A high observed substitution rate in the human mitochondrial DNA control region

Parsons, Thomas J.; Muniec, David; Sullivan, Kevin M.; Woodyatt, N.J; Alliston-Greiner, R.; Wilson, Mark; Berry, Dianna L.; Holland, Koren A.; Weedn, Victor W.; Gill, Peter; Holland, Mitchell M.

doi:10.1038/ng0497-363

Cited by 415 publications

(309 citation statements)

References 35 publications

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“…Typical values for accumulation of mtDNA point mutations in humans have been thought to be in the order of 10 Ð6 Ð10 Ð8 (estimated from Brown et al 1979; Kondo et al 1993). A recent study sequencing the hypervariable domains of the human control region from large pedigrees, however, indicates a per generation rate larger than previously reported and much more similar to those observed for mtVNTRs (Parsons et al 1997).…”

Section: Mutation Rates In Mtvntrsmentioning

confidence: 85%

Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology

1998

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Analysis of mitochondrial (mt)DNA size polymorphism in the form of variable number tandem repeats (mtVNTRs) has become an increasingly popular methodology for addressing questions in molecular ecology. When detected by PCR, mtVNTR analysis can provide a sensitive, rapid, and cost-effective measure of genetic variability that may be exploited in studies of population differentiation and biogeography. Despite the emergence of this approach, there has been little critical evaluation of its success or utility as a practical tool. In this review, we identify problematic methodological, theoretical and interpretive factors that can influence the utility of mtVNTR analysis. The reliability of the procedure is considered in terms of both detection of alleles and scoring of intra-individual allele frequencies. While many of the potential technical problems of the technique do not raise serious practical concerns, this rapid and sensitive methodology is seriously compromised by the difficulty of reliably assessing allele frequencies, of assaying only germline tissue, and in our ignorance of the mechanisms generating mtVNTR diversity. Thus, although there is a considerable potential for mtVNTR pilot studies to assess genetic diversity, the utility of the technique to resolve broader questions in molecular ecology should be treated cautiously until such a time as the system is better understood.

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Section: Mutation Rates In Mtvntrsmentioning

confidence: 85%

Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology

1998

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“…A recent study revealed a higher frequency of mtDNA variations in women with RPL [9]. Most of these mutations accumulate in the regulatory region or D-loop [10]. Since D-loop has a regulatory role on mtDNA replication and transcription, mutations in this region might have an important effect in copy number and gene expression of the mitochondrial genome, and could disturb mitochondrial function, oxidative phosphorylation (OXPHOS) and ATP production.…”

Section: Introductionmentioning

confidence: 99%

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

Seyedhassani

Houshmand

Kalantar

et al. 2010

J Assist Reprod Genet

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Purpose Repeated pregnancy loss (RPL) occurs in 1 out of 300 couples, and the cause of about 50% of them remains idiopathic. Mitochondria have an important role in human development through ATP production and their involvement in apoptosis. Methods 96 RPL and 96 control females were used to investigate the frequency of deletions and point mutations in the displacement loop (D-loop) on mitochondria. Multiplex PCR and DNA sequencing methods were used to detect possible variations in the mitochondrial DNA (mtDNA).Results No deletions but a high frequency of point mutations were found in RPL females; among 129 variations observed in RPL, 22 mutations were significant (P<0.05) and the insertion of C in nucleotide 114 was novel. Conclusion High rate of mutations in D-loop of mtDNA was observed in maternal blood, a fact that may have a direct or indirect role in inducing RPL. The results can be used in the assessment of RPL and designing possible treatments for improving assisted reproduction.

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“…This approach can also not detect insertion-deletion variation, which must be addressed by other means (Keightley & Eyre-Walker, 2000). Direct sequencing gives estimates of mutation rate an order of magnitude higher than do interspecific comparisons, suggesting that the bias is large (Howell et al, 1996 ;Parsons et al, 1997;Denver et al, 2000). However, it is not clear that direct sequencing is necessarily more accurate, because the impact of sequencing errors has yet to be adequately addressed.…”

Section: Introductionmentioning

confidence: 99%

Mutation accumulation and the effect of copia insertions in Drosophila melanogaster

Houle

Nuzhdin

2004

Genet. Res.

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SummaryRepeated efforts to estimate the genomic deleterious mutation rate per generation (U) in Drosophila melanogaster have yielded inconsistent estimates ranging from 0 . 01 to nearly 1. We carried out a mutation-accumulation experiment with a cryopreserved control population in hopes of resolving some of the uncertainties raised by these estimates. Mutation accumulation (MA) was carried out by brother-sister mating of 150 sublines derived from two inbred lines. Fitness was measured under conditions chosen to mimic the ancestral laboratory environment of these genotypes. We monitored the insertions of a transposable element, copia, that proved to accumulate at the unusually high rate of 0 . 24 per genome per generation in one of our MA lines. Mutational variance in fitness increased at a rate consistent with previous studies, yielding a mutational coefficient of variation greater than 3 %. The performance of the cryopreserved control relative to the MA lines was inconsistent, so estimates of mutation rate by the Bateman-Mukai method are suspect. Taken at face value, these data suggest a modest decline in fitness of about 0 . 3 % per generation. The element number of copia was a significant predictor of fitness within generations ; on average, insertions caused a 0 . 76 % loss in fitness, although the confidence limits on this estimate are wide.

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A high observed substitution rate in the human mitochondrial DNA control region

Cited by 415 publications

References 35 publications

Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology

Mitochondrial DNA variable number tandem repeats (VNTRs): utility and problems in molecular ecology

No mitochondrial DNA deletions but more D-loop point mutations in repeated pregnancy loss

Mutation accumulation and the effect of copia insertions in Drosophila melanogaster

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