Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

Gorelick, Alexander N.; Kim, Min‐Soo; Chatila, Walid K.; La, Konnor; Hakimi, A. Ari; Taylor, Barry S.; Gammage, Payam A.; Reznik, Ed

doi:10.1101/2020.08.18.256362

Cited by 2 publications

(2 citation statements)

References 52 publications

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“…While rapid mtDNA mutation rates of metazoans have proven useful for understanding the divergence of closely related species (Bernt et al 2013;Yang et al 2016), they also pose a serious challenge for organismal fitness (Gemmell et al 2004). In humans, mtDNA mutations cause genetic disorders (Longley et al 2005;Marni J. and Soondhiemer 2010), are associated with numerous cancers (Gorelick et al 2021), and accumulate with age (Kennedy et al 2013). Further, individuals suffering from agerelated diseases such as Parkinson's and Alzheimer's display increased mtDNA mutations compared to healthy individuals (Monzio Compagnoni et al 2020).…”

Section: Introductionmentioning

confidence: 99%

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Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Waneka

Svendsen

Havird

et al. 2021

Preprint

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Rapid mutation rates are typical of mitochondrial genomes (mtDNAs) in animals, but it is not clear why. The difficulty of obtaining measurements of mtDNA mutation that are not biased by natural selection has stymied efforts to distinguish between competing hypotheses about the causes of high mtDNA mutation rates. Several studies which have measured mtDNA mutations in nematodes have yielded small datasets with conflicting conclusions about the relative abundance of different substitution classes (i.e. the mutation spectrum). We therefore leveraged Duplex Sequencing, a high-fidelity DNA sequencing technique, to characterize de novo mtDNA mutations in Caenorhabditis elegans. This approach detected nearly an order of magnitude more mtDNA mutations than documented in any previous nematode mutation study. Despite an existing extreme AT bias in the C. elegans mtDNA (75.6% AT), we found that a significant majority of mutations increase genomic AT content. Compared to some prior studies in nematodes and other animals, the mutation spectrum reported here contains an abundance of CGAT transversions, supporting the hypothesis that oxidative damage may be a driver of mtDNA mutations in nematodes. Further, we found an excess of GT and CT changes on the coding DNA strand relative to the template strand, consistent with increased exposure to oxidative damage. Analysis of the distribution of mutations across the mtDNA revealed significant variation among protein-coding genes and as well as among neighboring nucleotides. This high-resolution view of mitochondrial mutations in C. elegans highlights the value of this system for understanding relationships among oxidative damage, replication error, and mtDNA mutation.

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Section: Introductionmentioning

confidence: 99%

“…In humans, mtDNA mutations cause genetic disorders (Longley et al . 2005; Marni J. and Soondhiemer 2010), are associated with numerous cancers (Gorelick et al . 2021), and accumulate with age (Kennedy et al .…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Waneka

Svendsen

Havird

et al. 2021

Preprint

View full text Add to dashboard Cite

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Mitochondrial DNA copy number in human disease: the more the better?

et al. 2020

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Most of the genetic information has been lost or transferred to the nucleus during the evolution of mitochondria. Nevertheless, mitochondria have retained their own genome that is essential for oxidative phosphorylation (OXPHOS). In mammals, a gene-dense circular mitochondrial DNA (mtDNA) of about 16.5 kb encodes 13 proteins, which constitute only 1% of the mitochondrial proteome. Mammalian mtDNA is present in thousands of copies per cell and mutations often affect only a fraction of them. Most pathogenic human mtDNA mutations are recessive and only cause OXPHOS defects if present above a certain critical threshold. However, emerging evidence strongly suggests that the proportion of mutated mtDNA copies is not the only determinant of disease but that also the absolute copy number matters. In this review, we critically discuss current knowledge of the role of mtDNA copy number regulation in various types of human diseases, including mitochondrial disorders, neurodegenerative disorders and cancer, and during ageing. We also provide an overview of new exciting therapeutic strategies to directly manipulate mtDNA to restore OXPHOS in mitochondrial diseases.

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Respiratory complex and tissue lineage drive mutational patterns in the tumor mitochondrial genome

Cited by 2 publications

References 52 publications

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Mitochondrial mutations inCaenorhabditis elegansshow signatures of oxidative damage and an AT-bias

Mitochondrial DNA copy number in human disease: the more the better?

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