Mechanistic Constraints on the Acquisition of Variation by Alphaviruses

甲病毒获得变异的机制限制

• 批准号: 1646530
• 金额: --
• 依托单位: University of Surrey
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-1646530
• 关键词: Mechanistic; Constraints; Acquisition; Variation; Alphaviruses

This project asks: Does the genome structure of RNA viruses place mechanistic constraints on acquisition of variation by the virus; and can these be defined in a way that aids the design of data handling and analysis algorithms for metasequencing applications? It addresses the BBSRC Theme 'Exploiting New Ways of Working': Strategic Priority 'Data Driven Biology'; Investigating links between phenotypic traits and variation in biological systems or processes. RNA polymerases of RNA viruses are error prone, introducing mutations at much higher rates than the proof-reading DNA polymerases of their hosts. The natural replication of RNA virus genomes is a potent source of genetic variation upon which both natural and artificial selection may act. Several notable emerging diseases are caused by RNA viruses. Their emergence has been attributed partly to the ability to evolve rapidly, but there is little quantitative data on what may constrain this. The high virulence of some RNA viruses has also led to concerns regarding intentional misuse. Consequently a greater understanding of viral evolution is required to help predict and understand emergence events, as well as to detect and distinguish natural and synthetic organisms rapidly and reliably. Studies of RNA viruses have demonstrated that codon usage can vary along the length of a polycistronic RNA, and this correlates with sites of co-translational modification. This may be an adaptive mechanism to slow the rate of translation at points along the polycistron to facilitate co-translational modification, and may represent a constraint on variability. Furthermore, some studies have connected virus RNA secondary structure with immune response induction, which may result in selection on the basis of genome structure. Beyond this, it is not clear what constraints on the acquisition of variation in RNA viruses apply, except those associated with non-silent mutations. DNA sequencing now allows metasequencing of complex biological milieux comprising multiple taxa, and identification of distinct genomes through data handling algorithms. The data handling challenges of metasequencing could be streamlined by algorithms to rank potential genomes during assembly, giving priority to those with a greater likelihood of being real. They could also be streamlined by algorithms to rapidly identify synthetic genomes in predominantly natural milieux. The project will examine the ability of a synthetic Hazard Group 2 alphavirus genome to evolve towards an optimal sequence, potentially passing through an intermediate that is less optimal than the initial modified form. It will compare wildtype and computationally optimized sequences; and the stability and direction-of-mutation of hybrid sequences. The project will produce quantitative data on the mutability of RNA viruses and factors which militate against variation, providing data for the future optimization of algorithms for sifting metasequence data to rapidly and reliably identify synthetic organisms; and for rapid identification and classification of previously unknown organisms, and emergent or potential pathogens in complex biological mixtures. The results will have applications in evolutionary biology, environmentalmonitoring, epidemiology, forensic science, and medical and veterinary diagnostics. The project combines Pirbright's expertise with recombinant alphaviruses with University Of Surrey's interest in genetic and phenotypic variation in zoonotic RNA viruses, and Dstl's interest in the dynamics of alphavirus quasispecies. The project will expand TPI's portfolio on the cell and molecular biology of alphaviruses; it will inform UoS' analyses of zoonotic viruses; and expand Dstl's portfolio with CL2 surrogates for biothreat viruses that help to understand the population dynamics of RNA viruses generally. It will begin to assess potential limits on the nature of threat from both nature of threat from both natural & synthetic sources.

这个项目的问题是：RNA病毒的基因组结构是否对病毒获取变异施加了机械性限制；这些限制是否可以被定义为有助于为元测序应用程序设计数据处理和分析算法的方式？它涉及BBSRC的主题“探索新的工作方式”：战略优先事项“数据驱动的生物学”；调查表型特征与生物系统或过程中的变异之间的联系。RNA病毒的RNA聚合酶容易出错，导致突变的速度比它们宿主的校对DNA聚合酶高得多。RNA病毒基因组的自然复制是遗传变异的一个重要来源，自然选择和人工选择都可能对其产生影响。一些值得注意的新出现的疾病是由RNA病毒引起的。它们的出现部分归因于快速进化的能力，但几乎没有定量数据来说明是什么限制了这一点。一些RNA病毒的高毒力也引起了人们对故意滥用的担忧。因此，需要更多地了解病毒的进化，以帮助预测和了解出现的事件，以及快速和可靠地检测和区分自然和合成生物体。对RNA病毒的研究表明，密码子的使用可以随着多顺反子RNA的长度而变化，这与共翻译修饰的位置有关。这可能是一种适应性机制，以减缓沿着多顺反子的点的翻译速度，以促进共翻译修饰，并可能代表对可变性的限制。此外，一些研究将病毒RNA二级结构与免疫诱导联系起来，这可能导致在基因组结构的基础上进行选择。除此之外，除了与非沉默突变相关的限制外，目前还不清楚对获得RNA病毒变异的限制是什么。DNA测序现在允许对包含多个分类群的复杂生物环境进行元测序，并通过数据处理算法识别不同的基因组。元测序的数据处理挑战可以通过在组装过程中对潜在基因组进行排序的算法来简化，优先考虑那些真实可能性更大的基因组。它们还可以通过算法来简化，以便在以自然环境为主的环境中快速识别合成基因组。该项目将检查合成危险第2组甲型病毒基因组朝着最佳序列进化的能力，潜在地通过比最初修改形式不那么理想的中间体。它将比较野生型和计算优化的序列，以及杂交序列的稳定性和突变方向。该项目将产生关于RNA病毒的变异性和抑制变异的因素的量化数据，为今后优化算法提供数据，以筛选元序列数据，以快速和可靠地识别合成生物体；快速识别和分类以前未知的生物体，以及复杂生物混合物中新出现的或潜在的病原体。这些结果将在进化生物学、环境监测、流行病学、法医学以及医学和兽医诊断学中得到应用。该项目将皮尔布赖特在重组甲型病毒方面的专业知识与萨里大学对人畜共患病RNA病毒的遗传和表型变异的兴趣以及DSTL对甲型病毒准种动态的兴趣结合在一起。该项目将扩大TPI在甲型病毒的细胞和分子生物学方面的产品组合；它将为UOS对人畜共患病毒的分析提供信息；并扩大DSTL的产品组合，使用CL2替代生物硫酸盐病毒，帮助了解RNA病毒的总体种群动态。它将开始评估来自自然和合成来源的威胁的性质的潜在限制。