Nuclear genetic control of mtDNA copy number and heteroplasmy in humans

Abstract

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 cis-acting genetic control over mtDNA abundance and is itself under trans-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.

Unveiling Peripheral Immune Dysfunction in Parkinson’s Disease through Analysis of Blood-based Mitochondrial DNA Copy Number

“…Using the GWAS summary statistics for both raw and adjusted blood mtDNA-CN from Gupta et al, 2023 9 , we constructed the polygenic risk scores (PRSs) per individual in AMP PD (Supplementary Table 1C). Subsequently, we assessed the relationships between the actual mtDNA-CN estimates and these PRSs.…”

“…9). This modest correlation can be attributed to the fact that mtDNA-CN is influenced by both genetic and environmental factors, with a SNP-based heritability of approximately 4% 9 . Additionally, the PRSs exhibit no correlation with mtDNA-CN estimates from brain samples (Supplementary Table 1D).…”

“…The summary-level data for PD risk was obtained from a recent meta-analysis of GWASs in the European population 48 . For blood-derived mtDNA-CN, we utilized three GWAS datasets employing different estimation methods, including estimates from WGS with and without adjusting for cell composition 9 , estimates from genotyping data 10 , and estimates from a combination of WES and genotyping arrays 49 . All mtDNA-CN GWAS studies were conducted using UKB data, and the majority of participants had European ancestry (Supplementary Table 1C).…”

Identification of eight genomic protective alleles for mitochondrial diabetes by Kinship‐graph convolutional network

“…Restabilizing the mitochondrial tRNA structures may also be useful, Perli et al utilized exogenous peptides to stabilize the mitochondrial tRNA structures, which rescued the defects caused by m.3243A > G. While the mitochondrial mutant influences multiple downstream pathways 8 , Chung et al found that the inhibition of PI3K, Akt, or mTORC1 could reduce the mtDNA mutant load and partially rescue cellular bioenergetic function 55 . In a GWAS of human mitochondrial DNA, the authors found 92 nuclear loci could control the copy number and heteroplasmy of mitochondrial DNA in humans 56 , indicating that nuclear loci may also play a regulatory role in the effect of m.3243A > G.…”

“…found that the inhibition of PI3K, Akt, or mTORC1 could reduce the mtDNA mutant load and partially rescue cellular bioenergetic function 55 . In a GWAS of human mitochondrial DNA, the authors found 92 nuclear loci could control the copy number and heteroplasmy of mitochondrial DNA in humans 56 , indicating that nuclear loci may also play a regulatory role in the effect of m.3243A > G.…”