genetic code

The sequence of nucleotides in DNA or RNA that determines the specific amino acid sequence in the synthesis of proteins. It is the biochemical basis of heredity and nearly universal in all organisms.

The rules by which the base sequences of deoxyribonucleic acid (DNA) are translated into the amino acid sequences of proteins. Each sequence of DNA that codes for a protein is transcribed or copied into messenger ribonucleic acid (mRNA). Following the rules of the code, discrete elements in the mRNA, known as codons, specify each of the 20 different amino acids that are the constituents of proteins. During translation, another class of RNAs, called transfer RNAs (tRNAs), are coupled to amino acids, bind to the mRNA, and, in a step-by-step fashion provide the amino acids that are linked together in the order called for by the mRNA sequence. The specific attachment of each amino acid to the appropriate tRNA, and the precise pairing of tRNAs via their anticodons to the correct codons in the mRNA, form the basis of the genetic code. See also Deoxyribonucleic acid (DNA); Protein; Ribonucleic acid (RNA).

The genetic information in DNA is found in the sequence or order of four bases that are linked together to form each strand of the two-stranded DNA molecule. The bases of DNA are adenine, guanine, thymine, and cytosine, which are abbreviated as A, G, T, and C. Chemically, A and G are purines, and C and T are pyrimidines. The two strands of DNA are wound about each other in a double helix that looks like a twisted ladder. Each rung of the ladder is formed by two bases, one from each strand, that pair with each other by means of hydrogen bonds. For a good fit, a pyrimidine must pair with a purine; in DNA, A bonds with T, and G bonds with C. See also Purine; Pyrimidine.

Ribonucleic acids such as mRNA or tRNA also comprise four bases, except that in RNA the pyrimidine uracil (U) replaces thymine. During transcription a single-stranded mRNA copy of one strand of the DNA is made.

If two bases at a time are grouped together, then only 4 × 4 or 16 different combinations are possible, a number that is insufficient to code for all 20 amino acids that are found in proteins. However, if the four bases are grouped together in threes, then there are 4 × 4 × 4 or 64 different combinations. Read sequentially without overlapping, those groups of three bases constitute a codon, the unit that codes for a single amino acid.

The 64 codons can be divided into 16 families of four (see illustration), in which each codon begins with the same two bases. With the number of codons exceeding the number of amino acids, several codons can code for the same amino acid. Thus, the code is degenerate. In eight instances, all four codons in a family specify the same amino acid. In the remaining families, the two codons that end with the pyrimidines U and C often specify one amino acid, whereas the two codons that end with the purines A and G specify another. Furthermore, three of the codons, UAA, UAG, and UGA, do not code for any amino acid but instead signal the end of the protein chain.

phenylalanine (Phe), leucine (Leu), isoleucine (Ile), methionine (Met), valine (Val), serine (Ser), proline (Pro), threonine (Thr), alanine (Ala), tyrosine (Tyr), histidine (His), glutamine (Gln), asparagine (Asn), lysine (Lys), aspartic acid (Asp), glutamic acid (Glu), cysteine (Cys), tryptophan (Trp), arginine (Arg), and glycine (Gly).">
Universal (standard) genetic code. Each of the 64 codons found in mRNA specifies an amino acid (indicated by the common three-letter abbreviation) or the end of the protein chain (stop). The amino acids are phenylalanine (Phe), leucine (Leu), isoleucine (Ile), methionine (Met), valine (Val), serine (Ser), proline (Pro), threonine (Thr), alanine (Ala), tyrosine (Tyr), histidine (His), glutamine (Gln), asparagine (Asn), lysine (Lys), aspartic acid (Asp), glutamic acid (Glu), cysteine (Cys), tryptophan (Trp), arginine (Arg), and glycine (Gly).

On the ribosome, the nucleic acid code of an mRNA is converted into an amino acid sequence with the aid of tRNAs. These RNAs are relatively small nucleic acids, varying from 75 to 93 bases in length, that are folded in three dimensions to form an L-shaped molecule to which an amino acid can be attached. At the other end of the tRNA molecule, three bases are free to pair with a codon in the mRNA. These three bases of a tRNA constitute the anticodon. Each amino acid has one or more tRNAs, and because of the degeneracy of the code, many of the tRNAs for a specific amino acid have different anticodon sequences. However, the tRNAs for one amino acid are capable of pairing their anticodons only with the codon or codons in the mRNA that specify that amino acid. The tRNAs act as interpreters of the code, providing the correct amino acid in response to each codon by virtue of precise codon-anticodon pairing. The tRNAs pair with the codons and sequentially insert their amino acids in the exact order specified by the sequence of codons in the mRNA. See also Ribosomes.

The rules of the genetic code are virtually the same for all organisms, but there are some interesting exceptions. In the microorganism Mycoplasma capricolum, UGA is not a stop codon; instead it codes for tryptophan. This alteration in the code is also found in the mitochondria of some organisms. In addition to changes in the meanings of codons, a modified system for reading codons that requires fewer tRNAs is found in mitochondria. See also Gene; Gene action; Genetics.

The sequence of nucleotides in DNA determines the sequence of amino acids found in all proteins. Since there are only four nucleotide "letters" in the DNA alphabet (A, C, G, T, which stand for adenine, cytosine, guanine, and thymine), but there are 20 different amino acids in the protein alphabet, it is clear that more than one nucleotide must be used to specify an amino acid. Even two nucleotides read at a time would not give sufficient combinations (4 × 4 = 16) to encode all 20 amino acids plus start and stop signals. Therefore it would require a minimum of three DNA nucleotides to "spell out" one amino acid, and indeed this is the number that is actually used. RNA also uses a four letter alphabet when it reads and transcribes DNA instructions during protein synthesis, but its set of nucleotides is somewhat different, substituting U (uracil) for T (thymine).

