The many flavours of genetic mutation

The many flavours of genetic mutation

I am often asked about mutations; the term used to describe a change in the genetic code. Mutations can result in human diseases and, unsurprisingly, some patients want to know more about the cause of their genetic condition. Perhaps more surprisingly, many genetic researchers have incomplete knowledge of the nature of mutations that cause human disease. In part this is because over the last 10 years there has been a strong focus one particular type of mutation: changing one letter of the code for another (called a SNP – pronounced 'snip'). Other types of mutation, many of which have a stronger link with human disease, have had rather less attention.

It is extremely important that clinicians and genetic researchers have full knowledge of the spectrum of mutations that do, and do not, cause medical problems. Without this, both the tests to detect mutations and the interpretation of the resulting data will be inadequate and possibly inaccurate. Below, I have attempted to explain some of the main types of mutations.

The genome is made of DNA which is made of four building blocks denoted by the letters A, C, T, G. There are many ways in which the genome code can be altered. For example:

  • One letter can be changed to a different letter.
  • One or more letters can be inserted or deleted.
  • The order of letters can be changed.

The effects of these changes/mutations are very variable, and mostly unknown. But we do know that each of us carries millions of mutations, some of which are very large, without any ill effects. In part this is because we have two copies of the genome entwined together in the double helix. Usually the mutation is only on one copy, the other copy has the normal code and can cover up for failings of the mutated copy.

Our genes carry the instructions for how our bodies work and make up 1/40th of the genome. Genes are one area of the genome where we have good understanding of what the code actually means: three consecutive letters in a gene (called a 'codon') code for an amino acid. The amino acids are put together to make proteins.

There are 64 codons but only 20 amino acids. This means different codons can code for the same amino acid and some mutations do not result in an amino acid change. For example GCC and GCG both code for the amino acid alanine. There are also 3 codons for STOP, to signal where the protein ends.

Mutations in genes can have variable effects. A single letter change may have no effect if it still codes for the same amino acid (silent mutation), or a profound effect, for example putting in the STOP code too early. Insertion or deletion of letters can alter the reading frame so that the wrong amino acids are included and the gene is all wrong.

There are many parallels with words and language. In the example below the letters are equivalent to the letters of the genome code. The words are each equivalent to an amino acid and the sentence is the gene. You can see how different mutations (in red) have different effects.


1. THE MAN SAW THE DOG HIT THE CAT. silent mutation (no impact)

2. THE MAN SAW THE DOG HIT THE CAN. missense mutation (minor impact)

3. THE MAN SAW THE XOG HIT THE CAT. missense mutation (larger impact)

4. THE MAN SAW TH. stop mutation

5. THE MNS AWT HED OGH ITT HEC deletion mutation ('A' deleted)

6. THE MAA GNS AWT HED OGH ITT HEC A insertion mutation ('AG' inserted)

Mutation types 1-3 are very common. We have millions of them in our genomes. These mutations only rarely cause problems, though if a single critical aminio acid is altered it can sometimes have a profound effect (mutation type 3). For example, Achondroplasia, the commonest cause of human dwarfism, is caused by changing letter 1138 from G to A in the FGFR3 gene.

Mutation types 4-6 are much rarer and much more likely to have a serious consequence. These mutations make the code unintelligible and the function of that copy of the gene is usually completely lost. Mutations in the breast cancer genes, BRCA1 and BRCA2, are typically of types 4-6. These mutations can be difficult to detect and the full gene needs to be very carefully analysed. Developing ways to robustly detect mutation types 5 and 6 remains a major challenge, one of foremost challenges that is impeding our ability to use new sequencing technologies in clinical medicine.