Митохондриялық ДНК-ның полиморфизмі және гетероплазмия

Polymorphism of organellar DNA sequences in a cell

Heteroplasmy is the presence of more than one type of organellar genome (mitochondrial DNA or plastid DNA) within a cell or individual. It is an important factor in considering the severity of mitochondrial diseases. Because most eukaryotic cells contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for mutations to affect only some mitochondria, leaving most unaffected. Although detrimental scenarios are well studied, heteroplasmy can also be beneficial. For example, centenarians show a higher than average degree of heteroplasmy. At birth, all copies of mitochondrial DNA are thought to be identical in most humans. Microheteroplasmy is mutations of up to about 2−5% of mitochondrial genomes, and is present in most adults. This refers to hundreds of independent mutations in one organism, with each mutation found in about 1–2% of all mitochondrial genomes. Very low level heteroplasmic variance is present in essentially all individuals, even those who are healthy, and is likely to be due to both inherited and somatic single base substitutions.

Microheteroplasmy is the presence of mutations levels of up to about 2−5% of mitochondrial genomes. In human mitochondrial DNA, microheteroplasmy constitutes hundreds of independent mutations in one organism, with each mutation usually found in 1–2% of all mitochondrial genomes. The distinction of microheteroplasmy and more gross heteroplasmy is dictated by technical considerations classical DNA sequencing of mitochondrial DNA by the use of PCR is capable only of detecting mutations at levels of 10% or more, as a result of which mutations at lower levels were never systematically observed until the work of Lin et al. As it became apparent after the use of Lin's cloning and sequencing strategy, capable of detecting mutations at levels of 1% or less, such low level heteroplasmy, or microheteroplasmy, is exceedingly common, and is in fact the most common form of mutational damage to human DNA found to date. In aged adults, each copy of mitochondrial DNA has on average 3.3 mutations changing protein structure. This exceeds previous estimates by more than three orders of magnitude. The discovery of microheteroplasmy lends support to the mitochondrial theory of aging, and has already been linked to the causation of Parkinson's disease.

In 1909, while studying chloroplast genomes, Erwin Baur made the first observations about organelle inheritance patterns. Organelle genome inheritance differs from nuclear genome, and this is illustrated by four violations of Mendel's laws. During asexual reproduction, nuclear genes never segregate during cellular divisions. This is to ensure that each daughter cell gets a copy of every gene. However, organelle genes in heteroplasmic cells can segregate because they each have several copies of their genome. This may result in daughter cells with differential proportions of organelle genotypes. with a recent mathematical and experimental metastudy providing evidence for a combination of random partitioning of mtDNAs at cell divisions and random turnover of mtDNA molecules within the cell. The mitochondrial bottleneck concept refers to the classic evolutionary term, which is used to explain an event that reduces and specifies a population. It was developed to describe why mitochondrial DNA in an embryo might be drastically different from that of its mother. When a large population of DNA is subsampled, each sample population will receive a slightly different proportion of mitochondrial genotypes. Consequently, when paired with a high degree of replication, a rare or mutated allele can begin to proportionally dominate. In theory, this makes possible a single generation shift of overall mitochondrial genotype.

Although it is not well characterized, selection can occur for organelle genomes in heteroplasmic cells. Intracellular ("within cells") selection occurs within individual cells. It refers to the selective segregation of certain genotypes in mitochondrial DNA that allows the favoured genotype to thrive. Intercellular ("between cells") selection occurs on a larger scale, and refers to the preferential growth of cells that have greater numbers of a certain mitochondrial genotype. Selective differences between naturally occurring mtDNA types may pose challenges for gene therapies. In mitochondrial DNA, there is evidence for potent germline purifying selection, as well as purifying selection during embryogenesis. Additionally, there is a dose dependent decrease in reproduction ability for females that have mutations in mitochondrial DNA. This demonstrates another selection mechanism to prevent the evolutionary preservation of harmful mutations.

One notable example of an otherwise healthy individual whose heteroplasmy was discovered incidentally is Nicholas II of Russia, whose heteroplasmy (and that of his brother) served to convince Russian authorities of the authenticity of his remains.