Back11. Gene Mutation, DNA Repair, and Homologous Recombination
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11. Gene Mutation, DNA Repair, and Homologous Recombination
Introduction
This chapter explores the molecular basis of gene mutation, the mechanisms by which cells repair DNA damage, and the genetic and phenotypic consequences of these processes. Understanding these mechanisms is fundamental to genetics, as mutations are the source of genetic variation and can lead to genetic disorders.
Mutations: Rarity, Randomness, and Measurement
Mutations Are Rare and Random
Gene mutations are random events that rarely occur in the genome.
Mutation rate is measured by:
Counting the number of mutations affecting a phenotype.
Determining the frequency of mutations per base pair.
Phenotypic mutation rates vary among organisms (about to ).
DNA-level mutation rates are lower and more consistent (about per replicated base pair).
Mutation Hotspots
Mutation hotspots are genes or regions with elevated mutation rates.
Large gene size is one reason for hotspots (e.g., DYS gene in Duchenne muscular dystrophy, NF1 gene in neurofibromatosis; mutation rate ≈ ).
Proof of the Random Mutation Hypothesis
The fluctuation test (Luria and Delbrück, 1943) demonstrated that bacterial resistance to bacteriophage arises from random mutations, not adaptive changes.
Random mutation hypothesis: Different cultures develop resistance at different times, resulting in variable numbers of resistant bacteria.
Adaptive mutation hypothesis: All cultures would have similar numbers of resistant bacteria if adaptation occurred after exposure.
Experimental results supported the random mutation hypothesis.
Types and Consequences of Mutations
Germ-Line and Somatic Mutations
Germ-line mutations: Occur in cells that give rise to gametes; heritable across generations.
Somatic mutations: Occur in non-germ cells; only affect the individual and are not inherited.
Somatic mutations are propagated by mitosis to descendant cells.
Point Mutations
Gene mutations often involve substitution, addition, or deletion of one or more DNA base pairs.
Point mutations: Localized changes at a specific position in a gene or genome.
Consequences depend on the type and location of the mutation.
Table: Types of Point Mutations and Their Consequences
Type | Consequence |
|---|---|
Coding-Sequence Mutations | |
Synonymous | No amino acid sequence change. |
Missense | Changes one amino acid. |
Nonsense | Creates stop codon, terminates translation. |
Frameshift | Wrong sequence of amino acids. |
Regulatory Mutations | |
Promoter | Changes timing or amount of transcription. |
Polyadenylation | Alters sequence of mRNA. |
Splice site | Improperly retains an intron or excludes an exon. |
DNA replication mutation (e.g., triplet-repeat expansion) | Increases or decreases number of short repeats of DNA. |
Base-Pair Substitution Mutations
Base-pair substitution: Replacement of one nucleotide base pair by another.
Transition mutation: Purine replaces purine (A ↔ G) or pyrimidine replaces pyrimidine (C ↔ T).
Transversion mutation: Purine replaces pyrimidine or vice versa (A/G ↔ C/T).
Three Types of Base-Pair Substitution Mutations
Synonymous mutation: No change in amino acid (silent mutation).
Missense mutation: Alters one amino acid in the protein.
Nonsense mutation: Converts a codon to a stop codon, truncating the protein.
Frameshift Mutations
Insertion or deletion of base pairs alters the reading frame of mRNA.
Results in an abnormal amino acid sequence from the mutation point onward; may introduce premature stop codons.
Regulatory Mutations
Point mutations in regulatory regions (promoters, introns, UTRs) can alter the amount of gene product without changing the protein sequence.
Three main types: promoter mutations, splicing mutations, and polyadenylation mutations.
Promoter Mutation
Alters consensus sequence nucleotides in promoters, affecting transcription initiation efficiency.
Can reduce or abolish transcription.
Example: Mutations in the human β-globin gene promoter reduce or eliminate gene expression.
Splicing Mutation
Mutations at intron-exon boundaries disrupt normal splicing, leading to retention of introns or exclusion of exons in mRNA.
Results in abnormal or nonfunctional proteins.
Cryptic Splice Sites
New splice sites created by base-pair substitutions can compete with authentic sites, leading to abnormal mRNA processing.
Example: G to A mutation at position 110 in human β-globin intron 1 creates a cryptic splice site, adding 19 nucleotides to mRNA.
Polyadenylation Mutations
Mutations in the polyadenylation signal sequence at the 3' end of mRNA can block proper mRNA processing.
Leads to reduced or absent protein production (e.g., α-globin gene mutation).
Forward Mutation and Reversion
Forward mutation: Wild-type allele becomes mutant.
Reverse mutation (reversion): Mutant allele reverts to wild-type or near wild-type.
True reversion: Second mutation restores the original DNA sequence within the same codon.
Intragenic reversion: Second mutation elsewhere in the same gene restores function.
Second-site reversion (suppressor mutation): Mutation in a different gene compensates for the original mutation.
Spontaneous Mutations and Their Mechanisms
Spontaneous Mutations
Occur without exposure to external mutagens.
Arise from errors in DNA replication or spontaneous chemical changes in nucleotides.
Spontaneous DNA Replication Errors
DNA polymerases have high fidelity due to proofreading and mismatch repair.
Replication errors (mismatches) occur at a rate of about per base pair in E. coli and eukaryotes.
Insertions and Deletions of Nucleotide Repeats
Strand slippage: DNA polymerase temporarily dissociates, forming a hairpin in the new strand, leading to repeat expansion.
Results in increased or decreased numbers of short DNA repeats.
Trinucleotide Repeat Expansion Disorders
Caused by strand slippage mutations that expand trinucleotide repeats beyond a threshold, leading to disease.
Wild-type alleles have variable repeat numbers; disease occurs when repeats exceed a critical value.
Table: Human Trinucleotide Repeat Disorders
Disease | Repeat Sequence | Normal Range | Disease Range | Principal Phenotype |
|---|---|---|---|---|
Fragile X syndrome | CGG | 6–50 | 200–2000 | Mental retardation |
Friedreich ataxia | GAA | 6–29 | 200–900 | Loss of coordination |
Huntington disease | CAG | 6–35 | 36–100 | Uncontrolled movement |
Myotonic dystrophy | CTG | 5–37 | 50–1000 | Muscle weakness |
Spinal and bulbar muscular atrophy | CAG | 11–33 | 38–62 | Muscle weakness |
Spinocerebellar ataxia (multiple forms) | CAG | 4–44 | 45–140 | Loss of coordination |
Mispaired Nucleotides
Non-Watson-and-Crick base pairing: Occasional mispairing (e.g., G with T, C with A) during replication.
Incorporated error: Mispairing event during replication.
Replicated error: If not repaired, the mispairing becomes a permanent mutation in subsequent replication cycles.
Additional info: Further sections of the chapter would cover induced mutations, DNA repair mechanisms, and the molecular details of homologous recombination, which are essential for a complete understanding of mutation and repair in genetics.
