C Model accounting for the apparently convergent translocation of the large non-coding region in bird mtDNAs 54 see text. The two differing arrangements gene orders B and C can be derived from that commonly found among vertebrates through a hypothetical intermediate with duplicated non-coding regions. Another possible example of an intermediate for this duplicationrandom loss model is in the mtDNA of the amphisbaenian reptile Bipes biporus However, in this case, loss of either of the remaining P genes would restore the original arrangement rather than lead to an exchange.
The rearrangements of bullfrog 59 and rice frog 42 are not found in Xenopus mtDNA Each has a similar translocation of the large non-coding region and movement of L CUN to a nearby position, although the arrangements are not identical. Considering the frequent implication of the non-coding region in gene translocations, one reconstruction of the rearrangement would be the translocation of L CUN to a position adjacent to the non-coding region, followed or accompanied by the duplication and translocation of the non-coding region and L CUN together, then the random loss of L CUN genes, with only rice frog mtDNA retaining the pseudogene and bullfrog losing the gene entirely.
All observed rearrangements among chordate mtDNAs fall into three categories: exchange in position of nearest neighbor genes or segments; changes near to one or the other origin of replication, sometimes with an accompanying duplication of non-coding sequences; or changes near the region that is primitively I - Q - M. While the significance is not obvious, the I - Q - M region also appears to be one of the most mobile in arthropod mtDNAs see below , where it is adjacent to the large non-coding region.
Could this signal some primitive functional significance to sequences near this region for chordates which might be implicated in these rearrangements?
All published mitochondrial gene arrangements of echinoderms are shown in Figure 2 29 , 61— Of the five extant echinoderm classes, crinoids are believed to be the most primitive. Although several rearrangements separate the crinoid gene order from those shared by other echinoderms, it cannot be reliably discerned whether the primitive echinoderm arrangement is more like that of the crinoid mtDNA or whether these rearrangements occurred within that lineage.
Within the remaining four classes jointly comprising the Eleutheria , there is a large inversion of the region bounded by P and lrRNA separating the gene arrangement shared by three echinoids sea urchins and a holothuroid sea cucumber from that shared by five asteroids sea stars and an ophiuroid brittle stars.
Cladistic analysis, using the gene arrangement typical of vertebrates as an outgroup, supports the view of a monophyletic Asterozoa Asteroidea plus Ophiuroidea , leaving undetermined whether the more basal Echinozoa Echinoidea plus Holothuroidea is monophyletic or paraphyletic Fig.
The best example of an intermediate in the duplication-random loss model of gene rearrangement see section above is in the mtDNA of the sea cucumber Cucumaria 69 Fig. As can be seen in Figure 2A , all other echinoderms have a similar or identical cluster of many tRNA genes. Because of the conservation of this arrangement and the nearly complete determination of the order of these genes in another holothuroid, Parastichopus , the primitive holothuroid arrangement can be confidently inferred.
These tRNA genes are widely spaced in each case, separated by the presumed disintegrating vestiges of tRNA pseudogenes rendered supernumerary by an earlier duplication of the entire cluster [or perhaps of the cluster minus D, Y, G and L UUR ]. It is noteworthy that this duplication also includes the large non-coding region, presumably containing the origin of replication, and that these duplicated non-coding regions retain significant sequence similarity.
Next to chordates, arthropods are the best studied phylum for mtDNA Fig. This translocation occurred at the base of an insect-crustacean clade and is a strong indicator of the close relationship of these groups to the exclusion of myriapods, chelicerates, tardigrades and onychophorans 30 , Generally, few rearrangements have been observed in arthropod mtDNAs and, other than in one group of ticks 73 , 74 see below , all have been translocations of only tRNA genes.
The crustacean Artemia 75 has a translocation of I - Q , apparently derived for this lineage since another branchiopod, Daphnia 76 , has these genes in the same arrangement as both Limulus and Drosophila. The mitochondrial gene arrangement of the hymenopteran Apis 80 requires a minimum of eight tRNA translocations to relate it to that of Drosophila. One of these translocations, a nearest neighbor exchange of D and K , it shares with two orthopterans 81 , Short sequences have been published for many other insects that have gene arrangements identical to those of Drosophila ; many of these references can be found at: www.
