genetic code

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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.

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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

EXCEPTIONS TO THE UNIVERSAL GENETIC CODE
Organism	Normal codon	Usual meaning	New meaning
Mammalian	AGA, AGG	Arginine	Stop codon
mitochondria	AUA	Isoleucine	Methionine
	UGA	Stop codon	Tryptophan
Drosophila	AGA, AGG	Arginine	Serine
mitochondria	AUA	Isoleucine	Methionine
	UGA	Stop codon	Tryptophan
Yeast	AUA	Isoleucine	Methionine
mitochondria	UGA	Stop codon	Tryptophan
	CUA, CUC, CUG, CUU	Leucine	Threonine
Higher plant	UGA	Stop codon	Tryptophan
mitochondria	CGG	Arginine	Tryptophan
Protozoan nuclei	UAA, UAG	Stop codons	Glutamine
Mycoplasma capricolum bacteria	UGA	Stop codon	Tryptophan

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

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.

Previous question:	What is a codon?
Next question:	What is a stop codon?

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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.”

All living things share the same genetic code, a fact that represents strong evidence for evolution. Unraveling the genetic code was one of the great scientific achievements of the twentieth century, and it opened the way to genetic engineering.

all the regularities in nucleotide sequence according to which genetic information for the sequences of all the polypeptides synthesized by transcription and translation is encoded in DNA (or RNA in some viruses). A sequence of three nucleotide residues (a codon) is required to code for one amino-acid residue, and since there are four different kinds of base in nucleic acids (apart from minor constituents), 4³ i.e. 64 different nucleotide triplets can exist. But only 20 different amino-acid residues in polypeptides can be coded for; therefore the code is degenerate in that most amino acids can be specified by more than one codon. In terms of the sequence of nucleotides in mRNA, i.e. the nucleotides complementary to those in the genetic material, the genetic code, reading from the 5′ end to the 3′ end of each codon, is given in the table. (The letter A symbolizes a nucleotide residue containing adenine; G, guanine; C, cytosine; and U, uracil; each amino-acid residue is represented by its usual three-letter symbol.)

UUU:Phe	UCU:Ser	UAU:Tyr	UGU:Cys
UUC:Phe	UCC:Ser	UAC:Tyr	UGC:Cys
UUA:Leu	UCA:Ser	UAA:Ter†	UGA:Ter†
UUG:Leu	UCG:Ser	UAG:Ter†	UGG:Trp
CUU:Leu	CCU:Pro	CAU:His	CGU:Arg
CUC:Leu	CCC:Pro	CAC:His	CGC:Arg
CUA:Leu	CCA:Pro	CAA:Gln	CGA:Arg
CUG:Leu	CCG:Pro	CAG:Gln	CGG:Arg
AUU:Ile	ACU:Thr	AAU:Asn	AGU:Ser
AUC:Ile	ACC:Thr	AAC:Asn	AGC:Ser
AUA:Ile	ACA:Thr	AAA:Lys	AGA:Arg
AUG:Met‡	ACG:Thr	AAG:Lys	AGG:Arg
GUU:Val	GCU:Ala	GAU:Asp	GGU:Gly
GUC:Val	GCC:Ala	GAC:Asp	GGC:Gly
GUA:Val	GCA:Ala	GAA:Glu	GGA:Gly
GUG:Val	GCG:Ala	GAG:Glu	GGG:Gly

† termination codon

UAA was once called ochre codon; UAG, amber codon; UGA, opal codon

‡ initiation codon. The methionine codon AUG is the most common starting point of translation of a genetic message but GUG sometimes serves.

The genetic code is almost universal but differences have been found in the DNA of mitochondria from a number of organisms. For example, in human mitochondria UGA codes for Trp and not for termination; AUA codes for Met and not for Ile; AGA and AGG are termination codons and do not code for Arg; AUA and possibly AUU act as initiation codons as well as AUG.

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For a list of words related to genetic code, see:

• Genetics, Heredity, and Evolution - genetic code: nucleotide triplet sequences in DNA and RNA that encode for protein synthesis

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