Mutations are the original source of genetic variation. A mutation is a permanent alteration to a DNA sequence. De novo (new) mutations occur when there is an error during DNA replication that is not corrected by DNA repair enzymes. It is only once the error is copied by DNA replication, and fixed in the DNA that it is considered to be a mutation (Figure 1). Mutations may be beneficial to the organism; deleterious (harmful) to the organism; or neutral (have no effect on the fitness of the organism).
Somatic mutations can accumulate in our cells and are mostly harmless. They can lead to local changes in tissues such as moles appearing on the skin, and can also have more serious effects – for example leading to cancer. To learn more about the role of somatic mutations in cancer have a look at this paper by Martincorena and Campbell1. In this course we focus on heritable genetic variation, i.e. variation that occurs in germ cells.
There are three types of DNA Mutations:
A. Base substitution
- Transition: this occurs when a purine is substituted with another purine or when a pyrimidine is substituted with another pyrimidine.
- Transversion: when a purine is substituted for a pyrimidine or a pyrimidine replaces a purine.
A deletion, resulting in a frameshift, results when one or more base pairs are lost from the DNA
The insertion of additional base pairs may lead to frameshifts depending on whether or not multiples of three base pairs are inserted. Combinations of insertions and deletions leading to a variety of outcomes are also possible.
What are the Causes of Mutations?
- Errors in DNA Replication
On very, very rare occasions DNA polymerase will incorporate a noncomplementary base into the daughter strand. During the next round of replication, the miss incorporated base would lead to a mutation. This, however, is very rare as the exonuclease functions as a proofreading mechanism recognizing mismatched base pairs and excising them.
- Errors in DNA Recombination
DNA often rearranges itself by a process called recombination which proceeds via a variety of mechanisms. Occasionally DNA is lost during replication leading to a mutation.
- Chemical Damage to DNA
Many chemical mutagens, some exogenous, some man-made, some environmental, are capable of damaging DNA. Many chemotherapeutic drugs and intercalating agent drugs function by damaging DNA.
Gamma rays, X-rays, even UV light can interact with compounds in the cell generating free radicals that cause chemical damage to DNA.