Editing Mutation (section)

=== 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" />