genetic code

{{Short description|Rules by which information encoded within genetic material is translated into proteins}}

File:RNA-codon.svg (mRNA) molecule. Each codon consists of three nucleotides, 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.]]

The genetic code is the set of rules used by living cells to translate information encoded within genetic material (DNA or RNA sequences of nucleotide triplets or codons) into proteins. Translation is accomplished by the ribosome, which links proteinogenic amino acids in an order specified by messenger RNA (mRNA), using transfer RNA (tRNA) molecules to carry amino acids and to read the mRNA three nucleotides 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,{{cite journal | vauthors = Turanov AA, Lobanov AV, Fomenko DE, Morrison HG, Sogin ML, Klobutcher LA, Hatfield DL, Gladyshev VN | title = Genetic code supports targeted insertion of two amino acids by one codon | journal = Science | volume = 323 | issue = 5911 | pages = 259–61 | date = Jan 2009 | pmid = 19131629 | pmc = 3088105 | doi = 10.1126/science.1164748 }} a three-nucleotide codon in a nucleic acid sequence specifies a single amino acid. The vast majority of genes are encoded with a single scheme (see the RNA codon table). That scheme is often called the canonical or standard genetic code, or simply the genetic code, though variant codes (such as in mitochondria) exist.

History

File:GeneticCode21-version-2.svg{{Further|Adaptor hypothesis}}

Efforts to understand how proteins are encoded began after 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.{{Cite journal |last1=Watson |first1=J. D. |last2=Crick |first2=F. H. |date=1953-05-30 |title=Genetical implications of the structure of deoxyribonucleic acid |url=https://pubmed.ncbi.nlm.nih.gov/13063483 |journal=Nature |volume=171 |issue=4361 |pages=964–967 |doi=10.1038/171964b0 |issn=0028-0836 |pmid=13063483 |bibcode=1953Natur.171..964W |s2cid=4256010}} Soviet-American physicist George Gamow was the first to give a workable scheme for protein synthesis from DNA.{{Cite journal |last=Stegmann |first=Ulrich E. |date=2016-09-01 |title='Genetic Coding' Reconsidered: An Analysis of Actual Usage |journal=The British Journal for the Philosophy of Science |language=en |volume=67 |issue=3 |pages=707–730 |doi=10.1093/bjps/axv007 |issn=0007-0882 |pmc=4990703 |pmid=27924115}} He postulated that sets of three bases (triplets) must be employed to encode the 20 standard amino acids used by living cells to build proteins, which would allow a maximum of {{nowrap|4{{smallsup|3}} {{=}} 64}} amino acids.{{cite book|first=Francis|last=Crick|title=What Mad Pursuit: A Personal View of Scientific Discovery|authorlink=Francis Crick|chapter-url={{google books|plainurl=y |id=awoXBQAAQBAJ|page=89}}|date=10 July 1990|publisher=Basic Books|oclc=1020240407|pages=89–101|isbn=9780465091386|chapter=Chapter 8: The Genetic Code}}{{Dead link|date=May 2024 |bot=InternetArchiveBot |fix-attempted=yes }} He named this DNA–protein interaction (the original genetic code) as the "diamond code".{{Cite journal |last=Hayes |first=Brian |date=1998 |title=Computing Science: The Invention of the Genetic Code |url=https://www.jstor.org/stable/27856930 |journal=American Scientist |volume=86 |issue=1 |pages=8–14 |doi=10.1511/1998.17.3338 |jstor=27856930 |s2cid=121907709 |issn=0003-0996}}

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 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.{{Cite journal |last=Strauss |first=Bernard S |date=2019-03-01 |title=Martynas Yčas: The "Archivist" of the RNA Tie Club |url=https://doi.org/10.1534/genetics.118.301754 |journal=Genetics |volume=211 |issue=3 |pages=789–795 |doi=10.1534/genetics.118.301754 |issn=1943-2631 |pmc=6404253 |pmid=30846543}}

