An Appraisal of Human Mitochondrial DNA Instability: New Insights into the Role of Non-Canonical DNA Structures and Sequence Motifs

Mitochondrial DNA (mtDNA) deletion mutations are frequently observed in aged postmitotic tissues and are the cause of a wide range of human disorders. Presently, the molecular bases underlying mtDNA deletion formation remain a matter of intense debate, and it is commonly accepted that several mechanisms contribute to the spectra of mutations in the mitochondrial genome. In this work we performed an extensive screening of human mtDNA deletions and evaluated the association between breakpoint density and presence of non-canonical DNA elements and over-represented sequence motifs. Our observations support the involvement of helix-distorting intrinsically curved regions and long G-tetrads in eliciting instability events. In addition, higher breakpoint densities were consistently observed within GC-skewed regions and in the close vicinity of the degenerate sequence motif YMMYMNNMMHM. A parallelism is also established with hot spot motifs previously identified in the nuclear genome, as well as with the minimal binding site for the mitochondrial transcription termination factor mTERF. This study extends the current knowledge on the mechanisms driving mitochondrial rearrangements and opens up exciting avenues for further research.

线粒体DNA（Mitochondrial DNA, mtDNA）缺失突变在衰老的有丝分裂后组织中频繁出现，且是多种人类疾病的致病诱因。当前，mtDNA缺失形成的分子基础仍存在激烈的学术争议，学界普遍认为线粒体基因组的突变谱由多种机制共同塑造。本研究对人类mtDNA缺失突变开展了大规模筛选，并评估了断点密度与非规范DNA元件、过代表序列基序之间的关联。我们的观测结果证实，使DNA螺旋发生扭曲的固有弯曲区域与长G四联体参与诱发了基因组不稳定事件。此外，更高的断点密度始终出现在GC偏斜区域，以及简并序列基序YMMYMNNMMHM的紧邻区域。本研究还发现，该断点分布特征与核基因组中此前已鉴定的热点基序存在相似性，同时也与线粒体转录终止因子mTERF的最小结合位点具有相关性。本研究拓展了当前对线粒体基因组重排驱动机制的认知，为后续相关研究开辟了极具潜力的方向。