Difference Between Haploinsufficiency and Dominant Negative

The key difference between haploinsufficiency and dominant negative is that haploinsufficiency involves the loss of function in just one copy of two alleles while dominant-negative involves the gain of function mutation.

Haploinsufficiency and dominant-negative are two types of dominant mutations. Haploinsufficiency is due to the loss of function while dominant-negative is due to the gain of function. In haploinsufficiency, the working allele is not sufficient to produce a sufficient amount of protein. Hence, an abnormal phenotype is formed. In dominant-negative, a change in protein function happens due to a mutation. The resulting protein contributes to the formation of dimmers or multimers leading to dominant-negative effect.

CONTENTS

1. Overview and Key Difference
2. What is Haploinsufficiency 
3. What is Dominant Negative
4. Similarities Between Haploinsufficiency and Dominant Negative
5. Side by Side Comparison – Haploinsufficiency vs Dominant Negative in Tabular Form
6. Summary

What is Haploinsufficiency?

Haploinsufficiency is the formation of an abnormal phenotype due to inactivation of one allele out of a pair of alleles of a gene. This is generally an unusual occurrence. This mutation is a type of dominant mutation. Therefore, the nonfunctional allele of a haploinsufficient gene is dominant. Haploinsufficiency arises from any mechanism that leads to loss of function. These mechanisms can be deletion, chromosomal translocation, truncation caused by nonsense or frameshift mutation, amino acid substitutions, etc.

Gene haploidy has a role in specific phenotypes which are abnormal. The working allele of the haploinsufficient gene is not sufficient for normal expression of the gene’s actual function. Hence, the loss of function of just one allele or 50% reduction of protein production turns out to be pathogenic and results in a disease condition. Alagylle syndrome, tricho-rhino-phalangeal syndrome and multiple exostosis are several diseases caused due to haploinsufficiency.

What is Dominant Negative?

Dominant-negative is a form of gain of function mutation. Therefore, the disease is not caused due to loss of protein function. It happens due to a change in protein function. It acts antagonistically in the wild-type allele by chemically interacting with the normal gene product and interfering the normal function. In this mutation, a mutant receptor interferes with the function of the wild-type version of the receptor. In simple words, in dominant-negative mutation, the mutant polypeptide reduces the activity of the co-expressed wild-type protein. As a result, the final protein is an altered gene product. Furthermore, this form of mutations are also called antimorphs. Besides, these mutations cause several disorders in humans including brittle bone disease.

What are the Similarities Between Haploinsufficiency and Dominant Negative?

• Both haploinsufficiency and dominant negative are dominant mutations.
• They are frequently involved in developmental malformations.

What is the Difference Between Haploinsufficiency and Dominant Negative?

Haploinsufficiency occurs when only a single copy of the gene is functional while dominant negative occurs when the mutant polypeptide reduces the activity of the co-expressed wild type protein. Thus, this is the key difference between haploinsufficiency and dominant negative. Furthermore, haploinsufficiency is a type of loss of function mutation while dominant negative is a type of gain of function mutation.

Below is a summary of the difference between haploinsufficiency and dominant negative in tabular form.

Summary – Haploinsufficiency vs Dominant Negative

In haploinsufficiency, total protein product is insufficient to produce the standard phenotype. In the haploinsufficient gene, one copy of the gene is missing. Hence, it does not produce the protein required. Therefore the working copy is not sufficient to produce the standard phenotype. In dominant negative, mutant gene product adversely affects the normal, wild-type gene product within the same cell. Mutant polypeptides disrupt the activity of the wild type gene product. Haploinsufficiency is a type of loss of function mutation while dominant negative is a type of gain of function mutation. Thus, this is the summary of the difference between haploinsufficiency and dominant negative.

Reference:

1. “Haploinsufficiency.” Breda Genetics Srl, 10 Feb. 2016, Available here.
2. “BIL 250 – Lecture 7”. Bio.Miami.Edu, 2020, Available here.

Image Courtesy:

1. “The two-hit hypothesis” By WassermanLab – Own work (CC BY-SA 4.0) via Commons Wikimeda