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. 1986 Oct;83(19):7542–7546. doi: 10.1073/pnas.83.19.7542

Recombination within the myelin basic protein gene created the dysmyelinating shiverer mouse mutation.

S M Molineaux, H Engh, F de Ferra, L Hudson, R A Lazzarini
PMCID: PMC386755  PMID: 2429310

Abstract

Shiverer (shi) is an autosomal recessive mutation in the mouse characterized by an almost total lack of central nervous system myelin. While small amounts of other myelin components are present in the brain of the shi mouse, the four forms of myelin basic protein (MBP) are not detectable. Previous investigations by us and others indicate that the MBP gene has undergone a major rearrangement in the shi mutant. Herein, we report in detail the nature and extent of the rearrangement: a 20-kilobase region within the MBP gene is missing in the mutant. We map the 5' breakpoint of the deletion to the second intron and the 3' breakpoint to a site 2 kilobases beyond the last MBP exon. The junction of the upstream and downstream portions of the gene contains only one nucleotide not accounted for by the wild-type MBP gene sequence. The 3' side of the deletion occurs in the 3rd of 11 tandem repeats of a 31-base-pair sequence. This region is rich in alternating purine and pyrimidine stretches, sequences that have been associated with both Z-DNA structures and gene rearrangements. The recombination junction shares several features with the junctions characterized by Anderson et al. [Anderson, R., Kato, S. & Camerini-Otero, D. (1984) Proc. Natl. Acad. Sci. USA 81, 206-210] in mouse L cells and is consistent with their model for a partially homologous recombination event. The structure of the shi recombination junction suggests that the donor DNA molecules were aligned in a partially homologous region before staggered cutting and joining occurred.

