Genetics, Physical Anthropology, and Animal Physiology Department, University of the Basque Country, Sarriena s/n, 48940 Leioa, Bizkaia, Spain.
J Dairy Sci. 2010 Dec;93(12):5950-8. doi: 10.3168/jds.2010-3340.
The intracellular pathogen resistance 1 (Ipr1) gene has been reported to play a role in mediating innate immunity in a mouse model of Mycobacterium tuberculosis infection, and polymorphisms of its human ortholog, SP110 nuclear body protein, have been suggested to be associated with tuberculosis. Thus, the bovine SP110 gene was considered to be a promising candidate for a genetic association study of bovine paratuberculosis, or Johne's disease, a chronic granulomatous enteritis caused by Mycobacterium avium ssp. paratuberculosis (MAP). Initially, single nucleotide polymorphisms (SNP) within the bovine SP110 gene were identified, and subsequently a population-based genetic association study was carried out. Seventeen new SNP along the SP110 gene were identified in Holstein-Friesian cattle, and 6 more were compiled from public databases. A total of 14 SNP were included in the association study of 2 independent populations. The SNP c.587A>G was found to be significantly associated with MAP infection, with the major allele A appearing to confer greater disease susceptibility in one of the analyzed populations. In addition, 2 haplotypes containing this SNP were also found to be associated with infection in the same population. The SNP c.587A>G is a nonsynonymous mutation that causes an amino acid change in codon 196 from asparagine to serine. In silico analyses point to SNP c.587A>G as a putative causal variant for susceptibility to MAP infection. The elucidation of the precise mechanism by which this SNP can exert its effect in the protein and, as a result, in the risk of infection, requires future functional analyses. Likewise, the absence of genetic association in one of the analyzed populations renders it necessary to carry out this study in other independent populations, with the aim of substantiating the repeatability of the present results. Nevertheless, the present results deepen our understanding of the genetic basis of susceptibility and resistance mechanisms related to MAP infection in cattle and, in turn, constitute a step forward toward the implementation of marker-assisted selection in breeding programs aimed at controlling paratuberculosis.
细胞内病原体抗性 1（Ipr1）基因已被报道在小鼠结核分枝杆菌感染模型中发挥介导先天免疫的作用，其人类同源物 SP110 核体蛋白的多态性被认为与结核病有关。因此，牛 SP110 基因被认为是牛副结核病（或 Johne 病）遗传关联研究的有前途的候选基因，牛副结核病是由牛分枝杆菌亚种。副结核分枝杆菌（MAP）引起的慢性肉芽肿性肠炎。最初，鉴定了牛 SP110 基因内的单核苷酸多态性（SNP），随后进行了基于群体的遗传关联研究。在荷斯坦-弗里森牛中鉴定了 SP110 基因内的 17 个新 SNP，另外 6 个从公共数据库中汇编。总共 14 个 SNP 被纳入 2 个独立群体的关联研究。发现 SNP c.587A>G 与 MAP 感染显著相关，分析人群之一中的主要等位基因 A 似乎赋予了更大的疾病易感性。此外，还发现包含该 SNP 的 2 个单倍型也与同一人群的感染相关。SNP c.587A>G 是一种非同义突变，导致密码子 196 中的天冬酰胺到丝氨酸的氨基酸变化。计算机分析表明，SNP c.587A>G 是 MAP 感染易感性的潜在因果变异。阐明该 SNP 如何在蛋白质中发挥作用，以及因此在感染风险中发挥作用的确切机制，需要未来的功能分析。同样，在分析的一个群体中没有遗传关联，使得有必要在其他独立群体中进行这项研究，以证实本研究结果的可重复性。尽管如此，本研究结果加深了我们对牛中与 MAP 感染相关的易感性和抗性机制的遗传基础的理解，并反过来为在旨在控制副结核病的育种计划中实施标记辅助选择奠定了基础。
