Mathematical Virology: A New Mathematical Approach to Viral Evolution Grounded in Experiment
Mathematical modelling of natural phenomena has the potential to be predictive but requires direct verification by experiment. Such models can then be very powerful indicators of our understanding and they permit in silico simulations of situations that are difficult to test experimentally. One area in need of such models is molecular evolution where a great deal of theory has been done, e.g. the development of Network Models to explain neo-Darwinian evolution, but these are limited and not very useful because they are not based on realistic information about fitness landscapes. In collaboration with the Twarock Group in York, we have been studying the fundamental assembly behaviour of simple, positive sense, single-stranded (ss) RNA viruses which include major pathogens of humans, animals and plants. We have discovered an apparently evolutionarily conserved aspect to this process that involves multiple, sequence-specific genomic RNA-coat protein (CP) interactions at dispersed sequence-degenerate sites we have termed packaging signals (PSs). PS-CP interactions result in favourable effects on the kinetics, yield and fidelity of capsid assembly. They act co-operatively throughout genomes explaining why simple deletion experiments in the past have failed to identify them. We have developed a model that demonstrates the selective advantages to viruses that operate via this mechanism. Experimentally we have exemplified the molecular details of PS-mediated assembly in both bacterial and plant model virus systems. We have also identified a series of putative PSs in a number of human viruses, including Parecho Virus 1, polio and HCV. Preliminary evidence suggests that the sites identified do act as PSs. Targeting PS-CP interactions with small molecular weight ligands provides a novel anti-viral strategy that we are exemplifying in our model systems.
The student will look at the phenomenon of transcapsidation by which the genomes of picornaviruses can steadily be encouraged to assemble within heterologous protein shells.
This project is eligible for funding from EPSRC. We welcome applicants with, or expecting, 2.1 or above in a relevant field. To be eligible for the studentship candidates must be either UK residents, or EU citizens who have lived in the UK for 3 or more years. The studentship will provide fees and stipend (£13,726) for the successful candidate.
Please note that the studentship will start in April 2014.
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FTE Category A staff submitted: 60.90
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