Skip to main content
NCBI home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1980 Dec 11;8(23):5579–5598. doi: 10.1093/nar/8.23.5579

Organization of the sequences flanking immunoglobulin heavy chain genes and their role in class switching.

B M Tyler, J M Adams
PMCID: PMC324327  PMID: 6780980

Abstract

We have used heteroduplex analysis to investigate the sequences surrounding the germline C gamma 1 and C gamma 3 genes, and to compare them with those surrounding the C mu gene. We detected an inverted pseudogene 5' to the C gamma 3 gene and 50-65% homologous to it. A 400 bp region of the C gamma 1 and C gamma 3 3' flanking sequences was conserved as strongly as the genes (65-80%), suggesting it may have a specific function. The sequences 5' to the C gamma 1 and C gamma 3 genes and possibly also the C mu gene are composed of tandem partially homologous repeats of a similar 250 bp unit, arranged in the case of the C gamma 1 gene, in 2-5 kb blocks of alternating orientation. These repeats comprised over 13 kb of the spacer region separating the C gamma 3 and C gamma 1 genes. Recombination sites for heavy chain class switching fell within these repeated sequences, suggesting that recombination between partially homologous blocks of repeat sequences 5' to CH genes generates the deletion responsible for class switching. This hypothesis was strongly supported by an examination of published nucleotide sequences around the recombination sites of rearranged C gamma 1 and C gamma 2b genes (1,2).

