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

在动物生产系统中，传染病因其对动物健康和福利、动物生产力以及在某些情况下对人类健康的影响而备受关注。长期以来，人们一直观察到个体克服感染能力的变异，这种变异有遗传成分，尽管具体的基因和遗传变异（多态性）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一种机制，至少在猪和猪呼吸与生殖综合征病毒（PRRSV）的情况下是这样。宿主基因GBP5的多态性会影响该基因的功能。携带两个不太活跃的基因副本的猪表现出生长下降和更高水平的病毒。虽然已知GBP5在其他物种的免疫反应中起作用，但它对猪病毒反应变化的贡献以前并不为人所知。我们最近的工作已经揭示了由于多态性而在个体之间表现出活性差异的其他几个基因，例如基因的某些版本（等位基因）导致宿主对PRRSV的更大抗性。我们将研究这些基因的表达，以更多地了解它们的作用，并验证多态性对其活性的影响。接下来，我们将利用以前和当前研究猪沙门氏菌感染的项目中收集的大量样本和表型（性状）数据，来确定这些基因和多态性是否也能提供一些预防沙门氏菌的保护。先前对其他物种的研究表明，这是对某些基因的合理预期。事实上，在小鼠中，GBP5活性和沙门氏菌生长之间的联系已经被发现。我们正在使用的方法有可能确定以前未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抗性或沙门氏菌抗性的基因和多态性可用于指导开发新的非药物基础策略来处理这些病原体。例如，当选择猪进行育种时，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.