A protein’s job comes from its shape, its shape comes from the order of its amino acids, and that order comes straight from the order of bases in a gene. So a change of one single base can, occasionally, change everything. Sickle cell disease is the classic example, and it comes down to one letter.
📘 What you need to know
The base sequence of a gene decides the amino acid sequence of a polypeptide, which decides how it folds, which decides what it can do.
A gene mutation is a change in the base sequence of DNA. It may produce a new allele.
Mutations happen randomly and constantly, mostly as copying errors when DNA is replicated in S phase of interphase.
A point mutation (substitution) changes one base. It can be silent, missense or nonsense.
Most mutations are harmful or neutral; a few are beneficial and are the raw material of evolution.
Mutations in body (somatic) cells are not inherited. Mutations in gametes can be passed on.
Sickle cell disease: GAG becomes GTG on the coding strand, the mRNA codon becomes GUG, and valine replaces glutamic acid at position 6 of the beta-globin chain.
Sequence, shape, job
Follow the chain of cause and effect, because almost every exam answer on this page is built from it.
The order of bases sets the order of amino acids. That order is the protein’s primary structure.
The chain then folds up. Which parts attract, repel or bond to each other depends entirely on which amino acids are where.
Folding gives the protein a precise 3D shape — an enzyme’s active site, a channel through a membrane, a pocket that holds oxygen.
The shape is the function. Change the shape and the protein does its job worse, differently, or not at all.
The chain to memorise
base sequence → amino acid sequence → folding → 3D shape → function
If a question asks you to “explain the effect of a mutation on a protein”, write that arrow chain out in words. Each arrow is usually worth a mark, and students who jump straight from “base changes” to “protein does not work” throw away three of them.
What a mutation actually is
A mutation is simply a change in the sequence of bases in a DNA molecule. Most arise as copying mistakes when DNA is replicated during the S phase of interphase, before a cell divides. They occur all the time, at random, and no cell is free of them.
Whether a mutation matters depends on which cell it happens in:
In a somatic (body) cell, the mutation disappears when that cell dies. It cannot be passed to offspring, although it can cause problems in the person, such as tumours.
In a gamete, the mutation is copied into every cell of any offspring produced. This is how heritable genetic conditions arise.
Not all bad news. Most mutations are neutral or harmful, but occasionally one improves a protein or produces a useful new version. Those rare beneficial mutations are where all genetic variation ultimately comes from.
Point mutations: three possible outcomes
A point mutation swaps one base for another. Because the code is degenerate, the outcome is not always dramatic.
Type
What happens to the codon
Effect on the polypeptide
Silent
The new codon still codes for the same amino acid, e.g. GGU to GGC
None — the protein is identical
Missense
The new codon codes for a different amino acid, e.g. GAG to GUG
One amino acid is swapped; effect ranges from nothing to severe
Nonsense
The new codon becomes a stop codon, e.g. UGG to UGA
Translation ends early, giving a short and usually useless protein
Whether a missense mutation matters depends on where it lands. Swap an amino acid buried in a quiet corner of the molecule and often nothing happens. Swap one in an enzyme’s active site, or one that controls how the protein packs together, and the whole thing can fail.
Case study: sickle cell disease
Haemoglobin carries oxygen in your red blood cells. One of its chains, the beta-globin chain, is coded for by a gene where a single base substitution causes sickle cell disease.
Most people carry the allele written HbA. The mutation produces a new allele, HbS. On the coding strand, the triplet GAG becomes GTG. That means the mRNA codon changes from GAG to GUG, and at translation valine is added instead of glutamic acid — at the sixth position of the chain.
Read straight down either column in an exam answer and you have the full explanation, from base to symptom.
Why the shape change causes illness
Glutamic acid is attracted to water; valine is not. Putting a water-repelling amino acid on the outside of the molecule makes haemoglobin molecules stick to one another in long fibres when oxygen levels are low. Those fibres pull the red blood cell out of shape into a stiff curve.