Any single set of three nucleotides is called a codon, and the set of all possible three-nucleotide combinations is called "the genetic code" or "triplet code." There are sixty-four different combinations or codons (4 × 4 × 4 = 64). We now know that three codons (UAA, UAG, and UGA) specify a "stop" signal, indicating the termination of the polypeptide chain being synthesized on the ribosome. Each of the remaining sixty-one codons encodes an amino acid. The "start" signal is the codon AUG, which also encodes the amino acid methionine. The codons are read from the messenger RNA molecule during protein synthesis, and, consequently, they are given in RNA bases rather than in the original DNA sequence. The reading of the codons is shown in Figure 1.

Translation

The gene is represented by the sequences of bases in the DNA molecule, which can, in a sense, be thought of as a "storage molecule" for genetic information. DNA is extremely stable, a property critical to the maintenance of the integrity of the gene. This stability is evidenced by the fact that DNA has been extracted from Egyptian mummies and extinct animals such as the woolly mammoth. It can be extracted from dried blood or from a single hair at a crime scene.

Each cell contains a complete set of genes, but only certain of these genes are active or "expressed" at any one time. When a gene is active, a "disposable" copy is transcribed from the gene into codons contained in a messenger RNA (mRNA) molecule. Unlike the DNA molecule, the mRNA molecule is relatively unstable and short-lived. This is so that when a gene is turned off, the mRNA does not remain in the cell forever, running off more proteins on the ribosomes that are no longer needed by the cell.

Another RNA molecule, called transfer RNA (tRNA), contains a specific region called the anticodon. The tRNA anticodon can base pair with the codon region of the mRNA during protein synthesis, using the base pairing rules of A-U, U-A, C-G, and G-C. Each tRNA carries a specific amino acid. Thus the tRNA carrying methionine has a UAC anticodon that pairs with the AUG codon of the mRNA bound to the ribosome. Similarly the tRNA for proline has a GGA anticodon.

In examining the table of codons (Table 1) you will see that there is more than one codon for each amino acid, except for methionine (AUG) and tryptophan (UGG). Different codons that code for the same amino acid are said to be "synonyms," and the code is said to be "degenerate" in the sense that there is not a single, unique codon for each of the twenty amino acids.

The "Wobble" Hypothesis

Even before the genetic code had been elucidated, Francis Crick postulated that base pairing of the mRNA codons with the tRNA anticodons would require precision in the first two nucleotide positions but not so in the third position (the precise conformation of base pairs, which refers to the hydrogen bonding between A-T (A-U in RNA) and C-G pairs is known as Watson-Crick base pairing). The third position, in general, would need to be only a purine (A or G) or a pyrimidine (C or U). Crick called this phenomenon "wobble."

This less-than-precise base pairing would require fewer tRNA species. For example, tRNA^Glu could pair with either GAA or GAG codons. In looking at the codon table, one can see that, for the most part, the first two letters are important to specify the particular amino acid. The only exceptions are AUG (Met) and UGG (Trp) which, as indicated above, have only one codon each.

The Code Has No Gaps or Overlaps

The 1960s were an exciting time for molecular biologists, for it was then that the genetic code was broken. Two possibilities had to be considered for the genetic code. It was possible that the code had gaps, that is, some sort of punctuation mark or a "spacer" nucleotide or nucleotides between coding groups. Second, the code could be either overlapping or nonoverlapping. These possibilities are illustrated in Figures 2 and 3. An overlapping code would have the advantage that more information could be contained in a smaller space.

However, in overlapping code a mutation that changed one base would lead to the changing of three consecutive amino acids in the protein sequence. Genetic evidence, available even before the code had been deciphered, indicated that a single point mutation, that is, a change in a single nucleotide, affected only one amino acid and thus suggested a nonoverlapping code.

Another possibility was that the code had punctuation marks, that is, a base (indicated by "p" in Figure 3) acting as a comma that would separate each codon. In this situation, if an additional base were inserted into a codon, then only that codon would be affected. In a code without punctuations or gaps, however, insertion of a single nucleotide would result in all codons from that point on being affected. This would in turn change the amino acid sequence in the protein from that point on. Again, genetic evidence ruled out a punctuated code, as base insertions do, in fact, affect the entire protein from the insertion point on, rather than just a single amino acid. This effect is called a frameshift mutation.

In the late 1970s DNA sequencing techniques were developed. A number of proteins had already been sequenced by protein sequencing methods. When the genes for these proteins were cloned and sequenced, the predicted protein sequence could be deduced. Agreement between the DNA and protein sequences confirmed the accuracy of the genetic code.

Exceptions to the Universal Genetic Code

After the original genetic code of E. coli was completed in 1968, the genetic code was subsequently determined for many other organisms ranging from bacteria to mammals, including humans. The codons were found to be the same for all organisms, leading to the idea that the genetic code is "universal." Furthermore, it also suggested that life on Earth had a single evolutionary origin, otherwise there would have been numerous genetic codes. The code was established during evolution, probably by chance, as there are no compelling reasons one codon should prevail over another. After it was established, any subsequent changes in the code would prove to be lethal, for if one codon changed, then all similar codons in the entire organism's genome would have to change simultaneously—a highly unlikely possibility.