The first scientific contribution of the club, later recorded as "one of the most important unpublished articles in the history of science"{{Cite web |title=Francis Crick - Profiles in Science Search Results |url=https://profiles.nlm.nih.gov/spotlight/sc/catalog?f%5breadonly_nlm-id_ssim%5d%5b%5d=101584582X73 |access-date=2022-07-21 |website=profiles.nlm.nih.gov}} and "the most famous unpublished paper in the annals of molecular biology",{{Cite journal |last=Fry |first=Michael |date=2022 |title=Crick's Adaptor Hypothesis and the Discovery of Transfer RNA: Experiment Surpassing Theoretical Prediction |url=https://journals.publishing.umich.edu/ptpbio/article/id/2628/ |journal=Philosophy, Theory, and Practice in Biology |volume=14 |doi=10.3998/ptpbio.2628 |issn=2475-3025 |s2cid=249112573|doi-access=free }} was made by Crick. Crick presented a type-written paper titled "On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club"{{Cite web |last=Crick |first=Francis |date=1955 |title=On Degenerate Templates and the Adaptor Hypothesis: A Note for the RNA Tie Club |url=https://collections.nlm.nih.gov/catalog/nlm:nlmuid-101584582X73-doc |access-date=2022-07-21 |website=National Library of Medicine}} to the members of the club in January 1955, which "totally changed the way we thought about protein synthesis", as Watson recalled.{{Cite book |last=Watson |first=James D. |url=https://books.google.com/books?id=mav7RvFfjDkC |title=Avoid Boring People: Lessons from a Life in Science |date=2007 |publisher=Oxford University Press |isbn=978-0-19-280273-6 |pages=112 |language=en |oclc=47716375}} The hypothesis states that the triplet code was not passed on to amino acids as Gamow thought, but carried by a different molecule, an adaptor, that interacts with amino acids. The adaptor was later identified as tRNA.{{Cite journal |last1=Barciszewska |first1=Mirosława Z. |last2=Perrigue |first2=Patrick M. |last3=Barciszewski |first3=Jan |date=2016 |title=tRNA--the golden standard in molecular biology |url=https://pubmed.ncbi.nlm.nih.gov/26549858 |journal=Molecular BioSystems |volume=12 |issue=1 |pages=12–17 |doi=10.1039/c5mb00557d |pmid=26549858}}

=Codons=

The 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.{{cite journal|last=Yanofsky|first=Charles|date=9 March 2007|title=Establishing the Triplet Nature of the Genetic Code|journal=Cell|volume=128|issue=5|pages=815–818|doi=10.1016/j.cell.2007.02.029|pmid=17350564|s2cid=14249277|doi-access=free}} They used a cell-free system to translate a poly-uracil RNA sequence (i.e., UUUUU...) and discovered that the polypeptide that they had synthesized consisted of only the amino acid phenylalanine.{{cite journal | vauthors = Nirenberg MW, Matthaei JH | title = The dependence of cell-free protein synthesis in E. coli upon naturally occurring or synthetic polyribonucleotides | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 47 | issue = 10 | pages = 1588–602 | date = Oct 1961 | pmid = 14479932 | pmc = 223178 | doi = 10.1073/pnas.47.10.1588 | bibcode = 1961PNAS...47.1588N | doi-access = free }} They thereby deduced that the codon UUU specified the amino acid phenylalanine.

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{{cite journal | vauthors = Gardner RS, Wahba AJ, Basilio C, Miller RS, Lengyel P, Speyer JF | title = Synthetic polynucleotides and the amino acid code. VII | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 48 | issue = 12 | pages = 2087–94 | date = Dec 1962 | pmid = 13946552 | pmc = 221128 | doi = 10.1073/pnas.48.12.2087 | bibcode = 1962PNAS...48.2087G | doi-access = free }} and that the poly-cytosine RNA sequence (CCCCC...) coded for the polypeptide poly-proline.{{cite journal | vauthors = Wahba AJ, Gardner RS, Basilio C, Miller RS, Speyer JF, Lengyel P | title = Synthetic polynucleotides and the amino acid code. VIII | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 49 | issue = 1 | pages = 116–22 | date = Jan 1963 | pmid = 13998282 | pmc = 300638 | doi = 10.1073/pnas.49.1.116 | bibcode = 1963PNAS...49..116W | doi-access = free }} Therefore, the codon AAA specified the amino acid lysine, and the codon CCC specified the amino acid proline. Using various copolymers most of the remaining codons were then determined.

