Next Lesson - DNA Repair and Cancer
Core
Mutation has two related definitions. A mutation is a change in the DNA sequence of a gene or chromosome (a change in an egg or sperm cell can be passed on to children, but a change in an ordinary body cell cannot), and mutation also refers to the process that produces this change.
Things which cause mutations are called mutagens. These can be exogenous (coming from outside the body) or endogenous (arising inside the body).
Common exogenous mutagens include ionising radiation (radiation with enough energy to damage DNA, such as X-rays) and ultraviolet (UV) light from the sun. Free radicals (highly reactive molecules that can damage DNA) can also come from outside the body, but they are made inside cells too. This is important to remember as some medical imaging modalities (types of imaging, such as X-ray and CT) use ionising radiation, which at sufficiently high or prolonged exposure can cause DNA damage. Therefore, imaging should be ordered only when necessary and should use a radiation dose that is as low as reasonably practicable (ALARP, the wording used in the UK Ionising Radiation (Medical Exposure) Regulations 2017). Other exogenous mutagens are chemicals and anti-cancer agents. Some anti-cancer agents (chemotherapy drugs) work by damaging the DNA of dividing cells, which stops cancer cells undergoing mitosis (cell division) and growing, and kills them.
Endogenous mutagens can be in the form of DNA replication defects (errors made when DNA is copied), free radicals made during normal metabolism, or transposable elements. Transposable elements (also known as 'jumping genes') are specific DNA sequences which move (transpose) to random sites in DNA, and can insert themselves into a gene and inactivate it.
Both exogenous and endogenous mutagens can lead to defective or error-prone DNA repair which eventually lead to mutations, or mutagens can directly affect a gene product (the protein or RNA that a gene codes for).
Mutations will do one of the following:
- Change the gene products.
- Change the amount of the gene product.
- Change the length of the polypeptide.
- Have no effect.
Mutations can have differing effects on the synthesis of a polypeptide, from no effect, to a large frameshift (a change in the way the code is read in groups of three bases, discussed later).
- Neutral Mutations - have neither a detrimental nor a beneficial effect on an organism’s survival.
- Silent Mutations - have no effect on an organism’s phenotype, e.g. if the mutation still leads to the same amino acid being coded for, because the genetic code is degenerate (most amino acids are coded for by more than one codon).
- Synonymous Mutations - a mutation that changes a codon to a different codon for the same amino acid. The term is often used interchangeably with silent mutations, however a synonymous mutation can affect transcription, splicing (removal of the non-coding sections from the RNA copy of a gene), mRNA transport, or translation; a change in any of these can affect phenotype.
- Missense Mutations - a mutation which results in a different codon for a different amino acid, thus affecting the polypeptide chain. Extension - There are two further classifications of missense mutation.
- Conservative Missense Mutations - a mutation results in a different amino acid with similar chemical properties to the original being incorporated into the polypeptide.
- Non-conservative Missense Mutations - a mutation results in a different amino acid with different chemical properties to the original being incorporated into the polypeptide.
- Nonsense Mutations - a mutation which results in the formation of a premature stop codon.
Diagram: Shows the types of different point mutations, and the effects these can have on the amino acid
Creative commons source by Jonsta247 [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
We can also classify mutations as somatic or germ-line. A somatic mutation occurs in a regular body cell, which will limit the effect of the mutation. A germ-line mutation occurs in a germ cell (a cell that becomes a sperm or an egg, such as a spermatocyte or an oocyte), which may have a drastic effect on an offspring who inherits this mutation.
Finally, mutations can either be dominant or recessive. Recessive mutations tend to cause a loss of function and often affect biochemical pathways. Dominant mutations often cause increased function, a harmful new function, or abnormal structural proteins. Some dominant mutations are different: in haploinsufficiency, one working copy of the gene does not make enough protein, and in a dominant negative effect, the abnormal protein interferes with the normal protein made from the other allele. These statements are not hard and fast rules, but instead trends which have been noted.
Most mutations are recessive: studies of mutagenesis in many organisms suggest that over 90% are. There are far more ways in which a gene can be inactivated, whereas it is much more difficult to introduce an activating mutation. Failure of one allele can be compensated for by a normally functioning allele, so the mutation is recessive. For example, overproduction caused by one allele cannot be compensated for by a normal allele, so a mutation of this kind is dominant.
