Mutation refers to the change in a DNA sequence, which may involve only a few
bases or the large-scale chromosome abnormality. This section covers the
small-scale mutations (substitution, deletion,
insertion) and the exon skipping
that results from mutation at the splice site. The chromosome abnormality
is discussed in Chapter 8 Section E.
Substitution
In the substitution mutation, one or more nucleotides are substituted by the
same number of different nucleotides. In most cases, only one nucleotide
is changed. Based on the change in the nucleotide type, the substitution mutation may be
divided into transition and transversion mutations. Based on the consequence of mutation, the substitution mutation may be
grouped into silent, missense and nonsense mutations.
Figure 7-E-1. The substitution mutation.
(a) Illustration of transition (blue) and transversion (red) mutations.
In the transition mutation, a pyrimidine (C or T) is substituted by another
pyrimidine,
or a purine (A or G) is substituted by another purine. The transversion
mutation involves the change from a pyrimidine to a purine, or vice versa.
(b) Examples
of silent, missense and nonsense mutations. The silent mutation
does not produce any change in the amino acid sequence, the missense mutation
results in a different amino acid, and the nonsense mutation generates a stop
signal.
Deletion
The deletion mutation involves elimination of one or more nucleotides from
a DNA sequence. It may cause frameshift, producing a non-functional
protein.
Figure 7-E-2. Real examples of deletion mutations
which cause diseases. (a) Deletion of "T"
from the sequence "TTTTT" in the CFTR gene.
(b)
Deletion of "AT" from the sequence "ATAT" in the CFTR
gene.
(c) Deletion of "TTG" from the sequence "TTGTTG" in
the FIX gene.
(d) Deletion of "ATAG" from
the sequence "ATAGATAG" in the APC gene.
Note that deletion and insertion mutations often occur in the repetitive
sequence. As explained in
the next section, they are usually caused by "replication
slippage".
Insertion
In the insertion mutation, one or more nucleotides are inserted into a
sequence. If the
number of inserted bases is not a multiple of 3, it will cause frameshift, resulting in
serious consequences. As shown in the following table, non-frameshift insertions
may also cause diseases.
Figure 7-E-1. Examples of diseases caused by insertion mutation.
Exon skipping
Figure 7-E-3. Example of
exon skipping. Splicing
of an intron requires an essential signal: "GT........AG". If
the splice acceptor site AG is mutated (e.g., A to C in this figure), the
splicing machinery will look for the next acceptor site. As a result, the
exon between two introns is also removed.
|