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.{{cite press release |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1959/index.html |title=The Nobel Prize in Physiology or Medicine 1959 |quote=The Nobel Prize in Physiology or Medicine 1959 was awarded jointly to Severo Ochoa and Arthur Kornberg 'for their discovery of the mechanisms in the biological synthesis of ribonucleic acid and deoxyribonucleic acid'. |publisher=The Royal Swedish Academy of Science |date=1959 |access-date=2010-02-27}}

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 ribosomes, the components of cells that 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.{{cite journal | vauthors = Nirenberg M, Leder P, Bernfield M, Brimacombe R, Trupin J, Rottman F, O'Neal C | title = RNA codewords and protein synthesis, VII. On the general nature of the RNA code | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 53 | issue = 5 | pages = 1161–8 | date = May 1965 | pmid = 5330357 | pmc = 301388 | doi = 10.1073/pnas.53.5.1161 | bibcode = 1965PNAS...53.1161N | doi-access = free }} Khorana, Holley and Nirenberg received the Nobel Prize (1968) for their work.{{cite press release |url=http://nobelprize.org/nobel_prizes/medicine/laureates/1968/index.html |title=The Nobel Prize in Physiology or Medicine 1968 |quote=The Nobel Prize in Physiology or Medicine 1968 was awarded jointly to Robert W. Holley, Har Gobind Khorana and Marshall W. Nirenberg 'for their interpretation of the genetic code and its function in protein synthesis'. |publisher=The Royal Swedish Academy of Science |date=1968 |access-date=2010-02-27}}

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.{{cite journal|date=Oct 2004|title=The genome of bacteriophage T4: an archeological dig|journal=Genetics|volume=168|issue=2|pages=575–82|pmc=1448817|pmid=15514035|vauthors=Edgar B|doi=10.1093/genetics/168.2.575}} The other two stop codons were named "ochre" and "opal" in order to keep the "color names" theme.

= Expanded genetic codes (synthetic biology) =

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.{{Cite book| title = The book at the Wiley Online Library

| doi = 10.1002/3527607188

| isbn = 9783527312436

|last1 = Budisa|first1 = Nediljko| date = 2005-12-23

}}

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.{{cite journal

| last1 = Kubyshkin | first1 = V.

| last2 = Budisa | first2 = N.

| year = 2018

| title = Synthetic alienation of microbial organisms by using genetic code engineering: Why and how?

| journal = Biotechnology Journal

| volume = 12

| issue = 8

| pages = 16000933

| doi = 10.1002/biot.201600097

| pmid = 28671771

}}

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.{{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 = 548–54 | date = December 2005 | pmid = 16260173 | doi = 10.1016/j.cbpa.2005.10.011 }}{{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 = 323–36 | date = March 2009 | pmid = 19318213 | pmc = 2696486 | doi = 10.1016/j.chembiol.2009.03.001 }}

H. Murakami and M. Sisido extended some codons to have four and five bases. Steven A. Benner constructed a functional 65th (in vivo) codon.{{cite book|first=Matthew |last=Simon | name-list-style = vanc | title = Emergent Computation: Emphasizing Bioinformatics|url={{google books |plainurl=y |id=Uxg51oZNkIsC|page=105}}|date=7 January 2005|publisher=Springer Science & Business Media|isbn=978-0-387-22046-8|pages=105–106}}

In 2015 N. Budisa, 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 bacterium E. coli.{{cite journal | last1 = Hoesl | first1 = M. G. | last2 = Oehm | first2 = S. | last3 = Durkin | first3 = P. | last4 = Darmon | first4 = E. | last5 = Peil | first5 = L. | last6 = Aerni | first6 = H.-R. | last7 = Rappsilber | first7 = J. | author-link7=Juri Rappsilber | last8 = Rinehart | first8 = J. | last9 = Leach | first9 = D. | last10 = Söll | first10 = D. | last11 = Budisa | first11 = N. | year = 2015 | title = Chemical evolution of a bacterial proteome | journal = Angewandte Chemie International Edition | volume = 54 | issue = 34 | pages = 10030–10034 | doi = 10.1002/anie.201502868 | pmc = 4782924 | pmid=26136259 }} NIHMSID: NIHMS711205

