Predicting the functional consequences of non-synonymous single nucleotidepolymorphisms: Structure-based assessment of amino acid variation

We have developed a formalism and a computational method for analyzing the potential functional consequences of non-synonymous single nucleotide polym orphisms. Our approach uses a structural model and phylogenetic information to derive a selection of structure and sequence-based features serving as indicators of an amino acid polymorphim's effect on function. The feature v alues can be integrated into a probabilistic assessment of whether an amino acid polymorphism will affect the function or stability of a target protei n. The method has been validated with data sets of unbiased mutations in th e lac repressor and lysoyzyme. Applying our methodology to recent surveys o f genetic variation in the coding regions of clinically important genes, we estimate that approximately 26-32% of the natural non-synonymous single nu cleotide polymorphisms have effects on function. This estimate suggests tha t a typical person will have about 6240-12,800 heterozygous loci that encod e proteins with functional variation due to natural amino acid polymorphism . (C) 2001 Academic Press.