Abstract

Since the first described disease-causing mitochondrial DNA (mtDNA) mutation in 1989, mtDNA disorders have emerged as a major cause of neuromuscular disease. Epidemiological studies have shown that mtDNA mutations account for ~2/3 of mitochondrial disorders, affecting approximately 1:10,000 of the population – but precisely how these mutations arise in the population and present in the neuromuscular clinic has remained a mystery. Unlike the nuclear genome, there are many copies of mtDNA within each cell – with tens of thousands present in skeletal muscle fibres. Ultimately, a mtDNA mutation affects a single molecule. Once a mutation occurs, there is a mixed population of mtDNA within the cell (heteroplasmy), and recent deep sequencing has shown that low percentage level heteroplasmic mtDNA mutations are an almost universal finding in the healthy human population. However, the level of heteroplasmy can change during the maternal inheritance of mtDNA. In several mammalian species, including humans, there is a decrease in the amount of mtDNA within the developing female germ line at an early stage, shortly after implantation of the blastocyst. This causes a genetic bottleneck leading to rapid shifts in the allele frequency within the dividing and migrating cell population that ultimately forms oocytes for the next generation. This explains why low level heteroplasmies in the background population can reach high levels that cause mitochondrial DNA diseases, but this process is not entirely random. Studying 53,300 people from the 100,000 Genomes Project, we have shown evidence of selection for and against mtDNA variants in different regions of the mitochondrial genome. We also saw the signature of nuclear genetic control over the segregation pattern. This has important implications for understanding how mtDNA variants reach high levels, and ultimately shape the landscape of mtDNA at the population level. Characterising the mechanisms involved will not only cast light on the underlying biology, but also presents new opportunities to manipulate heteroplasmy during transmission or within tissues and organs during life.