A Mitochondrial gene arrangements of echinoderms 29 , 61—69 emphasizing the large inversion separating the gene orders of Echinozoa Holothuroidea plus Echinoidea from that of Asterozoa Asteroidea plus Ophiuroidea.
B By omitting tRNA genes from the analysis and comparing to the common gene arrangement found in vertebrates, it can be seen that a lesser number of rearrangements would be required to describe a Vertebrata-Echinozoa-Asterozoa transition than a Vertebrata-Asterozoa-Echinozoa transition C The cluster of tRNAs inferred to be in the primitive arrangement for Holothuroidea along with the duplicated cluster found in Cucumaria Shaded boxes represent unassigned nucleotides of various length, presumably vestiges of tRNA genes from the original duplication see text.
Box sizes vary to aid alignment of homologous genes. The nt marked for one of the boxes is an estimated size based on fragment size of a region containing multiple repeated sequence elements. Genes are depicted and labeled as in Figure 1. The complete mtDNA sequence of the prostriate tick Ixodes 73 demonstrates a gene arrangement identical to that of another chelicerate Limulus. However, the metastriate tick Rhiphicephalus 73 has a translocation of a seven-gene block bounded by the genes ND1 and Q along with other tRNA translocations.
A broad sampling of gene boundaries 73 , 74 finds that all sampled metastriates share this rearrangement, whereas it is not found among prostriates. Three species of bark weevil, Pissodes nemorensis, Pissodes strobi and Pissodes terminalis , have been shown by Southern hybridization to Drosophila mtDNA probes to have a gene arrangement typical of insects. Otherwise, these genomes are much larger than those of other studied arthropods, up to 36 kb, and vary greatly in size both between and within individuals.
This larger size is due to a greatly expanded non-coding region containing multiple repeat units 7. This points to a role for the origins of replication in gene order translocation and, perhaps, suggests that a closer look be taken for a second-strand origin in arthropod mtDNA near the A - R - N - S AGN - E - F region. The mitochondrial gene arrangement of Mytilus 12 was the first among mollusks to be determined Fig. It has several highly unusual features: the gene arrangement is remarkably unlike that found for other mtDNAs; several genes deviate significantly in length from their homologs; there is an unusual number of non-coding nucleotides; and no gene for A8 can be found.
Whether A8 moved to the nucleus, became dispensable entirely, or had its function co-opted by one of the other ATPase subunits is unknown. This leads to speculation that only one of these methionine tRNAs might be charged with formyl-methionine to be used for protein initiation while the other functions only in elongation. However, mitochondrial tRNAs are known to have post-transcriptionally modified nucleotides and the mechanisms by which an initiation codon normally discriminates in favor of a formyl-methionine charged tRNA are unknown.
Mitochondrial gene arrangements of arthropods plus small segments of an onychophoran and a tardigrade 30—31 , 70—82 , — Metastriate ticks have a rearrangement of a seven-gene block bounded by ND1 and Q ; this is marked by a line connecting this block to the homologous genes of other chelicerates. Otherwise, only rearrangements of tRNA genes have been observed.
Asterisks mark all tRNA genes differing in location from the arrangement found in Limulus polyphemus , which has been inferred to be primitive for Arthropoda 30 , 31 , In a few cases, i.
In the cases of unconnected blocks of genes it is unknown if these are their actual relative locations; depiction is aligned with other corresponding genes for clarity only.
Opportunities to test this are available since this appears to be the mode of inheritance in other bivalves as well 85 , 86 , although no gene arrangement information is yet available. Furthermore, other bivalves, the scallops Pecten 87 , Patinopecten 88 and Placopecten 89 , have very unusual mtDNA structures, with extensive regions of repetitive DNA and, in some cases, extreme variations in size, even among conspecific individuals. The mode of mtDNA inheritance in scallops is unknown.
