Gene Mutations and DNA Repair

Learning Goals

• Understand key concepts of gene mutations and DNA repair mechanisms including:
  • Definition and types of mutations
  • Differences between somatic and germline mutations
  • Types of mutations: beneficial, neutral, and deleterious
  • Point mutations and their subtypes
  • Causes of mutations
  • Mechanisms of DNA repair

What is Mutation?

• Definition: A mutation is a process that results in a change in DNA or chromosome structure.
  • Can convert an allele to a new allele (new gene form).
  • Ranges from a single base change to alterations of whole chromosomes.

Types of Mutations

Somatic Mutations

• Occurs in body cells (non-germ cells) and cannot be inherited.
• Found only in the specific cells where they occur and their descendants.

Germline Mutations

• Occurs in sex cells (sperm and egg) during meiosis.
• Can be passed on to offspring, affecting every cell in the resultant organism.

Biological Impact of Mutations

Beneficial Mutations

• Increase the fitness of carriers; provide an advantage in certain environments.

Neutral Mutations

• Do not impact the fitness of the organism; have no effect on survival or reproduction.

Deleterious Mutations

• Decrease the fitness, potentially leading to diseases or health issues.

Types of Point Mutations

• Point Mutation: A single nucleotide change in the DNA sequence.
  • Silent Mutation: No change in the amino acid (e.g., TAT → TAC).
  • Missense Mutation: Changes the amino acid specified by codon (e.g., TAT → TGT changes Tyr to Cys).
  • Nonsense Mutation: Introduces a premature stop codon (e.g., TAT → TGA, results in stop).
  • Frameshift Mutation: Involves insertion or deletion of nucleotides altering the reading frame.

Examples of Point Mutations

• Sickle-cell Anemia:
  • Caused by a missense mutation in the β-globin gene, leading to sickle-shaped red blood cells.
• Mutant effects impact health significantly, resulting in conditions like anemia, organ damage, and infections.

Causes of Mutations

Spontaneous Mutations

• Occur naturally due to errors in DNA replication and processes like deamination or oxidation.

Induced Mutations

• Result from external factors such as:
  • Alkylating agents: Modify DNA bases.
  • Base analogs: Mimic bases during DNA replication.
  • Intercalating agents: Cause nucleotide skipping.
  • Radiation: Leads to thymine dimers and other DNA damage.

DNA Repair Mechanisms

Proofreading

• Corrects mismatched base pairings during DNA synthesis via DNA polymerase.

Nucleotide Excision Repair (NER)

• Removes and replaces damaged DNA segments, specifically those created by UV exposure (e.g., thymine dimers).

Mismatch Repair (MMR)

• Fixes errors that escape proofreading during DNA replication.

Double-Stranded Break Repair

• More complex; includes:
  • Homologous Recombination Repair (HRR): Uses a template DNA sequence to guide repair.
  • Non-homologous End Joining (NHEJ): Joins broken ends directly without a template, more error-prone.

CRISPR Technology

• Utilizes Cas9 to make precise mutations or insertions in the genome.
• Works in conjunction with NHEJ to incorporate mutations at specified locations in the DNA sequence.

Example of DNA Repair Conditions

• Xeroderma Pigmentosum (XP): Genetic disorder caused by mutations in NER proteins leading to extreme sensitivity to UV light and increased skin cancer risk.

Summary Table of Mutations

• Mutation Type and Effect
  | Type | Effect |
  |---------------|-----------------------------------------|
  | Silent | No phenotype change |
  | Missense | Changes phenotype |
  | Nonsense | Early stop codon |
  | Frameshift | Disrupts protein function |