What is the Difference Between Nonsense and Missense Mutation

The main difference between nonsense and missense mutation is that the nonsense mutation introduces a stop codon to the gene sequence, leading to premature chain termination whereas the missense mutation introduces a distinct codon to the gene sequence, not a stop codon, leading to a non-synonymous amino acid in the polypeptide chain. Furthermore, a nonsense mutation results in a truncated, incomplete, and usually, nonfunctional protein product while a missense mutation results in either a conservative or non-conservative change to the protein.

Nonsense and missense mutations are point mutations or the single nucleotide substitutions which introduce distinct changes in the ultimate protein product.

Key Areas Covered

1. What is a Nonsense Mutation
     – Definition, Mechanism, Effect
2. What is a Missense Mutation
     – Definition, Mechanism, Effect
3. What are the Similarities Between Nonsense and Missense Mutation
     – Outline of Common Features
4. What is the Difference Between Nonsense and Missense Mutation
     – Comparison of Key Differences

Key Terms

Conservative Mutation, Missense Mutations, Non-Synonymous Amino Acid, Nonsense Mutations, Point Mutations, Premature Chain Termination

What is a Nonsense Mutation

A nonsense mutation is a type of mutation which introduces a stop codon at the site of mutation by a nucleotide substitution. The three possible stop codons in the DNA sequence are TAG, TAA, and TGA. Here, these codons are transcribed into the mRNA sequence, producing three types of nonsense mutations called amber mutations (UAG), ochre mutations (UAA), and opal or umber mutations (UGA), respectively. However, these three types of mutations can also emerge by the insertion or the deletion of a single nucleotide in the nucleotide sequence.

Figure 1: Nonsense Mutation by Deletion

In mRNA, the remaining codons beyond the stop codon will not be translated, leading to a premature chain termination. Thus, this causes a truncated or incomplete protein, which is non-functional. However, the effect of the nonsense mutation depends on the proximity or the degree of inclusion of the functional domains of the affected protein.

What is a Missense Mutation

Missense mutations are a type of single nucleotide substitution which introduces a distinct codon to the nucleotide sequence of a gene. Since it changes the codon to another codon, which represents a distinct amino acid, we also call missense mutations as non-synonymous substitution. In comparison to nonsense mutations, which is another type of non-synonymous substitution, missense mutations do not introduce stop codons to the gene sequence.

Here, the new amino acid may contain similar properties to the original amino acid at the site of mutation. In this case, the missense mutation is called a conservative mutation. And, this mutated protein can exert a similar functionality to the original protein. Conversely, if the introducing amino acid bears different properties to the original amino acid, then, this type of missense mutation is called a non-conservative mutation. Here, the mutated protein may have a distinct function to the original protein, or else, the mutated protein becomes non-functional.

Figure 2: Types of Point Mutations

For instance, some missense mutations lead to the activation of the originally inactive proteins. This is called the gain of function. In addition, other types of missense mutations can inactivate the originally active proteins. We call this the loss of function.

If the point mutation introduces the same amino acid to the site of mutation with the use of the degeneracy of the genetic code, then, this point mutation becomes a silent mutation, which is the third type of point mutations.

Similarities Between Nonsense and Missense Mutation

• Nonsense and missense mutations are two types of point mutations.
• A single nucleotide in the gene sequence changes both types of mutations.
• Also, both result in the changes in the codon sequence.
• In addition, both may lead to the production of non-functional proteins.
• Thus, these mutations can lead to genetic disorders.
• Furthermore, both types of point mutations can arise due to errors in DNA replication. The error rate or the occurrence of point mutations during DNA replication is 5-10%.
• However, the 3’ to 5’ exonuclease activity of DNA polymerase can repair the errors during DNA replication.
• Besides, chemical mutagens including base analogues, deaminating agents, alkylating agents, and physical mutagens such as radiation and heat can also result in point mutations.
• DNA repair systems including direct repair, excision repair, and mismatch repair systems help in repairing these types of point mutations.

Difference Between Nonsense and Missense Mutation

Definition

A nonsense mutation refers to a mutation in which a sense codon that corresponds to one of the twenty amino acids specified by the genetic code is changed to a chain-terminating codon. While, a missense mutation refers to a single base pair substitution, which alters the genetic code in a way that produces an amino acid that is different from the usual amino acid at that position. Thus, these definitions contain the fundamental difference between nonsense and missense mutation.

Alteration in the Codon Sequence

Moreover, the main difference between nonsense and missense mutation is that the nonsense mutation introduces a stop codon to the codon sequence at the site of mutation while missense mutation introduces a distinct codon.

During Transcription

Furthermore, nonsense mutation results in a premature chain termination at the site of mutation while a missense mutation results in a distinct amino acid, which is conservative or non-conservative. Hence, this is also a difference between nonsense and missense mutation. 

Effect on the Protein

Effect on the protein is another difference between nonsense and missense mutation. Nonsense mutation results in an incomplete or truncated protein while missense mutation results in a conserved or non-conserved protein.

Functionality

Besides, the proteins produced by nonsense mutations are mostly non-functional while the proteins produced by the missense mutations are either functional, non-functional, or they have a distinct function from the original protein.

Genetic Disorders

Nonsense mutations may lead to genetic disorders including cystic fibrosis, beta-thalassemia, Duchenne muscular dystrophy (DMD), Hurler syndrome, and Dravet syndrome while missense mutations may lead to sickle-cell disease, Epidermolysis bullosa, and superoxide dismutase 1 (SOD1) mediated amyotrophic lateral sclerosis (ALS). Thus, the types of disorders caused by these mutations attribute to another difference between nonsense and missense mutation.

Conclusion

A nonsense mutation introduces a stop codon at the site of mutation, resulting in premature chain termination. Thus, this causes the production of truncated proteins that are non-functional. Besides, a missense mutation introduces a distinct codon at the site of mutation, resulting in the production of non-synonymous protein, which can be either conservative or non-conservative. Conservative mutations produce a protein with the same functionality with respect to the original protein while the non-conservative proteins are either non-functional or they have a distinct function. Therefore, the main difference between nonsense and missense mutation is the type of change in the codon sequence and the functionality of the mutated protein.

Reference:

1. Brown TA. Genomes. 2nd edition. Oxford: Wiley-Liss; 2002. Chapter 14, Mutation, Repair and Recombination. Available Here

Image Courtesy:

1. “Frameshift deletion (13062713935)” By Genomics Education Programme – Frameshift deletion (CC BY 2.0) via Commons Wikimedia  
2. “Point mutations-en” By Jonsta247 – Own work (CC BY-SA 4.0) via Commons Wikimedia