Full text

PDF
5579

Images in this article

5583Image
on p.5583
5588Image
on p.5588

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abney E. R., Cooper M. D., Kearney J. F., Lawton A. R., Parkhouse R. M. Sequential expression of immunoglobulin on developing mouse B lymphocytes: a systematic survey that suggests a model for the generation of immunoglobulin isotype diversity. J Immunol. 1978 Jun;120(6):2041–2049. [PubMed] [Google Scholar]
  2. Brack C., Hirama M., Lenhard-Schuller R., Tonegawa S. A complete immunoglobulin gene is created by somatic recombination. Cell. 1978 Sep;15(1):1–14. doi: 10.1016/0092-8674(78)90078-8. [DOI] [PubMed] [Google Scholar]
  3. Brutlag D., Fry K., Nelson T., Hung P. Synthesis of hybrid bacterial plasmids containing highly repeated satellite DNA. Cell. 1977 Mar;10(3):509–519. doi: 10.1016/0092-8674(77)90038-1. [DOI] [PubMed] [Google Scholar]
  4. Calame K., Rogers J., Early P., Davis M., Livant D., Wall R., Hood L. Mouse Cmu heavy chain immunoglobulin gene segment contains three intervening sequences separating domains. Nature. 1980 Apr 3;284(5755):452–455. doi: 10.1038/284452a0. [DOI] [PubMed] [Google Scholar]
  5. Cochet M., Gannon F., Hen R., Maroteaux L., Perrin F., Chambon P. Organization and sequence studies of the 17-piece chicken conalbumin gene. Nature. 1979 Dec 6;282(5739):567–574. doi: 10.1038/282567a0. [DOI] [PubMed] [Google Scholar]
  6. Cory S., Adams J. M. Deletions are associated with somatic rearrangement of immunoglobulin heavy chain genes. Cell. 1980 Jan;19(1):37–51. doi: 10.1016/0092-8674(80)90386-4. [DOI] [PubMed] [Google Scholar]
  7. Davidson E. H., Britten R. J. Regulation of gene expression: possible role of repetitive sequences. Science. 1979 Jun 8;204(4397):1052–1059. doi: 10.1126/science.451548. [DOI] [PubMed] [Google Scholar]
  8. Davis M. M., Calame K., Early P. W., Livant D. L., Joho R., Weissman I. L., Hood L. An immunoglobulin heavy-chain gene is formed by at least two recombinational events. Nature. 1980 Feb 21;283(5749):733–739. doi: 10.1038/283733a0. [DOI] [PubMed] [Google Scholar]
  9. Davis R. W., Hyman R. W. A study in evolution: the DNA base sequence homology between coliphages T7 and T3. J Mol Biol. 1971 Dec 14;62(2):287–301. doi: 10.1016/0022-2836(71)90428-1. [DOI] [PubMed] [Google Scholar]
  10. Dreyer W. J., Bennett J. C. The molecular basis of antibody formation: a paradox. Proc Natl Acad Sci U S A. 1965 Sep;54(3):864–869. doi: 10.1073/pnas.54.3.864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dunnick W., Rabbitts T. H., Milstein C. An immunoglobulin deletion mutant with implications for the heavy-chain switch and RNA splicing. Nature. 1980 Aug 14;286(5774):669–675. doi: 10.1038/286669a0. [DOI] [PubMed] [Google Scholar]
  12. Early P., Huang H., Davis M., Calame K., Hood L. An immunoglobulin heavy chain variable region gene is generated from three segments of DNA: VH, D and JH. Cell. 1980 Apr;19(4):981–992. doi: 10.1016/0092-8674(80)90089-6. [DOI] [PubMed] [Google Scholar]
  13. Early P., Rogers J., Davis M., Calame K., Bond M., Wall R., Hood L. Two mRNAs can be produced from a single immunoglobulin mu gene by alternative RNA processing pathways. Cell. 1980 Jun;20(2):313–319. doi: 10.1016/0092-8674(80)90617-0. [DOI] [PubMed] [Google Scholar]
  14. Fedoroff N. V., Brown D. D. The nucleotide sequence of oocyte 5S DNA in Xenopus laevis. I. The AT-rich spacer. Cell. 1978 Apr;13(4):701–716. doi: 10.1016/0092-8674(78)90220-9. [DOI] [PubMed] [Google Scholar]
  15. Fritsch E. F., Lawn R. M., Maniatis T. Molecular cloning and characterization of the human beta-like globin gene cluster. Cell. 1980 Apr;19(4):959–972. doi: 10.1016/0092-8674(80)90087-2. [DOI] [PubMed] [Google Scholar]
  16. Goldschmidt-Clermont M. Two genes for the major heat-shock protein of Drosophila melanogaster arranged as an inverted repeat. Nucleic Acids Res. 1980 Jan 25;8(2):235–252. doi: 10.1093/nar/8.2.235. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Gough N. M., Kemp D. J., Tyler B. M., Adams J. M., Cory S. Intervening sequences divide the gene for the constant region of mouse immunoglobulin mu chains into segments, each encoding a domain. Proc Natl Acad Sci U S A. 1980 Jan;77(1):554–558. doi: 10.1073/pnas.77.1.554. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hardison R. C., Butler E. T., 3rd, Lacy E., Maniatis T., Rosenthal N., Efstratiadis A. The structure and transcription of four linked rabbit beta-like globin genes. Cell. 1979 Dec;18(4):1285–1297. doi: 10.1016/0092-8674(79)90239-3. [DOI] [PubMed] [Google Scholar]
  19. Honjo T., Kataoka T. Organization of immunoglobulin heavy chain genes and allelic deletion model. Proc Natl Acad Sci U S A. 1978 May;75(5):2140–2144. doi: 10.1073/pnas.75.5.2140. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kataoka T., Kawakami T., Takahashi N., Honjo T. Rearrangement of immunoglobulin gamma 1-chain gene and mechanism for heavy-chain class switch. Proc Natl Acad Sci U S A. 1980 Feb;77(2):919–923. doi: 10.1073/pnas.77.2.919. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kemp D. J., Cory S., Adams J. M. Cloned pairs of variable region genes for immunoglobulin heavy chains isolated from a clone library of the entire mouse genome. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4627–4631. doi: 10.1073/pnas.76.9.4627. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kidd S. J., Glover D. M. A DNA segment from D. melanogaster which contains five tandemly repeating units homologous to the major rDNA insertion. Cell. 1980 Jan;19(1):103–119. doi: 10.1016/0092-8674(80)90392-x. [DOI] [PubMed] [Google Scholar]
