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A mouse model of mitochondrial disease reveals germline selection against severe mtDNA mutations

Weiwei Fan1, Katrina G Waymire, Navneet Narula

  • 1Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697, USA.

Science (New York, N.Y.)
|February 16, 2008
PubMed

Insights

Severe mitochondrial DNA (mtDNA) mutations are eliminated from the female germ line. Milder mtDNA mutations persist across generations, causing disease but not population-level impact.

Area of Science:

  • Genetics
  • Mitochondrial Biology
  • Evolutionary Biology

Background:

  • Mitochondrial DNA (mtDNA) mutations are implicated in numerous human diseases.
  • Most disease-causing mtDNA mutations are mild to moderate, but random mutations are often severe.
  • The evolutionary fate of severe mtDNA mutations remains unclear.

Purpose of the Study:

  • To investigate the selective pressures on severe mitochondrial DNA (mtDNA) mutations within the female germ line.
  • To determine the long-term effects of introducing deleterious mtDNA mutations into a population.

Main Methods:

  • Introduction of mtDNAs with specific oxidative phosphorylation mutations (ND6 and COI) into the female mouse germ line.
  • Tracking the segregation and elimination of mutant mtDNA across multiple generations.
  • Phenotypic analysis of offspring for signs of mitochondrial myopathy and cardiomyopathy.

Main Results:

  • The severe ND6 mutation was rapidly eliminated from the female germ line within four generations.
  • The milder COI mutation persisted across multiple generations.
  • Offspring carrying the persistent COI mutation exhibited mitochondrial myopathy and cardiomyopathy.

Conclusions:

  • Severe mtDNA mutations are subject to strong negative selection in the female germ line.
  • Milder mtDNA mutations can be maintained across generations, leading to chronic disease.
  • Germline selection against severe mtDNA mutations plays a role in maintaining population fitness.

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