Sickle-cell anaemia: mutation to phenotype

The big idea: Sickle-cell anaemia is caused by changing just one base in the gene for haemoglobin — the protein that carries oxygen in red blood cells.

That single change is called a base substitution: one base in the DNA is swapped for a different one.

Because the gene is the instruction for building haemoglobin, this tiny change ripples all the way up — through the mRNA, the protein, the red blood cell and finally the whole person's phenotype (their observable characteristics).

Haemoglobin

The protein inside red blood cells that binds and carries oxygen around the body.

Base substitution

A mutation in which one base in the DNA is replaced by a different base. Only a single base is changed.

Allele

One version of a gene. The base substitution creates a new allele of the haemoglobin gene.

Sickle-cell anaemia

An inherited condition in which red blood cells become rigid and sickle-shaped, so they carry oxygen poorly and block small blood vessels.

Phenotype

The observable characteristics of an organism — here, the symptoms and effects of sickle-cell anaemia.

Why one base matters so much: It feels surprising that swapping one base out of hundreds can cause a serious disease.

The reason: the gene is a code. One base change can change one codon, which changes one amino acid, which changes the shape and behaviour of the whole protein. Sickle-cell anaemia is the classic example of a small genetic change having a large effect.

To explain sickle-cell anaemia at the molecular level, follow the change up through each level in order.

Each step causes the next — this is a cause-and-effect chain, not a list of separate facts.

Codon

A group of three bases in the mRNA that codes for one amino acid.

Glutamic acid

The amino acid found at this position in NORMAL haemoglobin.

Valine

The amino acid that REPLACES glutamic acid in sickle-cell haemoglobin, because of the base substitution.

HbS (sickle haemoglobin)

The abnormal haemoglobin produced by the sickle-cell allele. It sticks together into fibres when oxygen levels are low.

Step 1 — the gene: In the haemoglobin gene, one base is substituted for another.

This creates a new allele of the gene. Only a single base is different from the normal version.

Step 2 — the mRNA: When the gene is transcribed, the changed base means one mRNA codon is different.

Just one three-base codon changes — the rest of the mRNA is copied normally.

Step 3 — the amino acid: During translation, the changed codon is read as a different amino acid.

Glutamic acid is replaced by valine in the haemoglobin chain. Only one amino acid out of about 146 is swapped.

Step 4 — the protein and the cell: That single amino acid swap produces abnormal haemoglobin (HbS).

When oxygen levels are low, HbS molecules stick together into long fibres that pull the red blood cell out of shape.

The cell collapses into a rigid sickle (crescent) shape instead of a flexible round disc.

Step 5 — the phenotype: The sickled cells cause the phenotype of sickle-cell anaemia:

they are rigid, so they get stuck and block small blood vessels (capillaries), causing pain; and they carry less oxygen and are destroyed faster, causing anaemia and tiredness.

The chain in one line: One base -> one codon -> one amino acid (glutamic acid -> valine) -> faulty haemoglobin -> sickled cells -> sickle-cell anaemia.

If you can recite this chain in order, you can answer almost any sickle-cell question.

How this is tested: The signature Paper 2 task here is a 4-mark Outline of how a single DNA base substitution leads to sickle-cell anaemia at the molecular level.

The marks come from naming the steps of the cascade in order: base substitution -> changed codon -> one amino acid changed (glutamic acid -> valine) -> abnormal haemoglobin -> sickled cells.

The same long question often continues into a Punnett grid for two carrier parents (covered in monohybrid crosses) and an Explain of why the sickle allele persists in malaria regions (covered in natural selection) — but the molecular cascade is the part tested here.

Why this scores full marks: It is a linked chain, each step causing the next — gene, then codon/amino acid, then protein, then cell.

An 'outline' worth 4 marks needs the steps in order, not four ways of saying 'one base changed'. The named swap (glutamic acid -> valine) is the detail that separates a top answer.