Types of Mutations

Think of the human genome as a big library that has an immense amount of books containing the recipes to make all the different proteins in our bodies. Sometimes, a recipe instruction gets changed by a mutation, and this change might lead to serious genetic disorders depending on the type of mutation.

What is a mutation?

Before diving into the types of mutations, let's review the fundamentals of genetics. DNA is the genetic material found in the nucleus of a cell. It consists of two strands coiled around each other in a double helix. The structure of DNA consists of chains of nucleotides. The complementary bases from each DNA strand are joined together by hydrogen bonds.

DNA contains genes, which are stretches of DNA that carry the information for a protein. Genes come in different forms called alleles. In diploid cells, there are two alleles per gene.

Genes are located at a specific locus in chromosomes. Diploid (2n) organisms have a pair of homologous chromosomes, and each chromosome of the pair carries different versions of the same genes (alleles).

Now, let's look at the definition of mutation.

These mutations can affect somatic cells (any cells in the body apart from the gametes) or gametes. Mutations in gametes are called germline mutations and can be passed on to the next generation.

What causes mutations? Mutations can be induced by mutagens such as UV rays, chemicals, or viruses, or they can occur spontaneously.

Mutations fall into two categories: gene mutations and chromosomal mutations.

• Gene mutations are mutations that cause alteration of the nucleotide sequence of genes,

• whereas chromosomal mutations are mutations that produce changes in whole chromosomes.

Types of mutations in DNA

Mutations in DNA are known as gene mutations. Gene mutations can be point mutations or frameshift mutations.

Point mutations (or base substitutions) are mutations involving the alteration of a single base pair of DNA or of a few adjacent base pairs. There are three main types of point mutations that you need to be familiar with:

1. Silent mutations: mutations that have no effect on the amino acid sequence.
2. Nonsense mutations: mutations that result in the change of one amino acid into a stop codon.
3. Missense mutations: A mutation in which an amino acid is changed into a different one.

When dealing with base substitutions, the result depends on whether that base pair replacement results in a new amino acid and how that amino acid affects the overall folding and function of the protein.

Figure 3. Point mutations.

In frameshift mutations, amino acid sequences in a protein are completely altered upon the insertion or deletion of a nucleotide. When a nucleotide gets added or deleted, the bases are still read in groups of three. However, those groupings shift in every codon that follows the mutation.

• An insertion involves the addition of at least one nucleotide.

• Deletions involve the removal of one or more nucleotides.

Point mutation

Now that we know what point mutations are, let's look at some examples of disorders associated with them.

Cystic fibrosis is an example of a genetic disorder mostly caused by a point mutation involving a three-base pair deletion in the CFTR gene. Specifically, it deletes the amino acid phenylalanine (Phe) at position 508. This mutation disrupts the chloride ion channels, resulting in the production of a viscous mucoid material that obstructs glandular ducts in salivary glands, bronchial glands, and pancreas.

Genetic changes found in cancers are sometimes also caused by point mutations. The most common example is the point mutation that converts the RAS gene into a cancer gene. Another example is the point mutation in tumor suppressor genes, leading to a reduction in its function.

Figure 5. Point mutation in RAS oncogene.

Missense mutation

We saw above that missense mutations are point mutations caused by a substitution that leads to a change in a single amino acid. Sickle-cell disease is an example of a disease caused by a missense mutation.

Sickle cell disease is a genetic disease in which hemoglobin molecules are abnormal and have a sickle shape. This sickle shape causes capillaries to clog, causing severe pain, weakness, and deterioration of vital organs. This disease is hereditary and gets passed on to offspring if both parents carry the defective gene. Sickle cell disease happens when a point mutation changes the hydrophilic amino acid glutamic acid (Glu) for valine (Val), which is a hydrophobic amino acid. This makes it hard for red blood cells to carry as much oxygen.

Types of chromosomal mutation

On to chromosomal mutations. Often, chromosomal mutations can result in changes in the location or number of genes on chromosomes. Chromosome mutations fall into four categories: deletion, duplication, inversion, and translocation.

Chromosomal deletion mutations involve the loss of all or part of the chromosome, removing one or more genes from the chromosome. Deletions in human chromosomes can cause serious problems.

Duplication mutations occur when a segment of a chromosome is copied and inserted into the homologous chromosome, resulting in extra genetic material.

In an inversion mutation, a segment of a chromosome gets removed and then reinserted opposite to its original orientation.

Lastly, we have translocation mutation. This type of mutation happens when part of one chromosome breaks off and is attached to another chromosome.

Examples of types of mutations

To finish off, let's explore some usually types of mutation in humans that you might not have even heard before!

Ectrodactyly, also known as "lobster claw syndrome" is a mutation that causes "split" hands and feet. Ectrodactyly is caused by deletions, translocation, or inversion mutations in chromosome 7.

A more severe, but rare genetic disorder is called Hutchinson-Gilford progeria. This disease is caused by accelerated ageing due to a mutation in the LMNA gene, a protein that provides support to the cell nucleus. Individuals suffering from progeria tend to die around the age of 13, typically of a heart attack or stroke.