Concepts Summary

Mutations are heritable changes in genetic information. They are important for the study of genetics and can be used to unravel other biological processes. Somatic mutations occur in somatic cells; germ-line mutations occur in cells that give rise to gametes. Gene mutations are genetic alterations that affect a single gene; chromosome mutations entail changes in the number or structure of chromosomes.

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 trinucleotide repeats are mutations in which the number of copies of a trinucleotide increases through 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 to 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).

Mutation rate is the frequency with which a particular mutation arises in a population, whereas mutation frequency is the incidence of a mutation in a population. Mutation rates are usually low and 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 may arise from strand slippage in replication or from unequal crossing over. Base analogs may become incorporated into DNA in 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, but the SOS response causes the occurrence of more replication errors. Pyrimidine dimers in eukaryotic cells can be bypassed by DNA polymerase ^ but may result in the placement of incorrect bases opposite the dimer.

The analysis of reverse mutations provides information about the molecular nature of the original mutation.

The Ames tests uses bacteria to assess the mutagenic potential of chemical substances.

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. Although the details of the different DNA repair mechanisms vary, most require two strands of DNA and exhibit some overlap in the types of damage repaired. Proofreading and mismatch repair correct errors that arise in replication. Direct-repair mechanisms change the altered nucleotides back into their original condition, whereas base-excision and nucleotide-excision repair mechanisms replace nucleotides around the damaged segment of the DNA.

Defects in DNA repair are the underlying cause of several genetic diseases.

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