Nuclear genetic control of mitochondrial DNA segregation

Battersby, Brendan J.; Loredo-Osti, J.C.; Shoubridge, Eric A.

doi:10.1038/ng1073

Cited by 144Mitochondrial Function and PathologyGenetic Associations and EpidemiologyForensic and Genetic Research

Nuclear genetic control of mitochondrial DNA segregation

Battersby, Brendan J., Loredo-Osti, J.C., Shoubridge, Eric A.·2003·Nature Genetics

DOI 10.1038/ng1073

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Abstract

Mammalian mitochondrial DNA (mtDNA) is a high copy-number, maternally inherited genome that codes for a small number of essential proteins involved in oxidative phosphorylation. Mutations in mtDNA are responsible for a broad spectrum of clinical disorders. The segregation pattern of pathogenic mtDNA mutants is an important determinant of the nature and severity of mitochondrial disease, but it varies with the specific mutation, cell type and nuclear background and generally does not correlate well with mitochondrial dysfunction. To identify nuclear genes that modify the segregation behavior of mtDNA, we used a heteroplasmic mouse model derived from two inbred strains (BALB/c and NZB; ref. 12), in which we had previously demonstrated tissue-specific and age-dependent directional selection for different mtDNA genotypes in the same mouse. Here we show that this phenotype segregates in F2 mice from a genetic cross (BALB/c x CAST/Ei) and that it maps to at least three quantitative-trait loci (QTLs). Genome-wide scans showed linkage of the trait to loci on Chromosomes 2, 5 and 6, accounting for 16-35% of the variance in the trait, depending on the tissue and age of the mouse. This is the first genetic evidence for nuclear control of mammalian mtDNA segregation.

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Directional selection for one mtDNA genotype in certain tissues, mediated by single tissue-specific factors, has been repeatedly observed.
“However, the repeated observation of directional selection for one mtDNA genotype in certain tissues [170], mediated by single tissue-specific factors [171], suggests these mouse models will be particularly important in our quest to understanding the basis of tissue specificity and mtDNA somatic segregation.”
From Mitochondrial DNA mutations and human disease (2010) · cites this paper as [170]

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Authors: Battersby, B. J., Loredo-Osti, J. C., & Shoubridge, E. A.
Affiliations: Montreal Neurological Institute and Hospital (CA)
Corresponding author: Shoubridge, Eric A.
ORCID: Battersby, Brendan J.
Shoubridge, Eric A.
Venue: Nature Genetics
Publisher: Springer Science and Business Media LLC
Published: 2003-01-21
Volume: 33
Issue: 2
Pages: 183-186
ISSN: 1061-4036 (ISSN-L)
1546-1718
DOI: 10.1038/ng1073
OpenAlex: W2054789602
Cited by: 144
References: 30
Citations by year: 2026: 1 · 2025: 2 · 2024: 5 · 2023: 5 · 2022: 4 · 2021: 7 · 2020: 6 · 2019: 5 · 2018: 5 · 2017: 2 · 2016: 2 · 2015: 8 · 2014: 3 · 2013: 3 · 2012: 6
FWCI: 3.91
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Genetics (publishedVersion)
PubMed (publishedVersion)
Funders: McGill University
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Forensic and Genetic Research
Keywords: mitochondrial DNA segregation, heteroplasmy, mitochondrial disease, quantitative trait loci, linkage mapping, nuclear-mitochondrial interactions, F2 segregation, mouse model
MeSH terms: Animals, Cell Nucleus, Crosses, Genetic, DNA, Mitochondrial, Female, Genotype, Kidney, Genetic Linkage, Liver, Male, Mice, Inbred C57BL, Mice, Inbred NZB, Mice, Transgenic, Models, Genetic, Organ Specificity, Oxidative Phosphorylation, Selection, Genetic, Spleen, Stem Cells, Genetic Variation, Muscle, Skeletal, Founder Effect, Chromosome Segregation, Quantitative Trait Loci, Mice

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Nuclear genetic control of mitochondrial DNA segregation

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