The drivers of MHC evolution during a viral pandemic

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Classical MHC genes are the most polymorphic region of most vertebrate genomes, and this variation affects susceptibility to infectious and autoimmune disease. It is generally accepted that selection by pathogens is maintaining this variation, based on very detailed experiments in the laboratory on the one hand, and on epidemiology in humans and anecdotal observations on wild and farm animals on the other hand. However, the molecular details of how and why selection alters MHC allele frequencies in natural populations are largely unexplored. We propose to do this by combining modern developments in both molecular immunology and ancient DNA sequencing with a unique natural experiment-rabbits and myxomatosis.

We recently reported that myxomatosis caused large shifts in MHC allele frequencies in French, UK and Australian rabbit populations. As we have access to both MHC molecules and viruses from before and after the myxomatosis pandemic, we are uniquely placed to understand their evolution. We will sequence rabbit MHC genes from the Neolithic to present day and identify alleles favoured following the release of myxomatosis. By cloning these alleles, we can reconstruct how natural selection has altered MHC expression and the repertoire of viral peptides that MHC molecules present. This will allow us to examine whether the selected MHC alleles simply bind the largest number of peptides or all bind a few particular (kinds of) peptides (the generalist versus specialist hypothesis), or whether the selected MHC alleles all bind the same (kinds of) peptides or have divergent peptide-binding properties (the supertype versus divergent allele hypotheses). Finally, we will compare viruses from the 1950s and modern populations, and examine whether they have evolved to escape host immunity by altering the peptides bound by MHC. While this is known to occur in small RNA viruses, it is unclear whether escape mutations are important in pathogens with larger genomes.

Pathways to Impact (for the grant but with parts focused on the Kaufman lab)

The Conservation and Control of Rabbits and Hares

Myxomatosis is of considerable economic and conservation importance in many regions of the world, and its impact is shaped by the evolution of resistance in the host populations. In Spain the disease was reported this year to have jumped into hares where it is causing widespread mortality. There has been concern that UK hares may succumb soon. Rabbit populations are still controlled by the disease. In the introduced range, notably Australia, this is viewed as a considerable economic and ecological benefit. However, in the native range of rabbits it is a conservation problem, especially to rabbit predators like lynx. Evolution in the rabbit and virus populations has led to large increases in rabbit population sizes since the virus was first released, so our fundamental research into viral resistance can inform these sectors.

We propose in engage with stakeholders in these areas. In this regard, the main activity to which the Kaufman group will contribute is a two day workshop at the start of Year 2 in Cambridge organised by the Jiggins group, to which representatives from these groups and other interested bodies will be invited. This will focus on the lessons that can be learnt from myxomatosis that can be applied to hares. For example, the genetics of immunity has turned out to be essential for evolving resistance to this virus, and therefore maintaining genetic diversity is important. The ability to understand and improve protective vaccine responses is another such message. This workshop will allow the lessons of our research to be disseminated to these groups.

Public Engagement

No other wildlife disease is as familiar to the public as myxomatosis- rabbits are abundant, the symptoms conspicuous, and rabbits die above ground and do not flee from encounters with humans. This public profile was reflected in the international media attention during 2019 following the publication of our paper on myxomatosis resistance. This makes our proposed work an excellent opportunity to engage the public. We therefore propose activities that aim to use our research to increase public understanding of wildlife disease, evolutionary genetics and immunity.

1) Edinburgh Science Festival: Like Cambridge, Edinburgh hosts a Science Festival, reputed to be one of Europe's largest (www.edinburghfestivalcity.com/festivals/edinburgh-science-festival), scheduled for April each year. Although the Kaufman lab is moving to Edinburgh only at the start of 2020 and therefore we have everything to learn about how it works, we intend to participate fully as we have every year in Cambridge.

2) Media: The Kaufman group has some experience with media and other forms of outreach. In particular, our 2013 PNAS paper describing the biological mechanisms by which a contagious cancer of Tasmanian devils evades the immune response led to over 30 interviews with print, radio and TV media, with an appearance of the PDRA at that time on BBC World News, and with several camera crews in the lab. It is well possible that a relatively simple and digestible message may emerge from the collaboration of the Jiggens and the Kaufman labs, particularly by abstraction of the lessons of myxomatosis to human infectious diseases like HIV/AIDS and to human cancer. Like Cambridge, the University of Edinburgh has a communications and outreach office which we will be in contact with to consider ways forward.