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A 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.

Pubmed ID: 18276892


  • Fan W
  • Waymire KG
  • Narula N
  • Li P
  • Rocher C
  • Coskun PE
  • Vannan MA
  • Narula J
  • Macgregor GR
  • Wallace DC


Science (New York, N.Y.)

Publication Data

February 15, 2008

Associated Grants

  • Agency: NIA NIH HHS, Id: AG13154
  • Agency: NIA NIH HHS, Id: AG16573
  • Agency: NIA NIH HHS, Id: AG24373
  • Agency: NIDDK NIH HHS, Id: DK73691
  • Agency: NICHD NIH HHS, Id: HD45913
  • Agency: NINDS NIH HHS, Id: NS21328
  • Agency: NICHD NIH HHS, Id: U01 HD045913-01
  • Agency: NICHD NIH HHS, Id: U01 HD045913-02
  • Agency: NICHD NIH HHS, Id: U01 HD045913-03
  • Agency: NICHD NIH HHS, Id: U01 HD045913-04

Mesh Terms

  • Animals
  • Cardiomyopathies
  • Cell Line
  • Crosses, Genetic
  • DNA, Mitochondrial
  • Electron Transport Complex I
  • Electron Transport Complex IV
  • Embryonic Stem Cells
  • Female
  • Frameshift Mutation
  • Germ-Line Mutation
  • Litter Size
  • Male
  • Mice
  • Mitochondria
  • Mitochondrial Myopathies
  • Mutation, Missense
  • Myocardium
  • NADH Dehydrogenase
  • Oocytes
  • Oogenesis
  • Oxidative Phosphorylation
  • Oxygen Consumption
  • Point Mutation
  • Selection, Genetic