Predicting the Functional Consequences of Non-Synonymous Single
 Nucleotide Polymorphisms:  Structure-Based Assessment of Amino Acid
 Variation

                         Dan Chasman
                         Variagenics 

                          Abstract

       We have developed a formalism and a computational method for
 analyzing the potential functional consequences of non-synonymous
 single nucleotide polymorphisms (nsSNPs).  Our approach uses a
 structural model  and phylogenetic information to derive a selection of
 structure-based and sequence-based features serving as indicators of an
 amino acid polymorphim's effect on function.  The feature values can be
 integrated into a probabilistic assessment of whether an amino acid
 polymorphism will affect  the function or stability of a target
 protein.  The method has been validated with data sets of unbiased
 mutations in the lac repressor and lysoyzyme.  Applying our methodology
 to recent surveys of genetic variation in the coding regions of
 clinically important genes, we estimate that approximately 26-32% of
 the natural nsSNPs have effects on function.  These predictions allow
 estimates of the number of heterozygous loci that encode proteins with
 functional variation due to natural amino acid polymorphism in typical
 individuals.