Molecular evolution of bovine Toll-like receptor 2 suggests substitutions of functional relevance.
Molecular evolution of bovine Toll-like receptor 2 suggests substitutions of functional relevance.
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牛Toll样受体2的分子进化表明了功能相关性的取代。
DOI：
10.1186/1471-2148-8-288
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发表时间：
2008-10-20
影响因子：
3.4
通讯作者：
Glass, Elizabeth J.
中科院分区：
文献类型：
--
作者：
Jann, Oliver C.;Werling, Dirk;Chang, Jung-Su;Haig, David;Glass, Elizabeth J.
越来越多的证据表明，Toll 样受体 (TLR) 基因的多态性可能与牲畜的抗病性或易感性相关。影响 TLR 功能的多态性位点应表现出正选择的特征，即非同义与同义核苷酸取代 (ω) 的高比例。因此，基于每个氨基酸位置的 ω 估计的密码子替换的系统发育模型可以提供一个有价值的工具来预测功能相关位点。我们已经使用这种方法来鉴定来自 10 个 Bos indicus 和 Bos taurus 牛品种的牛 TLR2 基因内的此类多态性位点。通过分析一组哺乳动物物种和一部分反刍动物物种中的 TLR2 基因系统发育，我们估计了各个位点和域的选择压力，并鉴定了推定功能重要性位点的多态性。 ω 在被认为负责配体结合的哺乳动物 TLR2 结构域中最高，在负责与其他 TLR 相关分子异二聚化的区域中最低。在配体结合域内或周围检测到几个正选位点。然而，反刍动物 TLR2 序列子集与整个哺乳动物序列组的比较表明，反刍动物之间的选择压力比整个哺乳动物的选择压力要小。这表明反刍动物进化过程中发生了功能变化。在牛中鉴定出二十个新发现的非同义多态性位点。其中三个位于反刍动物数据集中由正选择形成的位置（Leu227Phe、His305Pro、His326Gln）以及参与配体识别的域。 His326Gln 特别令人感兴趣，因为它由不同电荷氨基酸的交换组成，该位置先前已被证明对人 TLR2 中的配体结合至关重要。在牛 TLR2 中，氨基酸位置 227、305 和 326 的多态性映射到 TLR2 的功能重要位点，应被视为牛免疫相关性状的候选 SNP。它们功能相关性的最终证明需要进一步研究，以确定它们在用相关配体刺激后对免疫反应的功能影响和/或它们与动物免疫相关特征的关联。
There is accumulating evidence that polymorphism in Toll-like receptor (TLR) genes might be associated with disease resistance or susceptibility traits in livestock. Polymorphic sites affecting TLR function should exhibit signatures of positive selection, identified as a high ratio of non-synonymous to synonymous nucleotide substitutions (ω). Phylogeny based models of codon substitution based on estimates of ω for each amino acid position can therefore offer a valuable tool to predict sites of functional relevance. We have used this approach to identify such polymorphic sites within the bovine TLR2 genes from ten Bos indicus and Bos taurus cattle breeds. By analysing TLR2 gene phylogeny in a set of mammalian species and a subset of ruminant species we have estimated the selective pressure on individual sites and domains and identified polymorphisms at sites of putative functional importance. The ω were highest in the mammalian TLR2 domains thought to be responsible for ligand binding and lowest in regions responsible for heterodimerisation with other TLR-related molecules. Several positively-selected sites were detected in or around ligand-binding domains. However a comparison of the ruminant subset of TLR2 sequences with the whole mammalian set of sequences revealed that there has been less selective pressure among ruminants than in mammals as a whole. This suggests that there have been functional changes during ruminant evolution. Twenty newly-discovered non-synonymous polymorphic sites were identified in cattle. Three of them were localised at positions shaped by positive selection in the ruminant dataset (Leu227Phe, His305Pro, His326Gln) and in domains involved in the recognition of ligands. His326Gln is of particular interest as it consists of an exchange of differentially-charged amino acids at a position which has previously been shown to be crucial for ligand binding in human TLR2. Within bovine TLR2, polymorphisms at amino acid positions 227, 305 and 326 map to functionally important sites of TLR2 and should be considered as candidate SNPs for immune related traits in cattle. A final proof of their functional relevance requires further studies to determine their functional effect on the immune response after stimulation with relevant ligands and/or their association with immune related traits in animals.
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