Vital mitochondrial DNA (mtDNA) populations exist in cells and may consist of heteroplasmic mixtures of mtDNA types. The evolution of these heteroplasmic populations through development, ageing, and generations is central to genetic diseases, but is poorly understood in mammals. Here we dissect these population dynamics using a dataset of unprecedented size and temporal span, comprising 1947 single-cell oocyte and 899 somatic measurements of heteroplasmy change throughout lifetimes and generations in two genetically distinct mouse models. We provide a novel and detailed quantitative characterisation of the linear increase in heteroplasmy variance throughout mammalian life courses in oocytes and pups. We find that differences in mean heteroplasmy are induced between generations, and the heteroplasmy of germline and somatic precursors diverge early in development, with a haplotype-specific direction of segregation. We develop stochastic theory predicting the implications of these dynamics for ageing and disease manifestation and discuss its application to human mtDNA dynamics.

Biomodels Austria University of Veterinary Medicine Vienna Veterinaerplatz 1 1210 Vienna Austria

Department for Agrobiotechnology Biotechnology in Animal Production IFA Tulln 3430 Tulln Austria

Department for Biomedical Sciences Reproduction Centre Wieselburg University of Veterinary Medicine Vienna Austria

Department of Mathematics Imperial College London London SW7 2AZ UK

EPSRC Centre for the Mathematics of Precision Healthcare Imperial College London London SW7 2AZ UK

Genomics Core Facility VetCore University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Institute of Animal Breeding and Genetics University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Institute of Laboratory Animal Science University of Veterinary Medicine Vienna Veterinärplatz 1 1210 Vienna Austria

Nuffield Department of Women's and Reproductive Health University of Oxford Oxford United Kingdom

Research Facility Studenec Institute of Vertebrate Biology of the Czech Academy of Sciences Květná 8 603 65 Brno Czech Republic

School of Biosciences University of Birmingham Birmingham B15 2TT UK

University of Natural Resources and Life Sciences Konrad Lorenz Strasse 20 3430 Tulln Austria

Zobrazit více v PubMed

Wallace DC, Chalkia D. Mitochondrial DNA genetics and the heteroplasmy conundrum in evolution and disease. Cold Spring Harb. Perspect. Med. 2013;3:a021220. doi: 10.1101/cshperspect.a021220. PubMed DOI PMC

Hoitzing H., Johnston I. G., Jones N. S. in Stochastic Processes, Multiscale Modelling, and Numerical Methods for Computational CellularBiology (ed Holcman D.) (Springer, Switzerland, 2017).

Burgstaller JP, et al. mtDNA segregation in heteroplasmic tissues is common in vivo and modulated by haplotype differences and developmental stage. Cell Rep. 2014;7:2031–2041. doi: 10.1016/j.celrep.2014.05.020. PubMed DOI PMC

Burgstaller JP, Johnston IG, Poulton J. Mitochondrial DNA disease and developmental implications for reproductive strategies. Mol. Hum. Reprod. 2015;21:11–22. doi: 10.1093/molehr/gau090. PubMed DOI PMC

Hoitzing H., Gammage P. A., Minczuk M., Johnston I. G., Jones N. S. Energetic costs of cellular and therapeutic control of stochastic mtDNA populations. Preprint at https://www.biorxiv.org/content/early/2017/2006/2002/145292 (2017). PubMed PMC

Rossignol R, et al. Mitochondrial threshold effects. Biochem. J. 2003;370:751–762. doi: 10.1042/bj20021594. PubMed DOI PMC

Johnston IG, et al. Stochastic modelling, Bayesian inference, and new in vivo measurements elucidate the debated mtDNA bottleneck mechanism. eLife. 2015;4:e07464. PubMed PMC

Wilton PR, Zaidi A, Makova K, Nielsen R. A population phylogenetic view of mitochondrial heteroplasmy. Genetics. 2018;208:1261–1274. doi: 10.1534/genetics.118.300711. PubMed DOI PMC

