Human mitochondrial DNA.

Electron microscopy reveals mitochondrial DNA in discrete foci. Bars: 200 nm. (A) Cytoplasmic section after immunogold labelling with anti-DNA; gold particles marking mtDNA are found near the mitochondrial membrane. (B) Whole mount view of cytoplasm after extraction with CSK buffer and immunogold labelling with anti-DNA; mtDNA (marked by gold particles) resists extraction. From Iborra et al., 2004.^[1]

Mitochondrial DNA (mtDNA or mDNA^[2]) is the DNA located in organelles called mitochondria, structures within eukaryotic cells that convert the chemical energy from food into a form that cells can use, adenosine triphosphate (ATP). Most other DNA present in eukaryotic organisms is found in the cell nucleus.

Mitochondrial DNA can be regarded as the smallest chromosome, and was the first significant part of the human genome to be sequenced. In most species, including humans, mtDNA is inherited solely from the mother.

The DNA sequence of mtDNA has been determined from a large number of organisms and individuals (including some organisms that are extinct), and the comparison of those DNA sequences represents a mainstay of phylogenetics, in that it allows biologists to elucidate the evolutionary relationships among species. It also permits an examination of the relatedness of populations, and so has become important in anthropology and field biology.

Origin[link]

Nuclear and mitochondrial DNA are thought to be of separate evolutionary origin, with the mtDNA being derived from the circular genomes of the bacteria that were engulfed by the early ancestors of today's eukaryotic cells. This theory is called the endosymbiotic theory. Each mitochondrion is estimated to contain 2-10 mtDNA copies.^[3] In the cells of extant organisms, the vast majority of the proteins present in the mitochondria (numbering approximately 1500 different types in mammals) are coded for by nuclear DNA, but the genes for some of them, if not most, are thought to have originally been of bacterial origin, having since been transferred to the eukaryotic nucleus during evolution.

Mitochondrial inheritance[link]

In most multicellular organisms, mtDNA is inherited from the mother (maternally inherited). Mechanisms for this include simple dilution (an egg contains 100,000 to 1,000,000 mtDNA molecules, whereas a sperm contains only 100 to 1000), degradation of sperm mtDNA in the fertilized egg, and, at least in a few organisms, failure of sperm mtDNA to enter the egg. Whatever the mechanism, this single parent (uniparental) pattern of mtDNA inheritance is found in most animals, most plants and in fungi as well.

Female inheritance[link]

In sexual reproduction, mitochondria are normally inherited exclusively from the mother. The mitochondria in mammalian sperm are usually destroyed by the egg cell after fertilization. Also, most mitochondria are present at the base of the sperm's tail, which is used for propelling the sperm cells. Sometimes the tail is lost during fertilization. In 1999 it was reported that paternal sperm mitochondria (containing mtDNA) are marked with ubiquitin to select them for later destruction inside the embryo.^[4] Some in vitro fertilization techniques, particularly injecting a sperm into an oocyte, may interfere with this.

The fact that mitochondrial DNA is maternally inherited enables researchers to trace maternal lineage far back in time. ( Y-chromosomal DNA, paternally inherited, is used in an analogous way to trace the agnate lineage.) This is accomplished in humans by sequencing one or more of the hypervariable control regions (HVR1 or HVR2) of the mitochondrial DNA, as with a genealogical DNA test. HVR1 consists of about 440 base pairs. These 440 base pairs are then compared to the control regions of other individuals (either specific people or subjects in a database) to determine maternal lineage. Most often, the comparison is made to the revised Cambridge Reference Sequence. Vilà et al. have published studies tracing the matrilineal descent of domestic dogs to wolves.^[5] The concept of the Mitochondrial Eve is based on the same type of analysis, attempting to discover the origin of humanity by tracking the lineage back in time.

Because mtDNA is not highly conserved and has a rapid mutation rate, it is useful for studying the evolutionary relationships - phylogeny - of organisms. Biologists can determine and then compare mtDNA sequences among different species and use the comparisons to build an evolutionary tree for the species examined.

Because mtDNA is transmitted from mother to child (both male and female), it can be a useful tool in genealogical research into a person's maternal line.

