A monoallelic mutation is a change in the DNA sequence of a single copy of a gene. For the majority of genes, you inherit two copies, called alleles, one from each parent. These alleles can be identical or have slight variations. When a mutation occurs in just one of these two inherited copies, it is referred to as monoallelic. This single change can sometimes be sufficient to cause a genetic condition, even when the second copy of the gene remains normal and functional.
The Role of Alleles in Genetic Function
The way two different alleles interact determines how a trait is expressed. Some alleles are dominant, meaning only one copy is needed for its associated trait to be expressed. Other alleles are recessive, and their trait is only expressed when an individual has two copies of that allele. A dominant allele can mask the effects of a recessive one. For instance, in eye color, alleles for brown eyes are dominant over the recessive alleles for blue eyes, which is why a person with one brown-eye allele and one blue-eye allele will have brown eyes.
This relationship explains why having one functional copy of a gene is often enough to maintain health. The single normal allele can produce a sufficient amount of its corresponding protein for the body’s cells to function correctly. In these cases, the presence of a non-working, or mutated, recessive allele doesn’t result in disease because the dominant, functional allele compensates. This genetic backup system is a common feature of diploid organisms.
However, this is not always the case, as some mutations can cause disease even when a normal allele is present. These situations arise when the single mutated copy disrupts normal processes in ways that the healthy copy cannot overcome. The specific nature of the mutation and the function of the protein it codes for determine whether a monoallelic mutation will lead to disease.
Mechanisms of Monoallelic Disease
A single mutated allele can lead to disease through several distinct biological mechanisms.
One common mechanism is haploinsufficiency. This occurs when the single remaining functional allele is unable to produce enough protein to carry out its necessary function. The 50% reduction in quantity is not enough for the cell to operate correctly. Imagine a project that requires two workers; if one fails to show up, the remaining worker cannot perform the job of two, and the project falls behind.
Another mechanism is the dominant negative effect. In this scenario, the mutated allele produces an abnormal protein that actively interferes with the function of the normal protein. This is particularly common for proteins that need to assemble into larger complexes, where the faulty protein might join the complex and prevent it from working correctly.
A third mechanism is a gain-of-function mutation. This type of mutation causes the resulting protein to acquire a new, harmful function. The altered protein can become toxic to the cell, leading to damage and cell death, transforming a harmless component into a toxic one.
Inheritance Patterns and Risk
Conditions caused by monoallelic mutations are passed down through families in a pattern called autosomal dominant inheritance. The term “autosomal” means the mutated gene is located on one of the non-sex chromosomes (chromosomes 1-22). “Dominant” signifies that only one copy of the mutated allele is needed to cause the condition. This inheritance pattern means that males and females are affected equally, and the condition does not usually skip generations.
For an affected parent with one mutated allele and one normal allele, there is a 50% chance of passing the mutation on to each child. This can be visualized using a Punnett square, a simple diagram that illustrates genetic inheritance.
It is also possible for a monoallelic condition to appear in a family with no prior history of the disorder. This occurs through a “de novo” or new mutation. A de novo mutation is a genetic alteration that arises for the first time in a reproductive cell (sperm or egg) of one of the parents or in the fertilized egg itself. When this happens, the child will have the mutation in every cell, but the parents do not.
Associated Genetic Conditions
Several genetic conditions are caused by monoallelic mutations, providing examples of the mechanisms at work.
Marfan syndrome is a connective tissue disorder that can be caused by a monoallelic mutation in the FBN1 gene. This condition affects many parts of the body, including the heart, blood vessels, bones, and eyes. The FBN1 gene provides instructions for making fibrillin-1, a protein that is a component of microfibrils which provide strength and flexibility to connective tissue. Mutations in FBN1 are often believed to have a dominant negative effect, where the abnormal fibrillin-1 protein disrupts the formation of functional microfibrils.
Huntington’s disease is a neurodegenerative disorder caused by a specific type of monoallelic mutation in the HTT gene. This mutation is a gain-of-function, where an expansion of a DNA segment known as a CAG trinucleotide repeat leads to the production of an abnormally long version of the huntingtin protein. This altered protein is toxic to nerve cells, particularly in the brain, and its accumulation leads to the motor, cognitive, and psychiatric symptoms of the disease.