Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation¹. Heteroplasmy refers to the presence of a mixture of mtDNA alleles in an individual and has been associated with disease and ageing. Mechanisms underlying common variation in human heteroplasmy, and the influence of the nuclear genome on this variation, remain insufficiently explored. Here we quantify mtDNA copy number (mtCN) and heteroplasmy using blood-derived whole-genome sequences from 274,832 individuals and perform genome-wide association studies to identify associated nuclear loci. Following blood cell composition correction, we find that mtCN declines linearly with age and is associated with variants at 92 nuclear loci. We observe that nearly everyone harbours heteroplasmic mtDNA variants obeying two principles: (1) heteroplasmic single nucleotide variants tend to arise somatically and accumulate sharply after the age of 70 years, whereas (2) heteroplasmic indels are maternally inherited as mixtures with relative levels associated with 42 nuclear loci involved in mtDNA replication, maintenance and novel pathways. These loci may act by conferring a replicative advantage to certain mtDNA alleles. As an illustrative example, we identify a length variant carried by more than 50% of humans at position chrM:302 within a G-quadruplex previously proposed to mediate mtDNA transcription/replication switching^2,3. We find that this variant exerts cis-acting genetic control over mtDNA abundance and is itself associated in-trans with nuclear loci encoding machinery for this regulatory switch. Our study suggests that common variation in the nuclear genome can shape variation in mtCN and heteroplasmy dynamics across the human population.

线粒体 DNA （mtDNA） 是氧化磷酸化 ¹ 所需的母系遗传的高拷贝数基因组。异质性是指个体中存在 mtDNA 等位基因的混合物，并且与疾病和衰老有关。人类异质性常见变异的潜在机制以及核基因组对这种变异的影响仍未得到充分探索。在这里，我们使用来自 274,832 个个体的血液来源的全基因组序列量化 mtDNA 拷贝数 （mtCN） 和异质性，并进行全基因组关联研究以识别相关的核位点。经过血细胞组成校正后，我们发现 mtCN 随年龄线性下降，并与 92 个核位点的变异相关。我们观察到，几乎每个人都携带异质 mtDNA 变体，遵循两个原则：（1） 异质单核苷酸变体往往在体细胞中出现并在 70 岁后急剧积累，而 （2） 异质插入缺失作为混合物在母系遗传，其相对水平与 42 个参与 mtDNA 复制、维持和新途径的核基因座相关。这些位点可能通过赋予某些 mtDNA 等位基因复制优势来发挥作用。作为一个说明性的例子，我们确定了超过 50% 的人类在先前提出的介导 mtDNA 转录/复制转换 ^2,3 的 G 四链体中 chrM：302 位置携带的长度变体。我们发现这种变体对 mtDNA 丰度施加顺式作用遗传控制，并且本身与该调节开关的核位点编码机制反式相关。我们的研究表明，核基因组的常见变异可以影响整个人类群体中 mtCN 和异质性动力学的变异。