Towards a structural basis of human non-synonymous single nucleotide polymorphisms.

ascribed to single nucleotide polymorphism (SNP) allelic variants that occur at a frequency of .1% (Ref. 1). Owing to the application of high-throughput SNP detection techniques, the number of identified SNPs is growing rapidly, enabling detailed statistical studies2–5. These include studies of SNPs that affect the amino acid sequence of a gene product (non-synonymous SNPs); they complement the large body of literature on mutations that cause mendelian diseases, which represent the usually rare non-synonymous mutations with an allele frequency far below one percent3. To understand the relationship between genetic and phenotypic variation, it is essential to assess the structural consequences of the respective non-synonymous mutations in proteins. To quantify how often a disease phenotype can be explained by a destructive effect on protein structures or functions, we have mapped known disease mutations onto known three-dimensional structures of proteins. The results were compared with a control set of substitutions observed between these proteins and their closely related homologs from other species that are unlikely to cause severe effects on the phenotype. With the knowledge about the structural properties of these two sets, we have also mapped a large number of non-synonymous SNPs (which are usually thought to be neutral6, or to be the cause of only minor phenotypic effects) onto protein structures. This enables us to identify non-synonymous SNPs with Towards a structural basis of human non-synonymous single nucleotide polymorphisms Outlook GENOME ANALYSIS Non-synonymous SNPs and human genetic variation