Figure 4

Contribution of mutations at different amino acids to the overall mutation spectrum. (a) The fraction of mutations at different amino acids. The fractions are shown separately for benign, expected and disease mutations (normalized to 100% within each class). The contribution of mutations at different amino acids to the overall spectrum is highly heterogeneous. For example, mutations at arginine (R) constitute approximately 15% of all mutations. This is a direct consequence of a high mutability of the 5'-CpG dinucleotides in the arginine codons. (b) The relative probability that a random mutation at different amino acids will cause a genetic disease. Importantly, because the overall probability that a random mutation will cause a genetic disease is unknown, the probabilities in (b) have only relative meaning (for example, the probability that a random mutation will cause a disease mutation at alanine (A) versus valine (V)). For display purposes it was assumed that 1 in 100 random mutations causes a genetic disease. Mutations at tryptophan (W) and cysteine (C) have the highest probability of causing a disease. This correlates with the fact that these are the most highly conserved amino acids in evolution [10].