Mutations Chapter 18

Genetic Mutation

  • Definition: A change in a DNA base pair or chromosome.

Types of Mutations

  • Somatic Mutations:

    • Occur in cells that are not gametes.

    • Affect only the individual in which they arise.

  • Germ-line Mutations:

    • Occur in gametes.

    • Affect future generations.

Point Mutations

  • Base-Pair Substitutions:

    • Include two types:

    • Transitions: A purine-pyrimidine pair → the other purine-pyrimidine pair (Example: AT ↔ GC or TA ↔ CG).

    • Transversions: A purine-pyrimidine pair → a pyrimidine-purine pair (Example: AT ↔ TA or AT ↔ CG).

Effects of Base Pair Substitutions on Protein Sequence

  • Missense Mutations:

    • Change to a different mRNA codon → a different amino acid in the protein.

  • Neutral Mutations:

    • Change to a codon that specifies an amino acid with similar properties, resulting in no functional change in the protein (Example: AAA → AGA, arginine → lysine).

  • Nonsense Mutations:

    • Change to a stop (nonsense) codon, resulting in premature termination and usually a nonfunctional protein.

  • Silent Mutations:

    • Change that encodes the same amino acid, resulting in no change in the protein (Example: AAA → AAG, both encode lysine).

Other Types of Mutations

  • Insertions and Deletions:

    • Lead to Frameshift Mutations:

    • An insertion or deletion not in a multiple of 3 causes the reading frame to shift, leading to:

      • Incorrect amino acids being incorporated.

      • Premature stop codons may cause early termination.

      • Read-through of stop codons may result in longer proteins.

Example

  • Sickle Cell Anemia:

    • Normal Hemoglobin: TGA GGA CTC CTC TTT (Glutamic acid).

    • Sickling Hemoglobin: TGA GGA CAC CTC TTT (Valine).

Classification of Mutations

  • Cause: Insertion, Deletion, Substitution.

  • Effect on DNA: Transition, Transversion.

  • Effect on the Protein: Nonsense, Missense, Neutral, Silent, Frameshift.

Point Mutation Effects on Phenotype

  • Forward Mutations: Wild type → mutant.

  • Reverse Mutations: Mutant → wild type.

    • True Reversion: Reverts to the wild type amino acid.

    • Partial Reversion: Reverts to another amino acid that restores (at least partially) protein function.

Suppressor Mutations

  • Change at a site different from the original mutation that masks or compensates for it without reversing it.

    • Intragenic Suppressors: Occur within the same gene.

    • Example: An insertion frameshift can be suppressed by a nearby deletion.

    • May involve a different nucleotide within the same codon or a nucleotide in a different codon.

  • Intergenic Suppressors: Occur on a different gene from the original mutation.

    • Example: A nonsense suppressor gene codes for a tRNA that recognizes a nonsense mutation but attaches an amino acid, avoiding premature termination (mutated tRNA coded for in only one allele; the other produces the normal tRNA).

Mutagenesis

  • Definition: The creation of mutations.

    • Spontaneous Mutations:

    • Can occur during S, G1, and G2 phases or by transposon movement.

    • Mutation rates vary between species and depend on the condition of organisms.

    • Many spontaneous mutations are edited and not fixed in DNA.

    • Induced Mutations:

    • Caused by exposure to mutagens, which are physical or chemical agents that interact with DNA to cause mutations.

Mechanisms Leading to Point Mutations

  • Replication Errors: Can cause Point Mutations.

    • Tautomers: Rare alternative states of bases.

    • Non-Watson-Crick Base Pairing: Occurs between normal pyrimidines and rare forms of purines.

Replication Process Details

  • Mismatched G-T base pair can lead to a GC-to-AT transition mutation after the next DNA replication.

DNA Strand Looping Errors

  • Looping Out of DNA Strands: Causes insertions or deletions.

    • Can result in one base deletion or one base insertion on the new strand.

Spontaneous Chemical Changes

  • Depurination:

    • Loss of a purine from DNA due to hydrolysis of that bond, which can stall or dissociate DNA polymerase if not repaired.

  • Deamination:

    • Removal of an amino group from a base that can lead to transition mutations (CG → TA and GC → AT).

Induced Mutations by Radiation

  • Types of Radiation:

    • Natural sources (cosmic rays, decay of isotopes) and human-derived sources (X-rays).

    • Ionizing Radiation: Causes mutations; high doses kill cells (used in cancer treatment).

    • Non-Ionizing Radiation: Generally does not cause mutations except UV light.

  • Effects of UV Light:

    • Increases chemical energy of pyrimidines, leading to bonding between adjacent pyrimidines (e.g., thymine dimers T^T).

    • If not repaired, can prevent corresponding purines from binding, creating bulges or lesions in DNA strands.

Chemical Mutagens

  • Base Analogs: Bases similar to those naturally found in DNA.

    • Example: 5-bromouracil (5BU) behaves like thymine in its normal state but can act like cytosine in a rare state.

    • Mutagenic action can lead to AT-to-GC transition mutations.

  • Base-Modifying Agents: Mutagens changing the chemical structure and properties of bases.

    • Examples include Deaminating Agents, Hydroxylating Agents, and Alkylating Agents.

  • Intercalating Agents: Insert themselves between adjacent bases, causing insertions or deletions and leading to frameshift mutations.

Environmental Mutagens

  • Sources include Drugs, Cosmetics, Food Additives, Pesticides, and Industrial Compounds.

Detecting Mutations

  • Visible Mutants: Observable phenotypes.

  • Nutritional Mutants: Auxotrophic mutations that require additional nutrients.

  • Conditional Mutants: Temperature sensitivity or other conditional factors.

  • Resistance Mutants: Such as antibiotic resistance mutations.

DNA Repair Mechanisms

  • Occurs in both prokaryotes and eukaryotes with various mechanisms, including:

    • Reverse Repair: Reversing the damage.

    • Excision Repair: Excising damaged areas and repairing the gap (can be base or nucleotide excision).

Mismatch Repair

  • Methyl-Directed Mismatch Repair:

    • Occurs after replication, determining the template strand based on a methylated A in a GATC sequence.

    • The mismatch is removed with an exonuclease, and the gap is repaired.

Translesion DNA Synthesis and SOS Response

  • Initiated when DNA cannot replicate past a certain point to prevent cell death.

  • Specialized DNA polymerases synthesize past lesions; may introduce mutations but prevent cell death.

Example of Genetic Disease

  • Xeroderma Pigmentosa: Mutation in repair mechanisms for UV damage.

Transposable Elements

  • Definition: Segments of DNA capable of moving within the genome.

  • Two classes:

    • Encode proteins that facilitate movement or replicate themselves.

    • Make DNA copies from RNA transcripts (reverse transcriptase).

Bacterial Transposable Elements

  • Insertion Sequences: Encode for their own mobilization and insertion.

  • Transposons: Similar but carry more genes.

    • Composite Transposons: Have flanking elements on either side of genes.

    • Noncomposite Transposons: Contain only inverted repeats without flanking elements.

Eukaryotic Transposable Elements

  • Autonomy varies:

    • Autonomous Elements: Can transpose themselves.

    • Nonautonomous Elements: Depend on others for movement.

Retrotransposons in Humans

  • LINES: Autonomous transposons.

  • SINES: Nonautonomous transposons (e.g., Alu), relying on LINES for movement.

Example of Transposition Disease

  • Neurofibromatosis:

    • Autosomal dominant mutation related to an Alu sequence in the intron of the Neurofibromatosis gene.

    • Results in a longer-than-normal transcript and a short polypeptide, leading to production of a nonfunctional protein.