Abstract
Mitochondrial DNA (mtDNA) heteroplasmy (intra-individual variation) varies among different human tissues and increases with age, suggesting that the majority of mtDNA heteroplasmies are acquired, rather than inherited. However, the extent to which heteroplasmic sites are shared across a tissue remains an open question. We therefore investigated heteroplasmy in two liver samples (one from each primary lobe) from 83 Europeans, sampled at autopsy. Minor allele frequencies (MAF) at heteroplasmic sites were significantly correlated between the two liver samples from an individual, with significantly more sharing of heteroplasmic sites in the control region than in the non-control region. We show that this increased sharing for the control region cannot be explained by recent mutations at just a few specific heteroplasmic sites or by the possible presence of 7S DNA. Moreover, we carried out simulations to show that there is significantly more sharing than would be predicted from random genetic drift from a common progenitor cell. We also observe a significant excess of non-synonymous vs. synonymous heteroplasmies in the protein-coding region, but significantly more sharing of synonymous heteroplasmies. These contrasting patterns for the control vs. the non-control region, and for non-synonymous vs. synonymous heteroplasmies, suggest that selection plays a role in heteroplasmy sharing.
Highlights
The mitochondrial genome is present in many copies in a single cell, and intra-individual variation in the mitochondrial genome of an individual is called Mitochondrial DNA (mtDNA) heteroplasmy[1,2]
While most age-related heteroplasmies occur in the control region, human liver tissue is unusual in showing an excess of heteroplasmies involving non-synonymous mutations in the mtDNA protein-coding genes[8]
More heteroplasmic sites were observed in the non-control region (sites 577 to 16,023 in the revised Cambridge reference sequence) for liver (280 sites) compared to blood (64 sites), but the most abundant heteroplasmic sites in liver were in the control region, which were only rarely observed to be heteroplasmic in blood
Summary
The mitochondrial genome is present in many copies in a single cell, and intra-individual variation in the mitochondrial genome of an individual is called mtDNA heteroplasmy[1,2]. The tissue specificity of heteroplasmic sites and the association between the number of heteroplasmies and age would suggest that the majority of heteroplasmies are not inherited from the previous generation but are acquired during the lifetime of an individual in a tissue-dependent manner This raises the following question: do cells from the same tissue share a similar profile of heteroplasmic sites despite being separated from a common progenitor cell for many cell divisions? While most age-related heteroplasmies occur in the control region, human liver tissue is unusual in showing an excess of heteroplasmies involving non-synonymous mutations in the mtDNA protein-coding genes[8] This result is remarkable because these protein-coding region mutations are likely to have a functional effect[8], and protein-coding region mutations are strongly selected against during transmission from one generation to another[21]. MtDNA heteroplasmy was evaluated by capture-enrichment sequencing[8,22,23,24], and we analysed sharing of mtDNA heteroplasmy between the liver lobes for different regions of the mitochondrial genome
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