Editing Genetic code (section)

==Origin==
The genetic code is a key part of the [[origin of life|history of life]], according to one version of which self-replicating RNA molecules preceded life as we know it. This is the [[RNA world hypothesis]]. Under this hypothesis, any model for the emergence of the genetic code is intimately related to a model of the transfer from [[ribozyme]]s (RNA enzymes) to proteins as the principal enzymes in cells. In line with the RNA world hypothesis, transfer RNA molecules appear to have evolved before modern [[aminoacyl-tRNA synthetase]]s, so the latter cannot be part of the explanation of its patterns.<ref name=De1998>{{cite journal | vauthors = Ribas de Pouplana L, Turner RJ, Steer BA, Schimmel P | title = Genetic code origins: tRNAs older than their synthetases? | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 95 | issue = 19 | pages = 11295–300 | date = Sep 1998 | pmid = 9736730 | pmc = 21636 | doi = 10.1073/pnas.95.19.11295 | bibcode = 1998PNAS...9511295D | doi-access = free }}</ref>

A hypothetical randomly evolved genetic code further motivates a biochemical or evolutionary model for its origin. If amino acids were randomly assigned to triplet codons, there would be 1.5&nbsp;×&nbsp;10<sup>84</sup> possible genetic codes.<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>{{rp|[{{google books |plainurl=y |id=-YLBMmJE1WwC|page=163}} 163]}} This number is found by calculating the number of ways that  21 items (20 amino acids plus one stop) can be placed in 64 bins, wherein each item is used at least once.<ref>{{Cite web|url=http://community.wolfram.com/groups/-/m/t/319970|title=Mathematica function for # possible arrangements of items in bins? – Online Technical Discussion Groups—Wolfram Community|website=community.wolfram.com|language=en-US|access-date=2017-02-03}}</ref> However, the distribution of codon assignments in the genetic code is nonrandom.<ref name="pmid9732450">{{cite journal | vauthors = Freeland SJ, Hurst LD | s2cid = 20130470 | title = The genetic code is one in a million | journal = Journal of Molecular Evolution | volume = 47 | issue = 3 | pages = 238–48 | date = Sep 1998 | pmid = 9732450 | doi = 10.1007/PL00006381 | bibcode = 1998JMolE..47..238F }}</ref> In particular, the genetic code clusters certain amino acid assignments.

Amino acids that share the same biosynthetic pathway tend to have the same first base in their codons. This could be an evolutionary relic of an early, simpler genetic code with fewer amino acids that later evolved to code a larger set of amino acids.<ref name="pmid2650752">{{cite journal | vauthors = Taylor FJ, Coates D | title = The code within the codons | journal = Bio Systems | volume = 22 | issue = 3 | pages = 177–87 | date = 1989 | pmid = 2650752 | doi = 10.1016/0303-2647(89)90059-2 | bibcode = 1989BiSys..22..177T }}</ref> It could also reflect steric and chemical properties that had another effect on the codon during its evolution. Amino acids with similar physical properties also tend to have similar codons,<ref name="pmid2514270">{{cite journal | vauthors = Di Giulio M | s2cid = 20803686 | title = The extension reached by the minimization of the polarity distances during the evolution of the genetic code | journal = Journal of Molecular Evolution | volume = 29 | issue = 4 | pages = 288–93 | date = Oct 1989 | pmid = 2514270 | doi = 10.1007/BF02103616 | bibcode = 1989JMolE..29..288D }}</ref><ref name="pmid6928661">{{cite journal | vauthors = Wong JT | title = Role of minimization of chemical distances between amino acids in the evolution of the genetic code | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 77 | issue = 2 | pages = 1083–6 | date = Feb 1980 | pmid = 6928661 | pmc = 348428 | doi = 10.1073/pnas.77.2.1083 | bibcode = 1980PNAS...77.1083W | doi-access = free }}</ref> reducing the problems caused by point mutations and mistranslations.<ref name="pmid9732450"/>

Given the non-random genetic triplet coding scheme, a tenable hypothesis for the origin of genetic code could address multiple aspects of the codon table, such as absence of codons for D-amino acids, secondary codon patterns for some amino acids, confinement of synonymous positions to third position, the small set of only 20 amino acids (instead of a number approaching 64), and the relation of stop codon patterns to amino acid coding patterns.<ref name="pmid21779963">{{cite journal | vauthors = Erives A | title = A model of proto-anti-codon RNA enzymes requiring L-amino acid homochirality | journal = Journal of Molecular Evolution | volume = 73 | issue = 1–2 | pages = 10–22 | date = Aug 2011 | pmid = 21779963 |  doi = 10.1007/s00239-011-9453-4 | pmc=3223571| bibcode = 2011JMolE..73...10E }}</ref>

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>

*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="pmid4887876">{{cite journal | vauthors = Crick FH | title = The origin of the genetic code | journal = Journal of Molecular Evolution | volume = 38 | issue = 3 | pages = 367–79 | date = Dec 1968 | pmid = 4887876 | doi=10.1016/0022-2836(68)90392-6| s2cid = 4144681 }}</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="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"/>
*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>

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| url-access = subscription }}</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 | 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> 
* 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>
*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"/>