Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

C4 genes of the chimpanzee, gorilla, and orang-utan: evidence for extensive homogenization

  • 30 Accesses

  • 17 Citations


The human complement component 4 is encoded in two genes, C4A and C4B, residing between the class I and class II genes of the major histocompatibility complex. The C4A and C4B molecules differ in their biological activity, the former binding more efficiently to proteins than to carbohydrates while for the latter, the opposite holds true. To shed light on the origin of the C4 genes we isolated cosmid clones bearing the C4 genes of a chimpanzee, a gorilla, and an orang-utan. From the clones, we isolated the fragments coding for the C4d part of the gene (exons and introns) and sequenced them. Altogether we sequenced eight gene fragments: three chimpanzee (Patr-C4-1 *01, Patr-C4-1 *02, Patr-C4-2 *01), two gorilla (Gogo-C4-1 *01, Gogo-C4-2 *01), and three orang-utan (Popy-C4-1 *01, Popy-C4-2 *01, Popy-C4-3 *01). Comparison of the sequences with each other and with human C4 sequences revealed that in the region believed to be responsible for the functional difference between the C4A and C4B proteins the C4A genes of the different species fell into one group and the C4B genes fell into another. In the rest of the sequence, however, the C4A and C4B genes of each species resembled each other more than they did C4 genes of other species. These results are interpreted as suggesting extensive homogenization (concerted evolution) of the C4 genes in each species, most likely by repeated unequal, homologous, intragenic crossing-over.

This is a preview of subscription content, log in to check access.


  1. Belt, K. T., Carroll, M. C., and Porter, R. R.: The structural basis of the multiple forms of human complement component C4. Cell 36: 907–914, 1984

  2. Belt, K. T., Yu, C. Y., Carroll, M. C.,and Porter, R. R.: Polymorphism of human complement component C4. Immunogenetics 21: 173–180, 1985

  3. Bitter-Suermann, D., Krönke, M., Brade, V., and Hadding, U.: Inherited polymorphism of guinea pig factor B and C4: evidence for genetic linkage between the C4 and B floci. J Immunol 118: 1822–1826, 1977

  4. Carroll, M. C., Belt, T., Palsdottir, A., and Porter, R. R.: Structure and organization of the C4 genes. Philos Trans R Soc Lond [Biol] 306: 379–388, 1984

  5. Conner, B. J., Reyes, A. A., Morin, C., Itakura, K., Teplitz, R. L., and Wallace, R. B.: Detection of sickle cell βs-globin allele by hybridization with synthetic oligonucleotides. Proc Natl Acad Sci USA 80: 278–282, 1983

  6. Davis, L. G., Dibner, M. D., and Battey, J. F.: Basic Methods in Molecular Biology. Elsevier, New York, 1986

  7. De Kroon, A. I. P. M., Doxiadis, G., Doxiadis, I., and Hensen, E. J. Structure and polymorphism of the feline complement component C4. Immunogenetics 24: 202–205, 1986

  8. Dodds, A. W. and Law, A. S. K.: The complement component C4 of mammals. Biochem J 265: 495–502, 1990

  9. Dover, G., Brown, S., Coen, E., Dallas, J., Strachan, T., and Trick, M.: Dynamics of genome evolution and species differentiation. In G. A. Dover and R. B. Flavell (eds.): Genome Evolution, pp. 343–372, Academic Press, London, 1982

  10. Doxiadis, G., Rebmann, V., Doxiadis, I., Krumbacher, K., Vriesendorp, H. M., and Grosse-Wilde, H.: Polymorphism of the fourth complement component in the dog. Immunobiology 169: 563–569, 1985

  11. Felsenstein, J.: Phylogenies from molecular sequences: Inference and reliability. Annu Rev Genet 22: 521–565, 1988

  12. Granados, J., Awdeh, Z. L., Chen, J.-H., Giles, C. M., Balner, H., Yunis, E. J., and Alper, C. A.: There are two C4 genetic loci and a null allele in the chimpanzee. Immunogenetics 26: 344–350, 1987

  13. Hauptmann, G., Goetz, J., Uring-Lambert, B., and Grosshans, E.: Component deficiencies. 2. The fourth component. Prog Allergy 39: 232–249, 1986

  14. Insenman, D. E. and Young, J. R.: The molecular basis for the difference in immune hemolysis activity of the Chido and Rodgers isotypes of human complement component C4. J Immunol 132: 3019–3027, 1984

  15. Kawaguchi, H. and Klein, J.: Organization of C4 and CYP21 loci in gorilla and orang-utan. Hum Immunol, submitted 1991

  16. Kawaguchi, H., Golubic, M., Figueroa, F., and Klein, J.: Organization of the chimpanzee C4-CYP21 region: Implications for the evolution of human genes. Eur J Immunol 20: 739–745, 1990

  17. Kawaguchi, H., O'hUigin, C., and Klein, J.: Evolution of primate C4 and CYP21 genes. In J. Klein and D. Klein (eds.): Molecular Evolution of the Major Histocompatibility Complex, pp. 357–382, Springer, Heidelberg, 1991

  18. Kay, P. H. and Dawkins, R. L.: Genetic polymorphism of complement C4 in the dog. Tissue Antigens 23: 151–155, 1984

  19. Kimura, M.: A simple method for estimating evolutionary rates of base substitutions through comparative studies of nucleotide sequences. J Mol Evol 16: 111–120, 1980

