A gene can be thought of as a recipe in our DNA that provides instructions for building a specific protein, and an allele is a particular version of that recipe. Just as different chefs might have slightly different versions of the same recipe, organisms have different alleles for a single gene.
A loss-of-function allele is a version of this recipe that contains an error. This error means the resulting protein is either not made at all or is constructed in a way that prevents it from working correctly. The consequence is a reduction or complete absence of the protein’s normal activity. This functional deficit is what separates this type of allele from functional, or “wild-type,” versions of the gene.
How Loss of Function Mutations Occur
Loss-of-function alleles are the result of mutations, which are changes to the DNA sequence of a gene. One way this happens is through a nonsense mutation. This type of mutation changes a segment of the DNA that codes for an amino acid into a “stop” signal, which prematurely halts the protein-building process and results in a shortened, nonfunctional protein.
Another cause is a frameshift mutation, which occurs when DNA bases are inserted or deleted in a number not divisible by three. Since the cell reads DNA in three-letter “words” called codons, this shift scrambles the entire genetic message from the point of the mutation onward. The result is a completely different and nonfunctional protein sequence. A single nucleotide deletion can cause a frameshift that disrupts the protein.
Splice-site mutations affect how a gene’s instructions are processed before being used to create a protein. Genes contain coding regions (exons) and non-coding regions (introns), and the introns must be precisely removed. A splice-site mutation can interfere with this removal process, leading to an incorrect set of instructions and a defective protein. These mutations alter the protein’s structure so it cannot work correctly.
Classifying Loss of Function Alleles
Scientists classify loss-of-function alleles based on the severity of the functional reduction. The categories reflect a spectrum from partial to complete loss of the protein’s intended action.
The most severe type is the amorphic allele, often called a null allele. This allele leads to a total absence of gene function, meaning the protein might not be produced at all, or the one that is made is entirely non-functional. For genetic analysis, amorphic alleles are useful because they clearly show the effect of a complete lack of a specific protein.
A less severe category is the hypomorphic allele, sometimes referred to as a “leaky” allele. In this case, there is a partial loss of function. The allele directs the production of a protein that still works to some extent but is less effective or is produced in smaller quantities than the normal, wild-type version. This results in a reduced, but not absent, level of protein activity.
Inheritance Patterns and Effects
The way a loss-of-function allele affects an organism depends on its inheritance pattern. Many of these alleles are recessive. In diploid organisms, which have two copies of each gene, having one functional allele is often enough to produce sufficient protein to maintain a normal state, or phenotype. A trait or disease associated with the loss-of-function allele only appears if an individual inherits two copies of it.
In some cases, a loss-of-function allele can be dominant, a situation known as haploinsufficiency. This occurs when a single functional copy of a gene is not enough to produce the necessary amount of protein for a normal phenotype.
Examples in Human Genetic Disorders
Cystic fibrosis is a recessive disorder caused by mutations in the CFTR gene. The resulting loss-of-function alleles produce a nonfunctional version of a protein that regulates ion movement across cell membranes. An individual must inherit two of these faulty alleles to develop the disease.
Tay-Sachs disease is another recessive disorder. It results from loss-of-function mutations in the HEXA gene, which provides instructions for an enzyme that breaks down fatty substances in nerve cells. When an individual has two non-functional HEXA alleles, these substances accumulate to toxic levels, leading to severe neurological damage.
Marfan syndrome illustrates dominant loss of function through haploinsufficiency. The condition is caused by a mutation in one copy of the FBN1 gene, which codes for a protein called fibrillin-1, a component of connective tissue. Because one functional allele does not produce enough fibrillin-1 for normal tissue structure, the presence of a single loss-of-function allele is enough to cause the disorder’s effects on the skeleton, heart, and eyes.