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{{Short description|Rules by which information encoded within genetic material is translated into proteins}}
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[[File:RNA-codon.svg|thumb|A series of codons in part of a [[messenger RNA]] (mRNA) molecule. Each codon consists of three [[nucleotide]]s, usually corresponding to a single [[amino acid]]. The nucleotides are abbreviated with the letters A, U, G and C. This is mRNA, which uses U ([[uracil]]). DNA uses T ([[thymine]]) instead. This mRNA molecule will instruct a [[ribosome]] to synthesize a protein according to this code.]]
'''Genetic code''' is a set of rules used by living [[cell (biology)|cells]] to [[Translation (biology)|translate]] information encoded within genetic material ([[DNA]] or [[RNA]] sequences of nucleotide triplets or [[codon]]s) into [[protein]]s. Translation is accomplished by the [[ribosome]], which links [[proteinogenic amino acid]]s in an order specified by [[messenger RNA]] (mRNA), using [[transfer RNA]] (tRNA) molecules to carry amino acids and to read the mRNA three [[nucleotide]]s 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]]. With some exceptions,<ref name="
==History==
[[File:GeneticCode21-version-2.svg|thumb|upright=1.5|The genetic code]]{{Further|Adaptor hypothesis}}
Efforts to understand how proteins are encoded began after [[Nucleic acid double helix|DNA's structure]] was discovered in 1953. The key discoverers, English biophysicist [[Francis Crick]] and American biologist [[James Watson]], working together at the [[Cavendish Laboratory]] of the University of Cambridge, hypothesied that information flows from DNA and that there is a link between DNA and proteins.<ref>{{
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 [[Translation (biology)|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.<ref name="
The first scientific contribution of the club, later recorded as "one of the most important unpublished articles in the history of science"<ref>{{Cite web | title = Francis Crick - Profiles in Science Search Results | url = https://profiles.nlm.nih.gov/spotlight/sc/catalog/nlm:nlmuid-101584582X73-doc | access-date = 2022-07-21 | website = profiles.nlm.nih.gov }}</ref> and "the most famous unpublished paper in the annals of molecular biology",<ref name="
===Codons===
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The [[Crick, Brenner et al. experiment|Crick, Brenner, Barnett and Watts-Tobin experiment]] first demonstrated that '''codons''' consist of three DNA bases.
[[Marshall Nirenberg]] and [[J. Heinrich Matthaei]] were the first to reveal the nature of a codon in 1961.<ref>{{cite journal |
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]]<ref name="
Subsequent work by [[Har Gobind Khorana]] identified the rest of the genetic code. Shortly thereafter, [[Robert W. Holley]] determined the structure of [[transfer RNA]] (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]] of RNA synthesis.<ref name="Nobel_1959">{{cite press release | title = The Nobel Prize in Physiology or Medicine 1959 | date = 1959 | url = http://nobelprize.org/nobel_prizes/medicine/laureates/1959/index.html |
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]]s, the components of cells that [[Translation (biology)|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.<ref name="
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.<ref>{{cite journal |
=== Expanded genetic codes (synthetic biology) ===
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{{See also|Nucleic acid analogues}}
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.<ref>{{Cite book | vauthors = Budisa N | title = The book at the Wiley Online Library | date = 2005-12-23 | doi = 10.1002/3527607188 | isbn = 978-3-527-31243-6 }}</ref>
However, there are different opinions, concepts, approaches and ideas, which is the best way to change it experimentally.{{Clarify|reason=are the opinions differing on "which one method is the best to change the experiments"?|date=February 2025}} Even models are proposed that predict "entry points" for synthetic amino acid invasion of the genetic code.<ref>{{cite journal | vauthors = Kubyshkin V, Budisa N | title = Synthetic alienation of microbial organisms by using genetic code engineering: Why and how? | journal = Biotechnology Journal | volume = 12 | issue = 8 | pages = 16000933 | date = August 2017 | article-number = 1600097 | pmid = 28671771 | doi = 10.1002/biot.201600097 }}</ref>▼
▲However, there are different opinions, concepts, approaches and ideas, which is the best way to change it experimentally.{{Clarify|reason=are the opinions differing on "which one method is the best to change the experiments"?|date=February 2025}} Even models are proposed that predict "entry points" for synthetic amino acid invasion of the genetic code.<ref>{{cite journal
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.<ref name="
H. Murakami and M. Sisido extended some codons to have four and five bases. [[Steven A. Benner]] constructed a functional 65th (''[[in vivo]]'') codon.<ref name="
