|Title||SNPs, protein structure, and disease.|
|Publication Type||Journal Article|
|Year of Publication||2001|
|Authors||Wang, Z, Moult, J|
|Date Published||2001 Apr|
|Keywords||Allosteric Regulation, Catalysis, Computational Biology, Databases as Topic, Disulfides, Enzyme Stability, Genetic Diseases, Inborn, Genetic Predisposition to Disease, Humans, Hydrogen Bonding, Ligands, Models, Molecular, Multifactorial Inheritance, Mutation, Missense, Polymorphism, Single Nucleotide, Protein Binding, Protein Conformation, Protein Processing, Post-Translational, Proteins, Static Electricity, Structure-Activity Relationship, Thermodynamics|
Inherited disease susceptibility in humans is most commonly associated with single nucleotide polymorphisms (SNPs). The mechanisms by which this occurs are still poorly understood. We have analyzed the effect of a set of disease-causing missense mutations arising from SNPs, and a set of newly determined SNPs from the general population. Results of in vitro mutagenesis studies, together with the protein structural context of each mutation, are used to develop a model for assigning a mechanism of action of each mutation at the protein level. Ninety percent of the known disease-causing missense mutations examined fit this model, with the vast majority affecting protein stability, through a variety of energy related factors. In sharp contrast, over 70% of the population set are found to be neutral. The remaining 30% are potentially involved in polygenic disease.
|Alternate Journal||Hum. Mutat.|