Gupta Rahul, Kanai Masahiro, Durham Timothy J, Tsuo Kristin, McCoy Jason G, Chinnery Patrick F, Karczewski Konrad J, Calvo Sarah E, Neale Benjamin M, Mootha Vamsi K
Howard Hughes Medical Institute and Department of Molecular Biology, Massachusetts General Hospital, United States.
Broad Institute of MIT and Harvard, United States.
medRxiv. 2023 Jan 19:2023.01.19.23284696. doi: 10.1101/2023.01.19.23284696.
Human mitochondria contain a high copy number, maternally transmitted genome (mtDNA) that encodes 13 proteins required for oxidative phosphorylation. Heteroplasmy arises when multiple mtDNA variants co-exist in an individual and can exhibit complex dynamics in disease and in aging. As all proteins involved in mtDNA replication and maintenance are nuclear-encoded, heteroplasmy levels can, in principle, be under nuclear genetic control, however this has never been shown in humans. Here, we develop algorithms to quantify mtDNA copy number (mtCN) and heteroplasmy levels using blood-derived whole genome sequences from 274,832 individuals of diverse ancestry and perform GWAS to identify nuclear loci controlling these traits. After careful correction for blood cell composition, we observe that mtCN declines linearly with age and is associated with 92 independent nuclear genetic loci. We find that nearly every individual carries heteroplasmic variants that obey two key patterns: (1) heteroplasmic single nucleotide variants are somatic mutations that accumulate sharply after age 70, while (2) heteroplasmic indels are maternally transmitted as mtDNA mixtures with resulting levels influenced by 42 independent nuclear loci involved in mtDNA replication, maintenance, and novel pathways. These nuclear loci do not appear to act by mtDNA mutagenesis, but rather, likely act by conferring a replicative advantage to specific mtDNA molecules. As an illustrative example, the most common heteroplasmy we identify is a length variant carried by >50% of humans at position m.302 within a G-quadruplex known to serve as a replication switch. We find that this heteroplasmic variant exerts -acting genetic control over mtDNA abundance and is itself under -acting genetic control of nuclear loci encoding protein components of this regulatory switch. Our study showcases how nuclear haplotype can privilege the replication of specific mtDNA molecules to shape mtCN and heteroplasmy dynamics in the human population.
人类线粒体含有高拷贝数、母系遗传的基因组（mtDNA），该基因组编码氧化磷酸化所需的13种蛋白质。当多个mtDNA变体在个体中共存时会出现异质性，并且在疾病和衰老过程中可能表现出复杂的动态变化。由于所有参与mtDNA复制和维持的蛋白质都是由核基因编码的，原则上异质性水平可能受核基因控制，然而这在人类中从未得到证实。在此，我们开发了算法，利用来自274832名不同血统个体的血液全基因组序列来量化mtDNA拷贝数（mtCN）和异质性水平，并进行全基因组关联研究（GWAS）以确定控制这些性状的核基因座。在对血细胞组成进行仔细校正后，我们观察到mtCN随年龄呈线性下降，并且与92个独立的核基因座相关。我们发现几乎每个个体都携带遵循两种关键模式的异质性变体：（1）异质性单核苷酸变体是体细胞突变，在70岁后急剧积累，而（2）异质性插入缺失作为mtDNA混合物母系遗传，其产生的水平受42个参与mtDNA复制、维持和新途径的独立核基因座影响。这些核基因座似乎不是通过mtDNA诱变起作用，而是可能通过赋予特定mtDNA分子复制优势起作用。作为一个说明性例子，我们鉴定出的最常见异质性是一种长度变体，超过50%的人类在已知作为复制开关的G-四链体中的m.302位置携带该变体。我们发现这种异质性变体对mtDNA丰度发挥顺式作用的遗传控制，并且其本身受编码该调节开关蛋白质成分的核基因座的反式作用遗传控制。我们的研究展示了核单倍型如何使特定mtDNA分子的复制具有优势，从而塑造人类群体中的mtCN和异质性动态变化。
