Abstract
Mammalian mitochondrial DNA (mtDNA) is a highly polymorphic, high-copy-number genome that is maternally inherited. New mutations in mtDNA segregate rapidly in the female germline due to a genetic bottleneck in early oogenesis1–3 and as a result most individuals are homoplasmic for a single species of mtDNA. Sequence variants thus accumulate along maternal lineages without genetic recombination. Most of the extant variation in mtDNA in mammalian populations has been assumed to be neutral with respect to selection4; however, comparisons of the ratio of replacement to silent nucleotide substitutions between species suggest that the evolution of mammalian mtDNA is not strictly neutral5. To test directly whether polymorphic mtDNAs behave as neutral variants, we examined the segregation of two different mtDNA genotypes in the tissues of heteroplasmic mice. We find evidence for random genetic drift in some tissues, but in others strong, tissue-specific and age-related, directional selection for different mtDNA genotypes in the same animal. These surprising data suggest that the coding sequence of mtDNA may represent a compromise between the competing demands of different tissues and point to the existence of unknown, tissue-specific nuclear genes important in the interaction between the nuclear and mitochondrial genomes.
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References
Jenuth, J.P., Peterson, A.C., Fu, K. & Shoubridge, E.A. Random genetic drift in the female germline explains the rapid segregation of mammalian mitochondrial DNA. Nature Genet. 13, 146–151 (1996).
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).
Ashley, M.V., Laipis, P.J. & Hauswirth, W.W. Rapid segregation of heteroplasmic bovine mitochondria. Nud. Adds Res. 17, 7325–7331 (1989).
Cann, R.L., Stoneking, M. & Wilson, A.C. Mitochondrial DNA and human evolution. Nature 325, 31–36 (1987).
Nachman, M.W., Brown, W.M., Stoneking, M. & Aquadro, C.F. Nonneutral mitochondrial DNA variation in humans and chimpanzees. Genetics 142, 953–963 (1996).
McGrath, J. & Solter, D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion. Science 228, 1300–1302 (1983).
Loveland, B., Wang, C., Yonekawa, H., Hermel, E & Lindahl, K.F. Maternally inherited histocompatibility antigen of mice: A hydrophobic peptide of a mitochondrially encoded protein. cell 60, 971–980 (1990).
Merriwether, D.A. et al. The structure of human mitochondrial DNA variation. J. Mol. Evol. 33, 543–555 (1991).
Ponder, B.A.J. et al. Derivation of mouse intestinal crypts from single progenitor cells. Nature 313, 689–691 (1985).
Cheng, H. & Leblond, C.P., Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. V. Unitarian theory of the origin of the four epithelial cell types. Am. J. Nat. 141, 537–562 (1980).
Birky, C.W. Jr, Maruyama, T. & Fuerst, P. An approach to population andevolutionary genetic theory for genes in mitochondria and chloroplasts, and some results. Genetics 103, 513–517 (1983).
Cheng, H. & Leblond, C.P., Origin, differentiation and renewal of the four main epithelial cell types in the mouse small intestine. I. Columnar Cell. Am. J. Anat. 141, 461–480 (1980).
Matthews, P.M. et al. Comparison of the relative levels of the 3243 (A to G) mtDNA mutation in heteroplasmic adult and fetal tissues. J. Med Genet. 31, 41–44 (1994).
Harding, A.E., Holt, I.J., Sweeny, M.G., Brockington, M. & Davis, M.B. Prenatal diagnosis of mitochondrial DNA8993T to G disease. Am. J. Hum. Genet. 50, 629–633 (1992).
Dukes, K.R. Selective inheritance of mitochondrial DNA in heteroplasmic mice. MSc Thesis. University of Florida. (1995).
de Stordeur, E, Solignac, M, Monnerot, M & Mounolou, J.C The generation of transplasmic Drosophila simulans by cytoplasmic injection: effects of segregation and selection on the perpetuation of mitochondrial DNA heteroplasmy. Mol. Gen. Genet. 220, 127–132 (1989).
Zajicek, G., Oren, R. & Weinreb Jr, M. The streaming liver. Liver 5, 293–300 (1985).
Clayton, D.A. Transcription and replication of animal mitochondrial DNAs. Int. Rev. Cytol. 141, 217–232 (1992).
Shadel, G.S. & Clayton, D.A. Mitochondrial transcription initiation. Variation and conservation J. Biol. Chem. 268, 16083–16086 (1993).
Kennaway, N.G. et al. Isoforms of mammalian cytochrome c oxidase: correlation with human cytochrome c oxidase deficiency. Pediatr. Res. 28, 529–535 (1990).
Li, H., Cui, X. & Arnheim, N. Analysis of DNA sequence variation in single cells. Methods: A Companion to Methods Enzymol. 2, 49–59 (1991).
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Jenuth, J., Peterson, A. & Shoubridge, E. Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice. Nat Genet 16, 93–95 (1997). https://doi.org/10.1038/ng0597-93
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DOI: https://doi.org/10.1038/ng0597-93
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