Thus, it was surprising to find that there are, in fact, a few rare exceptions to the universal code. These exceptions are listed in Table 2. Most of these exceptions are found in the mitochondrial genome. The mitochondrion is thought to have evolved from an endosymbiotic bacterium at the time when the eukaryotic cell first arose. The mitochondrial genome is small, and most of the genes of the original endosymbiont have migrated to the nucleus.

Table 1

In examining the exceptions to the universal genetic code in Table 2, you can see that there are only a few changes, most notably the use of a standard "stop" codon to encode an amino acid. For example, UGA normally is a stop codon. But in the mitochondria of the fruit fly Drosophila melanogaster, it encodes the amino acid tryptophan.

A few additional exceptions to the universal genetic code have also been identified. These include the nuclear genome of a few protozoan species and also in the bacterium Mycoplasma capricolum. These exceptions, however, do not imply multiple evolutionary origins of life. What is most striking is that the "exceptional" meanings of most of the codons are identical across all the organisms in which they are found, not different. Had there been multiple origins, we would expect to see drastically different genetic codes in these exceptional organisms.

Bibliography

"The Genetic Code." Cold Spring Harbor Symposia on Quantitative Biology, vol. 31. Cold Spring Harbor, NY: Cold Spring Harbor Press, 1966.

Kay, Lily E. Who Wrote the Book of Life? A History of the Genetic Code. Stanford, CA: Stanford University Press, 2000.

Nirenberg, M. W., and J. H. Matthaei. "The Dependence of Cell-Free Protein Synthesis in E. coli upon Naturally Occurring or Synthetic Polyribonucleotides." Proceedings of the National Academy of Sciences 47 (1961): 1588-1602.

—Ralph R. Meyer

For more information on genetic code, visit Britannica.com.

The genetic code is a chart depicting the relationship between each of the possible mRNA codons and their associated amino acids. The codons are grouped according to the amino acid they code for. Present in the code as well are the "start" and "stop" codons. The start codon actually codes for methionine, which is always the first amino acid in the polypeptide sequence. Methionine may appear elsewhere in the polypeptide as well. Methionine is removed during post-translational processing.

Although the genetic code is not a "code" in the sense normally used in intelligence and espionage terminology, a fundamental understanding of the genetic code is essential to understanding the molecular basis of advanced DNA and genetic tests that are increasingly important in forensic science and identification technology.

The genetic information that is passed on from parent to offspring is carried by the DNA of a cell. The genes on the DNA code for specific proteins that determine appearance, different facets of personality, health etc. In order for the genes to produce the proteins, it must first be transcribed from DNA to RNA in a process known as transcription. Thus, transcription is defined as the transfer of genetic information from the DNA to the RNA. Translation is the process in which genetic information, carried by messenger RNA (mRNA), directs the synthesis of proteins from amino acids, whereby the primary structure of the protein is determined by the nucleotide sequence in the mRNA.

The genetic code is the set of correspondences between the nucleotide sequences of nucleic acids such as deoxyribonucleic acid (DNA), and the amino acid sequences of proteins (polypeptides). These correspondences enable the information encoded in the chemical components of DNA to be transferred to the ribonucleic acid messenger (mRNA) and then used to establish the correct sequence of amino acids in the polypeptide. The elements of the encoding system, the nucleotides, differ by only four different bases. These are known as adenine (A), guanine,(G), thymine (T) and cytosine (C), in DNA or uracil (U) in RNA. Thus RNA contains U in the place of C and the nucleotide sequence of DNA acts as a template for the synthesis of a complementary sequence of RNA, a process known as transcription. For historical reasons, the term genetic code in fact refers specifically to the sequence of nucleotides in mRNA, although today it is sometimes used interchangeably with the coded information in DNA.

Proteins found in nature consist of 20 naturally occurring amino acids. One important question is, how can four nucleotides code for 20 amino acids? This question was raised by scientists in the 1950s soon after the discovery that the DNA comprised the hereditary material of living organisms. It was reasoned that if a single nucleotide coded for one amino acid, then only four amino acids could be provided for. Alternatively, if two nucleotides specified one amino acid, then there could be a maximum number of 16 (4²) possible arrangements. If, however, three nucleotides coded for one amino acid, then there would be 64 (4³) possible permutations, more than enough to account for all the 20 naturally occurring amino acids. The latter suggestion was proposed by the Russian born physicist, George Gamow (1904–1968) and was later proved to be correct. It is now well known that every amino acid is coded by at least one nucleotide triplet or codon, and that some triplet combinations function as instructions for the termination or initiation of translation. Three combinations in tRNA, UAA, UGA and UAG, are termination codons, while AUG is a translation start codon.

The genetic code was solved between 1961 and 1963. The American scientist Marshall Nirenberg (1927–), working with his colleague Heinrich Matthaei, made the first breakthrough when they discovered how to make synthetic mRNA. They found that if the nucleotides of RNA carrying the four bases A, G, C and U, were mixed in the presence of the enzyme polynucleotide phosphorylase, a single stranded RNA was formed in the reaction, with the nucleotides being incorporated at random. This offered the possibility of creating specific mRNA sequences and then seeing which amino acids they would specify. The first synthetic mRNA polymer obtained contained only uracil (U) and when mixed in vitro with the protein synthesizing machinery of Escherichia coli it produced a polyphenylalanine—a string of phenylalanine. From this it was concluded that the triplet UUU coded for phenylalanine. Similarly, a pure cytosine (C) RNA polymer produced only the amino acid proline, so the corresponding codon for cytosine had to be CCC. This type of analysis was refined when nucleotides were mixed in different proportions in the synthetic mRNA and a statistical analysis was used to determine the amino acids produced. It was quickly found that a particular amino acid could be specified by more than one codon. Thus, the amino acid serine could be produced from any one of the combinations UCU, UCC, UCA, or UCG. In this way the genetic code is said to be degenerate, meaning that each of the 64 possible triplets have some meaning within the code and that several codons may encode a single amino acid.

