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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>
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="Xie_2005">{{cite journal | vauthors = Xie J, Schultz PG | title = Adding amino acids to the genetic repertoire | journal = Current Opinion in Chemical Biology | volume = 9 | issue = 6 | pages = 548–554 | date = December 2005 | pmid = 16260173 | doi = 10.1016/j.cbpa.2005.10.011 }}</ref><ref name="Wang_2009">{{cite journal | vauthors = Wang Q, Parrish AR, Wang L | title = Expanding the genetic code for biological studies | journal = Chemistry & Biology | volume = 16 | issue = 3 | pages = 323–336 | date = March 2009 | pmid = 19318213 | pmc = 2696486 | doi = 10.1016/j.chembiol.2009.03.001 }}</ref>
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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 | vauthors = Hoesl MG, Oehm S, Durkin P, Darmon E, Peil L, Aerni HR, Rappsilber J, Rinehart J, Leach D, Söll D, Budisa N | title = Chemical Evolution of a Bacterial Proteome | journal = Angewandte Chemie | volume = 54 | issue = 34 | pages = 10030–10034 | date = August 2015 | pmid = 26136259 | pmc = 4782924 | doi = 10.1002/anie.201502868 | bibcode = 2015ACIE...5410030H | author-link7 = Juri Rappsilber }} NIHMSID: NIHMS711205</ref>
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 | title = First stable semisynthetic organism created
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 | pages = 14568 | date = February 2017 | pmid = 28220771 | pmc = 5321798 | doi = 10.1038/ncomms14568 | bibcode = 2017NatCo...814568H | article-number = 14568 }}</ref>
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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="Zimmer_2019">{{cite news | vauthors = Zimmer C | title = Scientists Created Bacteria With a Synthetic Genome. Is This Artificial Life? - In a milestone for synthetic biology, colonies of E. coli thrive with DNA constructed from scratch by humans, not nature. | date = 15 May 2019 | url = https://www.nytimes.com/2019/05/15/science/synthetic-genome-bacteria.html | archive-url = https://ghostarchive.org/archive/20220102/https://www.nytimes.com/2019/05/15/science/synthetic-genome-bacteria.html | archive-date = 2022-01-02 | url-access = limited | url-status = live | work = [[The New York Times]] | access-date = 16 May 2019 }}{{cbignore}}</ref><ref name="Fredens_2019">{{cite journal | vauthors = Fredens J, Wang K, de la Torre D, Funke LF, Robertson WE, Christova Y, Chia T, Schmied WH, Dunkelmann DL, Beránek V, Uttamapinant C, Llamazares AG, Elliott TS, Chin JW | title = Total synthesis of Escherichia coli with a recoded genome | journal = Nature | volume = 569 | issue = 7757 | pages = 514–518 | date = May 2019 | pmid = 31092918 | pmc = 7039709 | doi = 10.1038/s41586-019-1192-5 | s2cid = 205571025 | bibcode = 2019Natur.569..514F }}</ref>
In 2025, researchers reported a new "Syn57" strain, which removes the use of 7 out of 64 codons completely.<ref>{{cite journal | vauthors = Robertson WE, Rehm FB, Spinck M, Schumann RL, Tian R, Liu W, Gu Y, Kleefeldt AA, Day CF, Liu KC, Christova Y, Zürcher JF, Böge FL, Birnbaum J, van Bijsterveldt L, Chin JW | title = <i>Escherichia coli</i> with a 57-codon genetic code | journal = Science |
==Features==
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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="Touriol_2003">{{cite journal | vauthors = Touriol C, Bornes S, Bonnal S, Audigier S, Prats H, Prats AC, Vagner S | title = Generation of protein isoform diversity by alternative initiation of translation at non-AUG codons | journal = Biology of the Cell | volume = 95 | issue = 3–4 | pages = 169–178 | date = 2003 | pmid = 12867081 | doi = 10.1016/S0248-4900(03)00033-9 | doi-access = free }}</ref>
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 =
===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 | chapter = Spontaneous mutations | title = An Introduction to Genetic Analysis | ___location = New York | date = 2000 |
[[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="Chang_1979">{{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 = 2886–2889 | date = June 1979 | pmid = 88735 | pmc = 383714 | doi = 10.1073/pnas.76.6.2886 | doi-access = free | bibcode = 1979PNAS...76.2886C }}</ref><ref name="Boillee_2006">{{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> 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 | vauthors = King RC, Mulligan P, Stansfield W | title = A Dictionary of Genetics | pages = 608 | date = 10 January 2013 | url = {{google books | plainurl = y | id = 5jhH0HTjEdkC}}|publisher=OUP USA|isbn=978-0-19-976644-4}}</ref>
