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.

ImtRDB: a database and software for mitochondrial imperfect interspersed repeats annotation

“…Interestingly, all previous works focused on major arc of mtDNA, but if authors take into account the whole mtDNA excluding D-loop (i.e. major and minor arcs together), the negative correlation disappeared [11]. Additionally, it has been shown that not only direct, but also inverted repeats negatively correlate with animal lifespan [3] probably by inducing mtDNA inversions and mitochondrial genome instability during mtDNA replication cycle [6].…”

Thermodynamic analysis of mitochondrial DNA breakpoints reveals mechanistic details of deletion mutagenesis

“…The mechanism of mtDNA deletion formation is of fundamental importance for understanding loss of mtDNA integrity and has been a subject of great interest and debate 12 . A commonly reported feature of mtDNA deletions is the presence of direct repeat (DR) sequences flanking the deletion breakpoints [13][14][15][16] . This observation has led to two major models of mtDNA deletion formation, namely the "slip-strand" model and the "double-strand break (DSB) repair error" model.…”

Risk of mitochondrial deletions is affected by the global secondary structure of the human mitochondrial genome

“…Furthermore, it has been shown that the number of the inverted repeats in mitochondrial genome is correlated with mammalian longevity (J.-N. Yang, Seluanov, and Gorbunova 2013) . Recently, however, it has been shown that this correlation is not driven by negative selection against direct repeats in long -lived mammals (Lakshmanan et al 2015) , questioning the results of previous works.…”