Figure 6

Cumulative probability of the Grantham ratio (GR) for different classes of residues in proteins. Black, all (wild-type) protein residues; blue, original (wild-type) residues at the sites of benign SNPs; green, mutant residues at the sites of benign SNPs; cyan, residues generated by computer simulation of random mutations based on the amino-acid mutation frequencies; red, disease-causing residues from MIM. The Grantham ratio characterizes the degree of the residue's dissimilarity to the amino acids observed at the same position in evolutionary homologs (see Materials and methods). High GR values indicate radical mutations, whereas GR values that are small or around 1 indicate conservative mutations. The GR distributions demonstrate how purifying selection affects the observed mutation spectra. Comparison of the GR scores for original residues (black and blue) and disease-causing residues shows that more than half of disease mutations are radical (GR > 2) and are almost never observed in evolution.