Amazing stuff!
"... mitochondria, have their own DNA that’s passed down from mother to child. The mitochondrial genome, which encodes just 13 proteins, is smaller and comparatively less well studied than the genome in the cell’s nucleus, even though mutations in mitochondrial DNA can cause a number of rare diseases.
Now a new study of both mitochondrial and nuclear genomes from hundreds of thousands of people may change how scientists think about the mitochondrial genome and how it interacts with the nuclear genome. The findings could inform future studies of how this crosstalk helps mitochondria power the cell, and shed light on when they cause disease.
Scientists have long known that cells can have hundreds, even thousands, of copies of the mitochondrial genome, and that this “copy number” can vary widely from one cell type to the next. There is also much variation in the sequences of all that mitochondrial DNA in a single cell, called heteroplasmy, which researchers had previously linked to rare inherited mitochondrial disease.
The new study ... has shown that the number of copies of the mitochondrial genome is a trait that varies from person to person and is controlled by the nuclear genome. The researchers also found that heteroplasmy is also influenced by mutations in the nuclear genome and is pervasive even among healthy people. ..."
From the abstract:
"Mitochondrial DNA (mtDNA) is a maternally inherited, high-copy-number genome required for oxidative phosphorylation. 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. 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."
Fig. 4: Pervasive nuclear genetic control over common mtDNA heteroplasmies.
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