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.

A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes

Abstract

Mammalian mitochondrial DNA (mtDNA) is inherited principally down the maternal line, but the mechanisms involved are not fully understood. Females harboring a mixture of mutant and wild-type mtDNA (heteroplasmy) transmit a varying proportion of mutant mtDNA to their offspring. In humans with mtDNA disorders, the proportion of mutated mtDNA inherited from the mother correlates with disease severity1,2,3,4. Rapid changes in allele frequency can occur in a single generation5,6. This could be due to a marked reduction in the number of mtDNA molecules being transmitted from mother to offspring (the mitochondrial genetic bottleneck), to the partitioning of mtDNA into homoplasmic segregating units, or to the selection of a group of mtDNA molecules to re-populate the next generation. Here we show that the partitioning of mtDNA molecules into different cells before and after implantation, followed by the segregation of replicating mtDNA between proliferating primordial germ cells, is responsible for the different levels of heteroplasmy seen in the offspring of heteroplasmic female mice.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: The amount of mtDNA in mature mouse oocytes and preimplantation mouse embryos.
Figure 2: Models of the mitochondrial genetic bottleneck.
Figure 3: Modeling the inheritance of mtDNA heteroplasmy in mice.

References

  1. 1

    Holt, I.J., Miller, D.H. & Harding, A.E. Genetic heterogeneity and mitochondrial DNA heteroplasmy in Leber's hereditary optic neuropathy. J. Med. Genet. 26, 739–743 (1989).

    CAS  Article  Google Scholar 

  2. 2

    Bolhuis, P.A. et al. Rapid shift on genotype of human mitochondrial DNA in a family with Leber's hereditary optic neuropathy. Biochem. Biophys. Res. Commun. 170, 994–997 (1990).

    CAS  Article  Google Scholar 

  3. 3

    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. 47, 95–100 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. 4

    Larsson, N.G. et al. 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. 51, 1201–1212 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. 5

    Upholt, W.B. & Dawid, I.B. Mapping of mitochondrial DNA of individual sheep and goats: rapid evolution in the D loop region. Cell 11, 571–583 (1977).

    CAS  Article  Google Scholar 

  6. 6

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

    CAS  Article  Google Scholar 

  7. 7

    Blok, R.B., Gook, D.A., Thorburn, D.R. & Dahl, H.H. Skewed segregation of the mtDNA nt 8993 (T to G) mutation in human oocytes. Am. J. Hum. Genet. 60, 1495–1501 (1997).

    CAS  Article  Google Scholar 

  8. 8

    Jenuth, J.P., Peterson, A.C., Fu, K. & Shoubridge, E.A. Random genetic drift in the female germ line explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 14, 146–151 (1996).

    CAS  Article  Google Scholar 

  9. 9

    Chinnery, P.F. et al. The inheritance of mtDNA heteroplasmy: random drift, selection or both? Trends Genet. 16, 500–505 (2000).

    CAS  Article  Google Scholar 

  10. 10

    Brown, D.T., Samuels, D.C., Michael, E.M., Turnbull, D.M. & Chinnery, P.F. Random genetic drift determines the level of mutant mitochondrial DNA in human primary oocytes. Am. J. Hum. Genet. 68, 533–536 (2001).

    CAS  Article  Google Scholar 

  11. 11

    Piko, 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).

    CAS  Article  Google Scholar 

  12. 12

    Steuerwald, N. et al. Quantification of mtDNA in single oocytes, polar bodies and subcellular components by real-time rapid cycle fluorescence monitored PCR. Zygote 8, 209–215 (2000).

    CAS  Article  Google Scholar 

  13. 13

    Larsson, N.G. et al. Mitochondrial transcription factor A is necessary for mtDNA maintenance and embryogenesis in mice. Nat. Genet. 18, 231–236 (1998).

    CAS  Article  Google Scholar 

  14. 14

    McLaren, A. & Lawson, K.A. How is the mouse germ-cell lineage established? Differentiation 73, 435–437 (2005).

    CAS  Article  Google Scholar 

  15. 15

    Payer, B. et al. Generation of stella-GFP transgenic mice: a novel tool to study germ cell development. Genesis 44, 75–83 (2006).

    CAS  Article  Google Scholar 

  16. 16

    Wright, S. Evolution and the Genetics of Populations (University of Chicago Press, Chicago, 1969).

