Genomic analysis of the canonical case of virulence evolution: Myxomatosis in Au

描述(申请人提供)：当病毒从其自然宿主跳入人类群体时，在任何后续疫情的早期，最紧迫的问题之一是，如果不能立即控制和根除病毒，病毒将如何演变。特别是，如果导致全球大流行，或者这种疾病成为人类的地方病，它的危害性会变得更大还是更小？疾病生态和进化的数学模型表明，当病毒适合性的某些关键表型决定因素已知时，就有可能预测随后毒力进化的方向。问题是，这些表型细节很难阐明。相比之下，分子生物学的进步意味着，当跨物种跳跃确实发生时，会产生大量的基因组数据，从而允许对疾病进化的遗传跟踪。这些基因组数据能让我们预测未来的风险吗？在这项提议中，我们试图确定这种高致命性粘液瘤病毒进化的分子遗传学基础，因为它在20世纪50年代被故意释放，作为一种生防剂在澳大利亚和欧洲两国都被用作兔子的生防剂。这些释放是病毒进化中的无意实验，即使在今天，黏液瘤病毒可能是任何脊椎动物疾病中毒力进化的最典型的病例。重要的是，病毒适合性的关键表型决定因素被很好地表征，因此自然选择导致粘液瘤毒力变化的原因是非常众所周知的。但毒力进化的遗传基础并非如此。我们将使用来自两个大陆的病毒分离株的基因组分析，包括那些在20世纪50年代采样的病毒分离株，以确定导致毒力进化的候选基因变化，然后利用这些突变设计病毒。然后，工程菌株将被用来确定突变在毒力进化中的因果作用。这项工作将产生一个案例研究，在这个研究中，我们可以在传播生态足够已知以预测进化的背景下，将基因型与表型联系起来。因此，我们将能够评估基因组分析预测未来风险的能力。

DESCRIPTION (provided by applicant): When viruses jump from their natural host into human populations, one of the most pressing questions early in any subsequent epidemic is how the virus will evolve if it cannot be immediately contained and eradicated. In particular, if global pandemics result, or the disease becomes endemic in humans, will it become more or less harmful? Mathematical models of disease ecology and evolution show that when certain key phenotypic determinants of viral fitness are known, it is possible to predict the subsequent direction of virulence evolution. The problem is that these phenotypic details are hard to elucidate. In contrast, advances in molecular biology mean that when cross-species jumps do occur, a deluge of genomic data is generated, allowing genetic tracking of disease evolution. Do these genomic data allow us to predict much about future risk? In this proposal we seek to determine the molecular genetic basis of the evolution of the highly lethal myxoma virus after it was deliberately released as a biocontrol agent against rabbits in both Australia and Europe in the 1950s. These releases were inadvertent experiments in virus evolution, and even today myxoma virus is perhaps the best characterized case of virulence evolution in any vertebrate disease. Critically, the key phenotypic determinants of viral fitness are well characterized, so that the reason natural selection caused changes in myxoma virulence are extremely well known. But the genetic basis of the virulence evolution is not. We will use genomic analysis of viral isolates from both continents, including those sampled in the 1950s, to identify candidate genetic changes responsible for virulence evolution, and then engineer viruses with those mutations. The engineered lines will then be used to determine the causal role of the mutations in the virulence evolution. This work will generate a case study where we can link genotype to phenotype in a context where the transmission ecology is well enough known to predict evolution. Thus, we will be able to assess the power of genomic analysis for predicting future risk.