Male inheritance[link]

It has been reported that mitochondria can occasionally be inherited from the father in some species such as mussels.^[6][7] Paternally inherited mitochondria have additionally been reported in some insects such as fruit flies,^[8] honeybees,^[9] and periodical cicadas.^[10]

Evidence supports rare instances of male mitochondrial inheritance in some mammals as well. Specifically, documented occurrences exist for mice,^[11][12] where the male-inherited mitochondria was subsequently rejected. It has also been found in sheep,^[13] and in cloned cattle.^[14] It has been found in a single case in a human male.^[15]

While many of these cases involve cloned embryos or subsequent rejection of the paternal mitochondria, others document in vivo inheritance and persistence under lab conditions.

Structure[link]

In most multicellular organisms the mtDNA is organized as a circular, covalently closed, double-stranded DNA. But in many unicellular (e.g. the ciliate Tetrahymena or the green alga Chlamydomonas reinhardtii) and in rare cases also in multicellular organisms (e.g. in some species of Cnidaria) the mtDNA is found as linearly organized DNA. Most of these linear mtDNA's possess telomerase independent telomers (i.e. the ends of the linear DNA) with different modes of replication, which have made them interesting objects of research, as many of these unicellular organisms with linear mtDNA are known pathogens.^[16]
In humans (and probably in metazoans in general), 100-10,000 separate copies of mtDNA are usually present per cell (egg and sperm cells are exceptions). In mammals, each double-stranded circular mtDNA molecule consists of 15,000-17,000 base pairs. The two strands of mtDNA are differentiated by their nucleotide content with the guanine rich strand referred to as the heavy strand, and the cytosine rich strand referred to as the light strand. The heavy strand encodes 28 genes, and the light strand encodes 9 genes for a total of 37 genes. Of the 37 genes, 13 are for proteins (polypeptides), 22 are for transfer RNA (tRNA) and two are for the small and large subunits of ribosomal RNA (rRNA). This pattern is also seen among most metazoans, although in some cases one or more of the 37 genes is absent and the mtDNA size range is greater. Even greater variation in mtDNA gene content and size exists among fungi and plants, although there appears to be a core subset of genes that are present in all eukaryotes (except for the few that have no mitochondria at all). Some plant species have enormous mtDNAs (as many as 2,500,000 base pairs per mtDNA molecule) but, surprisingly, even those huge mtDNAs contain the same number and kinds of genes as related plants with much smaller mtDNAs.^[17] The genome of the mitochondrion of the cucumber (Cucumis sativus) consists of three circular chromosomes (lengths 1556, 84 and 45 kilobases), which are entirely or largely autonomous with regard to their replication.^[18]

Replication[link]

mtDNA is replicated by the DNA polymerase gamma complex which is composed of a 140 kDa catalytic DNA polymerase encoded by the POLG gene and a 55 kDa accessory subunit encoded by the POLG2 gene. During embryogenesis, replication of mtDNA is strictly down-regulated from the fertilized oocyte through the preimplantation embryo.^[19] At the blastocyst stage, the onset of mtDNA replication is specific to the cells of the trophectoderm.^[19] In contrast, the cells of the inner cell mass restrict mtDNA replication until they receive the signals to differentiate to specific cell types.^[19]

Genes[link]

Note: The gene content of mitochondrial DNA varies among species. Information in this section is specific to human mitochondrial DNA

Electron transport chain[link]

The mitochondrial genome contains 13 protein-coding genes. Many of these genes encode proteins of the electron transport chain:

rRNA[link]

Mitochondrial rRNA is encoded by MT-RNR1 (12S) and MT-RNR2 (16S).

tRNA[link]

The following genes encode tRNA:

Mutations[link]

The involvement of mitochondrial DNA in several human diseases.

Susceptibility[link]

mtDNA is particularly susceptible to reactive oxygen species generated by the respiratory chain due to its proximity. Though mtDNA is packaged by proteins and harbors significant DNA repair capacity, these protective functions are less robust than those operating on nuclear DNA and therefore thought to contribute to enhanced susceptibility of mtDNA to oxidative damage. The outcome of mutation in mtDNA may be alteration in the coding instructions for some proteins,^[20] which may have an effect on organism metabolism and/or fitness.

