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

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.

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). | PubMed  | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ChemPort |
4. Ashley, M.V., Laipis, P.J. & Hauswirth, W.W. Rapid segregation of heteroplasmic bovine mitochondria. Nucl. Acids Res. 17, 7325−7331 (1989). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ChemPort |
7. Koehler, C.M. et al. Replacement of bovine mitochondrial DNA by a sequence variant within one generation. Genetics 129, 247−255 (1991). | PubMed  | ISI | ChemPort |
8. Larsson, N. et al. Segregation and manifestations of the mtDNA tRNALys AG(8344) mutation of myoclonus epilipsy and ragged-red fibers (MERRF) syndrome. Am. J. Hum. Genet. 51, 1201−1212 (1992). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
10. Santorelli, F.M. et al. A TC mutaion at nt 8993 of a mitochondrial DNA in a child with Leigh syndrome. Neurology 44, 972−974 (1994). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
13. Ginsburg, M., Snow, M.H.L. & McLaren, A. Primordial germ cells in the mouse embryo during gastrulation. Development 110, 521−528 (1990). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
15. Birky, C.W.Jr. Relaxed and stringent genomes: Why cytoplasmic genes don't obey Mendel's laws. J. Hered. 85, 355−365 (1994). | ISI |
16. Clayton, D.A. Replication of animal mitochondrial DNA. Cell 28, 693−705 (1982). | Article | PubMed  | ISI | ChemPort |
17. Gondos, B. Comparative studies of normal and neoplastic ovarian germ cells. Int. J. Gynecol. Path. 6, 114−123 (1987). | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ChemPort |
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). | PubMed  | ISI | ChemPort |
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  | ISI |
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). | ChemPort |
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 | PubMed  | ISI | ChemPort |
25. Wallace, D.C. Mitochondrial DNA mutations in diseases of energy metabolism. J. Bioenerget. Biomem. 26, 241−250 (1994). | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ChemPort |
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).
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). | PubMed  | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
33. Howell, N. et al. Mitochondrial gene segregation in mammals: Is the bottleneck always narrow? Hum. Genet. 90, 117−120 (1992). | PubMed  | ISI | ChemPort |
34. Takahata, N. Allelic geneology and human evolution. Mol. Biol. Evol. 10, 2−22 (1993). | PubMed  | ISI | ChemPort |
35. McGrath, J. & Solter, D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 228, 1300−1302 (1983).
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 | PubMed  | ISI | ChemPort |
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). | PubMed  | ISI | ChemPort |
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). | ChemPort |

	Top

	Top