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The genetics of the mtDNA differs from that of nuclear DNA in five important ways. First, the mtDNA is semi-autonomous, consistent with its endosymbiotic origin. The transfer of genes from the endosymbiont genome to the nucleus, over the past 1.5 billion years, has severely curtailed its autonomy. The mtDNA now only contains the genes for 20% of the oxidative phosphorylation pathways. All the other genes for mitochondrial functions are in the nuclear DNA. The second feature of mtDNA genetics is that it undergoes replicative segregation during both mitosis and meiosis. Each human cell has hundreds of mitochondria and thousands of mtDNAs; this means that cells and human lineages can harbour mixtures of mutant and normal (wild-type) mtDNAs (heteroplasmy). Thus the proportion of mutant and wild-type mtDNAs that are distributed to daughter cells fluctuates when cells |
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undergo the mitotic or meiotic process. Consequently, over repeated cell divisions, the mtDNA genotype can progressively shifts toward either a pure or a wild-type mtDNAs (homoplasmy). Thus, the percentage of mutant mtDNAs is proportional to the oxidative phosphorylation defects in the cell. Whereas heteroplasmy and replicative segregation mean that cells, or individuals with identical nuclear genotypes, can have different cytoplasmic genotypes and hence different phenotypes. A third feature of mtDNA genetics is a threshold expression. In patients harbouring mtDNA mutations, the phenotype is a product of the nature of the mutation and the percentage of mutant mtDNAs (i.e. the oxidative phosphorylation defects), and the relative reliance of each organ system on mitochondrial energy production. |
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Fourth, mtDNA genetics have a high sequence evolution rate, about 20 times higher than the nuclear DNA, notably because mitochondria do not contain reverse transcriptase. This means that deleterious mutations are far more probable in mtDNA than in nuclear DNA, creating extensive sequence variations among individuals and populations. However, while mtDNA does not code for any DNA repair proteins, it has been observed that a number of repair factors can be found in mitochondrial extracts. Thus, this could indicate the presence of a more complex repair process in mtDNA than in nuclear DNA. The fifth unique genetic characteristic of the mtDNA is a maternal inheritance. Indeed the egg harbours several hundred thousand mtDNAs from the mother, while the sperm has only a few hundred mtDNAs. Thus, the few sperm mtDNAs that enter into the egg have no effects on the genome. However, recently this has been called into question by the discovery of a linkage disequilibrium in human mitochondrial DNA that declines as function of the distance between sites that preferentially link two close alleles. This interesting distribution of mutations on the heavy strand of mtDNA seems only to be attributed to one mechanism, involving recombination between mother and father mtDNAs. |
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Heteroplasmy and mitotic segregation : During the cellular division process, mitochondria are randomly distributed into daughter cells. Their mitochondrial genotype will then evolve during the cellular division process into a normal or enriched mutant form. |