Abstract
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.
Highlights
The accumulation of heteroplasmic mitochondrial DNA mutations is a well-accepted facet of the biology of aging [1]
Additional clonal and non-clonal deletions in the major arc between the mitochondrial DNA (mtDNA) origins of Mitochondria are unique among animal organelles in that they contain their own multi-copy genome
Because individual mtDNA mutations are present at very low levels, few details are known about the spectrum of mutations associated with aging
Summary
The accumulation of heteroplasmic mitochondrial DNA (mtDNA) mutations is a well-accepted facet of the biology of aging [1]. Heteroplasmic deletions that fall in the major arc between the origins of replication accumulate with age These so-called ‘‘major arc’’ deletions are generally associated with pairs of direct repeats that flank the deleted region [2]. Somatic mtDNA mutations accumulate stochastically to very high levels in a minority of cells [8,9] through clonal expansion [10] of both de novo and inherited variants [11,12]. These mechanisms dictate that specific mtDNA variants are present at very low levels within a tissue [13].
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