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. 1986 May;83(10):3371–3375. doi: 10.1073/pnas.83.10.3371

Mitotic recombination in germ cells generated two major histocompatibility complex mutant genes shown to be identical by RNA sequence analysis: Kbm9 and Kbm6.

J Geliebter, R A Zeff, R W Melvold, S G Nathenson
PMCID: PMC323515  PMID: 3458188

Abstract

RNA sequencing represents a major procedural simplification for nucleotide sequence analysis of a transcribed gene. Using newly adapted mRNA and cDNA sequencing procedures, we have sequenced 855 nucleotides of Kbm9 mRNA, corresponding to the codons for the aminoterminal 285 amino acids. The inferred DNA sequence of the Kbm9 gene differs from the parental Kb sequence by single nucleotide alterations in each of codons 116 and 121, resulting in Tyr----Phe and Cys----Arg substitutions, respectively. The Kbm9 sequence is identical to that of another independently arising MHC mutant gene, Kbm6. As both the Kbm9 and Kbm6 genes were generated by recombination between the Kb and Q4 genes, our data indicate that the identical genetic interactions have occurred at least twice. The relatively large extent of identity between Q4 and Kb may be responsible for frequent recombination between the two genes. The parents of the original bm9 mutant mice had five identical mutant offspring, which can be explained by mitotic recombination in the germ cells, producing gonadal mosaicism in the C57BL/6 mother. Thus, mitotic recombination, and not meiotic recombination, appears to be responsible for the formation of at least some of the Kb mutants. Such a mechanism probably plays a major role in the generation of diversity in the major histocompatibility complex.

