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防御病原体的第一线。toll样受体4（TLR4）识别来自病原体的分子，在先天免疫系统中发挥重要作用。本研究提供的证据表明，TLR4基因在灵长类动物进化过程中受到了自然选择的压力。我们比较了7种灵长类动物TLR4基因的核苷酸序列。非同义/同义替换比分析显示，TLR4基因中存在严格保守区和快速进化区。编码细胞内Toll/白细胞介素1受体（TIR）结构域的基因组片段，表现出较低的非同义替代率，经历了纯化选择。相比之下，TLR4的细胞外结构域携带异常高比例的非同义替换，被发现是灵长类进化中达尔文选择的目标。然而，三维结构预测显示，7种灵长类动物TLR4胞外结构域的三维结构没有差异。我们还报道了MYD88与伯格氏病易感性的关联。

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.