Mutations: When the Code Changes
A mutation is a change in the base sequence of DNA - within a single gene, or across whole chromosomes. Mutations arise from errors during replication or cell division, or from mutagens: ionising radiation, mutagenic chemicals, high temperatures and some viruses. Changes in DNA are carried through to proteins by transcription and translation, so a mutation can lead to the alteration or absence of a protein. There are three main types of mutation:
- Point (base-pair substitution) mutations - one base is replaced by another.
- Frameshift mutations - a base is inserted or deleted.
- Chromosomal mutations - whole sections of a chromosome are rearranged.
POINT MUTATIONS
A point mutation substitutes a single base, so at most one codon changes. Because the code is read in triplets, the effect varies:
- Silent mutation - the new codon codes for the same amino acid (the code is redundant), so the protein is unchanged.
- Missense mutation - the new codon codes for a different amino acid (sickle-cell anaemia is the classic example).
- Nonsense mutation - the new codon is a STOP codon, so the polypeptide is cut short. How damaging this is depends on where in the gene it occurs.
A substitution changes at most one codon; an insertion shifts every codon after it.
FRAMESHIFT MUTATIONS
Insertion or deletion of a nucleotide shifts the codon reading frame downstream from the mutation - a frameshift. Every codon after that point is read differently, which can change the protein made and also its length: if a STOP codon happens to be created, translation terminates prematurely. Frameshifts are therefore usually far more damaging than substitutions.
A mutation can also have no effect at all: the code is redundant (several codons per amino acid), the change may fall in a non-coding region between genes, or it may be removed with an intron during splicing.
| Mutation | The change | Typical effect |
|---|---|---|
| Silent | base swap, same amino acid | none |
| Missense | base swap, new amino acid | altered protein - sickle-cell anaemia |
| Nonsense | base swap creates a STOP codon | shortened polypeptide |
| Frameshift | insertion or deletion | reading frame scrambled downstream |
| Chromosomal | large-scale rearrangement | many genes affected at once |
CHROMOSOMAL MUTATIONS
Mutations can also occur at a much larger scale, when whole sections of chromosomes are rearranged - often during meiosis, as chromosomes pair up and then separate into gametes. The main kinds are:
- Inversion - a base-pair sequence is flipped within one chromosome.
- Translocation - a base-pair sequence is moved from one chromosome to another.
- Duplication - a base-pair sequence appears two or more times within one chromosome.
Because the rearrangement can disturb the expression of many genes at once, chromosomal mutations usually have significant - and usually harmful - effects on the phenotype.
MUTAGENS
- UV light - creates additional bonds in the DNA that should not exist.
- X-rays - create ions that break the sugar-phosphate backbone or disrupt base pairing.
- Mutagenic chemicals - change bases, mimic the shape of normal bases, disrupt cell division, or directly damage chromosomes.
- High temperature - breaks bonds (and denatures the enzymes that maintain DNA).
- Viruses - cause mutations by incorporating viral DNA into the host genome.
SOMATIC AND GERMLINE MUTATIONS
- Somatic mutation - occurs in a body cell and is copied to daughter cells by mitosis, so it stays localised to one patch of tissue in one individual; it cannot be inherited.
- Germline mutation - occurs in the cells that form gametes. If the gamete is used, the mutation ends up in every cell of the offspring and can be inherited again by later generations.
A somatic mutation affects one patch of one individual; a germline mutation reaches every cell of the offspring.
Somatic mutations usually have little effect. However, if one strikes a proto-oncogene or a tumour suppressor gene, control of the cell cycle is lost, cells accumulate, and a tumour forms. A cancer that arises this way cannot be passed on to offspring.
| Somatic | Germline | |
|---|---|---|
| Occurs in | body cells | cells that form gametes |
| Spread by | mitosis, within one tissue | fertilisation, to every cell of offspring |
| Inherited? | no | yes - if the gamete is used |
| Example | most skin cancers | sickle-cell anaemia, haemophilia |
TWO EXAMPLES
- Sickle-cell anaemia - a germline missense substitution in the haemoglobin gene replaces glutamic acid with valine; red blood cells deform and carry less oxygen.
- Haemophilia - a germline, X-linked recessive condition (so it is far more common in males). Levels of functional clotting factors fall, the coagulation cascade is impaired, and lasting clots cannot form - a platelet plug is the best the blood can manage.
Inheritable mutations are the ultimate source of new alleles - the raw material for variation and evolution. Most are harmful or neutral, but a rare beneficial mutation can give a survival advantage and increase in frequency through natural selection.