Coaching Centre
Mutations
What mutations are, how they arise spontaneously and from mutagens, gene mutations (substitution, insertion, deletion) and their effects (silent, missense, nonsense, frameshift), chromosome mutations, somatic and germline mutations, and examples including sickle cell disease and cystic fibrosis.
You were born with about 50 to 100 brand-new mutations that neither of your parents had. Almost all of them do nothing at all. But change one particular base in the haemoglobin gene and red blood cells can bend into sickle shapes, a change that has shaped human history in Africa, India and the Mediterranean.
What is a mutation?
A mutation is any permanent change in the sequence of DNA. Mutations are the original source of all new alleles, so without them there would be no variation for evolution to act on. They happen in two ways:
- Spontaneous mutations are mistakes made when DNA is copied, or damage from normal chemical reactions in the cell. They happen all the time at a low rate.
- Induced mutations are caused by mutagens: things that damage DNA. These include ultraviolet radiation from the Sun, ionising radiation such as X-rays and gamma rays, many chemicals in tobacco smoke, some chemicals in burnt food and industrial pollution Some viruses, such as the human papillomavirus (HPV), can also insert their own genes or disrupt the cell's controls, which is one reason the HPV vaccine prevents cancer.
Cells have dozens of repair enzymes that fix most damage before it becomes permanent. A mutation is the damage that slips through.
Gene mutations
A gene mutation (or point mutation) changes one or a few bases within a gene.
- Substitution: one base is swapped for another.
- Insertion: an extra base is added.
- Deletion: a base is lost.
Because the code is read in threes, the effect on the protein depends on what kind of change it is and where it happens.
| Effect | What happens | Example of a codon change (mRNA) |
|---|---|---|
| Silent | The codon changes but codes for the same amino acid. The protein is unchanged. | CUG → CUC: both Leu |
| Missense | One amino acid is replaced by another. The effect can be none, mild or serious. | GAG → GUG: Glu → Val (sickle cell) |
| Nonsense | A codon becomes a stop codon, so the protein is cut short. | AAG → UAG: Lys → STOP |
| Frameshift | An insertion or deletion of one or two bases shifts the reading frame, so every codon after it is misread. | …CUG ACU CCU… → …CGA CUC CU… |
An analogy: the sentence THE FAT CAT ATE THE RAT. A substitution gives THE FAT CAT ATE THE HAT (one word changes). Delete the F and re-read in threes: THE ATC ATA TET HER AT. Everything after the deletion is nonsense.
One base, big consequences: sickle cell disease
Haemoglobin is made of four protein chains, two of them β-globin chains of 146 amino acids. In the sickle cell allele, a single substitution changes codon 6 of the finished chain from GAG to GTG in the DNA, so glutamic acid becomes valine. Valine is water-repelling, and when oxygen levels are low the faulty haemoglobin molecules stick together into long fibres. Red blood cells become stiff and curved like a sickle, block small blood vessels and break down early, causing pain, anaemia and organ damage.
People with one sickle allele and one normal allele are carriers (sickle cell trait). They are usually healthy, and they are partly protected from severe malaria, because infected red cells sickle and are destroyed before the parasite can multiply. That is why the allele is common where malaria has been common: it is a harmful mutation in one setting and a helpful one in another. In 2023 sickle cell disease became the first disease to be treated with a CRISPR gene-editing therapy (1J).
- Press Sickle cell. Which base changed, and which amino acid changed in the protein?
- Find a substitution of your own that is silent. Use the codon table in 1D to check.
- Delete one base near the start, then a second base and a third base right after it. Compare the protein after one deletion and after three.
- Try the Nonsense preset. How many amino acids long is the protein now?
Chromosome mutations
Larger changes affect whole sections of a chromosome, often many genes at once. They usually happen when chromosomes break and rejoin wrongly, for example during crossing over.
- Deletion: a section is lost.
- Duplication: a section is copied twice. Duplicated genes can later mutate to take on new jobs; our colour vision genes arose this way.
- Inversion: a section breaks out, flips and reattaches backwards.
- Translocation: a section moves to a different, non-homologous chromosome. In chronic myeloid leukaemia, part of chromosome 22 swaps with part of chromosome 9, joining two genes into one that drives blood cells to divide out of control.
Changes in the number of chromosomes, such as trisomy 21, are also counted as chromosome mutations (1B, 1C).
Where the mutation happens matters
- A somatic mutation happens in a body cell, such as a skin cell. It is passed to all the cells that descend from that cell by mitosis, but not to children. Somatic mutations in genes that control cell division can lead to cancer (Year 9, 4J).
- A germline mutation happens in cells that make eggs or sperm, or is present in the fertilised egg. It can be inherited, and will be in every cell of the child's body.
Most mutations are neutral: they are in DNA that does not code for anything, or are silent. Some are harmful. A few are beneficial in a particular environment. One example: most mammals lose the ability to digest lactose (milk sugar) after weaning, but mutations in the switch that controls the lactase gene keep it working in adults. These mutations spread in populations that farmed dairy cattle over the last 10 000 years.
Test yourself
A mutation changes the mRNA codon UCU (Ser) to UCC (Ser). This is a
Both codons code for serine, so the protein is unchanged.
Which mutation is most likely to change every amino acid after it?
It shifts the reading frame for the rest of the gene.
Which of these is a mutagen?
UV has enough energy to damage DNA bases.
A mutation in a lung cell of a smoker
Lung cells are body cells; their mutations can cause cancer but are not passed on.
Why is the sickle cell allele common in parts of Africa?
Carriers survive malaria better, so the allele has been favoured where malaria is common.
Describe each type of mutation.
Gene or chromosome mutation?
Things that damage DNA are called . A mutation that turns a codon into a stop codon is a mutation. Inserting one base causes a . A mutation in a body cell is a mutation, while one in an egg or sperm cell is a mutation.
Explain why inserting one base near the start of a gene usually has a much bigger effect than substituting one base.
The ribosome reads mRNA in groups of three bases (codons), starting from the start codon. A substitution changes only one codon, so at most one amino acid changes. It may even be silent, because most amino acids have several codons. Inserting one base near the start shifts the reading frame: every codon after the insertion is made of a different set of three bases, so almost every following amino acid is wrong, and a stop codon often appears early. The resulting protein will have a completely different sequence after that point, will not fold correctly, and will almost certainly not work.