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Selected References

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

  1. Arnold B., Burgert H. G., Archibald A. L., Kvist S. Complete nucleotide sequence of the murine H-2Kk gene. Comparison of three H-2K locus alleles. Nucleic Acids Res. 1984 Dec 21;12(24):9473–9487. doi: 10.1093/nar/12.24.9473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bina-Stein M., Thoren M., Salzman N., Thomspon J. A. Rapid sequence determination of late simian virus 40 16S mRNA leader by using inhibitors of reverse transcriptase. Proc Natl Acad Sci U S A. 1979 Feb;76(2):731–735. doi: 10.1073/pnas.76.2.731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Clarke S. H., Huppi K., Ruezinsky D., Staudt L., Gerhard W., Weigert M. Inter- and intraclonal diversity in the antibody response to influenza hemagglutinin. J Exp Med. 1985 Apr 1;161(4):687–704. doi: 10.1084/jem.161.4.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Egorov O. S., Egorov I. K. H-2bm23, a new Kb mutant similar to, but not identical with H-2bm3. Immunogenetics. 1984;20(1):83–87. doi: 10.1007/BF00373449. [DOI] [PubMed] [Google Scholar]
  5. Evans G. A., Margulies D. H., Camerini-Otero R. D., Ozato K., Seidman J. G. Structure and expression of a mouse major histocompatibility antigen gene, H-2Ld. Proc Natl Acad Sci U S A. 1982 Mar;79(6):1994–1998. doi: 10.1073/pnas.79.6.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Geliebter J., Zeff R. A., Schulze D. H., Pease L. R., Weiss E. H., Mellor A. L., Flavell R. A., Nathenson S. G. Interaction between Kb and Q4 gene sequences generates the Kbm6 mutation. Mol Cell Biol. 1986 Feb;6(2):645–652. doi: 10.1128/mcb.6.2.645. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Goodenow R. S., Vogel J. M., Linsk R. L. Histocompatibility antigens on murine tumors. Science. 1985 Nov 15;230(4727):777–783. doi: 10.1126/science.2997918. [DOI] [PubMed] [Google Scholar]
  8. Hamlyn P. H., Browniee G. G., Cheng C. C., Gait M. J., Milstein C. Complete sequence of constant and 3' noncoding regions of an immunoglobulin mRNA using the dideoxynucleotide method of RNA sequencing. Cell. 1978 Nov;15(3):1067–1075. doi: 10.1016/0092-8674(78)90290-8. [DOI] [PubMed] [Google Scholar]
  9. Jackson J. A., Fink G. R. Gene conversion between duplicated genetic elements in yeast. Nature. 1981 Jul 23;292(5821):306–311. doi: 10.1038/292306a0. [DOI] [PubMed] [Google Scholar]
  10. Kimball E. S., Coligan J. E. Structure of class I major histocompatibility antigens. Contemp Top Mol Immunol. 1983;9:1–63. doi: 10.1007/978-1-4684-4517-6_1. [DOI] [PubMed] [Google Scholar]
  11. Klein J. H-2 mutations: their genetics and effect on immune functions. Adv Immunol. 1978;26:55–146. doi: 10.1016/s0065-2776(08)60229-1. [DOI] [PubMed] [Google Scholar]
  12. Klein J. The major histocompatibility complex of the mouse. Science. 1979 Feb 9;203(4380):516–521. doi: 10.1126/science.104386. [DOI] [PubMed] [Google Scholar]
  13. Kmiec E. B., Angelides K. J., Holloman W. K. Left-handed DNA and the synaptic pairing reaction promoted by Ustilago rec1 protein. Cell. 1985 Jan;40(1):139–145. doi: 10.1016/0092-8674(85)90317-4. [DOI] [PubMed] [Google Scholar]
  14. Liskay R. M., Stachelek J. L., Letsou A. Homologous recombination between repeated chromosomal sequences in mouse cells. Cold Spring Harb Symp Quant Biol. 1984;49:183–189. doi: 10.1101/sqb.1984.049.01.021. [DOI] [PubMed] [Google Scholar]
  15. McGeoch D. J., Turnbull N. T. Analysis of the 3'-terminal nucleotide sequence of vesicular stomatitis virus N protein mRNA. Nucleic Acids Res. 1978 Nov;5(11):4007–4024. doi: 10.1093/nar/5.11.4007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. McIntyre K. R., Seidman J. G. Nucleotide sequence of mutant I-A beta bm12 gene is evidence for genetic exchange between mouse immune response genes. Nature. 1984 Apr 5;308(5959):551–553. doi: 10.1038/308551a0. [DOI] [PubMed] [Google Scholar]
  17. Mellor A. L., Weiss E. H., Kress M., Jay G., Flavell R. A. A nonpolymorphic class I gene in the murine major histocompatibility complex. Cell. 1984 Jan;36(1):139–144. doi: 10.1016/0092-8674(84)90082-5. [DOI] [PubMed] [Google Scholar]
  18. Mellor A. L., Weiss E. H., Ramachandran K., Flavell R. A. A potential donor gene for the bm1 gene conversion event in the C57BL mouse. Nature. 1983 Dec 22;306(5945):792–795. doi: 10.1038/306792a0. [DOI] [PubMed] [Google Scholar]
  19. Melvold R. W., Kohn H. I., Dunn G. R. History and genealogy of the H-2Kb mutants from the C57BL/6Kh colony. Immunogenetics. 1982;15(2):177–185. doi: 10.1007/BF00621950. [DOI] [PubMed] [Google Scholar]
  20. Meselson M. S., Radding C. M. A general model for genetic recombination. Proc Natl Acad Sci U S A. 1975 Jan;72(1):358–361. doi: 10.1073/pnas.72.1.358. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Michaelson J., Flaherty L., Hutchinson B., Yudkowitz H. Qa-2 does not display structural genetic polymorphism detectable on isoelectric-focusing gels. Immunogenetics. 1982;16(4):363–366. doi: 10.1007/BF00372308. [DOI] [PubMed] [Google Scholar]
  22. Nairn R., Yamaga K., Nathenson S. G. Biochemistry of the gene products from murine MHC mutants. Annu Rev Genet. 1980;14:241–277. doi: 10.1146/annurev.ge.14.120180.001325. [DOI] [PubMed] [Google Scholar]
  23. Nathenson S. G., Uehara H., Ewenstein B. M., Kindt T. J., Coligan J. E. Primary structural: analysis of the transplantation antigens of the murine H-2 major histocompatibility complex. Annu Rev Biochem. 1981;50:1025–1052. doi: 10.1146/annurev.bi.50.070181.005113. [DOI] [PubMed] [Google Scholar]
