Skip to main content
PMC home page
Nucleic Acids Research logoLink to Nucleic Acids Research
. 1990 Feb 11;18(3):561–567. doi: 10.1093/nar/18.3.561

Recombination via flanking direct repeats is a major cause of large-scale deletions of human mitochondrial DNA.

S Mita 1, R Rizzuto 1, C T Moraes 1, S Shanske 1, E Arnaudo 1, G M Fabrizi 1, Y Koga 1, S DiMauro 1, E A Schon 1
PMCID: PMC333462  PMID: 2308845

Abstract

Large-scale deletions of mitochondrial DNA (mtDNA) have been described in patients with progressive external ophthalmoplegia (PEO) and ragged red fibers. We have determined the exact deletion breakpoint in 28 cases with PEO, including 12 patients already shown to harbor an identical deletion; the other patients had 16 different deletions. The deletions fell into two classes. In Class I (9 deletions; 71% of the patients), the deletion was flanked by perfect direct repeats, located (in normal mtDNA) at the edges of the deletion. In Class II (8 deletions; 29% of patients), the deletions were not flanked by any obviously unique repeat element, or they were flanked by repeat elements which were located imprecisely relative to the breakpoints. Computer analysis showed a correlation between the location of the deletion breakpoints and sequences in human mtDNA similar to the target sequence for Drosophila topoisomerase II. It is not known how these deletions originate, but both slipped mispairing and legitimate recombination could be mechanisms playing a major role in the generation of the large mtDNA deletions found in PEO.

