Random intracellular drift explains the clonal expansion of mitochondrial DNA mutations with age

Human tissues acquire somatic mitochondrial DNA (mtDNA) mutations with age. Very high levels of specific mtDNA mutations accumulate within individual cells, causing a defect of mitochondrial oxidative metabolism. This is a fu ndamental property of nondividing tissues, but it is not known how it comes about. To explore this problem, we developed a model of mtDNA replication within single human cells. Using this model, we show that relaxed replicati on of mtDNA alone can lead, through random genetic drift, to the clonal exp ansion of single mutant events during human life. Significant expansions pr imarily develop from mutations acquired during a critical period in childho od or early adult life.