  17. 17

    Bendall, K.E., Macaulay, V.A., Baker, J.R. & Sykes, B.C. Heteroplasmic point mutations in the human mtDNA control region. Am. J. Hum. Genet. 59, 1276–1287 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. 18

    Poulton, J., Macaulay, V. & Marchington, D.R. Mitochondrial genetics '98: Is the bottleneck cracked? Am. J. Hum. Genet. 62, 752–757 (1998).

    CAS  Article  Google Scholar 

  19. 19

    Streffer, C., Van Beuningen, D., Mollis, M., Zamboglou, N. & Schultz, S. Kinetics of cell proliferation in the pre-implanted mouse embryo in vivo and in vitro. Cell Tissue Kinet. 13, 135–143 (1980).

    CAS  PubMed  Google Scholar 

  20. 20

    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 

  21. 21

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

    CAS  PubMed  Google Scholar 

  22. 22

    Downs, K.M. & Davies, T. Staging of gastrulating mouse embryos by morphological landmarks in the dissecting microscope. Development 118, 1255–1266 (1993).

    CAS  Google Scholar 

  23. 23

    Cao, L. et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat. Genet. 39, 386–390 (2007).

    CAS  Article  Google Scholar 

  24. 24

    Bergstrom, C.T. & Pritchard, J. Germline bottlenecks and the evolutionary maintenance of mitochondrial genomes. Genetics 149, 2135–2146 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. 25

    Spiropoulos, J., Turnbull, D.M. & Chinnery, P.F. Can mitochondrial DNA mutations cause sperm dysfunction? Mol. Hum. Reprod. 8, 719–721 (2002).

    CAS  Article  Google Scholar 

  26. 26

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

    CAS  Article  Google Scholar 

  27. 27

    Hogan, B., Beddington, R., Constantini, F. & Lacy, E. Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, USA, 1994).

  28. 28

    McGrath, J. & Solter, D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 220, 1300–1302 (1983).

    CAS  Article  Google Scholar 

  29. 29

    Mann, J.R., Gadi, I., Harbison, M.L., Abbondanzo, S.J. & Stewart, C.L. Androgenetic mouse embryonic stem cells are pluripotent and cause skeletal defects in chimeras: implications for genetic imprinting. Cell 62, 251–260 (1990).

    CAS  Article  Google Scholar 

  30. 30

    Jenuth, J.P., Peterson, A.C. & Shoubridge, E.A. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat. Genet. 16, 93–95 (1997).

    CAS  Article  Google Scholar 

Download references

Acknowledgements

P.F.C. is a Wellcome Trust Senior Fellow in Clinical Science and also receives funding from the United Mitochondrial Diseases Foundation and from the EU FP6 program EUmitocombat and MITOCIRCLE. H.-H.M.D. is a National Health and Medical Research Council (Australia) Principal Research Fellow, and his affiliations are with The Murdoch Children's Research Institute and the Department of Paediatrics (University of Melbourne), Royal Children's Hospital, Melbourne, Australia. We thank I. Dimmick for his assistance with the flow cytometry, D. Turnbull and B. Lightowlers for discussions, A. McLaren for her expertise on the cell dynamics of mouse development, and M. Azim Surani for providing the Stella-GFP mice. We also thank D. Thorburn for discussions and advice while studying the heteroplasmic mice, and both W. Hutchinson and S. White for experimental work on the heteroplasmic mice.

Author information

Affiliations

Authors

Contributions

This laboratory study was designed by P.F.C. and L.M.C. and carried out by L.M.C. The in silico modeling was designed by D.C.S., programmed by H.K.R. and carried out by D.C.S., H.K.R. and P.W. GFP-Stella mice were produced in the laboratory of M. Azim Surani by S.C.d.S.L. H.-H.M.D. designed and supervised the heteroplasmic mouse work. J.R.M. generated the heteroplasmic mice.

Corresponding author

Correspondence to Patrick F Chinnery.

Supplementary information

Supplementary Text and Figures

Supplementary Tables 1 and 2 and Supplementary Figure 1–3 (PDF 262 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Cree, L., Samuels, D., de Sousa Lopes, S. et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat Genet 40, 249–254 (2008). https://doi.org/10.1038/ng.2007.63

Download citation

Further reading

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