Nucleic Acids Research, 2003, Vol. 31, No. 20 6043-6052
© 2003 Oxford University Press
A compositional segmentation of the human mitochondrial genome is related to heterogeneities in the guanine mutation rate
Virginia Bioinformatics Institute, Virginia Polytechnic and State University, Blacksburg, VA 24061, USA, 1 School of Mathematics and Statistics, Newcastle University, Newcastle upon Tyne, UK, 2 Department of Statistics, The Open University, Milton Keynes, UK and 3 Department of Neurology, Newcastle University, Newcastle upon Tyne, UK
*To whom correspondence should be addressed. Tel: +1 540 231 8999; Fax: +1 540 231 2606; Email: dsamuels{at}vbi.vt.edu
We applied a hidden Markov model segmentation method to the human mitochondrial genome to identify patterns in the sequence, to compare these patterns to the gene structure of mtDNA and to see whether these patterns reveal additional characteristics important for our understanding of genome evolution, structure and function. Our analysis identified three segmentation categories based upon the sequence transition probabilities. Category 2 segments corresponded to the tRNA and rRNA genes, with a greater strand-symmetry in these segments. Category 1 and 3 segments covered the protein- coding genes and almost all of the non-coding D-loop. Compared to category 1, the mtDNA segments assigned to category 3 had much lower guanine abundance. A comparison to two independent databases of mitochondrial mutations and polymorphisms showed that the high substitution rate of guanine in human mtDNA is largest in the category 3 segments. Analysis of synonymous mutations showed the same pattern. This suggests that this heterogeneity in the mutation rate is partly independent of respiratory chain function and is a direct property of the genome sequence itself. This has important implications for our understanding of mtDNA evolution and its use as a ‘molecular clock’ to determine the rate of population and species divergence.
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