Mutations can occur at the level of single bases (micro) or at the level of chromosomes (macro).
Single Nucleotide Mutations (Micromutations)
There are 3 main categories of micromutation.
- Deletion
- A single base is removed from a strand of DNA.
- This causes a frameshift when it occurs within a coding region.
- Insertion
- A single base is added to a strand of DNA.
- This also causes a frameshift when it occurs within a coding region.
- Substitution
- A single base is exchanged for another one. There are two subtypes:
- Transition - a change of a purine (A or G) to a purine (A↔G) or a pyrimidine (C or T) to a pyrimidine (T↔C).
- Transversion - a change of a purine to a pyrimidine or vice versa (A/G↔C/T).
- Substitution will not cause a frameshift.
- A single base is exchanged for another one. There are two subtypes:
Frameshift occurs when the DNA reading frame (the way the bases are read in groups of three) is disrupted by the insertion or deletion of a number of nucleotides that is not a multiple of three (a single nucleotide is enough). This has a large downstream effect on all subsequent codons which results in many incorrect amino acids being incorporated into the polypeptide chain.
An example of a disease caused by a single nucleotide mutation is Sickle Cell Anaemia:
This is an inherited disorder of the haemoglobin gene HBB (the gene for beta-globin, one of the protein chains in haemoglobin). Sickle cell anaemia is the most common form of sickle cell disease, the term used by the NHS. This mutation makes haemoglobin stick together into long, rigid strands (polymers) when oxygen levels are low, which bends red blood cells into a characteristic sickle shape. The sickled cells break down early (haemolysis), which causes anaemia, and they can block small blood vessels, causing painful episodes called sickle cell crises. Other effects include a susceptibility to infections, weakness and impaired growth.
Diagram: Shows a blood film (a thin smear of blood viewed under a microscope) with sickled red blood cells. These are the abnormally shaped cells that look elongated.
Creative commons source by Ed Uthman [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
The mutation which causes this is a substitution (transversion) in codon 7 of HBB, where GAG -> GTG (in the older numbering this is codon 6, so the change is often written Glu6Val or E6V). This causes the normal amino acid glutamic acid to become valine.
Chromosomal Mutations (Macromutations)
As the name suggests, these mutations affect chromosomes rather than single bases. They can change the structure of a chromosome (the types listed below) or the number of whole chromosomes (see Nondisjunction).
- Deletion
- A large part of a chromosome is deleted.
- Duplication
- A large part of a chromosome is duplicated and inserted directly after the original part.
- Inversion
- A large part of a chromosome is flipped, so it is now ‘back-to-front’.
- Insertion
- A large part of a chromosome is inserted into another chromosome.
- Translocation
- A large part of a chromosome is swapped with a large part of another chromosome.
A microdeletion removes a submicroscopic chromosome segment (one too small to see under a microscope), while a microduplication adds an extra copy of one. Both are copy-number variants (changes in how many copies of a stretch of DNA a person has). Their effects depend on the size and position of the change and, especially, whether dosage-sensitive genes are lost or gained. People with the same copy-number variant can have different features because penetrance (how often a gene change has any visible effect) and expression (how strongly it shows) are not always uniform.
Test choice sets the resolution (the smallest change that can be seen) of what can be found. A conventional karyotype (a picture of the chromosomes under a microscope) shows whole-chromosome changes and large rearrangements, including balanced rearrangements (DNA is moved but none is gained or lost) that do not alter copy number. Chromosomal microarray (a chip-based test that counts copies of DNA across the genome) detects much smaller gains and losses, but usually cannot define a balanced translocation. Targeted FISH (fluorescence in situ hybridisation), MLPA (multiplex ligation-dependent probe amplification) or quantitative PCR (polymerase chain reaction) can answer a focused locus-level question (a question about one specific place in the genome). Sequence-based tests are better suited to small nucleotide variants and short insertions or deletions, although their performance for structural variants (large changes in chromosome structure) depends on the method and analysis. See Genetic Testing and Counselling for choosing tests, interpreting uncertain results and explaining limits before and after testing.
