POLYMORPHISMS OF DRUG TRANSPORTERS AND CLINICAL RELEVANCE - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 622

two-thirds were population specific, and more than half of these were rare mutations
found on only one of 494 chromosomes. A larger number of common population-
specific SNPs ( 5% minor allele frequency) were found in the African-American

population compared to the Caucasian population.
Interestingly, the number of synonymous (silent) and nonsynonymous (resulting
in an amino acid change) SNPs identified in the 24 membrane transporter genes was
also similar (175 and 155, respectively). 60 However, statistical genetic analysis of the
variation observed, which takes into account the frequency of the SNP and the number
of alleles that were screened (denoted as the average heterozygosity,

>

), revealed
that variation was about three- to fourfold more common at synonymous positions
than at nonsynonymous positions (Figure 21.1 a ). This suggests that there is some
selective pressure on membrane transporter genes to suppress dramatic changes in
transporter function. Genetic variation was strikingly low at nonsynonymous sites for

18

15
12
9
6
3
0

AA CA AS

(a)

10
8
6
4
2
0

SLC ABC

(b)

FIGURE 21.1. ( a ) Nucleotide diversity ( ) is greater at synonymous than at nonsynonymous
sites. The values are shown for synonymous (black bars), and nonsynonymous (open bars)
sites and were calculated separately for a population of 100 African Americans (AA), 100
Caucasians (CA), and 30 Asian Americans (AS). The values shown are the mean ± S.D. ( b )
Nucleotide diversity is generally higher in the loops than in the transmembrane domains and is
particularly low for evolutionarily conserved residues. The values are shown for all nonsyn-

onymous loop residues (black bars), evolutionarily conserved loop residues (diagonal lines),
evolutionarily unconserved loop residues (dotted bars), all nonsynonymous transmembrane
domain residues (open bars), evolutionarily conserved transmembrane domain residues (gray
bars), and evolutionarily unconserved transmembrane domain residues (stippled bars). The
values are shown separately for 18 SLC and 5 ABC transporters and are the mean ± S.D. (Data
from ref. 60.)