In 2015 [[Nediljko Budisa|N. Budisa]], [[Dieter Söll|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 [[Bacteria|bacterium]] ''[[Escherichia coli|E. coli]]''.<ref>{{cite journal |
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.<ref>{{cite web |
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.<ref>{{cite journal | vauthors = Han S, Yang A, Lee S, Lee HW, Park CB, Park HS | title = Expanding the genetic code of Mus musculus | journal = Nature Communications | volume = 8 |
In May 2019, researchers reported the creation of a new "Syn61" strain of the ''E. coli'' bacteria. This strain has a fully [[Synthetic biology#Synthetic life|synthetic]] 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 [[Genetic viability|viable]] and grows 1.6× slower than its wild-type counterpart "[[Escherichia coli#MDS42|MDS42]]".<ref name="
In 2025, researchers reported a new "Syn57" strain, which removes the use of 7 out of 64 codons completely.<ref>{{cite journal |
==Features==
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=== Start and stop codons ===
Translation starts with a chain-initiation codon or [[start codon]]. The start codon alone is not sufficient to begin the process. Nearby sequences such as the [[Shine-Dalgarno]] sequence in ''[[Escherichia coli|E. coli]]'' and [[initiation factor]]s are also required to start translation. The most common start codon is AUG, which is read as [[methionine]] or as [[N-Formylmethionine|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.<ref name="
The three [[stop codon]]s 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]] to bind to the ribosome instead.<ref name="urlHow nonsense mutations got their names">{{cite web | vauthors = Maloy S | title = How nonsense mutations got their names | date = 2003-11-29 | url = http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/rev-sup/amber-name.html |
===Effect of mutations===
[[File:Notable mutations.svg|upright=1.75|thumb|Examples of notable [[mutation]]s that can occur in humans<ref>References for the image are found in Wikimedia Commons page at: [[Commons:File:Notable mutations.svg#References]].</ref>]]<!-- EXPANSION OF THE IMAGE WITH MORE EXAMPLES IS EXPECTED (see its discussion page)-->
During the process of [[DNA replication]], errors occasionally occur in the [[polymerization]] of the second strand. These errors, [[mutation]]s, 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 (biology)|proofreading]]" ability of [[DNA polymerase]]s.<ref name="griffiths2000sect2706">{{cite book |
[[Missense mutation]]s and [[nonsense mutation]]s are examples of [[point mutation]]s that can cause genetic diseases such as [[sickle-cell disease]] and [[thalassemia]] respectively.<ref>{{cite journal | vauthors = Boillée S, Vande Velde C, Cleveland DW | title = ALS: a disease of motor neurons and their nonneuronal neighbors | journal = Neuron | volume = 52 | issue = 1 | pages = 39–59 | date = October 2006 | pmid = 17015226 | doi = 10.1016/j.neuron.2006.09.018 | doi-access = free }}</ref><ref name="
▲}}</ref><ref name="pmid88735">{{cite journal | vauthors = Chang JC, Kan YW | title = beta 0 thalassemia, a nonsense mutation in man | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 76 | issue = 6 | pages = 2886–9 | date = Jun 1979 | pmid = 88735 | pmc = 383714 | doi = 10.1073/pnas.76.6.2886 | bibcode = 1979PNAS...76.2886C | doi-access = free }}</ref><ref name="pmid17015226">{{cite journal | vauthors = Boillée S, Vande Velde C, Cleveland DW | title = ALS: a disease of motor neurons and their nonneuronal neighbors | journal = Neuron | volume = 52 | issue = 1 | pages = 39–59 | date = Oct 2006 | pmid = 17015226 | doi = 10.1016/j.neuron.2006.09.018 | doi-access = free }}</ref> 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]].<ref name="genetics_ dictionary">{{cite book | first1 = Robert C. | last1 = King | first2 = Pamela | last2 = Mulligan | first3 = William | last3 = Stansfield | name-list-style = vanc | title = A Dictionary of Genetics|url={{google books |plainurl=y |id=5jhH0HTjEdkC}}|date=10 January 2013 | publisher = OUP USA | isbn = 978-0-19-976644-4| pages = 608 }}</ref>
Mutations that disrupt the reading frame sequence by [[indels]] ([[gene insertion|insertions]] or [[genetic deletion|deletions]]) of a non-multiple of 3 nucleotide bases are known as [[frameshift mutation]]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.<ref name="
Although most mutations that change protein sequences are harmful or neutral, some mutations have benefits.<ref>{{cite journal | vauthors = Sawyer SA, Parsch J, Zhang Z, Hartl DL | title = Prevalence of positive selection among nearly neutral amino acid replacements in Drosophila | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 104 | issue = 16 | pages =
===Degeneracy===
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[[File:Genetic Code Simple Corrected.pdf|thumb|Grouping of codons by amino acid residue molar volume and [[hydropathicity]]. A [[:File:ELLIPTICAL GENETIC CODE Ian.png|more detailed version]] is available.]]
