FIGURE 4-2 Molecular mechanisms of genetic polymorphisms. The most common genetic variants are single nucleotide polymorphism substitutions (SNPs). Coding nonsynonymous SNPs result in a nucleotide substitution that changes the amino acid codon (here proline to glutamine), which could change protein structure, stability, substrate affinities, or introduce a stop codon. Coding synonymous SNPs do not change the amino acid codon, but may have functional consequences (transcript stability, splicing). Noncoding SNPs may be in promoters, introns, or other regulatory regions that may affect transcription factor binding, enhancers, transcript stability, or splicing. The second major types of polymorphism are indels (insertion/deletions). Indels can have any of the same effects as SNP substitutions: short repeats in the promoter (which can affect transcript amount), or larger insertions/deletions that add or subtract amino acids. Indels can also involve gene duplications, stably transmitted inherited germline gene replication that causes increased protein expression and activity, or gene deletions that result in the complete lack of protein production. All of these mechanisms have been implicated in common germline pharmacogenetic polymorphisms. TPMT, thiopurine methyltransferase; ABCB1, the multidrug resistance transporter (P-glycoprotein); CYP, cytochrome P450; CBS, cystathionine b-synthase; UGT, UDP-glucuronyl transferase; GST, glutathione-S-transferase.

Consider the coding region variants of two membrane transporters (Figure 4-3). Shown are nonsynonymous and synonymous SNPs; population-specific nonsynonymous cSNPs are indicated in the figure. The multidrug resistance associated protein, MRP2, has a large number of nonsynonymous cSNPs. There are fewer synonymous variants than nonsynonymous variants, but the allele frequencies of the synonymous variants are greater than those of the nonsynonymous variants. By comparison, the dopamine transporter DAT has a number of synonymous variants but no nonsyn-onymous variants, suggesting that selective pressures have acted against substitutions that led to changes in amino acids.

In a survey of coding region haplotypes in -300 different genes in 80 ethnically diverse DNA samples, most genes were found to have between 2 and 53 haplotypes, with the average number of haplotypes in a gene being 14. Like SNPs, haplotypes may be cosmopolitan or population specific and -20% of the over 4000 identified haplotypes were cosmopolitan. Considering the frequencies of the haplotypes, cosmopolitan haplotypes actually accounted for over 80% of all haplotypes, whereas population-specific haplotypes accounted for only 8%.

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