Structure of mtDNA

The complete sequence of human mtDNA was first determined in the laboratory of Frederick Sanger in Cambridge, England (Anderson et al., 1981). This human mtDNA sequence, also called Anderson reference, is designated as the Cambridge Reference Sequence (CRS). Following the sequencing of human mtDNA, mtDNA sequences of animals were determined. A comparison of sequences revealed that the gross structure and genetic arrangements are remarkably conserved among mammalian species. Human mtDNA is a double-stranded circular molecule 16 569 bp in length (Figure 8.1). Based upon differences in buoyant density, the strands are termed the heavy strand (H-strand) and the light strand (L-strand). The H-strand is rich in purines (A, G), whereas within the L-strand, pyrimidines (T, C) dominate. When metabolically active cells are observed by electron microscopy, a large population of mtDNA appears to contain a short three-strand structure. This structure represents an initial stage of replication and is called a displacement loop (D-loop) (Taanman, 1999; Brown et al., 2006).

According to the numbering system offered by the CRS, the initial position '1' was arbitrarily assigned near the middle of the control region. The base number then increases in the (5'^3') direction on the L-strand, and, because of its circular nature, the final position '16 569' is located next to '1' (Figure 8.1). The CRS was revised and termed the 'rCRS' (Andrews et al., 1999). By this revision, the original CRS, which had been determined from a single individual, was found to contain several rare polymorphisms. This discovery emphasized that the CRS (rCRS) cannot be regarded as the 'authentic' sequence but should be used as a 'reference' sequence to facilitate the comparison among sequences cited in the literature and those determined from samples. It is also noted that, because of the same gross structure and genetic arrangements among mammalians, animal mtDNAs can be numbered using CRS (rCRS).

Functionally, mammalian and hence human mtDNA is divided into coding and control regions (Holland and Parsons, 1999; Taanman, 1999). The coding region contains 37 intron-less genes encoding 2 ribosomal RNAs (12S and 16S rRNAs), 22 transfer RNAs (tRNAs) and 13 protein enzymes. The 22 tRNAs are the minimum set required for the translation of mtDNA, and all of the 13 proteins are involved in the process of oxidative phosphorylation.

The control region, which corresponds to the D-loop, is bound by the genes for tRNAphe and tRNApro (Figure 8.1). The length is 1122 bp (CRS) and may tRNAP*e>+<-

D-loop region

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