[[File:3D Genetic Code.jpg|thumb|Axes 1, 2, 3 are the first, second, and third positions in the codon. The 20 amino acids and stop codons (X) are shown in [[Amino acid#Table of standard amino acid abbreviations and properties|single letter code]].]]
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 [[DNA and RNA codon tables|codon tables]] below for the full correlation). For example, although codons GAA and GAG both specify [[glutamic acid]] (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 '''Y'''U'''R''' or CU'''N''' (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using [[Nucleic acid notation|IUPAC notation]]), while the amino acid [[serine]] is specified by UC'''N''' or AG'''Y''' (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position).<ref name="
Nevertheless, changes in the first position of the codons are more important than changes in the second position on a global scale.<ref name=
===Codon usage bias===
{{Main|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 (biology)|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.<ref>{{Cite web | title = Codon Usage Frequency Table(chart)-Genscript | url = https://www.genscript.com/tools/codon-frequency-table | access-date = 2022-02-04 | website = www.genscript.com }}</ref>
{{collapse top|title=Human genome codon frequency table<ref>{{Cite web | title = Codon usage table | url = http://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=9606&aa=1&style=N
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=== 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]] and UAG can code for [[pyrrolysine]]. Selenocysteine came to be seen as the 21st amino acid, and pyrrolysine as the 22nd.<ref name="Zhang2005" /> Both selenocysteine and pyrrolysine may be present in the same organism.<ref name=Zhang2005>{{cite journal | vauthors = Zhang Y, Baranov PV, Atkins JF, Gladyshev VN | title = Pyrrolysine and selenocysteine use dissimilar decoding strategies | journal = The Journal of Biological Chemistry | volume = 280 | issue = 21 | pages =
=== Variations ===
{{See also|List of genetic codes}}
[[File:FACIL genetic code logo.png|thumb|upright=2.3|Genetic code [[sequence logo|logo]] of the ''Globobulimina pseudospinescens'' mitochondrial genome by FACIL. The program is able to correctly infer that the [[The mold, protozoan, and coelenterate mitochondrial code and the mycoplasma/spiroplasma code|Protozoan Mitochondrial Code]] is in use.<ref name="
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".<ref name = "Crick_1968">{{
{{cite journal | vauthors = Barrell BG, Bankier AT, Drouin J |
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.<ref name="
Despite these differences, all known naturally occurring codes are very similar. The coding mechanism is the same for all organisms: three-base codons, [[Transfer RNA|tRNA]], ribosomes, single direction reading and translating single codons into single amino acids.<ref>{{cite journal | vauthors = Kubyshkin V, Acevedo-Rocha CG, Budisa N | title = On universal coding events in protein biogenesis | journal = Bio Systems | volume = 164 | pages = 16–25 | date = February 2018 | pmid = 29030023 | doi = 10.1016/j.biosystems.2017.10.004 | doi-access = free | bibcode = 2018BiSys.164...16K }}</ref> 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''<ref>{{cite journal | vauthors = Heaphy SM, Mariotti M, Gladyshev VN, Atkins JF, Baranov PV | title = Novel Ciliate Genetic Code Variants Including the Reassignment of All Three Stop Codons to Sense Codons in
The origins and variation of the genetic code, including the mechanisms behind the evolvability of the genetic code, have been widely studied,<ref>{{cite journal | vauthors = Koonin EV, Novozhilov AS | title = Origin and
=== Inference ===
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.<ref name="