This work confirmed the ideas of the British scientists Francis Crick (1916–) and Sydney Brenner (1927–). Brenner and Crick were working with mutations in the bacterial virus bacteriophage T4 and found that the deletion of a single nucleotide could abolish the function of a specific gene. However, a second mutation in which a nucleotide was inserted at a different, but nearby position, restored the function of that gene. These two mutations are said to be suppressors of each other, meaning that they cancel each other's mutant properties. It was concluded from this that the genetic code was read in a sequential manner starting from a fixed point in the gene. The insertion or deletion of a nucleotide shifted the reading frame in which succeeding nucleotides were read as codons, and was thus termed a frameshift mutation. It was also found that whereas two closely spaced deletions, or two closely spaced insertions, could not suppress each other, three closely spaced deletions or insertions could do so. Consequently, these observations established the triplet nature of the genetic code. The reading frame of a sequence is the way in which the sequence is divided into the triplets and is determined by the precise point at which translation is initiated. For example, the sequence CATCATCAT can be read CAT CAT CAT or C ATC ATC AT or CA TCA TCA T in the three possible reading frames. Sometimes, as in particular bacterial viruses, genes have been found that are contained within other genes. These are translated in different reading frames so the amino acid sequences of the proteins encoded by them are different. Such economy of genetic material is, however, quite rare.

The same genetic code appears to operate in all living things, but exceptions to this universality are known. In human mitochondrial mRNA, AGA and AGG are termination or stop codons. Other differences also exist in the correspondences between certain codon sequences and amino acids.

Further Reading

Books

Brenner, Sydney. My Life in Science. London: BioMed Central, Ltd., 2001.

Davies, Kevin. Cracking The Genome: Inside The Race To Unlock Human DNA. New York: Free Press, 2001.

Watson, James D. The Double Helix: A Personal Account of the Discovery of the Structure of DNA. Westport, CT: Touchstone Books, 2001.

——. DNA: The Secret of Life. New York: Knopf, 2003.

The code that translates the sequence of nucleotides in genes along the DNA strand into the structure of protein, which, through its action as an enzyme, governs one chemical reaction in the cell. A simple mnemonic is “One gene codes for one protein which runs one reaction.”

For a non-technical introduction to the topic, see Introduction to Genetics.

A series of codons in part of a mRNA molecule. Each codon consists of three nucleotides, usually representing a single amino acid.

The genetic code is the set of rules by which information encoded in genetic material (DNA or RNA sequences) is translated into proteins (amino acid sequences) by living cells. A more precise term for the concept might be "genetic cipher"^[1]. The code defines a mapping between tri-nucleotide sequences, called codons, and amino acids. A triplet codon in a nucleic acid sequence usually specifies a single amino acid (though in some cases the same codon triplet in different locations can code unambiguously for two different amino acids, the correct choice at each location being determined by context)^[2]. Because the vast majority of genes are encoded with exactly the same code (see the RNA codon table), this particular code is often referred to as the canonical or standard genetic code, or simply the genetic code, though in fact there are many variant codes. Thus the canonical genetic code is not universal. For example, in humans, protein synthesis in mitochondria relies on a genetic code that varies from the canonical code.

It is important to know that not all genetic information is stored using the genetic code. All organisms' DNA contain regulatory sequences, intergenic segments, and chromosomal structural areas that can contribute greatly to phenotype but operate using distinct sets of rules that may or may not be as straightforward as the codon-to-amino acid paradigm that usually underlies the genetic code (see epigenetics).

Contents 1 Cracking the genetic code 2 Transfer of information via the genetic code 3 RNA codon table 4 Salient features 4.1 Sequence reading frame 4.2 Start/stop codons 4.3 Effect of mutations 4.4 Degeneracy of the genetic code 5 Variations to the standard genetic code 5.1 Expanded genetic code 6 Theories on the origin of the genetic code 7 See also 8 References 9 Further reading 10 External links

Cracking the genetic code

The genetic code

After the structure of DNA was deciphered by James Watson, Francis Crick, Maurice Wilkins and Rosalind Franklin, serious efforts to understand the nature of the encoding of proteins began. George Gamow postulated that a three-letter code must be employed to encode the 20 standard amino acids used by living cells to encode proteins (because 3 is the smallest integer n such that 4ⁿ is at least 20).

The fact that codons did consist of three DNA bases was first demonstrated in the Crick, Brenner et al. experiment. The first elucidation of a codon was done by Marshall Nirenberg and Heinrich J. Matthaei in 1961 at the National Institutes of Health. They used a cell-free system to translate a poly-uracil RNA sequence (or UUUUU... in biochemical terms) and discovered that the polypeptide that they had synthesized consisted of only the amino acid phenylalanine. They thereby deduced from this poly-phenylalanine that the codon UUU specified the amino-acid phenylalanine. Extending this work, Nirenberg and Philip Leder were able to elucidate the triplet nature of the genetic code and allowed the codons of the standard genetic code to be deciphered. In these experiments, various combinations of mRNA were passed through a filter which contained ribosomes. Unique triplets promoted the binding of specific tRNAs to the ribosome. Leder and Nirenberg were able to determine the sequences of 54 out of 64 codons.

