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.
A nucleotide consists of a sugar, a phosphate group, and a base. There are four bases: adenine (A), guanine (G), thymine (T), and cytosine (C).
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.
For example, the combination of these two alleles determines characteristics like eye color.
Alleles are different forms of the same 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).
The nucleus contains chromosomes, which contain DNA and are composed of chromatin.
Now, let's look at the definition of mutation.
Mutations are errors or changes in the genetic code.
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.
Often, mutations occur during DNA replication, right before a cell divides.
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.
A gene mutation is a change in the sequence of base pairs in a DNA molecule.
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:
- Silent mutations: mutations that have no effect on the amino acid sequence.
- Nonsense mutations: mutations that result in the change of one amino acid into a stop codon.
- 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.
To better understand this, take a look a Figure 3. If we had a codon UGU, which codes for the amino acid cysteine and the last "U" got swapped for a "C", it would still result in cysteine since UGC also codes for cysteine. In this case, the resulting protein did not change, so we call it a silent mutation.
However, if the last "U" in the codon UGU got replaced by an "A", then it would result in UGA, which is a stop codon. Ribosomes stop building proteins when they encounter a stop codon. This kind of mutation is known as a nonsense mutation because it results in a shorter protein that cannot function properly.
Now, if the "G" in UGU got substituted for an "A", it would result in UAU, which codes for the amino acid tyrosine. In this case, we would call it a missense mutation.
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.
Notice that when no mutations are present, we have four codons:
- Codon 1 (ACA) codes for the amino acid threonine.
- Codon 2 (AAG) codes for lysine.
- Codon 3 (AGA) codes for arginine.
- Codon 4 (GGT) codes for glycine.
Now, if an insertion occurred and the base "G" got inserted right after codon 1 (ACA), all codons after the mutation until the stop codon would be altered.
- Codon 2 would become GAA and code for Glutamic acid instead of lysine.
- Codon 3 would become GAG and code for Glutamic acid instead of lysine.
- Codon 4 would become AGG and code for Arginine instead of glycine.
The same thing would happen if a deletion occurred. For example, if the first "A" in codon 2 got deleted, all codons would change and code for different amino acids.
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.
The tumor suppressor gene that is most affected by point mutations in cancer is called TP53.
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 mutations are mutations that affect multiple genes on a chromosome.
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.
For example, a specific deletion in chromosome 5 causes cri du chat ("cry of the cat") syndrome. This syndrome causes developmental disabilities, a high-pitched cry that sounds like that of a cat, and a small head with unusual facial features.
Duplication mutations occur when a segment of a chromosome is copied and inserted into the homologous chromosome, resulting in extra genetic material.
An example of a human disorder caused by duplication mutation is Charcot-Marie-Tooth disease type 1A. This disease can be caused by the duplication of the gene encoding peripheral myelin protein 22 (PMP22) on chromosome 17. This disease causes progressive muscular and sensory loss in their legs and arms.
In an inversion mutation, a segment of a chromosome gets removed and then reinserted opposite to its original orientation.
The disorder hemophilia is an example of inversion mutation in humans that occur on the X chromosome gene F8 which codes for clotting factor VIII. Hemophilia is a genetic disease characterized by the lack of one or more proteins required for blood clotting.
Lastly, we have translocation mutation. This type of mutation happens when part of one chromosome breaks off and is attached to another chromosome.
For example, chronic myelogenous leukemia happens due to a translocation mutation that exchanges a portion of chromosome 22 with a fragment of the tip of chromosome 9, leading to uncontrolled cell growth.
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.
Types of Mutations - Key takeaways
- Mutations are errors or changes in the genetic code.
- Mutations can arise spontaneously, or they can be induced by mutagens such as UV rays, chemicals, or even viruses.
- Gene mutations are mutations that cause alteration of the nucleotide sequence of a genes. Gene mutations can be point mutations or frameshift mutations.
- Chromosomal mutations are mutations that produce changes in chromosomes. There are four types of chromosomal mutations: deletion, duplication, inversion, and translocation.
References
- Campbell, N. A., Taylor, M. R., Simon, E. J., Dickey, J. L., Hogan, K., & Reece, J. B., Biology concepts & connections, 2019
- Campbell, N. A., Biology, 2017
- Brown, M., Everything you need to ace biology in one big fat notebook : the complete high school study guide, 2021
- Griffiths, A. J. F., & Al, E., Introduction to genetic analysis, 2012
- Hartwell, L., Goldberg, M. L., Fischer, J. A., & Hood, L. E., Genetics : from genes to genomes, 2021
- Mary Ann Clark, Jung Ho Choi, Douglas, M. M., & College, O., Biology 2e, 2018
- Top 10 Rare Mutations That Defy Our Definition of Human. (2017, April 16). Listverse.
- Listverse, Top 10 Rare Mutations That Defy Our Definition of Human, 16 April 2017
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