Loss of protein structure stability as a major causative factor in monogenic disease.

摘要: The most common cause of monogenic disease is a single base DNA variant resulting in an amino acid substitution. In previous study, we observed that high fraction these substitutions appear to result reduction stability the corresponding protein structure. We have now investigated this phenomenon more fully. A set structural effects, such as hydrophobic area, overpacking, backbone strain, and loss electrostatic interactions, used represent impact residue mutations on stability. support vector machine (SVM) was trained causative disease, control non-disease causing mutations. jack-knifed testing, method identifies 74% mutations, with false positive rate 15%. Evaluation vitro mutagenesis data SVM established majority affect by 1 3 kcal/mol. method's effective distinction between variants, strongly supports hypothesis major factor contributing disease.