Evolution of the Bovine TLR Gene Family and Member Associations with Mycobacterium avium Subspecies paratuberculosis Infection
Evolution of the Bovine TLR Gene Family and Member Associations with Mycobacterium avium Subspecies paratuberculosis Infection
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DOI：
10.1371/journal.pone.0027744
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发表时间：
2011-11-30
期刊：
影响因子：
3.7
通讯作者：
Seabury, Christopher M.
中科院分区：
文献类型：
--
作者：
Fisher, Colleen A.;Bhattarai, Eric K.;Seabury, Christopher M.
Toll 样受体 (TLR) 基因家族的成员在哺乳动物先天免疫系统中发挥着关键作用，充当检测入侵病原体的哨兵，然后激发宿主先天免疫反应。我们利用定制的下一代测序方法和等位基因特异性基因分型测定来检测和验证所有 10 个牛 TLR 基因的 280 个双等位基因变异，包括 71 个非同义单核苷酸多态性 (SNP) 和一个假定的无义 SNP。贝叶斯单倍型重建和中值连接网络揭示了牛和牛品种在每个基因座上共享单倍型，并且尽管平均多态性密度为 1 个标记/158 bp，但无法区分特殊的牛肉和奶制品品种。总的来说，160 个 tagSNP 和两个标签插入删除突变 (indels) 足以预测 Bos 亚种及其杂交种 280 个可变位点的 100% 变异，而 118 个 tagSNP 和 1 个 tagIndel 可以预测捕获 B. t. 235 个可变位点的 100% 变异。金牛座。对牛 TLR SNP 编码的氨基酸 (AA) 替换的 Polyphen 和 SIFT 分析表明，预计高达 32% 的 AA 替换会影响蛋白质功能。经典和新开发的多样性测试为平衡 TLR3 和 TLR8 上的选择以及作用于 TLR10 上的纯化选择提供了强有力的支持。对相邻可变位点之间连锁不平衡 (r(2) >= 0.50) 的持久性和连续性的研究也支持作用于 TLR3 和 TLR8 的选择的存在。一项病例对照研究采用识别细菌配体的牛 TLR 基因的经过验证的变体，揭示了 6 个 SNP 可能对奶牛对鸟分枝杆菌属副结核病感染的易感性产生微小影响。这项研究的结果将为探索牛翻译基因组学的几种途径以及标记辅助疫苗接种的潜力提供必要的基础，从而广泛影响家牛研究。
Members of the Toll-like receptor (TLR) gene family occupy key roles in the mammalian innate immune system by functioning as sentries for the detection of invading pathogens, thereafter provoking host innate immune responses. We utilized a custom next-generation sequencing approach and allele-specific genotyping assays to detect and validate 280 biallelic variants across all 10 bovine TLR genes, including 71 nonsynonymous single nucleotide polymorphisms (SNPs) and one putative nonsense SNP. Bayesian haplotype reconstructions and median joining networks revealed haplotype sharing between Bos taurus taurus and Bos taurus indicus breeds at every locus, and specialized beef and dairy breeds could not be differentiated despite an average polymorphism density of 1 marker/158 bp. Collectively, 160 tagSNPs and two tag insertion-deletion mutations (indels) were sufficient to predict 100% of the variation at 280 variable sites for both Bos subspecies and their hybrids, whereas 118 tagSNPs and 1 tagIndel predictively captured 100% of the variation at 235 variable sites for B. t. taurus. Polyphen and SIFT analyses of amino acid (AA) replacements encoded by bovine TLR SNPs indicated that up to 32% of the AA substitutions were expected to impact protein function. Classical and newly developed tests of diversity provide strong support for balancing selection operating on TLR3 and TLR8, and purifying selection acting on TLR10. An investigation of the persistence and continuity of linkage disequilibrium (r(2) >= 0.50) between adjacent variable sites also supported the presence of selection acting on TLR3 and TLR8. A case-control study employing validated variants from bovine TLR genes recognizing bacterial ligands revealed six SNPs potentially eliciting small effects on susceptibility to Mycobacterium avium spp paratuberculosis infection in dairy cattle. The results of this study will broadly impact domestic cattle research by providing the necessary foundation to explore several avenues of bovine translational genomics, and the potential for marker-assisted vaccination.