Nuclear genetic control of mtDNA copy number and heteroplasmy in humans

Rahul Gupta (), Masahiro Kanai, Timothy J. Durham, Kristin Tsuo, Jason G. McCoy, Anna V. Kotrys, Wei Zhou, Patrick F. Chinnery, Konrad J. Karczewski, Sarah E. Calvo, Benjamin M. Neale () and Vamsi K. Mootha ()
Additional contact information
Rahul Gupta: Massachusetts General Hospital
Masahiro Kanai: Broad Institute of MIT and Harvard
Timothy J. Durham: Massachusetts General Hospital
Kristin Tsuo: Broad Institute of MIT and Harvard
Jason G. McCoy: Massachusetts General Hospital
Anna V. Kotrys: Massachusetts General Hospital
Wei Zhou: Broad Institute of MIT and Harvard
Patrick F. Chinnery: University of Cambridge
Konrad J. Karczewski: Broad Institute of MIT and Harvard
Sarah E. Calvo: Massachusetts General Hospital
Benjamin M. Neale: Broad Institute of MIT and Harvard
Vamsi K. Mootha: Massachusetts General Hospital

Nature, 2023, vol. 620, issue 7975, 839-848

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41586-023-06426-5

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