A Mitochondrial gene arrangements of Mollusca 12 , 19 , 90—93 , 95 , S2 of Mytilus is shown here in a different place from the original publication; recent studies comparing sequences of several Mytilus species and performing northern blot analysis of tRNA expression have demonstrated that the sequence originally proposed as S2 is not detected as a tRNA-sized message and that the location depicted here is of the actual S2 D.
Wolstenholme, personal communication. B Complete mitochondrial gene arrangement of the oligochaete annelid Lumbricus 97 along with published, small segments of the polychaete annelid Platynereis , the hirudinid annelid Helobdella , the pogonophoran Galatheolinum , and the echiuran Urechis C Mitochondrial gene arrangements of Nematoda 9— D Mitochondrial gene arrangement of a platyhelminth E Mitochondrial gene arrangements of Cnidaria 13— Genes are depicted and labeled as in Figure 1 with a few additions.
Two of the cnidarians also contain a gene homologous to the bacterial mismatch repair gene mutS. The complete mtDNA sequences of three land snails, Euhadra herklotsi 90 , Cepaea nemoralis 91 and Albinaria coerulea 92 , and the partial sequence of Albinaria turrita 93 , have been published.
These pulmonates share a nearly identical gene arrangement that is highly divergent from those of any other animals. These shared gene arrangements, then, unite these two classes of Gastropoda to the exclusion of the prosobranch gastropod Plicopurpura 30 , since partial gene arrangement data for this animal show several genes in the same order as many outgroups to Gastropoda.
Initially, based on gene sequence, it appeared that the tRNAs of pulmonate snails had aberrant structures, but it has been now shown that several undergo post-transcriptional processing to restore base pairing of their aminoacyl acceptor stem In contrast to these highly rearranged mollusk mitochondrial genomes, that of the chiton Katharina tunicata 95 can be related to those of Drosophila or vertebrates by a moderate number of rearrangements.
It is less clear how much rearrangement has occurred in the fourth class of Mollusca that has been sampled, Cephalopoda.
This class is represented by only a single partial sequence of squid mtDNA 96 containing 15 genes. There are two blocks of genes in similar arrangement to Katharina , but several other genes are differently located. Rather, the data indicate periods of stasis and of saltatory rearrangements. For example, after the opisthobranch-pulmonate clade split from the ancestral mollusk, there must have been rearrangements involving nearly every gene to generate their shared but highly derived gene order.
Then, during the long period of evolution since these two gastropod classes split, there have been only very few rearrangements in either lineage. For deriving phylogeny from this type of data, there seems to be no accurate a priori estimation possible of the level of relationship likely to be characterized by a gene rearrangement.
Only one complete annelid mtDNA sequence has been determined, that of the oligochaete Lumbricus terrestris 97 ; small portions have been published of two other annelids, Platynereis and Helobdella , and of the related taxa Galatheolinum phylum Pogonophora and Urechis phylum Echiura 31 Fig.
Unlike most studied mtDNAs, all Lumbricus mitochondrial genes are encoded on the same strand. That is, if rearrangements were to place all genes on one strand, it would be expected that transcription of the other strand would soon cease, since presumably selection would not maintain the necessary signaling elements and the futile transcription would be an energetic burden.
This would then constitute an effective barrier to further inversions which would place a gene on the non-transcribed strand unless that inversion also carried with it the necessary sequence elements to resume its expression. In several respects Lumbricus mtDNA is quite conventional: only ATG is used as an initiation codon, whereas most mtDNAs use a variety of alternatives 18 ; the tRNAs have uncommonly uniform potential secondary structures; nucleotide composition is more balanced than for most mtDNAs; and non-coding nucleotides are very few.
It is unknown whether this is also the mode of translation of these two genes in other organisms, although, if so, it could explain their nearly universal juxtaposition. It may be that loss of co-translation of this bicistron is a derived feature of the Eutrochozoa; this could be studied in members that retain A8 adjacent to A6 , such as the polyplacophoran mollusk Katharina These two animals share an identical gene arrangement Fig. Two other members of this class Secernentea, Meloidogyne 10 and Onchocerca 9 , have unique gene arrangements; the three gene arrangements of these four nematodes differ at nearly every gene boundary from all other mtDNAs.
