GCRF-BBR: Beyond the genome: Enabling tropical livestock EWAS of infectious diseases Cattle are a vital component of the economies of low and middle income countries across the globe. They are a source of meat and dairy products, provide leather and other by-products and are often used as working animals. Cattle can be grazed where crops are not easily grown, provide manure as effective fertiliser and can convert forage into high-protein food. Often cattle are the most valuable possession individuals in low and middle income countries own, but are susceptible to a range of infectious diseases, which not only inflict a heavy economic burden on these countries but can also often be transmissible to humans.  Over two-thirds of the global cattle population are in low and middle income countries. Reducing the burden of cattle infectious diseases would consequently have major benefits to these areas. However for many diseases no vaccine or treatment is available. Where they are available, poor veterinary services generally mean the livestock keepers must pay for vaccines and treatments themselves. Consequently these diseases are major barriers to escaping poverty.   Due to the co-evolution of pathogens and cattle there are various examples of cattle breeds that show natural tolerance or resistance to important infectious diseases. Although these breeds are often less productive, making them less attractive to LMIC farmers, if the mechanisms underlying their resistance could be identified and harnessed, then breeds of both higher productivity and tolerance could potentially be developed.  The aim of this project is to develop the framework to enable the identification of genomic regions linked to tolerance/resistance via epigenome-wide association studies (EWAS). Differences in the epigenome, chemical modifications that overlay the genome, are linked to phenotypes through their association with gene regulation. By comparing the epigenomes of tolerant and susceptible animals it is possible to determine regions linked to disease resistance. However, at present we lack even baseline information on the epigenomes of LMIC cattle breeds, and the tools and resources for undertaking blood-based EWAS. In particular, as blood samples are a composite of various cell types, each with a distinct epigenome profile, it is necessary to disentangle any epigenetic alterations linked to disease tolerance from differences resulting purely from variation in cell-type composition between samples. We will address this by generating an epigenome atlas of major immune cell types across the two major sub-species of cattle prevalent in LMICs. Using this resource we will create a web portal to enable users to estimate the cell-type composition in their samples, allowing downstream EWAS not confounded by between sample composition variations, providing a greater ability to identify true epigenome differences linked to infectious diseases. The Global Challenges Research Fund (GCRF) supports cutting-edge research to address challenges faced by developing countries. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world. The fund addresses the UN sustainable development goals. It aims to maximise the impact of research and innovation to improve lives and opportunity in the developing world.