Full text

PDF
561

Selected References

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

  1. Ahne A., Müller-Derlich J., Merlos-Lange A. M., Kanbay F., Wolf K., Lang B. F. Two distinct mechanisms for deletion in mitochondrial DNA of Schizosaccharomyces pombe mutator strains. Slipped mispairing mediated by direct repeats and erroneous intron splicing. J Mol Biol. 1988 Aug 20;202(4):725–734. doi: 10.1016/0022-2836(88)90553-0. [DOI] [PubMed] [Google Scholar]
  2. Albertini A. M., Hofer M., Calos M. P., Miller J. H. On the formation of spontaneous deletions: the importance of short sequence homologies in the generation of large deletions. Cell. 1982 Jun;29(2):319–328. doi: 10.1016/0092-8674(82)90148-9. [DOI] [PubMed] [Google Scholar]
  3. Almasan A., Mishra N. C. Molecular characterization of the mitochondrial DNA of a new stopper mutant ER-3 of Neurospora crassa. Genetics. 1988 Dec;120(4):935–945. doi: 10.1093/genetics/120.4.935. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Anderson S., Bankier A. T., Barrell B. G., de Bruijn M. H., Coulson A. R., Drouin J., Eperon I. C., Nierlich D. P., Roe B. A., Sanger F. Sequence and organization of the human mitochondrial genome. Nature. 1981 Apr 9;290(5806):457–465. doi: 10.1038/290457a0. [DOI] [PubMed] [Google Scholar]
  5. Boursot P., Yonekawa H., Bonhomme F. Heteroplasmy in mice with deletion of a large coding region of mitochondrial DNA. Mol Biol Evol. 1987 Jan;4(1):46–55. doi: 10.1093/oxfordjournals.molbev.a040421. [DOI] [PubMed] [Google Scholar]
  6. Canning S., Dryja T. P. Short, direct repeats at the breakpoints of deletions of the retinoblastoma gene. Proc Natl Acad Sci U S A. 1989 Jul;86(13):5044–5048. doi: 10.1073/pnas.86.13.5044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chang D. D., Clayton D. A. Mouse RNAase MRP RNA is encoded by a nuclear gene and contains a decamer sequence complementary to a conserved region of mitochondrial RNA substrate. Cell. 1989 Jan 13;56(1):131–139. doi: 10.1016/0092-8674(89)90991-4. [DOI] [PubMed] [Google Scholar]
  8. Clayton D. A. Replication of animal mitochondrial DNA. Cell. 1982 Apr;28(4):693–705. doi: 10.1016/0092-8674(82)90049-6. [DOI] [PubMed] [Google Scholar]
  9. Devereux J., Haeberli P., Smithies O. A comprehensive set of sequence analysis programs for the VAX. Nucleic Acids Res. 1984 Jan 11;12(1 Pt 1):387–395. doi: 10.1093/nar/12.1part1.387. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dieckmann C. L., Gandy B. Preferential recombination between GC clusters in yeast mitochondrial DNA. EMBO J. 1987 Dec 20;6(13):4197–4203. doi: 10.1002/j.1460-2075.1987.tb02767.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. 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]
  12. Farabaugh P. J., Schmeissner U., Hofer M., Miller J. H. Genetic studies of the lac repressor. VII. On the molecular nature of spontaneous hotspots in the lacI gene of Escherichia coli. J Mol Biol. 1978 Dec 25;126(4):847–857. doi: 10.1016/0022-2836(78)90023-2. [DOI] [PubMed] [Google Scholar]
  13. Foury F., Lahaye A. Cloning and sequencing of the PIF gene involved in repair and recombination of yeast mitochondrial DNA. EMBO J. 1987 May;6(5):1441–1449. doi: 10.1002/j.1460-2075.1987.tb02385.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gross S. R., Hsieh T. S., Levine P. H. Intramolecular recombination as a source of mitochondrial chromosome heteromorphism in Neurospora. Cell. 1984 Aug;38(1):233–239. doi: 10.1016/0092-8674(84)90545-2. [DOI] [PubMed] [Google Scholar]
  15. Holt I. J., Harding A. E., Morgan-Hughes J. A. Deletions of muscle mitochondrial DNA in mitochondrial myopathies: sequence analysis and possible mechanisms. Nucleic Acids Res. 1989 Jun 26;17(12):4465–4469. doi: 10.1093/nar/17.12.4465. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Holt I. J., Harding A. E., Morgan-Hughes J. A. Deletions of muscle mitochondrial DNA in patients with mitochondrial myopathies. Nature. 1988 Feb 25;331(6158):717–719. doi: 10.1038/331717a0. [DOI] [PubMed] [Google Scholar]
  17. Johns D. R., Rutledge S. L., Stine O. C., Hurko O. Directly repeated sequences associated with pathogenic mitochondrial DNA deletions. Proc Natl Acad Sci U S A. 1989 Oct;86(20):8059–8062. doi: 10.1073/pnas.86.20.8059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. King S. R., Krolewski M. A., Marvo S. L., Lipson P. J., Pogue-Geile K. L., Chung J. H., Jaskunas S. R. Nucleotide sequence analysis of in vivo recombinants between bacteriophage lambda DNA and pBR322. Mol Gen Genet. 1982;186(4):548–557. doi: 10.1007/BF00337963. [DOI] [PubMed] [Google Scholar]
  19. Kobayashi I., Stahl M. M., Stahl F. W. The mechanism of the chi-cos interaction in RecA-RecBC-mediated recombination in phage lambda. Cold Spring Harb Symp Quant Biol. 1984;49:497–506. doi: 10.1101/sqb.1984.049.01.056. [DOI] [PubMed] [Google Scholar]
  20. Koll F., Belcour L. Are intron-encoded specific endonucleases responsible for nonhomologous recombination? Trends Genet. 1989 Jun;5(6):173–173. doi: 10.1016/0168-9525(89)90071-1. [DOI] [PubMed] [Google Scholar]
  21. Mita S., Schmidt B., Schon E. A., DiMauro S., Bonilla E. Detection of "deleted" mitochondrial genomes in cytochrome-c oxidase-deficient muscle fibers of a patient with Kearns-Sayre syndrome. Proc Natl Acad Sci U S A. 1989 Dec;86(23):9509–9513. doi: 10.1073/pnas.86.23.9509. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Moon E., Kao T. H., Wu R. Rice mitochondrial genome contains a rearranged chloroplast gene cluster. Mol Gen Genet. 1988 Aug;213(2-3):247–253. doi: 10.1007/BF00339588. [DOI] [PubMed] [Google Scholar]
  23. Moraes C. T., DiMauro S., Zeviani M., Lombes A., Shanske S., Miranda A. F., Nakase H., Bonilla E., Werneck L. C., Servidei S. Mitochondrial DNA deletions in progressive external ophthalmoplegia and Kearns-Sayre syndrome. N Engl J Med. 1989 May 18;320(20):1293–1299. doi: 10.1056/NEJM198905183202001. [DOI] [PubMed] [Google Scholar]
