The Structure and Function of DNA: Mutations

CHAPTER TEN THE STRUCTURE AND FUNCTION OF DNA

Mutations

Since discovering how genes are translated into proteins, scientists have been able to describe many heritable differences in molecular terms. For instance, sickle-cell disease can be traced to a change in a single amino acid in one of the polypeptides in the hemoglobin protein. This difference is caused by a single nucleotide difference in the DNA coding for that polypeptide.

A single molecular "typo" in DNA can result in a life-threatening disease.

Any change in the nucleotide sequence of a cell's DNA is called a mutation. Mutations can involve large regions of a chromosome or just a single nucleotide pair, as in sickle-cell disease. Occasionally, a base substitution leads to an improved protein or one with new capabilities that enhance the success of the mutant organism and its descendants. Much more often, though, mutations are harmful. Think of a mutation as a typo in a recipe; occasionally, such a typo might lead to an improved recipe, but much more often it will be neutral, mildly bad, or disastrous. Let's consider how mutations involving only one or a few nucleotide pairs can affect gene translation.

Types of Mutations

Mutations within a gene can be divided into two general categories: nucleotide substitutions and nucleotide insertions or deletions. A substitution is the replacement of one nucleotide and its base-pairing partner with another nucleotide pair. For example, in the second row, A replaces G in the fourth codon of the mRNA. What effect can a substitution have? Because the genetic code is redundant, some substitution mutations have no effect at all. For example, if a mutation causes an mRNA codon to change from GAA to GAG, no change in the protein product would result because GAA and GAG both code for the same amino acid, Glu. Such a change is called a silent mutation. In our recipe example, changing "one and one-fourths cup sugar" to "one and one-fifth cup sugor"

would probably be translated the same way, just like the translation of a silent mutation does not change the meaning of the message.

Other substitutions involving a single nucleotide do change the amino acid coding. Such mutations are called missense mutations. For example, if a mutation causes an mRNA codon to change from GGC to AGC, the resulting protein will have a serine instead of a glycine at this position. Some missense mutations have little or no effect on the shape or function of the resulting protein; imagine changing a recipe from "one and one-fourths cups sugar" to "one and one-fifth cups sugar"-this will probably have a negligible effect on your final product. However, other substitutions, as we saw in the sickle-cell case, cause changes in the protein that prevent it from performing normally. This would be like changing "one percent cups sugar" to "sixteen-fourteenths cups sugar"-this one change is enough to ruin the recipe.

Some substitutions, called nonsense mutations, change an amino acid codon into a stop codon. For example, if an AGA, Arg, codon is mutated to a UGA, stop, codon, the result will be a prematurely terminated protein, which probably will not function properly. In our recipe analogy, this would be like stopping food preparation before the end of the recipe, which is almost certainly going to ruin the dish.

Mutations involving the deletion or insertion of one or more nucleotides in a gene, called frameshift mutations, often have disastrous effects. Because mRNA is read as a series of nucleotide triplets during translation, adding or subtracting nucleotides may alter the triplet grouping of the genetic message. All the nucleotides after the insertion or deletion will be regrouped into different codons. Consider this recipe example: Add one cup egg nog. Deleting the second letter produces an entirely nonsensical message- ado nec upe ggn og-which will not produce a useful product. Similarly, a frameshift mutation most often produces a nonfunctioning polypeptide.