 |
Genes & Disease
Types of mutations
There are three types of possible mutations:
|
Single base substitutions
A single nucleotide base becomes replaced by another. These single base changes are also called point mutations. If a purine (a, t) replaces a purine or a pyrimidine (c, g) replaces a pyrimidine, it is called a transition. If a purine replaces a pyrimidine or vice-versa, the substitution is called a transversion.
 Missense mutations
- In a missense mutation, the new base alters a codon resulting in a different amino acid being incorporated into the protein chain. This is what happens in sickle cell anaemia. The 17th nucleotide of the gene for the beta chain of haemoglobin is changed from an 'a' to a 't'. This changes the codon from 'gag' to 'ggt' resulting in the 6th amino acid of the chain being changed from glutamic acid to valine. This apparently trivial alteration to the beta globin gene alters the quaternary structure of haemoglobin, which has a profound influence on the physiology and wellbeing of the individual.
 Nonsense mutations
- In a nonsense mutation, the new base changes a codon that specified an amino acid into one of the stop codons (taa, tag, tga). This will cause translation of the mRNA to stop prematurely and a truncated protein to be produced. This truncated protein will be unlikely to function correctly. Nonsense mutations occur in between 15% to 30% of all inherited diseases including cystic fibrosis, haemophilia, retinitis pigmentosa and duchenne muscular dystrophy.
The picture on the right shows an example of a nonsense mutation, where 'c' in the second codon is changed to 't'. In the normal nucleotide sequence the second codon 'cag' codes for glutamine (Q) whilst in the mutated second codon 'tag' codes for Stop leading to premature termination of the protein.
 Silent mutations
-
Silent mutations are those that cause no change in the final protein product and can only be detected by sequencing the gene. Most amino acids that make up a protein are encoded by several different codons (see genetic code). So, if for example, the third base in the 'cag' codon is changed to an 'a' to give 'caa', a glutamine (Q) would still be incorporated into the protein product, because the mutated codon still codes for the same amino acid. These types of mutations are 'silent' and have no detrimental effect.
- Splice site mutations
- Introns must be spliced from mRNA to produce the correct protein. This process must be carried out very accurately and it is guided by the nucleotide signals at the splice sites. If a mutation alters these signals, the intron may not be removed and an incorrect protein will be produced.
Insertions and deletions
 Extra base pairs may be added or deleted from the DNA of a gene. The number of bases can range from a few to thousands. Insertions and deletions of one or two bases or multiples of one or two cause frameshifts (shift the reading frame). These can have devastating effects because the mRNA is translated in new groups of three nucleotides and the protein being produced may be useless.
The picture on the right shows an example of a frameshift mutation, in the second codon the deletion of 'c' leads to a shift in reading frame and multiple amino acid substitutions in the subsequent protein.
Insertions and deletions of 3 or multiples of three bases may be less serious because they preserve the open reading frame. However, a number of trinucleotide repeat diseases exist including Huntingtons disease and fragile X syndrome.
In Huntingtons disease, the repeated trinucleotide is 'cag'. This adds a string of glutamines to the Huntington protein. The abnormal protein produced interferes with synaptic transmission in parts of the brain leading to involuntary movements and loss of motor control. Fragile X syndrome is caused when a locus on the X chromosome contains a stretch of nucleotides in which the triplet 'cag' is repeated (as many as 400 times). This causes a constriction in the x chromosome making it quite fragile. Males who inherit this X chromosome are mentally retarded. Females are only mildly affected.
Chromosomal mutations
A chromosome mutation is any change in the structure or arrangement of the chromosomes. Mutations to chromosomes happen most frequently during the crossing over stage of meiosis. There are many different types of mutation that can change the chromosome structure resulting in detrimental changes to the genotype and phenotype of the organism. Chromosomal mutations effecting essential parts of the DNA can result in the abortion of the foetus before birth.
- Translocations
- Translocations are the transfer of a piece of one chromosome to a non-homologous chromosome. They are often reciprocal, with the two chromosomes swapping segments with each other.
In most cases of chronic myelogenous leukaemia (CML), the leukaemic cells share a chromosomal abnormality known as Philadelphia chromosome. This abnormality is the result of a reciprocal translocation between chromosomes 9 and 22. An abnormal hybrid gene is created leading to the production of a novel protein that is not normally found in the cell. This protein prevents normal growth and development, leading to leukaemia.
- Inversion
- A region of DNA on the chromosome can flip its orientation with respect to the rest of the chromosome.
- Deletions
- A large section of a chromosome can be deleted resulting in the loss of a number of genes.
- Duplications
- In this mutation, some genes are duplicated and displayed twice on the same chromosome.
- Chromosome non-disjunction
- During cell division, the chromosomes fail to successfully separate to opposite poles, resulting in one of the daughter cells having an extra chromosome and the other daughter cell lacking one.
If this non-disjunction occurs in chromosome 21 of a human egg cell, a condition called Downs syndrome (DS) occurs. A person suffering with DS has 47 chromosomes in every cell instead of the normal 46. They suffer from heart defects, mental retardation and stunted growth. However, it must be pointed out that the distributions of IQs of people with DS overlaps
considerably with the IQ distribution of 'normal' (non-DS) population,
mainly due to changes in education policy in the last 30 years.
To see graphical examples of chromosomal mutations click here.
Mutation case study : Cystic Fibrosis
 Cystic fibrosis is a severe, genetically determined disease that involves both the lungs and the gastrointestinal tract. It occurs in about one in every two thousand births among white children and at a far lower rate in asian and black children. There are now more than 500 different mutations known to cause the disease. These mutations occur in a huge gene (>6000 nucleotides) on chromosome 7 that encodes a protein of 1480 amino acids called the cystic fibrosis transmembrane conductance regulator (CFTR).
This protein transports chloride ions out of cells. People with cystic fibrosis must inherit two mutant genes to develop the disease but these mutations need not be the same.
This disease results from a number of different mutations in the CFTR gene.
The most commonly observed mutations that have been observed include deletion of a codon resulting in the deletion of the amino acid phenylalanine at position 508, a missense mutation resulting in an aspartic acid being substituted for a glutamic acid at position 551, a nonsense mutation at position 542 resulting in a stop codon instead of one that codes for glycine and hence a truncated protein and mutations at the splice sites of intron 8.
|
|