  24. Pease L. R. Diversity in H-2 genes encoding antigen-presenting molecules is generated by interactions between members of the major histocompatibility complex gene family. Transplantation. 1985 Mar;39(3):227–231. doi: 10.1097/00007890-198503000-00001. [DOI] [PubMed] [Google Scholar]
  25. Pease L. R., Schulze D. H., Pfaffenbach G. M., Nathenson S. G. Spontaneous H-2 mutants provide evidence that a copy mechanism analogous to gene conversion generates polymorphism in the major histocompatibility complex. Proc Natl Acad Sci U S A. 1983 Jan;80(1):242–246. doi: 10.1073/pnas.80.1.242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reeder R. H., Roan J. G., Dunaway M. Spacer regulation of Xenopus ribosomal gene transcription: competition in oocytes. Cell. 1983 Dec;35(2 Pt 1):449–456. doi: 10.1016/0092-8674(83)90178-2. [DOI] [PubMed] [Google Scholar]
  27. Rich A., Nordheim A., Wang A. H. The chemistry and biology of left-handed Z-DNA. Annu Rev Biochem. 1984;53:791–846. doi: 10.1146/annurev.bi.53.070184.004043. [DOI] [PubMed] [Google Scholar]
  28. Sasavage N. L., Smith M., Gillam S., Astell C., Nilson J. H., Rottman F. Use of oligodeoxynucleotide primers to determine poly(adenylic acid) adjacent sequences in messenger ribonucleic acid. 3'-Terminal noncoding sequence of bovine growth hormone messenger ribonucleic acid. Biochemistry. 1980 Apr 29;19(9):1737–1743. doi: 10.1021/bi00550a003. [DOI] [PubMed] [Google Scholar]
  29. Schulze D. H., Pease L. R., Geier S. S., Reyes A. A., Sarmiento L. A., Wallace R. B., Nathenson S. G. Comparison of the cloned H-2Kbm1 variant gene with the H-2Kb gene shows a cluster of seven nucleotide differences. Proc Natl Acad Sci U S A. 1983 Apr;80(7):2007–2011. doi: 10.1073/pnas.80.7.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Sood A. K., Pereira D., Weissman S. M. Isolation and partial nucleotide sequence of a cDNA clone for human histocompatibility antigen HLA-B by use of an oligodeoxynucleotide primer. Proc Natl Acad Sci U S A. 1981 Jan;78(1):616–620. doi: 10.1073/pnas.78.1.616. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Watt V. M., Ingles C. J., Urdea M. S., Rutter W. J. Homology requirements for recombination in Escherichia coli. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4768–4772. doi: 10.1073/pnas.82.14.4768. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Weiss E. H., Golden L., Fahrner K., Mellor A. L., Devlin J. J., Bullman H., Tiddens H., Bud H., Flavell R. A. Organization and evolution of the class I gene family in the major histocompatibility complex of the C57BL/10 mouse. Nature. 1984 Aug 23;310(5979):650–655. doi: 10.1038/310650a0. [DOI] [PubMed] [Google Scholar]
  33. Weiss E. H., Mellor A., Golden L., Fahrner K., Simpson E., Hurst J., Flavell R. A. The structure of a mutant H-2 gene suggests that the generation of polymorphism in H-2 genes may occur by gene conversion-like events. Nature. 1983 Feb 24;301(5902):671–674. doi: 10.1038/301671a0. [DOI] [PubMed] [Google Scholar]
  34. Weiss E., Golden L., Zakut R., Mellor A., Fahrner K., Kvist S., Flavell R. A. The DNA sequence of the H-2kb gene: evidence for gene conversion as a mechanism for the generation of polymorphism in histocompatibilty antigens. EMBO J. 1983;2(3):453–462. doi: 10.1002/j.1460-2075.1983.tb01444.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Widera G., Flavell R. A. The I region of the C57BL/10 mouse: characterization and physical linkage to H-2K of an SB beta-like class II pseudogene, psi A beta 3. Proc Natl Acad Sci U S A. 1985 Aug;82(16):5500–5504. doi: 10.1073/pnas.82.16.5500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Widera G., Flavell R. A. The nucleotide sequence of the murine I-E beta b immune response gene: evidence for gene conversion events in class II genes of the major histocompatibility complex. EMBO J. 1984 Jun;3(6):1221–1225. doi: 10.1002/j.1460-2075.1984.tb01956.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Yamaga K. M., Pfaffenbach G. M., Pease L. R., McGovern D., Nisizawa T., Melvold R. W., Kohn H. I., Nathenson S. G. Biochemical studies of H-2K antigens from a group of related mutants. I. Identification of a shared mutation in B6-H-2bm5 and B6-H-2bm16. Immunogenetics. 1983;17(1):19–29. doi: 10.1007/BF00364286. [DOI] [PubMed] [Google Scholar]
  38. Yamaga K. M., Pfaffenbach G. M., Pease L. R., McGovern D., Nisizawa T., Melvold R. W., Kohn H. I., Nathenson S. G. Biochemical studies of H-2K antigens from a group of related mutants. II. Identification of a shared mutation in B6-H-2bm6, B6.C-H-2bm7, and B6.C-H-2bm9. Immunogenetics. 1983;17(1):31–41. doi: 10.1007/BF00364287. [DOI] [PubMed] [Google Scholar]
  39. Yokoyama K., Stockert E., Old L. J., Nathenson S. G. Structural comparisons of TL antigens derived from normal and leukemia cells of Tl+ and TL- strains and relationship to genetically linked H-2 major histocompatibility complex products. Proc Natl Acad Sci U S A. 1981 Nov;78(11):7078–7082. doi: 10.1073/pnas.78.11.7078. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Zimmern D., Kaesberg P. 3'-terminal nucleotide sequence of encephalomyocarditis virus RNA determined by reverse transcriptase and chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4257–4261. doi: 10.1073/pnas.75.9.4257. [DOI] [PMC free article] [PubMed] [Google Scholar]

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