  23. Konkel D. A., Maizel J. V., Jr, Leder P. The evolution and sequence comparison of two recently diverged mouse chromosomal beta--globin genes. Cell. 1979 Nov;18(3):865–873. doi: 10.1016/0092-8674(79)90138-7. [DOI] [PubMed] [Google Scholar]
  24. Laird C. D., McConaughy B. L., McCarthy B. J. Rate of fixation of nucleotide substitutions in evolution. Nature. 1969 Oct 11;224(5215):149–154. doi: 10.1038/224149a0. [DOI] [PubMed] [Google Scholar]
  25. Leder A., Miller H. I., Hamer D. H., Seidman J. G., Norman B., Sullivan M., Leder P. Comparison of cloned mouse alpha- and beta-globin genes: conservation of intervening sequence locations and extragenic homology. Proc Natl Acad Sci U S A. 1978 Dec;75(12):6187–6191. doi: 10.1073/pnas.75.12.6187. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lomedico P., Rosenthal N., Efstratidadis A., Gilbert W., Kolodner R., Tizard R. The structure and evolution of the two nonallelic rat preproinsulin genes. Cell. 1979 Oct;18(2):545–558. doi: 10.1016/0092-8674(79)90071-0. [DOI] [PubMed] [Google Scholar]
  27. Maki R., Traunecker A., Sakano H., Roeder W., Tonegawa S. Exon shuffling generates an immunoglobulin heavy chain gene. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2138–2142. doi: 10.1073/pnas.77.4.2138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Miller J. R., Cartwright E. M., Brownlee G. G., Fedoroff N. V., Brown D. D. The nucleotide sequence of oocyte 5S DNA in Xenopus laevis. II. The GC-rich region. Cell. 1978 Apr;13(4):717–725. doi: 10.1016/0092-8674(78)90221-0. [DOI] [PubMed] [Google Scholar]
  29. Miyata T., Yasunaga T., Yamawaki-Kataoka Y., Obata M., Honjo T. Nucleotide sequence divergence of mouse immunoglobulin gamma 1 and gamma 2b chain genes and the hypothesis of intervening sequence-mediated domain transfer. Proc Natl Acad Sci U S A. 1980 Apr;77(4):2143–2147. doi: 10.1073/pnas.77.4.2143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Nishioka Y., Leder A., Leder P. Unusual alpha-globin-like gene that has cleanly lost both globin intervening sequences. Proc Natl Acad Sci U S A. 1980 May;77(5):2806–2809. doi: 10.1073/pnas.77.5.2806. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Oi V. T., Bryan V. M., Herzenberg L. A., Herzenberg L. A. Lymphocyte membrane IgG and secreted IgG are structurally and allotypically distinct. J Exp Med. 1980 May 1;151(5):1260–1274. doi: 10.1084/jem.151.5.1260. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Parkhouse R. M., Lifter J., Choi Y. S. Chemical characterisation of the Fab and Fc fragments from surface immunoglobulin. Nature. 1980 Mar 20;284(5753):280–281. doi: 10.1038/284280a0. [DOI] [PubMed] [Google Scholar]
  33. Sakano H., Maki R., Kurosawa Y., Roeder W., Tonegawa S. Two types of somatic recombination are necessary for the generation of complete immunoglobulin heavy-chain genes. Nature. 1980 Aug 14;286(5774):676–683. doi: 10.1038/286676a0. [DOI] [PubMed] [Google Scholar]
  34. Sakano H., Rogers J. H., Hüppi K., Brack C., Traunecker A., Maki R., Wall R., Tonegawa S. Domains and the hinge region of an immunoglobulin heavy chain are encoded in separate DNA segments. Nature. 1979 Feb 22;277(5698):627–633. doi: 10.1038/277627a0. [DOI] [PubMed] [Google Scholar]
  35. Schaffner W., Kunz G., Daetwyler H., Telford J., Smith H. O., Birnstiel M. L. Genes and spacers of cloned sea urchin histone DNA analyzed by sequencing. Cell. 1978 Jul;14(3):655–671. doi: 10.1016/0092-8674(78)90249-0. [DOI] [PubMed] [Google Scholar]
  36. Shen C. K., Maniatis T. The organization of repetitive sequences in a cluster of rabbit beta-like globin genes. Cell. 1980 Feb;19(2):379–391. doi: 10.1016/0092-8674(80)90512-7. [DOI] [PubMed] [Google Scholar]
  37. Sures I., Lowry J., Kedes L. H. The DNA sequence of sea urchin (S. purpuratus) H2A, H2B and H3 histone coding and spacer regions. Cell. 1978 Nov;15(3):1033–1044. doi: 10.1016/0092-8674(78)90287-8. [DOI] [PubMed] [Google Scholar]
  38. Tonegawa S., Hozumi N., Matthyssens G., Schuller R. Somatic changes in the content and context of immunoglobulin genes. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):877–889. doi: 10.1101/sqb.1977.041.01.097. [DOI] [PubMed] [Google Scholar]
  39. Tyler B. M., Adams J. M. Enrichment of specific genes from genomic DNA or from clone library DNA, using R-looping. Gene. 1980 Jul;10(2):147–155. doi: 10.1016/0378-1119(80)90132-8. [DOI] [PubMed] [Google Scholar]
  40. Wellauer P. K., Dawid I. B., Brown D. D., Reeder R. H. The molecular basis for length heterogeneity in ribosomal DNA from Xenopus laevis. J Mol Biol. 1976 Aug 25;105(4):461–486. doi: 10.1016/0022-2836(76)90229-1. [DOI] [PubMed] [Google Scholar]
  41. Yamawaki-Kataoka Y., Sato K., Shimizu A., Kataoka T., Mano Y., Ono M., Kawakami M., Honjo T. Mutual homology of mouse immunoglobulin gamma-chain gene sequences. Biochemistry. 1979 Feb 6;18(3):490–494. doi: 10.1021/bi00570a018. [DOI] [PubMed] [Google Scholar]
  42. van den Berg J., van Ooyen A., Mantei N., Schamböck A., Grosveld G., Flavell R. A., Weissmann C. Comparison of cloned rabbit and mouse beta-globin genes showing strong evolutionary divergence of two homologous pairs of introns. Nature. 1978 Nov 2;276(5683):37–44. doi: 10.1038/276037a0. [DOI] [PubMed] [Google Scholar]

Articles from Nucleic Acids Research are provided here courtesy of Oxford University Press

RESOURCES