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.{{cite web|url=http://www.kurzweilai.net/first-stable-semisynthetic-organism-created|title=First stable semisynthetic organism created {{!}} KurzweilAI|date=3 February 2017|website=www.kurzweilai.net|access-date=2017-02-09}}{{cite journal | vauthors = Zhang Y, Lamb BM, Feldman AW, Zhou AX, Lavergne T, Li L, Romesberg FE | title = A semisynthetic organism engineered for the stable expansion of the genetic alphabet| journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 6 | pages = 1317–1322 | date = February 2017 | pmid = 28115716 | doi = 10.1073/pnas.1616443114 | pmc=5307467| bibcode = 2017PNAS..114.1317Z| doi-access = free}}

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.{{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 | doi = 10.1038/ncomms14568 | pmc=5321798| bibcode = 2017NatCo...814568H }}

In May 2019, researchers reported the creation of a new "Syn61" strain of the E. coli bacteria. This strain has a fully 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 viable and grows 1.6× slower than its wild-type counterpart "MDS42".{{cite news |last=Zimmer |first=Carl |author-link=Carl Zimmer |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. |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 |date=15 May 2019 |work=The New York Times |access-date=16 May 2019 }}{{cbignore}}{{cite journal |author=Fredens, Julius |s2cid=205571025 |display-authors=et al. |title=Total synthesis of Escherichia coli with a recoded genome |date=15 May 2019 |journal=Nature |volume=569 |issue=7757 |pages=514–518 |doi=10.1038/s41586-019-1192-5 |pmid=31092918 |pmc=7039709 |bibcode=2019Natur.569..514F }}

Features

File:Homo sapiens-mtDNA~NC 012920-ATP8+ATP6 Overlap.svg and MT-ATP6 (in black: positions 8,525 to 8,580 in the sequence accession NC_012920Homo sapiens mitochondrion, complete genome. [https://www.ncbi.nlm.nih.gov/nuccore/NC_012920.1 "Revised Cambridge Reference Sequence (rCRS): accession NC_012920"], National Center for Biotechnology Information. Retrieved on 27 December 2017.). There are three possible reading frames in the 5' → 3' forward direction, starting on the first (+1), second (+2) and third position (+3). For each codon (square brackets), the amino acid is given by the vertebrate mitochondrial code, either in the +1 frame for MT-ATP8 (in red) or in the +3 frame for MT-ATP6 (in blue). The MT-ATP8 genes terminates with the TAG stop codon (red dot) in the +1 frame. The MT-ATP6 gene starts with the ATG codon (blue circle for the M amino acid) in the +3 frame.]]

=Reading frame=

A reading frame is defined by the initial triplet of nucleotides from which translation starts. It sets the frame for a run of successive, non-overlapping codons, which is known as an "open reading frame" (ORF). For example, the string 5'-AAATGAACG-3' (see figure), if read from the first position, contains the codons AAA, TGA, and ACG ; if read from the second position, it contains the codons AAT and GAA ; and if read from the third position, it contains the codons ATG and AAC. Every sequence can, thus, be read in its 5' → 3' direction in three reading frames, each producing a possibly distinct amino acid sequence: in the given example, Lys (K)-Trp (W)-Thr (T), Asn (N)-Glu (E), or Met (M)-Asn (N), respectively (when translating with the vertebrate mitochondrial code). When DNA is double-stranded, six possible reading frames are defined, three in the forward orientation on one strand and three reverse on the opposite strand.{{rp|330}} Protein-coding frames are defined by a start codon, usually the first AUG codon in the RNA, (ATG in DNA) sequence.

In eukaryotes, open reading frames in exons are often interrupted by introns.

= 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 E. coli and initiation factors are also required to start translation. The most common start codon is AUG, which is read as methionine or as 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.{{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 = 169–78 | date = 2003 | pmid = 12867081 | doi = 10.1016/S0248-4900(03)00033-9 | doi-access = free }}

The three stop codons 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.{{cite web | url = http://www.sci.sdsu.edu/~smaloy/MicrobialGenetics/topics/rev-sup/amber-name.html | title = How nonsense mutations got their names | author = Maloy S | date = 2003-11-29 | work = Microbial Genetics Course | publisher = San Diego State University | access-date = 2010-03-10 }}

=Effect of mutations=

File:Notable mutations.svgs that can occur in humansReferences for the image are found in Wikimedia Commons page at: Commons:File:Notable mutations.svg#References.]]

