Editing Mutation (section)

== Compensated pathogenic deviations ==
Compensated pathogenic deviations refer to amino acid residues in a protein sequence that are pathogenic in one species but are wild type residues in the functionally equivalent protein in another species. Although the amino acid residue is pathogenic in the first species, it is not so in the second species because its pathogenicity is compensated by one or more amino acid substitutions in the second species. The compensatory mutation can occur in the same protein or in another protein with which it interacts.<ref name="Barešić-2011">{{Cite journal |last1=Barešić |first1=Anja |last2=Martin |first2=Andrew C.R. |date=1 August 2011 |title=Compensated pathogenic deviations |journal=BioMolecular Concepts |volume=2 |issue=4 |pages=281–292 |doi=10.1515/bmc.2011.025 |pmid=25962036 |s2cid=6540447 |issn=1868-503X|doi-access=free }}</ref>

It is critical to understand the effects of compensatory mutations in the context of fixed deleterious mutations due to the population fitness decreasing because of fixation.<ref name="Whitlock-2003">{{Cite journal |last1=Whitlock |first1=Michael C. |last2=Griswold |first2=Cortland K. |last3=Peters |first3=Andrew D. |date=2003 |title=Compensating for the meltdown: The critical effective size of a population with deleterious and compensatory mutations |url=https://www.jstor.org/stable/23736523 |journal=Annales Zoologici Fennici |volume=40 |issue=2 |pages=169–183 |jstor=23736523 |issn=0003-455X}}</ref> Effective population size refers to a population that is reproducing.<ref name="Lanfear-2014">{{Cite journal |last1=Lanfear |first1=Robert |last2=Kokko |first2=Hanna |last3=Eyre-Walker |first3=Adam |date=1 January 2014 |title=Population size and the rate of evolution |url=https://www.sciencedirect.com/science/article/pii/S0169534713002322 |journal=Trends in Ecology & Evolution |language=en |volume=29 |issue=1 |pages=33–41 |doi=10.1016/j.tree.2013.09.009 |pmid=24148292 |bibcode=2014TEcoE..29...33L |issn=0169-5347|url-access=subscription }}</ref> An increase in this population size has been correlated with a decreased rate of genetic diversity.<ref name="Lanfear-2014" /> The position of a population relative to the critical effect population size is essential to determine the effect deleterious alleles will have on fitness.<ref name="Whitlock-2003" /> If the population is below the critical effective size fitness will decrease drastically, however if the population is above the critical effect size, fitness can increase regardless of deleterious mutations due to compensatory alleles.<ref name="Whitlock-2003" />

=== Compensatory mutations in RNA ===
As the function of a RNA molecule is dependent on its structure,<ref>{{Cite journal |last=Doudna |first=Jennifer A. |title=Structural genomics of RNA |date=1 November 2000 |url=http://www.nature.com/doifinder/10.1038/80729 |journal=Nature Structural Biology |volume=7 |pages=954–956 |doi=10.1038/80729|pmid=11103998 |s2cid=998448 |url-access=subscription }}</ref> the structure of RNA molecules is evolutionarily conserved. Therefore, any mutation that alters the stable structure of RNA molecules must be compensated by other compensatory mutations. In the context of RNA, the sequence of the RNA can be considered as ' genotype' and the structure of the RNA can be considered as its 'phenotype'. Since RNAs have relatively simpler composition than proteins, the structure of RNA molecules can be computationally predicted with high degree of accuracy. Because of this convenience, compensatory mutations have been studied in computational simulations using RNA folding algorithms.<ref>{{Cite journal |last1=Cowperthwaite |first1=Matthew C. |last2=Bull |first2=J. J. |last3=Meyers |first3=Lauren Ancel |date=20 October 2006 |title=From Bad to Good: Fitness Reversals and the Ascent of Deleterious Mutations |journal=PLOS Computational Biology |language=en |volume=2 |issue=10 |pages=e141 |doi=10.1371/journal.pcbi.0020141 |issn=1553-7358 |pmc=1617134 |pmid=17054393|bibcode=2006PLSCB...2..141C |doi-access=free }}</ref><ref>{{Cite journal |last1=Cowperthwaite |first1=Matthew C. |last2=Meyers |first2=Lauren Ancel |date=1 December 2007 |title=How Mutational Networks Shape Evolution: Lessons from RNA Models |url=https://www.annualreviews.org/doi/10.1146/annurev.ecolsys.38.091206.095507 |journal=Annual Review of Ecology, Evolution, and Systematics |language=en |volume=38 |issue=1 |pages=203–230 |doi=10.1146/annurev.ecolsys.38.091206.095507 |issn=1543-592X|url-access=subscription }}</ref>

