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A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.
- Source :
-
Nucleic acids research [Nucleic Acids Res] 2021 Nov 08; Vol. 49 (19), pp. 11103-11118. - Publication Year :
- 2021
-
Abstract
- Mutations in mitochondrial DNA (mtDNA) cause maternally inherited diseases, while somatic mutations are linked to common diseases of aging. Although mtDNA mutations impact health, the processes that give rise to them are under considerable debate. To investigate the mechanism by which de novo mutations arise, we analyzed the distribution of naturally occurring somatic mutations across the mouse and human mtDNA obtained by Duplex Sequencing. We observe distinct mutational gradients in G→A and T→C transitions delimited by the light-strand origin and the mitochondrial Control Region (mCR). The gradient increases unequally across the mtDNA with age and is lost in the absence of DNA polymerase γ proofreading activity. In addition, high-resolution analysis of the mCR shows that important regulatory elements exhibit considerable variability in mutation frequency, consistent with them being mutational 'hot-spots' or 'cold-spots'. Collectively, these patterns support genome replication via a deamination prone asymmetric strand-displacement mechanism as the fundamental driver of mutagenesis in mammalian DNA. Moreover, the distribution of mtDNA single nucleotide polymorphisms in humans and the distribution of bases in the mtDNA across vertebrate species mirror this gradient, indicating that replication-linked mutations are likely the primary source of inherited polymorphisms that, over evolutionary timescales, influences genome composition during speciation.<br /> (© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.)
- Subjects :
- Aging metabolism
Animals
Chromosome Mapping
DNA Polymerase gamma deficiency
DNA Polymerase gamma genetics
DNA, Mitochondrial metabolism
Genetic Speciation
High-Throughput Nucleotide Sequencing
Humans
Male
Mice
Mice, Inbred C57BL
Mitochondria metabolism
Mutation Rate
Polymorphism, Single Nucleotide
Aging genetics
DNA Replication
DNA, Mitochondrial genetics
Genome, Mitochondrial
Germ-Line Mutation
Mitochondria genetics
Mutation Accumulation
Subjects
Details
- Language :
- English
- ISSN :
- 1362-4962
- Volume :
- 49
- Issue :
- 19
- Database :
- MEDLINE
- Journal :
- Nucleic acids research
- Publication Type :
- Academic Journal
- Accession number :
- 34614167
- Full Text :
- https://doi.org/10.1093/nar/gkab901