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 disorders1. 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 dysfunction2,3,4,5,6,7,8,9,10,11. 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 mouse13. Here we show that this phenotype segregates in F2 mice from a genetic cross (BALB/c × 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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Acknowledgements
We thank D. Malo, A. Suomalainen, K. Hastings, S. Leary, J. Caron and K. Morgan for discussion and N. Hanna and B. Lauzon for technical assistance. This work was supported by grants from the Canadian Institutes of Health Research and the Howard Hughes Medical Institute to E.A.S. E.A.S. is an international scholar of the Howard Hughes Medical Institute and a Senior Investigator of the Canadian Institutes of Health Research. B.J.B. is supported by a Doctoral Award from the Canadian Institutes of Health Research. J.C.L.-O. is supported by funds to K. Morgan from the Canadian Genetic Diseases Network of Centres of Excellence program.
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Battersby, B., Loredo-Osti, J. & Shoubridge, E. Nuclear genetic control of mitochondrial DNA segregation. Nat Genet 33, 183–186 (2003). https://doi.org/10.1038/ng1073
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DOI: https://doi.org/10.1038/ng1073
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