A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations

doi:10.1126/science.1147786

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Science 15 February 2008:
Vol. 319. no. 5865, pp. 958 - 962
DOI: 10.1126/science.1147786

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A Mouse Model of Mitochondrial Disease Reveals Germline Selection Against Severe mtDNA Mutations

Weiwei Fan,¹^,2 Katrina G. Waymire,¹^,2 Navneet Narula,³ Peng Li,⁴ Christophe Rocher,¹^,2 Pinar E. Coskun,¹^,2 Mani A. Vannan,⁴ Jagat Narula,⁴ Grant R. MacGregor,¹^,5^,6 Douglas C. Wallace¹^,2^,7^*

The majority of mitochondrial DNA (mtDNA) mutations that causehuman disease are mild to moderately deleterious, yet many randommtDNA mutations would be expected to be severe. To determinethe fate of the more severe mtDNA mutations, we introduced mtDNAscontaining two mutations that affect oxidative phosphorylationinto the female mouse germ line. The severe ND6 mutation wasselectively eliminated during oogenesis within four generations,whereas the milder COI mutation was retained throughout multiplegenerations even though the offspring consistently developedmitochondrial myopathy and cardiomyopathy. Thus, severe mtDNAmutations appear to be selectively eliminated from the femalegerm 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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