Characterization of compensated mutations in terms of structural and physico-chemical properties

The study of the evolution of compensatory mechanisms among amino acids is paramount to our understanding of intramolecular epistatic interactions. It has been addressed from different points of view, for example much effort has been devoted to establish the number of compensatory mutations required per deleterious mutation. However, we still do not know how the nature of the compensated mutation determines the existence of compensatory mutations. Within this context, recent studies have produced several instances of an interesting phenomenon: human disease-associated residues may sometimes appear as wild-type residues in non-human proteins. This can be explained in terms of compensatory mutations, present in the non-human protein, which would neutralize the damage caused by the disease-associated residue. Therefore, comparison between these compensated mutations and non-compensated pathological mutations provides a simple approach to understand how the nature of the compensated deleterious mutation determines the existence of compensatory mutations. To address this issue, we have obtained a large set of compensated mutations and characterised them with a series of different properties. When comparing the resulting distributions with those from pathological mutations we find that in general compensated mutations are milder than pathological mutations. More precisely, we find that the probability that a compensatory mutation will evolve is directly related (i) to the location in the protein structure and (ii) to changes in physicochemical properties (e.g. amino acid volume or hydrophobicity) of the compensated mutation.