Meeting Abstract
The epistatic effects of amino acid substitutions exert a strong influence on protein evolution trajectories. A substitution that is pathogenic in one genetic background may be neutral or even beneficial in the presence of other substitutions that interact with the pathogenic substitution. Many disease-associated missense mutations or ‘Pathogenic Deviations (PDs)’ in humans are observed to occur as native, wild-type residues in other non- human species. This particular class of missense mutations is known as ‘Compensated Pathogenic Deviations (CPDs)’ as in order to become fixed in the non-human species, their pathogenic effects must be compensated by one or more substitutions at other sites in the same protein or in an interacting protein. Defects of the mitochondrial respiratory chain are especially interesting as the respiratory chain is the only metabolic pathway in the cell controlled by both the mitochondrial and the nuclear DNA. To investigate the structural nature of these epistatic compensatory interactions, we identify PDs and CPDs from MITOMAP’s database of human mitochondrial disease mutations and map them onto three- dimensional protein structure models. To further understand whether the nature of compensated mutations (CPDs) is different than that of uncompensated mutations (PDs), we examine several structural effects concerning protein stability as well as binding effects. We also compare and contrast the patterns observed in mitochondrial diseases with previous studies that primarily focused on diseases caused by mutations in the nuclear DNA.
