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A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.

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.

SUBMITTER: Sanchez-Contreras M

PROVIDER: S-EPMC8565317 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.

Sanchez-Contreras Monica M Sweetwyne Mariya T MT Kohrn Brendan F BF Tsantilas Kristine A KA Hipp Michael J MJ Schmidt Elizabeth K EK Fredrickson Jeanne J Whitson Jeremy A JA Campbell Matthew D MD Rabinovitch Peter S PS Marcinek David J DJ Kennedy Scott R SR

Nucleic acids research 20211101 19

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 ...[more]

PMID: 34614167

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Project description:BackgroundThe mutational profile of cancer reflects the activity of the mutagenic processes which have been operative throughout the lineage of the cancer cell. These processes leave characteristic profiles of somatic mutations called mutational signatures. Mutational signatures, including single-base substitution (SBS) signatures, may reflect the effects of exogenous or endogenous exposures.MethodsWe used polygenic risk scores (PRS) to summarize common germline variation associated with cancer risk and other cancer-related traits and examined the association between somatic mutational profiles and germline PRS in 12 cancer types from The Cancer Genome Atlas. Somatic mutational profiles were constructed from whole-exome sequencing data of primary tumors. PRS were calculated for the 12 selected cancer types and 9 non-cancer traits, including cancer risk determinants, hormonal factors, and immune-mediated inflammatory diseases, using germline genetic data and published summary statistics from genome-wide association studies.ResultsWe found 17 statistically significant associations between somatic mutational profiles and germline PRS after Bonferroni correction (p < 3.15 × 10-5), including positive associations between germline inflammatory bowel disease PRS and number of somatic mutations attributed to signature SBS1 in prostate cancer and APOBEC-related signatures in breast cancer. Positive associations were also found between age at menarche PRS and mutation counts of SBS1 in overall and estrogen receptor-positive breast cancer. Consistent with prior studies that found an inverse association between the pubertal development PRS and risk of prostate cancer, likely reflecting hormone-related mechanisms, we found an inverse association between age at menarche PRS and mutation counts of SBS1 in prostate cancer. Inverse associations were also found between several cancer PRS and tumor mutation counts.ConclusionsOur analysis suggests that there are robust associations between tumor somatic mutational profiles and germline PRS. These may reflect the mechanisms through hormone regulation and immune responses that contribute to cancer etiology and drive cancer progression.

Dataset Information

A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.

Publications

A replication-linked mutational gradient drives somatic mutation accumulation and influences germline polymorphisms and genome composition in mitochondrial DNA.

Similar Datasets

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