Analysis of age-associated mitochondrial DNA deletion breakpoint regions from mice suggests a novel model of deletion formation

Abstract

Mitochondrial genomes with multiple types of DNA deletions have been shown to accumulate with age in various tissues from humans, monkeys, rats, mice, and C. elegans. The deleted genomes have been classified based on characteristics of the deletion breakpoints such as the presence (or absence) of direct repeat sequences. The prevalence of direct repeats located precisely at deletion breakpoints in human mitochondrial DNA deleted genomes has led several investigators to propose slip replication or recombination as mechanisms of deletion formation. Other sequence motifs such as topoisomerase II cleavage recognition sites and secondary or tertiary structures have also been implicated in aiding deletion formation. We have characterized, from mouse skeletal muscle and brain tissues, the breakpoint regions from 36 mitochondrial genomes with deletions. Based on the large number of deletion breakpoints precisely flanked by small (2–4 nucleotides) direct repeats, we propose “replication jumping” as an important mechanism of deletion formation. In this model, the polymerase stutters during replication, possibly in an area that has been oxidatively modified. The nascent strand then anneals to a complementary downstream region and replication continues after the removal of any single-stranded “excess” DNA up to a double-stranded region, resulting in a mutant genome.