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]] database. Despite the NCBI already providing 27 translation tables, the authors were able to find new 5 genetic code variations (corroborated by tRNA mutations) and correct several misattributions.<ref>{{cite journal |
==Origin==
The genetic code is a key part of the [[origin of life|history of life]]. Under the [[RNA world hypothesis]], self-replicating RNA molecules preceded significant use of proteins. Under the nucleopeptide world hypothesis, significant use of peptides preceded the genetic code and was concurrent with early life's sophisticated use of RNA.<ref>{{cite journal |
Any evolutionary model for the code's origin must account for its [[Robustness (evolution)|robustness]] of encoded proteins to errors during DNA replication and during translation. Many single nucleotide errors are [[Synonymous substitution|synonymous]], and those that are not tend to cause the [[Conservative replacement|substitution of a biochemically similar amino acid]]. Even holding the structure of the code the same such that clusters of codons encode the same amino acid, which amino acids are encoded by which sets of codons is "one in a million" with respect to robustness.<ref name="
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.<ref name="
Three main hypotheses address the origin of the genetic code. Many models belong to one of them or to a hybrid:<ref name="
*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 [[peptide]]s were coded for, any major random change in the genetic code would have been lethal; hence it became "frozen".<ref name="Crick_1968" />
▲Three main hypotheses address the origin of the genetic code. Many models belong to one of them or to a hybrid:<ref name="pmid10742043">{{cite journal | vauthors = Freeland SJ, Knight RD, Landweber LF, Hurst LD | title = Early fixation of an optimal genetic code | journal = Molecular Biology and Evolution | volume = 17 | issue = 4 | pages = 511–18 | date = Apr 2000 | pmid = 10742043 | doi=10.1093/oxfordjournals.molbev.a026331| doi-access = free }}</ref>
*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.<ref name="
*Optimality: the genetic code continued to evolve after its initial creation, so that the current code maximizes some [[fitness (biology)|fitness]] function, usually some kind of error minimization.<ref name="
* Chemical principles govern specific RNA interaction with amino acids. Experiments with [[aptamer]]s showed that some amino acids have a selective chemical affinity for their codons.<ref name="
▲*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.<ref name="pmid21779963"/><ref name="pmid279919">{{cite journal | vauthors = Hopfield JJ | title = Origin of the genetic code: a testable hypothesis based on tRNA structure, sequence, and kinetic proofreading | journal = PNAS | volume = 75 | issue = 9 | pages = 4334–4338 | date = 1978 | pmid = 279919 | doi=10.1073/pnas.75.9.4334 | pmc=336109| bibcode = 1978PNAS...75.4334H | doi-access = free}}</ref><ref name="pmid19795157"/>
* 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.<ref>{{cite journal | vauthors = Sengupta S, Higgs PG
▲*Optimality: the genetic code continued to evolve after its initial creation, so that the current code maximizes some [[fitness (biology)|fitness]] function, usually some kind of error minimization.<ref name="pmid21779963"/><ref name="pmid10742043"/><ref>{{cite journal |last1=Brown |first1=Sean M. |last2=Voráček |first2=Václav |last3=Freeland |first3=Stephen |title=What Would an Alien Amino Acid Alphabet Look Like and Why? |journal=Astrobiology |date=5 April 2023 |volume=23 |issue=5 |pages=536–549 |doi=10.1089/ast.2022.0107|pmid=37022727 |bibcode=2023AsBio..23..536B |s2cid=257983174 }}</ref>
* Natural selection has led to codon assignments of the genetic code that minimize the effects of [[mutation]]s.<ref name="
* Information channels: [[information theory|Information-theoretic]] approaches model the process of translating the genetic code into corresponding amino acids as an error-prone information channel.<ref name="
