GCRF-BBR: Beyond the genome: Enabling tropical livestock EWAS of infectious diseases

牛是全球低收入和中等收入国家经济的重要组成部分。它们是肉类和乳制品的来源，提供皮革和其他副产品，经常被用作工作动物。牛可以在作物不容易种植的地方放牧，提供粪便作为有效的肥料，并可以将饲料转化为高蛋白食物。牛往往是低收入和中等收入国家个人拥有的最有价值的财产，但容易感染一系列传染病，这些疾病不仅给这些国家带来沉重的经济负担，而且往往还可能传染给人类。全球牛种群的三分之二以上在低收入和中等收入国家。因此，减轻牛传染性疾病的负担将给这些地区带来重大好处。然而，对于许多疾病，没有疫苗或治疗方法。在可获得的地方，糟糕的兽医服务通常意味着牲畜饲养者必须自己支付疫苗和治疗费用。因此，这些疾病是摆脱贫困的主要障碍。由于病原体和牛的共同进化，出现了对重要传染病表现出自然耐受性或抵抗力的各种牛品种。虽然这些品种往往生产力较低，对LMIC农民的吸引力也较小，但如果能够识别和利用它们的抗性机制，那么就有可能开发出生产力和耐受性都更高的品种。本项目的目的是开发框架，通过表观基因组范围关联研究(Ewas)来识别与耐性/抗性相关的基因组区域。表观基因组的差异是覆盖在基因组上的化学修饰，通过它们与基因调控的关联，与表型有关。通过比较耐受和敏感动物的表观基因组，有可能确定与抗病相关的区域。然而，目前我们甚至缺乏关于LMIC牛品种表观基因组的基线信息，以及开展基于血液的Ewas的工具和资源。特别是，由于血液样本是各种细胞类型的复合体，每种细胞都有不同的表观基因组图谱，因此有必要将与疾病耐受性有关的任何表观遗传学变化与纯粹由于样本之间细胞类型组成的差异而导致的差异区分开来。我们将通过生成LMICs中流行的两个主要牛亚种的主要免疫细胞类型的表观基因组图谱来解决这个问题。利用这一资源，我们将创建一个门户网站，使用户能够估计其样本中的细胞类型组成，从而使下游的EWAs不会被样本组成之间的变化所混淆，从而提供更大的能力来识别与传染病有关的真正的表观基因组差异。

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.