A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population. Two major types of sequence variation have been associated with variation in human phenotype: single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) (Figure 4-2). SNPs are present in the human genome at approximately one SNP every few hundred to a thousand base pairs, depending on the gene region. Indels are much less frequent, particularly in coding regions of genes.
SNPs in the coding region are termed cSNPs and are further classified as nonsynonymous (or missense) if the base pair change results in an amino acid substitution, synonymous (or sense) if the base pair substitution within a codon does not alter the encoded amino acid, and nonsense if they introduce a stop codon. Typically, substitutions of the third base pair in a codon, the wobble position, do not alter the encoded amino acid. In addition, about 10% of SNPs can have more than two possible alleles (e.g., a C can be replaced by either an A or G), so that the same polymorphic site can be associated with amino acid substitutions in some alleles but not others.
Polymorphisms in noncoding regions of genes may occur in the 5' and 3' untranslated regions, in promoter or enhancer regions, in intronic regions, or in large intergenic regions between genes. Intronic polymorphisms found near exon-intron boundaries are often treated as a distinct category from other intronic polymorphisms, since they may affect splicing and thereby affect function. Noncoding SNPs in promoters/enhancers or in 5' and 3' untranslated regions may affect gene transcription or transcript stability. Noncoding SNPs in introns or exons may create alternative splicing sites, and the altered transcript may have fewer or more exons, or shorter or larger exons, than the wild-type transcript. Introduction or deletion of exonic sequence can cause a frame shift in the translated protein and thereby change protein structure or function, or can result in an early stop codon, producing an unstable or nonfunctional protein. Because 95% of the genome is intergenic, most polymorphisms are unlikely to directly affect the encoded transcript or protein. However, intergenic polymorphisms may have biological consequences by affecting DNA tertiary structure, interaction with chromatin and topoisomerases, or DNA replication. Thus, intergenic polymorphisms cannot be assumed to be pharmacogenetically insignificant.
A remarkable degree of diversity is evident in the types of insertions/deletions that are tolerated as germline polymorphisms. One common polymorphism in glutathione-S-transferase Ml (GSTM1) is caused by a 50-kilobase (kb) germline deletion; the null allele has a population frequency of 0.3-0.5, depending on race/ethnicity. In biochemical studies, homozygous null individuals have only -50% of the liver glutathione conjugating capacity of those with at least one copy of the GSTM1 gene. In the UGT1A1 promoter, the number of TA repeats affects the quantitative
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