The consequences follow from the shape:
Sickled cells carry less oxygen, so tissues are short of oxygen.
They are stiff and pointed, so they block capillaries and stop normal cells getting through.
The result is acute pain, fatigue and anaemia.
The blockage is physical, not chemical. A rigid crescent simply cannot bend through a vessel narrower than itself.
Why has such a harmful allele survived?
Map sickle cell disease and map malaria and the two overlap closely. People who carry one copy of the HbS allele have some resistance to the malaria parasite, so in areas where malaria is common, carriers survive better than people with two normal alleles. The allele stays in the population because in that environment it is an advantage to carry one copy.
This is a correlation question waiting to happen. Say “there is a correlation between the distribution of malaria and the frequency of the sickle cell allele”, and explain it through carriers having increased resistance. Do not claim the malaria causes the mutation — it does not.
Worked examples
WORKED EXAMPLE
Following the sickle cell mutation through
On the coding strand of the beta-globin gene, GAG is changed to GTG. Work through to the amino acid produced, showing the template strand and the mRNA codon.
Step 1: Template strands, before and afterGAG → CTC (normal)GTG → CAC (mutated)Step 2: Transcribe each template into an mRNA codonCTC → GAG and CAC → GUGStep 3: Look them upGAG = glutamic acid GUG = valineValine replaces glutamic acid at position 6This is a missense mutation — one amino acid swapped, chain length unchanged.
WORKED EXAMPLE
Classifying three mutations
Classify each change to an mRNA codon as silent, missense or nonsense: (a) GGU to GGA, (b) AAA to AGA, (c) UAU to UAA.
(a) GGU to GGA
Both code for glycine → silent(b) AAA to AGA
Lysine becomes arginine → missense(c) UAU to UAA
Tyrosine becomes a stop signal → nonsense(a) silent (b) missense (c) nonsenseNonsense is usually the most damaging: the chain is cut short and cannot fold properly.
WORKED EXAMPLE
Explaining a loss of enzyme activity
A substitution changes one amino acid in the active site of an enzyme, and the enzyme stops working. Explain why.
Step 1: Start at the sequence
The base change alters the amino acid sequence (the primary structure).
Step 2: Sequence controls folding
The bonds formed as the chain folds depend on which amino acids are present, so the 3D shape changes.
Step 3: Shape controls function
The active site is no longer complementary to the substrate, so no enzyme–substrate complexes form.
Altered shape of the active site means the substrate no longer fitsSay “no longer complementary” — that is the phrase examiners look for.
💡 Exam tip
Write the full arrow chain from base sequence to function. Marks are given for the steps, not just the conclusion.
For sickle cell, learn the four facts: GAG to GTG, mRNA codon GUG, valine replaces glutamic acid, at position 6.
Say which strand you are quoting. GAG to GTG is the coding strand; on the template it is CTC to CAC.
Use the word allele, not “gene”, when talking about the different versions produced by a mutation.
Be precise about inheritance: only mutations in gametes can be passed on.
If a mutation appears to have no effect, the reason is almost always degeneracy of the genetic code.
⚠ Common mix-up
Saying every mutation changes the protein. Silent mutations do not, because the code is degenerate.
Saying sickle cell “changes the DNA into RNA wrongly”. Transcription works perfectly; it is faithfully copying an already changed base.
Getting the amino acids the wrong way round. Glutamic acid is normal; valine is the sickle cell version.
Claiming malaria causes the sickle cell mutation. Mutations are random. Malaria only affects which carriers survive.
Mixing up somatic and gamete mutations. Body cell mutations die with the cell.
Forgetting position 6. Questions often award a mark specifically for naming the position in the chain.
Up next: The Mechanism of Transcription — back to the nucleus, but in far more detail this time: how RNA polymerase knows where to start, which direction it travels in, and what all that non-coding DNA is doing.
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