Intramolecular Epistatic Interactions in Genetic Diseases

A key factor influencing the structural and functional impact of amino acid substitutions in disease-associated genes involves the background genetic variation. Epistatic interactions between co-evolving positions in the same gene result in the interdependence of each site with its interacting partners. Evidence supporting the role of these interactions is exemplified in the occurrence of human disease-associated alleles in the genome of non-human species. Although several explanations can contribute to this phenomenon, one possibility is the occurrence of compensatory interacting sites that can fully, or partially, restore the pathogenic effect, contributing to the maintenance of protein structure and proper function. These interactions create genetic contexts that are revisited here through the analysis of literature data for specific proteins, with a particular focus on proteins involved in inborn errors of metabolism.