Mitochondrial DNA Genetics and the Heteroplasmy Conundrum in Evolution and Disease

Abstract

The unorthodox genetics of the mtDNA is providing new perspectives on the etiology of the common "complex" diseases. The maternally inherited mtDNA codes for essential energy genes, is present in thousands of copies per cell, and has a very high mutation rate. New mtDNA mutations arise among thousands of other mtDNAs. The mechanisms by which these "heteroplasmic" mtDNA mutations come to predominate in the female germline and somatic tissues is poorly understood, but essential for understanding the clinical variability of a range of diseases. Maternal inheritance and heteroplasmy also pose major challengers for the diagnosis and prevention of mtDNA disease. THE GENETIC CHALLENGES OF mtDNA DISEASES

Extensive tissue-related and allele-related mtDNA heteroplasmy suggests positive selection for somatic mutations

“…There is a significant correlation between age and the occurrence of heteroplasmy in each individual tissue ( Fig. 3), in agreement with previous studies (10,20,21). Moreover, many individual HFHs are also significantly correlated with age (SI Appendix, Fig.…”

“…For example, although certain nucleotide positions (nps) in the mtDNA genome are prone to heteroplasmy (2,4,11), it is not clear to what extent these positions simply have a high mutation rate, and thus are more prone to heteroplasmy across all tissues, vs. a role for tissue-specific processes in heteroplasmy (i.e., certain tissues may be more prone to heteroplasmy due to their metabolic requirements, rate of cellular turnover, etc.). Tissue-specific patterns of heteroplasmy are commonly observed with mtDNA mutations associated with disease and are thought to reflect the differing bioenergetic requirements of different tissues (10). Moreover, mice constructed to be heteroplasmic for different haplotypes show tissue-specific patterns of segregation over time (12,13), suggesting positive selection related to mtDNA function in different tissues.…”

“…In addition, elevated levels of nonsynonymous (NS) heteroplasmies within individuals relative to NS polymorphisms among individuals (2) suggest that there is negative selection against heteroplasmies that involve deleterious amino acid changes. In other words, deleterious amino acid changes can be observed as heteroplasmies as long as the allele frequency stays below a certain threshold and "normal" mitochondrial function is maintained; exceeding this threshold results in impaired mitochondrial function, as is commonly observed for diseaseassociated mtDNA mutations (10).…”

Oocyte mitochondria: role on fertility and disease transmission

“…The high levels of reactive oxygen species (ROS) generated in mitochondria make mtDNA high susceptible to oxidative damage (Wallace and Chalkia, 2013). Yet, given that mitochondria are inherited exclusive from the mother, several mechanisms seem to have evolved in oocytes to prevent them from accumulating mtDNA damage (Fan et al, 2008;Stewart et al, 2008;Sharpley et al, 2012;Floros et al, 2018).…”

The DLK1-MEG3 locus in malignant cells of proposed primordial germ cell origins.

“…The appearance of PGCs at the allantois, a region of the extraembryonic yolk sac, at E7.5 occurs at a similar time and region as the first appearance of hemangioblasts and hematopoietic islands [90,91]. Similarly, PGCs enter the aorta-gonad-mesonsephros region of the embryo at E11, which is the region where HSCs first appear and where Oct3/4-expressing cells were recently isolated which could form hematopoietic colonies in vitro [42,92].…”