There are a number of ways to classify gene mutations. Some classification schemes are based on the nature of the phenotypic effect, others are based on the causative agent of the mutation, and still others focus on the molecular nature of the defect. Here, we will categorize mutations primarily on the basis of their molecular nature, but we will also encounter some terms that relate to the causes and the phenotypic effects of mutations.

BASE SUBSTITUTIONS The simplest type of gene mutation is a base substitution, the alteration of a single nucleotide in the DNA (Figure 13.2a). There are two types of base substitutions. In a transition, a purine is replaced by a different purine or, alternatively, a pyrimidine is replaced by a different pyrimidine (Figure 13.3). In a transversion, a purine is replaced by a pyrimidine or a pyrimidine is replaced by a purine. The number of possible transversions (see Figure 13.3) is twice the number of possible transitions, but transitions arise more frequently because transforming a purine into different purine or a pyrimidine into different pyrimidine is easier than transforming a purine into pyrimidine, or vice versa. TRY PROBLEM 13

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INSERTIONS AND DELETIONS Another class of gene mutations contains insertions and deletions (collectively called indels): the addition or removal, respectively, of one or more nucleotide pairs (Figure 13.2b and c). Although base substitutions are often assumed to be the most common type of mutation, molecular analysis has revealed that insertions and deletions are frequently more common. Insertions and deletions within sequences that encode proteins may lead to frameshift mutations: changes in the reading frame (Chapter 11) of the gene. Frameshift mutations usually alter all amino acids encoded by the nucleotides following the mutation, so they generally have drastic effects on the phenotype. Some frameshifts also introduce premature stop codons, terminating protein synthesis early and resulting in a shortened (truncated) protein. Not all insertions and deletions lead to frameshifts, however; insertions and deletions consisting of any multiple of three nucleotides leave the reading frame intact, although the addition or removal of one or more amino acids may still affect the phenotype. Indels that do not affect the reading frame are called in-frame insertions and in-frame deletions.

EXPANDING NUCLEOTIDE REPEATS Mutations in which the number of copies of a set of nucleotides increases are called expanding nucleotide repeats. This type of mutation was first observed in 1991 in a gene called FMR-1, which causes fragile-X syndrome, the most common hereditary cause of intellectual disability. The disorder is so named because, in specially treated cells from persons having the condition, the tip of each long arm of the X chromosome is attached by only a slender-appearing part of the chromosome (Figure 13.4). The normal FMR-1 allele (not containing the mutation) has 60 or fewer copies of CGG, but in persons with fragile-X syndrome, the allele may harbor hundreds or even thousands of copies.

Expanding nucleotide repeats have been found in a number of other human genetic diseases, several of which are listed in Table 13.1. Most of these diseases are caused by the expansion of a set of three nucleotides (called a trinucleotide), most often CNG, where N can be any nucleotide. However, some diseases are caused by repeats of four, five, and even twelve nucleotides. The number of copies of the nucleotide repeat often correlates with the severity or age of onset of the disease. The number of copies of the repeat also corresponds to its instability: when more repeats are present, the probability of expansion to even more repeats increases.

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Increases in the number of nucleotide repeats can produce disease symptoms in different ways. In several diseases (e.g., Huntington disease), the nucleotide expansion occurs within the coding part of a gene, producing a toxic protein that has extra glutamine residues (the amino acid encoded by CAG). In other diseases, the repeat is outside the coding region of a gene and affects its expression. In fragile-X syndrome, the additional copies of the nucleotide repeat cause the DNA to become methylated, which turns off the transcription of an essential gene.

A possible source of nucleotide repeat expansion is the formation of hairpins and other special DNA structures, which can cause nucleotides in the template strand to be replicated twice, thus increasing the number of repeats on the newly synthesized strand (Figure 13.5). Watching Animation 13.1 will help you understand how the nucleotide repeats increase in number.