Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA

Nature Genetics volume 14, pages 146–151 (1996)Cite this article

Abstract

Mitochondrial DNA (mtDNA) is maternally inherited in mammals. Despite the high genome copy number in mature oocytes (105) and the relatively small number of cell divisions in the female germline, mtDNA sequence variants segregate rapidly between generations. To investigate the molecular basis for this apparent paradox we created lines of heteroplasmic mice carrying two mtDNA genotypes. We show that the pattern of segregation can be explained by random genetic drift ocurring in early oogenesis, and that the effective number of segregating units for mtDNA is ∼200 in mice. These results provide the basis for estimating recurrence risks for mitochondrial disease due to pathogenic mtDNA mutations and for predicting the rate of fixation of neutral mtDNA mutations in maternal lineages.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Brown, W.M., George, M. Jr. & Wilson, A.C. Rapid evolution of animal mitochondrial DNA. Proc. Natl. Acad. Sci. USA 76, 1967–1971 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Brown, W.M., Prager, E., Wang, A. & Wilson, A.C. Mitochonodrial DNA sequences of primates: tempo and mode of evolution. J. Mol. Evol. 18, 225–239 (1982).

    Article  CAS  PubMed  Google Scholar 

  3. Hauswirth, W.W. & Laipis, P.J. Mitochondrial DNA polymorphism in a maternal lineage of Holstein cows. Proc. Natl. Acad. Sci. USA 79, 4686–4690 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ashley, M.V., Laipis, P.J. & Hauswirth, W.W. Rapid segregation of heteroplasmic bovine mitochondria. Nucl. Acids Res. 17, 7325–7331 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Olivo, P.D. Van de Walle, M.J., Laipis, P.J. & Hauswirth, W.W. Nucleotide sequence evidence for rapid genomic shifts in the bovine mitochondrial DNA D-loop. Nature 306, 400–402 (1983).

    Article  CAS  PubMed  Google Scholar 

  6. Laipis, P.J. Van de Walle, M.J. & Hauswirth, W.W. Unequal partitioning of bovine mitochondrial genotypes among siblings. Proc. Natl. Acad. Sci. USA 85, 8107–8110 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Koehler, C.M. et al. Replacement of bovine mitochondrial DNA by a sequence variant within one generation. Genetics 129, 247–255 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Larsson, N. et al. Segregation and manifestations of the mtDNA tRNALys A→G(8344) mutation of myoclonus epilipsy and ragged-red fibers (MERRF) syndrome. Am. J. Hum. Genet. 51, 1201–1212 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Ghosh, S.S., Fahy, E., Bodis-Wollner, I., Sherman, J. & Howell, N. Longitudinal study of a heteroplasmic 3460 hereditary optic neuropathy family by multiplexed primer-extention analysis and nucleotide sequencing. Am. J. Hum. Genet. 58, 325–334 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Santorelli, F.M. et al. A T→C mutaion at nt 8993 of a mitochondrial DNA in a child with Leigh syndrome. Neurology 44, 972–974 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Pikó, L. & Taylor, K.D. Amounts of mitochondrial DNA and abundance of some mitochondrial gene transcripts in early mouse embryos. Dev. Biol. 123, 364–374 (1987).

    Article  PubMed  Google Scholar 

  12. Handyside, A.H. & Hunter, S. A rapid procedure for visualizing the inner cell mass and trophectoderm nuclei of mouse blastocysts in situ using polynucleotide-specific flourochromes. J. Exp. Zool. 231, 429–434 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. Ginsburg, M., Snow, M.H.L. & McLaren, A. Primordial germ cells in the mouse embryo during gastrulation. Development 110, 521–528 (1990).

    CAS  PubMed  Google Scholar 

  14. Tam, P.P.L. & Snow, M.H.L. Proliferation and migration of primordial germ cells during compensatory growth in mouse embryos. J. Embryol. Exp. Morph. 64, 133–147 (1981).

    CAS  PubMed  Google Scholar 

  15. Birky, C.W. Jr. Relaxed and stringent genomes: Why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85, 355–365 (1994).

    Article  Google Scholar 

  16. Clayton, D.A. Replication of animal mitochondrial DNA. Cell 28, 693–705 (1982).

    Article  CAS  PubMed  Google Scholar 

  17. Gondos, B. Comparative studies of normal and neoplastic ovarian germ cells. Int. J. Gynecol. Path. 6, 114–123 (1987).

    Article  CAS  Google Scholar 

  18. Nogawa, T., Sung, W.K., Jagiello, G.M. & Bowne, W. A quantitative analysis of mitochondria during fetal mouse oogenesis. J. Morph. 195, 225–234 (1988).

    Article  CAS  PubMed  Google Scholar 

  19. Nass, M.M.K. Mitochondrial DNA I. Intramitochondrial distribution and structural relations of single-and double-length circular DNA. J. Mol. Biol. 42, 521–528 (1969).

    Article  CAS  PubMed  Google Scholar 

  20. Shmookler Reis, R.J. & Goldstein, S. Mitochondrial DNA in mortal and immortal cells. Genome number, integrity, and methylation. J. Biol. Chem. 258, 9078–9085. (1983).

