The genetic code is a set of rules that maps information encoded in DNA sequences to amino acid sequences (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. This was first discovered in the 1960's.
Genome expression
The genetic information carried by an organism - its genome - is inscribed in one or more DNA, or in some cases RNA, molecules. Each functional portion of a DNA or RNA 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, messenger RNA (mRNA). 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.)
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 (Asn), and cysteine (Cys) is represented by UGU and by UGC.
Table 1: RNA codon table
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.
Table 2: Reverse codon table
This table shows the 20 standard 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 |
Stop |
UAG, UGA, UAA |
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
Translation starts with a chain initiation codon (start codon). Unlike stop codons, the codon alone is not sufficient to begin the process, nearby sequences are also required to start translation upon binding by ribosomes. The most common start codon is AUG, which also codes for methionine, but other start codons are also used.
In classical genetics, the three 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. Stop codons are also called termination codons.
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 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, 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 ß-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 here). If read starting from the third position, GAA and ACC. Every 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). On double stranded DNA there are six possible reading frames, three forward and three reverse.
The actual frame a protein sequence is translated in is defined by a start codon, usually the first occurrence of AUG in the mRNA sequence. Mutations that disrupt the reading frame (i.e. insertions or deletions of one or two nucleotide bases, frameshift mutations) 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 that reside inside eukaryotic cells. 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 addition in some rare cases certain proteins may also use alternate initiation (start) codons.
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.
Origin of the genetic code
Despite the variations that exist, 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 of the many other 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.
There are three themes running through the many theories that seek to explain the evolution of the genetic code (and hence the origin of these patterns)1. One is illustrated by recent aptamer experiments which show that some amino acids have a selective chemical affinity for the base triplets that code for them.2 This suggests that the current, complex transcription mechanism involving tRNA and associated enzymes may be a later development, and that originally, protein sequences were directly templated on base sequences. Another is that the standard genetic code that we see today grew from a simpler, earlier code through a process of "biosynthetic expansion". Here the idea is that primordial life 'invented' 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 indicate that originally the number of different amino acids used may have been considerably smaller than today3, precise and detailed hypotheses about exactly which amino acids entered the code in exactly what order has proved far more controversial4,5. A third is that natural selection organized the codon assignments of the genetic code to minimize the effects of genetic errors (mutations)6.
Other resources
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.
- Griffiths, Anthony J.F.; Miller, Jeffrey H.; Suzuki, David T.; Lewontin, Richard C.; Gelbart, William M. (1999). Introduction to Genetic Analysis (7th ed.). New York: W. H. Freeman & Co. ISBN 0-7167-3771-X
- Alberts, Bruce; Johnson, Alexander; Lewis, Julian; Raff, Martin; Roberts, Keith; Walter, Peter. (2002). Molecular Biology of the Cell (4th ed.). New York: Garland Publishing. ISBN 0815332181
- Lodish, Harvey; Berk, Arnold; Zipursky, S. Lawrence; Matsudaira, Paul; Baltimore, David; Darnell, James E. (1999). Molecular Cell Biology (4th ed.). New York: W. H. Freeman & Co. ISBN 0-7167-3706-X
There is also a themed wiki devoted to the topic of how the genetic code evolved, and its effects on the subsequent evolution of the genome:
References
- Note 1: e.g. see Knight, R.D.; Freeland S. J. and Landweber, L.F. (1999) The 3 Faces of the Genetic Code. Trends in the Biochemical Sciences 24(6), 241-247.
- Note 2: 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 3: 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.
- Note 4: Amirnovin R. (1997) An analysis of the metabolic theory of the origin of the genetic code. Journal of Molecular Evolution 44(5), 473-6.
- Note 5: Ronneberg T.A.; Landweber L.F. and Freeland S.J. (2000) Testing a biosynthetic theory of the genetic code: Fact or artifact? Proceedings of the National Academy of Sciences, USA 97(25), 13690-13695.
- Note 6: e.g. see review by Freeland S.J.; Wu T. and Keulmann N. (2003) The Case for an Error Minimizing Genetic Code. Orig Life Evol Biosph. 33(4-5), 457-77.
See also
External links