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The genetic code is the set of rules used by living
cells Cell most often refers to: * Cell (biology), the functional basic unit of life Cell may also refer to: Locations * Monastic cell, a small room, hut, or cave in which a religious recluse lives, alternatively the small precursor of a monastery w ...
to translate information encoded within genetic material ( DNA or
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
sequences of nucleotide triplets, or codons) into proteins. Translation is accomplished by the
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
, which links proteinogenic amino acids in an order specified by
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the p ...
(mRNA), using
transfer RNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...
(tRNA) molecules to carry amino acids and to read the mRNA three nucleotides at a time. The genetic code is highly similar among all organisms and can be expressed in a simple table with 64 entries. The codons specify which amino acid will be added next during
protein biosynthesis Protein biosynthesis (or protein synthesis) is a core biological process, occurring inside cells, balancing the loss of cellular proteins (via degradation or export) through the production of new proteins. Proteins perform a number of critical ...
. With some exceptions, a three-nucleotide codon in a nucleic acid sequence specifies a single amino acid. The vast majority of genes are encoded with a single scheme (see the RNA codon table). That scheme is often referred to as the canonical or standard genetic code, or simply ''the'' genetic code, though variant codes (such as in
mitochondria A mitochondrion (; ) is an organelle found in the Cell (biology), cells of most Eukaryotes, such as animals, plants and Fungus, fungi. Mitochondria have a double lipid bilayer, membrane structure and use aerobic respiration to generate adenosi ...
) exist.


History

Efforts to understand how proteins are encoded began after DNA's structure was discovered in 1953. The key discoverers, English biophysicist
Francis Crick Francis Harry Compton Crick (8 June 1916 – 28 July 2004) was an English molecular biologist, biophysicist, and neuroscientist. He, James Watson, Rosalind Franklin, and Maurice Wilkins played crucial roles in deciphering the helical struc ...
and American biologist
James Watson James Dewey Watson (born April 6, 1928) is an American molecular biologist, geneticist, and zoologist. In 1953, he co-authored with Francis Crick the academic paper proposing the double helix structure of the DNA molecule. Watson, Crick and ...
, working together at the
Cavendish Laboratory The Cavendish Laboratory is the Department of Physics at the University of Cambridge, and is part of the School of Physical Sciences. The laboratory was opened in 1874 on the New Museums Site as a laboratory for experimental physics and is named ...
of the University of Cambridge, hypothesied that information flows from DNA and that there is a link between DNA and proteins. Soviet-American physicist George Gamow was the first to give a workable scheme for protein synthesis from DNA. He postulated that sets of three bases (triplets) must be employed to encode the 20 standard amino acids used by living cells to build proteins, which would allow a maximum of amino acids. He named this DNA–protein interaction (the original genetic code) as the "diamond code." In 1954, Gamow created an informal scientific organisation the RNA Tie Club, as suggested by Watson, for scientists of different persuasions who were interested in how proteins were synthesised from genes. However, the club could have only 20 permanent members to represent each of the 20 amino acids; and four additional honorary members to represent the four nucleotides of DNA. The first scientific contribution of the club, later recorded as "one of the most important unpublished articles in the history of science" and "the most famous unpublished paper in the annals of molecular biology," was made by Crick. Crick presented a type-written paper titled "On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club" to the members of the club in January 1955, which "totally change the way we thought about protein synthesis", as Watson recalled. The hypothesis states that the triplet code was not passed on to amino acids as Gamow thought, but carried by a different molecule, an adaptor, that interacts with amino acids. The adaptor was later identified as tRNA.


