Abstract
Mice bearing the H-2 w7 haplotype have five C4-related genes and constitutively express the Slp antigen. To understand the structure and evolution of the five C4-related genes of the C3H.W7 mouse, we have determined nucleotide sequences of the 5′ end region of these genes. A C4/Slp hybrid nature was confirmed for three of five C4-related genes as predicted previously by restriction enzyme analysis. The nucleotide sequences of the 5′ flanking regions of these three hybrid genes showed close similarity to that of the C4 gene, while the 3′ side of the ninth exon of the three hybrid genes showed close similarity to that of the Slp gene. In contrast, the regions between the first exon and the middle of the ninth exon of the three hybrid genes showed a mosaic structure of C4-like and Slp-like sequences. Moreover, the boundaries of the C4-like and Slp-like sequences were quite different among the three hybrid genes. The pattern of nucleotide sequence diversity in this region among the five C4-related sequences could be mainly explained not by point mutations but by gene conversions or unequal crossovers. These results suggest that multiple genetic recombinational events between two homologous sequences played an important role in the generation and diversification of the extra copies of the C4/Slp gene in the H-2 w7 mouse.
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Atkinson, J. P., Karp, D. R., Seeskin, E. P., Killion, C. C., Rosa, P. A., Newell, S. L., and Shreffler, D. C.: H-2 S region determined by polymorphic variants of the C4, Slp, C2, and B complement proteins: a compilation. Immunogenetics 16: 617–623, 1982
Brown, L. J. and Shreffler, D. C.: Female expression of the H-2-linked sex-limited protein (Slp) due to non-H-2 genes. Immunogenetics 10: 19–29, 1980
Carroll, M. C., Campbell, R. D., Bentley, D. R., and Porter, R. R.: A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B. Nature 307: 237–241, 1984
Chaplin, D., Sackstein, R., Perlmutter, D. H., Weiss, J.H.., Kruse, A., Coligan, J., Colten, H. R., and Seidman, J. G.: Expression of hemolytically active murine fourth component of complement in transfected L-cells. Cell 37: 569–576, 1984
Ferreira, A., Nussenzweig, V., and Gigli, I.: Structural and functional differences between the H-2 controlled Ss and Slp proteins. J Exp Med 148: 1186–1197, 1978
Hansen, T. H. and Shreffler, D. C.: Characterization of a contitutive variant of the murine serum protein allotype, Slp. J Immunol 117: 1507–1513, 1976
Heinlein, U. A. D., Lange-Sablitzky, R., Schaal, H., and Wille, W.: Molecular characterization of the MT-family of dispersed middle-repetitive DNA in rodent genome. Nucleic Acids Res 14: 6403–6416, 1986
Karp, D. R., Atkinson, J. P., and Shreffler, D. C.: Genetic variation in glycosylation of the fourth component of murine complement: association with hemolytic activity. J Biol Chem 257: 7330–7335, 1982
Klein, J.: Histocompatibility-2 system in wild mice. I. Identification five new H-2 chromosomes. Transplantation 13: 291–299, 1972
Klein, J.: A case of no sex-limitation of Slp in the murine H-2 complex. Immunogenetics 2: 297–299, 1975
Kobori, J. A., Strauss, E., Minard, K., and Hood, L.: Molecular analysis of the hotspot of recombination in the murine major histocompatibility complex. Science 234: 173–179, 1986
Lafuse, W. P., Berg, N., Savarirayan, S., and David, C. S.: Mapping of a second recombination hot spot within the I-E region of the mouse H-2 gene complex. J Exp Med 163: 1518–1528, 1986
Lévi-Strauss, M., Tosi, M., Steinmetz, M., Klein, J., and Meo, T.: Multiple duplications of C4 genes correlate with H-2 controlled testosterone-independent expression of its sex-limited isoform, C4-Slp. Proc Natl Acad Sci USA 82: 1746–1750, 1985
Nakayama, K., Nonaka, M., Yokoyama, S., Yu, D.-Y., Pattanakitsakul, S., and Takahashi, M.: Recombination of two homologous MHC class III genes of the mouse (C4 and Slp) that accounts for the loss of testosterone dependence of sex-limited protein expression. J Immunol 138: 620–627, 1987
