A point mutation is the addition or subtraction of a single nucleotide, or the substitution of one nucleotide base for another. There are two kinds of base substitution:

A point mutation in the coding region of a gene will result in an alteration in the mRNA sequence. But remember: a change in the mRNA does not necessarily mean a change in the protein that gets translated from it at the ribosome. As we just mentioned, a silent mutation has no effect on the amino acid sequence of an encoded polypeptide. By contrast, missense, nonsense, and frame-shift mutations do result in changes in the protein, some of them drastic (Figure 15.2).

MISSENSE MUTATIONS Missense mutations are *base substitution changes that alter the genetic code such that one amino acid substitutes for another in a protein (see Figure 15.2C). A specific example is the mutation that causes sickle-cell disease, a serious heritable blood disorder. The disease occurs in people who carry two copies of the sickle allele of the gene for β-globin—a subunit of hemoglobin, the protein in human blood that carries oxygen. The sickle allele differs from the wild-type allele by one base pair, resulting in a polypeptide that differs by one amino acid from the wild-type protein. Individuals who are homozygous for this recessive allele have defective, sickle-shaped red blood cells:

A missense mutation may result in a defective protein, but often has no effect on the protein’s function. For example, a hydrophilic amino acid may be substituted for another hydrophilic amino acid, so that the shape of the protein is unchanged. Or a missense mutation might reduce the functional efficiency of a protein rather than completely inactivating it. Therefore individuals homozygous for a missense mutation in a protein essential for life may survive if enough of the protein’s function is retained.

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In some cases, a gain-of-function missense mutation occurs. An example is a mutation in the human P53 gene, which codes for a tumor suppressor—a protein that inhibits the cell cycle (see Key Concept 11.7). Certain mutations of the P53 gene cause this protein to no longer inhibit cell division, but instead to promote it and prevent programmed cell death.

NONSENSE MUTATIONS A nonsense mutation involves a base substitution that causes a stop codon (for translation) to form somewhere in the mRNA (see Figure 15.2D). A nonsense mutation results in a shortened protein, since translation does not proceed beyond the point where the mutation occurred. For example, a common mutation causing thalassemia (another blood disorder affecting hemoglobin) in Mediterranean populations is a nonsense mutation that drastically shortens the β-globin subunit. Shortened proteins are usually not functional; however, if the nonsense mutation occurs near the 3′ end of the gene, it may have no effect on function.

FRAME-SHIFT MUTATIONS Not all point mutations are base substitutions. One or two nucleotides may be inserted into, or deleted from, a sequence of DNA. Such mutations in coding sequences are known as frame-shift mutations because they alter the reading frame (that is, consecutive triplets) in which the codons are read during translation (see Figure 15.2E). Think again of *codons as three-letter words, each corresponding to a particular amino acid. Translation proceeds codon by codon; if a nucleotide is added to the mRNA or subtracted from it, then the three-letter “words” are altered as translation proceeds beyond that point, and the result is a completely different amino acid sequence. Frame-shift mutations almost always lead to the production of nonfunctional proteins.

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MUTATIONS OUTSIDE THE CODING REGION As discussed in Chapter 17, in genomes like ours, much of the DNA does not contain protein-coding genes. If there is a mutation in a region that is not involved with a protein-coding gene, it often does not have a phenotypic effect, although it is still a mutation—an inherited change in DNA. Recall from Chapter 14 that protein-coding genes have stretches of DNA that do not encode amino acids, such as promoters and introns. Mutations in these regions may have significant effects. For example: