Organization and Reorganization of Constant Region Genes of Immunoglobulin Heavy Chains: Genetic Basis for Class Switching
We have determined the complete organization of the mouse CH gene family, which is comprised of the 8 CH genes in the order 5’-JH-6.5kb-Cμ-4.5kb-Cδ-55kb-Cγ3-34kb-Cγ1-21kb-Cγ2b-15kb-Cγ2a-14kb-Cε-12kb-Cα-3’. The S regions, which contain characteristic tandemly repeated unit sequences, are located 5’ to each CH gene except for the Cδ gene. There are at least two types of repetitive sequences dispersed in this 200 kb region. No pseudogenes are present. The arrangements of the CH genes in BALB/c and C57BL mice are similar, but the lengths of the S regions vary. The basic structures of all the CH genes are similar in that coding sequences are interrupted at the junctions of the domains and the hinge regions. Comparison of the nucleotide sequences of the CH genes revealed that sequence segments have been exchanged among members of the CH gene family. Cloning and characterization of human Cγ genes, i.e. Cγ1, Cγ2, Cγ3, Cγ4 and φCγ, indicate that the human Cγ gene family evolved by dynamic DNA rearrangements, including gene duplication, exon duplication, and exon reassortment by unequal crossing-over. A human pseudo-epsilon gene (Cε3) is a processed gene that has completely spliced out introns. The presence of movable genetic elements surrounding the Cε3 gene suggests that the Cε gene evolved by a translocation mechanism. Although S-S recombination has been shown to take place in myelomas and hybridomas secreting a large amount of immunoglobulin, analyses of the CH gene organization in normal spleen B cells bearing immunoglobulin on their surface suggest that RNA splicing may be responsible for the first step in class switching, followed by S-S recombination. The nucleotide sequences of S regions contain short common sequences, TGGG(G) and (G)AGCT. Comparison of nucleotide sequences surrounding recombination sites revealed common sequences TGAG and TGGG. A sister chromatid exchange model was proposed to explain deletion of CH genes accompanying S-S recombination. We have found that the S region serves as a preferred recombination site in E.coli extracts.
KeywordsHinge Region Sister Chromatid Exchange Constant Region Recombination Site Class Switch Recombination
Unable to display preview. Download preview PDF.
- Kalpaktsoglou, P.K., Hong, R. and Good, R.A. (1973) Immunol. 24, 303–314.Google Scholar
- Kataoka, T., Takeda, S. and Honjo, T. (1982) submitted.Google Scholar
- Kishimoto, T. (1982) Prog. Allergy (ed. P. Kailos, K. Ishizaka and B. Waksman) Kalger Pub. Inc., Basel, in press (1982).Google Scholar
- Lawton, A.R., Kearney, J.F. and Cooper, M.D. (1977) Progress in Immunology 3, 171–182.Google Scholar
- Nakai, S., Vernon, O., Herzenberg, L.A., Yamagishi, H., and Honjo, T. (1982) Biomed. Res. 3, 37–45.Google Scholar
- Natvig, J.B., Kunkel, H.G. and Litwin, S.D. (1967) Cold Spring Harbor Symp. on Quant. Biol. 32, 173–180.Google Scholar
- Perlmutter, A. P. and Gilbert, W. (1982) Proc. Natl. Acad. Sci. USA, in press.Google Scholar
- Sakoyama, Y., Yaoita, Y. and Honjo, T. (1982) Nucl. Acids Res. in press.Google Scholar
- Sher, I., Ahmed, A., Strong, D.M., Steinberg, A.D. and Paul, W.E. (1975) J. Exp. Med. 141, 788–803.Google Scholar
- Takahashi, N., Shimizu, A., Obata, M., Nishida, Y., Nakai, S., Nikaido, T., Kataoaka, T., Yamawaki-Kataoka, Y., Yaoita, Y., Ishida, N. and Honjo, T. (1981) C. Janeway, E.E. Sercarz and H. Wigzell, eds. ( New York: Academic Press ), pp 123–134.Google Scholar
- van der Loo, W., Gronowicz, E.S., Strober, S. and Herzenberg, L.A. (1979) J. Immunology 122, 1203–1208.Google Scholar
- Yaoita, Y. and Honjo, T. (1980a) Biomed. Res. 1, 164–175.Google Scholar