Heteroplasmy is the presence of more than one type of
organellar
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' the ...
genome
In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding g ...
(
mitochondrial DNA
Mitochondrial DNA (mtDNA or mDNA) is the DNA located in mitochondria, cellular organelles within eukaryotic cells that convert chemical energy from food into a form that cells can use, such as adenosine triphosphate (ATP). Mitochondrial D ...
or
plastid DNA) within a cell or individual. It is an important factor in considering the severity of
mitochondrial disease
Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
s. Because most
eukaryotic cells
Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bact ...
contain many hundreds of mitochondria with hundreds of copies of mitochondrial DNA, it is common for
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s to affect only some mitochondria, leaving most unaffected.
Although detrimental scenarios are well-studied, heteroplasmy can also be beneficial. For example,
centenarian
A centenarian is a person who has reached the age of 100 years. Because life expectancies worldwide are below 100 years, the term is invariably associated with longevity. In 2012, the United Nations estimated that there were 316,600 living centen ...
s 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.
[
]
Types of heteroplasmy
In order for heteroplasmy to occur, organelles
In cell biology, an organelle is a specialized subunit, usually within a cell, that has a specific function. The name ''organelle'' comes from the idea that these structures are parts of cells, as organs are to the body, hence ''organelle,'' th ...
must contain a genome and, in turn, a genotype. In animals, mitochondria are the only organelles that contain their own genomes, so these organisms will only have mitochondrial heteroplasmy. In contrast, photosynthetic plants contain mitochondria and chloroplasts
A chloroplast () is a type of membrane-bound organelle known as a plastid that conducts photosynthesis mostly in plant and algal cells. The photosynthetic pigment chlorophyll captures the energy from sunlight, converts it, and stores it in ...
, each of which contains plastid genome
Chloroplast DNA (cpDNA) is the DNA located in chloroplasts, which are photosynthetic organelles located within the cells of some eukaryotic organisms. Chloroplasts, like other types of plastid, contain a genome separate from that in the cell nuc ...
s. Therefore, plant heteroplasmy occurs in two dimensions.
Microheteroplasmy
Microheteroplasmy is the presence of mutations levels of up to about 2−5% of mitochondrial genomes. In human mitochondrial DNA
Human mitochondrial genetics is the study of the genetics of human mitochondrial DNA (the DNA contained in human mitochondria). The human mitochondrial genome is the entirety of hereditary information contained in human mitochondria. Mitochondri ...
, 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
Cloning is the process of producing individual organisms with identical or virtually identical DNA, either by natural or artificial means. In nature, some organisms produce clones through asexual reproduction. In the field of biotechnology, c ...
and sequencing strategy, capable of detecting mutations at levels of 1% or less, such low-level heteroplasmy
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 c ...
, 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
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
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
Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms becom ...
.
Organelle inheritance patterns
In 1909, while studying chloroplast genomes, Erwin Baur Erwin Baur (16 April 1875, in Neuried, Ichenheim, Grand Duchy of Baden – 2 December 1933) was a German geneticist and botanist. Baur worked primarily on plant genetics. He was director of the Kaiser Wilhelm Institute for Breeding Research (since 1 ...
made the first observations about organelle inheritance patterns. Organelle genome inheritance differs from nuclear genome
Nuclear DNA (nDNA), or nuclear deoxyribonucleic acid, is the DNA contained within each cell nucleus of a eukaryotic organism. It encodes for the majority of the genome in eukaryotes, with mitochondrial DNA and plastid DNA coding for the rest. I ...
, and this is illustrated by four violations of Mendel's laws.
# During asexual reproduction
Asexual reproduction is a type of reproduction that does not involve the fusion of gametes or change in the number of chromosomes. The offspring that arise by asexual reproduction from either unicellular or multicellular organisms inherit the fu ...
, 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.
# Mendel states that nuclear alleles always segregate during meiosis. However, organelle alleles may or may not do this.
# Nuclear genes are inherited from a combination of alleles from both parents, making inheritance biparental. Conversely, organelle inheritance is uniparental, meaning the genes are all inherited from one parent.
# It is also unlikely for organelle alleles to segregate independently, like nuclear alleles do, because plastid genes are usually on a single chromosome and recombination is limited by uniparental inheritance.
Vegetative segregation
Vegetative segregation, the random partitioning of cytoplasm, is a distinguishable characteristic of organelle heredity. During cell division, the organelles are divided equally, providing each daughter cell with a random selection of plasmid genotypes.
Uniparental inheritance
Uniparental inheritance refers to the fact that, in most organisms, many offspring inherit organelle genes from only one parent. However, this is not a general law. Many organisms that have the ability to differentiate maternal and paternal sexes will produce offspring with a mixture of maternal, paternal, and biparental mitochondrial DNA.
Mitochondrial bottleneck
Entities undergoing uniparental inheritance and with little to no recombination may be expected to be subject to Muller's ratchet
In evolutionary genetics, Muller's ratchet (named after Hermann Joseph Muller, by analogy with a ratchet effect) is a process through which, in the absence of recombination (especially in an asexual population), an accumulation of irreversible d ...
