Mitochondrial genetic variation across tissues of the human body

Each mitochondrion contains 2-10 copies of the mitochondrial genome. Multiple mitochondria in a cell allow for mitochondrial genomes carrying different variants to co-exist within a cell or tissue, termed heteroplasmy. The extent to which mitochondrial genetic variation differs across tissues of the human body and the origins of heteroplasmic variants is largely unknown. Using next-generation sequencing of 47 paired tissues from 947 donors in the Genotype-Tissue Expression dataset, we found that 39% of unique mitochondrial DNA variants identified were present in one tissue (tissue-specific) and 7% of unique variants were found in several but not all tissues of a donor. Tissue-specific variants were more likely to be transversions, nonsynonymous, deleterious, and present at lower variant allele fractions compared to variants shared across all tissues within a donor. Tissues primarily composed of proliferative cell types had the most tissue-specific variants, while highly energetic tissues had the least. The number of tissue-specific variants was associated with donor age for the tissues with the most tissue-specific variants. We determined that most of the heteroplasmic variants likely arise de novo after tissue differentiation. Our study suggests that mitochondrial DNA variants arise throughout an individual's lifetime in a tissue-dependent manner, which may have disease implications.