Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Full Paper
  • Published:

Identification, characterization, and evolution of a primate β-defensin gene cluster

Genes & Immunity volume 6, pages 203–210 (2005)Cite this article

Abstract

Defensins are members of a large diverse family of cationic antimicrobial peptides that share a signature pattern consisting of six conserved cysteine residues. Defensins have a wide variety of functions and their disruption has been implicated in various human diseases. Here we report the characterization of DEFB119–DEFB123, five genes in the human β-defensin cluster locus on chromosome 20q11.1. The genomic structures of DEFB121 and DEFB122 were determined in silico. Sequences of the five macaque orthologs were obtained and expression patterns of the genes were analyzed in humans and macaque by semiquantitative reverse transcription polymerase chain reaction. Expression was restricted to the male reproductive tract. The genes in this cluster are differentially regulated by androgens. Evolutionary analyses suggest that this cluster originated by a series of duplication events and by positive selection. The evolutionary forces driving the proliferation and diversification of these defensins may be related to reproductive specialization and/or the host–parasite coevolutionary process.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8

Similar content being viewed by others

References

  1. Ganz T . Defensins: antimicrobial peptides of innate immunity. Nat Rev Immunol 2003; 3: 710–720.

    Article  CAS  PubMed  Google Scholar 

  2. Schutte BC, Mitros JP, Bartlett JA et al. Discovery of five conserved beta-defensin gene clusters using a computational search strategy. Proc Natl Acad Sci USA 2002; 99: 2129–2133.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rodriguez-Jimenez F-J, Krause A, Schulz S et al. Distribution of new human [beta]-defensin genes clustered on chromosome 20 in functionally different segments of epididymis. Genomics 2003; 81: 175–183.

    Article  CAS  PubMed  Google Scholar 

  4. Semple C, Rolfe M, Dorin J . Duplication and selection in the evolution of primate beta-defensin genes. Genome Biol 2003; 4: R31.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yang D, Biragyn A, Hoover DM, Lubkowski J, Oppenheim JJ . Multiple roles of antimicrobial defensins, cathelicidins, and eosinophil-derived neurotoxin in host defense. Annu Rev Immunol 2004; 22: 181–215.

    Article  PubMed  Google Scholar 

  6. Goldman MJ, Anderson GM, Stolzenberg ED, Kari UP, Zasloff M, Wilson JM . Human beta-defensin-1 is a salt-sensitive antibiotic in lung that is inactivated in cystic fibrosis. Cell 1997; 88: 553–560.

    Article  CAS  PubMed  Google Scholar 

  7. Schroder JM, Harder J . Human beta-defensin-2. Int J Biochem Cell Biol 1999; 31: 645–651.

    Article  CAS  PubMed  Google Scholar 

  8. Lehrer RI . Primate defensins. Nat Rev Microbiol 2004; 2: 727–738.

    Article  CAS  PubMed  Google Scholar 

  9. Garcia JR, Jaumann F, Schulz S et al. Identification of a novel, multifunctional beta-defensin (human beta-defensin 3) with specific antimicrobial activity. Its interaction with plasma membranes of Xenopus oocytes and the induction of macrophage chemoattraction. Cell Tissue Res 2001; 306: 257–264.

    Article  CAS  PubMed  Google Scholar 

  10. Yang D, Chertov O, Bykovskaia SN et al. Defensins: linking innate and adaptive immunity through dendritic and T cell CCR6. Science 1999; 286: 525–528.

    Article  CAS  PubMed  Google Scholar 

  11. Yamaguchi Y, Nagase T, Makita R et al. Identification of multiple novel epididymis-specific {beta}-defensin isoforms in humans and mice. J Immunol 2002; 169: 2516–2523.

    Article  CAS  PubMed  Google Scholar 

  12. Avellar MCW, Honda L, Hamil KG et al. Differential expression and antibacterial activity of epididymis protein 2 isoforms in the male reproductive tract of human and rhesus monkey (Macaca mulatta). Biol Reprod 2004; 71: 1453–1460.

    Article  CAS  PubMed  Google Scholar 

  13. Yudin AI, Tollner TL, Li MW, Treece CA, Overstreet JW, Cherr GN . ESP13.2, a member of the beta-defensin family, is a macaque sperm surface-coating protein involved in the capacitation process. Biol Reprod 2003; 69: 1118–1128.

