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) 是氧化磷酸化所需的母系遗传的高拷贝数基因组¹ 。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机制以及核基因组对这种变异的影响尚未得到充分探索。在这里，我们使用来自 274,832 个人的血液来源的全基因组序列来量化 mtDNA 拷贝数 (mtCN) 和异质性，并进行全基因组关联研究来识别相关的核位点。经过血细胞成分校正后，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，几乎每个人都含有遵循两个原则的异质性 mtDNA 变异：(1) 异质单核苷酸变异往往在体细胞中出现，并在 70 岁后急剧积累，而 (2) 异质插入缺失是母系遗传的，其相对水平与42 个核位点参与 mtDNA 复制、维护和新途径。这些基因座可能通过赋予某些 mtDNA 等位基因复制优势来发挥作用。作为一个说明性的例子，我们鉴定了超过 50% 的人类在先前提出介导 mtDNA 转录/复制转换的 G 四联体中 chrM:302 位置携带的长度变异^2,3 。我们发现这种变体对 mtDNA 丰度发挥顺式作用遗传控制，并且其本身与编码这种调节开关的核基因座编码机制相关。 我们的研究表明，核基因组中的常见变异可以影响人类群体中 mtCN 和异质性动态的变化。