Duplication and triplication with staggered breakpoints in human mitochondrial DNA

We identified a tandem duplication and triplication of a mitochondrial DNA (mtDNA) segment in the muscle of a 57-year-old man with no evidence of a neuromuscular disorder. A large triplication of a mtDNA coding region has not been previously reported in humans. Furthermore, the rearrangements (comprising 10-12% of the muscle mtDNA pool in the propositus) were unique because the breakpoints were staggered at both ends (between mtDNA positions 3263-3272 and 16065-16076) and contained no identifiable direct repeats. Both sides of the breakpoint were located approximately 35 bp downstream of regions that undergo frequent strand displacement by either transcription (positions 3263-3272) or replication (positions 16065-16076), suggesting that topological changes generated by the movement of RNA/DNA polymerases may be associated with the genesis of a subclass of mtDNA rearrangements. The presence of low levels of these rearrangements in other normal adults also suggest that these mutations are not rare. The characterization of these rearrangements shed light on potential alternative mechanisms for the genesis of mtDNA rearrangements. (C) 1998 Elsevier Science B.V.