The impact of nucleotide differences is variable and elusive, but is clearly dependent upon the location of the polymorphism in the genome. Although the majority of SNPs are likely to occur outside of actual gene encoding regions, polymorphisms located within the context of a gene (Figure 2) need not be involved in protein encoding to result in a functional change. Nucleotide differences in regions upstream of the protein-encoding gene regions may influence the binding of promotors or repressors, resulting in differential regulation of transcription. Polymorphisms at intron/exon boundaries may effect exonic or intronic splicing enhancer or silencer positions, or especially conserved GT donor or AC acceptor positions, modifying the resulting polypeptide. There is even demonstrated potential for phenotypic effects from non-coding or synonymous SNPs through alteration of RNA secondary structure (3). Similarly, untranslated distal 3' differences may have additional effects, including interruption of poly-adenylation, which would alter the template effectiveness.