From the Guidelines
Non-synonymous mutations, also known as missense mutations, lead to a change in one amino acid and may affect a critical functional domain, although most do not, as reported in the study on BRCA1 and BRCA2 genetic testing 1. These mutations occur when a DNA base pair substitution leads to a codon that encodes a different amino acid than the original sequence. Unlike synonymous mutations, which don't alter the protein structure, non-synonymous mutations can significantly impact protein function because they modify the protein's building blocks. Some key points to consider about non-synonymous mutations include:
- They can have various effects ranging from no functional change to complete loss of protein function, depending on the location and nature of the mutation 1.
- The impact of non-synonymous mutations depends on where the mutation occurs in the protein—changes in functional domains or active sites typically cause more severe consequences than mutations in less critical regions.
- Non-synonymous mutations are particularly important in disease development, especially cancer and hereditary disorders, as they can disrupt critical cellular processes, as discussed in the context of BRCA1 and BRCA2 genes 1.
- It's essential to consider the frequency and distribution of non-synonymous mutations in different populations, as well as the challenges in interpreting genetic variability information, including the use of standardized nomenclature and curated databases 1.
From the Research
Non-Synonymous Mutations
- Non-synonymous mutations change the protein sequences and are frequently subjected to natural selection 2
- These mutations can have significant effects on the function and structure of proteins, leading to various diseases 3
- The distribution of fitness effects (DFE) describes the proportions of new mutations that have different effects on reproductive fitness, and accurate measurements of the DFE are important for understanding evolutionary genetics 4
Effects on Protein-Protein Interactions
- Non-synonymous single nucleotide polymorphisms (nsSNPs) can affect protein-protein interactions by introducing structural changes, altering disorder, gaining interaction, or modifying post-translational modifications 3
- nsSNPs can also impact human-pathogen protein-protein interfaces, leading to changes in disease susceptibility and progression 3
Relationship with Cancer-Related Genes
- Nonsynonymous, synonymous, and nonsense mutations in cancer-related genes undergo stronger purifying selections than expected 2
- The lower nonsynonymous to synonymous ratio observed in cancer-related genes suggests the suppression of amino acid substitutions in these genes 2
- Synonymous mutations in cancer-related genes can exhibit preferred changes in codon usage and higher codon frequencies, indicating constraint on these mutations 2