This has established the view that nematodes are characterized by very rapid rates of mitochondrial gene rearrangement. However, this may more properly be considered a trait of the Secernentea; Trichinella , a representative of the other nematode class, Adenophorea, has a mitochondrial gene arrangement easily related to those of protostomes by a moderate number of changes unpublished.
Multiple, unrelated repeated sequences are also present in Meloidogyne mtDNA. The only gene arrangement known of any flatworm is from a 3. All 11 of these Fasciola genes are transcribed from the same strand.
The complete mitochondrial gene arrangements of three cnidarians have been published, those of the anthozoans Metridium senile 15 , 18 , Renilla kolikeri 13 and Sarcophyton glaucum 16 , 17 Fig. Introns have been found in animal mtDNA only here and in two other species of the same order, Actiniaria, and are known to be absent from these genes in the mtDNAs of a number of other cnidarians The intron in COI contains an ORF similar to some intron-encoded endonucleases that are active in their transposition.
Presumably the other necessary tRNAs are imported nuclear products. All have a tRNA for methionine, which may be necessary to provide the formyl-methionine which initiates mitochondrial proteins but not nuclear proteins, so the cytoplasm may not contain such a tRNA.
Metridium mtDNA also contains a tRNA gene for tryptophan, perhaps to accommodate a variation in the genetic code common in mitochondria. The more closely related pair, Renilla and Sarcophyton both in the group Octocorallia , have an identical mitochondrial gene arrangement, and also share having an extra gene not otherwise found in animal mtDNAs, a homolog to the bacterial mismatch repair gene mutS.
This paucity of tRNA genes is certainly derived for the Anthozoa or for a larger, subsuming clade, rather than the primitive state for multicellular animals. There are three other cnidarian classes: Cubozoa, Scyphozoa and Hydrozoa. Each of these has been found to have linear mtDNA chromosomes 6 , a unique feature among animal mitochondrial genomes.
Linear mtDNA appears to have evolved a single time in their common ancestor, indicating a shared evolutionary history to the exclusion of the remaining class, Anthozoa, which retains the primitive for Cnidaria condition of circular mtDNA. No information on the gene content of these linear mitochondrial chromosomes is yet available, nor have any studies addressed the unique molecular feature of linear animal mtDNA, such as mechanisms for replicating the chromosome ends.
The molecular biology of mitochondrial systems has been studied for only a few model organisms, with nearly all information being from mammals or Drosophila. Many of the views that have become nearly axiomatic are challenged by newly determined mtDNA sequences.
For example, the view that animal mtDNAs are selected for extreme economy of size, while apparent in some cases, is refuted by mitochondrial genomes with very large amounts of non-coding sequence, as has been found in some arthropods, mollusks and nematodes 7 , 8 , 87—89 , Further, those arranged with clustered tRNA genes and without compensatory intergenic secondary structures must somehow produce genespecific messages.
Aspects of genome evolution, including changes in rate and modes of transcription, message processing, regulation of replication, interactions among various molecular factors, the role of selection on base composition in determining gene evolution, changes in the secondary structures of tRNAs and rRNAs, changes in the genetic code—all are especially tractable in mitochondrial systems.
Comparison of mitochondrial genome arrangements has promise for resolving some of the controversial evolutionary relationships among major animal groups.
Obviously, only a minority of phylogenetic relationships will be addressed using this type of comparison. No rearrangements may have occurred during a period of shared history or subsequent rearrangements may have eroded the shared features. The greatest advantage of this data set is that there is significant confidence in evolutionary branches characterized by complex shared rearrangements.
As a corollary to this, one might wisely view as less significant rearrangements that are simple, especially an exchange in position of nearest neighbor genes, a movement of a non-coding region, or rearrangements of genes adjacent to the origin of replication.
These types of changes appear to be more common than others and are explained by relatively simple mechanisms, so are less likely to be unique events.
