The drivers of MHC evolution during a viral pandemic

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Within animal populations including humans, there is considerable variation between individuals in their immune responses, and among the most important causes of this variation are the MHC molecules, which allow immune systems to detect and respond to infection. MHC molecules are extremely variable between individuals, and for any given infectious organism (pathogen), some MHC molecules are more efficient than others. However, this variation not only determines whether humans and other animals can defend themselves against infection, but also whether they develop autoimmune disorders such as arthritis and asthma. Despite decades of research, there is still much to understand about how and why these genes become so variable. Studying MHC variation in humans, biomedical model organisms such as mice, and in farm animal species such as chickens has provided much fundamental information, but many factors complicate such studies. For instance, among a number of limitations, the availability of modern medical interventions in humans is difficult to disentangle from the effects of natural selection. Because MHC variation is a consequence of animals adapting to the ever-changing array of pathogens that they encounter in nature, it is essential to study MHC evolution in natural populations.We recently found that the MHC of rabbits evolved rapidly after the pandemic of the viral disease myxomatosis that has devastated rabbit populations over the last 70 years, with the same changes occurring independently in Australia, France and the UK. We propose to use these natural experiments to understand both how the properties of MHC molecules change as an animal population evolves resistance to a new pathogen, and how the pathogen counters these defences to escape the immune response. This is a unique opportunity to understand MHC evolution as not only do we have access to the 1950s and modern forms of both the MHC molecules and the virus, but we have three independent replications of the experiment in Australia, France and the UK. First, we will sequence the MHC genes from archaeological remains, museum specimens and wild rabbits. This will reveal how MHC molecules evolved over the last 5000 years, and how they changed with the arrival of myxomatosis. Using these sequences, we will then investigate how the properties of the MHC molecules have changed. In particular we can test a new hypothesis we have proposed, that epidemics of a single pathogen select for MHC molecules that not only recognise that pathogen very well but are also highly abundant within cells. Finally, by comparing 1950s and modern viruses, we can test whether the virus has evolved to escape recognition by MHC molecules. While this latter process is known to occur in small viruses like HIV, this process is not understood for larger more complex viruses. Our study is unique in utilising cutting-edge technologies for studying the molecular functioning of immune systems and applying them to understand evolution in a natural ecological setting. By using the myxomatosis pandemic-a simple natural experiment replicated several times-we will gain fundamental insights into the reasons why animal immune systems are so variable, with potential application to human biomedicine, veterinary medicine and conservation.