Substitution scores

A potential source of inaccuracy in the MDM model comes from the extrapolation of alignments of closely related sequences to model distant relationships. For example, closely related sequences are dominated by 

Although the BLOSUM model is not explicitly evolutionary, the clumping procedure, which is required to construct a series of matrices, may be interpreted in evolutionary terms. The restriction of counts to conserved regions makes these matrices especially appropriate for database searching, where distant relationships are detected primarily because conserved positions are shared. 

Substitution matrices have also been modeled on amino acid or protein structural properties rather than on alignment data (Grantham, 1974 Miyata et al., 1979 Rao, 1987). However, the relationship between scores and target frequencies means that any imaginable set of scores has an implicit set of target frequencies, and obtaining these from the alignment data itself is the most direct approach (Altschul, 1991). 

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Formally, 400 (20 X 20) substitution scores are needed, one for each possible pair of the 20 amino acids, and for gapped alignments, up to... 

Workers who used methylene chloride in making acetate film had sleepiness and fatigue and decreased digit symbol substitution scores and lengthened reaction time. Use of methylene chloride in closed spaces has been fatal with brain edema, elevated blood levels of carboxyhemoglobin and caused temporary right hemispheric paralysis and/or unconsciousness. Chronic exposure has been associated with dementia, headache, dizziness and disturbed gait. ... 

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