Background Acquired human mitochondrial genome (mtDNA) deletions are symptoms and drivers of focal mitochondrial respiratory deficiency, a pathological hallmark of aging and late-onset mitochondrial disease. Results To decipher connections between these processes, we create LostArc, an ultrasensitive method for quantifying deletions in circular mtDNA molecules. LostArc reveals 35 million deletions (~ 470,000 unique spans) in skeletal muscle from 22 individuals with and 19 individuals without pathogenic variants in POLG. This nuclear gene encodes the catalytic subunit of replicative mitochondrial DNA polymerase γ. Ablation, the deleted mtDNA fraction, suffices to explain skeletal muscle phenotypes of aging and POLG-derived disease. Unsupervised bioinformatic analyses reveal distinct age- and disease-correlated deletion patterns. Conclusions These patterns implicate replication by DNA polymerase γ as the deletion driver and suggest little purifying selection against mtDNA deletions by mitophagy in postmitotic muscle fibers. Observed deletion patterns are best modeled as mtDNA deletions initiated by replication fork stalling during strand displacement mtDNA synthesis.

中文翻译：

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超灵敏的缺失检测将线粒体 DNA 复制、疾病和衰老联系起来

背景 获得性人类线粒体基因组 (mtDNA) 缺失是局灶性线粒体呼吸缺陷的症状和驱动因素，是衰老和迟发性线粒体疾病的病理标志。结果 为了破译这些过程之间的联系，我们创建了 LostArc，这是一种用于量化环状 mtDNA 分子缺失的超灵敏方法。LostArc 揭示了 POLG 中有 22 个个体和 19 个没有致病性变异的个体的骨骼肌中有 3500 万个缺失（约 470,000 个独特的跨度）。该核基因编码复制线粒体 DNA 聚合酶 γ 的催化亚基。消融，删除的 mtDNA 部分，足以解释衰老和 POLG 衍生疾病的骨骼肌表型。无监督的生物信息学分析揭示了不同的年龄和疾病相关的缺失模式。结论 这些模式暗示 DNA 聚合酶 γ 的复制是缺失驱动因素，并且表明在有丝分裂后肌纤维中通过线粒体自噬几乎没有针对 mtDNA 缺失的纯化选择。观察到的缺失模式最好建模为在链置换 mtDNA 合成过程中由复制叉停滞引发的 mtDNA 缺失。