=== Evolutionary mechanism of compensation ===
Compensatory mutations can be explained by the genetic phenomenon epistasis whereby the phenotypic effect of one mutation is dependent upon mutation(s) at other loci. While epistasis was originally conceived in the context of interaction between different genes, intragenic epistasis has also been studied recently.<ref name="Azbukina-2022">{{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 |pmid=36345285 |pmc=9636336 |issn=1867-2469}}</ref> Existence of compensated pathogenic deviations can be explained by 'sign epistasis', in which the effects of a deleterious mutation can be compensated by the presence of an epistatic mutation in another loci. For a given protein, a deleterious mutation (D) and a compensatory mutation (C) can be considered, where C can be in the same protein as D or in a different interacting protein depending on the context. The fitness effect of C itself could be neutral or somewhat deleterious such that it can still exist in the population, and the effect of D is deleterious to the extent that it cannot exist in the population. However, when C and D co-occur together, the combined fitness effect becomes neutral or positive.<ref name="Barešić-2011"/> Thus, compensatory mutations can bring novelty to proteins by forging new pathways of protein evolution : it allows individuals to travel from one fitness peak to another through the valleys of lower fitness.<ref name="Azbukina-2022" />

DePristo et al. 2005 outlined two models to explain the dynamics of compensatory pathogenic deviations (CPD).<ref name="DePristo-2005">{{Cite journal |last1=DePristo |first1=Mark A. |last2=Weinreich |first2=Daniel M. |last3=Hartl |first3=Daniel L. |date=September 2005 |title=Missense meanderings in sequence space: a biophysical view of protein evolution |url=https://pubmed.ncbi.nlm.nih.gov/16074985/ |journal=Nature Reviews. Genetics |volume=6 |issue=9 |pages=678–687 |doi=10.1038/nrg1672 |issn=1471-0056 |pmid=16074985|s2cid=13236893 }}</ref> In the first hypothesis P is a pathogenic amino acid mutation that and C is a neutral compensatory mutation.<ref name="DePristo-2005" /> Under these conditions, if the pathogenic mutation arises after a compensatory mutation, then P can become fixed in the population.<ref name="DePristo-2005" /> The second model of CPDs states that P and C are both deleterious mutations resulting in fitness valleys when mutations occur simultaneously.<ref name="DePristo-2005" /> Using publicly available, Ferrer-Costa et al. 2007 obtained compensatory mutations and human pathogenic mutation datasets that were characterized to determine what causes CPDs.<ref name="Ferrer-Costa-2007">{{Cite journal |last1=Ferrer-Costa |first1=Carles |last2=Orozco |first2=Modesto |last3=Cruz |first3=Xavier de la |date=5 January 2007 |title=Characterization of Compensated Mutations in Terms of Structural and Physico-Chemical Properties |url=https://www.sciencedirect.com/science/article/pii/S0022283606012770 |journal=Journal of Molecular Biology |language=en |volume=365 |issue=1 |pages=249–256 |doi=10.1016/j.jmb.2006.09.053 |pmid=17059831 |issn=0022-2836|url-access=subscription }}</ref> Results indicate that the structural constraints and the location in protein structure determine whether compensated mutations will occur.<ref name="Ferrer-Costa-2007" />

=== 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|url-access=subscription }}</ref><ref name="Reynolds-2000" /><ref name="Gagneux-2006" />