Defined candidate genes, DNA segments of several kilobascs, were comparatively sequenced in larger numbers of individuals.24-34 These first, studies reflect, as closely as possible the molecular truth. They revealed abundant gene sequence diversity,31,35 about one SNP every 160 to 180 bp, and revised the classical measures of genetic variability.35-37 They also demonstrated unpredictable patterns of LD even within short distances of several hundred basepairs, much higher numbers of haplotypes, sometimes exceeding a hundred, and Inhibitors,research,lifescience,medical much more complex haplotype structures38

than suggested by the previous studies. To conclude, the higher the resolution, the higher the variability, and the more complex the picture.39 It is now important to develop a critical awareness for such differences

in resolution. It is important, to know where one stands relative to the virtual optimum, maximum resolution, and to be able to put results into perspective. This is particularly important Inhibitors,research,lifescience,medical in order to make inferences on the validity of genotype-phenotype relationships as they have been established in the studies of interest. Comprehensive knowledge on amount, nature, and structure of genetic variation: an see more essential prerequisite This article first provides Inhibitors,research,lifescience,medical an overview of methods and approaches to the analysis of genetic variation as they have developed over time, reflecting a gradual transition from the indirect, random assessment of variations basically guided by chance, to the increasingly Inhibitors,research,lifescience,medical systematic and complete resolution of defined candidate gene regions. The emphasis on the historical dimension should facilitate the distinction of different, and currently

coexisting, approaches. Second, Inhibitors,research,lifescience,medical the importance of a whole gene sequence-based, systematic analysis of genetic variation and its underlying haplotype structures will be outlined. Third, a state-of-the-art summary of present data describing genetic variation in candidate genes – its amount, nature, and structure at the highest, possible level of resolution to date will be given. These data reveal an abundant, sequence diversity as well over as complex haplotype structures. This demonstrates at the experimental level that it is essential to resolve genetic variation and its underlying structures as systematically as possible, in order to design successful association studies and establish meaningful relationships with gene function and phenotype. The implications of given natural variability for pharmacogenomics and a personalized medicine will then be summarized in the following section. Finally, the tremendous challenges posed by both variability and the complex nature of pharmacogenetically relevant, traits will be addressed and first, solutions and future perspectives outlined.