Nuclear genetic control of mitochondrial DNA segregation.
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.
Battersby
Brendan J
BJ
Montreal Neurological Institute and Department of Human Genetics, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
Loredo-Osti
J C
JC
Shoubridge
Eric A
EA
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics* / Q000378:metabolism; D020090:Chromosome Segregation; D003433:Crosses, Genetic; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D008040:Genetic Linkage; D014644:Genetic Variation; D005838:Genotype; D007668:Kidney / Q000502:physiology; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic / Q000235:genetics*; D008957:Models, Genetic; D018482:Muscle, Skeletal / Q000502:physiology; D009928:Organ Specificity; D010085:Oxidative Phosphorylation; D040641:Quantitative Trait Loci; D012641:Selection, Genetic; D013154:Spleen / Q000502:physiology; D013234:Stem Cells / Q000502:physiology
D004272:DNA, Mitochondrial