The INDIVIDUALIST

A Wiki about biochemical individuality

Genomics

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Description

Mitochondrial genetics are the genetics of the DNA contained in mitochondria, eukaryotic cell organelles that generate adenosine triphosphate from pyruvic acid and are hence referred to as the "powerhouses" of the cell. Mitochondrial DNA (mtDNA) is not transmitted through nuclear DNA, and in most multicellular organisms, virtually all mitochondria are inherited from the mother's ovum.

Mitochondrial inheritance is therefore non-Mendelian, as Mendelian inheritance presumes that half the genetic material of a zygote derives from either parent. Furthermore, some coniferous families show paternal inheritance of mitochondria, and some organisms such as Cryptosporidium have mitochondria with no DNA whatsoever.

Eighty percent of mitochondrial DNA codes for functional mitochondrial proteins, and therefore most mitochondrial DNA mutations lead to functional problems, which may be manifested as myopathies (muscle disorders).

Genome

Mitochondrial DNA (mtDNA) is present in mitochondria as a circular molecule and in most species codes for 13 or 14 proteins involved in the electron transfer chain, 2 rRNA subunits and 22 tRNA molecules (all necessary for protein synthesis). The number of proteins involved in the electron transfer chain is much larger than 13 or 14, but the remainder is in fact coded by the nuclear DNA.

In total, the mitochondrion hosts about 3000 proteins, but only about 37 of them are coded on the mitochondrial DNA. Most of the 3000 genes are involved in a variety of processes other than ATP production, such as porphyrin synthesis. Only about 3% of them code for ATP production proteins. This means most of the genetic information coding for the protein makeup of mitochondria is in chromosomal DNA and is involved in processes other than ATP synthesis. This increases the chances that a mutation that will affect a mitochondrion will occur in chromosomal DNA, which is inherited in a Mendelian pattern. Another result is that a chromosomal mutation will affect a specific tissue due to its specific needs, whether those may be high energy requirements or a need for the catabolism or anabolism of a specific neurotransmitter or nucleic acid. Because several copies of the mitochondrial genome are carried by the each mitochondrion (2-10 in humans), mitochondrial mutations can be inherited maternally by mtDNA mutations which are present in mitochondria inside the oocyte before fertilization, or (as stated above) through mutations in the chromosomes.

In humans, the heavy strand of mtDNA carries 28 genes and the light strand of mtDNA carries only 9 genes. Eight of the 9 genes on the light strand code for mitochondrial tRNA molecules. Human mtDNA consists of 16,569 nucleotide pairs. The entire molecule is regulated by only one regulatory region which contains the origins of replication of both heavy and light strands. The entire human mitochondrial DNA molecule has been mapped[1][2]. The rate of mutation in mtDNA is calculated to be about ten times greater than that of nuclear DNA, possibly due to a paucity of DNA repair mechanisms. This high mutation rate leads to a high variation between mitochondria, not only among different species but even within the same species. It is calculated that if two humans are chosen randomly and their mtDNA is tested, they will have an average of between fifty and seventy different nucleotides. This may not seem like much, but when compared to the total number of nucleotides of a human mitochondrial DNA molecule (16,569), as much as .42% of the mtDNA varies between two people.

Genetic code variants

The genetic code is, for the most part, universal, with few exceptions: mitochondrial genetics includes some of these. For most organisms the "stop codons" are 'UAA', 'UAG', and 'UGA'. In vertebrate mitochondria 'AGA' and 'AGG' are also stop codons, but not 'UGA', which codes for tryptophan instead. 'AUA' codes for isoleucine in most organisms but for methionine in vertebrate mitochondrial mRNA/tRNA.

There are many other variations among the codes used by other mitochondrial m/tRNA, which happened not to be harmful to their organisms, and which can be used as a tool (along with other mutations among the mtDNA/RNA of different species) to determine relative proximity of common ancestry of related species. (The more related two species are, the more mtDNA/RNA mutations will be the same in their mitochondrial genome).

Using these techniques, it is estimated that the first mitochondrion evolved, was consumed, or developed around 1.5 billion years ago, as an aerobic prokaryote in a symbiotic relationship within an anaerobic eukaryote.

Inheritance patterns

Because mitochondrial diseases (diseases due to malfunction of mitochondria) can be inherited both maternally and through chromosomal inheritance, the way in which they are passed on from generation to generation can vary greatly depending on the disease. Mitochondrial genetic mutations that occur in the nuclear DNA can occur in any of the chromosomes (depending on the species). Mutations inherited through the chromosomes can be autosomal dominant or recessive and can also be sex-linked dominant or recessive. Chromosomal inheritance follows normal Mendelian laws, despite the fact that the phenotype of the disease may be masked. Because of the complex ways in which mitochondrial and nuclear DNA "communicate" and interact, even seemingly simple inheritance is hard to diagnose. A mutation in chromosomal DNA may change a protein that regulates (an increase or decrease) the production of another certain protein in the mitochondria or the cytoplasm and may lead to slight, if any, noticeable symptoms. On the other hand, there are some devastating mtDNA mutations that are easy to diagnose because of their widespread damage to muscular, neural, and/or hepatic (among other high energy and metabolism dependent) tissues and due to the fact that they are present in the mother and all the offspring. Mitochondrial genome mutations are passed on 100% of the time from mother to all her offspring. Because the mitochondria within the fertilized oocyte is what the new life will have to begin with (in terms of mtDNA), and because the number of affected mitochondria varies from cell (in this case, the fertilized oocyte) to cell depending both on the number it inherited from its mother cell and environmental factors which may favor mutant or wild type mitochondrial DNA, and because the number of mtDNA molecules in the mitochondria varies from around two to ten, the number of affected mtDNA molecules inherited to a specific offspring can vary greatly. It is possible, even in twin births, for one baby to receive more than half mutant mtDNA molecules while the other twin may receive only a tiny fraction of mutant mtDNA molecules with respect to wild type (depending on how the twins divide from each other and how many mutant mitochondria happen to be on each side of the division). In a few cases, some mitochondria or a mitochondrion from the sperm cell enters the oocyte but paternal mitochondria are actively decomposed.

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