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The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes

Nature Genetics volume 40, pages 1484–1488 (2008)Cite this article

Abstract

In mammals, mitochondrial DNA (mtDNA) sequence variants are observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte. This has led to the concept of a genetic bottleneck for the transmission of mtDNA1,2,3, but the mechanism remains contentious. Several studies have suggested that the bottleneck occurs during embryonic development, as a result of a marked reduction in germline mtDNA copy number4,5. Mitotic segregation of mtDNAs during preimplantation5, or during the expansion of primordial germ cells (PGCs) before they colonize the gonad4,5, is thought to account for the increase in genotypic variance observed among mature oocytes from heteroplasmic mothers. This view has, however, been challenged by studies suggesting that the bottleneck occurs without a reduction in germline mtDNA content6. To resolve this controversy, we measured mtDNA heteroplasmy and copy number in single germ cells isolated from heteroplasmic mice. By directly tracking the evolution of mtDNA genotypic variance during oogenesis, we show that the genetic bottleneck occurs during postnatal folliculogenesis and not during embryonic oogenesis.

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Figure 1: Changes in mtDNA copy number during female germline development.
Figure 2: Replicating mtDNA visualized in vivo by incorporation of BrdU.
Figure 3: Transmission electronmicroscopy and immunogold labeling in primary oocytes.
Figure 4: The distribution of mtDNA nucleoids in primary oocytes.
Figure 5: Model for the transmission of mtDNA in the female germline.

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Acknowledgements

We thank L. Villeneuve for help with confocal microscopy; J. Mui for assistance with electron microscopy; T. Johns, F. Jones and D. Sabour for technical assistance; and J. Correa for statistical design. We are grateful for antibodies directed against TFAM (B. Kaufman, MNI), mt-SSB (M. Zeviani, Instituto Carlo Besta) and POLG (W. Copeland, US National Institutes of Health). The OCT4Δ PE-EGFP mice were obtained from H.R. Scholer (University of Pennsylvania). This research was supported by the Canadian Institutes of Health Research and the US National Institutes of Health. E.A.S. is an International Scholar of the Howard Hughes Medical Institute.

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Authors and Affiliations

  1. Montreal Neurological Institute and Department of Human Genetics, McGill University, Montreal, H3A 2B4, Canada

    Timothy Wai, Daniella Teoli & Eric A Shoubridge

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  1. Timothy Wai
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  2. Daniella Teoli
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  3. Eric A Shoubridge
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Contributions

T.W. and E.A.S. designed the study and wrote the manuscript. D.T. performed genotyping, and T.W. did all other experiments.

Corresponding author

Correspondence to Eric A Shoubridge.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Supplementary Tables 1 and 2 (PDF 1950 kb)

Supplementary Video 1

3D view of the merged maximum projection close-up for primary oocytes in Fig. 2 (MOV 234 kb)

Supplementary Video 2

3D view of the merged maximum projection close-up for neonatal heart in Fig. 2 (MOV 463 kb)

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Wai, T., Teoli, D. & Shoubridge, E. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat Genet 40, 1484–1488 (2008). https://doi.org/10.1038/ng.258

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