Abstract
Mitochondrial DNA (mtDNA) heteroplasmy is the presence of mtDNA molecules with different sequences in the same individual. Previous studies have shown that different tissues have different heteroplasmic patterns in an individual. However, to date patterns of heteroplasmy within a single tissue have not been investigated. We therefore investigated heteroplasmy in blood (Bl) and two liver (Liv) samples (one from each lobe) from 85 humans, sampled at autopsy. Minor allele frequencies (MAF) at heteroplasmic sites were significantly correlated between liver samples from an individual, with more sharing of heteroplasmic sites in the control region than in the coding region. Neither specific sites nor the presence of 7S DNA can explain this pattern. While age was highly correlated with an increase in the total number of heteroplasmic sites, the correlation of MAFs between liver samples of an individual was independent of age. Although there was a significant excess of non-synonymous heteroplasmies in the coding region, synonymous heteroplasmies were more likely to be shared. While several mechanisms could potentially explain these results, the most likely is transfer of DNA between cells, with fragments originating from the mtDNA control region more likely to serve as primers for mtDNA replication than fragments from the coding region. The result is an integration of the same mutant alleles into the genomes of new cells. However, the significant association of synonymous mutations with heteroplasmy sharing between tissue regions indicates that the mechanisms of intercellular DNA exchange is more complex than previously suspected, and may reflect different processes.
