Mutations, which are changes in the DNA base sequence, are raw materials for evolution. Let us understand how changes arise at the molecular level and how they lead to the evolution of species.
Basic Knowledge
Classification of mutations: ① Point mutation (base substitution): a change in one base. A synonymous substitution does not change the amino acid because of the degenerate code, whereas a nonsynonymous substitution changes the amino acid. ② Frameshift mutation: insertion or deletion of 1–2 bases shifts the codon reading frame and greatly changes the amino acid sequence thereafter. ③ Chromosomal mutation: large-scale changes in chromosome structure, such as deletion, duplication, inversion, and translocation. ④ Genomic mutation: polyploidy and aneuploidy (increases or decreases in chromosome number).
Causes of mutations: ① Spontaneous mutations = DNA replication errors and chemical changes in bases (deamination and depurination). ② Induced mutations = ultraviolet light (thymine-dimer formation), chemical mutagens (alkylating agents), and radiation.
DNA repair: ① mismatch repair (correction of replication errors) ② base-excision repair (removal and replacement of altered bases) ③ nucleotide-excision repair (repair of large damage such as UV damage) ④ SOS response (emergency response in Escherichia coli).
Molecular evolution and the neutral theory: Motoo Kimura’s neutral theory (1968) states that most mutations at the molecular level are neutral with respect to natural selection, become fixed in populations at a constant rate through genetic drift, and can be used as a molecular clock. The rate of nonsynonymous substitutions is less than the rate of synonymous substitutions because natural selection acts on phenotypes.
Explain why frameshift mutations are more likely to be harmful than substitutions of the same number of bases.
Answer: Because the genetic code is read in groups of three bases (codons), insertion or deletion of 1–2 bases shifts the reading frame of every codon after the mutation. As a result, the entire amino acid sequence from the mutation to the stop codon changes, and protein function is often completely lost. In contrast, a base substitution usually changes only one amino acid (or causes no change because of degeneracy), so its effect is limited.
- Base substitution = point mutation; synonymous/nonsynonymous substitution
- Frameshift = shifted reading frame; all subsequent amino acids change
- UV = thymine-dimer formation → nucleotide-excision repair
- DNA replication errors = corrected by mismatch repair
- Neutral theory (Kimura) = most molecular changes are neutral and fixed at a constant rate
- Molecular clock = sequence differences are proportional to time and estimate divergence dates
- Synonymous substitution rate > nonsynonymous substitution rate (difference in selection pressure)
Points to Note
① A mutation may be harmful, neutral, or advantageous, and its effect can change depending on the environment. ② A thymine dimer is a representative type of DNA damage caused by UV (ultraviolet light) and is related to the risk of skin cancer. ③ Synonymous substitutions are common because they do not change amino acids and therefore are not subject to natural selection. Many nonsynonymous substitutions are harmful and are removed by selection.
Practice
- What is a frameshift mutation? Explain it using an example of a one-base insertion.
- State the type of DNA damage caused by ultraviolet irradiation and the pathway that repairs it.
- Explain why the synonymous substitution rate is higher than the nonsynonymous substitution rate from the perspective of natural selection.