Mutations may cause loss-of-function or gain-of-function

KEY TERMS:

• A null mutation completely eliminates the function of a gene.
• Leaky mutations leave some residual function, for instance when the mutant protein is partially active (in the case of a missense mutation), or when read-through produces a small amount of wild-type protein (in the case of a nonsense mutation).
• A loss-of-function mutation eliminates or reduces the activity of a gene. It is often, but not always, recessive.
• A gain-of-function mutation usually refers to a mutation that causes an increase in the normal gene activity. It sometimes represents acquisition of certain abnormal properties. It is often, but not always, dominant.
• Silent mutations do not change the sequence of a protein because they produce synonymous codons.
• Neutral substitutions in a protein cause changes in amino acids that do not affect activity.

KEY CONCEPTS:

• Recessive mutations are due to loss-of-function by the protein product.
• Dominant mutations result from a gain-of-function.
• Testing whether a gene is essential requires a null mutation (one that completely eliminates its function).
• Silent mutations have no effect, either because the base change does not change the sequence or amount of protein, or because the change in protein sequence has no effect.
• Leaky mutations do affect the function of the gene product, but are not revealed in the phenotype because sufficient activity remains. 

The various possible effects of mutation in a gene are summarized in Figure 1.28.

When a gene has been identified, insight into its function in principle can be gained by generating a mutant organism that entirely lacks the gene. A mutation that completely eliminates gene function, usually because the gene has been deleted, is called a null mutation. If a gene is essential, a null mutation is lethal.

To determine what effect a gene has upon the phenotype, it is essential to characterize a null mutant. When a mutation fails to affect the phenotype, it is always possible that this is because it is a leaky mutation—enough active product is made to fulfill its function, even though the activity is quantitatively reduced or qualitatively different from the wild type. But if a null mutant fails to affect a phenotype, we may safely conclude that the gene function is not necessary.

Null mutations, or other mutations that impede gene function (but do not necessarily abolish it entirely) are called loss-of-function mutations. A loss-of-function mutation is recessive (as in the example of Figure 1.26). Sometimes a mutation has the opposite effect and causes a protein to acquire a new function; such a change is called a gain-of-function mutation. A gain-of-function mutation is dominant.

Not all mutations in DNA lead to a detectable change in the phenotype. Mutations without apparent effect are called silent mutations. They fall into two types. Some involve base changes in DNA that do not cause any change in the amino acid present in the corresponding protein. Others change the amino acid, but the replacement in the protein does not affect its activity; these are called neutral substitutions.