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 eviden ce of a neuromuscular disorder. A large triplication of a mtDNA coding region has not been previously reported in humans. Furthermore, the r earrangements (comprising 10-12% of the muscle mtDNA pool in the propo situs) 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 stran d displacement by either transcription (positions 3263-3272) or replic ation (positions 16065-16076), suggesting that topological changes gen erated by the movement of RNA/DNA polymerases may be associated with t he genesis of a subclass of mtDNA rearrangements. The presence of low levels of these rearrangements in other normal adults also suggest tha t these mutations are not rare. The characterization of these rearrang ements shed light on potential alternative mechanisms for the genesis of mtDNA rearrangements. (C) 1998 Elsevier Science B.V.