During the process of DNA replication, errors occasionally occur in the polymerization of the second strand. These errors, mutations, 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" ability of DNA polymerases.{{cite book |editor1-first=Anthony J. F. |display-editors=4 |editor1-last=Griffiths |editor2-first=Jeffrey H. |editor2-last=Miller |editor3-first=David T. |editor3-last=Suzuki |editor4-first=Richard C. |editor4-last=Lewontin |editor5-last=Gelbart | name-list-style = vanc |title=An Introduction to Genetic Analysis |date=2000 |isbn=978-0-7167-3520-5 |edition=7th |publisher=W. H. Freeman |location=New York |chapter-url=https://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=iga.section.2706 |chapter=Spontaneous mutations }}{{cite journal | vauthors = Freisinger E, Grollman AP, Miller H, Kisker C | title = Lesion (in)tolerance reveals insights into DNA replication fidelity | journal = The EMBO Journal | volume = 23 | issue = 7 | pages = 1494–505 | date = Apr 2004 | pmid = 15057282 | pmc = 391067 | doi = 10.1038/sj.emboj.7600158 }}

Missense mutations and nonsense mutations are examples of point mutations that can cause genetic diseases such as sickle-cell disease and thalassemia respectively.{{Cite journal

| pmid = 17015226

| year = 2006

| last1 = Boillée

| first1 = S

| title = ALS: A disease of motor neurons and their nonneuronal neighbors

| journal = Neuron

| volume = 52

| issue = 1

| last2 = Vande Velde

| first2 = C

| last3 = Cleveland

| first3 = D. W.

| pages = 39–59

| doi = 10.1016/j.neuron.2006.09.018

| doi-access = free

}}{{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 }}{{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 }} 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.{{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 }}

Mutations that disrupt the reading frame sequence by indels (insertions or deletions) of a non-multiple of 3 nucleotide bases are known as frameshift mutations. 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.{{cite journal | vauthors = Isbrandt D, Hopwood JJ, von Figura K, Peters C | title = Two novel frameshift mutations causing premature stop codons in a patient with the severe form of Maroteaux-Lamy syndrome | journal = Human Mutation | volume = 7 | issue = 4 | pages = 361–3 | date = 1996 | pmid = 8723688 | doi = 10.1002/(SICI)1098-1004(1996)7:4<361::AID-HUMU12>3.0.CO;2-0 | s2cid = 22693748 | doi-access = free }} These mutations may impair the protein's function and are thus rare in in vivo protein-coding sequences. One reason inheritance of frameshift mutations is rare is that, if the protein being translated is essential for growth under the selective pressures the organism faces, absence of a functional protein may cause death before the organism becomes viable.{{cite journal | vauthors = Crow JF | title = How much do we know about spontaneous human mutation rates? | journal = Environmental and Molecular Mutagenesis | volume = 21 | issue = 2 | pages = 122–9 | date = 1993 | pmid = 8444142 | doi = 10.1002/em.2850210205 | bibcode = 1993EnvMM..21..122C | s2cid = 32918971 }} Frameshift mutations may result in severe genetic diseases such as Tay–Sachs disease.{{cite book | last = Lewis | first = Ricki | name-list-style = vanc | title = Human Genetics: Concepts and Applications | edition = 6th | publisher = McGraw Hill | location = Boston, Mass | date = 2005| pages = 227–228| isbn = 978-0-07-111156-0 }}

