Are mutagenic non D-loop direct repeat motifs in mitochondrial DNA under a negative selection pressure?

Lakshmi Narayanan Lakshmanan,Jan Gruber,Rudiyanto Gunawan,Barry Halliwell

doi:10.1093/nar/gkv299

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.

Highlights

Mutations in mitochondrial DNA have been associated with mitochondrial dysfunction, diseases and the ageing process [1,2]
Our analysis of human mitochondrial DNA (mtDNA) showed that the native mtDNA contained more direct repeats (DRs) than any of the selectively randomized sequences considered in this study
We found that global sequence properties, nucleotide composition and synonymous codon usage (SCU) bias, are strong determinants of DRs in human mtDNA

Summary

Introduction

Mutations in mitochondrial DNA (mtDNA) have been associated with mitochondrial dysfunction, diseases and the ageing process [1,2]. The accumulation of mtDNA deletions in cells plays a causal role in age-related skeletal muscle fiber atrophy in sarcopenia and neuronal loss in the substantia nigra of aged individuals and Parkinson’s disease patients [3,4]. These deletions typically involve the loss of coding-genes in mtDNA outside the D-loop region. While the mechanism of deletion mutagenesis is not precisely known, direct repeat (DR) motifs have been frequently observed flanking the breakpoints of mtDNA deletions in different organisms including human [5,6,7,8]. Held hypotheses on mtDNA deletion mutagenesis further assert a causal relationship, in which DRs mediate mtDNA misalignments during mtDNA replication or recombination, leading to the formation of mtDNA deletions [11,12]

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Results

Conclusion