Animal Breeding and Genomics Centre, Wageningen University, P.O. Box 338, Wageningen, The Netherlands.
Centre for Genetic Improvement of Livestock, University of Guelph, Guelph, ON, Canada.
BMC Genomics. 2018 Sep 21;19(1):694. doi: 10.1186/s12864-018-5062-6.
Natural antibodies (NAb) are an important component of the innate immune system, and fight infections as a part of the first line defence. NAb are poly-reactive and can respond non-specifically to antigens. Therefore, NAb may be a key trait when evaluating an animal's potential natural disease resistance. Variation in NAb is caused by both genetic and environmental factors. In this study genetic parameters of NAb were estimated and a genome-wide association study (GWAS) was performed to gain further understanding on the genes that are responsible for the observed genetic variation of NAb in Canadian Holsteins.
In total, blood samples of 1327 cows from 64 farms were studied. NAb binding to keyhole limpet hemocyanin (KLH) were determined via indirect ELISA. Immunoglobulin (Ig) isotypes, IgG and IgM, were evaluated. From the sample population, 925 cows were genotyped for 45,187 markers and each individual marker was tested to detect genetic variation in NAb levels. The relationships among animals was accounted for with genomic relationship. Results show heritabilities of 0.27 ± 0.064 (IgG) and 0.31 ± 0.065 (IgM). In total, 23 SNPs were found to be associated with IgG, but no SNPs were associated with IgM (FDR p-value < 0.05). The significant SNPs were located on autosomal chromosomes 1, 20 and 21 of the cow genome. Functional annotation analysis of the positional candidate genes revealed two sets of genes with biologically relevant functions related to NAb. In one set, seven genes with crucial roles in the production of antibody in B cells were associated with the trafficking of vesicles inside the cells between organelles. In the second set, two genes among positional candidate genes were associated with isotype class-switching and somatic hypermutation of B cells.
This study demonstrated the possibility of increasing NAb through selective breeding. In addition, the effects of two candidate pathways are proposed for further investigation of NAb production in Holsteins.
天然抗体（NAb）是先天免疫系统的重要组成部分，作为第一道防线的一部分抵御感染。NAb 具有多反应性，可以非特异性地响应抗原。因此，NAb 可能是评估动物潜在天然疾病抵抗力的关键特征。NAb 的变异既受遗传因素影响，也受环境因素影响。在这项研究中，我们估计了 NAb 的遗传参数，并进行了全基因组关联研究（GWAS），以进一步了解导致加拿大荷斯坦奶牛 NAb 观察到的遗传变异的基因。
总共研究了来自 64 个农场的 1327 头奶牛的血液样本。通过间接 ELISA 测定 NAb 与血蓝蛋白（KLH）的结合。评估了免疫球蛋白（Ig）同种型 IgG 和 IgM。在样本人群中，对 45187 个标记物对 925 头奶牛进行了基因分型，每个个体标记物都经过检测，以检测 NAb 水平的遗传变异。利用基因组关系来解释动物之间的关系。结果显示 IgG 的遗传力为 0.27±0.064，IgM 的遗传力为 0.31±0.065。总共发现 23 个 SNP 与 IgG 相关，但没有 SNP 与 IgM 相关（FDR p 值<0.05）。显著 SNP 位于牛基因组的 1、20 和 21 号常染色体上。候选基因位置的功能注释分析揭示了与 NAb 相关的两组具有生物学相关功能的基因。在一组中，与细胞内细胞器之间囊泡运输有关的 7 个基因在 B 细胞产生抗体方面发挥着关键作用。在第二组中，候选基因位置的两个基因与 B 细胞的同种型类别转换和体细胞超突变有关。
本研究表明通过选择性育种提高 NAb 水平的可能性。此外，还提出了两条候选途径的作用，以进一步研究荷斯坦奶牛 NAb 的产生。