Although most mutations that change protein sequences are harmful or neutral, some mutations have benefits.{{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 = 6504–10 | date = Apr 2007 | pmid = 17409186 | pmc = 1871816 | doi = 10.1073/pnas.0701572104 | bibcode = 2007PNAS..104.6504S | doi-access = free }} These mutations may enable the mutant organism to withstand particular environmental stresses better than wild type organisms, or reproduce more quickly. In these cases a mutation will tend to become more common in a population through natural selection.{{cite journal |author=Bridges KR |title=Malaria and the Red Cell |journal=Harvard |date=2002 |url=http://sickle.bwh.harvard.edu/malaria_sickle.html |url-status=dead |archive-url=https://web.archive.org/web/20111127201806/http://sickle.bwh.harvard.edu/malaria_sickle.html |archive-date=27 November 2011 |df=dmy-all }} Viruses that use RNA as their genetic material have rapid mutation rates,{{cite journal | vauthors = Drake JW, Holland JJ | title = Mutation rates among RNA viruses | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 24 | pages = 13910–3 | date = Nov 1999 | pmid = 10570172 | pmc = 24164 | doi = 10.1073/pnas.96.24.13910 | bibcode = 1999PNAS...9613910D | doi-access = free }} which can be an advantage, since these viruses thereby evolve rapidly, and thus evade the immune system defensive responses.{{cite journal | vauthors = Holland J, Spindler K, Horodyski F, Grabau E, Nichol S, VandePol S | title = Rapid evolution of RNA genomes | journal = Science | volume = 215 | issue = 4540 | pages = 1577–85 | date = Mar 1982 | pmid = 7041255 | doi = 10.1126/science.7041255 | bibcode = 1982Sci...215.1577H }} In large populations of asexually reproducing organisms, for example, E. coli, multiple beneficial mutations may co-occur. This phenomenon is called clonal interference and causes competition among the mutations.{{cite journal | vauthors = de Visser JA, Rozen DE | title = Clonal interference and the periodic selection of new beneficial mutations in Escherichia coli | journal = Genetics | volume = 172 | issue = 4 | pages = 2093–100 | date = Apr 2006 | pmid = 16489229 | pmc = 1456385 | doi = 10.1534/genetics.105.052373 }}

=Degeneracy=

File:Genetic Code Simple Corrected.pdf. A more detailed version is available.]]

File:3D Genetic Code.jpg.]]

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 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 YUR or CUN (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using IUPAC notation), while the amino acid serine is specified by UCN or AGY (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position).{{cite book|first=James D. |last=Watson|title=Molecular Biology of the Gene|url={{google books |plainurl=y |id=MByWPwAACAAJ}}|year=2008|publisher=Pearson/Benjamin Cummings|isbn=978-0-8053-9592-1}} {{rp|[{{google books |plainurl=y |id=MByWPwAACAAJ|page=102}} 102–117]}} {{rp|[{{google books |plainurl=y |id=MByWPwAACAAJ|page=521}} 521–522]}} A practical consequence of redundancy is that errors in the third position of the triplet codon cause only a silent mutation or an error that would not affect the protein because the hydrophilicity or hydrophobicity is maintained by equivalent substitution of amino acids; for example, a codon of NUN (where N = any nucleotide) tends to code for hydrophobic amino acids. NCN yields amino acid residues that are small in size and moderate in hydropathicity; NAN encodes average size hydrophilic residues. The genetic code is so well-structured for hydropathicity that a mathematical analysis (Singular Value Decomposition) of 12 variables (4 nucleotides x 3 positions) yields a remarkable correlation (C = 0.95) for predicting the hydropathicity of the encoded amino acid directly from the triplet nucleotide sequence, without translation.{{cite book|first=Maria Elisabeth |last=Michel-Beyerle|title=Reaction centers of photosynthetic bacteria: Feldafing-II-Meeting|url={{google books |plainurl=y |id=xD5OAQAAIAAJ}}|year=1990|publisher=Springer-Verlag|isbn=978-3-540-53420-4}}Füllen G, Youvan DC (1994). "Genetic Algorithms and Recursive Ensemble Mutagenesis in Protein Engineering". Complexity International 1. Note in the table, below, eight amino acids are not affected at all by mutations at the third position of the codon, whereas in the figure above, a mutation at the second position is likely to cause a radical change in the physicochemical properties of the encoded amino acid.