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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 = Crick FH | title = The origin of the genetic code | journal = Journal of Molecular Biology | volume = 38 | issue = 3 | pages = 367–379 | date = December 1968 | pmid = 4887876 | doi = 10.1016/0022-2836(68)90392-6 }}</ref> The first variation was discovered in 1979, by researchers studying [[human mitochondrial genetics|human mitochondrial genes]].<ref>
{{cite journal | vauthors = Barrell BG, Bankier AT, Drouin J | title = A different genetic code in human mitochondria | journal = Nature | volume = 282 | issue = 5735 | pages = 189–194 | date = November 1979 | pmid = 226894 | doi = 10.1038/282189a0 | bibcode = 1979Natur.282..189B | s2cid = 4335828 }} ([https://www.ncbi.nlm.nih.gov/pubmed/226894])</ref> Many slight variants were discovered thereafter,<ref name="Elzanowski_2008" /> including various alternative mitochondrial codes.<ref>{{cite journal | vauthors = Jukes TH, Osawa S | title = The genetic code in mitochondria and chloroplasts | journal = Experientia | volume = 46 | issue = 11–12 | pages = 1117–1126 | date = December 1990 | pmid = 2253709 | doi = 10.1007/BF01936921 | s2cid = 19264964 }}</ref> These minor variants for example involve translation of the codon UGA as [[tryptophan]] in ''[[Mycoplasma]]'' species, and translation of CUG as a serine rather than leucine in yeasts of the "CTG clade" (such as ''[[Candida albicans]]'').<ref>{{cite journal | vauthors = Fitzpatrick DA, Logue ME, Stajich JE, Butler G | title = A fungal phylogeny based on 42 complete genomes derived from supertree and combined gene analysis | journal = BMC Evolutionary Biology | volume = 6 | pages = 99 | date = November 2006 | pmid = 17121679 | pmc = 1679813 | doi = 10.1186/1471-2148-6-99 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Santos MA, Tuite MF | title = The CUG codon is decoded in vivo as serine and not leucine in Candida albicans | journal = Nucleic Acids Research | volume = 23 | issue = 9 | pages = 1481–1486 | date = May 1995 | pmid = 7784200 | pmc = 306886 | doi = 10.1093/nar/23.9.1481 }}</ref><ref>{{cite journal | vauthors = Butler G, Rasmussen MD, Lin MF, Santos MA, Sakthikumar S, Munro CA, Rheinbay E, Grabherr M, Forche A, Reedy JL, Agrafioti I, Arnaud MB, Bates S, Brown AJ, Brunke S, Costanzo MC, Fitzpatrick DA, de Groot PW, Harris D, Hoyer LL, Hube B, Klis FM, Kodira C, Lennard N, Logue ME, Martin R, Neiman AM, Nikolaou E, Quail MA, Quinn J, Santos MC, Schmitzberger FF, Sherlock G, Shah P, Silverstein KA, Skrzypek MS, Soll D, Staggs R, Stansfield I, Stumpf MP, Sudbery PE, Srikantha T, Zeng Q, Berman J, Berriman M, Heitman J, Gow NA, Lorenz MC, Birren BW, Kellis M, Cuomo CA | title = Evolution of pathogenicity and sexual reproduction in eight Candida genomes | journal = Nature | volume = 459 | issue = 7247 | pages = 657–662 | date = June 2009 | pmid = 19465905 | pmc = 2834264 | doi = 10.1038/nature08064 | bibcode = 2009Natur.459..657B }}</ref> 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 [[totivirus]]es have adapted to the host's genetic code modification.<ref name="Taylor_2013">{{cite journal | vauthors = Taylor DJ, Ballinger MJ, Bowman SM, Bruenn JA | title = Virus-host co-evolution under a modified nuclear genetic code | journal = PeerJ | volume = 1 | pages = e50 | date = 2013 | pmid = 23638388 | pmc = 3628385 | doi = 10.7717/peerj.50 | doi-access = free }}</ref> In [[bacteria]] and [[archaea]], GUG and UUG are common start codons. In rare cases, certain proteins may use alternative start codons.<ref name="Elzanowski_2008">{{cite web | vauthors = Elzanowski A, Ostell J | title = The Genetic Codes | date = 2008-04-07 | url = https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi?mode=c | publisher = National Center for Biotechnology Information (NCBI) | access-date = 2010-03-10 }}</ref>
