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Observed substitutions

Scoring schemes based on observed substitutions are derived by analysing the substitution frequencies seen in alignments of sequences. This is something of a chicken and egg problem, since in order to generate the alignments, one really needs a scoring scheme but in order to derive the scoring scheme one needs the alignments! Early schemes based on observed substitutions worked from closely related sequences that could easily be aligned by eye. More recent schemes have had the benefit of the earlier substitution matrices to generate alignments on which to build. Long experience with scoring schemes based on observed substitutions suggests that they are superior to simple identity, genetic code, or intuitive physico-chemical property schemes.