Genetic code: Difference between revisions

Revision as of 14:36, 31 October 2024

Revision as of 07:39, 2 November 2024

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[[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>Francis Crick, 1968. "The Origin of the Genetic Code". J. Mol. Biol.</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 | doi-broken-date = 31 October 2024 }}</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 | doi-broken-date = 31 October 2024 | 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 ===

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Hypotheses have addressed a variety of scenarios:<ref name="pmid10366854">{{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 = 241–7 | date = Jun 1999 | pmid = 10366854|doi=10.1016/S0968-0004(99)01392-4|url=https://www.sciencedirect.com/science/article/abs/pii/S0968000499013924}}</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="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" /><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 | doi-broken-date = 31 October 2024 | 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}}</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>

* 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 | pages = 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>