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Genetic code


The genetic code is a set of rules, which 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.

Contents

Genome expression

The genetic information carried by an organism - its genome - is inscribed in a DNA molecule. Each functional portion of this 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 only consist of 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.)

The standard genetic code is shown in the following tables. Table 1 shows what amino acid each of the 64 codons specifies. Table 2 shows what codons specify each of the 20 standard amino acids involved in translation. These are called forward and reverse codon tables, respectively. For example, the codon AAU represents the amino acid asparagine (Asp), and cysteine (Cys) is represented by UGU and by UGC.

Table 1: RNA Codon table

This table shows the 64 codons and the amino acid each codon codes for.
2nd base
U C A G
1st
base
U

UUU (Phe/F)Phenylalanine
UUC (Phe/F)Phenylalanine
UUA (Leu/L)Leucine
UUG (Leu/L)Leucine, Start

UCU (Ser/S)Serine
UCC (Ser/S)Serine
UCA (Ser/S)Serine
UCG (Ser/S)Serine

UAU (Tyr/Y)Tyrosine
UAC (Tyr/Y)Tyrosine
UAA Ochre (Stop)
UAG Amber (Stop)

UGU (Cys/C)Cysteine
UGC (Cys/C)Cysteine
UGA Opal (Stop)
UGG (Trp/W)Tryptophan

C

CUU (Leu/L)Leucine
CUC (Leu/L)Leucine
CUA (Leu/L)Leucine
CUG (Leu/L)Leucine, Start

CCU (Pro/P)Proline
CCC (Pro/P)Proline
CCA (Pro/P)Proline
CCG (Pro/P)Proline

CAU (His/H)Histidine
CAC (His/H)Histidine
CAA (Gln/Q)Glutamine
CAG (Gln/Q)Glutamine

CGU (Arg/R)Arginine
CGC (Arg/R)Arginine
CGA (Arg/R)Arginine
CGG (Arg/R)Arginine

A

AUU (Ile/I)Isoleucine, Start2
AUC (Ile/I)Isoleucine
AUA (Ile/I)Isoleucine
AUG (Met/M)Methionine, Start1

ACU (Thr/T)Threonine
ACC (Thr/T)Threonine
ACA (Thr/T)Threonine
ACG (Thr/T)Threonine

AAU (Asn/N)Asparagine
AAC (Asn/N)Asparagine
AAA (Lys/K)Lysine
AAG (Lys/K)Lysine

AGU (Ser/S)Serine
AGC (Ser/S)Serine
AGA (Arg/R)Arginine
AGG (Arg/R)Arginine

G

GUU (Val/V)Valine
GUC (Val/V)Valine
GUA (Val/V)Valine
GUG (Val/V)Valine, Start2

GCU (Ala/A)Alanine
GCC (Ala/A)Alanine
GCA (Ala/A)Alanine
GCG (Ala/A)Alanine

GAU (Asp/D)Aspartic acid
GAC (Asp/D)Aspartic acid
GAA (Glu/E)Glutamic acid
GAG (Glu/E)Glutamic acid

GGU (Gly/G)Glycine
GGC (Gly/G)Glycine
GGA (Gly/G)Glycine
GGG (Gly/G)Glycine

1The codon AUG both codes for methionine and serves as an initiation site: the first AUG in an mRNA's coding region is where translation into protein begins.
2This is a start codon for prokaryotes only.

Table 2: Reverse codon table

This table shows the 20 amino acids used in proteins, and the codons that code for each amino acid.
Ala A GCU, GCC, GCA, GCG Leu L UUA, UUG, CUU, CUC, CUA, CUG
Arg R CGU, CGC, CGA, CGG, AGA, AGG Lys K AAA, AAG
Asn N AAU, AAC Met M AUG
Asp D GAU, GAC Phe F UUU, UUC
Cys C UGU, UGC Pro P CCU, CCC, CCA, CCG
Gln Q CAA, CAG Ser S UCU, UCC, UCA, UCG, AGU,AGC
Glu E GAA, GAG Thr T ACU, ACC, ACA, ACG
Gly G GGU, GGC, GGA, GGG Trp W UGG
His H CAU, CAC Tyr Y UAU, UAC
Ile I AUU, AUC, AUA Val V GUU, GUC, GUA, GUG
Start AUG, GUG Stop UAG, UGA, UAA


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

Technical details

Stop Codons

In classical genetics, the stop codons were given names: UAG was amber, UGA was opal, 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). But unlike stop codons, these are 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 work.

Degeneracy of the genetic code

Many codons are degenerate or redundant, meaning that two or more codons may code for the same amino acid. Degenerate codons typically differ in their third positions; e.g. both GAA and GAG code for the amino acid glutamine. 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.

These properties of the genetic code make it more fault-tolerant for mutations. For example, four-fold degenerate codons can tolerate any mutation at the third position; two-fold degenerate codons can tolerate one out of the three possible 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.

The codons attempt to ensure that minor errors in the genetic code either only causes a silent mutation or an error that would not affect the amino acid's hydrophilic/hydrophobic property, eg. a codon of XUX (where X = any nucleotide) tends to code for hydrophobic amino acids. However, the genetic code is not perfect as minor changes such as the single-base substitution in sickle cell anaemia is disasterous. The hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val) which reduces the solubility of -globin. This causes haemoglobin to form linear polymers linked by the hydrophobic interaction between the valine groups causing sickle cell deformation of erythrocytes.

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 protein-coding sequences, since they do not often survive purifying selection .

Origin of the genetic code

Numerous variations of the standard genetic code are found in mitochondria, which are energy-producing organelles. 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 some species of bacteria and archaea, a few non-standard amino acids are substituted for standard stop codons; UGA can code for selenocysteine and UAG can code for pyrrolysine. There may be other non-standard interpretations that are not known.

Despite these variations, the genetic codes used by all known forms of life on Earth are very similar. Since there are many possible genetic codes that are thought to have similar utility to the one used by Earth life, the theory of evolution suggests that the genetic code was established very early in the history of life.

One can ask the question: is the genetic code completely random, just one set of codon-amino acid correspondences that happened to establish itself and be "frozen in" early in evolution, although functionally any other of the near-infinite set of possible transcription tables would have done just as well? Already a cursory look at the table shows patterns that suggest that this is not the case.

Recent aptamer experiments have shown that amino acids have indeed a selective chemical affinity for the base triplets that code for them. This suggests that the current, complex transcription mechanism involving tRNA and associated enzymes is a later development, and that originally, protein sequences were directly templated on base sequences. Also, evidence has been found that originally the number of different amino acids used may have been considerably smaller than today.2

References

There are several books available online that go into great detail on this topic. They are available through the NCBI Bookshelf, maintained by the United States National Institutes of Health. In particular the following books would be useful to consult:

Following are references cited in the text of the article.

Knight, R.D. and Landweber, L.F.  (1998).  Rhyme or reason: RNA-arginine interactions and the genetic code.  Chemistry & Biology 5(9), R215-R220.    PDF version of manuscript

Note 2: Brooks, Dawn J.; Fresco, Jacques R.; Lesk, Arthur M.; and Singh, Mona. (2002). Evolution of Amino Acid Frequencies in Proteins Over Deep Time: Inferred Order of Introduction of Amino Acids into the Genetic Code. Molecular Biology and Evolution 19, 1645-1655.

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