Gene mutations
What mutations are, the mutagens that cause them, point mutations (silent, missense, nonsense, frameshift), their effects, and why mutations matter for evolution and health.
What is a mutation?
A mutation is a sudden, random and heritable change in the genetic material. It may be a change in the sequence of bases in a gene (gene or point mutation) or a change in the structure or number of chromosomes (chromosomal mutation, next lesson). A mutation in a body (somatic) cell is passed on only to the cells that descend from it (as in a cancer), but a mutation in a cell that forms gametes (germline mutation) can be inherited by the offspring. A mutation creates a new allele, which is why it is the original source of all genetic variation.
Causes of mutation
- Spontaneous mutations arise by chance, mainly as errors in DNA replication that escape the proofreading and repair systems. The rate in humans is about one error in $10^8$ to $10^9$ bases copied.
- Mutagens raise the rate. Physical mutagens: ultraviolet light (causes thymine dimers, linked to skin cancer), X-rays, gamma rays and other ionising radiation (break DNA). Chemical mutagens: mustard gas, benzopyrene in tobacco smoke, nitrous acid and base analogues, and aflatoxin from moulds on stored groundnuts and grains. Biological mutagens: some viruses (e.g. human papillomavirus) that insert into DNA.
Gene (point) mutations
A change in one or a few nucleotides of a gene. The effects depend on how the new codon is read (the genetic code and translation are described in Unit 7).
| Type | What happens | Effect |
|---|---|---|
| Substitution (one base replaced by another) | ||
| Silent | The new codon codes for the same amino acid (the code is degenerate) | No change in the protein |
| Missense | The new codon codes for a different amino acid | One amino acid changed; effect depends on where it is (sickle-cell anaemia) |
| Nonsense | The new codon is a stop codon | Protein is shortened and usually non-functional |
| Insertion or deletion of bases | ||
| Frameshift | A number of bases that is not a multiple of three is added or lost, so the reading frame shifts | Every codon after the change is altered; usually a non-functional protein |
| In-frame insertion or deletion | A multiple of three bases changes | Amino acids added or lost, with the rest unchanged |
A substitution changes only one codon. An insertion or deletion of one base is generally more harmful because it changes the whole message after that point.
Worked example: The mRNA codons AUG AAA CGU GGC UAA code for Met–Lys–Arg–Gly–stop. (a) What is the effect of changing the third base of CGU to C? (b) of changing AAA to GAA? (c) of changing AAA to UAA? (d) of inserting G after AUG? (a) CGC still codes for Arg: silent. (b) GAA codes for Glu: missense, one amino acid changed. (c) UAA is a stop codon: nonsense, the protein ends after Met. (d) The message reads AUG GAA ACG UGG CUA…: frameshift, Met–Glu–Thr–Trp–Leu… all later amino acids are changed.
Effects of mutations
- Harmful. Loss of an enzyme or a structural protein gives a genetic disorder (cystic fibrosis, phenylketonuria). Mutations in genes that control the cell cycle cause cancer: a mutated proto-oncogene becomes an oncogene that drives division, and mutations in tumour-suppressor genes (such as $p53$) remove the brakes. Cancer usually needs several mutations.
- Neutral. Silent mutations and changes in non-coding DNA have no effect on fitness.
- Beneficial. A mutation that helps in a given environment is favoured by natural selection: antibiotic resistance in bacteria, resistance to insecticides in mosquitoes, lactase persistence in adults who drink milk, the sickle-cell allele (heterozygotes resist malaria). New alleles give the variation on which evolution depends (Unit 3).
Cells have DNA repair enzymes that correct most damage, so the actual mutation rate is far lower than the damage rate. Mutation rate is increased by mutagens and by some inherited defects in repair (xeroderma pigmentosum).
Mutation breeding uses radiation or chemicals on seeds to produce useful new varieties of crops such as rice.
Exam tip: Say clearly which level the change is at: DNA (base), mRNA (codon), protein (amino acid). A silent mutation changes the DNA and perhaps the mRNA but not the protein. The effect of a missense mutation depends on which amino acid is replaced and whether it is in the active site or the structural core.