55,56 This gene, the product of which represents a key component, of the central and peripheral autonomous nervous systems, is an important candidate for a spectrum of diseases including neuropsychiatrie

and cardiovascular disorders. It is also the target, for most, commonly ATM inhibitor prescribed drugs.6 Comparative sequence analysis of the gene including its regulatory and coding sequences in several hundred individuals resulted in the discovery of a total of 15 variants,55 four of which induced an amino acid mutation and were each shown to be functionally significant in vitro.57-59 Inhibitors,research,lifescience,medical In addition, a number of variants were identified in the 5′ regulatory region. In a preliminary casecontrol study, individuals who carried a. specific combination

of seven variants (haplotype) (blue in Inhibitors,research,lifescience,medical Figure 2) were significantly more frequently earning a predisposition to essential hypertension.55 This potential risk profile included three SNPs in the 5′ regulatory region, and one SNP in the 5′ untranslated region (5′UTR) at position -20, and three amino acid mutations in the Inhibitors,research,lifescience,medical leader peptide (-47) and amino terminal of the receptor protein (46 and 79). Figure 2 Haplotypes of the human β2-adrenergic receptor gene and identification of genetic risk profiles. This figure represents, from left to right, the specific alleles at each of 11 variable positions (relative to the translation initiation site) in … The

variant at position 46 relative to the translation initiation site induces a functionally significant Arg>Gly exchange60 and was the most, frequently used variant in association studies; the combination of the three mutations at positions Inhibitors,research,lifescience,medical -47, 46, and 79 were used in some association studies.61 Neither of these were found to distinguish between high- and no-risk alleles. The last, four variants (marked in gray) had no impact statistically, which beautifully reflects biology: these variants affected the third base and were silent mutations.55 Moreover, Inhibitors,research,lifescience,medical this example illustrates that complete sequence analysis is necessary to focus subsequent functional experiments on all variants of potential functional significance. Of those seven variants in LD, one, several, or all variants in interaction may contribute to functional differences. either Finally, this example demonstrates the complexity of functional annotation, given that, regulatory and coding variants occur in combinations. Gene-based functional haplotypes versus gene-based complex genetic markers The definition of a gene-based functional haplotype that requires complete DNA sequence information in all individuals is, admittedly, somewhat, futuristic at this stage of human genome research. In many cases, reality may allow different stages of approximation only.