Mitochondrial Genome (mtDNA)
Introduction
Although most of the genome is present in the nucleus of an organism’s cell but there is small amount of DNA present in the mitochondria. This is known as the mitochondrial DNA or Mitochondrial genome. For certain cellular activities mt-DNA is important. A machinery is reserved which ensure its expression and transfer. It has a wide range of copy number from a few to thousands in number. It consists of multiple and identical, circular chromosomes. It has large diversity even in the eukaryotes. Like in humans it is approximately from 15 to 16 kb. And in plants its size is much large than humans i.e. around 200 kb to 2500 kb. Noted that more than 95% of the proteins of the mitochondria is encoded in nuclear genome. The genome of mitochondria is often rich in Adenine and Thymine nitrogenous bases. In human as the mitochondria comes from mother so mt-genome comes along it. And mitochondrial genome evolves faster than the nuclear genome and helps in the evolutionary and phylogenetic studies. Mitochondrial genome also proved very helpful in the biogeography and anthropology.
Origin
It is believed that mitochondria are the result of endosymbiosis. Though both main DNA (nuclear) and mitochondrial DNA have different evolutionary origins. So the mitochondrial genome may be came from the bacterial cell, which was engulfed by the forefathers of the current eukaryotes. This happened 2000 million years ago. Then they lost a large amount genes. Each mitochondrion may have 2 to 10 copies of DNA. Although most of the amino-acid peptides are being coded form the nuclear genome, the mtDNA still retains some genes. The reason of this retention is still unknown. They encode fewer than 40 genes. In some species it doesn’t have genes.
Structure
In most of the organisms the mt-DNA is closed circular, double stranded. It is well organized and covalently bonded. But in unicellular and even some multicellular it is present in linear fashion. This linear formation helps them in the replication and are mostly pathogens.
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I In Mammals
The human mitochondrial genome sequence was published by Anderson. In humans it is 16.6 kb and double stranded closed circular, covalently bonded mt-DNA. The two strands are different in bases composition from one another. One of the strands has lager number of bases called the heavy strands (H-strand) and the other one has lesser number of bases as compared to heavy strand, known as light strand (L-strand). The Heavy-strand is rich in guanine and the Light-strand is rich in cytosine content. Genes are present on both strands. Obviously more genes will be present on the heavier strand than the lighter strand. In each somatic cell there are around 10 thousand copies present of mtDNA separately. There are total of 37 genes present in human mtDNA. H-strand encodes around 28 genes while the Light-strand encodes nine genes. And among these there are 13 genes for polypeptides i.e. proteins. Besides this 22 genes are used for the tRNA and 2 for rRNA, for it small subunit and large subunit. There are very rare overlapping genes are present in case of animal mt-genome. But in cases of humans ATP8, ATP6, ND4L and ND are the overlapping gene which is present in the human mt-genome. It is not hard and fast the gene density is dependent on the size of mtDNA, there some organisms which have larger size of genome but some of the genes are absent. In case of mtDNA only 60 codons out of 64 code for amino acids.
Genes
Human mitochondrial genome is well packed. Introns are absent in most genes. They have lack some function which were expected to have in case of human genome. Mitochondrial mRNA do not have non-translated leading and trailing ends, and also certain cases do not have stop codons. Polyadenylation usually does the stops when a U is added to AUU. The mt-genetic codes are different than the nuclear genome. UGA reads as tryptophan rather a stop code. AGA, AGG normally code for Arginine but here it is regarded as stop codon. AUA is methionine and not Isoleucine. Start codon are usually AUA and AUU in mt-genes. The codons are not even universal among the mitochondrion of different organism as in case of nuclear genome.
Even though the mt-genome is compactly packed but not all genes are transcribed in the same direction. Conventionally a plus and a minus strand is assigned to circular mtDNA, most of the genes are transcribed by the plus strand. Very little are transcribed by the minus strand in opposite direction.
D-loop
It is region in the circular chromosome of mt-genome which is non-coding. There is no sequence of coding genes present at this site. It may be around 1121 bp long. It is region of DNA triple-helix. There are two overlapping copies of H-strand are present at this site. Most of the transcription and translation is controlled in this region. Regions in D-loop are responsible to begin the Replication, and it has transcription sites. In the D-loop region transcription of the mt-DNA strand accomplished. Also there are some others regions called hypervariable regions, in this mutation rate is very high. So this region is highly valuable in making assumption about human genetic variations.
In Plants
Plants have high number of base pairs in mt-genome than humans. Their mt-DNA constitutes about 2-hundred kilobases to 250 kilobases. Even some of the plants have very large number of bases as in silene colica, which consists of round 11,300,000 base pairs. Although this such a large amount of bases in mt-DNA but they have almost same number of genes as in the other plants. In cucumber the genome of mitochondria contains three circular chromosomes which are also large. There is a large variations is present between the mt-genome of fungi and plants. These variations are based on size and gene content of the genome.