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="Hofhuis_2016">{{cite journal | vauthors = Hofhuis J, Schueren F, Nötzel C, Lingner T, Gärtner J, Jahn O, Thoms S | title = The functional readthrough extension of malate dehydrogenase reveals a modification of the genetic code | journal = Open Biology | volume = 6 | issue = 11 | pages = 160246 | date = November 2016 | pmid = 27881739 | pmc = 5133446 | doi = 10.1098/rsob.160246 }}</ref> This type of recoding is induced by a high-readthrough stop codon context<ref name="Schueren_2014">{{cite journal | vauthors = Schueren F, Lingner T, George R, Hofhuis J, Dickel C, Gärtner J, Thoms S | title = Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals | journal =
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 Condylostoma magnum | journal = Molecular Biology and Evolution | volume = 33 | issue = 11 | pages = 2885–2889 | date = November 2016 | pmid = 27501944 | pmc = 5062323 | doi = 10.1093/molbev/msw166 }}</ref> or trigger [[ribosomal frameshift]]ing as in ''[[Euplotes]]''.<ref>{{cite journal | vauthors = Lobanov AV, Heaphy SM, Turanov AA, Gerashchenko MV, Pucciarelli S, Devaraj RR, Xie F, Petyuk VA, Smith RD, Klobutcher LA, Atkins JF, Miceli C, Hatfield DL, Baranov PV, Gladyshev VN | title = Position-dependent termination and widespread obligatory frameshifting in Euplotes translation | journal = Nature Structural & Molecular Biology | volume = 24 | issue = 1 | pages = 61–68 | date = January 2017 | pmid = 27870834 | pmc = 5295771 | doi = 10.1038/nsmb.3330 }}</ref>
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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="Dutilh_2011">{{cite journal | vauthors = Dutilh BE, Jurgelenaite R, Szklarczyk R, van Hijum SA, Harhangi HR, Schmid M, de Wild B, Françoijs KJ, Stunnenberg HG, Strous M, Jetten MS, Op den Camp HJ, Huynen MA | title = FACIL: Fast and Accurate Genetic Code Inference and Logo | journal = Bioinformatics | volume = 27 | issue = 14 | pages = 1929–1933 | date = July 2011 | pmid = 21653513 | pmc = 3129529 | doi = 10.1093/bioinformatics/btr316 }}</ref>
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 | vauthors = Shulgina Y, Eddy SR | title = A computational screen for alternative genetic codes in over 250,000 genomes | 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 | vauthors = Fried SD, Fujishima K, Makarov M, Cherepashuk I, Hlouchova K | title = Peptides before and during the nucleotide world: an origins story emphasizing cooperation between proteins and nucleic acids | journal = Journal of the Royal Society, Interface | volume = 19 | issue = 187 |
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="Freeland_1998">{{cite journal | vauthors = Freeland SJ, Hurst LD | title = The genetic code is one in a million | journal = Journal of Molecular Evolution | volume = 47 | issue = 3 | pages = 238–248 | date = September 1998 | pmid = 9732450 | doi = 10.1007/PL00006381 | s2cid = 20130470 | bibcode = 1998JMolE..47..238F }}</ref> Biochemically similar amino acids tend to share the same middle nucleotide, while synonymous changes generally happen at the third nucleotide.
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Hypotheses have addressed a variety of scenarios:<ref name="Knight_1999">{{cite journal | vauthors = Knight RD, Freeland SJ, Landweber LF | title = Selection, history and chemistry: the three faces of the genetic code | journal = Trends in Biochemical Sciences | volume = 24 | issue = 6 | pages = 241–247 | date = June 1999 | pmid = 10366854 | doi = 10.1016/S0968-0004(99)01392-4 }}</ref>
* 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="Knight_1998">{{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–R220 | date = September 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="Yarus_2010">{{cite book | vauthors = Yarus M | title = Life from an RNA World: The Ancestor Within | year = 2010 | url = {{google books | plainurl = y | id = -YLBMmJE1WwC}}|publisher=Harvard University Press|isbn=978-0-674-05075-4}}</ref><ref name="Yarus_2009">{{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 = 406–429 | date = November 2009 | pmid = 19795157 | doi = 10.1007/s00239-009-9270-1 | doi-access = free | bibcode = 2009JMolE..69..406Y }}</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 | title = Pathways of Genetic Code Evolution in Ancient and Modern Organisms | journal = Journal of Molecular Evolution | volume = 80 | issue = 5–6 | pages = 229–243 | date = June 2015 | pmid = 26054480 | doi = 10.1007/s00239-015-9686-8 | s2cid = 15542587 | 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="Brooks_2002">{{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 = 1645–1655 | date = October 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="Amirnovin_1997">{{cite