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. 1997 Feb;145(2):445–451. doi: 10.1093/genetics/145.2.445

Mitochondrial Genotype Segregation in a Mouse Heteroplasmic Lineage Produced by Embryonic Karyoplast Transplantation

F V Meirelles 1, L C Smith 1
PMCID: PMC1207808  PMID: 9071597

Abstract

Mitochondrial genotypes have been shown to segregate both rapidly and slowly when transmitted to consecutive generations in mammals. Our objective was to develop an animal model to analyze the patterns of mammalian mitochondrial DNA (mtDNA) segregation and transmission in an intraspecific heteroplasmic maternal lineage to investigate the mechanisms controlling these phenomena. Heteroplasmic progeny were obtained from reconstructed blastocysts derived by transplantation of pronuclear-stage karyoplasts to enucleated zygotes with different mtDNA. Although the reconstructed zygotes contained on average 19% mtDNA of karyoplast origin, most progeny contained fewer mtDNA of karyoplast origin and produced exclusively homoplasmic first generation progeny. However, one founder heteroplasmic adult female had elevated tissue heteroplasmy levels, varying from 6% (lung) to 69% (heart), indicating that stringent replicative segregation had occurred during mitotic divisions. First generation progeny from the above female were all heteroplasmic, indicating that, despite a meiotic segregation, they were derived from heteroplasmic founder oocytes. Some second and third generation progeny contained exclusively New Zealand Black/BINJ mtDNA, suggesting, but not confirming, an origin from an homoplasmic oocyte. Moreover, several third to fifth generation individuals maintained mtDNA from both mouse strains, indicating a slow or persistent segregation pattern characterized by diminished tissue and litter variability beyond second generation progeny. Therefore, although some initial lineages appear to segregate rapidly to homoplasmy, within two generations other lineages transmit stable amounts of both mtDNA molecules, supporting a mechanism where mitochondria of different origin may fuse, leading to persistent intraorganellar heteroplasmy.

