Nonsense mutation

In genetics, a nonsense mutation is a point mutation in a sequence of DNA that results in a nonsense codon, or a premature stop codon in the transcribed mRNA, and leads to a truncated, incomplete, and possibly nonfunctional protein product. Nonsense mutations are not always harmful; the functional effect of a nonsense mutation depends on many aspects, such as the location of the stop codon within the coding DNA. For example, the effect of a nonsense mutation depends on the proximity of the nonsense mutation to the original stop codon, and the degree to which functional subdomains of the protein are affected. As nonsense mutations lead to premature termination of polypeptide chains, they are also called chain termination mutations.
Missense mutations differ from nonsense mutations since they are point mutations that exhibit a single nucleotide change to cause substitution of a different amino acid. A nonsense mutation also differs from a nonstop mutation, which is a point mutation that removes a stop codon. About 10% of patients facing genetic diseases have involvement with nonsense mutations. Some of the diseases that these mutations can cause are Duchenne muscular dystrophy, cystic fibrosis, spinal muscular atrophy, cancers, metabolic diseases, and neurologic disorders. The rate of nonsense mutations is variable from gene-to-gene and tissue-to-tissue, but gene silencing occurs in every patient with a nonsense mutation.

Simple example

: 5′—ATG ACT CAC CGA GCG CGA AGC TGA—3′
3′—TAC TGA GTG GCT CGC GCT TCG ACT—5′
mRNA: 5′—AUG ACU CAC CGA GCG CGA AGC UGA—3′
Protein: N—Met Thr His Arg Ala Arg Ser Stop—C
The example above begins with a 5' DNA sequence with 24 nucleotides seen and its complementary strand shown below. The next row highlights the 5' mRNA strand, which is generated through transcription. Lastly, the final row showcases which the amino acids that are translated from each respective codon, with the eighth and final codon representing the stop codon. The codons corresponding to the fourth amino acid, Arginine, are highlighted because they will undergo a nonsense mutation in the following figure of this example.
DNA: 5′—ATG ACT CAC TGA GCG CGA AGC TGA—3′
3′—TAC TGA GTG ACT CGC GCT TCG ACT—5′
mRNA: 5′—AUG ACU CAC UGA GCG CGU AGC UGA—3′
Protein: N—Met Thr His Stop—C
Now, suppose that a nonsense mutation was introduced at the fourth codon in the 5′ DNA sequence causing the cytosine to be replaced with thymine, yielding TGA in the 5′ DNA sequence and ACT in the complementary strand. Because ACT is transcribed as UGA, it is translated as a stop codon. This leads the remaining codons of the mRNA to not be translated into protein because the stop codon is prematurely reached during translation. This can yield a truncated protein product, which quite often lacks the functionality of the normal, non-mutant protein.

amber mutations	ochre mutations	opal mutations
AAG → UAG CAG → UAG GAG → UAG UCG → UAG UGG → UAG UUG → UAG UAC → UAG UAU → UAG	AAA → UAA CAA → UAA GAA → UAA UCA → UAA UUA → UAA UAC → UAA UAU → UAA	AGA → UGA CGA → UGA GGA → UGA UCA → UGA UUA → UGA UGC → UGA UGG → UGA UGU → UGA

Possible outcomes

Deleterious

Deleterious outcomes represent the majority of nonsense mutations and are the most common outcome that is observed naturally. Deleterious nonsense mutations decreases the overall fitness and reproductive success of the organism. For example, a nonsense mutation occurring in a gene encoding a protein can cause structural or functional defects in the protein that disrupt cellular biology. Depending on the significance of the functions of this protein, this disruption now could be detrimental to the fitness and survival of that organism.

Neutral

When a nonsense mutation is neutral, it does not provide benefits or harm. These occur when the effects of the mutation are unnoticed. In other words, this means that the mutation does not positively or negatively affect the organism. As this effect is unnoticed, there is a lack of papers describing such mutations. An example of this type of nonsense mutation is one that occurs directly before the original stop codon for that given protein. Because this mutation occurred in such close proximity to the end of the protein chain, the impact of this change might not be as significant. This would suggest that this amino acid that was mutated did not have a large impact on the overall structure or function of the protein or the organism as a whole. This scenario is rare, but possible.

Beneficial

Beneficial nonsense mutations are considered as the rarest of possible nonsense mutation outcomes. Beneficial nonsense mutations increase the overall fitness and reproductive success of an organism, opposite of the effects of a deleterious mutation. Because a nonsense mutation introduces a premature stop codon within a sequence of DNA, it is extremely unlikely that this scenario can actually benefit the organism. An example of this would occur with a nonsense mutation that impacts a dysfunctional protein that releases toxins. The stop codon that this mutation brings would stop this dysfunctional protein from properly carrying out its function. Stopping this protein from performing at full strength causes less toxin to be released and the fitness of the organism to be improved. These types of situations with nonsense mutations occur a lot less frequently than the deleterious outcomes.