Concepts Summary

• Mutations are heritable changes in genetic information. Somatic mutations occur in somatic cells; germ-line mutations occur in cells that give rise to gametes.
• The simplest type of mutation is a base substitution, a change in a single base pair of DNA. Transitions are base substitutions in which purines are replaced by purines or pyrimidines are replaced by pyrimidines. Transversions are base substitutions in which a purine replaces a pyrimidine or a pyrimidine replaces a purine.
• Insertions are the addition of nucleotides, and deletions are the removal of nucleotides; these mutations often change the reading frame of the gene.
• Expanding nucleotide repeats are mutations in which the number of copies of a set of nucleotides increases with the passage of time; they are responsible for several human genetic diseases.
• A missense mutation alters the coding sequence so that one amino acid substitutes for another. A nonsense mutation changes a codon that specifies an amino acid into a termination codon. A silent mutation produces a synonymous codon that specifies the same amino acid as the original sequence, whereas a neutral mutation alters the amino acid sequence but does not change the functioning of the protein. A suppressor mutation reverses the effect of a previous mutation at a different site and may be intragenic (within the same gene as the original mutation) or intergenic (within a different gene).
• The mutation rate is the frequency with which a particular mutation arises in a population. Mutation rates are influenced by both genetic and environmental factors.
• Some mutations occur spontaneously. These mutations include the mispairing of bases in replication and spontaneous depurination and deamination.
• Insertions and deletions can arise from strand slippage in replication or from unequal crossing over.
• Base analogs can become incorporated into DNA in the course of replication and pair with the wrong base in subsequent replication events. Alkylating agents and hydroxylamine modify the chemical structure of bases and lead to mutations. Intercalating agents insert into the DNA molecule and cause single-nucleotide additions and deletions. Oxidative reactions alter the chemical structures of bases.
• Ionizing radiation is mutagenic, altering base structures and breaking phosphodiester bonds. Ultraviolet light produces pyrimidine dimers, which block replication. Bacteria use the SOS response to overcome replication blocks produced by pyrimidine dimers and other lesions in DNA.
• The Ames test uses bacteria to assess the mutagenic potential of chemical substances.
• Transposable elements are mobile DNA sequences that insert into many locations within a genome and often cause mutations and DNA rearrangements.
• Most transposable elements have two common characteristics: terminal inverted repeats and the generation of short direct repeats in DNA at the point of insertion.
• Transposition may take place through a DNA molecule or through the production of an RNA molecule that is then reverse transcribed into DNA. Transposition may be replicative, in which the transposable element is copied and the copy moves to a new site, or nonreplicative, in which the transposable element excises from the old site and moves to a new site.
• Retrotransposons transpose through RNA molecules that undergo reverse transcription to produce DNA.
• Insertion sequences are small bacterial transposable elements that carry only the information needed for their own movement. Composite transposons in bacteria are more complex elements that consist of DNA between two insertion sequences. Some complex transposable elements in bacteria do not contain insertion sequences.
• DNA transposons in eukaryotic cells are similar to those found in bacteria, ending in short inverted repeats and producing flanking direct repeats at the point of insertion. Others are retrotransposons, similar in structure to retroviruses and transposing through RNA intermediates.
• Transposons have played an important role in genome evolution.
• Most damage to DNA is corrected by DNA-repair mechanisms. These mechanisms include mismatch repair, direct repair, base-excision repair, nucleotide-excision repair, and other repair pathways. Most require two strands of DNA and exhibit some overlap in the types of damage repaired.
• Double-strand breaks are repaired by homologous recombination and nonhomologous end joining. Special translesion DNA polymerases allow replication to proceed past bulky distortions in the DNA.
• Defects in DNA repair are the underlying cause of several genetic diseases.