Subsequent work by Har Gobind Khorana identified the rest of the code, and shortly thereafter Robert W. Holley determined the structure of transfer RNA, the adapter molecule that facilitates translation. This work was based upon earlier studies by Severo Ochoa, who received the Nobel prize in 1959 for his work on the enzymology of RNA synthesis. In 1968, Khorana, Holley and Nirenberg received the Nobel Prize in Physiology or Medicine for their work.

Transfer of information via the genetic code

The genome of an organism is inscribed in DNA, or in some viruses RNA. The portion of the genome that codes for a protein or an RNA is referred to as a gene. Those genes that code for proteins are 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. 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 the double-helix configuration, two strands of DNA are joined to each other by hydrogen bonds in an arrangement known as base pairing. These bonds almost always form between an adenine base on one strand and a thymine on the other strand and between a cytosine base on one strand and a guanine base on the other. This means that the number of A and T residues will be the same in a given double helix, as will the number of G and C residues. In RNA, thymine (T) is replaced by uracil (U), and the deoxyribose is substituted by ribose.

Each protein-coding gene is transcribed into a template molecule of the related polymer RNA, known as messenger RNA or mRNA. This, in turn, is translated on the ribosome into an amino acid chain or polypeptide. The process of translation requires transfer RNAs specific for individual amino acids with the amino acids covalently attached to them, guanosine triphosphate as an energy source, and a number of translation factors. tRNAs have anticodons complementary to the codons in mRNA and can be "charged" covalently with amino acids at their 3' terminal CCA ends. Individual tRNAs are charged with specific amino acids by enzymes known as aminoacyl tRNA synthetases, which have high specificity for both their cognate amino acids and tRNAs. The high specificity of these enzymes is a major reason why the fidelity of protein translation is maintained.

There are 4³ = 64 different codon combinations possible with a triplet codon of three nucleotides; all 64 codons are assigned for either amino acids or stop signals during translation. If, for example, an RNA sequence, UUUAAACCC is considered and the reading-frame starts with the first U (by convention, 5' to 3'), there are three codons, namely, UUU, AAA and CCC, each of which specifies one amino acid. This RNA sequence will be translated into an amino acid sequence, three amino acids long. A comparison may be made with computer science, where the codon is similar to a word, which is the standard "chunk" for handling data (like one amino acid of a protein), and a nucleotide is similar to a bit, in that it is the smallest unit.

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, and UGU and UGC represent cysteine (standard three-letter designations, Asn and Cys, respectively).

RNA codon table

nonpolar

polar

basic

acidic

(stop codon)

The table shows the 64 codons and the amino acid for each. The direction of the mRNA is 5' to 3'.

		2nd base
		U	C	A	G
1st base	U	UUU (Phe/F) Phenylalanine UUC (Phe/F) Phenylalanine	UCU (Ser/S) Serine UCC (Ser/S) Serine	UAU (Tyr/Y) Tyrosine UAC (Tyr/Y) Tyrosine	UGU (Cys/C) Cysteine UGC (Cys/C) Cysteine
		UUA (Leu/L) Leucine	UCA (Ser/S) Serine	UAA Ochre (Stop)	UGA Opal (Stop)
		UUG (Leu/L) Leucine	UCG (Ser/S) Serine	UAG Amber (Stop)	UGG (Trp/W) Tryptophan
	C	CUU (Leu/L) Leucine CUC (Leu/L) Leucine	CCU (Pro/P) Proline CCC (Pro/P) Proline	CAU (His/H) Histidine CAC (His/H) Histidine	CGU (Arg/R) Arginine CGC (Arg/R) Arginine
		CUA (Leu/L) Leucine CUG (Leu/L) Leucine	CCA (Pro/P) Proline CCG (Pro/P) Proline	CAA (Gln/Q) Glutamine CAG (Gln/Q) Glutamine	CGA (Arg/R) Arginine CGG (Arg/R) Arginine
	A	AUU (Ile/I) Isoleucine AUC (Ile/I) Isoleucine	ACU (Thr/T) Threonine ACC (Thr/T) Threonine	AAU (Asn/N) Asparagine AAC (Asn/N) Asparagine	AGU (Ser/S) Serine AGC (Ser/S) Serine
		AUA (Ile/I) Isoleucine	ACA (Thr/T) Threonine	AAA (Lys/K) Lysine	AGA (Arg/R) Arginine
		AUG[A] (Met/M) Methionine	ACG (Thr/T) Threonine	AAG (Lys/K) Lysine	AGG (Arg/R) Arginine
	G	GUU (Val/V) Valine GUC (Val/V) Valine	GCU (Ala/A) Alanine GCC (Ala/A) Alanine	GAU (Asp/D) Aspartic acid GAC (Asp/D) Aspartic acid	GGU (Gly/G) Glycine GGC (Gly/G) Glycine
		GUA (Val/V) Valine GUG (Val/V) Valine	GCA (Ala/A) Alanine GCG (Ala/A) Alanine	GAA (Glu/E) Glutamic acid GAG (Glu/E) Glutamic acid	GGA (Gly/G) Glycine GGG (Gly/G) Glycine

^A  The 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^[3].