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Selected References

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

  1. Anderson R. A., Kato S., Camerini-Otero R. D. A pattern of partially homologous recombination in mouse L cells. Proc Natl Acad Sci U S A. 1984 Jan;81(1):206–210. doi: 10.1073/pnas.81.1.206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Barbarese E., Nielson M. L., Carson J. H. The effect of the shiverer mutation on myelin basic protein expression in homozygous and heterozygous mouse brain. J Neurochem. 1983 Jun;40(6):1680–1686. doi: 10.1111/j.1471-4159.1983.tb08142.x. [DOI] [PubMed] [Google Scholar]
  3. Billings-Gagliardi S., Hall A. L., Stanhope G. B., Altschuler R. J., Sidman R. L., Wolf M. K. Cultures of shiverer mutant cerebellum injected with normal oligodendrocytes make both normal and shiverer myelin. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2558–2561. doi: 10.1073/pnas.81.8.2558. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bird T. D., Farrell D. F., Sumi S. M. Brain lipid composition of the shiverer mouse: (genetic defect in myelin development). J Neurochem. 1978 Jul;31(1):387–391. doi: 10.1111/j.1471-4159.1978.tb12479.x. [DOI] [PubMed] [Google Scholar]
  5. Biro P. A., Carr-Brown A., Southern E. M., Walker P. M. Partial sequence analysis of mouse satellite DNA evidence for short range periodicities. J Mol Biol. 1975 May 5;94(1):71–86. doi: 10.1016/0022-2836(75)90405-2. [DOI] [PubMed] [Google Scholar]
  6. Campagnoni A. T., Campagnoni C. W., Bourre J. M., Jacque C., Baumann N. Cell-free synthesis of myelin basic proteins in normal and dysmyelinating mutant mice. J Neurochem. 1984 Mar;42(3):733–739. doi: 10.1111/j.1471-4159.1984.tb02744.x. [DOI] [PubMed] [Google Scholar]
  7. Chernoff G. F. Shiverer: an autosomal recessive mutant mouse with myelin deficiency. J Hered. 1981 Mar-Apr;72(2):128–128. doi: 10.1093/oxfordjournals.jhered.a109442. [DOI] [PubMed] [Google Scholar]
  8. Davis M. M., Kim S. K., Hood L. E. DNA sequences mediating class switching in alpha-immunoglobulins. Science. 1980 Sep 19;209(4463):1360–1365. doi: 10.1126/science.6774415. [DOI] [PubMed] [Google Scholar]
  9. Dupouey P., Jacque C., Bourre J. M., Cesselin F., Privat A., Baumann N. Immunochemical studies of myelin basic protein in shiverer mouse devoid of major dense line of myelin. Neurosci Lett. 1979 Apr;12(1):113–118. doi: 10.1016/0304-3940(79)91490-3. [DOI] [PubMed] [Google Scholar]
  10. Efstratiadis A., Posakony J. W., Maniatis T., Lawn R. M., O'Connell C., Spritz R. A., DeRiel J. K., Forget B. G., Weissman S. M., Slightom J. L. The structure and evolution of the human beta-globin gene family. Cell. 1980 Oct;21(3):653–668. doi: 10.1016/0092-8674(80)90429-8. [DOI] [PubMed] [Google Scholar]
  11. Frischauf A. M., Lehrach H., Poustka A., Murray N. Lambda replacement vectors carrying polylinker sequences. J Mol Biol. 1983 Nov 15;170(4):827–842. doi: 10.1016/s0022-2836(83)80190-9. [DOI] [PubMed] [Google Scholar]
  12. Gerondakis S., Cory S., Adams J. M. Translocation of the myc cellular oncogene to the immunoglobulin heavy chain locus in murine plasmacytomas is an imprecise reciprocal exchange. Cell. 1984 Apr;36(4):973–982. doi: 10.1016/0092-8674(84)90047-3. [DOI] [PubMed] [Google Scholar]
  13. Greenfield S., Brostoff S., Eylar E. H., Morell P. Protein composition of myelin of the peripheral nervous system. J Neurochem. 1973 Apr;20(4):1207–1216. doi: 10.1111/j.1471-4159.1973.tb00089.x. [DOI] [PubMed] [Google Scholar]
  14. Hamada H., Kakunaga T. Potential Z-DNA forming sequences are highly dispersed in the human genome. Nature. 1982 Jul 22;298(5872):396–398. doi: 10.1038/298396a0. [DOI] [PubMed] [Google Scholar]
  15. Hamada H., Petrino M. G., Kakunaga T. A novel repeated element with Z-DNA-forming potential is widely found in evolutionarily diverse eukaryotic genomes. Proc Natl Acad Sci U S A. 1982 Nov;79(21):6465–6469. doi: 10.1073/pnas.79.21.6465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Haniford D. B., Pulleyblank D. E. Facile transition of poly[d(TG) x d(CA)] into a left-handed helix in physiological conditions. Nature. 1983 Apr 14;302(5909):632–634. doi: 10.1038/302632a0. [DOI] [PubMed] [Google Scholar]
  17. Inouye H., Ganser A. L., Kirschner D. A. Shiverer and normal peripheral myelin compared: basic protein localization, membrane interactions, and lipid composition. J Neurochem. 1985 Dec;45(6):1911–1922. doi: 10.1111/j.1471-4159.1985.tb10551.x. [DOI] [PubMed] [Google Scholar]
  18. Jelinek W. R., Schmid C. W. Repetitive sequences in eukaryotic DNA and their expression. Annu Rev Biochem. 1982;51:813–844. doi: 10.1146/annurev.bi.51.070182.004121. [DOI] [PubMed] [Google Scholar]