*Game theory: Models based on [[signaling game]]s 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.<ref name="
*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]] error.<ref>{{cite journal | vauthors = Itzkovitz S, Alon U | title = The genetic code is nearly optimal for allowing additional information within protein-coding sequences | journal = Genome Research | volume = 17 | issue = 4 | pages = 405–412 | date = April 2007 | pmid = 17293451 | pmc = 1832087 | doi = 10.1101/gr.5987307
== See also ==▼
▲* Chemical principles govern specific RNA interaction with amino acids. Experiments with [[aptamer]]s showed that some amino acids have a selective chemical affinity for their codons.<ref name="pmid9751648">{{cite journal | vauthors = Knight RD, Landweber LF | title = Rhyme or reason: RNA-arginine interactions and the genetic code | journal = Chemistry & Biology | volume = 5 | issue = 9 | pages = R215–20 | date = Sep 1998 | pmid = 9751648 | doi = 10.1016/S1074-5521(98)90001-1 | doi-access = free }}</ref> Experiments showed that of 8 amino acids tested, 6 show some RNA triplet-amino acid association.<ref name="isbn0-674-05075-4">{{cite book|first=Michael |last=Yarus|author-link=Michael Yarus|title=Life from an RNA World: The Ancestor Within|url={{google books |plainurl=y |id=-YLBMmJE1WwC}}|year=2010|publisher=Harvard University Press|isbn=978-0-674-05075-4}}</ref><ref name="pmid19795157">{{cite journal | vauthors = Yarus M, Widmann JJ, Knight R | title = RNA-amino acid binding: a stereochemical era for the genetic code | journal = Journal of Molecular Evolution | volume = 69 | issue = 5 | pages = 406–29 | date = Nov 2009 | pmid = 19795157 | doi = 10.1007/s00239-009-9270-1 | bibcode = 2009JMolE..69..406Y | doi-access = free }}</ref>
▲* 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.<ref>{{cite journal | vauthors = Sengupta S, Higgs PG | s2cid = 15542587 | year = 2015 | title = Pathways of genetic code evolution in ancient and modern organisms | journal = Journal of Molecular Evolution | volume = 80 | issue = 5–6| pages = 229–243 | doi=10.1007/s00239-015-9686-8 | pmid=26054480| bibcode = 2015JMolE..80..229S}}</ref> Although much circumstantial evidence has been found to suggest that fewer amino acid types were used in the past,<ref name="pmid12270892">{{cite journal | vauthors = Brooks DJ, Fresco JR, Lesk AM, Singh M | title = Evolution of amino acid frequencies in proteins over deep time: inferred order of introduction of amino acids into the genetic code | journal = Molecular Biology and Evolution | volume = 19 | issue = 10 | pages = 1645–55 | date = Oct 2002 | pmid = 12270892 | doi = 10.1093/oxfordjournals.molbev.a003988 | doi-access = free }}</ref> precise and detailed hypotheses about which amino acids entered the code in what order are controversial.<ref name="pmid9115171">{{cite journal | vauthors = Amirnovin R | s2cid = 23334860 | title = An analysis of the metabolic theory of the origin of the genetic code | journal = Journal of Molecular Evolution | volume = 44 | issue = 5 | pages = 473–6 | date = May 1997 | pmid = 9115171 | doi = 10.1007/PL00006170 | bibcode = 1997JMolE..44..473A }}</ref><ref name="pmid11087835">{{cite journal | vauthors = Ronneberg TA, Landweber LF, Freeland SJ | title = Testing a biosynthetic theory of the genetic code: fact or artifact? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 25 | pages = 13690–5 | date = Dec 2000 | pmid = 11087835 | pmc = 17637 | doi = 10.1073/pnas.250403097 | bibcode = 2000PNAS...9713690R | doi-access = free }}</ref> 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.<ref>{{Cite journal|last=Trifonov|first=Edward N.|date=September 2009|title=The origin of the genetic code and of the earliest oligopeptides|url=https://linkinghub.elsevier.com/retrieve/pii/S0923250809000576|journal=Research in Microbiology|language=en|volume=160|issue=7|pages=481–486|doi=10.1016/j.resmic.2009.05.004|pmid=19524038|url-access=subscription}}</ref><ref>{{Cite journal|last1=Higgs|first1=Paul G.