Editing Mutation (section)

=== Experimental evidence of compensatory mutations ===

==== Experiment in bacteria ====
Lunzer et al.<ref>{{Cite journal |last1=Lunzer |first1=Mark |last2=Golding |first2=G. Brian |last3=Dean |first3=Antony M. |date=21 October 2010 |title=Pervasive Cryptic Epistasis in Molecular Evolution |journal=PLOS Genetics |language=en |volume=6 |issue=10 |pages=e1001162 |doi=10.1371/journal.pgen.1001162 |issn=1553-7404 |pmc=2958800 |pmid=20975933 |doi-access=free }}</ref> tested the outcome of swapping divergent amino acids between two orthologous proteins of isopropymalate dehydrogenase (IMDH). They substituted 168 amino acids in ''Escherichia coli'' IMDH that are wild type residues in IMDH ''Pseudomonas aeruginosa''. They found that over one third of these substitutions compromised IMDH enzymatic activity in the ''Escherichia coli'' genetic background. This demonstrated that identical amino acid states can result in different phenotypic states depending on the genetic background. Corrigan et al. 2011 demonstrated how ''Staphylococcus aureus'' was able to grow normally without the presence of lipoteichoic acid due to compensatory mutations.<ref name="Corrigan-2011">{{Cite journal |last1=Corrigan |first1=Rebecca M. |last2=Abbott |first2=James C. |last3=Burhenne |first3=Heike |last4=Kaever |first4=Volkhard |last5=Gründling |first5=Angelika |date=1 September 2011 |title=c-di-AMP Is a New Second Messenger in Staphylococcus aureus with a Role in Controlling Cell Size and Envelope Stress |journal=PLOS Pathogens |volume=7 |issue=9 |pages=e1002217 |doi=10.1371/journal.ppat.1002217 |issn=1553-7366 |pmc=3164647 |pmid=21909268 |doi-access=free }}</ref> Whole genome sequencing results revealed that when Cyclic-di-AMP phosphodiesterase (GdpP) was disrupted in this bacterium, it compensated for the disappearance of the cell wall polymer, resulting in normal cell growth.<ref name="Corrigan-2011" />

Research has shown that bacteria can gain drug resistance through compensatory mutations that do not impede or having little effect on fitness.<ref name="Comas-2012">{{Cite journal |last1=Comas |first1=Iñaki |last2=Borrell |first2=Sonia |last3=Roetzer |first3=Andreas |last4=Rose |first4=Graham |last5=Malla |first5=Bijaya |last6=Kato-Maeda |first6=Midori |last7=Galagan |first7=James |last8=Niemann |first8=Stefan |last9=Gagneux |first9=Sebastien |date=January 2012 |title=Whole-genome sequencing of rifampicin-resistant Mycobacterium tuberculosis strains identifies compensatory mutations in RNA polymerase genes |journal=Nature Genetics |language=en |volume=44 |issue=1 |pages=106–110 |doi=10.1038/ng.1038 |pmid=22179134 |pmc=3246538 |issn=1546-1718}}</ref> Previous research from Gagneux et al. 2006 has found that laboratory grown ''Mycobacterium tuberculosis'' strains with rifampicin resistance have reduced fitness, however drug resistant clinical strains of this pathogenic bacteria do not have reduced fitness.<ref name="Gagneux-2006">{{Cite journal |last1=Gagneux |first1=Sebastien |last2=Long |first2=Clara Davis |last3=Small |first3=Peter M. |last4=Van |first4=Tran |last5=Schoolnik |first5=Gary K. |last6=Bohannan |first6=Brendan J. M. |date=30 June 2006 |title=The competitive cost of antibiotic resistance in Mycobacterium tuberculosis |url=https://pubmed.ncbi.nlm.nih.gov/16809538/ |journal=Science |volume=312 |issue=5782 |pages=1944–1946 |doi=10.1126/science.1124410 |issn=1095-9203 |pmid=16809538|bibcode=2006Sci...312.1944G |s2cid=7454895 }}</ref> Comas et al. 2012 used whole genome comparisons between clinical strains and lab derived mutants to determine the role and contribution of compensatory mutations in drug resistance to rifampicin.<ref name="Comas-2012" /> Genome analysis reveal rifampicin resistant strains have a mutation in rpoA and rpoC.<ref name="Comas-2012" /> A similar study investigated the bacterial fitness associated with compensatory mutations in rifampin resistant ''Escherichia coli''.<ref name="Reynolds-2000">{{Cite journal |last=Reynolds |first=M. G. |date=December 2000 |title=Compensatory evolution in rifampin-resistant Escherichia coli |journal=Genetics |volume=156 |issue=4 |pages=1471–1481 |doi=10.1093/genetics/156.4.1471 |issn=0016-6731 |pmc=1461348 |pmid=11102350}}</ref> Results obtained from this study demonstrate that drug resistance is linked to bacterial fitness as higher fitness costs are linked to greater transcription errors.<ref name="Reynolds-2000" />