Methods for computer reconstructions of gene rearrangements are being developed and debated , , but no algorithm yet exists which will exhaustively search all possible solutions and guarantee an exact, most parsimonious reconstruction. Furthermore, little is known about the molecular processes that lead to rearrangement, making unclear the relative likelihood of inversions, translocations or duplications with subsequent random gene loss 5 , 58 as mechanisms of change.
Ultimately the most accurate models for reconstructing mitochondrial genome rearrangements must integrate information on molecular mechanisms. So far, only a small sample of the Metazoa has been studied for mtDNA sequences, gene arrangements and molecular mechanisms. Mitochondrial genomics has great potential for resolving ancient patterns of evolutionary history and for serving as a model of genome evolution. Many patterns of evolution, both of organisms and of genomes, may in the near future be better understood through the comparison of mitochondrial genomic systems.
More information can be found at: www. Google Scholar. The mitochondrial DNA is critically important for many of the pathways that produce energy within the mitochondria. And if there's a defect in some of those mitochondrial DNA bases, that is to say a mutation, you will have a mitochondrial disease, which will involve the inability to produce sufficient energy in things like the muscle and the brain, and the kidney.
So this is very helpful sometimes in determining how a person has a certain disorder in the family. Sometimes a disease will be inherited through the mother's line, as opposed to both parents.
You can tell from a pedigree or a group of family history whether or not this is a mitochondrial disease because of that. William Gahl, M. This damage results from a buildup of harmful molecules called reactive oxygen species, which are byproducts of energy production in mitochondria.
Mitochondrial DNA is especially vulnerable because it has a limited ability to repair itself. As a result, reactive oxygen species easily damage mitochondrial DNA, causing cells to malfunction and ultimately to die. Cells that have high energy demands, such as those in the inner ear that are critical for hearing, are particularly sensitive to the effects of mitochondrial DNA damage.
This damage can irreversibly alter the function of the inner ear, leading to hearing loss. Some cases of cyclic vomiting syndrome, particularly those that begin in childhood, may be related to changes in mitochondrial DNA. This disorder causes recurrent episodes of nausea, vomiting, and tiredness lethargy. Some of the genetic changes alter single DNA building blocks nucleotides , whereas others rearrange larger segments of mitochondrial DNA.
These changes likely impair the ability of mitochondria to produce energy. Researchers speculate that the impaired mitochondria may affect certain cells of the autonomic nervous system, which is the part of the nervous system that controls involuntary body functions such as heart rate, blood pressure, and digestion.
However, it remains unclear how these changes could cause the recurrent episodes characteristic of cyclic vomiting syndrome. Mutations in at least three mitochondrial genes can cause cytochrome c oxidase deficiency, which is a condition that can affect several parts of the body, including the muscles used for movement skeletal muscles , the heart, the brain, or the liver.
The mitochondrial genes associated with cytochrome c oxidase deficiency provide instructions for making proteins that are part of a large enzyme group complex called cytochrome c oxidase also known as complex IV.
Cytochrome c oxidase is responsible for the last step in oxidative phosphorylation before the generation of ATP. The mtDNA mutations that cause this condition alter the proteins that make up cytochrome c oxidase. As a result, cytochrome c oxidase cannot function. A lack of functional cytochrome c oxidase disrupts oxidative phosphorylation, causing a decrease in ATP production. Researchers believe that impaired oxidative phosphorylation can lead to cell death in tissues that require large amounts of energy, such as the brain, muscles, and heart.
Cell death in these and other sensitive tissues likely contribute to the features of cytochrome c oxidase deficiency. The deletions range from 1, to 10, nucleotides, and the most common deletion is 4, nucleotides. Kearns-Sayre syndrome primarily affects the eyes, causing weakness of the eye muscles ophthalmoplegia and breakdown of the light-sensing tissue at the back of the eye retinopathy. The mitochondrial DNA deletions result in the loss of genes that produce proteins required for oxidative phosphorylation, causing a decrease in cellular energy production.
Researchers have not determined how these deletions lead to the specific signs and symptoms of Kearns-Sayre syndrome, although the features of the condition are probably related to a lack of cellular energy.
It has been suggested that eyes are commonly affected by mitochondrial defects because they are especially dependent on mitochondria for energy. These genes provide instructions for making proteins that are part of a large enzyme complex.
