Point mutations
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Mutations are changes in the genetic information of a cell, arising from various sources, including errors during DNA replication and repair. While some mutations lead to large-scale changes in the genome, such as chromosomal translocations, others, known as point mutations, involve alterations of a single base pair in the DNA. Point mutations are the most common type of mutation and are the focus of this chapter.
Mutations can occur in either germline cells, which give rise to gametes and can be passed on to offspring, or somatic cells, which make up the body but are not involved in reproduction. Germline mutations can be inherited by future generations, while somatic mutations are only passed on to descendant cells during cell division. Accumulation of somatic mutations over time can lead to the development of cancer.
Most mutations in the human genome occur in non-coding DNA regions and thus have no or little impact on the phenotype. Mutations causing significant consequences usually occur in the genes or their regulatory regions.
Substitution is a type of mutation in which one nucleotide in the DNA sequence is replaced by another (e.g. adenine is substituted by guanine).
These substitutions can have varying effects on the resulting protein. Silent mutations occur when the substitution does not alter the amino acid sequence of the protein due to the redundancy of the genetic code. In other words, the codon affected by a silent mutation still codes for the same amino acid, so the protein's function remains unchanged.
Missense mutations result in the substitution of one amino acid for another in the protein sequence. Depending on the location and type of the alteration, missense mutations vary in their effect. Some missense mutations may only cause subtle changes in protein function, while others can significantly alter the protein's structure or activity e.g. when a mutation changes the shape of an enzyme's active site.
Nonsense mutations are substitutions that change a codon coding for an amino acid into a stop codon. This premature termination of translation leads to the production of a truncated protein, which is often non-functional.
The effects of adding (insertion) or removing (deletion) a nucleotide from the DNA sequence in a coding region are often detrimental. Because the genetic code is read in sets of three nucleotides (codons), the addition or deletion of a single nucleotide causes a frameshift. Deletions and insertions change the reading frame and thus the whole sequence of codons downstream from the mutation. This results in totally different amino acids and, since a stop codon usually appears close to a frameshift mutation, in a truncated polypeptide.
