The INDIVIDUALIST

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Genomics

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Description

The genetic code is a set of rules that maps DNA sequences to proteins in the living cell, and is employed in the process of protein synthesis. Nearly all living things use the same genetic code, called the standard genetic code, although a few organisms use minor variations of the standard code.

Genome expression

The genetic information carried by an organism - its genome - is inscribed in one or more DNA molecules. Each functional portion of a DNA molecule is referred to as a gene. Each gene is transcribed into a short template molecule of the related polymer RNA, which is better suited for protein synthesis. This in turn is translated by mediation of a machinery consisting of ribosomes and a set of transfer RNAs and associated enzymes into an amino acid chain (polypeptide), which will then be folded into a protein.

The gene sequence inscribed in DNA, and in RNA, is composed of tri-nucleotide units called codons, each coding for a single amino acid. Each nucleotide sub-unit consists of a phosphate, deoxyribose sugar and one of the 4 nitrogenous nucleotide bases grouped into 2 categories, purine and pyrimidine. The purine bases adenine (A) and guanine (G) are larger and consist of two aromatic rings. The pyrimidine bases cytosine (C) and thymine (T) are smaller and consist of only one aromatic ring. In RNA, however, thymine (T) is substituted by uracil (U), and the deoxyribose is substituted by ribose.

Overall, there are 43 = 64 different codon combinations. For example, the RNA sequence UUUAAACCC contains the codons UUU, AAA and CCC, each of which specifies one amino acid. So, this RNA sequence represents a protein sequence, three amino acids long. (DNA is also a sequence of nucleotide bases, but there thymine takes the place of uracil.) For example, the codon AAU represents the amino acid asparagine (Asn), and cysteine (Cys) is represented by UGU and by UGC.

http://upload.wikimedia.org/wikipedia/en/c/cd/RNA-codon.png

Marshall W. Nirenberg and Heinrich J. Matthaei at the National Institutes of Health performed the experiments that first elucidated the correspondence between the codons and the amino acids that they code. Har Gobind Khorana expanded on Nirenberg's work and found the codes for the amino acids that Nirenberg's methods could not find. Khorana and Nirenberg won a share of the 1968 Nobel Prize in Physiology or Medicine for this work.

Technical details

Start/stop codons

In classical genetics, the stop codons were given names: UAG was amber, UGA was opal (sometimes also called umber), and UAA was ochre. These names were originally the names of the specific genes in which mutation of each of these stop codons was first detected.

Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process; nearby initiation sequences are also required to induce transcription into mRNA and binding by ribosomes. The most notable start codon is AUG, which also codes for methionine. CUG and UUG, and in prokaryotes GUG and AUU, also function as start codons, but occur much less frequently.

Stop codons are also called terminators.

Degeneracy of the genetic code

Many codons are redundant, meaning that two or more codons can code for the same amino acid. Degenerate codons may differ in their third positions; e.g., both GAA and GAG code for the amino acid glutamic acid. A codon is said to be four-fold degenerate if any nucleotide at its third position specifies the same amino acid; it is said to be two-fold degenerate if only two of four possible nucleotides at its third position specify the same amino acid. In two-fold degenerate codons, the equivalent third position nucleotides are always either two purines (A/G) or two pyrimidines (C/T). The degeneracy of the genetic code is what accounts for the existence of silent mutations.

Degeneracy is mandatory in order to produce enough different codons to code for 20 amino acids and a stop and start codon. Because there are four bases, triplet codons are required to produce at least 22 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4�=16). Because at least 22 codes are required, then 4� gives 64, which is the number of possible codons.

These properties of the genetic code make it more fault-tolerant for point mutations. For example, four-fold degenerate codons can tolerate any point mutation at the third position; two-fold degenerate codons can tolerate one out of the three possible point mutations at the third position. Since transition mutations (purine to purine or pyrimidine to pyrimidine mutations) are more likely than transversion (purine to pyrimidine or vice-versa) mutations, the equivalence of purines or that of pyrimidines at two-fold degenerate sites adds a further fault-tolerance.

A practical consequence of redundancy is that some errors in the genetic code only cause a silent mutation or an error that would not affect the amino acid's hydrophilic/hydrophobic property; e.g., a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. Even so, it is a single point mutation that causes a modified hemoglobin molecule in sickle-cell disease. The hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), which reduces the solubility of �-globin. This causes hemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle-cell deformation of erythrocytes. Sickle-cell disease is generally not caused by a de novo mutation. Rather it is selected for in malarial regions (in a similar way to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage).

In general, these properties are widely interpreted to form part of the reason for the origin of the standard genetic code [see below].

These variable codes for amino acids are possible because of modified bases in the first base of the anticodon, and the basepair formed is called a wobble base pair. The modified bases include inosine and the U-G basepair.

Only two amino acids are specified by a single codon; one of these is the amino-acid methionine, specified by the codon AUG, which also specifies the start of transcription; the other is tryptophan, specified by the codon UGG.

Phase or reading frame of a sequence

Note that a "codon" is entirely defined by your starting position. For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA and CCC. If read from the second position, it contains the codons GGA and AAC (partial codons being ignored). If read starting from the third position, GAA and ACC. Every DNA sequence can thus be read in three reading frames, each of which will produce a radically different amino acid sequence (in our example, Gly-Lys-Pro, Gly-Asp, and Glu-Thr, respectively). The actual frame a protein sequence is translated in is defined by a start codon, usually the first occurrence of AUG in the RNA sequence. Mutations that disrupt the reading frame (i.e. insertions or deletions of one or two nucleotide bases) severely impair the function of a protein and are thus exceedingly rare in in vivo protein-coding sequences, since they often lead to death before an organism is viable.

Variations

Numerous variations of the standard genetic code are found in mitochondria, which are energy-producing organelles. Mycoplasma translate the codon UGA as tryptophan. Ciliate protozoa also have some variation in the genetic code: UAG and often UAA code for Glutamine (a variant also found in some green algae), or UGA codes for Cysteine. Another variant is found in some species of the yeast candida, where CUG codes for Serine.

In certain proteins, non-standard amino acids are substituted for standard stop codons, depending upon associated signal sequences in the messenger RNA: UGA can code for selenocysteine and UAG can code for pyrrolysine (for details, see the articles on these two amino acids). There may be other non-standard interpretations that are not yet known.

A detailed description of variations in the genetic code can be found at the NCBI web site.

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Attribution

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