, the inexorable accumulation of deleterious mutations until functionality is lost. Animal populations of mitochondria avoid this buildup through a developmental process known as the mtDNA bottleneck. The bottleneck exploits stochastic processes in the cell to increase in the cell-to-cell variability in mutant load as an organism develops: a single egg cell with some proportion of mutant mtDNA thus produces an embryo where different cells have different mutant loads. Cell-level selection may then act to remove those cells with more mutant mtDNA, leading to a stabilisation or reduction in mutant load between generations. The mechanism underlying the bottleneck is debated, 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.
Selection
Although it is not well characterized, selection can occur for organelle genomes in heteroplasmic cells. Intracellular
This glossary of biology terms is a list of definitions of fundamental terms and concepts used in biology, the study of life and of living organisms. It is intended as introductory material for novices; for more specific and technical definitions ...
("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 can occur between naturally occurring, non-pathological mtDNA types when mixed in cells, and may depend on tissue type, age, and genetic distance. Selective differences between naturally occurring mtDNA types may pose challenges for gene therapies.
In mitochondrial DNA, there is evidence for potent germline purifying selection
In natural selection, negative selection or purifying selection is the selective removal of alleles that are deleterious. This can result in stabilising selection through the purging of deleterious genetic polymorphisms that arise through random ...
, as well as purifying selection
In natural selection, negative selection or purifying selection is the selective removal of alleles that are deleterious. This can result in stabilising selection through the purging of deleterious genetic polymorphisms that arise through random ...
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.
Reduced recombination
It is very rare for organelle genes from different lineages to recombine. These genomes are usually inherited uniparentally, which does not provide a recombination opportunity. If they are inherited biparentally, it is unlikely that the organelles from the parents will fuse, meaning they will not share genomes.
However, it is possible for organelle genes from the same lineage to recombine. Intramolecular and intermolecular recombination can cause inversions and repeats in chloroplast DNA, and can produce subgenomic circles in mitochondrial DNA.
Mitochondrial mutations in disease
Mutations in mitochondrial DNA are usually single nucleotide substitutions, single base insertions, or deletions.
Because each cell contains thousands of mitochondria, nearly all organisms house low levels of mitochondrial variants, conferring some degree of heteroplasmy. Although a single mutational event might be rare in its generation, repeated mitotic segregation and clonal expansion can enable it to dominate the mitochondrial DNA pool over time. When this occurs, it is known as reaching threshold, and it usually results in physiological consequences.
Severity and time to presentation
Symptoms of severe heteroplasmic mitochondrial disorders do not usually appear until adulthood. Many cell divisions and a great deal of time are required for a cell to accumulate enough mutant mitochondria to cause symptoms. An example of this phenomenon is Leber optic atrophy. Generally, individuals with this condition do not experience vision difficulties until they have reached adulthood. Another example is MERRF syndrome
MERRF syndrome (or myoclonic epilepsy with ragged red fibers) is a mitochondrial disease. It is extremely rare, and has varying degrees of expressivity owing to heteroplasmy. MERRF syndrome affects different parts of the body, particularly the ...
(or Myoclonic Epilepsy with Ragged Red Fibers). In MELAS
Melas may refer to:
* Plural of mela
People
* Melas (mythology), a number of different characters in Greek mythology
* Pavlos Melas (1870–1904), a Hellenic Army officer and a symbol of the Greek Struggle for Macedonia
* Chloe Melas, an Ameri ...
, heteroplasmy explains the variation in severity of the disease among siblings.
Screening
Preimplantation genetic screening (PGS) can be used to quantitate the risk of a child of being affected by a mitochondrial disease. In most cases, a muscle mutation level of approximately 18% or less confers a 95% risk reduction.
Notable cases
One notable example of an otherwise healthy individual whose heteroplasmy was discovered incidentally is Nicholas II of Russia
Nicholas II or Nikolai II Alexandrovich Romanov; spelled in pre-revolutionary script. ( 186817 July 1918), known in the Russian Orthodox Church as Saint Nicholas the Passion-Bearer,. was the last Emperor of Russia, King of Congress Pola ...
, whose heteroplasmy (and that of his brother
A brother is a man or boy who shares one or more parents with another; a male sibling. The female counterpart is a sister. Although the term typically refers to a familial relationship, it is sometimes used endearingly to refer to non-familia ...
) served to convince Russia
Russia (, , ), or the Russian Federation, is a List of transcontinental countries, transcontinental country spanning Eastern Europe and North Asia, Northern Asia. It is the List of countries and dependencies by area, largest country in the ...
n authorities of the authenticity of his remains.
See also
* Homoplasmy
Homoplasmy is a term used in genetics to describe a eukaryotic cell whose copies of mitochondrial DNA are all identical.
* Microheteroplasmy
* Mitochondrial diseases
Mitochondrial disease is a group of disorders caused by mitochondrial dysfunction. Mitochondria are the organelles that generate energy for the cell and are found in every cell of the human body except red blood cells. They convert the energy of ...
Notes and references
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Mutation
Genetic genealogy
de:Mitochondriopathie#Erbgang