Genetic polymorphism is a hallmark of human biology and the basis for individuality. Although the completion of the human genome project provides the first reference sequence of all human chromosomes the challenge remains to identify and characterize the frequency of deviations from this reference among populations with different ethnic background as well as individuals carrying distinct traits within a population (1). Approximately, 1.8 million polymorphic sites mostly consisting of single nucleotide polymorphisms (SNPs) have been so far discovered throughout the human genome (; SNP/). The approximate frequency of SNP occurrence is one per kilobase (2, 3). Detection of SNPs due to genetic variation in a given population (polymorphisms) or subsequent genetic adaptations occurring throughout life (mutations) has gained increasing attention due to the functional implications that SNPs in coding and non-coding regions bear on biological and pathological events. In fact, 25% of the known non-synonymous SNPs could affect the function of the correspondent gene product (4-7). Therefore, detection of SNPs due to genetic variation in a given population may have important implications in the natural history of disease and its response to therapy (8). Yet, for several reasons it is still unclear whether the prevalence of common diseases can be truly attributed, at least in part, to SNPs. The main reason is that the prevalence of SNPs throughout the genome in a given population is known only for few genes as exemplified by the human leukocyte antigen (HLA) complex which has been extensively studied due to the significance that polymorphic sites bear on allo-immunization. A lesson learned from the study of the HLA region is that the number of polymorphisms recognized in a given population is highly correlated with the accuracy and resolution of the method used. Therefore, as an example, with the ever-growing interest in the study of polymorphic sites of genes associated with immune function (9-12), it is likely that the number of recognized variations will continue to grow in the coming years. This rate of discovery will be enhanced by the high-throughput technologies that are continuously developed for SNPs to cover the complexity and heterogeneity of human biology and pathology. While, experimentally, tools are available for limited population studies, in clinical research a large number of individuals may need to be screened when investigating associations between genetic variation and disease susceptibility or responsiveness to therapy. In such an endeavor, a tool capable of efficiently and economically identifying known and flagging unknown SNPs could dramatically increase the understanding of human pathology making feasible the direct application of genome-wide investigation during the conduct of clinical trials (13).

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