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Disruptive mutations in the genetic code: What are nonsense mutations?
In genomics, a nonsense mutation is a point mutation that changes the DNA sequence and results in the generation of a nonsense codon, which is a premature termination of the transcribed mRNA. Condition. This often results in the production of incomplete, truncated, and possibly non-functional proteins. Although the effects of nonsense mutations are often considered negative, they are not necessarily harmful to the organism.
The functional impact of a nonsense mutation depends on many factors, including the location of the stop codon within the coding DNA.
For example, the impact of a nonsense mutation may depend on how far the mutation is from the original stop codon and how much it affects the functional subdomain. Since nonsense mutations lead to premature termination of the polypeptide chain, they are also called chain-terminating mutations. The impact of these mutations varies, and the rate of impact on different genes and tissues varies. Approximately 10% of patients facing genetic diseases are associated with nonsense mutations.
Consequences of nonsense mutations
Harmful consequences
In most cases, nonsense mutations lead to harmful consequences and are the most common natural phenomenon. Deleterious nonsense mutations can reduce the overall fitness and reproductive success of an organism. For example, a nonsense mutation occurring in a gene encoding a particular protein may result in structural or functional defects in the protein, which may have a significant impact on the survival of the organism.
Neutral resultsNeutral nonsense mutations do not cause any benefit or harm to the organism. In this case, the effect of the mutation is muted, meaning the change has no positive or negative impact on the organism. Some mutations may occur close to the original stop codon, so their effects may not be obvious. That being said, this situation is relatively rare.
Beneficial ResultsBeneficial nonsense mutations are considered the rarest mutational outcomes. Such mutations would actually improve the overall fitness and reproductive success of the organism. Although premature stop codons introduced by nonsense mutations usually cause damage, in some cases such mutations may interrupt the production of certain abnormal or toxic proteins, thereby improving the survival of the organism.
Mechanisms for suppressing nonsense mutations
To suppress the negative effects of nonsense mutations, many organisms, including humans, use the nonsense-mediated mRNA decay (NMD) pathway. This mechanism degrades mRNA containing nonsense mutations before protein synthesis, thereby avoiding the production of nonfunctional polypeptides.
Some organisms can also suppress the damage of nonsense mutations by changing tRNA; this type of tRNA is called suppressor tRNA.
Common nonsense mutations associated with disease
Nonsense mutations account for approximately 20% of single nucleotide substitutions associated with human diseases. The pathology of these mutations is often due to a reduction in the amount of intact protein, as only 5–25% of transcripts containing nonsense mutations do not undergo decay.
Treatment strategies for nonsense mutation diseases
For diseases caused by nonsense mutations, therapeutic strategies aim to restore normal function by reducing the efficiency of NMD, promoting the neglect of early stop codons during translation, or directly editing nonsense mutations in the genome. Recent studies have explored antisense oligonucleotides to inhibit NMD, and some synthetic suppressor tRNAs have been used as potential therapeutics.
Drugs like Ataluren help selectively read abnormal stop codons, making them potential options for treating diseases associated with nonsense mutations.
In short, nonsense mutations play an important role in the genome. From the occurrence of diseases to the exploration of treatments, the impact of nonsense mutations is far-reaching and complex. So, in future gene therapy, can we find more effective ways to combat these effects?
