MUTATIONS
1. POINT MUTATIONS: one nucleotide is affected.
Types of point mutations:
a. Missense mutations:
- the new nucleotide alters the codon so as to produce an altered amino acid
in the protein product.
-example: in sickle cell anemia, the replacement of A by T at the 17th
nucleotide of the gene for the beta chain of hemoglobin changes the codon
GAG (for glutamic acid) to GTG ( for valine). Thus the 6th amino acid in
the chain becomes valine instead of glutamic acid.
b. Nonsense mutations:
-the new nucleotide changes a codon that specified an amino acid to one of
the STOP codons (TAA, TAG, or TGA). Therefore, translation of the
messenger RNA will stop prematurely. The earlier in the gene that this
occurs, the shorter the protein product and the more likely that it will be
unable to function.
-example: cystic fibrosis. A huge gene encodes a protein (of 1480 amino
acids) called the cystic fibrosis transmembrane conductance regulator
(CFTR). The protein is responsible for transporting chloride ions out of
cells. The gene encompasses over 6000 nucleotides spread over 27 exons on
chromosome 7. In some cases of cystic fibrosis, the substitution of a T for a
C at nucleotide 1609 converts a glutamine codon (CAG) to a STOP codon
(TAG). The protein produced has only the first 493 amino acids of the
normal chain of 1480 and can not function. ( over 1000 possible mutations
have been found in individuals with cystic fibrosis)
c. Silent mutations:
- they cause no change in their product and cannot be detected without
sequencing the gene
-Most amino acids are encoded by several different codons. For example, if
the third base in the TCT codon for serine is changed to any one of the
other three bases, serine will still be encoded. (Wobble effect)
d. Insertions and deletions:
-extra base pairs may be added or deleted from the DNA of a gene
-These cause frame-shift errors, as seen below
- They often create new STOP codons.
- if the insertions or deletions are in groups of three nucleotides, then extra
amino acids may be added to the protein, or amino acids may be lost form
the protein.
-Ex: Huntington’s Disease: In this disorder, the repeated trinucleotide is
CAG, which adds a string of glutamines (Gln) to the encoded protein (called
huntingtin). The abnormal protein interferes with synaptic transmission in
parts of the brain and leads to the death of these brain cells.
2. Duplications:
- Duplications are a doubling of a section of the genome. During meiosis,
crossing over between sister chromatids that are out of alignment can
produce one chromatid with a duplicated gene and one chromatid having
two genes with deletions.
Ex:
- this new gene carries inappropriate promoters at its 5' end (acquired from
the 11-beta hydroxylase gene) that cause it to be expressed more strongly
than the normal gene. The mutant gene is dominant: all members of one
family (through four generations) who inherited at least one chromosome
carrying this duplication suffered from high blood pressure and were prone
to early death from stroke.
-Duplications can be beneficial. Sometimes the new gene can acquire new
functions and provide the basis for adaptive evolution. As well, changes in
duplicated changes may lead to post-zygotic barriers and speciation.
3. Translocations:
-involve large segments of DNA and are apparent at the chromosomal level.
- transfer of a piece of one chromosome to a nonhomologous chromosome.
-can affect the phenotype in different ways:
 a break within a gene will destroy its function
 translocated genes may come under the influence of different
promoters and enhancers so that their expression is altered.
 the breakpoint may occur within a gene creating a hybrid gene. This
may be transcribed and translated into a fusion protein, with a
completely altered function
FREQUENCY OF MUTATIONS:
Mutations are rare events.
This is surprising. Humans inherit 3 x 109 base pairs of DNA from each
parent. this means that each cell has 6 billion (6 x 109) different base pairs
that can be the target of a point mutation. Point mutations are most likely to
occur when DNA is being copied (S phase of cell cycle)
It has been estimated that in humans and other mammals, mutations occur at
the rate of about 1 in every 50 million (5 x 107) nucleotides added to the
chain But with 6 x 109 base pairs in a human cell, that mean that each new
cell contains some 120 new mutations. But, most (as much as 97%) of our
DNA does not encode anything. The wobble effect also results in many
silent mutations.