Universal heteroplasmy of human mitochondrial DNA

Citations Over TimeTop 1% of 2012 papers

Abstract

Mammalian cells contain thousands of copies of mitochondrial DNA (mtDNA). At birth, these are thought to be identical in most humans. Here, we use long read length ultra-deep resequencing-by-synthesis to interrogate regions of the mtDNA genome from related and unrelated individuals at unprecedented resolution. We show that very low-level heteroplasmic variance is present in all tested healthy individuals, and is likely to be due to both inherited and somatic single base substitutions. Using this approach, we demonstrate an increase in mtDNA mutations in the skeletal muscle of patients with a proofreading-deficient mtDNA polymerase γ due to POLG mutations. In contrast, we show that OPA1 mutations, which indirectly affect mtDNA maintenance, do not increase point mutation load. The demonstration of universal mtDNA heteroplasmy has fundamental implications for our understanding of mtDNA inheritance and evolution. Ostensibly de novo somatic mtDNA mutations, seen in mtDNA maintenance disorders and neurodegenerative disease and aging, will partly be due to the clonal expansion of low-level inherited variants.

Related Papers

• → Metabolically induced heteroplasmy shifting and l-arginine treatment reduce the energetic defect in a neuronal-like model of MELAS(2012)45 cited
• → Comparison of the relative levels of the 3243 (A-->G) mtDNA mutation in heteroplasmic adult and fetal tissues.(1994)92 cited
• → Extreme variability of clinical symptoms among sibs in a MELAS family correlated with heteroplasmy for the mitochondrial A3243G mutation(1994)49 cited
• → A specific point mutation in the mitochondrial genome of Caucasians with MELAS(1991)34 cited
• [Mitochondrial encephalomyopathies: 3243 mutation as a central matter].(1995)