Abstract
Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and also accumulate during normal human ageing. The mechanisms underlying mtDNA deletions remain unknown although several models have been proposed. Here we use deep sequencing to characterize abundant mtDNA deletions in patients with mutations in mitochondrial DNA replication factors, and show that these have distinct directionality and repeat characteristics. Furthermore, we recreate the deletion formation process in vitro using only purified mitochondrial proteins and defined DNA templates. Based on our in vivo and in vitro findings, we conclude that mtDNA deletion formation involves copy-choice recombination during replication of the mtDNA light strand.
Highlights
Mitochondrial DNA deletions are associated with mitochondrial disease, and accumulate during normal human ageing
The majority of Mitochondrial DNA (mtDNA) deletions seen in mitochondrial disease and formed during ageing are located in the major arc between the two origins of mtDNA replication (OriH and OriL)
We first decided to analyse repeated sequence elements associated with deletion breakpoints in patients with inherited disorders of mtDNA maintenance
Summary
Mitochondrial DNA (mtDNA) deletions are associated with mitochondrial disease, and accumulate during normal human ageing. The most frequently reported mtDNA deletion is the loss of a ~5.0 kb region between two direct repeats of 13 bp (ACCTCCCTCACCA), beginning at position 8470 and position 13447. In this so called “common deletion”, one of the repeats is retained and the other lost together with the intervening sequence during the rearrangement process, leading to a deficiency of essential mitochondrial genes encoding both mRNAs and tRNAs. The common deletion was first detected in patients with mitochondrial myopathy[12], but was later shown to accumulate during normal ageing in humans[1]
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