Award details

The drivers of MHC evolution during a viral pandemic

Reference	BB/V000667/1
Principal Investigator / Supervisor	Prof. Frank Jiggins
Co-Investigators / Co-Supervisors
Institution	University of Cambridge
Department	Genetics
Funding type	Research
Value (£)	453,221
Status	Current
Type	Research Grant
Start date	01/06/2021
End date	31/05/2024
Duration	36 months

Abstract

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.

Summary

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.

Impact Summary

Human and animal health. Polymorphisms in MHC genes have a considerable influence on human and animal health. They can have a major effect on susceptibility to autoimmune and infectious disease, alter the outcome of interventions such as vaccination, and play a key role in animal selective breeding programs aimed at increasing disease resistance. The rabbit-myxomatosis system is an excellent model to understand principles that govern the evolution of MHC in the field. Our work on chickens has shown that insights gained in model systems can be directly transferred to other species, including humans. For example, a realisation that MHC alleles that confer strong resistance to one pathogen may provide poor resistance against a different pathogen has clear relevance to breeding programs, as would knowing the speed that DNA viruses evolve immune escape. While this work is on a model system and therefore not intended to be immediately applicable, the insights gained will underpin more applied research. Myxomatosis is of particular concern at the moment as earlier this year it was reported to have evolved to be able to infect hares as well as rabbits in Spain. There is a high risk for hares in the UK. This poses a threat to hares in the UK, and as part of this project we will forge links between ourselves and other academics working on myxomatosis in rabbits and conservation bodies. Public understanding of science and outreach. Anyone who enjoys an occasional ramble through the British countryside has likely encountered a rabbit with myxomatosis, which makes this project an excellent way to engage with the public about complex science (our recent paper on myxomatosis received international press coverage). The Jiggins lab has recently organised an event at a local school, a stall at a science festival, and organised outreach events that provide lab experience to young people from backgrounds that are under-represented in science. During this project we will continuethis work, and we have proposed specific events linked to our research. Training of skilled people for non-academic professions. There is considerable demand in the pharmaceutical, biotech and technology industry for researchers to analyse large and complex genetic datasets, especially relating to health and disease. The Jiggins lab specialises in this area, and has a track record of training post-doctoral researchers with a background in biology in data-analysis skills that have allowed them to taking senior positions in pharmaceutical, biotech and tech industries in recent years (Magwire: Monsanto, Lewis: Astra Zeneca, McGonigle: Congenica, Juneja: Bayer, Quinn: Uber). The PDRA will have suitable training for a career in industry.

Committee	Research Committee A (Animal disease, health and welfare)
Research Topics	Animal Health, Immunology, Structural Biology
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

Associated awards:

BB/V000756/1 The drivers of MHC evolution during a viral pandemic

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