  19. Kataoka T., Miyata T., Honjo T. Repetitive sequences in class-switch recombination regions of immunoglobulin heavy chain genes. Cell. 1981 Feb;23(2):357–368. doi: 10.1016/0092-8674(81)90131-8. [DOI] [PubMed] [Google Scholar]
  20. Kimura M., Inoko H., Katsuki M., Ando A., Sato T., Hirose T., Takashima H., Inayama S., Okano H., Takamatsu K. Molecular genetic analysis of myelin-deficient mice: shiverer mutant mice show deletion in gene(s) coding for myelin basic protein. J Neurochem. 1985 Mar;44(3):692–696. doi: 10.1111/j.1471-4159.1985.tb12870.x. [DOI] [PubMed] [Google Scholar]
  21. Kirschner D. A., Ganser A. L. Compact myelin exists in the absence of basic protein in the shiverer mutant mouse. Nature. 1980 Jan 10;283(5743):207–210. doi: 10.1038/283207a0. [DOI] [PubMed] [Google Scholar]
  22. 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]
  23. Marotta C. A., Wilson J. T., Forget B. G., Weissman S. M. Human beta-globin messenger RNA. III. Nucleotide sequences derived from complementary DNA. J Biol Chem. 1977 Jul 25;252(14):5040–5053. [PubMed] [Google Scholar]
  24. Maxam A. M., Gilbert W. Sequencing end-labeled DNA with base-specific chemical cleavages. Methods Enzymol. 1980;65(1):499–560. doi: 10.1016/s0076-6879(80)65059-9. [DOI] [PubMed] [Google Scholar]
  25. Nordheim A., Rich A. Negatively supercoiled simian virus 40 DNA contains Z-DNA segments within transcriptional enhancer sequences. Nature. 1983 Jun 23;303(5919):674–679. doi: 10.1038/303674a0. [DOI] [PubMed] [Google Scholar]
  26. Nordheim A., Rich A. The sequence (dC-dA)n X (dG-dT)n forms left-handed Z-DNA in negatively supercoiled plasmids. Proc Natl Acad Sci U S A. 1983 Apr;80(7):1821–1825. doi: 10.1073/pnas.80.7.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Roach A., Boylan K., Horvath S., Prusiner S. B., Hood L. E. Characterization of cloned cDNA representing rat myelin basic protein: absence of expression in brain of shiverer mutant mice. Cell. 1983 Oct;34(3):799–806. doi: 10.1016/0092-8674(83)90536-6. [DOI] [PubMed] [Google Scholar]
  28. Roach A., Takahashi N., Pravtcheva D., Ruddle F., Hood L. Chromosomal mapping of mouse myelin basic protein gene and structure and transcription of the partially deleted gene in shiverer mutant mice. Cell. 1985 Aug;42(1):149–155. doi: 10.1016/s0092-8674(85)80110-0. [DOI] [PubMed] [Google Scholar]
  29. Rosenbluth J. Central myelin in the mouse mutant shiverer. J Comp Neurol. 1980 Dec 1;194(3):639–648. doi: 10.1002/cne.901940310. [DOI] [PubMed] [Google Scholar]
  30. Rosenbluth J. Peripheral myelin in the mouse mutant Shiverer. J Comp Neurol. 1980 Oct 1;193(3):729–739. doi: 10.1002/cne.901930310. [DOI] [PubMed] [Google Scholar]
  31. Sanger F., Coulson A. R., Barrell B. G., Smith A. J., Roe B. A. Cloning in single-stranded bacteriophage as an aid to rapid DNA sequencing. J Mol Biol. 1980 Oct 25;143(2):161–178. doi: 10.1016/0022-2836(80)90196-5. [DOI] [PubMed] [Google Scholar]
  32. Sidman R. L., Conover C. S., Carson J. H. Shiverer gene maps near the distal end of chromosome 18 in the house mouse. Cytogenet Cell Genet. 1985;39(4):241–245. doi: 10.1159/000132151. [DOI] [PubMed] [Google Scholar]
  33. Singer M. F. Highly repeated sequences in mammalian genomes. Int Rev Cytol. 1982;76:67–112. doi: 10.1016/s0074-7696(08)61789-1. [DOI] [PubMed] [Google Scholar]
  34. Slightom J. L., Blechl A. E., Smithies O. Human fetal G gamma- and A gamma-globin genes: complete nucleotide sequences suggest that DNA can be exchanged between these duplicated genes. Cell. 1980 Oct;21(3):627–638. doi: 10.1016/0092-8674(80)90426-2. [DOI] [PubMed] [Google Scholar]
  35. Soares M. B., Schon E., Efstratiadis A. Rat LINE1: the origin and evolution of a family of long interspersed middle repetitive DNA elements. J Mol Evol. 1985;22(2):117–133. doi: 10.1007/BF02101690. [DOI] [PubMed] [Google Scholar]
  36. Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
  37. Stringer J. R. Recombination between poly[d(GT).d(CA)] sequences in simian virus 40-infected cultured cells. Mol Cell Biol. 1985 Jun;5(6):1247–1259. doi: 10.1128/mcb.5.6.1247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Takahashi N., Roach A., Teplow D. B., Prusiner S. B., Hood L. Cloning and characterization of the myelin basic protein gene from mouse: one gene can encode both 14 kd and 18.5 kd MBPs by alternate use of exons. Cell. 1985 Aug;42(1):139–148. doi: 10.1016/s0092-8674(85)80109-4. [DOI] [PubMed] [Google Scholar]
  39. de Ferra F., Engh H., Hudson L., Kamholz J., Puckett C., Molineaux S., Lazzarini R. A. Alternative splicing accounts for the four forms of myelin basic protein. Cell. 1985 Dec;43(3 Pt 2):721–727. doi: 10.1016/0092-8674(85)90245-4. [DOI] [PubMed] [Google Scholar]

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