==== Experiment in virus ====
Gong et al.<ref>{{Cite journal |last1=Gong |first1=Lizhi Ian |last2=Suchard |first2=Marc A |last3=Bloom |first3=Jesse D |date=14 May 2013 |editor-last=Pascual |editor-first=Mercedes |title=Stability-mediated epistasis constrains the evolution of an influenza protein |journal=eLife |volume=2 |pages=e00631 |doi=10.7554/eLife.00631 |issn=2050-084X |pmc=3654441 |pmid=23682315 |doi-access=free }}</ref> collected obtained genotype data of influenza nucleoprotein from different timelines and temporally ordered them according to their time of origin. Then they isolated 39 amino acid substitutions that occurred in different timelines and substituted them in a genetic background that approximated the ancestral genotype. They found that 3 of the 39 substitutions significantly reduced the fitness of the ancestral background. Compensatory mutations are new mutations that arise and have a positive or neutral impact on a populations fitness.<ref name="Davis-2009">{{Cite journal |last1=Davis |first1=Brad H. |last2=Poon |first2=Art F.Y. |last3=Whitlock |first3=Michael C. |date=22 May 2009 |title=Compensatory mutations are repeatable and clustered within proteins |journal=Proceedings of the Royal Society B: Biological Sciences |volume=276 |issue=1663 |pages=1823–1827 |doi=10.1098/rspb.2008.1846 |issn=0962-8452 |pmc=2674493 |pmid=19324785}}</ref> Previous research has shown that populations have can compensate detrimental mutations.<ref name="Barešić-2011"/><ref name="Davis-2009" /><ref>{{Cite journal |last1=Azbukina |first1=Nadezhda |last2=Zharikova |first2=Anastasia |last3=Ramensky |first3=Vasily |date=1 October 2022 |title=Intragenic compensation through the lens of deep mutational scanning |url=https://doi.org/10.1007/s12551-022-01005-w |journal=Biophysical Reviews |language=en |volume=14 |issue=5 |pages=1161–1182 |doi=10.1007/s12551-022-01005-w |issn=1867-2469 |pmc=9636336 |pmid=36345285}}</ref> Burch and Chao tested [[Fisher's geometric model]] of adaptive evolution by testing whether bacteriophage φ6 evolves by small steps.<ref name="Burch-1999">{{Cite journal |last1=Burch |first1=Christina L |last2=Chao |first2=Lin |date=1 March 1999 |title=Evolution by Small Steps and Rugged Landscapes in the RNA Virus ϕ6 |url=https://academic.oup.com/genetics/article/151/3/921/6034699 |journal=Genetics |language=en |volume=151 |issue=3 |pages=921–927 |doi=10.1093/genetics/151.3.921 |issn=1943-2631 |pmc=1460516 |pmid=10049911}}</ref> Their results showed that [[bacteriophage]] φ6 fitness declined rapidly and recovered in small steps .<ref name="Burch-1999" /> Viral nucleoproteins have been shown to avoid cytotoxic T lymphocytes (CTLs) through arginine-to glycine substitutions.<ref name="Rimmelzwaan-2005">{{Cite journal |last1=Rimmelzwaan |first1=G. F. |last2=Berkhoff |first2=E. G. M. |last3=Nieuwkoop |first3=N. J. |last4=Smith |first4=D. J. |last5=Fouchier |first5=R. A. M. |last6=Osterhaus |first6=A. D. M. E.YR 2005 |title=Full restoration of viral fitness by multiple compensatory co-mutations in the nucleoprotein of influenza A virus cytotoxic T-lymphocyte escape mutants |journal=Journal of General Virology |year=2005 |volume=86 |issue=6 |pages=1801–1805 |doi=10.1099/vir.0.80867-0 |pmid=15914859 |issn=1465-2099|doi-access=free |hdl=1765/8466 |hdl-access=free }}</ref> This substitution mutations impacts the fitness of viral nucleoproteins, however compensatory co-mutations impede fitness declines and aid the virus to avoid recognition from CTLs.<ref name="Rimmelzwaan-2005" /> Mutations can have three different effects; mutations can have deleterious effects, some increase fitness through compensatory mutations, and lastly mutations can be counterbalancing resulting in compensatory neutral mutations.<ref>{{Cite journal |last=Kimura |first=Motoo |date=1 July 1985 |title=The role of compensatory neutral mutations in molecular evolution |url=https://doi.org/10.1007/BF02923549 |journal=Journal of Genetics |language=en |volume=64 |issue=1 |pages=7–19 |doi=10.1007/BF02923549 |s2cid=129866 |issn=0973-7731}}</ref><ref name="Reynolds-2000" /><ref name="Gagneux-2006" />