This enzyme, known as complex I, is necessary for oxidative phosphorylation. The mutations responsible for Leber hereditary optic neuropathy change single amino acids in these proteins, which may affect the generation of ATP within mitochondria.
However, it remains unclear why the effects of these mutations are often limited to the nerve that relays visual information from the eye to the brain the optic nerve. Additional genetic and environmental factors probably contribute to vision loss and the other medical problems associated with Leber hereditary optic neuropathy.
Mutations in one of several different mitochondrial genes can cause Leigh syndrome, which is a progressive brain disorder that usually appears in infancy or early childhood. Affected children may experience delayed development, muscle weakness, problems with movement, or difficulty breathing.
Some of the genes associated with Leigh syndrome provide instructions for making proteins that are part of the large enzyme complexes necessary for oxidative phosphorylation.
For example, the most commonly mutated mitochondrial gene in Leigh syndrome, MT-ATP6 , provides instructions for a protein that makes up one part of complex V, an important enzyme in oxidative phosphorylation that generates ATP in the mitochondria.
The other genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. Many of these proteins play an important role in oxidative phosphorylation.
The mitochondrial gene mutations that cause Leigh syndrome impair oxidative phosphorylation. Although the mechanism is unclear, it is thought that impaired oxidative phosphorylation can lead to cell death in sensitive tissues, which may cause the signs and symptoms of Leigh syndrome.
People with this condition have diabetes and sometimes hearing loss, particularly of high tones. In certain cells in the pancreas beta cells , mitochondria help monitor blood sugar levels. In response to high levels of sugar, mitochondria help trigger the release of a hormone called insulin, which controls blood sugar levels. Researchers believe that the disruption of mitochondrial function lessens the mitochondria's ability to help trigger insulin release.
In people with MIDD, diabetes results when the beta cells do not produce enough insulin to regulate blood sugar effectively. Researchers have not determined how mutations in these genes lead to hearing loss. When caused by mutations in this gene, the condition is usually characterized by muscle weakness myopathy and pain, especially during exercise exercise intolerance.
More severely affected individuals may have problems with other body systems, including the liver, kidneys, heart, and brain. This protein is one component of complex III, one of several complexes that carry out oxidative phosphorylation. Most MT-CYB gene mutations involved in mitochondrial complex III deficiency change single amino acids in the cytochrome b protein or lead to an abnormally short protein.
These cytochrome b alterations impair the formation of complex III, severely reducing the complex's activity and oxidative phosphorylation. Damage to the skeletal muscles or other tissues and organs caused by the lack of cellular energy leads to the features of mitochondrial complex III deficiency.
Some of these genes provide instructions for making proteins that are part of a large enzyme complex, called complex I, that is necessary for oxidative phosphorylation.
This mutation, written as AG, replaces the nucleotide adenine with the nucleotide guanine at position in the MT-TL1 gene. The mutations that cause MELAS impair the ability of mitochondria to make proteins, use oxygen, and produce energy. They continue to investigate the effects of mitochondrial gene mutations in different tissues, particularly in the brain.
These genes provide instructions for making tRNA molecules, which are essential for protein production within mitochondria. This mutation, written as AG, replaces the nucleotide adenine with the nucleotide guanine at position in the MT-TK gene. It remains unclear how mutations in these genes lead to the muscle problems and neurological features of MERRF. The MT-ATP6 gene provides instructions for making a protein that is essential for normal mitochondrial function.
This protein forms one part subunit of an enzyme called ATP synthase. This enzyme, which is also known as complex V, is responsible for the last step of oxidative phosphorylation, in which a molecule called adenosine diphosphate ADP is converted to ATP.
It is unclear how this disruption in mitochondrial energy production leads to muscle weakness, vision loss, and the other specific features of NARP. Mutations in mitochondrial DNA are associated with nonsyndromic hearing loss, which is loss of hearing that is not associated with other signs and symptoms.
This molecule helps assemble protein building blocks known as amino acids into functioning proteins that carry out oxidative phosphorylation within mitochondria.
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