One major characteristic of these studies is that, they generated a vast,

body of controversial results; a typical example is the story of the dopamine D2 receptor gene and alcoholism.49 In the late 1990s, it became feasible to systematically evaluate genetic Tasocitinib chemical structure variation at the ultimate level of resolution, ie, the DNA sequence, as demonstrated in a series of comparative sequencing studies. 24,25,27-33 These studies revealed presence of abundant sequence diversity and far more complex underlying LD structures than had previously been anticipated.24,25,27,29,31-33,38,50 This substantially changed the view of the amount, pattern, and structure of genetic variability Inhibitors,research,lifescience,medical in genes and genomes.35 Evidence of abundant, sequence diversity began to raise doubts about the validity of traditional single SNP approaches.30,38 Apart, from theoretical considerations,29 it was shown that multiple variants can exist, within genes and that, the combinations of variants on each

Inhibitors,research,lifescience,medical of the two copies of a gene (haplotypes) should become the focus of analysis. First, systematic comparative sequencing studies demonstrated that the analysis of haplotypes defined by the grouping and interaction of several variants Inhibitors,research,lifescience,medical rather than any individual SNP were correlated with complex phenotypes, such as drug response and common disease.24,29,51 Finally, when evidence for a haplotype structure of the human genome was obtained, it was explicitly recognized that, single SNP-based

candidate gene approaches may be statistically weak and have no clear end point; true associations may be missed because of the incomplete information provided by individual SNPs; negative results exclude Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical particular SNPs as playing a role, but cannot exclude a gene.20 This was the beginning of the end of single SNP approaches; haplotype-based approaches to candidate gene analysis and disease gene discovery had at last, become the state of the art.39 The systematic analysis of candidate genes: a necessary precondition to establish links to gene function, disease, and drug response The importance of haplotypes: context matters Only the entire gene sequence, given in its individually variable forms, can be correlated with the function, regulation, and expression of the protein and, MRIP ultimately, phenotype. “Since it, is the entire gene and its encoded protein that act as the units of function potentially affecting a phenotype (and ultimately allow initial conclusions on disease mechanisms), we must, analyze the entire sequences of the individual genes including their regulatory and intronic regions. It is therefore essential in diploid organisms (such as humans) to determine the specific combinations of all given gene sequence variants for each of the two chromosomes defined here as haplotypes.