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ReportsA Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations
The majority of mitochondrial DNA (mtDNA) mutations that cause human disease are mild to moderately deleterious, yet many random mtDNA mutations would be expected to be severe. To determine the fate of the more severe mtDNA mutations, we introduced mtDNAs containing two mutations that affect oxidative phosphorylation into the female mouse germ line. The severe ND6 mutation was selectively eliminated during oogenesis within four generations, whereas the milder COI mutation was retained throughout multiple generations even though the offspring consistently developed mitochondrial myopathy and cardiomyopathy. Thus, severe mtDNA mutations appear to be selectively eliminated from the female germ line, thereby minimizing their impact on population fitness.
1 Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697, USA.
2 Department of Biological Chemistry, University of California, Irvine, CA 92697, USA. 3 Department of Pathology, University of California, Irvine, CA 92697, USA. 4 Division of Cardiology, Department of Medicine, University of California, Irvine, CA 92697, USA. 5 Department of Developmental and Cell Biology, University of California, Irvine, CA 92697, USA. 6 Developmental Biology Center, University of California, Irvine, CA 92697, USA. 7 Departments of Ecology and Evolutionary Biology and Pediatrics, University of California, Irvine, CA 92697, USA. * To whom correspondence should be addressed. E-mail: dwallace{at}uci.edu
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Science. ISSN 0036-8075 (print), 1095-9203 (online)
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