A chromosomal mutation in a somatic cell passes only to that cell’s descendants, so its effect on the body is often limited. The effect depends on the size and position of the change and on whether genetic material is gained or lost, and chromosomal changes are common in cancer cells (for example, the translocation between chromosomes 9 and 22 that forms the Philadelphia chromosome in chronic myeloid leukaemia, a blood cancer). However, problems tend to arise in germ-line cells through meiosis, as two of the four daughter cells will contain copies of the mutated chromosome.
A special kind of translocation called Robertsonian translocation can lead to trisomy (three copies of a chromosome instead of two) in offspring. Robertsonian translocation can only occur in acrocentric chromosomes (chromosomes whose centromere, the pinched point where the two arms join, is near one end, so that the short ‘p’ arm is very short). Humans have five pairs of these: chromosomes 13, 14, 15, 21 and 22. So chromosome 21 can be affected, as can the other four. A Robertsonian translocation occurs when the ‘p’ arms of two different acrocentric chromosomes (for example 14 and 21) break off and are lost. The remaining long (‘q’) arms then fuse together, creating one ‘big’ chromosome. The carrier usually still has all of their genes, so is usually healthy. This causes issues if occurring in the germ line as the ‘big’ chromosome enter one cell and be inherited meaning the fertilised egg will contain 3 copies of the genetic information two of which on the ‘big’ chromosome.
Nondisjunction is a type of chromosome mutation which usually occurs during meiosis, when homologous chromosomes (the matching pair, one from each parent) or sister chromatids (the two identical copies of a chromosome) fail to separate correctly. The pair then moves together to the same pole during anaphase (the stage when chromosomes are pulled apart). This results in one daughter cell receiving two copies of a chromosome, and the other cell receiving no copies. Anaphase lag is a separate mechanism, in which a chromosome is lost instead, so that one daughter cell has one copy fewer. Nondisjunction can also occur in mitosis (ordinary cell division), which leaves some cells with an extra or missing chromosome and others normal (mosaicism). If it happens in meiosis, an egg or sperm cell with an extra or missing chromosome can lead to an embryo with trisomy (three copies of a chromosome) or monosomy (one copy). Most of these embryos are lost in pregnancy, but some survive, for example Down syndrome (trisomy 21) and Turner syndrome (monosomy X).
Cells receiving two copies of a chromosome will have an increase in the expression of the genes contained on the extra chromosome. If the genes function to slow cell growth, they may be fatal to the cell. If the genes promote growth, the cell may grow uncontrollably which may lead to cancer.
Mutations in mitochondrial DNA (mtDNA) can cause mitochondrial disease, as can mutations in nuclear genes that code for mitochondrial proteins. Mitochondrial diseases are more pronounced if they were caused by a germ-line mutation, because diseased mitochondria are then present in multiple organ systems. Severity also depends on heteroplasmy (the proportion of mutated mtDNA mixed with normal mtDNA in a cell): symptoms appear only once the level of mutated mtDNA passes a threshold, and this level can differ between tissues. The effects of these conditions are most observed in organs and tissues which require a lot of energy e.g. the heart, brain, and muscles.
Frequently observed symptoms include: muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, dementia, hearing loss, and abnormalities involving vision.
Mutations in mtDNA are only passed on down the maternal line. Mitochondria in sperm are used to provide movement. When a sperm fertilises an oocyte (egg cell), its mitochondria enter the oocyte but are then broken down, so the child’s mitochondrial DNA comes from the mother.
Somatic mutations in mitochondria build up over time, due to the limited ability of mtDNA to repair itself. A build-up of these mutations has been linked to some forms of cancer, and increased risk of age-related diseases like heart disease, Alzheimer’s disease, and Parkinson’s disease.
Mutations in Early Embryogenesis
Imagine if there was a mitotic chromosomal mutation (one that arises during mitosis) in one of the cells at the two cell or four cell stage of embryogenesis (the early development of the embryo). All the descendants of that cell carry the mutation, so it will be present in a large number of cells in the body of the fully grown individual. This makes the genetic information inside the body’s cells heterogeneous (some cells carry the mutation and others do not). Having cells with different genetic information in one person is called mosaicism.
Diagram: Illustrates how a genetic mutation at an early stage in embryonic development can be present at many different locations in a full grown adult.
Creative commons source by Genomics Education Programme [CC BY-SA 4.0 (https://creativecommons.org/licenses/by-sa/4.0)]
Edited by: Dr. Ben Appleby and Dr. Bethany Turner
Reviewed by: Dr. Marcus Judge
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