  20. Klein, J., Bontrop, R. E., Dawkins, R. L., Erlich, H. A., Gyllensten, U. B., Heise, E. R., Jones, P. P., Wakeland, E. K., and Watkins, D. I.: Nomenclature for the major histocompatibility complexes of different species: A proposal. Immunogenetics 31: 217–219, 1990

  21. Law, S. K. A., Dodds, A. W., and Porter, R. R.: A comparison of the properties of two classes, C4A and C4B, of the human complement component C4. EMBO J 3: 1819–1823, 1984

  22. Lévi-Strauss, M., Tosi, M., Steinmetz, M., Klein, J., and Meo, T.: Multiple duplications of complement C4 gene correlate with H-2-controlled testosterone-independent expression of its sex-limited isoform, C4-Slp. Proc Natl Acad Sci USA 82: 1746–1750, 1985

  23. Maniatis, T., Fritsch, E. F., and Sambrook, J.: Molecular Cloning: A Laboratory Manual. Cold Spring Harbor Press, Cold Spring Harbor, 1982

  24. Mauff, G., Alper, C. A., Awdeh, Z., Batchelor, J. R., Bertrams, T., Braun-Petersen, G., Dawkins, R. L., Demant, P., Edwards, J., Grosse-Wilde, H., Hauptmann, G., Klouda, P., Lamm, L., Mullenhauer, E., Nerl, C., Olaisen, B., O'Neill, G. O., Rittner, C., Roos, M. H., Skanes, V., Teisberg, P., and Wells, L.: Statement on the nomenclature of human C4 allotypes. Immunobiology 164: 184–191, 1983

  25. Mayer, W. E., Jonker, M., Klein, D., Ivanyi, P., van Seventer, G., and Klein, J.: Nucleotide sequences of chimpanzee MHC class I alleles: Evidence for trans-species mode of evolution. EMBO J 7: 2765–2774, 1988

  26. O'Neill, G. J., Yang, S. Y., and Dupont, B.: Two HLA-linked loci controlling the fourth component of human complement. Proc Natl Acad Sci USA 75: 5165–5169, 1978

  27. Rasheed, S. A., Rongey, R. W., Bruszweski, J., Nelson-Rees, W. A., Rabin, H., Neubauer, R. H., Esra, G., and Gardner, M. B.: Establishment of a cell line with associated Epstein-Barr-like virus from a leukemic orang-utan. Science 198: 407–409, 1977

  28. Reid, K. B. M.: Application of molecular cloning to studies of the complement system. Immunology 55: 185–196, 1985

  29. Ripley, L. S. and Glickman, B. W.: Unique self-complementarity of palindromic sequences provides DNA structural intermediates for mutation. Cold Spring Harbor Symp Quant Biol 47: 851–861, 1982

  30. Roos, M. H., Atkinson, J. P., and Shreffler, D. C.: Molecular characterization of the Ss and Slp (C4) proteins of the mouse H-2 complex: Subunit composition, chain-size polymorphism, and an intracellular (Pro-Ss) precursor. J Immunol 121: 1106–1115, 1978

  31. Ross, G. D. (ed.): Immunobiology of the Complement System. An Introduction for Research and Clinical Medicine. Academic Press, Orlando, 1986

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

  33. Sanger, F., Nicklen, S., and Coulson, A. R.: DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci USA 74: 5463–5467, 1977

  34. Schneider, P. M., Carroll, M. S., Alper, C. A., Rittner, C., Whitehead, A. S., Yunis, E. J., and Colten, H. R.: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. J Clin Inv 78: 650–657, 1986

  35. Spilliaert, R., Palsdottir, A., and Arnason, A.: Analysis of the C4 genes in baleen whales using a human cDNA probe. Immunogenetics 32: 73–76, 1990

  36. Steinmetz, M., Stephan, D., Dastronikoo, G. R., Gibb, E., and Romaniuk, R. In J. Lefkovits and B. Pernis (eds.): Immunological Methods. Academic Press, New York, 1985

  37. Tosi, M., Lévi-Strauss, M., Duponchel, C., and Meo, T.: Sequence heterogeneity of murine complementary DNA clones related to the C4 and C4-Slp isoforms of the fourth complement component. Philos Trans R Soc Lond [Biol] 306: 389–394, 1984

  38. Yu, C. Y.: The complete exon-intron structure of a human complement component C4A gene. DNA sequences, polymorphism, and linkage to the 21-hydroxylase gene. J Immunol 146: 1057–1066, 1991

  39. Yu, C. Y., Belt, K. T., Giles, C. M., Campbell, R. D., and Porter, R. R.: Structural basis of the polymorphism of human complement components C4A and C4B: gene size, reactivity and antigenicity. EMBO J 5: 2873–2881, 1986

  40. Yu, C. Y., Campbell, R. D., and Porter, R. R.: A structural model for the location of the Rodgers and the Chido antigenic determinants and their correlation with the human complement C4A/C4B isotypes. Immunogenetics 27: 399–405, 1988

Download references

Author information

Additional information

Address correspondence and offprint requests to: J. Klein.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kawaguchi, H., Zaleska-Rutczynska, Z., Figueroa, F. et al. C4 genes of the chimpanzee, gorilla, and orang-utan: evidence for extensive homogenization. Immunogenetics 35, 16–23 (1992). https://doi.org/10.1007/BF00216622

Download citation


  • Carbohydrate
  • Biological Activity
  • Major Histocompatibility Complex
  • Gene Fragment
  • Functional Difference