An integrative genomics approach to uncover genetic mechanisms underlying susceptibility to important infectious diseases in pigs

在动物生产系统中，传染病非常令人担忧，因为它们影响动物的健康和福利、动物的生产力，在某些情况下还影响人类的健康。长期以来，人们观察到个体克服感染的能力存在差异，这种差异具有遗传成分，尽管具体的基因和遗传变异(多态)在很大程度上是未知的。最近的工作已经确定了宿主对感染反应变化的机制之一，至少在猪和猪呼吸与生殖综合征病毒(PRRSV)的情况下是这样。一种名为GBP5的宿主基因的多态性会影响该基因的功能。携带该基因较不活跃版本的两个副本的猪表现出生长减慢和病毒水平较高。虽然GBP5在其他物种的免疫应答中具有已知的作用，但它对猪病毒应答变异的作用以前并不清楚。我们最近的工作发现了另外几个基因，由于多态性，这些基因的活性在个体之间似乎不同，这样，某些版本的基因(等位基因)会导致宿主对PRRSV产生更大的抵抗力。我们将研究这些基因的表达，以更多地了解它们的功能，并验证多态对其活性的影响。接下来，我们将利用现有的大量样本和来自以前和当前调查猪沙门氏菌感染的项目的表型(性状)数据，来确定这些基因和多态是否也可以提供一些针对沙门氏菌的保护。之前对其他物种的研究表明，对于某些基因来说，这是一个合理的预期。事实上，在小鼠中，已经确定了GBP5活性和沙门氏菌生长之间的联系。我们正在使用的方法有可能识别以前没有在猪或其他物种中描述的病原体抗性机制。此外，我们确认的影响PRRSV耐药性或沙门氏菌耐药性的基因和多态可以用来指导开发新的非药物为基础的策略来应对这些病原体。例如，当选择猪进行繁殖时，可以努力避免携带大量易感等位基因的个体。

In animal production systems infectious diseases are of great concern due to their effects on animal health and welfare, animal productivity, and in some cases human health. Variation in the ability of individuals to overcome infection has long been observed, and this variation has a genetic component, although the particular genes and genetic variants (polymorphisms) are largely unknown. Recent work has identified one of the mechanisms underlying variation in host response to infection, at least in the case of pigs and the porcine respiratory and reproductive syndrome virus (PRRSV). A polymorphism in a host gene called GBP5 affects the ability of the gene to function. Pigs with two copies of the less active version of the gene show reduced growth and higher levels of the virus. Although GBP5 has a known role in immune response in other species, its contribution to variation in viral response in pigs was previously not known. Our more recent work has revealed several additional genes that appear to differ in activity among individuals because of polymorphisms, such that certain versions of the gene (alleles) lead to greater host resistance to PRRSV. We will study the expression of these genes to learn more about what they do, and to verify the effects of polymorphisms on their activity. Next we will leverage a large existing collection of samples and phenotypic (trait) data from previous and current projects investigating Salmonella infection in pigs, to determine if these genes and polymorphisms can also provide some protection against Salmonella. Previous studies in other species suggest that this is a reasonable expectation for some genes. Indeed, in mice a link between GBP5 activity and Salmonella growth has been previously identified. The approaches we are using have the potential to identify mechanisms of pathogen resistance not previously described in pigs or other species. Moreover, the genes and polymorphisms we confirm to influence PRRSV resistance or Salmonella resistance can be used to guide the development of new non-drug based strategies for dealing with these pathogens. For example, when pigs are selected for breeding, efforts can be made to avoid individuals that carry an abundance of susceptible alleles.**