In Paramecium
These are unicellular eukaryotes, belongs to protests. They have smallest mitochondrial genome. Paramecium is a parasite whose mtDNA is sequenced up to date. Mt-genome of paramecium is composed of around 5967 bp.
Genomic Diversities of Mitochondrial Genome
|
Characteristic |
Animals |
Plants and Fungi |
Protists |
|
Shape |
Circular |
Circular |
Circular |
|
Introns |
No |
No |
No |
|
Size |
11-28 kb |
20-1000 kb |
1-200 kb |
|
Other Difference |
Only one type of
genome is found, and a single molecule |
Three different
type are found, molecules are large, plasmid like appearance, |
Five different
type of genome found, homogenous/heterogenous
group of molecules, |
Holts and co-workers in 2000 suggested that the mitochondrial genome has two type of replication. The 1st one involves the asymmetric replication of leading and lagging strand while in the 2nd mode of mt-genome replication involves the formation of replication intermediates, in 2D gels which suggested the replication. It involves the coupled leading and lagging strand synthesis in mt-DNA. Many factors involves in mt-DNA replication which are subunit α, β and γ of polymerase. Mitochondrial RNA polymerase, SSB-binding proteins, mt-transcription factors and processing enzymes. DNA polymerase gamma complex replicate the mt-DNA.
POLG and POLG, and polymerase form the replisome. SSB-protein and TWINKLE acts as helicase in case of mt-genome replication, they unwind the double stranded.
Transcription in Mitochondrial Genome
There are two transcriptional initiations sites present in human mtDNA. One is on the d-loop region and the other is promoter region. Although H-stand and L-strand are very close but studies demonstrate that these are functionally independent of each other. A polycistronic RNA molecule is produced by transcribing the each mt-DNA strand in case of animals. In most of cases between the coding regions the tRNA are present. The mRNA are recognized by an enzyme due to their characteristics and cleaved at specific sites.
Importance of Mitochondrial Genome
There are many functions mt-DNA performs. As mitochondrion is the place where production of ATP for the cell occurs, thus it DNA is very necessary for the proper functioning of the respiration process. Other functions include processing the cell’s metabolism and steroid synthesis.
Role in genetic Relationships
mtDNA has crucial role in finding the relationship among the individuals and to quantify these relationships. mtDNA helps the scientist to construct link among different sequences. These sequences become larger which shows the distant relationships between species. mtDNA is highly susceptible to mutations, such mutation leads to disease, thus helps in finding the disease history. These mutation may inherited or somatic in nature.
Anthropology related to mtDNA
mtDNA Polymorphisms Track Human Migration
With help of studies conducted on mt-genome to track the human migration, shows that all the humans migrated from a small group people in Africa. This group of folks originated in Asia later on around some 200000 years ago. Initially this group of people was very small may be around 100-1000 persons. So mt-genome helps us to track the human earlier living places millions of years ago.
Role in paleontology
The genome of mitochondria is always area of study from scientists. Because each mitochondria contain around 2 to 10 copies of mtDNA and mtDNA do not undergo recombination process. So there would be 1000s of copies present of this mt-DNA and only one pair of nuclear genome. Thus more samples could be available to for genetical or sometimes paleontological studies. Recent studies on yeast mt-genome reveals that how humans are originated. Some studies of the fossils also indicate that the land is papalized around millions of years before (100M). Humans diversities disappeared around 30 million years ago and they diversified into their current form. This is also studies through mt-genome. From recent analysis of mt-DNA from the Neanderthals' bones, it is obvious that these Neanderthals' were the part of our species at some time. As the mt-DNA mutations occurs at random and uniform rate, say every 3000 years, then we can estimate the distance between two species by examining the mutations in their mt-DNA.
Uses in Disease Diagnosis
There many disease which are being diagnosed with the help mt-DNA. Recently a prostate cancer is diagnosed by using mt-DNA. Some other forms of cancers are also diagnosed. This by this diagnoses helps to cure these effectively and to discover appropriate drugs. Breast cancer and some metabolic diseases and many others are found related to mt-DNA.
Mitochondrial DNA and Aging
Mitochondrial processes control the aging thus aging does effects the mt-DNA. When mutations occurs in mt-DNA, it disrupts the normal creation of Reactive Oxygen Specie. It changes the normal enzymatic activities. High synthesis of ROS also linked with MRC dysfunction. These contribute to the premature aging. Between mitochondrial-genome biochemical composition and aging process there is a association and is observed and methods are being developed to combat the aging. Aging can cause mutations in mt-DNA and nuclear.
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