Figure 1.

Schematic overview of the human mtDNA genome, its replication and the formation of deletions. (a) The structure of mtDNA highlighting the arrangement of protein coding genes, rRNAs (orange) and tRNAs (yellow). The replication origins of the heavy and light strand (OriH and OriL, respectively) are highlighted. (b) Enlargement of the mtDNA non-coding region (NCR) depicting the arrangement of the heavy strand promoter (HSP) and light strand promoter (LSP), the three conserved sequence boxes (CSB), OriH and the termination-associated sequence (TAS). The premature termination of the DNA synthesis of the H-strand at TAS results in the formation of a triple-stranded displacement-loop structure termed the D-loop. The short double stranded product formed within the D-loop is termed 7S DNA. (c) mtDNA replication is initiated at OriH and proceeds unidirectionally until OriL is reached. At this point, DNA synthesis of the light strand is initiated, and both strands are synthesised simultaneously until two completely replicated genomes are produced. The two replicated genomes are physically interlinked by a single-stranded overlap structure, termed a hemicatenane. This structure is resolved by topoisomerase 3α (TOP3α) to produce two separate mtDNA molecules. (d) Copy choice recombination model for the formation of mtDNA deletions. mtDNA deletions generally occur in the major arc. The replication of a repeat sequence in the template heavy strand (yellow boxes) can lead to stalling of POLγ which results in its dissociation from the newly synthesised DNA-end. When Polγ reanneals, it may associate at another repeat sequence further along the template. Following the completion of replication, this slippage event produces two mtDNA genomes; one full length molecule and a second heteroduplex molecule (which has a full-length heavy strand alongside a deletion-containing light strand). The subsequent replication of the heteroduplex molecule culminates in the formation of mtDNA harbouring the deletion.