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These weights were calculated according to the method of Henikoff & Henikoff [ 21 ] , which is based on the residue diversity at each position of the alignment.
In the report by Chasman and Adams, evolutionary information was predicted to be a useful component in determining whether a mutation is deleterious [ 13 14 ] . Disease causing mutations are also likely structurally perturbing at the protein level [ 15 ] . Ng and Henikoff have introduced SIFT, a method for predicting functional SNPs from a database of unannotated polymorphisms [ 16 17 ] .
This was done by the method of Henikoff & Henikoff [ 19 ] , as previously described [ 20 ] . In summary, the first step was to weight each sequence in a multiple sequence alignment block according to its degree of similarity to the other sequences, which has the effect of minimizing the influence of highly redundant sequences in the final profile.