Molecular evolution of the TLR4 gene in the course of primate evolution and their sensitivities to the response to endotoxin

先天免疫系统构成了宿主抵御病原体的前线。Toll样受体4(TLR4)识别病原体来源的分子，在天然免疫系统中发挥重要作用。在这里，我们提供了TLR4基因在灵长类进化过程中受到自然选择压力的证据。我们比较了7种灵长类动物TLR4基因的核苷酸序列。对非同义/同义替换率的分析表明，TLR4基因既存在严格保守的区域，也存在快速进化的区域。编码细胞内Toll/白细胞介素1受体(TIR)结构域的基因组片段具有较低的非同义替换率，已经进行了纯化选择。相反，TLR4的胞外区，携带着异常高比例的非同义替换，被发现是灵长类进化中积极达尔文选择的目标。然而，三维结构预测显示，TLR4胞外区的三维结构在7个灵长类物种之间没有差异。我们还报道了MYD88与Buerger病易感性的关系。

The innate immune system constitutes the front line of host defense against pathogens. Toll-like receptor 4(TLR4) recognize molecules derived from pathogens and play crucial roles in the innate immune system. Here we provide evidence that the TLR4 gene have come under natural selection pressure in the course of primate evolution. We compared the nucleotide sequences of TLR4 gene among seven primate species. Analysis of the non-synonymous/synonymous substitution ratio revealed the presence of both strictly conserved and rapidly evolving regions in the TLR4 gene. The genomic segments encoding the intracellular Toll/interleukin 1 receptor(TIR) domains, which exhibited lower rates of non-synonymous substitution, have undergone purifying selection. In contrast, the extracellular domain of TLR4, which carried an unusually high proportion of non-synonymous substitutions, was found to have been the target of positive Darwinian selection in primate evolution. However, the 3D structural prediction showed no difference in the 3D structure of extracellular domain of TLR4 among seven primate species. We also reported the association of MYD88 with the susceptibility to Buerger's disease.