Genetic illness[link]

Mutations of mitochondrial DNA can lead to a number of illnesses including exercise intolerance and Kearns-Sayre syndrome (KSS), which causes a person to lose full function of heart, eye, and muscle movements. Some evidence suggests that they might be major contributors to the aging process and age-associated pathologies.^[21]

Use in Disease Diagnosis[link]

Recently a mutation in mtDNA has been used to help diagnose prostate cancer in patients with negative prostate biopsy. ^[22][23]

Use in identification[link]

In humans, mitochondrial DNA spans 16,569 DNA base pairs,^[24] representing a fraction of the total DNA in cells. Unlike nuclear DNA, which is inherited from both parents and in which genes are rearranged in the process of recombination, there is usually no change in mtDNA from parent to offspring. Although mtDNA also recombines, it does so with copies of itself within the same mitochondrion. Because of this and because the mutation rate of animal mtDNA is higher than that of nuclear DNA,^[25] mtDNA is a powerful tool for tracking ancestry through females (matrilineage) and has been used in this role to track the ancestry of many species back hundreds of generations.

Human mtDNA can also be used to help identify individuals.^[26] Forensic laboratories occasionally use mtDNA comparison to identify human remains, and especially to identify older unidentified skeletal remains. Although unlike nuclear DNA, mtDNA is not specific to one individual, it can be used in combination with other evidence (anthropological evidence, circumstantial evidence, and the like) to establish identification. mtDNA is also used to exclude possible matches between missing persons and unidentified remains.^[27] Many researchers believe that mtDNA is better suited to identification of older skeletal remains than nuclear DNA because the greater number of copies of mtDNA per cell increases the chance of obtaining a useful sample, and because a match with a living relative is possible even if numerous maternal generations separate the two. American outlaw Jesse James's remains were identified using a comparison between mtDNA extracted from his remains and the mtDNA of the son of the female-line great-granddaughter of his sister.^[28] Similarly, the remains of Alexandra Feodorovna (Alix of Hesse), last Empress of Russia, and her children were identified by comparison of their mitochondrial DNA with that of Prince Philip, Duke of Edinburgh, whose maternal grandmother was Alexandra’s sister Victoria of Hesse.^[29] Similarly to identify Emperor Nicholas II remains his mitochondrial DNA was compared with that of James Carnegie, 3rd Duke of Fife, whose maternal great-grandmother Alexandra of Denmark (Queen Alexandra) was sister of Nicholas II mother Dagmar of Denmark (Empress Maria Feodorovna).^[30]

The low effective population size and rapid mutation rate (in animals) makes mtDNA useful for assessing genetic relationships of individuals or groups within a species and also for identifying and quantifying the phylogeny (evolutionary relationships; see phylogenetics) among different species, provided they are not too distantly related. To do this, biologists determine and then compare the mtDNA sequences from different individuals or species. Data from the comparisons is used to construct a network of relationships among the sequences, which provides an estimate of the relationships among the individuals or species from which the mtDNAs were taken. This approach has limits that are imposed by the rate of mtDNA sequence change. In animals, the high mutation rate makes mtDNA most useful for comparisons of individuals within species and for comparisons of species that are closely or moderately-closely related, among which the number of sequence differences can be easily counted. As the species become more distantly related, the number of sequence differences becomes very large; changes begin to accumulate on changes until an accurate count becomes impossible.

History[link]

Mitochondrial DNA was discovered in the 1960s by Margit M. K. Nass and Sylvan Nass by electron microscopy as DNase-sensitive thread inside mitochondria,^[31] and by Ellen Haslbrunner, Hans Tuppy and Gottfried Schatz by biochemical assays on highly purified mitochondrial fractions.^[32]

See also[link]

CORR Hypothesis Haplogroup Heteroplasmy Human mitochondrial DNA haplogroup Human mitochondrial genetics Mitochondrial disease Mitochondrial DNA (journal) Mitochondrial Eve Mitochondrial rCRS Paternal mtDNA transmission Single origin theory Supercluster (genetic) TIM/TOM Complex

Archaeogenetics of the Near East Genetics and archaeogenetics of South Asia Genetic history of Africa Genetic history of Europe Genetic history of Italy Genetic history of North Africa Genetic history of indigenous peoples of the Americas Genetic history of the Iberian Peninsula Genetic history of the British Isles

Molecular Anthropology portal Evolutionary biology portal

References[link]