Lakshmanan Lakshmi Narayanan, Gruber Jan, Halliwell Barry, Gunawan Rudiyanto
Institute for Chemical and Bioengineering, ETH Zurich, Zurich 8093, Switzerland Department of Chemical and Biomolecular Engineering, National University of Singapore, Singapore 117585, Singapore.
Yale-NUS College, Department of Biochemistry, Neurobiology and Ageing Program, National University of Singapore, Singapore 117599, Singapore.
Nucleic Acids Res. 2015 Apr 30;43(8):4098-108. doi: 10.1093/nar/gkv299. Epub 2015 Apr 8.
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.
线粒体DNA（mtDNA）中的非D环直接重复序列（DRs）通常与神经肌肉疾病和衰老相关的mtDNA缺失的诱变有关。此外，这些DRs被认为对哺乳动物的寿命有限制作用，并处于负选择压力之下。我们使用294种哺乳动物mtDNA的汇编，重新审视了物种寿命与此类DRs诱变能力之间的关系。与普遍的假设相反，我们没有发现显著证据表明长寿哺乳动物比短寿哺乳动物拥有更少的诱变DRs。通过将人类mtDNA中的DR计数与选择性随机序列中的DR计数进行比较，我们还表明，人类mtDNA中DRs的数量主要由mtDNA的整体特性决定，例如同义密码子使用偏好（SCU）和核苷酸组成。我们发现mtDNA中的SCU偏好与DR计数呈正相关，其中一部分密码子的重复使用导致DR出现更频繁。虽然SCU和核苷酸组成的偏好归因于核苷酸突变偏好，但哺乳动物mtDNA仍然表现出比这种突变偏好预期更高的SCU偏好和DR计数，这表明对非D环DRs缺乏负选择。