Codons

The Crick, Brenner, Barnett and Watts-Tobin experiment first demonstrated that codons consist of three DNA bases. Marshall Nirenberg and
Heinrich J. Matthaei Johannes Heinrich Matthaei (born 4 May 1929) is a German biochemist. He is best known for his unique contribution to solving the genetic code on 15 May 1961. Career Whilst a post-doctoral visitor in the laboratory of Marshall Warren Nirenber ...
were the first to reveal the nature of a codon in 1961. They used a cell-free system to translate a poly- uracil RNA sequence (i.e., UUUUU...) and discovered that the
polypeptide Peptides (, ) are short chains of amino acids linked by peptide bonds. Long chains of amino acids are called proteins. Chains of fewer than twenty amino acids are called oligopeptides, and include dipeptides, tripeptides, and tetrapeptides. A p ...
that they had synthesized consisted of only the amino acid
phenylalanine Phenylalanine (symbol Phe or F) is an essential α-amino acid with the formula . It can be viewed as a benzyl group substituted for the methyl group of alanine, or a phenyl group in place of a terminal hydrogen of alanine. This essential amino a ...
. They thereby deduced that the codon UUU specified the amino acid phenylalanine. This was followed by experiments in Severo Ochoa's laboratory that demonstrated that the poly- adenine RNA sequence (AAAAA...) coded for the polypeptide poly-
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
and that the poly- cytosine RNA sequence (CCCCC...) coded for the polypeptide poly-
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
. Therefore, the codon AAA specified the amino acid
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. It contains an α-amino group (which is in the protonated form under biological conditions), an α-carboxylic acid group (which is in the deprotonated −C ...
, and the codon CCC specified the amino acid
proline Proline (symbol Pro or P) is an organic acid classed as a proteinogenic amino acid (used in the biosynthesis of proteins), although it does not contain the amino group but is rather a secondary amine. The secondary amine nitrogen is in the prot ...
. Using various copolymers most of the remaining codons were then determined. Subsequent work by Har Gobind Khorana identified the rest of the genetic code. Shortly thereafter, Robert W. Holley determined the structure of
transfer RNA Transfer RNA (abbreviated tRNA and formerly referred to as sRNA, for soluble RNA) is an adaptor molecule composed of RNA, typically 76 to 90 nucleotides in length (in eukaryotes), that serves as the physical link between the mRNA and the amino ac ...
(tRNA), the adapter molecule that facilitates the process of translating RNA into protein. This work was based upon Ochoa's earlier studies, yielding the latter the Nobel Prize in Physiology or Medicine in 1959 for work on the
enzymology Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
of RNA synthesis. Extending this work, Nirenberg and Philip Leder revealed the code's triplet nature and deciphered its codons. In these experiments, various combinations of mRNA were passed through a filter that contained
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
s, the components of cells that translate RNA into protein. 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 in their experiments. Khorana, Holley and Nirenberg received the 1968 Nobel for their work. The three stop codons were named by discoverers Richard Epstein and Charles Steinberg. "Amber" was named 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.


Expanded genetic codes (synthetic biology)

In a broad academic audience, the concept of the evolution of the genetic code from the original and ambiguous genetic code to a well-defined ("frozen") code with the repertoire of 20 (+2) canonical amino acids is widely accepted. However, there are different opinions, concepts, approaches and ideas, which is the best way to change it experimentally. Even models are proposed that predict "entry points" for synthetic amino acid invasion of the genetic code. Since 2001, 40 non-natural amino acids have been added into proteins 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 proteins. H. Murakami and M. Sisido extended some codons to have four and five bases.
Steven A. Benner Steven Albert Benner (born October 23, 1954) has been a professor at Harvard University, ETH Zurich, and the University of Florida where he was the V.T. & Louise Jackson Distinguished Professor of Chemistry. In 2005, he founded The Westheimer In ...
constructed a functional 65th (''in vivo'') codon. In 2015 N. Budisa, D. Söll and co-workers reported the full substitution of all 20,899 tryptophan residues (UGG codons) with unnatural thienopyrrole-alanine in the genetic code of the bacterium ''Escherichia coli''. In 2016 the first stable semisynthetic organism was created. It was a (single cell) bacterium with two synthetic bases (called X and Y). The bases survived cell division. In 2017, researchers in South Korea reported that they had engineered a mouse with an extended genetic code that can produce proteins with unnatural amino acids. In May 2019, researchers reported the creation of a new "Syn61" strain of the bacterium '' Escherichia coli''. This strain has a fully
synthetic Synthetic things are composed of multiple parts, often with the implication that they are artificial. In particular, 'synthetic' may refer to: Science * Synthetic chemical or compound, produced by the process of chemical synthesis * Synthetic o ...
genome that is refactored (all overlaps expanded), recoded (removing the use of three out of 64 codons completely), and further modified to remove the now unnecessary tRNAs and release factors. It is fully viable and grows 1.6× slower than its wild-type counterpart "MDS42".