Wonnapinij P, Chinnery PF, Samuels DC. Previous estimates of mitochondrial DNA mutation level variance did not account for sampling error: comparing the mtDNA genetic bottleneck in mice and humans. Am. J. Hum. Genet. 2010;86:540–550. doi: 10.1016/j.ajhg.2010.02.023. PubMed DOI PMC

Burr SP, Pezet M, Chinnery PF. Mitochondrial DNA Heteroplasmy and Purifying Selection in the Mammalian Female Germ Line. Dev. Growth Differ. 2018;60:21–32. doi: 10.1111/dgd.12420. PubMed DOI

Floros VI, et al. Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos. Nat. Cell Biol. 2018;20:144–151. doi: 10.1038/s41556-017-0017-8. PubMed DOI PMC

Elson J, Samuels D, Turnbull D, Chinnery P. Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age. Am. J. Hum. Genet. 2001;68:802–806. doi: 10.1086/318801. PubMed DOI PMC

Wonnapinij P, Chinnery PF, Samuels DC. The distribution of mitochondrial DNA heteroplasmy due to random genetic drift. Am. J. Hum. Genet. 2008;83:582–593. doi: 10.1016/j.ajhg.2008.10.007. PubMed DOI PMC

Chinnery PF, et al. The inheritance of mitochondrial DNA heteroplasmy: random drift, selection or both? Trends Genet. 2000;16:500–505. doi: 10.1016/S0168-9525(00)02120-X. PubMed DOI

Jenuth JP, Peterson AC, Fu K, Shoubridge EA. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nat. Genet. 1996;14:146–151. doi: 10.1038/ng1096-146. PubMed DOI

Howell N, et al. Mitochondrial gene segregation in mammals: is the bottleneck always narrow? Hum. Genet. 1992;90:117–120. doi: 10.1007/BF00210753. PubMed DOI

Wilson IJ, et al. Mitochondrial DNA sequence characteristics modulate the size of the genetic bottleneck. Hum. Mol. Genet. 2016;25:1031–1041. doi: 10.1093/hmg/ddv626. PubMed DOI PMC

Wolff JN, White DJ, Woodhams M, White HE, Gemmell NJ. The strength and timing of the mitochondrial bottleneck in salmon suggests a conserved mechanism in vertebrates. PLOS ONE. 2011;6:e20522. doi: 10.1371/journal.pone.0020522. PubMed DOI PMC

Li M, et al. Transmission of human mtDNA heteroplasmy in the Genome of the Netherlands families: support for a variable-size bottleneck. Genome Res. 2016;26:417–426. doi: 10.1101/gr.203216.115. PubMed DOI PMC

Johnston IG, Jones NS. Evolution of cell-to-cell variability in stochastic, controlled, heteroplasmic mtDNA populations. Am. J. Hum. Genet. 2016;99:1150–1162. doi: 10.1016/j.ajhg.2016.09.016. PubMed DOI PMC

Tam ZY, Gruber J, Halliwell B, Gunawan R. Context-dependent role of mitochondrial fusion-fission in clonal expansion of mtDNA mutations. PLOS Comput. Biol. 2015;11:e1004183. doi: 10.1371/journal.pcbi.1004183. PubMed DOI PMC

Jenuth JP, Peterson AC, Shoubridge EA. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat. Genet. 1997;16:93–95. doi: 10.1038/ng0597-93. PubMed DOI

Fan W, et al. A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations. Science. 2008;319:958–962. doi: 10.1126/science.1147786. PubMed DOI PMC

Freyer C, et al. Variation in germline mtDNA heteroplasmy is determined prenatally but modified during subsequent transmission. Nat. Genet. 2012;44:1282–1285. doi: 10.1038/ng.2427. PubMed DOI PMC

