Journal of Genetics

, Volume 90, Issue 3, pp 401–408 | Cite as

Domain combination of the vertebrate-like TLR gene family: implications for their origin and evolution

  • ZENGLIANG BAIEmail author
Research Article


Domain shuffling, which is an important mechanism in the evolution of multi-domain proteins, has shaped the evolutionary development of the immune system in animals. Toll and Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate and adaptive immune systems. Draft genome sequences provide the opportunity to compare the Toll/TLR gene repertoire among representative metazoans. In this study, we investigated the combination of Toll/interleukin-1 receptor (TIR) and leucine-rich repeat (LRR) domains of metazoan Toll/TLRs. Before Toll with both domains occurred in Cnidaria (sea anemone, Nematostella vectensis), through domain combinations, TIR-only and LRR-only proteins had already appeared in sponges (Amphimedon queenslandica). Although vertebrate-like TIR (V-TIR) domain already appeared in Cnidaria, the vertebrate-like TLR (V-TLR) with both domains appeared much later. The first combination between V-TIR domain and vertebrate-like LRR (V-LRR) domain for V-TLR may have occurred after the divergence of Cnidaria and bilateria. Then, another combination for V-TLR, a recombination of both domains, possibly occurred before or during the evolution of primitive vertebrates. Taken together, two rounds of domain combinations may thus have co-shaped the vertebrate TLRs.