    Article  CAS  PubMed  Google Scholar 

  14. Zhou CX, Zhang YL, Xiao L et al. An epididymis-specific beta-defensin is important for the initiation of sperm maturation. Nat Cell Biol 2004; 6: 458–464.

    Article  CAS  PubMed  Google Scholar 

  15. Rodriguez C, Kirby J, Hinton B . Regulation of gene transcription in the epididymis. Reproduction 2001; 122: 41–48.

    Article  CAS  PubMed  Google Scholar 

  16. Orgebin-Crist MC . Androgens and epididymal function. In: Bhasin SGH, Spieler JM, Swerdloff RE, Wang C, Kelly C (eds). Pharmacology, Biology, and Clinical Applications of Androgens. Wiley-Liss: New York, 1996, pp 27–38.

    Google Scholar 

  17. Hinton BT, Lan ZJ, Rudolph DB, Labus JC, Lye RJ . Testicular regulation of epididymal gene expression. J Reprod Fertil Suppl 1998; 53: 47–57.

    CAS  PubMed  Google Scholar 

  18. Gould KG, Young LG . Acquisition of fertilizing capacity by chimpanzee sperm. Folia Primatol (Basel) 1990; 54: 105–108.

    Article  CAS  Google Scholar 

  19. Morrison GM, Semple CA, Kilanowski FM, Hill RE, Dorin JR . Signal sequence conservation and mature peptide divergence within subgroups of the murine beta-defensin gene family. Mol Biol Evol 2003; 20: 460–470.

    Article  CAS  PubMed  Google Scholar 

  20. Swanson WJ, Vacquier VD . The rapid evolution of reproductive proteins. Nat Rev Genet 2002; 3: 137–144.

    Article  CAS  PubMed  Google Scholar 

  21. Hughes AL, Yeager M . Coordinated amino acid changes in the evolution of mammalian defensins. J Mol Evol 1997; 44: 675–682.

    Article  CAS  PubMed  Google Scholar 

  22. Boniotto M, Tossi A, DelPero M et al. Evolution of the beta defensin 2 gene in primates. Genes Immun 2003; 4: 251–257.

    Article  CAS  PubMed  Google Scholar 

  23. Maxwell AI, Morrison GM, Dorin JR . Rapid sequence divergence in mammalian beta-defensins by adaptive evolution. Mol Immunol 2003; 40: 413–421.

    Article  CAS  PubMed  Google Scholar 

  24. Swanson WJ, Nielsen R, Yang Q . Pervasive adaptive evolution in mammalian fertilization proteins. Mol Biol Evol 2003; 20: 18–20.

    Article  CAS  PubMed  Google Scholar 

  25. Liu Q, Hamil KG, Sivashanmugam P et al. Primate epididymis-specific proteins: characterization of ESC42, a novel protein containing a trefoil-like motif in monkey and human. Endocrinology 2001; 142: 4529–4539.

    Article  CAS  PubMed  Google Scholar 

  26. Yenugu S, Hamil KG, Radhakrishnan Y, French FS, Hall SH . The androgen-regulated epididymal sperm-binding protein, human beta-defensin 118 (DEFB118) (formerly ESC42), is an antimicrobial beta-defensin. Endocrinology 2004; 145: 3165–3173.

    Article  CAS  PubMed  Google Scholar 

  27. Saitou N, Nei M . The neighbor-joining method: a new method for reconstructing phylogenetic trees. Mol Biol Evol 1987; 4: 406–425.

    CAS  PubMed  Google Scholar 

  28. Kumar S, Hedges SB . A molecular timescale for vertebrate evolution. Nature 1998; 392: 917–920.

    Article  CAS  PubMed  Google Scholar 

  29. Hwang PM, Vogel HJ . Structure–function relationships of antimicrobial peptides. Biochem Cell Biol 1998; 76: 235–246.

    Article  CAS  PubMed  Google Scholar 

  30. White SH, Wimley WC, Selsted ME . Structure, function, and membrane integration of defensins. Curr Opin Struct Biol 1995; 5: 521–527.

    Article  CAS  PubMed  Google Scholar 

  31. Li P, Chan HC, He B et al. An antimicrobial peptide gene found in the male reproductive system of rats. Science 2001; 291: 1783–1785.

    Article  CAS  PubMed  Google Scholar 

  32. Murphy CJ, Foster BA, Mannis MJ, Selsted ME, Reid TW . Defensins are mitogenic for epithelial cells and fibroblasts. J Cell Physiol 1993; 155: 408–413.