|last2=Pudritz|first2=Ralph E.|date=June 2009|title=A Thermodynamic Basis for Prebiotic Amino Acid Synthesis and the Nature of the First Genetic Code|url=http://www.liebertpub.com/doi/10.1089/ast.2008.0280|journal=Astrobiology|language=en|volume=9|issue=5|pages=483–490|doi=10.1089/ast.2008.0280|pmid=19566427|issn=1531-1074|arxiv=0904.0402|bibcode=2009AsBio...9..483H|s2cid=9039622}}</ref><ref>{{Cite journal|last1=Chaliotis|first1=Anargyros|last2=Vlastaridis|first2=Panayotis|last3=Mossialos|first3=Dimitris|last4=Ibba|first4=Michael|last5=Becker|first5=Hubert D.|last6=Stathopoulos|first6=Constantinos|last7=Amoutzias|first7=Grigorios D.|date=2017-02-17|title=The complex evolutionary history of aminoacyl-tRNA synthetases|url= |journal=Nucleic Acids Research|language=en|volume=45|issue=3|pages=1059–1068|doi=10.1093/nar/gkw1182|issn=0305-1048|pmc=5388404|pmid=28180287}}</ref><ref>{{Cite journal|last1=Ntountoumi|first1=Chrysa|last2=Vlastaridis|first2=Panayotis|last3=Mossialos|first3=Dimitris|last4=Stathopoulos|first4=Constantinos|last5=Iliopoulos|first5=Ioannis|last6=Promponas|first6=Vasilios|last7=Oliver|first7=Stephen G|last8=Amoutzias|first8=Grigoris D|date=2019-11-04|title=Low complexity regions in the proteins of prokaryotes perform important functional roles and are highly conserved|url= |journal=Nucleic Acids Research|language=en|volume=47|issue=19|pages=9998–10009|doi=10.1093/nar/gkz730|issn=0305-1048|pmc=6821194|pmid=31504783}}</ref> An alternative analysis of amino acid usage in the [[Last Universal Common Ancestor]] concluded that the amino acids came in the following order: Val, Gly, Ile, Met, Ala, Thr, His, Glu, Cys, Pro, Lys, Ser, Asp, Leu, Asn, Arg, Phe, Tyr, Gln, Trp.<ref name="wehbi2024">{{cite journal |last1=Wehbi |first1=Sawsan |last2=Wheeler |first2=Andrew |last3=Morel |first3=Benoit |last4=Manepalli |first4=Nandini |last5=Minh |first5=Bui Quang |last6=Lauretta |first6=Dante S. |last7=Masel |first7=Joanna |title=Order of amino acid recruitment into the genetic code resolved by last universal common ancestor's protein domains |journal=Proceedings of the National Academy of Sciences |date=24 December 2024 |volume=121 |issue=52 |pages=e2410311121 |doi=10.1073/pnas.2410311121 |pmid=39665745 |pmc=11670089 |bibcode=2024PNAS..12110311W }}</ref> It was pointed out that the late appearance of sulfur-containing cysteine and methionine was concluded in part from their absence of the sulfur-free [[Miller–Urey experiment]], that early life is believed to have used [[S-adenosyl methionine]], and that while histidine is hard to make abiotically, it is straightforward to synthesize in an organism that already has sophisticated RNA and hence purine synthesis.<ref name="wehbi2024"/>
▲* Natural selection has led to codon assignments of the genetic code that minimize the effects of [[mutation]]s.<ref name="pmid14604186">{{cite journal | vauthors = Freeland SJ, Wu T, Keulmann N | s2cid = 18823745 | title = The case for an error minimizing standard genetic code | journal = Origins of Life and Evolution of the Biosphere | volume = 33 | issue = 4–5 | pages = 457–77 | date = Oct 2003 | pmid = 14604186 | doi = 10.1023/A:1025771327614 | bibcode = 2003OLEB...33..457F }}</ref> A recent hypothesis<ref name="pmid19479032">{{cite journal | vauthors = Baranov PV, Venin M, Provan G | title = Codon size reduction as the origin of the triplet genetic code | journal = PLOS ONE | volume = 4 | issue = 5 | pages = e5708 | date = 2009 | pmid = 19479032 | pmc = 2682656 | doi = 10.1371/journal.pone.0005708 | editor1-last = Gemmell | bibcode = 2009PLoSO...4.5708B | editor1-first = Neil John | doi-access = free }}</ref> 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]], such as before cells began making ribosomes.
