title: Are mutagenic non D-loop direct repeat motifs in mitochondrial DNA under a negative selection pressure?
abstract: Non D-loop direct repeats (DRs) in mitochondrial DNA (mtDNA) have been commonly implicated in the mutagenesis of mtDNA deletions associated with neuromuscular disease and ageing. Further, these DRs have been hypothesized to put a constraint on the lifespan of mammals and are under a negative selection pressure. Using a compendium of 294 mammalian mtDNA, we re-examined the relationship between species lifespan and the mutagenicity of such DRs. Contradicting the prevailing hypotheses, we found no significant evidence that long-lived mammals possess fewer mutagenic DRs than short-lived mammals. By comparing DR counts in human mtDNA with those in selectively randomized sequences, we also showed that the number of DRs in human mtDNA is primarily determined by global mtDNA properties, such as the bias in synonymous codon usage (SCU) and nucleotide composition. We found that SCU bias in mtDNA positively correlates with DR counts, where repeated usage of a subset of codons leads to more frequent DR occurrences. While bias in SCU and nucleotide composition has been attributed to nucleotide mutational bias, mammalian mtDNA still exhibit higher SCU bias and DR counts than expected from such mutational bias, suggesting a lack of negative selection against non D-loop DRs.
authors: Institute for Chemical and Bioengineering, ETH Zurich, Zurich 8093, Switzerland Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
authors: Lakshmi Narayanan
authors: LN
authors: Lakshmanan
authors: Yale-NUS College, Department of Biochemistry, Neurobiology and Ageing Program, National University of Singapore, Singapore 117599, Singapore.
authors: Jan
authors: J
authors: Gruber
authors: Department of Biochemistry, Neurobiology and Ageing Program, Centre for Life Sciences (CeLS), National University of Singapore, Singapore 117599, Singapore.
authors: Barry
authors: B
authors: Halliwell
authors: Institute for Chemical and Bioengineering, ETH Zurich, Zurich 8093, Switzerland Swiss Institute of Bioinformatics, Quartier Sorge - Batiment Genopode, 1015 Lausanne, Switzerland rudi.gunawan@chem.ethz.ch.
authors: Rudiyanto
authors: R
authors: Gunawan
mesh_terms: D000818:Animals; D003062:Codon; D004272:DNA, Mitochondrial / Q000737:chemistry*; D006801:Humans; D008136:Longevity / Q000235:genetics; D008322:Mammals / Q000235:genetics; D016296:Mutagenesis; D059372:Nucleotide Motifs; D012091:Repetitive Sequences, Nucleic Acid
chemical_list: D003062:Codon; D004272:DNA, Mitochondrial