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Tissue-specific selection for different mtDNA genotypes in heteroplasmic mice
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 oogenesis 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 selection; however, comparisons of the ratio of replacement to silent nucleotide substitutions between species suggest that the evolution of mammalian mtDNA is not strictly neutral. 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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“The first heteroplasmic mice were generated by cytoplasmic fusion of two normal mouse strains carrying distinct haplotypes [74,169].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [169]
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“Whilst there is concern whether the mutation load detected in the prenatal sample would accurately reflect the heteroplasmy levels in other foetal tissues, present evidence suggests that this should not be a problem [169,249].”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [169]
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Self-citationKadam, P. S., Yang, Z., Lu, Y., Zhu, H., Atiyas, Y., Shah, N., Fisher, S. A., Nordgren, E., Kim, J., Issadore, D., et al. (2024) · BMC Biology · doi:10.1186/s12915-024-01953-7 · Cited by 5
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Metadata
- Authors
- Jenuth, J. P., Peterson, A. C., & Shoubridge, E. A.
- Affiliations
- Montreal Neurological Institute and Hospital (CA)
- McGill University (CA)
- Corresponding author
- Shoubridge, Eric A.
- Venue
- Nature Genetics
- Published
- 1997-05
- Volume
- 16
- Issue
- 1
- Pages
- 93-95
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2080844913
- Cited by
- 415
- References
- 21
- Citations by year
- 2026: 2 · 2025: 7 · 2024: 35 · 2023: 12 · 2022: 8 · 2021: 13 · 2020: 11 · 2019: 12 · 2018: 11 · 2017: 7 · 2016: 8 · 2015: 22 · 2014: 17 · 2013: 11 · 2012: 12
- FWCI
- 10.51
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
- Keywords
- mitochondrial DNA, heteroplasmy, genetic drift, mtDNA polymorphisms, neutral evolution, nuclear-mitochondrial interactions, nuclear genes
- MeSH terms
- Age Factors, Animals, Animals, Newborn, Blastocyst, Blood Physiological Phenomena, Colon, DNA, Mitochondrial, Female, Kidney, Liver, Male, Mice, Inbred C57BL, Mice, Inbred NZB, Mice, Inbred Strains, Mice, Transgenic, Models, Genetic, Organ Specificity, Selection, Genetic, Spleen, Stem Cells, Genetic Variation, Mice
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