    CAS  PubMed  Google Scholar 

  21. Bogenhagen, D. & Clayton, D.A. The number of mitochondrial deoxyribonucleic acid genomes in mouse L and human HeLa cells. J. Biol. Chem. 249, 7991–7995 (1974).

    CAS  PubMed  Google Scholar 

  22. Birky, C.W. Jr., Maruyama, T. & Fuerst, P. An appraoch to population and evolutionary genetic theory for genes in mitochondria and chloroplasts and some results. Genetics 103, 513–527. (1983).

    PubMed  PubMed Central  Google Scholar 

  23. Solignac, M., Génermont, J., Monnerot, M. & Mounolou, J. Génetics of mitochondria in Drosophila: mtDNA inheritance in heteroplasmic strains of D. mauritiana. Mol. Gen. Genet. 197, 183–188 (1984).

    Article  CAS  Google Scholar 

  24. Hauswirth, W.W., Van De Walle, M.J. & Laipis, P.J. Heterogeneous mitochondrial DNA D–loop sequences in bovine tissue. Cell 37, 1001–1007 (1984).

    Article  CAS  PubMed  Google Scholar 

  25. Wallace, D.C. Mitochondrial DNA mutations in diseases of energy metabolism. J. Bioenerget. Biomem. 26, 241–250 (1994).

    Article  CAS  Google Scholar 

  26. Boulet, L., Karpati, G. & Shoubridge, E.A. Distribution and threshold expression of the tRNAlys mutaion in skeletal muscle of patients with myoclonic epilepsy and ragged-red fibers (MERRF). Am. J. Hum. Genet. 51, 1187–1200 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Chomyn, A. et al. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no changes in levels of upstream and downstream mature transcripts. Proc. Natl. Acad. Sci. USA 89, 4221–4225 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Baker, G.T.A. A quantitative and cytologicai study of germ cells in human ovaries. Proc. Roy. Soc. 158, 417–423. (1963). in Medical Embryology (ed. Langman, J.) 11–18 (Williams & Wilkins, Baltimore, 1975).

    Google Scholar 

  29. Larsson, N., Tulinius, M.H., Holme, E., Oldfors, A. Pathogenic aspects of the A8344G mutation of mitochondrial DNA associated with MERRF syndrome and multiple symmetric lipomas. Muscle Nerve 3, S102–S106 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Howell, N., Xu, M., Halvorson, S., Bodis-Wollner, I. & Sherman, J. A heteroplasmic LHON family: Tissue distribution and transmission of the 11778 mutation. Am. J. Hum. Genet. 55, 203–206 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Zhu, D., Economou, E.P., Antonarakis, S.E. & Maumenee, I.H. Mitochondrial DNA mutation and heteroplasmy in type I leber hereditary optic neuropathy. Am. J. Med. Genet. 42, 173–179 (1992).

    Article  CAS  PubMed  Google Scholar 

  32. Howell, N., et. al. Bindoff, L.A., McCullough, D.A., Kubacka, I., Poulton, J., Mackey, D., Taylor,L. & Tumbull, D.M. Leber hereditary optic neuropathy: Identification of the same mrtochondrial ND1 mutation in six pedigrees. Am. J. Hum. Genet. 49, 939–950 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Howell, N. et al. Mitochondrial gene segregation in mammals: Is the bottleneck always narrow? Hum. Genet. 90, 117–120 (1992).

    Article  CAS  PubMed  Google Scholar 

  34. Takahata, N. Allelic geneology and human evolution. Mol. Biol. Evol. 10, 2–22 (1993).

    CAS  PubMed  Google Scholar 

  35. McGrath, J. & Solter, D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 228, 1300–1302 (1983).

    Article  Google Scholar 

  36. Loveland, B., Wang, C.R., Yonekawa, H., Hermel, E. & Lindahl, K.F. Maternally transmitted histocompatability antigen of mice: a hydrophobic peptide of a mitochondrially encoded protein. Cell 60, 971–980 (1990).

    Article  CAS  PubMed  Google Scholar 

  37. Mangia, F. & Epstein, C.J. Biochemical studies of growing mouse oocytes: Preparation of oocytes and analysis of glucose-6-phosphate dehydrogenase and lactate dehydrogenase and lactate dehydrogenase activities. Dev. Biol. 45, 211–220 (1975).

    Article  CAS  PubMed  Google Scholar 

  38. Li, H., Cui, X. & Amheim, N. Analysis of DNA sequence variation in single cells. in Methods: A Companion to Methods in Enzymology 2, 49–59 (1991).

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada, H3A 2B4

    Jack P. Jenuth, Alan C. Peterson, Katherine Fu & Eric A. Shoubridge

  2. Departmentof Human Genetics, McGill University, 1205 avenue Dr. Penfield, Montreal, Quebec, Canada, H3A 1B1

    Katherine Fu & Eric A. Shoubridge

  3. Molecular Oncology Group McGill University, 687 Pine Avenue West, Montreal, Quebec, Canada, H3A 1A1

    Jack P. Jenuth & Alan C. Peterson

Authors
  1. Jack P. Jenuth
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan C. Peterson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Katherine Fu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Eric A. Shoubridge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Eric A. Shoubridge.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jenuth, J., Peterson, A., Fu, K. et al. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat Genet 14, 146–151 (1996). https://doi.org/10.1038/ng1096-146

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1096-146

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing