Chemical dissimilarities between original and mutant amino acids versus observed mutation frequencies. (a) The amino-acid dissimilarities versus the frequencies of disease mutations. (b) The amino-acid dissimilarities versus the relative frequencies of genetic disease mutations (normalized by site mutabilities). The chemical dissimilarities between amino acids were characterized using the Grantham score . Each point in the figure represents a certain type of amino-acid to amino-acid mutation. Only amino-acid transitions resulting from single-nucleotide mutations in amino-acid codons were considered. The mutation frequencies in (a) were normalized to 100. The relative frequencies in (b) were determined as the ratio between the disease and the expected mutation frequencies (see Figure 1). The relative frequencies are proportional to the relative probabilities of amino-acid mutations causing a disease. No correlation between the disease mutation frequencies and chemical dissimilarities is evident (a), but there is a significant correlation between the normalized frequencies and the chemical dissimilarities (b).