    Article  CAS  PubMed  Google Scholar 

  33. Ezer N, Robaire B . Gene expression is differentially regulated in the epididymis after orchidectomy. Endocrinology 2003; 144: 975–988.

    Article  CAS  PubMed  Google Scholar 

  34. Zhang J, Dyer KD, Rosenberg HF . Evolution of the rodent eosinophil-associated RNase gene family by rapid gene sorting and positive selection. Proc Natl Acad Sci USA 2000; 97: 4701–4706.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Nei M, Gu X, Sitnikova T . Evolution by the birth-and-death process in multigene families of the vertebrate immune system. Proc Natl Acad Sci USA 1997; 94: 7799–7806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Del Pero M, Boniotto M, Zuccon D et al. Beta-defensin 1 gene variability among non-human primates. Immunogenetics 2002; 53: 907–913.

    Article  CAS  PubMed  Google Scholar 

  37. Antcheva N, Boniotto M, Zelezetsky I et al. Effects of positively selected sequence variations in human and Macaca fascicularis beta-defensins 2 on antimicrobial activity. Antimicrob Agents Chemother 2004; 48: 685–688.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Yenugu S, Richardson RT, Sivashanmugam P et al. Antimicrobial activity of human EPPIN, an androgen-regulated, sperm-bound protein with a whey acidic protein motif. Biol Reprod 2004; 71: 1484–1490.

    Article  CAS  PubMed  Google Scholar 

  39. O’Rand MG, Widgren EE, Sivashanmugam P et al. Reversible immunocontraception in male monkeys immunized with eppin. Science 2004; 306: 1189–1190.

    Article  PubMed  Google Scholar 

  40. Nielsen H, Engelbrecht J, Brunak S, von Heijne G . A neural network method for identification of prokaryotic and eukaryotic signal peptides and prediction of their cleavage sites. Int J Neural Syst 1997; 8: 581–599.

    Article  CAS  PubMed  Google Scholar 

  41. Hamil KG, Liu Q, Sivashanmugam P et al. LCN6, a novel human epididymal lipocalin. Reprod Biol Endocrinol 2003; 1: 112.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Young SL, Lyddon TD, Jorgenson RL, Misfeldt ML . Expression of Toll-like receptors in human endometrial epithelial cells and cell lines. Am J Reprod Immunol 2004; 52: 67–73.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Kumar S, Tamura K, Nei M . MEGA3: integrated software for molecular evolutionary genetics analysis and sequence alignment. Brief Bioinform 2004; 5: 150–163.

    Article  CAS  PubMed  Google Scholar 

  44. Felsenstein J . Confidence limits on phylogenies: an approach using the bootstrap. Evolution 1985; 39: 783–791.

    Article  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms Graziela Valente and Dr Sudhir Kumar from the Arizona State University for their help in evolutionary analysis and in the critical reading of the manuscript. We thank Dr Hemant Kelkar and Dr Jianping Jin, Center for Bioinformatics, University of North Carolina, Chapel Hill, for their suggestions. Support for this project (CIG-96-06-A) was provided by the CICCR Program of the Contraceptive Research and Development Program (CONRAD), Eastern Virginia Medical School. The views expressed by us do not necessarily reflect the views of CONRAD or CICCR. This work was also supported by grants from The Andrew W Mellon Foundation and by National Institutes of Health grants R37-HD04466 and U54-HD35041 as part of the Specialized Cooperative Centers Program in Reproduction Research, and by the Fogarty International Center Training and Research in Population and Health grant D43TW/HD00627.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill, NC, USA

    Y Radhakrishnan, K G Hamil, S Yenugu, F S French & S H Hall

  2. Department of Obstetrics and Gynecology, Laboratories for Reproductive Biology, University of North Carolina, Chapel Hill, NC, USA

    S L Young

Authors
  1. Y Radhakrishnan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. K G Hamil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Yenugu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S L Young
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. F S French
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. S H Hall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S H Hall.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Radhakrishnan, Y., Hamil, K., Yenugu, S. et al. Identification, characterization, and evolution of a primate β-defensin gene cluster. Genes Immun 6, 203–210 (2005). https://doi.org/10.1038/sj.gene.6364184

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.gene.6364184

Keywords

This article is cited by

Search

Advanced search

Quick links