journal | vauthors = Amirnovin R | title = An analysis of the metabolic theory of the origin of the genetic code | journal = Journal of Molecular Evolution | volume = 44 | issue = 5 | pages = 473–476 | date = May 1997 | pmid = 9115171 | doi = 10.1007/PL00006170 | s2cid = 23334860 | bibcode = 1997JMolE..44..473A }}</ref><ref name="Ronneberg_2000">{{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 = 13690–13695 | date = December 2000 | pmid = 11087835 | pmc = 17637 | doi = 10.1073/pnas.250403097 | doi-access = free | bibcode = 2000PNAS...9713690R }}</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 | vauthors = Trifonov EN | title = The origin of the genetic code and of the earliest oligopeptides | journal = Research in Microbiology | volume = 160 | issue = 7 | pages = 481–486 | date = September 2009 | pmid = 19524038 | doi = 10.1016/j.resmic.2009.05.004 }}</ref><ref>{{cite journal | vauthors = Higgs PG, Pudritz RE | title = A thermodynamic basis for prebiotic amino acid synthesis and the nature of the first genetic code | journal = Astrobiology | volume = 9 | issue = 5 | pages = 483–490 | date = June 2009 | pmid = 19566427 | doi = 10.1089/ast.2008.0280 | arxiv = 0904.0402 | s2cid = 9039622 | bibcode = 2009AsBio...9..483H }}</ref><ref>{{cite journal | vauthors = Chaliotis A, Vlastaridis P, Mossialos D, Ibba M, Becker HD, Stathopoulos C, Amoutzias GD | title = The complex evolutionary history of aminoacyl-tRNA synthetases | journal = Nucleic Acids Research | volume = 45 | issue = 3 | pages = 1059–1068 | date = February 2017 | pmid = 28180287 | pmc = 5388404 | doi = 10.1093/nar/gkw1182 }}</ref><ref>{{cite journal | vauthors = Ntountoumi C, Vlastaridis P, Mossialos D, Stathopoulos C, Iliopoulos I, Promponas V, Oliver SG, Amoutzias GD | title = Low complexity regions in the proteins of prokaryotes perform important functional roles and are highly conserved | journal = Nucleic Acids Research | volume = 47 | issue = 19 | pages = 9998–10009 | date = November 2019 | pmid = 31504783 | pmc = 6821194 | doi = 10.1093/nar/gkz730 }}</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="Wehbi_2024">{{cite journal | vauthors = Wehbi S, Wheeler A, Morel B, Manepalli N, Minh BQ, Lauretta DS, Masel J | 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 of the United States of America | volume = 121 | issue = 52 |
* Natural selection has led to codon assignments of the genetic code that minimize the effects of [[mutation]]s.<ref name="Freeland_2003">{{cite journal | vauthors = Freeland SJ, Wu T, Keulmann N | 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 = 457–477 | date = October 2003 | pmid = 14604186 | doi = 10.1023/A:1025771327614 | s2cid = 18823745 | bibcode = 2003OLEB...33..457F }}</ref> A recent hypothesis<ref name="Baranov_2009">{{cite journal | vauthors = Baranov PV, Venin M, Provan G | title = Codon size reduction as the origin of the triplet genetic code | journal =
* 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="Tlusty_2007">{{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 = 331–342 | date = November 2007 | pmid = 17826800 | doi = 10.1016/j.jtbi.2007.07.029 | arxiv = 1007.4122 | s2cid = 12206140 | bibcode = 2007JThBi.249..331T }}</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 | ___location = New York | pages = 377–397 | date = 1965 | publisher = Academic Press }}</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 | pages = 048101 | date = February 2008 | pmid = 18352335 | doi = 10.1103/PhysRevLett.100.048101 | arxiv = 1007.4149 | s2cid = 12246664 | bibcode = 2008PhRvL.100d8101T | article-number = 048101 }}</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="Sella_2006">{{cite journal | vauthors = Sella G, Ardell DH | 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 = September 2006 | pmid = 16838217 | doi = 10.1007/s00239-004-0176-7 | s2cid = 1260806 | bibcode = 2006JMolE..63..297S }}</ref> for error-tolerance<ref name="Freeland_2003" /> 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 = 362–376 | date = September 2010 | pmid = 20558115 | doi = 10.1016/j.plrev.2010.06.002 | arxiv = 1007.3906 | s2cid = 1845965 | bibcode = 2010PhLRv...7..362T }}</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="Jee_2013">{{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 = November 2013 | pmid = 23985735 | pmc = 3785830 | doi = 10.1098/rsif.2013.0614 }}</ref>
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