Sharpley MS, et al. Heteroplasmy of mouse mtDNA is genetically unstable and results in altered behavior and cognition. Cell. 2012;151:333–343. doi: 10.1016/j.cell.2012.09.004. PubMed DOI PMC

Cree LM, et al. A reduction of mitochondrial DNA molecules during embryogenesis explains the rapid segregation of genotypes. Nat. Genet. 2008;40:249–254. doi: 10.1038/ng.2007.63. PubMed DOI

Stewart JB, et al. Strong purifying selection in transmission of mammalian mitochondrial DNA. PLOS Biol. 2008;6:e10. doi: 10.1371/journal.pbio.0060010. PubMed DOI PMC

Lee HS, et al. Rapid mitochondrial DNA segregation in primate preimplantation embryos precedes somatic and germline bottleneck. Cell Rep. 2012;1:506–515. doi: 10.1016/j.celrep.2012.03.011. PubMed DOI PMC

Stewart JB, Chinnery PF. The dynamics of mitochondrial DNA heteroplasmy: implications for human health and disease. Nat. Rev. Genet. 2015;16:530–542. doi: 10.1038/nrg3966. PubMed DOI

de Stordeur E, Solignac M, Monnerot M, Mounolou JC. The generation of transplasmic Drosophila simulans by cytoplasmic injection: effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy. Mol. Gen. Genet. 1989;220:127–132. doi: 10.1007/BF00260866. PubMed DOI

Kann LM, Rosenblum EB, Rand DM. Aging, mating, and the evolution of mtDNA heteroplasmy in Drosophila melanogaster. Proc. Natl Acad. Sci. USA. 1998;95:2372–2377. doi: 10.1073/pnas.95.5.2372. PubMed DOI PMC

Solignac M, Génermont J, Monnerot M, Mounolou JC. Drosophila mitochondrial genetics: evolution of heteroplasmy through germ line cell divisions. Genetics. 1987;117:687–696. PubMed PMC

Cao L, et al. The mitochondrial bottleneck occurs without reduction of mtDNA content in female mouse germ cells. Nat. Genet. 2007;39:386–390. doi: 10.1038/ng1970. PubMed DOI

Wai T, Teoli D, Shoubridge EA. The mitochondrial DNA genetic bottleneck results from replication of a subpopulation of genomes. Nat. Genet. 2008;40:1484–1488. doi: 10.1038/ng.258. PubMed DOI

Lane N. The problem with mixing mitochondria. Cell. 2012;151:246–248. doi: 10.1016/j.cell.2012.09.028. PubMed DOI

Rebolledo-Jaramillo B, et al. Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proc. Natl Acad. Sci. USA. 2014;111:15474–15479. doi: 10.1073/pnas.1409328111. PubMed DOI PMC

Røyrvik E, Burgstaller JP, Johnston IG. mtDNA diversity in human populations highlights the merit of haplotype matching in gene therapies. Mol. Hum. Reprod. 2016;22:809–817. doi: 10.1093/molehr/gaw062. PubMed DOI

Paull D, et al. Nuclear genome transfer in human oocytes eliminates mitochondrial DNA variants. Nature. 2013;493:632–637. doi: 10.1038/nature11800. PubMed DOI PMC

Steinborn R, et al. Mitochondrial DNA heteroplasmy in cloned cattle produced by fetal and adult cell cloning. Nat. Genet. 2000;25:255–257. doi: 10.1038/77000. PubMed DOI

Tachibana M, et al. Towards germline gene therapy of inherited mitochondrial diseases. Nature. 2013;493:627–631. doi: 10.1038/nature11647. PubMed DOI PMC

Bustin SA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clin. Chem. 2009;55:611–622. doi: 10.1373/clinchem.2008.112797. PubMed DOI

Mitochondria in human reproduction: novel paradigm in the onset of neurodegenerative disorders

Mitochondrially-Targeted Therapeutic Strategies for Alzheimer's Disease