They also reflect different, stages of approximation to completeness at an early stage. Sequencing at this stage is still too laborand cost-intensive. It is generally

not especially feasible to sequence all functionally relevant regions of the entire gene (even if they were all known) in every member of a defined population in order to identify all given variants and their frequencies. Just to give some impression of the scale of the undertaking: in order to systematically analyze genetic variation in a typical G protein-coupled receptor gene including regulatory, exonic and intronic sequences (exon-intron boundaries) Inhibitors,research,lifescience,medical in 250 cases and controls, about 1.7 finished megabases (ie, about, twice the amount of raw sequence data to obtain maximum accuracy) need to be generated,29 comparable to the

size of a bacterial genome. For completeness of genomic organization, we should refer to examples that have Inhibitors,research,lifescience,medical demonstrated, for instance, a disease-related regulatory variant, about 14 kb 5_ upstream of the translation initiation codon or regulatory elements in intronic sequences of extensive lengths.39 Thus, functionally important regions of the gene can at this stage be included in Inhibitors,research,lifescience,medical as representative a way as possible. Present approaches may still miss what we term the causative variant(s). Thus, in practice, we are still dealing (at a comparatively advanced level) with marker or subset Inhibitors,research,lifescience,medical approaches, where identified variants represent, only a selection of all naturally existing variants. Against, this background, the genebased haplotypes will be categorized as complex genetic markers.39 A critical question is

then whether the subsets of variation extracted do in fact validly Inhibitors,research,lifescience,medical represent, given LD and haplotype structures of a gene. In this case, the resulting gene-based haplotypes have been shown to be superior as markers in comparison to any single SNP, because they contain more information (heterozygosity) than any of the individual markers, or SNPs that comprise them.33,48 Multiple correlations with neighboring, Cilengitide or embedded, unobserved variants may be possible. Thus, a neither multisite gene-based haplotype (higher-order marker) will have greater power than any individual SNP to detect, an unobserved – but evolutionarily linked – variable causative site.48 Such haplotype signatures may, moreover, have significantly greater power to predict disease risk and drug response than any individual SNP within a gene.24,29,48,51,62 In the overall process of disease gene identification, it merits serious consideration to restrict, investigations in the first, pass to haplotype marker screening, the apparently less investment-intensive marker approach. It should nevertheless be emphasized that if an association is found, the ultimate challenge to generate complete sequence information will remain.