IMAT Biology · Molecular Biology and Gene Expression
Mutations at the Level of DNA
A gene mutation is a permanent change in the base sequence; its effect on the protein depends on whether it swaps, adds or removes bases and on how the codons are then read.
Why this matters
Mutation questions give a normal and a changed sequence and ask what kind of change explains them (2014, 2015, 2019), or ask what a single-base change can do to the protein (2020). Large chromosome changes and inheritance belong to the genetics chapter.
Concept 1 of 3: Point mutations: silent, missense, nonsense and frameshift
Changing one letter of a sentence may change nothing, change one word, or end the sentence early. Adding or losing a letter is worse: every word after it is read wrongly. Mutations in DNA behave the same way, because the ribosome reads codons in a fixed frame of three.
Definition
A point mutation changes a single base pair: a substitution, an insertion or a deletion.
- A substitution may be silent, missense or nonsense, depending on the new codon.
- An insertion or deletion of a number of bases that is not a multiple of 3 causes a frameshift.
- So a single-base change can leave the protein unchanged, change one amino acid (possibly altering its folding and tertiary structure), make it shorter, or, if a stop codon is lost, make it longer.
- Example: in sickle-cell anaemia, one substitution in the β-globin gene (GAG to GTG on the coding strand) replaces glutamic acid with valine.
| Type | Change in the DNA | Effect on the protein |
|---|---|---|
| Silent | substitution giving a codon for the same amino acid | no change |
| Missense | substitution giving a codon for a different amino acid | one amino acid replaced; the protein may fold differently |
| Nonsense | substitution giving a stop codon | a shorter protein, usually not functional |
| Frameshift | insertion or deletion of 1, 2, 4 ... bases (not a multiple of 3) | every codon after it read wrongly, often reaching an early stop |
| In-frame insertion or deletion | 3 bases (or a multiple of 3) added or lost | one amino acid gained or lost; the rest unchanged |
Practice this conceptself-check · 3 quick reps
A single-base change can have any of several effects
Do not assume a point mutation always changes the protein, or always ruins it. The same kind of event can be silent, change one amino acid, shorten the protein or shift the frame. A 'which effects are possible' question usually wants all of them.
Concept 2 of 3: Reading two sequences to name the mutation
Most mutation questions are a comparison. Line the two sequences up, find where they first differ, check whether the length changed, and then read both in codons from the start. The codons tell you the effect on the protein.
Definition
A method for any sequence comparison:
- Line up the normal and mutant sequences and find the first difference.
- Count the bases: same length suggests a substitution; one more or one fewer suggests an insertion or a deletion.
- Convert to mRNA codons if needed (coding strand with U for T), reading in threes from the start.
- Translate the changed codons with the table given, and name the effect: silent, missense, nonsense or frameshift.
- Same length does not prove a substitution: an insertion and a nearby deletion together keep the length but shift the frame between them.
Worked example
The coding strand of a gene begins 5′-ATG GCT TGG AAA-3′. Name the effect of each mutant. Mutant 1: 5′-ATG GCC TGG AAA-3′. Mutant 2: 5′-ATG GCT TGA AAA-3′. Mutant 3: the G of the second codon is lost. Use: AUG = Met, GCU and GCC = Ala, UGG = Trp, AAA = Lys, UGA = stop, CUU = Leu, GGA = Gly.
Practice this conceptself-check · 3 quick reps
Equal length does not rule out insertion or deletion
If one base is inserted and another deleted a few bases later, the length is unchanged but the codons between them are read in the wrong frame. When two sequences of equal length differ in a run of bases, consider substitution, insertion and deletion together.
Concept 3 of 3: Causes of mutation, repair and inheritance of mutations
Mutations arise from rare copying mistakes and from damage by radiation or chemicals. Cells repair most of the damage, so only a few changes become permanent. Whether a mutation reaches the next generation depends on which cell it happens in.
Definition
A mutation is a permanent change in the base sequence of DNA; a mutagen is an agent that raises the mutation rate.
- Mutations are random: a mutagen does not aim at a useful gene.
- Somatic mutations (in body cells) are not inherited; they can cause cancer.
- Germ-line mutations (in cells that make eggs or sperm) can pass to offspring.
- Many mutations are neutral (in non-coding DNA, or silent); some are harmful; a few are useful. They are the raw material for evolution.
| Source or system | What it does to DNA |
|---|---|
| Copying errors | a wrong base slips past DNA polymerase; after proofreading and repair about 1 base in to copied stays wrong |
| Ultraviolet light | joins neighbouring thymines into thymine dimers, which distort the helix |
| Ionising radiation (X-rays, gamma rays) | breaks one or both strands of the backbone |
| Chemical mutagens | alter bases or slip between them (intercalating agents cause frameshifts); tobacco smoke contains several |
| Repair systems | proofreading by DNA polymerase, mismatch repair, and excision repair of damaged bases |
Practice this conceptself-check · 3 quick reps
Mutations are random, not directed by need
A mutagen raises the rate of mutation everywhere in the genome. It does not produce the change an organism needs; natural selection later acts on whatever variation arises.
Summary — formulas & gotchas at a glance
A revision cheat-sheet for the formulas and gotchas above. Click any concept name to jump back to its full explanation.
Reference tables (2)
Point mutations: silent, missense, nonsense and frameshift5 rows
| Type | Change in the DNA | Effect on the protein |
|---|---|---|
| Silent | substitution giving a codon for the same amino acid | no change |
| Missense | substitution giving a codon for a different amino acid | one amino acid replaced; the protein may fold differently |
| Nonsense | substitution giving a stop codon | a shorter protein, usually not functional |
| Frameshift | insertion or deletion of 1, 2, 4 ... bases (not a multiple of 3) | every codon after it read wrongly, often reaching an early stop |
| In-frame insertion or deletion | 3 bases (or a multiple of 3) added or lost | one amino acid gained or lost; the rest unchanged |
Causes of mutation, repair and inheritance of mutations5 rows
| Source or system | What it does to DNA |
|---|---|
| Copying errors | a wrong base slips past DNA polymerase; after proofreading and repair about 1 base in to copied stays wrong |
| Ultraviolet light | joins neighbouring thymines into thymine dimers, which distort the helix |
| Ionising radiation (X-rays, gamma rays) | breaks one or both strands of the backbone |
| Chemical mutagens | alter bases or slip between them (intercalating agents cause frameshifts); tobacco smoke contains several |
| Repair systems | proofreading by DNA polymerase, mismatch repair, and excision repair of damaged bases |
Watch out for (3)
- A single-base change can have any of several effects→ Point mutations: silent, missense, nonsense and frameshift
- Equal length does not rule out insertion or deletion→ Reading two sequences to name the mutation
- Mutations are random, not directed by need→ Causes of mutation, repair and inheritance of mutations
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