Nevertheless, changes in the first position of the codons are more important than changes in the second position on a global scale.{{Cite journal|last=Fricke|first=Markus|s2cid=51968530|title=Global importance of RNA secondary structures in protein coding sequences|journal=Bioinformatics|volume=35|issue=4|pages=579–583|doi=10.1093/bioinformatics/bty678|pmid=30101307|year=2019|pmc=7109657}} The reason may be that charge reversal (from a positive to a negative charge or vice versa) can only occur upon mutations in the first position of certain codons, but not upon changes in the second position of any codon. Such charge reversal may have dramatic consequences for the structure or function of a protein. This aspect may have been largely underestimated by previous studies.

=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. 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.{{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}}

{{collapse top|title=Human genome codon frequency table{{Cite web|url=http://www.kazusa.or.jp/codon/cgi-bin/showcodon.cgi?species=9606&aa=1&style=N|title=Codon usage table|website=www.kazusa.or.jp}}}}

{|class="wikitable" style="text-align: center;"

!Codon || AA{{ref label|start|C|C}} || Fraction{{ref label|start|D|D}} || Freq ‰{{ref label|start|E|E}} || Number{{ref label|start|F|F}}

|rowspan=17|

!Codon || AA || Fraction || Freq ‰ || Number

|rowspan=17|

!Codon || AA || Fraction || Freq ‰ || Number

|rowspan=17|

!Codon || AA || Fraction || Freq ‰ || Number

|UUU||F||0.46||17.6||714,298||UCU||S||0.19||15.2||618,711||UAU||Y||0.44||12.2||495,699||UGU||C||0.46||10.6||430,311

|UUC||F||0.54||20.3||824,692||UCC||S||0.22||17.7||718,892||UAC||Y||0.56||15.3||622,407||UGC||C||0.54||12.6||513,028

|UUA||L||0.08||7.7||311,881||UCA||S||0.15||12.2||496,448||UAA||*||0.30||1.0||40,285||UGA||*||0.47||1.6||63,237

|UUG||L||0.13||12.9||525,688||UCG||S||0.05||4.4||179,419||UAG||*||0.24||0.8||32,109||UGG||W||1.00||13.2||535,595

|CUU||L||0.13||13.2||536,515||CCU||P||0.29||17.5||713,233||CAU||H||0.42||10.9||441,711||CGU||R||0.08||4.5||184,609

|CUC||L||0.20||19.6||796,638||CCC||P||0.32||19.8||804,620||CAC||H||0.58||15.1||613,713||CGC||R||0.18||10.4||423,516

|CUA||L||0.07||7.2||290,751||CCA||P||0.28||16.9||688,038||CAA||Q||0.27||12.3||501,911||CGA||R||0.11||6.2||250,760

|CUG||L||0.40||39.6||1,611,801||CCG||P||0.11||6.9||281,570||CAG||Q||0.73||34.2||1,391,973||CGG||R||0.20||11.4||464,485

|AUU||I||0.36||16.0||650,473||ACU||T||0.25||13.1||533,609||AAU||N||0.47||17.0||689,701||AGU||S||0.15||12.1||493,429

|AUC||I||0.47||20.8||846,466||ACC||T||0.36||18.9||768,147||AAC||N||0.53||19.1||776,603||AGC||S||0.24||19.5||791,383

|AUA||I||0.17||7.5||304,565||ACA||T||0.28||15.1||614,523||AAA||K||0.43||24.4||993,621||AGA||R||0.21||12.2||494,682

|AUG||M||1.00||22.0||896,005||ACG||T||0.11||6.1||246,105||AAG||K||0.57||31.9||1,295,568||AGG||R||0.21||12.0||486,463

|GUU||V||0.18||11.0||448,607||GCU||A||0.27||18.4||750,096||GAU||D||0.46||21.8||885,429||GGU||G||0.16||10.8||437,126

|GUC||V||0.24||14.5||588,138||GCC||A||0.40||27.7||1,127,679||GAC||D||0.54||25.1||1,020,595||GGC||G||0.34||22.2||903,565

|GUA||V||0.12||7.1||287,712||GCA||A||0.23||15.8||643,471||GAA||E||0.42||29.0||1,177,632||GGA||G||0.25||16.5||669,873

|GUG||V||0.46||28.1||1,143,534||GCG||A||0.11||7.4||299,495||GAG||E||0.58||39.6||1,609,975||GGG||G||0.25||16.5||669,768

Alternative genetic codes

= 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. Both selenocysteine and pyrrolysine may be present in the same organism.{{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 }} 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.{{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 }}

= Variations =

File:FACIL genetic code logo.png of the Globobulimina pseudospinescens mitochondrial genome by FACIL. The program is able to correctly infer that the Protozoan Mitochondrial Code is in use. 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".{{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 }} The first variation was discovered in 1979, by researchers studying human mitochondrial genes.

