Somatic vs Germinal Mutations in Mitochondrial DNA: Is There Any Relation with Human Health and Aging?

Mitochondrial DNA (mtDNA) heteroplasmy is an almost universal condition in humans. The proportion of heteroplasmic mtDNA mutations that is heritable rather than accumulated during life has, however, remained almost unknown. The main goal of this work was to investigate the contribution of germinal versus somatic heteroplasmy, exploring its impact on health and aging. Blood samples from 101 individuals were previously used to generate full mtDNA sequences. Taking into account the embryonic origin of the tissues and the heterogeneity of site specific mutation rate of mtDNA robust criteria of heteroplasmy classification was applied. The mtDNA regions encompassing the 28 heteroplasmic positions detected in blood samples were sequenced in buccal epithelial samples as a reference from an alternative tissue with different embryonic origin. Based on the proposed classification data published by Li et al. (2015) was reanalyzed. Moreover, the predicted functional impact of non-synonymous mutations was evaluated. Most of heteroplasmies detected were germinal or somatic prior gastrulation and most of the somatic heteroplasmies were present in a single tissue. Somatic heteroplasmies were mostly present in older individuals, suggesting that they could be related to aging process. Three out of five non-synonymous mutations in heteroplasmy (all of them classified as germinal or somatic prior gastrulation) occurred in highly conserved positions, presenting a probability >60% of being deleterious. Although germinal heteroplasmies (or somatic prior gastrulation) can contribute to the development of disease and to the aging process, most of the heteroplasmies detected in both studies present a level of the alternative allele frequency below 60%, likely not affecting fitness and escaping selection.

Keywords: Age, Disposable soma theory, Embryonic origin, Germinal, Health, Heteroplasmy, MtDNA, Mutation accumulation theory, Purifying selection, Somatic.