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Selected References

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  1. Ashley M. V., Laipis P. J., Hauswirth W. W. Rapid segregation of heteroplasmic bovine mitochondria. Nucleic Acids Res. 1989 Sep 25;17(18):7325–7331. doi: 10.1093/nar/17.18.7325. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Attardi G., Yoneda M., Chomyn A. Complementation and segregation behavior of disease-causing mitochondrial DNA mutations in cellular model systems. Biochim Biophys Acta. 1995 May 24;1271(1):241–248. doi: 10.1016/0925-4439(95)00034-2. [DOI] [PubMed] [Google Scholar]
  3. Bendall K. E., Sykes B. C. Length heteroplasmy in the first hypervariable segment of the human mtDNA control region. Am J Hum Genet. 1995 Aug;57(2):248–256. [PMC free article] [PubMed] [Google Scholar]
  4. Bibb M. J., Van Etten R. A., Wright C. T., Walberg M. W., Clayton D. A. Sequence and gene organization of mouse mitochondrial DNA. Cell. 1981 Oct;26(2 Pt 2):167–180. doi: 10.1016/0092-8674(81)90300-7. [DOI] [PubMed] [Google Scholar]
  5. Chatot C. L., Ziomek C. A., Bavister B. D., Lewis J. L., Torres I. An improved culture medium supports development of random-bred 1-cell mouse embryos in vitro. J Reprod Fertil. 1989 Jul;86(2):679–688. doi: 10.1530/jrf.0.0860679. [DOI] [PubMed] [Google Scholar]
  6. Gyllensten U., Wharton D., Josefsson A., Wilson A. C. Paternal inheritance of mitochondrial DNA in mice. Nature. 1991 Jul 18;352(6332):255–257. doi: 10.1038/352255a0. [DOI] [PubMed] [Google Scholar]
  7. Gyllensten U., Wharton D., Wilson A. C. Maternal inheritance of mitochondrial DNA during backcrossing of two species of mice. J Hered. 1985 Sep-Oct;76(5):321–324. doi: 10.1093/oxfordjournals.jhered.a110103. [DOI] [PubMed] [Google Scholar]
  8. Hao H., Bonilla E., Manfredi G., DiMauro S., Moraes C. T. Segregation patterns of a novel mutation in the mitochondrial tRNA glutamic acid gene associated with myopathy and diabetes mellitus. Am J Hum Genet. 1995 May;56(5):1017–1025. [PMC free article] [PubMed] [Google Scholar]
  9. Harding A. E., Holt I. J., Sweeney M. G., Brockington M., Davis M. B. Prenatal diagnosis of mitochondrial DNA8993 T----G disease. Am J Hum Genet. 1992 Mar;50(3):629–633. [PMC free article] [PubMed] [Google Scholar]
  10. Hauswirth W. W., Laipis P. J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc Natl Acad Sci U S A. 1982 Aug;79(15):4686–4690. doi: 10.1073/pnas.79.15.4686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Holt I. J., Harding A. E., Petty R. K., Morgan-Hughes J. A. A new mitochondrial disease associated with mitochondrial DNA heteroplasmy. Am J Hum Genet. 1990 Mar;46(3):428–433. [PMC free article] [PubMed] [Google Scholar]
  12. Howell N., Halvorson S., Kubacka I., McCullough D. A., Bindoff L. A., Turnbull D. M. Mitochondrial gene segregation in mammals: is the bottleneck always narrow? Hum Genet. 1992 Sep-Oct;90(1-2):117–120. doi: 10.1007/BF00210753. [DOI] [PubMed] [Google Scholar]
  13. Huston M. M., Smith R., 3rd, Hull R., Huston D. P., Rich R. R. Mitochondrial modulation of maternally transmitted antigen: analysis of cell hybrids. Proc Natl Acad Sci U S A. 1985 May;82(10):3286–3290. doi: 10.1073/pnas.82.10.3286. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Koehler C. M., Lindberg G. L., Brown D. R., Beitz D. C., Freeman A. E., Mayfield J. E., Myers A. M. Replacement of bovine mitochondrial DNA by a sequence variant within one generation. Genetics. 1991 Sep;129(1):247–255. doi: 10.1093/genetics/129.1.247. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Laipis P. J., Van de Walle M. J., Hauswirth W. W. Unequal partitioning of bovine mitochondrial genotypes among siblings. Proc Natl Acad Sci U S A. 1988 Nov;85(21):8107–8110. doi: 10.1073/pnas.85.21.8107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Larsson N. G., Tulinius M. H., Holme E., Oldfors A., Andersen O., Wahlström J., Aasly J. Segregation and manifestations of the mtDNA tRNA(Lys) A-->G(8344) mutation of myoclonus epilepsy and ragged-red fibers (MERRF) syndrome. Am J Hum Genet. 1992 Dec;51(6):1201–1212. [PMC free article] [PubMed] [Google Scholar]
  17. McGrath J., Solter D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science. 1983 Jun 17;220(4603):1300–1302. doi: 10.1126/science.6857250. [DOI] [PubMed] [Google Scholar]
  18. Pikó L., Taylor K. D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev Biol. 1987 Oct;123(2):364–374. doi: 10.1016/0012-1606(87)90395-2. [DOI] [PubMed] [Google Scholar]
  19. Shoffner J. M., Lott M. T., Lezza A. M., Seibel P., Ballinger S. W., Wallace D. C. Myoclonic epilepsy and ragged-red fiber disease (MERRF) is associated with a mitochondrial DNA tRNA(Lys) mutation. Cell. 1990 Jun 15;61(6):931–937. doi: 10.1016/0092-8674(90)90059-n. [DOI] [PubMed] [Google Scholar]
  20. Smith L. C., Alcivar A. A. Cytoplasmic inheritance and its effects on development and performance. J Reprod Fertil Suppl. 1993;48:31–43. [PubMed] [Google Scholar]
  21. Smith L. C., Wilmut I., Hunter R. H. Influence of cell cycle stage at nuclear transplantation on the development in vitro of mouse embryos. J Reprod Fertil. 1988 Nov;84(2):619–624. doi: 10.1530/jrf.0.0840619. [DOI] [PubMed] [Google Scholar]
  22. Smith R., 3rd, Huston M. M., Jenkins R. N., Huston D. P., Rich R. R. Mitochondria control expression of a murine cell surface antigen. Nature. 1983 Dec 8;306(5943):599–601. doi: 10.1038/306599a0. [DOI] [PubMed] [Google Scholar]
  23. Upholt W. B., Dawid I. B. Mapping of mitochondrial DNA of individual sheep and goats: rapid evolution in the D loop region. Cell. 1977 Jul;11(3):571–583. doi: 10.1016/0092-8674(77)90075-7. [DOI] [PubMed] [Google Scholar]
  24. Vilkki J., Savontaus M. L., Nikoskelainen E. K. Segregation of mitochondrial genomes in a heteroplasmic lineage with Leber hereditary optic neuroretinopathy. Am J Hum Genet. 1990 Jul;47(1):95–100. [PMC free article] [PubMed] [Google Scholar]
  25. Yoneda M., Miyatake T., Attardi G. Complementation of mutant and wild-type human mitochondrial DNAs coexisting since the mutation event and lack of complementation of DNAs introduced separately into a cell within distinct organelles. Mol Cell Biol. 1994 Apr;14(4):2699–2712. doi: 10.1128/mcb.14.4.2699. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Yoneda M., Miyatake T., Attardi G. Heteroplasmic mitochondrial tRNA(Lys) mutation and its complementation in MERRF patient-derived mitochondrial transformants. Muscle Nerve Suppl. 1995;3:S95–101. doi: 10.1002/mus.880181420. [DOI] [PubMed] [Google Scholar]
  27. Yonekawa H., Moriwaki K., Gotoh O., Miyashita N., Migita S., Bonhomme F., Hjorth J. P., Petras M. L., Tagashira Y. Origins of laboratory mice deduced from restriction patterns of mitochondrial DNA. Differentiation. 1982;22(3):222–226. doi: 10.1111/j.1432-0436.1982.tb01255.x. [DOI] [PubMed] [Google Scholar]

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