{{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]) Many slight variants were discovered thereafter, including various alternative mitochondrial codes.{{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 }} 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).{{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 }}{{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 }}{{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 }} 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 totiviruses have adapted to the host's genetic code modification.{{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 }} In bacteria and archaea, GUG and UUG are common start codons. In rare cases, certain proteins may use alternative start codons.{{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 }}

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.{{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}} This type of recoding is induced by a high-readthrough stop codon context{{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 }} and it is referred to as functional translational readthrough.{{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 }}

Despite these differences, all known naturally occurring codes are very similar. The coding mechanism is the same for all organisms: three-base codons, tRNA, ribosomes, single direction reading and translating single codons into single amino acids.{{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 }} 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{{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 }} or trigger ribosomal frameshifting as in Euplotes.{{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 }}

The origins and variation of the genetic code, including the mechanisms behind the evolvability of the genetic code, have been widely studied,{{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 }}{{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 }} and some studies have been done experimentally evolving the genetic code of some organisms.{{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 }}{{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 }}{{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 }}{{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 }}

= 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.{{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}}

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.{{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 }} Codetta was later used to analyze genetic code change in ciliates.{{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}}

Origin

The genetic code is a key part of the 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 ribozymes (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 synthetases, so the latter cannot be part of the explanation of its patterns.{{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 }}

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 × 10⁸⁴ possible genetic codes.{{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}}{{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.{{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}} However, the distribution of codon assignments in the genetic code is nonrandom.{{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 }} 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.{{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 }} 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,{{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 }}{{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 }} reducing the problems caused by point mutations and mistranslations.

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.{{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 }}

Three main hypotheses address the origin of the genetic code. Many models belong to one of them or to a hybrid:{{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 }}

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 peptides were coded for, any major random change in the genetic code would have been lethal; hence it became "frozen".{{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 }}
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.{{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}}
Optimality: the genetic code continued to evolve after its initial creation, so that the current code maximizes some fitness function, usually some kind of error minimization.{{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 }}

Hypotheses have addressed a variety of scenarios:{{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}}

Chemical principles govern specific RNA interaction with amino acids. Experiments with aptamers showed that some amino acids have a selective chemical affinity for their codons.{{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 }} Experiments showed that of 8 amino acids tested, 6 show some RNA triplet-amino acid association.{{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 }}
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.{{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}} Although much circumstantial evidence has been found to suggest that fewer amino acid types were used in the past,{{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 }} precise and detailed hypotheses about which amino acids entered the code in what order are controversial.{{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 }}{{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 }} 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.{{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}}{{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}}{{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}}{{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}}
Natural selection has led to codon assignments of the genetic code that minimize the effects of mutations.{{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 }} A recent hypothesis{{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 }} 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-theoretic approaches model the process of translating the genetic code into corresponding amino acids as an error-prone information channel.{{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 }} 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{{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}} while accurately and efficiently translating information? These "rate-distortion" models{{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 }} suggest that the genetic code originated as a result of the interplay of the three conflicting evolutionary forces: the needs for diverse amino acids,{{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 }} for error-tolerance 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.{{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 }}
Game theory: Models based on signaling games 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.{{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 }}
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.{{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}} In contrast, some stereochemical molecular models explain the origin of stop codons as "unassignable".

References

External links

[https://www.ncbi.nlm.nih.gov/Taxonomy/taxonomyhome.html/index.cgi?chapter=cgencodes The Genetic Codes: Genetic Code Tables]
The [http://www.kazusa.or.jp/codon/ Codon Usage Database] — Codon frequency tables for many organisms
[http://history.nih.gov/exhibits/nirenberg/ History of deciphering the genetic code]

Category:Gene expression

Category:Genetics

Category:Molecular genetics

Category:Molecular biology

Category:Protein biosynthesis