Features


Reading frame

A reading frame is defined by the initial triplet of nucleotides from which translation starts. It sets the frame for a run of successive, non-overlapping codons, which is known as an " open reading frame" (ORF). For example, the string 5'-AAATGAACG-3' (see figure), if read from the first position, contains the codons AAA, TGA, and ACG ; if read from the second position, it contains the codons AAT and GAA ; and if read from the third position, it contains the codons ATG and AAC. Every sequence can, thus, be read in its 5' → 3' direction in three reading frames, each producing a possibly distinct amino acid sequence: in the given example, Lys (K)-Trp (W)-Thr (T), Asn (N)-Glu (E), or Met (M)-Asn (N), respectively (when translating with the vertebrate mitochondrial code). When DNA is double-stranded, six possible reading frames are defined, three in the forward orientation on one strand and three reverse on the opposite strand. Protein-coding frames are defined by a
start codon The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The ...
, usually the first AUG (ATG) codon in the RNA (DNA) sequence. In
eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...
s, ORFs in
exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
s are often interrupted by
intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
s.


Start and stop codons

Translation starts with a chain-initiation codon or
start codon The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome. The start codon always codes for methionine in eukaryotes and Archaea and a N-formylmethionine (fMet) in bacteria, mitochondria and plastids. The ...
. The start codon alone is not sufficient to begin the process. Nearby sequences such as the Shine-Dalgarno sequence in ''
E. coli ''Escherichia coli'' (),Wells, J. C. (2000) Longman Pronunciation Dictionary. Harlow ngland Pearson Education Ltd. also known as ''E. coli'' (), is a Gram-negative, facultative anaerobic, rod-shaped, coliform bacterium of the genus ''Escher ...
'' and initiation factors are also required to start translation. The most common start codon is AUG, which is read as
methionine Methionine (symbol Met or M) () is an essential amino acid in humans. As the precursor of other amino acids such as cysteine and taurine, versatile compounds such as SAM-e, and the important antioxidant glutathione, methionine plays a critical ro ...
or as formylmethionine (in bacteria, mitochondria, and plastids). Alternative start codons depending on the organism include "GUG" or "UUG"; these codons normally represent valine and leucine, respectively, but as start codons they are translated as methionine or formylmethionine. The three stop codons have names: UAG is ''amber'', UGA is ''opal'' (sometimes also called ''umber''), and UAA is ''ochre''. Stop codons are also called "termination" or "nonsense" codons. They signal release of the nascent polypeptide from the ribosome because no cognate tRNA has anticodons complementary to these stop signals, allowing a
release factor A release factor is a protein that allows for the termination of translation by recognizing the termination codon or stop codon in an mRNA sequence. They are named so because they release new peptides from the ribosome. Background During t ...
to bind to the ribosome instead.


Effect of mutations

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, mutations, can affect an organism's phenotype, especially if they occur within the protein coding sequence of a gene. Error rates are typically 1 error in every 10–100 million bases—due to the "proofreading" ability of DNA polymerases. Missense mutations and nonsense mutations are examples of point mutations that can cause genetic diseases such as sickle-cell disease and
thalassemia Thalassemias are inherited blood disorders characterized by decreased hemoglobin production. Symptoms depend on the type and can vary from none to severe. Often there is mild to severe anemia (low red blood cells or hemoglobin). Anemia can result ...
respectively. Clinically important missense mutations generally change the properties of the coded amino acid residue among basic, acidic, polar or non-polar states, whereas nonsense mutations result in a stop codon. Mutations that disrupt the reading frame sequence by indels ( insertions or deletions) of a non-multiple of 3 nucleotide bases are known as
frameshift mutation A frameshift mutation (also called a framing error or a reading frame shift) is a genetic mutation caused by indels ( insertions or deletions) of a number of nucleotides in a DNA sequence that is not divisible by three. Due to the triplet nature ...
s. These mutations usually result in a completely different translation from the original, and likely cause a stop codon to be read, which truncates the protein. These mutations may impair the protein's function and are thus rare in '' in vivo'' protein-coding sequences. One reason inheritance of frameshift mutations is rare 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 death before the organism becomes viable. Frameshift mutations may result in severe genetic diseases such as Tay–Sachs disease. Although most mutations that change protein sequences are harmful or neutral, some mutations have benefits. These mutations may enable the mutant organism to withstand particular environmental stresses better than wild type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection. Viruses that use
RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
as their genetic material have rapid mutation rates, which can be an advantage, since these viruses thereby evolve rapidly, and thus evade the immune system defensive responses. In large populations of asexually reproducing organisms, for example, ''E. coli'', multiple beneficial mutations may co-occur. This phenomenon is called clonal interference and causes competition among the mutations.


