Figure 1. Xeroderma pigmentosa is a condition in which thymine dimerization from exposure to UV is not repaired. Exposure to sunlight results in skin lesions. (credit: James Halpern et al.)

A well-studied example of a mutation is seen in people affected by xeroderma pigmentosa (Figure 1). Affected individuals have skin that is highly sensitive to UV rays from the sun.

When individuals are exposed to UV, pyrimidine dimers, especially those of thymine, are formed; people with xeroderma pigmentosa are not able to repair the damage. These are not repaired because of a defect in the nucleotide excision repair enzymes, whereas in normal individuals, the thymine dimers are excised and the defect is corrected. The thymine dimers distort the structure of the DNA double helix, and this may cause problems during DNA replication. People with xeroderma pigmentosa may have a higher risk of contracting skin cancer than those who don’t have the condition.

Types of Mutations

Errors during DNA replication are not the only reason why mutations arise in DNA. Mutations, variations in the nucleotide sequence of a genome, can also occur because of damage to DNA. Such mutations may be of two types: induced or spontaneous. Induced mutations are those that result from an exposure to chemicals, UV rays, x-rays, or some other environmental agent. Spontaneous mutations occur without any exposure to any environmental agent; they are a result of natural reactions taking place within the body.

Mutations in DNA sequences that code for proteins can be detrimental to how the protein forms. A change in the DNA sequence can effect how the mRNA coding for a protein gets translated, and therefore how a protein folds—as proteins fold according to the sequence of their amino acids. A difference in the shape of the protein impacts the protein’s ability to perform its function. 

Substitutions

Mutations may have a wide range of effects. Substitutions, also known as point mutations, are those mutations that affect a single base pair. The most common nucleotide mutations are substitutions, in which one base is replaced by another. Substitutions can be of two types, either transitions or transversions. Transition substitution refers to a purine or pyrimidine being replaced by a base of the same kind; for example, a purine such as adenine may be replaced by the purine guanine. Transversion substitution refers to a purine being replaced by a pyrimidine, or vice versa; for example, cytosine, a pyrimidine, is replaced by adenine, a purine. 

Some point mutations have no impact on an organism; these are known as silent mutations. In the case of silent mutations, the substituted base pair still results in the overall codon it lies within to code for the same amino acid, due to the degeneracy of the genetic code. Silent mutations are usually due to a substitution in the third base of a codon, known as the wobble position, which often represents the same amino acid as the original codon.

There are some point mutations that do result in changing the amino acid the codon codes for. These point mutations can result in two outcomes: a missense mutation or a nonsense mutation. A missense mutation is when the substitution results in a codon for a different amino acid. Because a protein’s structure is determined by the sequence of its amino acids, this can result in the protein folding into a shape different than it was intended to and therefore may have effects on its function. A nonsense mutation occurs when the substitution results in the formation of a stop codon. This causes the ribosome translating the mRNA from the mutated sequence to stop prematurely in response to the new stop codon. This can have a drastic impact on how the protein folds and therefore whether it can carry out its function. 

Figure 2. Mutations can lead to changes in the protein sequence encoded by the DNA

Insertions and Deletions

Mutations can also be the result of the addition of a base, known as an insertion, or the removal of a base, also known as deletion. Sometimes a set of three nucleotides are inserted or deleted, which results in the addition or removal of a whole amino acid during translation of an mRNA created from the mutated gene in the DNA. However, sometimes only one nucleotide is inserted or deleted. These are referred to as frameshift mutations, as they shift the reading frame of the codons. For example, take the sequence AUG CAG UCG: if you insert one nucleotide somewhere, say AUG CAA GUC G, you affect not only the amino acid being coded for at the site of the mutated codon, but also every codon after it. A similar shift of the reading frame would occur with the deletion of a single nucleotide from the sequence. Frameshift mutations have a significant impact on the folding of the resulting protein, as they drastically alter the subsequent sequence of amino acids. Sometimes, frameshift mutations can result in a premature stop codon somewhere in the sequence, truncating the protein and potentially rendering the protein nonfunctional. 

Sometimes a piece of DNA from one chromosome may get moved to another chromosome or to another region of the same chromosome; this is also known as translocation. This is a large scale mutation, and causes an insertion in one region where the segment is moved to, and a deletion in the region where the segment came from. Some mutations can result in an increased number of copies of the same codon. These are called trinucleotide repeat expansions and result in repeated regions of the same amino acid. 

The Impact of Mutations

Mutations in repair genes have been known to cause cancer. Many mutated repair genes have been implicated in certain forms of pancreatic cancer, colon cancer, and colorectal cancer. Mutations can affect either somatic cells or germ cells. If many mutations accumulate in a somatic cell, they may lead to problems such as the uncontrolled cell division observed in cancer. If a mutation takes place in germ cells, the mutation will be passed on to the next generation, as in the case of hemophilia and xeroderma pigmentosa.

Causes of Genetic Mutations