  24. Naito A., Naito S., Ikeda H. Homology is not required for recombination mediated by DNA gyrase of Escherichia coli. Mol Gen Genet. 1984;193(2):238–243. doi: 10.1007/BF00330674. [DOI] [PubMed] [Google Scholar]
  25. Nalbantoglu J., Hartley D., Phear G., Tear G., Meuth M. Spontaneous deletion formation at the aprt locus of hamster cells: the presence of short sequence homologies and dyad symmetries at deletion termini. EMBO J. 1986 Jun;5(6):1199–1204. doi: 10.1002/j.1460-2075.1986.tb04347.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Ogihara Y., Terachi T., Sasakuma T. Intramolecular recombination of chloroplast genome mediated by short direct-repeat sequences in wheat species. Proc Natl Acad Sci U S A. 1988 Nov;85(22):8573–8577. doi: 10.1073/pnas.85.22.8573. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Pikó L., Matsumoto L. Number of mitochondria and some properties of mitochondrial DNA in the mouse egg. Dev Biol. 1976 Mar;49(1):1–10. doi: 10.1016/0012-1606(76)90253-0. [DOI] [PubMed] [Google Scholar]
  28. Pribnow D., Sigurdson D. C., Gold L., Singer B. S., Napoli C., Brosius J., Dull T. J., Noller H. F. rII cistrons of bacteriophage T4. DNA sequence around the intercistronic divide and positions of genetic landmarks. J Mol Biol. 1981 Jul 5;149(3):337–376. doi: 10.1016/0022-2836(81)90477-0. [DOI] [PubMed] [Google Scholar]
  29. Rotig A., Colonna M., Bonnefont J. P., Blanche S., Fischer A., Saudubray J. M., Munnich A. Mitochondrial DNA deletion in Pearson's marrow/pancreas syndrome. Lancet. 1989 Apr 22;1(8643):902–903. doi: 10.1016/s0140-6736(89)92897-3. [DOI] [PubMed] [Google Scholar]
  30. Saiki R. K., Scharf S., Faloona F., Mullis K. B., Horn G. T., Erlich H. A., Arnheim N. Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science. 1985 Dec 20;230(4732):1350–1354. doi: 10.1126/science.2999980. [DOI] [PubMed] [Google Scholar]
  31. Sander M., Hsieh T. S. Drosophila topoisomerase II double-strand DNA cleavage: analysis of DNA sequence homology at the cleavage site. Nucleic Acids Res. 1985 Feb 25;13(4):1057–1072. doi: 10.1093/nar/13.4.1057. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Schaaper R. M., Danforth B. N., Glickman B. W. Mechanisms of spontaneous mutagenesis: an analysis of the spectrum of spontaneous mutation in the Escherichia coli lacI gene. J Mol Biol. 1986 May 20;189(2):273–284. doi: 10.1016/0022-2836(86)90509-7. [DOI] [PubMed] [Google Scholar]
  33. Schon E. A., Rizzuto R., Moraes C. T., Nakase H., Zeviani M., DiMauro S. A direct repeat is a hotspot for large-scale deletion of human mitochondrial DNA. Science. 1989 Apr 21;244(4902):346–349. doi: 10.1126/science.2711184. [DOI] [PubMed] [Google Scholar]
  34. Shoffner J. M., Lott M. T., Voljavec A. S., Soueidan S. A., Costigan D. A., Wallace D. C. Spontaneous Kearns-Sayre/chronic external ophthalmoplegia plus syndrome associated with a mitochondrial DNA deletion: a slip-replication model and metabolic therapy. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7952–7956. doi: 10.1073/pnas.86.20.7952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Spitzner J. R., Muller M. T. A consensus sequence for cleavage by vertebrate DNA topoisomerase II. Nucleic Acids Res. 1988 Jun 24;16(12):5533–5556. doi: 10.1093/nar/16.12.5533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Studier F. W., Rosenberg A. H., Simon M. N., Dunn J. J. Genetic and physical mapping in the early region of bacteriophage T7 DNA. J Mol Biol. 1979 Dec 25;135(4):917–937. doi: 10.1016/0022-2836(79)90520-5. [DOI] [PubMed] [Google Scholar]
  37. Tanaka M., Sato W., Ohno K., Yamamoto T., Ozawa T. Direct sequencing of deleted mitochondrial DNA in myopathic patients. Biochem Biophys Res Commun. 1989 Oct 16;164(1):156–163. doi: 10.1016/0006-291x(89)91696-3. [DOI] [PubMed] [Google Scholar]
  38. Turker M. S., Domenico J. M., Cummings D. J. Excision-amplification of mitochondrial DNA during senescence in Podospora anserina. A potential role for an 11 base-pair consensus sequence in the excision process. J Mol Biol. 1987 Nov 20;198(2):171–185. doi: 10.1016/0022-2836(87)90304-4. [DOI] [PubMed] [Google Scholar]
  39. Vanin E. F., Henthorn P. S., Kioussis D., Grosveld F., Smithies O. Unexpected relationships between four large deletions in the human beta-globin gene cluster. Cell. 1983 Dec;35(3 Pt 2):701–709. doi: 10.1016/0092-8674(83)90103-4. [DOI] [PubMed] [Google Scholar]
  40. Winship P. R. An improved method for directly sequencing PCR amplified material using dimethyl sulphoxide. Nucleic Acids Res. 1989 Feb 11;17(3):1266–1266. doi: 10.1093/nar/17.3.1266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Zeviani M., Moraes C. T., DiMauro S., Nakase H., Bonilla E., Schon E. A., Rowland L. P. Deletions of mitochondrial DNA in Kearns-Sayre syndrome. Neurology. 1988 Sep;38(9):1339–1346. doi: 10.1212/wnl.38.9.1339. [DOI] [PubMed] [Google Scholar]
  42. Zeviani M., Servidei S., Gellera C., Bertini E., DiMauro S., DiDonato S. An autosomal dominant disorder with multiple deletions of mitochondrial DNA starting at the D-loop region. Nature. 1989 May 25;339(6222):309–311. doi: 10.1038/339309a0. [DOI] [PubMed] [Google Scholar]
  43. Zinn A. R., Pohlman J. K., Perlman P. S., Butow R. A. In vivo double-strand breaks occur at recombinogenic G + C-rich sequences in the yeast mitochondrial genome. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2686–2690. doi: 10.1073/pnas.85.8.2686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. vom Stein J., Hachtel W. Deletions/insertions, short inverted repeats, sequences resembling att-lambda, and frame shift mutated open reading frames are involved in chloroplast DNA differences in the genus Oenothera subsection Munzia. Mol Gen Genet. 1988 Aug;213(2-3):513–518. doi: 10.1007/BF00339624. [DOI] [PubMed] [Google Scholar]

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

RESOURCES