Inverse table

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	STOP	UAA, UGA, UAG

Salient features

Sequence reading frame

A codon is defined by the initial nucleotide from which translation starts. For example, the string GGGAAACCC, if read from the first position, contains the codons GGG, AAA and CCC; and, if read from the second position, it contains the codons GGA and AAC; if read starting from the third position, GAA and ACC. Partial codons have been ignored in this example. Every sequence can thus be read in three reading frames, each of which will produce a different amino acid sequence (in the given example, Gly-Lys-Pro, Gly-Asn, or Glu-Thr, respectively). With double-stranded DNA there are six possible reading frames, three in the forward orientation on one strand and three reverse (on the opposite strand).

The actual frame in which a protein sequence is translated is defined by a start codon, usually the first AUG codon in the mRNA sequence. Mutations that disrupt the reading frame by insertions or deletions of a non-multiple of 3 nucleotide bases are known as frameshift mutations. These mutations may impair the function of the resulting protein, if it is formed, and are thus rare in in vivo protein-coding sequences. Often such misformed proteins are targeted for proteolytic degradation. In addition, a frame shift mutation is very likely to cause a stop codon to be read, which truncates the creation of the protein.^[4] One reason for the rareness of frame-shifted mutations' being inherited is that, if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause lethality before the organism is viable.

Start/stop codons

Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process. Nearby sequences (such as the Shine-Dalgarno sequence in E. Coli) and initiation factors are also required to start translation. The most common start codon is AUG which is read as methionine or, in bacteria, as formylmethionine. Alternative start codons (depending on the organism), include "GUG" or "UUG", which normally code for valine or leucine. However, when used as a start codon, these alternative start codons are translated as methionine or formylmethionine.^[5]

The three stop codons have been given names: UAG is amber, UGA is opal (sometimes also called umber), and UAA is ochre. "Amber" was named by discoverers Richard Epstein and Charles Steinberg after their friend Harris Bernstein, whose last name means "amber" in German. The other two stop codons were named "ochre" and "opal" in order to keep the "color names" theme. Stop codons are also called "termination" or "nonsense" codons and they signal release of the nascent polypeptide from the ribosome due to binding of release factors in the absence of cognate tRNAs with anticodons complementary to these stop signals.^[6]

Effect of mutations

Selection of notable mutations.^[7]

Frameshift mutations altering the sequence reading frame, and nonsense mutations causing a stop codon are examples of point mutations. In addition, there may be missense mutations that cause exchange of one amino acid for another. Clinically important missense mutations generally change the properties of the coded amino acid residue between being basic, acidic polar or nonpolar, while nonsense mutations result in a stop codon.

Degeneracy of the genetic code

The genetic code has redundancy but no ambiguity (see the codon tables above for the full correlation). For example, although codons GAA and GAG both specify glutamic acid (redundancy), neither of them specifies any other amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example the amino acid glutamic acid is specified by GAA and GAG codons (difference in the third position), the amino acid leucine is specified by UUA, UUG, CUU, CUC, CUA, CUG codons (difference in the first or third position), while the amino acid serine is specified by UCA, UCG, UCC, UCU, AGU, AGC (difference in the first, second or third position).

A position of a codon is said to be a fourfold degenerate site if any nucleotide at this position specifies the same amino acid. For example, the third position of the glycine codons (GGA, GGG, GGC, GGU) is a fourfold degenerate site, because all nucleotide substitutions at this site are synonymous; i.e., they do not change the amino acid. Only the third positions of some codons may be fourfold degenerate. A position of a codon is said to be a twofold degenerate site if only two of four possible nucleotides at this position specify the same amino acid. For example, the third position of the glutamic acid codons (GAA, GAG) is a twofold degenerate site. In twofold degenerate sites, the equivalent nucleotides are always either two purines (A/G) or two pyrimidines (C/U), so only transversional substitutions (purine to pyrimidine or pyrimidine to purine) in twofold degenerate sites are nonsynonymous. A position of a codon is said to be a non-degenerate site if any mutation at this position results in amino acid substitution. There is only one threefold degenerate site where changing three of the four nucleotides may have no effect on the amino acid (depending on what it is changed to), while changing the fourth possible nucleotide always results in an amino acid substitution. This is the third position of an isoleucine codon: AUU, AUC, or AUA all encode isoleucine, but AUG encodes methionine. In computation this position is often treated as a twofold degenerate site.

There are three amino acids encoded by six different codons: serine, leucine, arginine. 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 translation; the other is tryptophan, specified by the codon UGG. The degeneracy of the genetic code is what accounts for the existence of synonymous mutations.

Degeneracy results because a triplet code designates 20 amino acids and a stop codon. Because there are four bases, triplet codons are required to produce at least 21 different codes. For example, if there were two bases per codon, then only 16 amino acids could be coded for (4²=16). Because at least 21 codes are required, then 4³ gives 64 possible codons, meaning that some degeneracy must exist.

These properties of the genetic code make it more fault-tolerant for point mutations. For example, in theory, fourfold degenerate codons can tolerate any point mutation at the third position, although codon usage bias restricts this in practice in many organisms; twofold 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 twofold degenerate sites adds a further fault-tolerance.

Grouping of codons by amino acid residue molar volume and hydropathy.

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 protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathy; NAN encodes average size hydrophilic residues; UNN encodes residues that are not hydrophilic.^[8][9] These tendencies may result from that the aminoacyl tRNA synthetases related the such codons share a common ancestry.

Even so, single point mutations can still cause dysfunctional proteins. For example, a mutated hemoglobin gene causes sickle-cell disease. In the mutant hemoglobin a hydrophilic glutamate (Glu) is substituted by the hydrophobic valine (Val), that is, GAA or GAG becomes GUA or GUG. The substitution of glutamate by valine reduces the solubility of β-globin which 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 way similar to thalassemia), as heterozygous people have some resistance to the malarial Plasmodium parasite (heterozygote advantage).

