Does Human mtDNA Recombine?

Eyre‐Walker, Adam; Awadalla, Philip

doi:10.1007/s002390010232

Cited by 72 publications

(34 citation statements)

References 49 publications

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“…Past recombinations are detected by comparing the pattern of sequence variations among individuals in a population, whereas real-time recombinations report the novel sequence patterns in the progeny that can be directly compared with those in their parents. Numerous polymorphism analyses for past recombination have provided evidence supporting widespread mitochondrial recombination across the animal kingdom (66)(67)(68), although some skepticism has been expressed about the power of this type of analysis (63,65,69). Data strongly supporting past recombination events have come from the analyses of mtDNA in lizard and salmon populations.…”

Section: Mtdna Recombination In Mammalsmentioning

confidence: 99%

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Chen

2013

Microbiol Mol Biol Rev

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SUMMARY Homologous recombination is a universal process, conserved from bacteriophage to human, which is important for the repair of double-strand DNA breaks. Recombination in mitochondrial DNA (mtDNA) was documented more than 4 decades ago, but the underlying molecular mechanism has remained elusive. Recent studies have revealed the presence of a Rad52-type recombination system of bacteriophage origin in mitochondria, which operates by a single-strand annealing mechanism independent of the canonical RecA/Rad51-type recombinases. Increasing evidence supports the notion that, like in bacteriophages, mtDNA inheritance is a coordinated interplay between recombination, repair, and replication. These findings could have profound implications for understanding the mechanism of mtDNA inheritance and the generation of mtDNA deletions in aging cells.

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Section: Mtdna Recombination In Mammalsmentioning

confidence: 99%

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Chen

2013

Microbiol Mol Biol Rev

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“…Although analogies with nuclear genome association studies may suggest this approach to be advantageous in terms of locating the underlying genetic variant, it should be remembered that the mitochondrial DNA is essentially a recombination "coldspot", and this prohibits the localization of causal variants through association. (Despite some initial reports [Awadalla et al 1999], there appears to be little evidence for widespread recombination between mitochondrial genomes [Eyre-Walker and Awadalla 2001;McVean et al 2002].) Here, the power of the SNP-based approach to mitochondrial association studies is investigated and a comparison of the power of association studies on mitochondrial DNA relative to genomewide association studies is made.…”

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confidence: 99%

Power and SNP tagging in whole mitochondrial genome association studies

McRae¹,

Byrne²,

Zhao³

et al. 2008

Genome Res.

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The application of genetic association studies to detect mitochondrial variants responsible for phenotypic variation has recently been demonstrated. However, the only power estimates currently available are based on the use of mitochondrial haplogroups, which can only tag a small fraction of the common variation in the mitochondrial genome. Here, power estimates are derived for a SNP-based study design for both disease (case-control) and quantitative trait mapping studies. Power is estimated using simulations based on a collection of publicly available mitochondrial sequences of European origin. The power when testing all common mitochondrial SNPs is shown to be equivalent to that when testing only tagging SNPs, despite the relatively high ratio of tagging SNPs to total SNPs resulting from the tagging of all SNPs with a minor allele frequency greater than 1%. The sample size requirements of mitochondrial genome association studies are compared with that of nuclear whole-genome studies. Remarkably, the trade off between the number of tests being performed and the proportion of phenotypic variance explained for a fixed effect size results in approximately equal sample sizes required for both study types, although the per individual cost for the mitochondrial association study is much less. To test the representation of the sequences used in the power simulations, a sample of 3839 individuals from 1037 Australian families was genotyped for 69 tagging SNPs. The strong concordance in allele frequencies and linkage disequilibrium between the European sequences and the Australian sample indicates that the results presented here are transferable across populations of European descent.

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“…Replication of the S. cerevisiae mtDNA is initiated from multiple sites of the ϳ86-kb genome, and the mtDNA molecules frequently undergo recombination. In contrast, the smaller mammalian mtDNAs (ϳ16 kb) initiate DNA replication from two specific origins of replication, oriH and oriL, and recombination is a rare or possibly even non-existent phenomenon (2).…”

mentioning

confidence: 99%

TWINKLE Has 5′ → 3′ DNA Helicase Activity and Is Specifically Stimulated by Mitochondrial Single-stranded DNA-binding Protein

Korhonen

Gaspari

Falkenberg

2003

Journal of Biological Chemistry

251

261

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Mutations in TWINKLE cause autosomal dominant progressive external ophthalmoplegia, a human disorder associated with multiple deletions in the mitochondrial DNA. TWINKLE displays primary sequence similarity to the phage T7 gene 4 primase-helicase, but no specific enzyme activity has been assigned to the protein. We have purified recombinant TWINKLE to near homogeneity and demonstrate here that TWINKLE is a DNA helicase with 5 to 3 directionality and distinct substrate requirements. The protein needs a stretch of 10 nucleotides of single-stranded DNA on the 5-side of the duplex to unwind duplex DNA. In addition, helicase activity is not observed unless a short single-stranded 3-tail is present. The helicase activity has an absolute requirement for hydrolysis of a nucleoside 5-triphosphate, with UTP being the optimal substrate. DNA unwinding by TWINKLE is specifically stimulated by the mitochondrial single-stranded DNA-binding protein.Our enzymatic characterization strongly supports the notion that TWINKLE is the helicase at the mitochondrial DNA replication fork and provides evidence for a close relationship of the DNA replication machinery in bacteriophages and mammalian mitochondria.The molecular mechanisms by which mtDNA is replicated in mammalian cells are of fundamental biological interest. Saccharomyces cerevisiae has served as a model system for studies of mammalian mtDNA replication, but there are significant differences between yeast and mammalian cells (1). Replication of the S. cerevisiae mtDNA is initiated from multiple sites of the ϳ86-kb genome, and the mtDNA molecules frequently undergo recombination. In contrast, the smaller mammalian mtDNAs (ϳ16 kb) initiate DNA replication from two specific origins of replication, oriH and oriL, and recombination is a rare or possibly even non-existent phenomenon (2).Mammalian mtDNA contains two major promoters, the light and heavy strand promoters, which produce near genomic length transcripts that, after RNA processing, release individual mRNAs, tRNAs, and rRNAs. A separate transcription unit for the rRNA genes in mammalian mitochondria has also been reported (3). Transcription from light strand promoters is not only necessary for gene expression but also produces the RNA primers required for initiation of mtDNA replication at oriH (1, 4). DNA synthesis from oriH is unidirectional and proceeds to displace the parental heavy strand. The nascent H strands frequently terminate 700 bp downstream of oriH, giving rise to 7 S DNA (D-loop strand). This termination event produces a characteristic triple-stranded structure, called the D-loop (5). The function of the D-loops is unknown, but they presumably play a role in regulating mtDNA replication.The mitochondrial DNA polymerase ␥ is a heterodimer comprising catalytic (A) and accessory (B) subunits of 140 and 54 kDa, respectively. The accessory subunit, polymerase ␥ B, which is not present in yeast, has been characterized as a processivity factor for the polymerase (6, 7). Polymerase ␥ B increases the affinity of the ...

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Does Human mtDNA Recombine?

Cited by 72 publications

References 49 publications

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Mechanism of Homologous Recombination and Implications for Aging-Related Deletions in Mitochondrial DNA

Power and SNP tagging in whole mitochondrial genome association studies

TWINKLE Has 5′ → 3′ DNA Helicase Activity and Is Specifically Stimulated by Mitochondrial Single-stranded DNA-binding Protein

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