人细胞核调控线粒体DNA（mtDNA）拷贝数和异质性，这一成果由美国麻省总医院Vamsi K. Mootha、Rahul Gupta和麻省理工学院和哈佛大学布罗德研究所Benjamin M. Neale研究组合作。该研究成果发表在2023年8月16日出版的国际学术期刊《自然》上。

研究人员对274，832个体血液来源全基因组序列中的mtDNA拷贝数（mtCN）和异质性进行了量化，并进行全基因组关联研究以确定相关的核位点。在血细胞组成校正后，研究发现mtCN随着年龄的增长呈线性下降，并且与92个核位点的变异有关。研究人员观察到，几乎每个人携带的异质mtDNA变异都遵循以下两个原则：（1）异质单核苷酸突变倾向于在70岁后以体细胞形式出现并急剧积累，而（2）异质性插入缺失来源于母系遗传，其由42个与mtDNA复制、维持和新途径相关核位点有关。

这些位点可能通过赋予某些mtDNA等位基因复制优势来起作用。例如研究人员在之前提出的介导mtDNA转录/复制切换的G-四链体中发现了在chrM：302位置携带50%的人长度变异。研究发现这种变体对mtDNA丰度起顺式遗传调控功能，并且与调控该开关的核位点编码机制相关。该研究表明，核基因组的共同变异可以重塑整个人群中的mtCN和异质动力学变异。

据悉，mtDNA是氧化磷酸化所需的母系遗传、高拷贝数基因组。异质性是指个体中存在mtDNA等位基因的杂合，其与疾病和衰老有关。人类异质性变异的机制以及核基因组对这种变异的影响仍然未知。

附：英文原文

Title: Nuclear genetic control of mtDNA copy number and heteroplasmy in humans

Author: Gupta, Rahul, Kanai, Masahiro, Durham, Timothy J., Tsuo, Kristin, McCoy, Jason G., Kotrys, Anna V., Zhou, Wei, Chinnery, Patrick F., Karczewski, Konrad J., Calvo, Sarah E., Neale, Benjamin M., Mootha, Vamsi K.

Issue&Volume: 2023-08-16

Abstract: 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 switching2,3. 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.

DOI: 10.1038/s41586-023-06426-5

Source: https://www.nature.com/articles/s41586-023-06426-5