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

Variations to the standard genetic code

While slight variations on the standard code had been predicted earlier,^[10] none were discovered until 1979, when researchers studying human mitochondrial genes discovered they used an alternative code. Many slight variants have been discovered since,^[11] including various alternative mitochondrial codes,^[12] as well as small variants such as Mycoplasma translating the codon UGA as tryptophan and Candida species translating CUG as a serine rather than a leucine.^[13][14] In bacteria and archaea, GUG and UUG are common start codons. However, in rare cases, certain specific proteins may use alternative initiation (start) codons not normally used by that species.^[15]

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 as discussed in the relevant articles. Selenocysteine is now viewed as the 21st amino acid, and pyrrolysine is viewed as the 22nd. A detailed description of variations in the genetic code can be found at the NCBI web site.

Notwithstanding these differences, all known codes have strong similarities to each other, and the coding mechanism is the same for all organisms: three-base codons, tRNA, ribosomes, reading the code in the same direction and translating the code three letters at a time into sequences of amino acids.

Expanded genetic code

Main article: Expanded genetic code

Since 2001, 40 non-natural amino acids have been added into protein by creating a unique codon (recoding) and a corresponding transfer-RNA:aminoacyl – tRNA-synthetase pair to encode it with diverse physicochemical and biological properties in order to be used as a tool to exploring protein structure and function or to create novel or enhanced protein.^[16]

Theories on the origin of the genetic code

Despite the variations that exist, the genetic codes used by all known forms of life 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. Phylogenetic analysis of transfer RNA suggests that tRNA molecules evolved before the present set of aminoacyl-tRNA synthetases.^[17]

The genetic code is not a random assignment of codons to amino acids.^[18] For example, amino acids that share the same biosynthetic pathway tend to have the same first base in their codons,^[19] and amino acids with similar physical properties tend to have similar codons.^[20][21]

There are four themes running through the many theories that seek to explain the evolution of the genetic code (and hence the origin of these patterns).^[22]:

• Recent aptamer experiments show that some amino acids have a selective chemical affinity for the base triplets that code for them.^[23] This suggests that the current complex translation mechanism involving tRNA and associated enzymes may be a later development, and that originally, protein sequences were directly templated on base sequences.
• That the standard modern genetic code grew from a simpler earlier code through a process of "biosynthetic expansion". Here the idea is that primordial life 'discovered' new amino acids (e.g., as by-products of metabolism) and later back-incorporated some of these into the machinery of genetic coding. Although much circumstantial evidence has been found to suggest that fewer different amino acids were used in the past than today,^[24] precise and detailed hypotheses about exactly which amino acids entered the code in exactly what order has proved far more controversial.^[25][26]
• That natural selection has led to codon assignments of the genetic code that minimize the effects of mutations.^[27]
• That viral agents that are competent in molecular syntax generate, arrange, rearrange and repair nucleotide sequences. According to the theory of biocommunication randomly derived mixtures of nucleotides (mutations) therefore doesn't play important roles in the evolution of the genetic code,^[28]

