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Disease genetics

Double danger from mitochondrial mutations

Nature Reviews Genetics volume 14, pages 678–679 (2013)Cite this article

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To dissect the roles of inherited and somatic mtDNA mutations, Ross et al. carried out various mouse crosses involving a defective allele of DNA polymerase-γ (PolgAmut). This enzyme functions in the replication of mtDNA but is encoded by the nuclear genome. Somatic mtDNA mutations are known to accumulate in heterozygous PolgAwt/mut mice and more so in homozygous PolgAmut/mut mice.

Characterization of PolgAwt/mut mice revealed reproductive impairments such as reduced litter size. To dissect the contribution of inherited mtDNA mutations to the phenotype, the authors reintroduced 'wild-type' mtDNA (that is, mtDNA not previously exposed to the PolgAmut allele) by crossing wild-type females to PolgAwt/mut males. Importantly, the PolgAwt/mut offspring of this cross were generally normal, but their subsequent intercrossing resulted in reproductive defects that became progressively more severe in successive generations of PolgAwt/mut mice. This indicates that the mutational load of inherited mtDNA is an important phenotypic determinant.

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References

  1. Ross, J. M. et al. Germline mitochondrial DNA mutations aggravate ageing and can impair brain development. Nature http://dx.doi.org/10.1038/nature12474 (2013)

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  1. Darren J. Burgess
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Schon, E. A., DiMauro, S & Hirano, M. Human mitochondrial DNA: roles of inherited and somatic mutations. Nature Rev. Genet. 13, 878–890 (2012)

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Burgess, D. Double danger from mitochondrial mutations. Nat Rev Genet 14, 678–679 (2013). https://doi.org/10.1038/nrg3581

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