Editing Genetic code (section)

==Features==
[[File:Homo sapiens-mtDNA~NC 012920-ATP8+ATP6 Overlap.svg|thumb|right|Reading frames in the DNA sequence of a region of the human mitochondrial genome coding for the genes ''[[MT-ATP8]]'' and ''[[MT-ATP6]]'' (in black: positions 8,525 to 8,580 in the sequence accession NC_012920<ref name="NCBI NC_012920">''Homo 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.</ref>). 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===
{{Main article|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' to 3'|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.<ref name="genetics_ dictionary"/>{{rp|330}} Protein-coding frames are defined by a [[start codon]], usually the first AUG codon in the RNA, (ATG in DNA) sequence.

In [[eukaryote]]s, open reading frames in [[exon]]s are often interrupted by [[intron]]s.

=== 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 ''[[Escherichia coli|E. coli]]'' and [[initiation factor]]s are also required to start translation. The most common start codon is AUG, which is read as [[methionine]] or as [[N-Formylmethionine|formylmethionine]] (in bacteria, mitochondria, and plastids). Alternative start codons depending on the organism include "GUG" or "UUG"; these codons normally represent [[valine]] and [[leucine]], respectively, but as start codons they are translated as methionine or formylmethionine.<ref name="pmid12867081">{{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 }}</ref>

The three [[stop codon]]s have names: UAG is ''amber'', UGA is ''opal'' (sometimes also called ''umber''), and UAA is ''ochre''. Stop codons are also called "termination" or "nonsense" codons. They signal release of the nascent polypeptide from the ribosome because no cognate tRNA has anticodons complementary to these stop signals, allowing a [[release factor]] to bind to the ribosome instead.<ref name="urlHow nonsense mutations got their names">{{cite web | 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 }}</ref>

===Effect of mutations===
[[File:Notable mutations.svg|upright=1.75|thumb|Examples of notable [[mutation]]s that can occur in humans<ref>References for the image are found in Wikimedia Commons page at: [[Commons:File:Notable mutations.svg#References]].</ref>]]<!-- EXPANSION OF THE IMAGE WITH MORE EXAMPLES IS EXPECTED (see its discussion page)-->

During the process of [[DNA replication]], errors occasionally occur in the [[polymerization]] of the second strand. These errors, [[mutation]]s, can affect an organism's [[phenotype]], especially if they occur within the protein coding sequence of a gene. Error rates are typically 1 error in every 10–100&nbsp;million bases—due to the "[[Proofreading (biology)|proofreading]]" ability of [[DNA polymerase]]s.<ref name=griffiths2000sect2706>{{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 }}</ref><ref name=Kunkel>{{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 }}</ref>

[[Missense mutation]]s and [[nonsense mutation]]s are examples of [[point mutation]]s that  can cause genetic diseases such as [[sickle-cell disease]] and [[thalassemia]] respectively.<ref>{{Cite journal
 | 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
}}</ref><ref name="pmid88735">{{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 }}</ref><ref name="pmid17015226">{{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 }}</ref> Clinically important missense mutations generally change the properties of the coded amino acid residue among basic, acidic, polar or non-polar states, whereas nonsense mutations result in a [[stop codon]].<ref name="genetics_ dictionary">{{cite book | 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 }}</ref>

Mutations that disrupt the reading frame sequence by [[indels]] ([[gene insertion|insertions]] or [[genetic deletion|deletions]]) of a non-multiple of 3 nucleotide bases are known as [[frameshift mutation]]s. 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.<ref name="pmid8723688">{{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 }}</ref> 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.<ref name="pmid8444142">{{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 }}</ref> Frameshift mutations may result in severe genetic diseases such as [[Tay–Sachs disease]].<ref name="isbn0-07-111156-5">{{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 }}</ref>

Although most mutations that change protein sequences are harmful or neutral, some mutations have benefits.<ref>{{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 }}</ref> 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]].<ref>{{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 }}</ref> [[Virus]]es that use [[RNA]] as their genetic material have rapid mutation rates,<ref>{{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 }}</ref> which can be an advantage, since these viruses thereby evolve rapidly, and thus evade the [[immune system]] defensive responses.<ref>{{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 }}</ref> 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.<ref>{{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 }}</ref>

===Degeneracy===
{{Main|Codon degeneracy}}
[[File:Genetic Code Simple Corrected.pdf|thumb|Grouping of codons by amino acid residue molar volume and [[hydropathicity]].  A [[:File:ELLIPTICAL GENETIC CODE Ian.png|more detailed version]] is available.]]
[[File:3D Genetic Code.jpg|thumb|Axes 1, 2, 3 are the first, second, and third positions in the codon. The 20 amino acids and stop codons (X) are shown in [[Amino acid#Table of standard amino acid abbreviations and properties|single letter code]].]]
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 [[DNA and RNA codon tables|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 '''Y'''U'''R''' or CU'''N''' (UUA, UUG, CUU, CUC, CUA, or CUG) codons (difference in the first or third position indicated using [[Nucleic acid notation|IUPAC notation]]), while the amino acid [[serine]] is specified by UC'''N''' or AG'''Y''' (UCA, UCG, UCC, UCU, AGU, or AGC) codons (difference in the first, second, or third position).<ref name="MBG">{{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]}}</ref> 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|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.''<ref name="Michel-Beyerle1990">{{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}}</ref><ref>Füllen G, Youvan DC (1994). "Genetic Algorithms and Recursive Ensemble Mutagenesis in Protein Engineering". Complexity International 1.</ref>  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.<ref name=Fricke>{{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}}</ref>  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.<ref name=Fricke/>

===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 (biology)|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.<ref>{{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}}</ref>

{{collapse top|title=Human genome codon frequency table<ref>{{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}}</ref>}}
{|class="wikitable" style="text-align: center;"
|-
!Codon || AA{{ref label|start|C|C}} || Fraction{{ref label|start|D|D}} || Freq [[per thousand|‰]]{{ref label|start|E|E}} || Number{{ref label|start|F|F}}
|rowspan=17|
!Codon || AA || Fraction || Freq [[per thousand|‰]] || Number
|rowspan=17|
!Codon || AA || Fraction || Freq [[per thousand|‰]] || Number 
|rowspan=17|
!Codon || AA || Fraction || Freq [[per thousand|‰]] || 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
|}
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