Editing Genetic code (section)

==Alternative genetic codes==
{{See also|DNA and RNA codon tables#Alternative codons}}

=== 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 = 20740–51 | date = May 2005 | pmid = 15788401 | doi = 10.1074/jbc.M501458200 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1071&context=biochemgladyshev | doi-access = free }}</ref> Although the genetic code is normally fixed in an organism, the achaeal prokaryote ''[[Acetohalobium arabaticum]]'' can expand its genetic code from 20 to 21 amino acids (by including pyrrolysine) under different conditions of growth.<ref name=Prat2012>{{cite journal | vauthors = Prat L, Heinemann IU, Aerni HR, Rinehart J, O'Donoghue P, Söll D | title = Carbon source-dependent expansion of the genetic code in bacteria | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 51 | pages = 21070–5 | date = Dec 2012 | pmid = 23185002 | pmc = 3529041 | doi = 10.1073/pnas.1218613110 | bibcode = 2012PNAS..10921070P | doi-access = free }}</ref>

=== 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="DutilhJurgelenaite2011"/> The logo shows the 64 codons from left to right, predicted alternatives in red (relative to the standard genetic code). Red line: stop codons. The height of each amino acid in the stack shows how often it is aligned to the codon in homologous protein domains. The stack height indicates the support for the prediction.]]
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>{{Cite journal |last=Crick |first=F.H.C. |date=1968-12-28 |title=The origin of the genetic code |url=https://linkinghub.elsevier.com/retrieve/pii/0022283668903926 |journal=Journal of Molecular Biology |language=en |volume=38 |issue=3 |pages=367–379 |doi=10.1016/0022-2836(68)90392-6|pmid=4887876 |url-access=subscription }}</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 |date=1979 |title=A different genetic code in human mitochondria |journal=Nature |volume=282 |issue=5735 |pages=189–194 |bibcode=1979Natur.282..189B |doi=10.1038/282189a0 |pmid=226894 |s2cid=4335828}} ([https://www.ncbi.nlm.nih.gov/pubmed/226894])</ref> Many slight variants were discovered thereafter,<ref name="url_The_Genetic_Codes_NCBI"/> including various alternative mitochondrial codes.<ref>{{cite journal | vauthors = Jukes TH, Osawa S | s2cid = 19264964 | title = The genetic code in mitochondria and chloroplasts | journal = Experientia | volume = 46 | issue = 11–12 | pages = 1117–26 | date = Dec 1990 | pmid = 2253709 | doi = 10.1007/BF01936921 }}</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 = 1 January 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 = 1481–6 | 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 | display-authors = 3 | title = Evolution of pathogenicity and sexual reproduction in eight Candida genomes | journal = Nature | volume = 459 | issue = 7247 | pages = 657–62 | date = Jun 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="pmid23638388">{{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="url_The_Genetic_Codes_NCBI">{{cite web | url = https://www.ncbi.nlm.nih.gov/Taxonomy/Utils/wprintgc.cgi?mode=c | title = The Genetic Codes | vauthors = Elzanowski A, Ostell J | date = 2008-04-07| 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="pmid27881739">{{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 Biol | volume = 6 | issue = 11 | pages = 160246 | date = 2016 | pmid = 27881739 | doi = 10.1098/rsob.160246 | pmc=5133446}}</ref> This type of recoding is induced by a high-readthrough stop codon context<ref name="pmid25247702">{{cite journal | vauthors = Schueren F, Lingner T, George R, Hofhuis J, Gartner J, Thoms S | title = Peroxisomal lactate dehydrogenase is generated by translational readthrough in mammals | journal = eLife | volume = 3 | pages = e03640 | date = 2014 | pmid = 25247702 | doi = 10.7554/eLife.03640 | pmc=4359377 | doi-access = free }}</ref> and it is referred to as ''functional translational readthrough''.<ref name="PMC4973966">{{cite journal|author=F. Schueren und S. Thoms |title=Functional Translational Readthrough: A Systems Biology Perspective |journal=PLOS Genetics |volume=12 |issue=8 |page=e1006196  |date=2016 |pmid=27490485 |pmc=4973966 |doi=10.1371/journal.pgen.1006196 |doi-access=free }}</ref>

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 | display-authors = 6 | 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>

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 Evolution of the Genetic Code: The Universal Enigma | journal = IUBMB Life | volume = 61 | issue = 2 | pages = 91–111 | date = February 2009 | doi = 10.1002/iub.146 | pmid = 19117371 | pmc = 3293468 }}</ref><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 | doi = 10.1007/s00239-015-9686-8 | pmid = 26054480 | bibcode = 2015JMolE..80..229S | s2cid = 15542587 }}</ref> and some studies have been done experimentally evolving the genetic code of some organisms.<ref>{{cite journal | vauthors = Xie J, Schultz PG | title = A chemical toolkit for proteins--an expanded genetic code | journal = Nature Reviews Molecular Cell Biology | volume = 7 | issue = 10 | pages = 775–782 | date = August 2006 | doi = 10.1038/nrm2005 | pmid = 16926858 | s2cid = 19385756 }}</ref><ref>{{cite journal | vauthors = Neumann H, Wang K, Davis L, Garcia-Alai M, Chin JW | title = Encoding multiple unnatural amino acids via evolution of a quadruplet-decoding ribosome | journal = Nature | volume = 18 | issue = 464 | pages = 441–444 | date = March 2010 | doi = 10.1038/nrm2005 | pmid = 16926858 | s2cid = 19385756 }}</ref><ref>{{cite journal | vauthors = Liu CC, Schultz PG | title = Adding new chemistries to the genetic code | journal = Annual Review of Biochemistry | volume = 79 | pages = 413–444 | date = 2010 | doi = 10.1146/annurev.biochem.052308.105824 | pmid = 20307192 }}</ref><ref>{{cite journal | vauthors = Chin JW | title = Expanding and reprogramming the genetic code of cells and animals | journal = Annual Review of Biochemistry | volume = 83 | pages = 379–408 | date = February 2014 | doi = 10.1146/annurev-biochem-060713-035737 | pmid = 24555827 }}</ref>

=== 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="DutilhJurgelenaite2011">{{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 = 1929–33 | date = Jul 2011 | pmid = 21653513 | doi = 10.1093/bioinformatics/btr316 | pmc=3129529}}</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 |last1=Shulgina |first1=Y |last2=Eddy |first2=SR |title=A computational screen for alternative genetic codes in over 250,000 genomes. |journal=eLife |date=9 November 2021 |volume=10 |doi=10.7554/eLife.71402 |pmid=34751130|pmc=8629427 |doi-access=free }}</ref> Codetta was later used to analyze genetic code change in [[ciliates]].<ref>{{cite journal |last1=Chen |first1=W |last2=Geng |first2=Y |last3=Zhang |first3=B |last4=Yan |first4=Y |last5=Zhao |first5=F |last6=Miao |first6=M |title=Stop or Not: Genome-Wide Profiling of Reassigned Stop Codons in Ciliates. |journal=Molecular Biology and Evolution |date=4 April 2023 |volume=40 |issue=4 |doi=10.1093/molbev/msad064 |pmid=36952281 |pmc=10089648}}</ref>