▲* Information channels: [[information theory|Information-theoretic]] approaches model the process of translating the genetic code into corresponding amino acids as an error-prone information channel.<ref name="pmid17826800">{{cite journal | vauthors = Tlusty T | title = A model for the emergence of the genetic code as a transition in a noisy information channel | journal = Journal of Theoretical Biology | volume = 249 | issue = 2 | pages = 331–42 | date = Nov 2007 | pmid = 17826800 | doi = 10.1016/j.jtbi.2007.07.029 | arxiv = 1007.4122 | bibcode = 2007JThBi.249..331T | s2cid = 12206140 }}</ref> 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<ref>{{cite book | vauthors = Sonneborn TM | veditors =Bryson V, Vogel H | title = Evolving genes and proteins |publisher=Academic Press|___location=New York |date=1965|pages=377–397}}</ref> while accurately and efficiently translating information? These [[rate-distortion theory|"rate-distortion"]] models<ref name="pmid 18352335">{{cite journal | vauthors = Tlusty T | title = Rate-distortion scenario for the emergence and evolution of noisy molecular codes | journal = Physical Review Letters | volume = 100 | issue = 4 | article-number = 048101 | date = Feb 2008 | pmid = 18352335 | doi = 10.1103/PhysRevLett.100.048101 | arxiv = 1007.4149 | bibcode = 2008PhRvL.100d8101T | s2cid = 12246664 }}</ref> suggest that the genetic code originated as a result of the interplay of the three conflicting evolutionary forces: the needs for diverse amino acids,<ref name="pmid16838217">{{cite journal | vauthors = Sella G, Ardell DH | s2cid = 1260806 | title = The coevolution of genes and genetic codes: Crick's frozen accident revisited | journal = Journal of Molecular Evolution | volume = 63 | issue = 3 | pages = 297–313 | date = Sep 2006 | pmid = 16838217 | doi = 10.1007/s00239-004-0176-7 | bibcode = 2006JMolE..63..297S }}</ref> for error-tolerance<ref name="pmid14604186" /> 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]].<ref name="pmid 20558115">{{cite journal | vauthors = Tlusty T | title = A colorful origin for the genetic code: information theory, statistical mechanics and the emergence of molecular codes | journal = Physics of Life Reviews | volume = 7 | issue = 3 | pages = 362–76 | date = Sep 2010 | pmid = 20558115 | doi = 10.1016/j.plrev.2010.06.002 | arxiv = 1007.3906 | bibcode = 2010PhLRv...7..362T | s2cid = 1845965 }}</ref>
▲*Game theory: Models based on [[signaling game]]s 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.<ref name="pmid23985735">{{cite journal | vauthors = Jee J, Sundstrom A, Massey SE, Mishra B | title = What can information-asymmetric games tell us about the context of Crick's 'frozen accident'? | journal = Journal of the Royal Society, Interface | volume = 10 | issue = 88 | pages = 20130614 | date = Nov 2013 | pmid = 23985735 | pmc = 3785830 | doi = 10.1098/rsif.2013.0614 }}</ref>
▲*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]] error.<ref>{{cite journal | vauthors = Itzkovitz S, Alon U | title = The genetic code is nearly optimal for allowing additional information within protein-coding sequences | journal = Genome Research | volume = 17| issue = 4 | pages = 405–412 | date = 2007| doi = 10.1101/gr.5987307 | pmid=17293451 | pmc=1832087}}</ref> In contrast, some stereochemical molecular models explain the origin of stop codons as "unassignable".<ref name="pmid21779963"/>
▲==See also==
* [[List of genetic engineering software]]
* [[Codon tables]]
== References ==
{{Reflist}}
== Further reading ==
{{Refbegin}}
* {{cite book |
* {{cite book |
* {{cite book |
* {{cite journal | vauthors = Caskey CT, Leder P | title = The RNA code: nature's Rosetta Stone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 111 | issue = 16 | pages =
{{Refend}}
== External links ==
{{Commons category|Genetic code}}
* [https://www.ncbi.nlm.nih.gov/Taxonomy/taxonomyhome.html/index.cgi?chapter=cgencodes The Genetic Codes: Genetic Code Tables]
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