Age-related human mtDNA deletions: A heterogeneous set of deletions arising at a single pair of directly repeated sequences
- Monash Univ., Victoria (Australia)
Deletions in mtDNA accumulate during the human aging process, arising from either intramolecular illegitimate recombination or strand slippage during replication, which results in subgenomic mtDNA molecules. The authors identify here two classes of mtDNA deletions - class A deletions, which are homogeneous at the breakpoints, with all subgenomic molecules therefore being identical in size, and class B deletions, which arise from a less stringent process that gives rise to heterogeneity at the breakpoints, with the subgenomic molecules being of slightly different sizes. A novel approach is described that offers a global overview of the populations of different deletions in individual tissues. It is based on PCR cycle-sequencing reactions that are carried out directly on mtDNA segments, amplified by PCR from total cellular DNA. The results show a clear size homogeneity of the subgenomic mtDNA molecules representative of class A, which carry a commonly detected 4,977-bp deletion occurring at a pair of 13-bp directly repeated sequences. In this case, precisely one copy of the repeat is retained in the subgenomic molecules. The authors then describe a class B situation comprising a family of at least nine closely related 8.04-kb deletions involving the same pair of 5-bp direct repeats. In this situation, the breakpoints differ at the base-pair level (8,037-8.048-bp deletions); the subgenomic molecules retain >1 copy, 1 copy, or <1 copy of the 5-bp repeat. In different tissues from either the same individual or among different individuals, there is a widely variable occurrence of particular deletions in the subgenomic mtDNA population within this class B set. Class B deletions offer a new approach for studying the accumulation of mtDNA deletions, thereby providing insight into the independent somatic origin of mutated mtDNA molecules, both in aging and in mitochondrial diseases. 42 refs., 4 figs., 2 tabs.
- OSTI ID:
- 7182527
- Journal Information:
- American Journal of Human Genetics; (United States), Vol. 54:4; ISSN 0002-9297
- Country of Publication:
- United States
- Language:
- English
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