Paratuberculosis is a contagious and incurable disease that is caused by Mycobacterium avium subsp. paratuberculosis (MAP) with significant negative effects on animal welfare and farm profitability. Based on a large naturally infected flock over 12 years, we analyzed repeated enzyme-linked immunosorbent assay tests (ELISA), OvineSNP50 BeadChip genotypes and whole-genome sequences imputed from 56 influential animals. The main goals were to estimate the genetic parameters of proxy traits for resistance to MAP, identify genomic regions associated with the host’s immune response against MAP and search for candidate genes and causative mutations through association and functional annotation analyses of polymorphisms identified by sequencing. Two variables were derived from ELISA tests. The first, a binary variable, assessed the infection status of each animal over the entire productive life, while the second considered the level of antibody recorded over time. Very similar results were obtained for both variables. Heritability estimates of about 0.20 were found and a significant region capturing 18% and 13% of the genetic variance was detected on ovine chromosome 20 by linkage disequilibrium and linkage analysis on OvineSNP50 positions. Functional annotation and association analyses on the imputed sequence polymorphisms that were identified in this region were carried out. No significant variants showed a functional effect on the genes that mapped to this region, most of which belong to the major histocompatibility complex class II (MHC II). However, the conditional analysis led to the identification of two significant polymorphisms that can explain the genetic variance associated with the investigated genomic region. Our results confirm the involvement of the host’s genetics in susceptibility to MAP in sheep and suggest that selective breeding may be an option to limit the infection. The estimated heritability is moderate with a relevant portion being due to a highly significant region on ovine chromosome 20. The results of the combined use of sequence-based data and functional analyses suggest several genes belonging to the MHC II as the most likely candidates, although no mutations in their coding regions showed a significant association. Nevertheless, information from genotypes of two highly significant polymorphisms in the region can enhance the efficiency of selective breeding programs.

中文翻译：

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通过遗传力估计和 LDLA 作图分析以及使用基于序列的数据研究候选区域，在理解绵羊副结核病抗体反应的遗传结构方面取得进展


副结核病是一种传染性且无法治愈的疾病，由鸟分枝杆菌亚种引起。副结核病（MAP）对动物福利和农场盈利能力具有显着的负面影响。基于 12 年来的大型自然感染鸡群，我们分析了重复的酶联免疫吸附测定测试 (ELISA)、OvineSNP50 BeadChip 基因型和来自 56 只有影响的动物的全基因组序列。主要目标是估计 MAP 抗性代理性状的遗传参数，识别与宿主针对 MAP 的免疫反应相关的基因组区域，并通过测序鉴定的多态性的关联和功能注释分析来搜索候选基因和致病突变。两个变量来自 ELISA 测试。第一个是二元变量，评估每只动物在整个生产生活中的感染状态，而第二个则考虑随时间记录的抗体水平。两个变量都获得了非常相似的结果。通过对 OvineSNP50 位置的连锁不平衡和连锁分析，发现了约 0.20 的遗传力估计值，并且在绵羊 20 号染色体上检测到捕获 18% 和 13% 遗传变异的显着区域。对该区域中鉴定的推算序列多态性进行了功能注释和关联分析。没有显着的变异显示出对映射到该区域的基因的功能影响，其中大多数属于主要组织相容性复合物 II 类 (MHC II)。然而，条件分析导致鉴定出两个显着的多态性，这可以解释与所研究的基因组区域相关的遗传变异。 我们的结果证实了宿主遗传因素与绵羊对 MAP 的易感性有关，并表明选择性育种可能是限制感染的一种选择。估计的遗传力是中等的，相关部分是由于绵羊 20 号染色体上的一个非常重要的区域造成的。基于序列的数据和功能分析的结合使用的结果表明，属于 MHC II 的几个基因是最有可能的候选基因，尽管其编码区的突变没有显示出显着的关联。然而，来自该地区两个高度显着的多态性的基因型信息可以提高选择性育种计划的效率。