心。

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. PUBLIC HEALTH RELEVANCE: Faster evolving RNA viruses are more difficult to control and treat than slower evolving RNA viruses, but we have not identified many traits that cause viruses to evolve more quickly. This research tests whether enteric viruses, those that infect the mammalian gastrointestinal tract such as poliovirus, norovirus and rotavirus, evolve more quickly than their relatives that infect other mammalian tissues. If infecting enteric tissue leads to faster rates of viral evolution, virologists will know to take more care can when developing vaccines and durable antivirals for enteric viruses.