Degeneracy

Degeneracy is the redundancy of the genetic code. This term was given by Bernfield and Nirenberg. The genetic code has redundancy but no ambiguity (see the codon tables below for the full correlation). For example, although codons GAA and GAG both specify
glutamic acid Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can synt ...
(redundancy), neither specifies another amino acid (no ambiguity). The codons encoding one amino acid may differ in any of their three positions. For example, the amino acid leucine is specified by YUR or CUN (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using IUPAC notation), while the amino acid
serine Serine (symbol Ser or S) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α-amino group (which is in the protonated − form under biological conditions), a carboxyl group (which is in the deprotonated − form un ...
is specified by UCN or AGY (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position). A practical consequence of redundancy is that errors in the third position of the triplet codon cause only 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
hydropathicity Hydrophobicity scales are values that define the relative hydrophobicity or hydrophilicity of amino acid residues. The more positive the value, the more hydrophobic are the amino acids located in that region of the protein. These scales are commonly ...
; NAN encodes average size hydrophilic residues. The genetic code is so well-structured for hydropathicity that a mathematical analysis ( Singular Value Decomposition) of 12 variables (4 nucleotides x 3 positions) yields a remarkable correlation (C = 0.95) for predicting the hydropathicity of the encoded amino acid directly from the triplet nucleotide sequence, ''without translation.'' Note in the table, below, eight amino acids are not affected at all by mutations at the third position of the codon, whereas in the figure above, a mutation at the second position is likely to cause a radical change in the physicochemical properties of the encoded amino acid. Nevertheless, changes in the first position of the codons are more important than changes in the second position on a global scale. The reason may be that charge reversal (from a positive to a negative charge or vice versa) can only occur upon mutations in the first position of certain codons, but not upon changes in the second position of any codon. Such charge reversal may have dramatic consequences for the structure or function of a protein. This aspect may have been largely underestimated by previous studies.


Codon usage bias

The frequency of codons, also known as codon usage bias, can vary from species to species with functional implications for the control of translation. The codon varies by organism; for example, most common proline codon in E. coli is CCG, whereas in humans this is the least used proline codon.


Alternative genetic codes


Non-standard amino acids

In some proteins, non-standard amino acids are substituted for standard stop codons, depending on associated signal sequences in the messenger RNA. For example, UGA can code for
selenocysteine Selenocysteine (symbol Sec or U, in older publications also as Se-Cys) is the 21st proteinogenic amino acid. Selenoproteins contain selenocysteine residues. Selenocysteine is an analogue of the more common cysteine with selenium in place of the s ...
and UAG can code for
pyrrolysine Pyrrolysine (symbol Pyl or O; encoded by the 'amber' stop codon UAG) is an α-amino acid that is used in the biosynthesis of proteins in some methanogenic archaea and bacteria; it is not present in humans. It contains an α-amino group (which is ...
. Selenocysteine came to be seen as the 21st amino acid, and pyrrolysine as the 22nd. Unlike selenocysteine, pyrrolysine-encoded UAG is translated with the participation of a dedicated aminoacyl-tRNA synthetase. Both selenocysteine and pyrrolysine may be present in the same organism. Although the genetic code is normally fixed in an organism, the achaeal prokaryote ''
Acetohalobium arabaticum ''Acetohalobium arabaticum'' is the type species of the genus '' Acetohalobium''. It is a prokaryote that can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth. Strains Strain Z-7 ...
'' can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth.