Toll-like receptors TIR domain LRR domain domain combination 


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  1. Abascal F., Zardoya R. and Posada D. 2005 ProtTest: selection of best-fit models of protein evolution. Bioinformatics 21, 2104–2105.PubMedCrossRefGoogle Scholar
  2. Chang M. M., Zhang J. and Miao D. 2006 A lamprey from the Cretaceous Jehol biota of China. Nature 441, 972–974.PubMedCrossRefGoogle Scholar
  3. Davidson C. R., Best N. M., Francis J. W., Cooper E. L. and Wood T. C. 2008 Toll-like receptor genes (TLRs) from Capitella capitata and Helobdella robusta (Annelida). Dev. Comp. Immunol. 32, 608–612.PubMedCrossRefGoogle Scholar
  4. Gess R. W., Coates M. I. and Rubidge B. S. 2006 A lamprey from the Devonian period of South Africa. Nature 443, 981–984.PubMedCrossRefGoogle Scholar
  5. Guindon S., Lethiec F., Duroux P. and Gascuel O. 2005 PHYML Online-a web server for fast maximum likelihood-based phylogenetic inference. Nucleic Acids Res. 33, W557–W559.CrossRefGoogle Scholar
  6. Guo P., Hirano M., Herrin B. R., Li J., Yu C., Sadlonova A. et al. 2009 Dual nature of the adaptive immune system in lampreys. Nature 459, 796–801.PubMedCrossRefGoogle Scholar
  7. Hemmrich G., Miller D. J. and Bosch T. C. 2007 The evolution of immunity: a low-life perspective. Trends Immunol. 28, 449–454.PubMedCrossRefGoogle Scholar
  8. Hibino T., Loza-Coll M., Messier C., Majeske A. J., Cohen A. H., Terwilliger D. P. et al. 2006 The immune gene repertoire encoded in the purple sea urchin genome. Dev. Biol. 300, 349–365.PubMedCrossRefGoogle Scholar
  9. Huang S., Yuan S., Guo L., Yu Y., Li J., Wu T. et al. 2008 Genomic analysis of the immune gene repertoire of amphioxus reveals extraordinary innate complexity and diversity. Genome Res. 18, 1112–1126.PubMedCrossRefGoogle Scholar
  10. Ishii A., Kawasaki M., Matsumoto M., Tochinai S. and Seya T. 2007a Phylogenetic and expression analysis of amphibian Xenopus Toll-like receptors. Immunogenetics 59, 281–293.PubMedCrossRefGoogle Scholar
  11. Ishii A., Matsuo A., Sawa H., Tsujita T., Shida K., Matsumoto M. et al. 2007b Lamprey TLRs with properties distinct from those of the variable lymphocyte receptors. J. Immunol. 178, 397–406.PubMedGoogle Scholar
  12. Kasamatsu J., Oshiumi H., Matsumoto M., Kasahara M. and Seya T. 2010 Phylogenetic and expression analysis of Lamprey Toll-like receptors. Dev. Comp. Immunol. 34, 855–865.PubMedCrossRefGoogle Scholar
  13. Larkin M. A., Blackshields G., Brown N. P., Chenna R., McGettigan P. A., McWilliam H. et al. 2007 Clustal W and Clustal X version 2.0. Bioinformatics 23, 2947–2948.PubMedCrossRefGoogle Scholar
  14. LeBouder E., Rey-Nores J. E., Rushmere N. K., Grigorov M., Lawn S. D., Affolter M. et al. 2003 Soluble forms of Toll-like receptor (TLR)2 capable of modulating TLR2 signaling are present in human plasma and breast milk. J. Immunol. 171, 6680–6689.PubMedGoogle Scholar
  15. Lemaitre B., Nicolas E., Michaut L., Reichhart J. M. and Hoffmann J. A. 1996 The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell 86, 973–983.PubMedCrossRefGoogle Scholar
  16. Medzhitov R., Preston-Hurlburt P. and Janeway Jr C. A. 1997 A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388, 394–397.PubMedCrossRefGoogle Scholar
  17. Miller D. J., Hemmrich G., Ball E. E., Hayward D. C., Khalturin K., Funayama N. et al. 2007 The innate immune repertoire in cnidaria–ancestral complexity and stochastic gene loss. Genome Biol. 8, R59.CrossRefGoogle Scholar
  18. Oshiumi H., Tsujita T., Shida K., Matsumoto M., Ikeo K. and Seya T. 2003 Prediction of the prototype of the human Toll-like receptor gene family from the pufferfish, Fugu rubripes, genome. Immunogenetics 54, 791–800.PubMedGoogle Scholar
  19. Pasare C. and Medzhitov R. 2004 Toll-like receptors and acquired immunity. Semin. Immunol. 16, 23–26.PubMedCrossRefGoogle Scholar
  20. Roach J. C., Glusman G., Rowen L., Kaur A., Purcell M. K., Smith K. D. et al. 2005 The evolution of vertebrate Toll-like receptors. Proc. Natl. Acad. Sci. USA 102, 9577–9582.PubMedCrossRefGoogle Scholar
  21. Sasaki N., Ogasawara M., Sekiguchi T., Kusumoto S. and Satake H. 2009 Toll-like receptors of the ascidian Ciona intestinalis: prototypes with hybrid functionalities of vertebrate Toll-like receptors. J. Biol. Chem. 284, 27336–27343.PubMedCrossRefGoogle Scholar
  22. Takeda K. and Akira S. 2005 Toll-like receptors in innate immunity. Int. Immunol. 17, 1–14.PubMedCrossRefGoogle Scholar
  23. Tamura K., Dudley J., Nei M. and Kumar S. 2007 MEGA4: Molecular evolutionary genetics analysis (MEGA) software version 4.0. Mol. Biol. Evol. 24, 1596–1599.PubMedCrossRefGoogle Scholar
  24. Tsujita T., Tsukada H., Nakao M., Oshiumi H., Matsumoto M. and Seya T. 2004 Sensing bacterial flagellin by membrane and soluble orthologs of Toll-like receptor 5 in rainbow trout (Onchorhynchus mikiss). J. Biol. Chem. 279, 48588–48597.PubMedCrossRefGoogle Scholar
  25. Tsukada H., Fukui A., Tsujita T., Matsumoto M., Iida T. and Seya T. 2005 Fish soluble Toll-like receptor 5 (TLR5S) is an acute-phase protein with integral flagellin-recognition activity. Int. J. Mol. Med. 15, 519–525.PubMedGoogle Scholar
  26. Wiens M., Korzhev M., Perovic-Ottstadt S., Luthringer B., Brandt D., Klein S. et al. 2007 Toll-like receptors are part of the innate immune defense system of sponges (demospongiae: Porifera). Mol. Biol. Evol. 24, 792–804.PubMedCrossRefGoogle Scholar
  27. Yilmaz A., Shen S., Adelson D. L., Xavier S. and Zhu J. J. 2005 Identification and sequence analysis of chicken Toll-like receptors. Immunogenetics 56, 743–753.PubMedCrossRefGoogle Scholar
  28. Yuan S., Huang S., Zhang W., Wu T., Dong M., Yu Y. et al. 2009 An amphioxus TLR with dynamic embryonic expression pattern responses to pathogens and activates NF-kappaB pathway via MyD88. Mol. Immunol. 46, 2348–2356.PubMedCrossRefGoogle Scholar
  29. Zhang Q., Zmasek C. M., Dishaw L. J., Mueller M. G., Ye Y., Litman G. W. et al. 2008 Novel genes dramatically alter regulatory network topology in amphioxus. Genome Biol. 9, R123.CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2011

Authors and Affiliations

    • 1
    • 1
    • 2
    • 3
    • 4
    • 1
    Email author
  1. 1.Laboratory of Developmental Immunology, School of Life ScienceShandong UniversityJinanPeople’s Republic of China
  2. 2.Framingham Heart Study, National Heart, Lung, and Blood InstituteFraminghamUSA
  3. 3.Institute of Biomedical Engineering, School of MedicineShandong UniversityJinanPeople’s Republic of China
  4. 4.Center for Disease Control and Prevention of Shizhong DistrictJiningPeople’s Republic of China

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