MoBio Mutations and Consequences Chapter 7

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.

Image

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.

Image

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.

Table 7-E-1. Examples of diseases caused by insertion mutation.

Image

Exon Skipping

Image

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.