A polymorphic locus is one whose alleles or variants are such that the most common variant among them occurs with less than 99% frequency in the population at large, for example, if the locus is biallelic, the rarer allele must occur with a frequency greater than 1% in the population. The availability of a reference sequence of the human genome provides the basis for studying the nature of sequence variation, particularly single nucleotide polymorphisms (SNPs), in human populations. SNPs occur at a frequency of approximately 0.5-1 SNP/kb throughout the genome when the sequence of individuals is compared (Mullikin et al. 2000; The genome international sequencing consortium 2001; Venter et al. 2001). SNP typing is a powerful tool for genetic analysis because sequence variants are responsible for the genetic component of individuality, disease susceptibility, and drug response. The latter point will have an important impact on drug design, therapeutic regimes and side effects. This field just starts to develop in GPCR research. To date, a large number of variants in GPCR genes has been identified (for review see Rana et al. 2001). For example, the most prevalent SNP in the ^ opioid receptor gene is a nucleotide substitution at position 118, displaying an allelic frequency of approximately 10%. The resulting amino acid change at a putative N-glycosylation site (N40D) of the ^ opioid receptor increases the binding affinity and the potency of ^-endorphin and may have implications for normal physiology, therapeutics, and vulnerability to develop addictive diseases (Bond et al. 1998). With growing efforts in identifying SNPs, it is likely that mutation-induced alterations in receptor function will become a major focus of future drug-development efforts (Kopin et al. 2000; Brodde et al. 2001).
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