The vast majority of an organism’s genetic material is contained within the nucleus of its cells, organized into chromosomes. However, cells also contain smaller, independent genetic structures outside the nucleus. This non-nuclear DNA has a unique set of rules governing its structure, inheritance, and expression.
Defining Homoplasmy and Heteroplasmy
Homoplasmy describes the state in which all copies of organelle DNA within a cell are genetically identical. This means there is complete uniformity in the genetic information found in these structures, involving either a normal DNA sequence or one that contains a specific mutation.
The contrasting condition is heteroplasmy, the coexistence of two or more distinct genetic versions of organelle DNA within a single cell or individual. In a heteroplasmic state, some copies might be the original sequence, while others carry a mutation.
The degree of heteroplasmy is determined by the ratio of mutant DNA to the total population of organelle DNA copies. This proportion can vary significantly between different cells, tissues, and individuals. A high level of heteroplasmy means a large percentage of the DNA copies carry a particular variant, which can have significant biological consequences.
Where This DNA Resides
This unique, non-nuclear DNA is primarily found within two types of organelles: mitochondria and chloroplasts. Mitochondria are present in nearly all eukaryotic cells, where their primary function is to generate the cell’s energy supply through oxidative phosphorylation.
The DNA found inside mitochondria is known as mitochondrial DNA (mtDNA). This genetic material is relatively small and circular, encoding a limited number of genes necessary for mitochondrial function. Changes to the mtDNA sequence are impactful due to its role in cellular energy production.
Plant cells also contain chloroplasts, which are the sites of photosynthesis and contain plastid DNA. While both organelles possess distinct genomes, the study of human health generally focuses on mtDNA due to its connection to human cellular metabolism.
How Homoplasmy is Passed Down
The transmission of organelle DNA follows a pattern called maternal inheritance. Offspring inherit their mitochondrial DNA exclusively from their mother, as the father’s mtDNA is typically degraded shortly after fertilization. This means all of a mother’s children inherit the same population of mtDNA molecules she possesses.
The proportion of mtDNA types passed to a child is subject to the genetic bottleneck effect. During the development of female germline cells, the total number of mtDNA copies is drastically reduced to a small sample size. This reduction limits the number of molecules passed into the mature egg cell.
Because the selection of these few molecules is a random sampling event, the proportion of a particular mtDNA variant can shift dramatically between generations. A heteroplasmic mother may produce an egg that, by chance, has a significantly higher or lower percentage of mutant DNA. This random sorting and subsequent amplification drives shifts toward new states of homoplasmy or heteroplasmy in the offspring.
When Homoplasmy Shifts
A shift in the proportion of mutant organelle DNA is directly relevant to the expression of inherited conditions, particularly mitochondrial diseases. These diseases are associated with a shift from a heteroplasmic state toward one where the mutant DNA dominates. The resulting reduction in energy production severely impairs the function of high-energy-demand organs, such as the brain, muscles, and eyes.
The clinical manifestation of a mitochondrial disease is governed by the threshold effect. Symptoms do not appear until the percentage of mutated mtDNA surpasses a specific functional limit. Cells possess spare capacity, allowing normal mtDNA copies to compensate for the compromised function of mutant copies up to a certain point.
For many mitochondrial disorders, the biochemical defect only becomes detectable when the mutant load exceeds a high threshold, often ranging between 60% and 90% of the total mtDNA copies. Below this threshold, the cell generally maintains normal function. Once the proportion crosses this line, the cell’s energy system collapses, leading to tissue-specific symptoms.