Ultra-Deep Sequencing of Mouse Mitochondrial DNA: Mutational Patterns and Their Origins

Abstract

Somatic mutations of mtDNA are implicated in the aging process, but there is no universally accepted method for their accurate quantification. We have used ultra-deep sequencing to study genome-wide mtDNA mutation load in the liver of normally- and prematurely-aging mice. Mice that are homozygous for an allele expressing a proof-reading-deficient mtDNA polymerase (mtDNA mutator mice) have 10-times-higher point mutation loads than their wildtype siblings. In addition, the mtDNA mutator mice have increased levels of a truncated linear mtDNA molecule, resulting in decreased sequence coverage in the deleted region. In contrast, circular mtDNA molecules with large deletions occur at extremely low frequencies in mtDNA mutator mice and can therefore not drive the premature aging phenotype. Sequence analysis shows that the main proportion of the mutation load in heterozygous mtDNA mutator mice and their wildtype siblings is inherited from their heterozygous mothers consistent with germline transmission. We found no increase in levels of point mutations or deletions in wildtype C57Bl/6N mice with increasing age, thus questioning the causative role of these changes in aging. In addition, there was no increased frequency of transversion mutations with time in any of the studied genotypes, arguing against oxidative damage as a major cause of mtDNA mutations. Our results from studies of mice thus indicate that most somatic mtDNA mutations occur as replication errors during development and do not result from damage accumulation in adult life.

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Cited by papers we hold 9

• Mitochondrial Dysfunction in the Aging Retina · 2019
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• Mitochondrial dysfunction in neurodegenerative diseases and the potential countermeasure · 2019
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• Aging Hallmarks: The Benefits of Physical Exercise · 2018
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• Parkinson's disease as a result of aging · 2015
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• Changes in Regenerative Capacity through Lifespan · 2015
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• Oxidative Stress Is Not a Major Contributor to Somatic Mitochondrial DNA Mutations · 2014
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• Clonal Expansion of Early to Mid-Life Mitochondrial DNA Point Mutations Drives Mitochondrial Dysfunction during Human Ageing · 2014
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• Ultra-Sensitive Sequencing Reveals an Age-Related Increase in Somatic Mitochondrial Mutations That Are Inconsistent with Oxidative Damage · 2013
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• The role of mitochondrial DNA mutations and free radicals in disease and ageing · 2013
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