Another way that mutations are classified is on the basis of their phenotypic effects. At the most general level, we can distinguish a mutation on the basis of its phenotype compared with the wild-type phenotype. A mutation that alters the wild-type allele is called a forward mutation, whereas a reverse mutation (a reversion) changes a mutant allele back into the wild-type allele.

Geneticists use other terms to describe the effects of mutations on protein structure. A base substitution that results in a different amino acid in the protein is referred to as a missense mutation (Figure 13.6a). A nonsense mutation changes a sense codon (one that specifies an amino acid) into a nonsense codon (one that terminates translation), as shown in Figure 13.6b. If a nonsense mutation occurs early in the mRNA sequence, the protein will be truncated and usually nonfunctional.

Because of the redundancy of the genetic code, some different codons specify the same amino acid (see Figure 11.5). A silent mutation changes a codon to a synonymous codon that specifies the same amino acid (Figure 13.6c), altering the DNA sequence without changing the amino acid sequence of the protein. Not all silent mutations, however, are truly silent: some do have phenotypic effects. For example, different tRNAs (called isoaccepting tRNAs, see Chapter 11) are used for different synonymous codons. Because some isoaccepting tRNAs are more abundant than others, which synonymous codon is used may affect the rate of protein synthesis. The rate of protein synthesis can influence the phenotype by affecting the amount of protein present in the cell and, in a few cases, the folding of the protein. Other silent mutations can alter sequences near the exon–intron junctions that affect splicing (see Chapter 10). Additional silent mutations can influence the binding of miRNAs to complementary sequences in the mRNA, which determines whether the mRNA is translated (see Chapter 10).

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A neutral mutation is a missense mutation that alters the amino acid sequence of a protein but does not significantly change its function. Neutral mutations occur when one amino acid is replaced by another that is chemically similar or when the affected amino acid has little influence on protein function. For example, some neutral mutations occur in the genes that encode hemoglobin; although these mutations alter the amino acid sequence of hemoglobin, they do not affect its ability to transport oxygen.

Loss-of-function mutations cause the complete or partial absence of normal protein function. A loss-of-function mutation so alters the structure of the protein that the protein no longer works correctly, or occurs in regulatory regions that affect the transcription, translation, or splicing of the protein. Loss-of-function mutations are frequently recessive, in which case an individual diploid organism must be homozygous for the mutation before the effects of the loss of the functional protein can be exhibited. The mutations that cause cystic fibrosis are loss-of-function mutations: these mutations produce a nonfunctional form of the cystic fibrosis transmembrane conductance regulator protein, which normally regulates the movement of chloride ions into and out of the cell (see Chapter 4).

In contrast, a gain-of-function mutation causes the cell to produce a protein or gene product whose function is not normally present. The result could be an entirely new gene product or one produced in an inappropriate tissue or at an inappropriate time in development. For example, a mutation in a gene that encodes a receptor for a growth factor might cause the mutated receptor to stimulate growth all the time, even in the absence of the growth factor. Gain-of-function mutations are frequently dominant in their expression because a single copy of the mutation leads to the presence of a new gene product.

Still other types of mutations are conditional mutations, which are expressed only under certain conditions. For example, some conditional mutations affect the phenotype only at elevated temperatures. Another type of mutation is a lethal mutation, one that causes premature death (Chapter 4). TRY PROBLEM 17