Variations

There was originally a simple and widely accepted argument that the genetic code should be universal: namely, that any variation in the genetic code would be lethal to the organism (although Crick had stated that viruses were an exception). This is known as the "frozen accident" argument for the universality of the genetic code. However, in his seminal paper on the origins of the genetic code in 1968, Francis Crick still stated that the universality of the genetic code in all organisms was an unproven assumption, and was probably not true in some instances. He predicted that "The code is universal (the same in all organisms) or nearly so". The first variation was discovered in 1979, by researchers studying
human mitochondrial genes Humans (''Homo sapiens'') are the most abundant and widespread species of primate, characterized by bipedality, bipedalism and exceptional cognitive skills due to a large and complex Human brain, brain. This has enabled the development of ad ...
. Many slight variants were discovered thereafter, including various alternative mitochondrial codes. These minor variants for example involve translation of the codon UGA as tryptophan in ''
Mycoplasma ''Mycoplasma'' is a genus of bacteria that, like the other members of the class ''Mollicutes'', lack a cell wall around their cell membranes. Peptidoglycan (murein) is absent. This characteristic makes them naturally resistant to antibiotics ...
'' species, and translation of CUG as a serine rather than leucine in yeasts of the "CTG clade" (such as '' Candida albicans''). Because viruses must use the same genetic code as their hosts, modifications to the standard genetic code could interfere with viral protein synthesis or functioning. However, viruses such as totiviruses have adapted to the host's genetic code modification. In bacteria and
archaea Archaea ( ; singular archaeon ) is a domain of single-celled organisms. These microorganisms lack cell nuclei and are therefore prokaryotes. Archaea were initially classified as bacteria, receiving the name archaebacteria (in the Archaebac ...
, GUG and UUG are common start codons. In rare cases, certain proteins may use alternative start codons. Surprisingly, variations in the interpretation of the genetic code exist also in human nuclear-encoded genes: In 2016, researchers studying the translation of malate dehydrogenase found that in about 4% of the mRNAs encoding this enzyme the stop codon is naturally used to encode the amino acids tryptophan and arginine. This type of recoding is induced by a high-readthrough stop codon context and it is referred to as ''functional translational readthrough''. Despite these differences, all known naturally occurring codes are very similar. The coding mechanism is the same for all organisms: three-base codons, tRNA, ribosomes, single direction reading and translating single codons into single amino acids. The most extreme variations occur in certain ciliates where the meaning of stop codons depends on their position within mRNA. When close to the 3' end they act as terminators while in internal positions they either code for amino acids as in '' Condylostoma magnum'' or trigger ribosomal frameshifting as in ''
Euplotes ''Euplotes'' is a genus of ciliates in the subclass Euplotia. Species are widely distributed in marine and freshwater environments, as well as soil and moss. Most members of the genus are free-living, but two species have been recorded as commens ...
''. The origins and variation of the genetic code, including the mechanisms behind the evolvability of the genetic code, have been widely studied, and some studies have been done experimentally evolving the genetic code of some organisms.


Inferrence

Variant genetic codes used by an organism can be inferred by identifying highly conserved genes encoded in that genome, and comparing its codon usage to the amino acids in homologous proteins of other organisms. For example, the program FACIL infers a genetic code by searching which amino acids in homologous protein domains are most often aligned to every codon. The resulting amino acid (or stop codon) probabilities for each codon are displayed in a genetic code logo. As of January 2022, the most complete survey of genetic codes is done by Shulgina and Eddy, who screened 250,000 prokaryotic genomes using their Codetta tool. This tool uses a similar approach to FACIL with a larger
Pfam Pfam is a database of protein families that includes their annotations and multiple sequence alignments generated using hidden Markov models. The most recent version, Pfam 35.0, was released in November 2021 and contains 19,632 families. Uses ...
database. Despite the NCBI already providing 33 translation tables, the authors were able to find new 5 genetic code variations (corroborated by tRNA mutations) and correct several misattributions.


