Result: All amino acids changed beyond the insertion

Think again of codons as three-letter words, each corresponding to a particular amino acid. Translation proceeds codon by codon; if a base is added to the message or subtracted from it, translation proceeds perfectly until it comes to the one-base insertion or deletion. From that point on, the three-letter words in the message are one letter out of register. In other words, such mutations shift the "reading frame" of the genetic message. Frame-shift mutations almost always lead to the production of nonfunctional proteins.

Chromosomal mutations are extensive changes in the genetic material

Changes in single nucleotides are not the most dramatic changes that can occur in the genetic material. Whole DNA molecules can break and rejoin, grossly disrupting the sequence of genetic information. There are four types of such chromosomal mutations: deletions, duplications, inversions, and translocations (Figure 12.18). These mutations can be caused by severe damage to chromosomes resulting from mutagens or by drastic errors in chromosome replication.

► Deletions remove part of the genetic material (Figure 12.18a). Like frame-shift point mutations, their consequences can be severe unless they affect unnecessary genes or are masked by the presence, in the same cell, of normal alleles of the deleted genes. It is easy to imagine one mechanism that could produce deletions: A DNA molecule might break at two points, and the two end pieces might rejoin, leaving out the DNA between the breaks.

► Duplications can be produced at the same time as deletions (Figure 12.18fr). Duplication would arise if homologous chromosomes broke at different positions and then reconnected to the wrong partners. One of the two molecules produced by this mechanism would lack a seg

^ Deletion is the loss of a chromosome segment. j

Duplication and deletion result when homologous chromosomes break at different points...

Duplication and deletion result when homologous chromosomes break at different points...

Inversion results when a broken segment is inserted in reverse order.

Inversion results when a broken segment is inserted in reverse order.

Reciprocal translocation results when nonhomologous chromosomes exchange segments.

Reciprocal translocation results when nonhomologous chromosomes exchange segments.

12.18 Chromosomal Mutations Chromosomes may break during replication, and parts of chromosomes may then rejoin incorrectly.

12.18 Chromosomal Mutations Chromosomes may break during replication, and parts of chromosomes may then rejoin incorrectly.

ment of DNA (it would have a deletion), and the other would have two copies (a duplication) of the segment that was deleted from the first.

► Inversions also result from breaking and rejoining. A segment of DNA may be removed and reinserted into the same location in the chromosome, but "flipped" end over end so that it runs in the opposite direction (Figure 12.18c). If the break site for an inversion includes part of a DNA segment that codes for a protein, the resulting protein will be drastically altered and almost certainly nonfunctional.

► Translocations result when a segment of DNA breaks off, moves from its chromosome, and is inserted into a different chromosome. Translocations may be reciprocal, as in Figure 12.18d, or nonreciprocal, as the mutation involving duplication and deletion in Figure 12.18b illustrates. Translocations often lead to duplications and deletions, and may result in sterility if normal chromosome pairing in meiosis cannot occur.

Mutations can be spontaneous or induced

It is useful to distinguish two types of mutations in terms of their causes. Spontaneous mutations are permanent changes in the genome that occur without any outside influence. In other words, they occur simply because the machinery of the cell is imperfect. Induced mutations occur when some agent outside the cell—a mutagen—causes a permanent change in DNA.

Spontaneous mutations may occur by several mechanisms:

► The four nucleotide bases of DNA are somewhat unstable. They can exist in two different forms (called tautomers), one of which is common and one rare. When a base temporarily forms its rare tautomer, it can pair with a different base. For example, C normally pairs with G. But if C is in its rare tautomer at the time of DNA replication, it pairs with (and DNA polymerase will insert) A. The result is a point mutation: G ^ A (Figure 12.19a, c).

► Bases may change because of a chemical reaction. For example, loss of an amino group in cytosine (a reaction called deamination) forms uracil. When DNA replicates, instead of a G opposite what was C, DNA polymerase adds an A (base-pairs with U).

► DNA polymerase makes errors in replication (see Chapter 11); for example, inserting a T opposite a G. Most of these errors are repaired by the proofreading function of the replication complex, but some errors escape and become permanent.

► Meiosis is not perfect. Nondisjunction can occur, leading to one too many or one too few chromosomes (aneu-ploidy; see Figure 9.18). Random chromosome breaks and rejoining can produce deletions, duplications, and inversions, or, when involving nonhomologous chromosomes, translocations.

Mutagens can also alter DNA by several mechanisms:

► Some chemicals can covalently alter the nucleotide bases. For example, nitrous acid (HNO2) and its relatives can turn cytosine in DNA into uracil by deamination: they convert an amino group on cytosine (—NH2) into a keto group (—C=O). This alteration has the same result as a spontaneous deamination: instead of a G, DNA poly-merase inserts an A (base-pairs with U) (Figure 12.19b,c).

► Some chemicals add groups to the bases. For instance, ben-zpyrene, a component of cigarette smoke, adds a large chemical group to guanine, making it unavailable for base pairing. When DNA polymerase reaches such a modified guanine, it inserts any of the four bases; of course, three-fourths of the time the inserted base will not be cytosine, and a mutation results.

► Radiation damages the genetic material in two ways. Ionizing radiation (X rays) produces highly reactive chemical

(a) A spontaneous mutation

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