Nonaka, M., Nakayama, K., Yu, D.-Y., and Takahashi, M.: Complete nucleotide and derived amino acid sequences of sex-limited-protein (Slp), nonfunctional isotype of the fourth component of mouse complement (C4). J Immunol 136: 2989–2993, 1986a
Nonaka, M., Kimura, H., Yul, D.-Y., Yokoyama, S., Nakayama, K., and Takahashi, M.: Identification of the 5′-flanking regulatory region responsible for the difference in transcriptional control between mouse complement C4 and Slp genes. Proc Natl Acad Sci USA 83: 7883–7887, 1986b
Ogata, R. T. and Sepich, D. S.: Murine sex-limited protein: complete cDNA sequence and comparison with murine fourth complement component. J Immunol 135: 4239–4244, 1985
Ogata, R. T., Rosa, P. A., and Zepf, N. E.: Sequence of the gene for murine complement component C4. J Biol Chem 264: 16565–16572, 1989
Rosa, P. A., Sepich, D. S., Shreffler, D. C., and Ogata, R. T.: Mice constitutive for sex-limited protein (Slp) expression contain multiple Slp gene sequences. J Immunol 135: 627–631, 1985
Rosa, P. A., Sepich, D. S., Robins, D. M., and Ogata, R. T.: Constitutive expression of Slp genes in mouse strain B10.WR directed by C4 regulatory sequences. J Immunol 139: 1568–1577, 1987
Sanger, F., Nicklen, S., and Coulson, A. R.: DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74: 5463–5467, 1977
Schneider, P. M., Carroll, M., Alper, C., Rittner, C., Whitehead, A., Yunis, E., and Colten, H.: Polymorphism of the human complement C4 and steroid 21-hydroxylase genes: restriction fragment length polymorphisms revealing structural deletion, homoduplications and size variants. J Clin Invest 78: 650–657, 1986
Sepich, D. S., Rosa, P. A., and Ogata, R. T.: cDNA sequence of a novel sex-limited protein (Slp) from mice constitutive for Slp expression. J Biol Chem 262: 4935–4938, 1987
Shiroishi, T., Hanzawa, N., Sagai, T., Ishiura, M., Gojobori, T., Steinmetz, M., and Moriwaki, K.: Recombinational hotspot specific to female meiosis in the mouse major histocompatibility complex. Immunogenetics 31: 79–88, 1990
Shreffler, D. C., Atkinson, J. P., Chan, A. C., Karp, D. R., Killion, C. C., Ogata, R. T., and Rosa, P. A.: The C4 and Slp genes of the complement region of the murine H-2 major histocompatibility complex. Philos Trans R Soc Lond [Biol] 306: 395–403, 1984
Stavenhagen, J., Loreni, F., Hemenway, C., Kalff, M., and Robins, D. M.: Molecular genetics of androgen-dependent and-independent expression of mouse sex-limited protein. Mol Cell Biol 7: 1716–1724, 1987
Steinmetz, M., Minard, K., Horvath, S., McNicholas, J., Frelinger, J., Wake, C., Long, E., Mach, B., and Hood, L.: A molecular map of the immune response region from the major histocompatibility complex. Nature 300: 35–42, 1982
Steinmetz, M., Stephan, D., and Fischer Lindahl, K.: Gene organization and recombinational hosspot in the murine major histocompatibility complex. Cell 44: 895–904, 1986
Uematsu, Y., Keifer, H., Schulze, R., Fischer Lindahl, K., and Steinmetz, M.: Molecular characterization of a meiotic recombinational hotspot enhancing homologous equal crossing-over. EMBO J 5: 2123–2129, 1986
Zaleska-Rutczynska, Z. and Klein, J.: Histocompatibility-2 system in wild mice. V. Serologic analysis of sixteen B10.W congenic lines. J Immunol 119: 1903–1911, 1977
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The nucleotide sequence data reported in this paper have been submitted to the DDBJ, EMBL, and GenBank nucleotide sequence databases and have been assigned the accession numbers D90167-71.
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Pattanakitsakul, Sn., Nakayama, K., Takahashi, M. et al. Three extra copies of a C4-related gene in H-2 w7 mice are C4/Slp hybrid genes generated by multiple recombinational events. Immunogenetics 32, 431–439 (1990). https://doi.org/10.1007/BF00241638
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DOI: https://doi.org/10.1007/BF00241638