Origin

The genetic code is a key part of the history of life, according to one version of which self-replicating RNA molecules preceded life as we know it. This is the RNA world hypothesis. Under this hypothesis, any model for the emergence of the genetic code is intimately related to a model of the transfer from ribozymes (RNA enzymes) to proteins as the principal enzymes in cells. In line with the RNA world hypothesis, transfer RNA molecules appear to have evolved before modern aminoacyl-tRNA synthetases, so the latter cannot be part of the explanation of its patterns. A hypothetical randomly evolved genetic code further motivates a biochemical or evolutionary model for its origin. If amino acids were randomly assigned to triplet codons, there would be 1.5 × 1084 possible genetic codes. This number is found by calculating the number of ways that 21 items (20 amino acids plus one stop) can be placed in 64 bins, wherein each item is used at least once. However, the distribution of codon assignments in the genetic code is nonrandom. In particular, the genetic code clusters certain amino acid assignments. Amino acids that share the same biosynthetic pathway tend to have the same first base in their codons. This could be an evolutionary relic of an early, simpler genetic code with fewer amino acids that later evolved to code a larger set of amino acids. It could also reflect steric and chemical properties that had another effect on the codon during its evolution. Amino acids with similar physical properties also tend to have similar codons, reducing the problems caused by point mutations and mistranslations. Given the non-random genetic triplet coding scheme, a tenable hypothesis for the origin of genetic code could address multiple aspects of the codon table, such as absence of codons for D-amino acids, secondary codon patterns for some amino acids, confinement of synonymous positions to third position, the small set of only 20 amino acids (instead of a number approaching 64), and the relation of stop codon patterns to amino acid coding patterns. Three main hypotheses address the origin of the genetic code. Many models belong to one of them or to a hybrid: *Random freeze: the genetic code was randomly created. For example, early tRNA-like ribozymes may have had different affinities for amino acids, with codons emerging from another part of the ribozyme that exhibited random variability. Once enough peptides were coded for, any major random change in the genetic code would have been lethal; hence it became "frozen". *Stereochemical affinity: the genetic code is a result of a high affinity between each amino acid and its codon or anti-codon; the latter option implies that pre-tRNA molecules matched their corresponding amino acids by this affinity. Later during evolution, this matching was gradually replaced with matching by aminoacyl-tRNA synthetases. *Optimality: the genetic code continued to evolve after its initial creation, so that the current code maximizes some fitness function, usually some kind of error minimization. Hypotheses have addressed a variety of scenarios: * Chemical principles govern specific RNA interaction with amino acids. Experiments with aptamers showed that some amino acids have a selective chemical affinity for their codons. Experiments showed that of 8 amino acids tested, 6 show some RNA triplet-amino acid association. * Biosynthetic expansion. The genetic code grew from a simpler earlier code through a process of "biosynthetic expansion". Primordial life "discovered" new amino acids (for example, as by-products of metabolism) and later incorporated some of these into the machinery of genetic coding. Although much circumstantial evidence has been found to suggest that fewer amino acid types were used in the past, precise and detailed hypotheses about which amino acids entered the code in what order are controversial. However, several studies have suggested that Gly, Ala, Asp, Val, Ser, Pro, Glu, Leu, Thr may belong to a group of early-addition amino acids, whereas Cys, Met, Tyr, Trp, His, Phe may belong to a group of later-addition amino acids. * Natural selection has led to codon assignments of the genetic code that minimize the effects of mutations. A recent hypothesis suggests that the triplet code was derived from codes that used longer than triplet codons (such as quadruplet codons). Longer than triplet decoding would increase codon redundancy and would be more error resistant. This feature could allow accurate decoding absent complex translational machinery such as the
ribosome Ribosomes ( ) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order specified by the codons of messenger RNA (mRNA) molecules to ...
, such as before cells began making ribosomes. * Information channels: Information-theoretic approaches model the process of translating the genetic code into corresponding amino acids as an error-prone information channel. The inherent noise (that is, the error) in the channel poses the organism with a fundamental question: how can a genetic code be constructed to withstand noise while accurately and efficiently translating information? These "rate-distortion" models suggest that the genetic code originated as a result of the interplay of the three conflicting evolutionary forces: the needs for diverse amino acids, for error-tolerance and for minimal resource cost. The code emerges at a transition when the mapping of codons to amino acids becomes nonrandom. The code's emergence is governed by the topology defined by the probable errors and is related to the map coloring problem. *Game theory: Models based on signaling games combine elements of game theory, natural selection and information channels. Such models have been used to suggest that the first polypeptides were likely short and had non-enzymatic function. Game theoretic models suggested that the organization of RNA strings into cells may have been necessary to prevent "deceptive" use of the genetic code, i.e. preventing the ancient equivalent of viruses from overwhelming the RNA world. *Stop codons: Codons for translational stops are also an interesting aspect to the problem of the origin of the genetic code. As an example for addressing stop codon evolution, it has been suggested that the stop codons are such that they are most likely to terminate translation early in the case of a
frame shift Ribosomal frameshifting, also known as translational frameshifting or translational recoding, is a biological phenomenon that occurs during translation that results in the production of multiple, unique proteins from a single mRNA. The process can ...
error. In contrast, some stereochemical molecular models explain the origin of stop codons as "unassignable".


See also

* List of genetic engineering software * Codon tables


References


Further reading

* * * *


External links


The Genetic Codes: Genetic Code Tables
* Th
Codon Usage Database
— Codon frequency tables for many organisms
History of deciphering the genetic code
{{DEFAULTSORT:Genetic Code Gene expression Genetics Molecular genetics Molecular biology Protein biosynthesis