Mutations are permanent changes in the DNA sequence that can alter the structure and function of proteins. The degree of impact varies depending on the type of mutation and how it affects transcription or translation.
Order of severity: Silent < Missense < Nonsense < Frameshift
Point (Single Nucleotide) Mutations
Point mutations involve the substitution of a single base pair in DNA. These are repaired primarily by DNA polymerase and DNA ligase.
| Type | Definition | Example | Effect on Protein |
|---|---|---|---|
| Silent Mutation | Base change codes for the same amino acid (often 3rd codon position; tRNA wobble). | Example: GAA → GAG (both code for Glutamate). | No change in protein sequence. |
| Missense Mutation | Base change codes for a different amino acid. Conservative if the new AA has similar properties. | Example: Sickle cell disease (Glu → Val in β-globin). | Altered protein function or stability. |
| Nonsense Mutation | Base change converts codon into stop codon (UAA, UAG, UGA). | Example: β-thalassemia variant. | Truncated, nonfunctional protein. |
Transition vs. Transversion
| Type | Definition | Example |
|---|---|---|
| Transition | Purine ↔ Purine (A ↔ G) or Pyrimidine ↔ Pyrimidine (C ↔ T) | A→G or C→T |
| Transversion | Purine ↔ Pyrimidine (A or G ↔ C or T) | A→T, G→C |
Frameshift Mutations
Frameshift mutations occur due to the insertion or deletion of nucleotides not divisible by 3, leading to downstream misreading of codons.
| Cause | Effect | Examples |
|---|---|---|
| Deletion or insertion not in multiples of 3 | Alters the entire reading frame | Duchenne muscular dystrophy, Tay-Sachs disease, Cystic fibrosis |
| DNA polymerase slippage at repetitive sequences | May lengthen or shorten protein; anticipation possible | Seen in Huntington’s disease (CAG repeat expansion) |
Splice Site Mutations: Occur at intron-exon junctions, leading to retention of introns or loss of exons in mRNA.
Clinical Examples:
- β-Thalassemia
- Gaucher disease
- Marfan syndrome
- Some cancers and neurodegenerative disorders
Visual Summary
| Type of Mutation | DNA Change | Resulting mRNA Codon | Protein Outcome |
|---|---|---|---|
| Silent | GAG → GAA | GAA | Glutamate (no change) |
| Missense | GAG → GTG | GUG | Valine (different AA) |
| Nonsense | GAG → TAG | UAG | Stop codon (truncated) |
| Frameshift (insertion) | Add “T” | GGA → GAT | Alters all downstream codons |
Key Points to Remember
- Missense = altered protein (Sickle Cell Disease).
- Nonsense = stop codon → truncated protein.
- Frameshift = most severe; affects all downstream codons.
- Splice site mutations = intron retention → dysfunctional protein.
- Slipped-strand mispairing causes anticipation (expanding repeats over generations).
Learning Objective
By the end of this module, students should be able to differentiate between the main types of DNA mutations, describe their molecular consequences, and identify clinical disorders associated with each type.
