Gene Mutations

Changes to a DNA base sequence are called gene mutations. These usually occur during DNA replication. Genes code for polypeptides, proteins or functional RNA products. Each gene is read in sequences of three bases or triplets, meaning every three nucleotides correspond to one amino acid. These triplets are called codons. Changes to a codon may have a knock-on effect on the products the gene codes for. For example, this could mean the protein produced will be altered as a result. Sometimes, there is no effect, as we will learn later. Regardless, any change to our DNA can potentially change the proteins in our cells.

Types of gene mutations

Gene mutations fall into three categories, depending on the type of change to the DNA sequence:

• Substitution
• Insertion
• Deletion

If only one nucleotide is substituted, deleted or inserted, it is called a point mutation. We will explore each type of gene mutation here.

Fig. 1 - Different types of mutations

Substitution

Substitutions occur when an incorrect nucleotide replaces the original nucleotide.

It is important to note that some substitutions do not always lead to a change in the amino acid sequence, due to the degenerate nature of the genetic code. "Degenerate" in this context means that more than one codon can code for the same amino acid.

Insertion

Insertions occur when a new nucleotide is added to the DNA base sequence. As a result, adding just one nucleotide can change every successive triplet after the mutation. This addition is called a frameshift mutation, which we will explain in the following section.

Deletion

Deletions describe the removal of a nucleotide from the DNA base sequence. Again, this is also a frameshift mutation, as every successive triplet is changed.

Effects of gene mutations

Many students think all mutations cause detrimental effects on the organism, but that is not always the case. Mutations can be categorized into four different types, depending on their functional effects:

• Silent mutation
• Nonsense mutation
• Missense mutation
• Frameshift mutation

We will explore each effect in detail here.

Silent mutations

Silent mutations occur when a substitution event still codes for the original amino acid.

This is due to the degeneracy of the genetic code, which means that more than one codon can code for the same amino acid. The mutations are neutral and do not alter the function of the protein.

Nonsense mutations

Nonsense mutations occur when a substitution, deletion, or insertion results in a codon becoming a stop codon. A stop codon terminates a polypeptide's elongation and does not code for an amino acid.

The three stop codons are TAG, TAA and TGA (in DNA). The polypeptide is terminated prematurely when this occurs, producing a non-functional protein. These mutations are largely detrimental to the organism.

Fig. 2 - The effects of gene mutations include, silent, nonsense, missense and frameshift mutations

Missense mutations

Missense mutations occur when an incorrect amino acid is coded for, usually caused by substitution events. The effects of this type of mutation depend heavily on the differences in chemical properties between the original amino acid and the incorrect amino acid.

These mutations can also lead to beneficial effects if the new protein product helps the organism's survival.

Frameshift mutations

Frameshift mutations describe the changes in every successive triplet code following a deletion or insertion event. This event causes a change in every amino acid following the mutation. The ‘reading frame’ describes the codon sequence from which the ribosomes translate the RNA triplets into amino acids. These mutations "shift" this reading frame.

The effect of this mutation is very pronounced, as all amino acids after the mutation could be entirely different, meaning the chemical interactions within the protein will be substantially affected. The protein will most likely be non-functional.

Causes of gene mutations

Gene mutations occur spontaneously due to errors in DNA replication. This includes defects in DNA polymerase, the enzymatic driver of semi-conservative replication. The basal mutation rate for point mutations is approximately 7 x 10^-9 per base pair per generation. However, this rate can increase as a result of mutagen exposure. Scientists can also modify DNA sequences and insert point mutations in specific regions.

Physical mutagens

Physical mutagens include ionizing radiation, such as X-rays, and non-ionising radiation, such as ultraviolet (UV) light. These can alter the structure of nucleotides and break DNA strands which increases the mutation rate.

Fig. 3 - The effect of ionising and non-ionising radiation in DNA

Chemical mutagens

Chemical mutagens include alkylating agents and base analogues.

Alkylating agents insert methyl or ethyl groups to nucleotides, and this causes errors in base-pairing, which changes the nucleotide structure. Base analogues resemble nucleotides, and these are incorporated into DNA which again induces base-pairing errors.

Biological mutagens

Viruses can be biological mutagens, as these can cause changes in our DNA by inserting their own genomes into their host's DNA. The human immunodeficiency virus (HIV) is one example.

Gene mutation examples

Now that we have a broader understanding of what gene mutations are, their effects and the causes, let’s take a real-life look at individuals who harbour mutations. We will explore the following examples, but don’t worry; you won’t need to know all these details for your exam. It’s just a great way to apply your knowledge.

Tumour suppressor gene mutations

Tumour suppressor genes encode transcription factors that regulate the cell cycle and DNA replication by preventing uncontrolled divisions and blocking mutated cells from dividing. These are negative regulators as they stop the cell cycle from being over-activated.

For example, the tumour suppressor gene, p53, monitors DNA and detects mutations under normal conditions. If a DNA mutation is detected in the cell, p53 will induce cell cycle arrest whereby the DNA is repaired. If the DNA damage is too extensive, p53 will induce apoptosis. Therefore, p53 is a master regulator that prevents mutated DNA from replicating.

The p53 gene undergoes frequent missense mutations, resulting in the loss of the transcription factor’s ability to bind to DNA. Consequently, this promotes tumour development, and cells have a greater chance of becoming cancerous.

MTHFR gene mutation

The MTHFR gene encodes the methylenetetrahydrofolate reductase enzyme, which is involved in folate metabolism. Folate metabolism is important as it synthesizes nucleotides and amino acids. This enzyme is needed in protein synthesis and DNA methylation, important cellular processes.

One of the most common gene mutations occurs when a C is substituted with T, called the C677T mutation. This mutation increases an individual’s susceptibility to cardiovascular and hormonal conditions, such as blood clots and hypothyroidism. This is an example of how mutations can induce health risks to an individual.