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

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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.