, Volume 60, Issue 12, pp 727–735

Natural selection in the TLR-related genes in the course of primate evolution

  • Toshiaki Nakajima
  • Hitoshi Ohtani
  • Yoko Satta
  • Yasuhiro Uno
  • Hirofumi Akari
  • Takafumi Ishida
  • Akinori Kimura
Original Paper


The innate immune system constitutes the front line of host defense against pathogens. Toll-like receptors (TLRs) recognize molecules derived from pathogens and play crucial roles in the innate immune system. Here, we provide evidence that the TLR-related genes have come under natural selection pressure in the course of primate evolution. We compared the nucleotide sequences of 16 TLR-related genes, including TLRs (TLR1–10), MYD88, TILAP, TICAM1, TICAM2, MD2, and CD14, 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 TLR-related genes. The genomic segments encoding the intracellular Toll/interleukin 1 receptor domains, which exhibited lower rates of non-synonymous substitution, have undergone purifying selection. In contrast, TLR4, which carried a high proportion of non-synonymous substitutions in the part of extracellular domain spanning 200 amino acids, was found to have been the suggestive target of positive Darwinian selection in primate evolution. However, sequence analyses from 25 primate species, including eight hominoids, six Old World monkeys, eight New World monkeys, and three prosimians, showed no evidence that the pressure of positive Darwinian selection has shaped the pattern of sequence variations in TLR4 among New World monkeys and prosimians.


Toll-like receptor Natural selection Primate evolution 

Supplementary material

251_2008_332_MOESM1_ESM.ppt (246 kb)
ESM Fig. 1Phylogenetic tree and the value of bn and bs for the selection target in TLR7 and MYD88 among seven primate species. The ratio of bn/bs for each branch is shown in parenthesis (PPT 248 KB)
251_2008_332_MOESM2_ESM.ppt (1.5 mb)
ESM Fig. 2The values of bn and bs in the sliding window plot analysis for the lineages of orangutan (A), gorilla (B), and the lineage just after the split of ancestors of four great apes (gorilla, bonobo, chimpanzee, and human) (C). The dot lines indicate the estimated value of bn for entire TLR4 coding sequences for each lineage (PPT 1.52 MB)
251_2008_332_MOESM3_ESM.doc (149 kb)
Table S1Accession numbers for TLR-related genes analyzed in this study (DOC 149 KB)
251_2008_332_MOESM4_ESM.doc (105 kb)
Table S2The values of bn and bs in individual branches of the primate phylogenetic tree based on the Bn–Bs program. Numbered circles in individual branches are referred to Fig. 4a (DOC 105 KB)
251_2008_332_MOESM5_ESM.doc (314 kb)
Table S3Ka (a), Ks (b), and Ka/Ks ratio (c) at the target segment of TLR4 among 21 primate species (DOC 314 KB)


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Toshiaki Nakajima
    • 1
    • 2
  • Hitoshi Ohtani
    • 1
  • Yoko Satta
    • 3
  • Yasuhiro Uno
    • 4
  • Hirofumi Akari
    • 5
  • Takafumi Ishida
    • 6
  • Akinori Kimura
    • 1
    • 2
  1. 1.Laboratory of Genome Diversity, School of Biomedical ScienceTokyo Medical and Dental UniversityTokyoJapan
  2. 2.Department of Molecular Pathogenesis, Medical Research InstituteTokyo Medical and Dental UniversityTokyoJapan
  3. 3.Department of Biosystems ScienceGraduate University for Advanced StudiedHayamaJapan
  4. 4.Pharmacokinetics and Bioanalysis Center, Shin Nippon Biomedical Laboratories, Ltd.KainanJapan
  5. 5.Tsukuba Primate Research CenterNational Institute of Biomedical InnovationTsukubaJapan
  6. 6.Unit of Human Biology and Genetics, Graduate School of ScienceThe University of TokyoTokyoJapan

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