See also

• Codon Dictionary

References

1. ^ Crick, Francis (1988). What mad pursuit. HarperCollinsPublishers. p. 90. ISBN 0-465-09138-5. 
2. ^ Turanov AA, Lobanov AV, Fomenko DE, et al. (January 2009). "Genetic code supports targeted insertion of two amino acids by one codon". Science 323 (5911): 259–61. doi:10.1126/science.1164748. PMID 19131629. http://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=19131629. 
3. ^ Nakamoto T (March 2009). "Evolution and the universality of the mechanism of initiation of protein synthesis". Gene 432 (1-2): 1–6. doi:10.1016/j.gene.2008.11.001. PMID 19056476. http://linkinghub.elsevier.com/retrieve/pii/S0378-1119(08)00570-2. 
4. ^ Isbrandt D, Hopwood JJ, von Figura K, Peters C (1996). "Two novel frameshift mutations causing premature stop codons in a patient with the severe form of Maroteaux-Lamy syndrome". Hum. Mutat. 7 (4): 361–3. doi:10.1002/(SICI)1098-1004(1996)7:4<361::AID-HUMU12>3.0.CO;2-0 (inactive 2009-07-09). PMID 8723688. 
5. ^ Touriol C, Bornes S, Bonnal S, et al. (2003). "Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons". Biology of the cell / under the auspices of the European Cell Biology Organization 95 (3-4): 169–78. PMID 12867081. 
6. ^ How nonsense mutations got their names
7. ^ References for the image are found in Wikimedia Commons page at: Commons:File:Notable mutations.svg#References.
8. ^ Yang et al. (1990). Michel-Beyerle, M. E.. ed. Reaction centers of photosynthetic bacteria: Feldafing-II-Meeting. 6. Berlin: Springer-Verlag. pp. 209–18. ISBN 3-540-53420-2. 
9. ^ Füllen G, Youvan DC (1994). "Genetic Algorithms and Recursive Ensemble Mutagenesis in Protein Engineering". Complexity International 1. http://www.complexity.org.au/ci/vol01/fullen01/html/. 
10. ^ Crick FHC, Orgel LE (1973). "Directed panspermia". Icarus 19: 341–6. doi:10.1016/0019-1035(73)90110-3. "It is a little surprising that organisms with somewhat different codes do not coexist.".  (p. 344) (Further discussion)
11. ^ NCBI: "The Genetic Codes", Compiled by Andrzej (Anjay) Elzanowski and Jim Ostell
12. ^ Jukes TH, Osawa S (December 1990). "The genetic code in mitochondria and chloroplasts". Experientia 46 (11-12): 1117–26. doi:10.1007/BF01936921. PMID 2253709. 
13. ^ Santos, M.A.; Tuite, M.F. (1995). "The CUG codon is decoded in vivo as serine and not leucine in Candida albicans". Nucleic Acids Research 23: 1481–6. doi:10.1093/nar/23.9.1481. PMID 7784200. 
14. ^ Butler, G. et al. (2009). "Evolution of pathogenicity and sexual reproduction in eight Candida genomes". Nature 459: 657–62. doi:10.1038/nature08064. PMID 19465905. 
15. ^ Genetic Code page in the NCBI Taxonomy section (Downloaded 27 April 2007.)
16. ^ Xie J, Schultz PG. Adding amino acids to the genetic repertoire. Curr Opin Chem Biol. 2005 Dec;9(6):548-54. Epub 2005 Nov 2. Review. PMID: 16260173
    Wang Q, Parrish AR, Wang L. Expanding the genetic code for biological studies. Chem Biol. 2009 Mar 27;16(3):323-36. Review. PMID: 19318213
17. ^ De Pouplana, L.R.; Turner, R.J.; Steer, B.A.; Schimmel, P. (1998). "Genetic code origins: tRNAs older than their synthetases?". Proceedings of the National Academy of Sciences 95 (19): 11295. doi:10.1073/pnas.95.19.11295. PMID 9736730. http://www.pnas.org/cgi/content/full/95/19/11295. 
18. ^ Freeland SJ, Hurst LD (September 1998). "The genetic code is one in a million". J. Mol. Evol. 47 (3): 238–48. doi:10.1007/PL00006381. PMID 9732450. http://link.springer-ny.com/link/service/journals/00239/bibs/47n3p238.html. 
19. ^ Taylor FJ, Coates D (1989). "The code within the codons". BioSystems 22 (3): 177–87. doi:10.1016/0303-2647(89)90059-2. PMID 2650752. 
20. ^ Di Giulio M (October 1989). "The extension reached by the minimization of the polarity distances during the evolution of the genetic code". J. Mol. Evol. 29 (4): 288–93. doi:10.1007/BF02103616. PMID 2514270. 
21. ^ Wong JT (February 1980). "Role of minimization of chemical distances between amino acids in the evolution of the genetic code". Proc. Natl. Acad. Sci. U.S.A. 77 (2): 1083–6. doi:10.1073/pnas.77.2.1083. PMID 6928661. 
22. ^ Knight RD, Freeland SJ, Landweber LF (June 1999). "Selection, history and chemistry: the three faces of the genetic code". Trends Biochem. Sci. 24 (6): 241–7. doi:10.1016/S0968-0004(99)01392-4. PMID 10366854. http://linkinghub.elsevier.com/retrieve/pii/S0968-0004(99)01392-4. 
23. ^ Knight RD, Landweber LF (September 1998). "Rhyme or reason: RNA-arginine interactions and the genetic code". Chem. Biol. 5 (9): R215–20. doi:10.1016/S1074-5521(98)90001-1. PMID 9751648. http://linkinghub.elsevier.com/retrieve/pii/S1074-5521(98)90001-1. 
24. ^ Brooks DJ, Fresco JR, Lesk AM, Singh M (October 2002). "Evolution of amino acid frequencies in proteins over deep time: inferred order of introduction of amino acids into the genetic code". Mol. Biol. Evol. 19 (10): 1645–55. PMID 12270892. http://mbe.oupjournals.org/cgi/content/full/19/10/1645. 
25. ^ Amirnovin R (May 1997). "An analysis of the metabolic theory of the origin of the genetic code". J. Mol. Evol. 44 (5): 473–6. doi:10.1007/PL00006170. PMID 9115171. http://link.springer-ny.com/link/service/journals/00239/bibs/44n5p473.html. 
26. ^ Ronneberg TA, Landweber LF, Freeland SJ (December 2000). "Testing a biosynthetic theory of the genetic code: fact or artifact?". Proc. Natl. Acad. Sci. U.S.A. 97 (25): 13690–5. doi:10.1073/pnas.250403097. PMID 11087835. PMC 17637. http://www.pnas.org/cgi/content/full/97/25/13690. 
27. ^ Freeland SJ, Wu T, Keulmann N (October 2003). "The case for an error minimizing standard genetic code". Orig Life Evol Biosph 33 (4-5): 457–77. doi:10.1023/A:1025771327614. PMID 14604186. http://www.kluweronline.com/art.pdf?issn=0169-6149&volume=33&page=457. 
28. ^ Witzany, G (2009) Biocommunication and Natural Genome Editing. Springer, Netherlands.

Further reading

• Griffiths, Anthony J. F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. (1999). An Introduction to genetic analysis (7th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-3771-X. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=iga.TOC. 
• Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter (2002). Molecular biology of the cell (4th ed.). New York: Garland Science. ISBN 0-8153-3218-1. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2. 
• Lodish, Harvey F.; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. (2000). Molecular cell biology (4th ed.). San Francisco: W.H. Freeman. ISBN 0-7167-3706-X. http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mcb.TOC. 

External links

• The Genetic Codes → Genetic Code Tables
• Online DNA → Amino Acid Converter
• Online DNA Sequence → Protein Sequence converter
• Online DNA to protein translation (6 frames/17+ genetic codes)
• The Codon Usage Database → Codon frequency tables for many organisms
• Symmetries in the genetic code

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