Somatic mtDNA Mutation Spectra in the Aging Human Putamen

Williams, Siôn L.; Mash, Deborah C.; Züchner, Stephan; Moraes, Carlos T.
December 2013
PLoS Genetics;Dec2013, Vol. 9 Issue 12, p1
Academic Journal
The accumulation of heteroplasmic mitochondrial DNA (mtDNA) deletions and single nucleotide variants (SNVs) is a well-accepted facet of the biology of aging, yet comprehensive mutation spectra have not been described. To address this, we have used next generation sequencing of mtDNA-enriched libraries (Mito-Seq) to investigate mtDNA mutation spectra of putamen from young and aged donors. Frequencies of the “common” deletion and other “major arc” deletions were significantly increased in the aged cohort with the fold increase in the frequency of the common deletion exceeding that of major arc deletions. SNVs also increased with age with the highest rate of accumulation in the non-coding control region which contains elements necessary for translation and replication. Examination of predicted amino acid changes revealed a skew towards pathogenic SNVs in the coding region driven by mutation bias. Levels of the pathogenic m.3243A>G tRNA mutation were also found to increase with age. Novel multimeric tandem duplications that resemble murine control region multimers and yeast ρ− mtDNAs, were identified in both young and aged specimens. Clonal ∼50 bp deletions in the control region were found at high frequencies in aged specimens. Our results reveal the complex manner in which the mitochondrial genome alters with age and provides a foundation for studies of other tissues and disease states.


Related Articles

  • Evidence for Multiple Reversals of Asymmetric Mutational Constraints during the Evolution of the Mitochondrial Genome of Metazoa, and Consequences for Phylogenetic Inferences. Hassanin, Alexander; Léger, Nelly; Deutsch, Jean // Systematic Biology;Apr2005, Vol. 54 Issue 2, p277 

    Mitochondrial DNA (mtDNA) sequences are commonly used for inferring phylogenetic relationships. However, the strand-specific bias in the nucleotide composition of the mtDNA, which is thought to reflect asymmetric mutational constraints, combined with the important compositional heterogeneity...

  • The generation of mitochondrial DNA large-scale deletions in human cells. Chen, Tao; He, Jing; Huang, Yushan; Zhao, Weiwei // Journal of Human Genetics;Oct2011, Vol. 56 Issue 10, p689 

    Large-scale deletions of human mitochondrial DNA (mtDNA) are a common cause of mitochondrial diseases. In order to prevent and treat these mitochondrial diseases, it is important and necessary to understand the mechanisms behind the generation of these deletions. Generally, there exist three...

  • Mathematical Modeling of the Role of Mitochondrial Fusion and Fission in Mitochondrial DNA Maintenance. Tam, Zhi Yang; Gruber, Jan; Halliwell, Barry; Gunawan, Rudiyanto // PLoS ONE;Oct2013, Vol. 8 Issue 10, p1 

    Accumulation of mitochondrial DNA (mtDNA) mutations has been implicated in a wide range of human pathologies, including neurodegenerative diseases, sarcopenia, and the aging process itself. In cells, mtDNA molecules are constantly turned over (i.e. replicated and degraded) and are also exchanged...

  • Replicative Age Induces Mitotic Recombination in the Ribosomal RNA Gene Cluster of Saccharomyces cerevisiae. Lindstrom, Derek L.; Leverich, Christina K.; Henderson, Kiersten A.; Gottschling, Daniel E. // PLoS Genetics;Mar2011, Vol. 7 Issue 3, preceding p1 

    No abstract available.

  • Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. Stewart, J. D.; Tennant, S.; Powell, H.; Pyle, A.; Blakely, E. L.; He, L.; Hudson, G.; Roberts, M.; du Plessis, D.; Gow, D.; Mewasingh, L. D.; Hanna, M. G.; Omer, S.; Morris, A. A.; Roxburgh, R.; Livingston, J. H.; McFarland, R.; Turnbull, D. M.; Chinnery, P. F.; Taylor, R. W. // Journal of Medical Genetics;Mar2009, Vol. 46 Issue 3, p209 

    Background: The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease....

  • Transcription-associated mutational asymmetry in mammalian evolution. Green, Phil; Ewing, Brent; Miller, Webb; Thomas, Pamela J.; Green, Eric D. // Nature Genetics;Apr2003, Vol. 33 Issue 4, p514 

    Although mutation is commonly thought of as a random process, evolutionary studies show that different types of nucleotide substitution occur with widely varying rates that presumably reflect biases intrinsic to mutation and repair mechanisms[SUP1-4]. A strand asymmetry[SUP5,6], the occurrence...

  • The Impact of Lagging Strand Replication Mutations on the Stability of CAG Repeat Tracts in Yeast. Ireland, Malia J.; Reinke, Shanda S. // Genetics;Aug2000, Vol. 155 Issue 4, p1657 

    Examines the impact of lagging strand replication mutations on the stability of CAG repeat tracts in yeast. Analysis on the frequency of tract-length changes in unstable orientations; Destabilization of tracts in both stable and unstable orientations by a mutation in primase; Influence of...

  • A Novel Method for Estimating Substitution Rate Variation Among Sites in a Large Dataset of.... Pesole, Graziano; Saccone, Cecilia // Genetics;Feb2001, Vol. 157 Issue 2, p859 

    Examines the method to estimate site-specific relative variability in large sets of homologous DNA sequences. Related studies on nucleotide substitution; Description of relative variability in phylogenetic tree; Analysis of nucleotide states; Identification of pathogenic mitochondrial DNA...

  • The G16319A substitution frequency in a hemorrhagic stroke. Gaweł, Barbara; Głogowska-Ligus, Joanna; Mazurek, Urszula // Annals of Indian Academy of Neurology;Jul2008, Vol. 11 Issue 3, p154 

    Background: The aim of this paper is to trace the nucleotide alterations within the D-loop region of the mitochondrial DNA, affecting both the mtDNA ability to replicate and the transcription activity of the coding genes located in the H and L threads, in Caucasian patients with an ischemic and...


Read the Article


Sorry, but this item is not currently available from your library.

Try another library?
Sign out of this library

Other Topics