{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Gupta R"],"funding":["NIA NIH HHS","NIMH NIH HHS","NHGRI NIH HHS","Wellcome Trust","NIGMS NIH HHS"],"pagination":["839-848"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10447254"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["620(7975)"],"pubmed_abstract":["Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation<sup>1</sup>. 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<sup>2,3</sup>. 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."],"journal":["Nature"],"pubmed_title":["Nuclear genetic control of mtDNA copy number and heteroplasmy in humans."],"pmcid":["PMC10447254"],"funding_grant_id":["R01 MH101244","212219/Z/18/Z","R35 GM122455","K99 HG012222","F30 AG074507","R37 MH107649"],"pubmed_authors":["Gupta R","Kotrys AV","Calvo SE","Tsuo K","Chinnery PF","Mootha VK","Kanai M","Karczewski KJ","Zhou W","Durham TJ","McCoy JG","Neale BM"],"additional_accession":[]},"is_claimable":false,"name":"Nuclear genetic control of mtDNA copy number and heteroplasmy in humans.","description":"Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation<sup>1</sup>. 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<sup>2,3</sup>. 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.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Aug","modification":"2024-11-13T15:29:47.998Z","creation":"2024-11-13T15:29:47.998Z"},"accession":"S-EPMC10447254","cross_references":{"pubmed":["37587338"],"doi":["10.1038/s41586-023-06426-5"]}}