Insights into Disease-Associated Mutations in the Human Proteome through Protein Structural Analysis

Most known disease-associated mutations are missense mutations involving changes of amino acids of proteins encoded by their genes. Given the plethora of genetic studies, sequenced exomes, and new protein structures determined each year, it is appropriate to revisit the role that structure plays in providing insights into the molecular basis of disease-associated mutations. In that regard, a large-scale structural analysis of 6,025 disease-associated mutations as well as 4,536 neutral variations for comparison was performed. While buried amino acids are common among the disease-associated mutations, as reported previously, more are statistically significantly enriched at observed or predicted functional sites. Interesting findings are that ligand-binding sites adjacent to protein-protein interfaces and residues involved in enzymatic function are especially vulnerable to disease-associated mutations. Finally, a compositional analysis of disease-associated mutations in comparison with variants identified in the 1000 Genomes Project provides a structural rationalization of the most disease-associated residue types.