Human Genetics 30

Class Announcements

  • If students have more than two classes at the same time, contact faculty for possible alternatives.

  • Faculty may still accommodate schedule conflicts past deadlines.

Key Concepts in DNA Mutations and Repair

Background

  • DNA replication generally accurate, with one mutation in about one million base pairs.

  • Human genome consists of approximately 6,000,000,000 nucleotides, leading to about 60 mutations per cell division.

  • Mutations, if not repaired, can result in cancer.

DNA Repair Mechanisms

  • DNA Repair Enzymes: Recognize and repair mutations to prevent the development of cancer.

  • Some individuals may have deficiencies in these enzymes, affecting their repair capability.

  • Most DNA replication errors are successfully corrected, but some mutations persist.

Types of DNA Repair

  1. Excision Repair: Targeting errors in the DNA sequence to cut out and replace damaged segments.    - Nucleotide Excision Repair (NER): About 30 nucleotides removed and replaced.    - Base Excision Repair (BER): 1 to 5 nucleotides removed, specifically addressing oxidative damage.

  2. Mismatch Repair (MMR): Detects and corrects mismatched base pairs during DNA replication.    - Enzymes detect bulges or changes in DNA helix width due to mismatched nucleotides.

Mechanisms of Repair

Photo-reactivation Repair

  • In organisms like fungi: Uses enzymes called photolyases that absorb visible light energy to bind and repair pyrimidine dimers caused by UV light.

  • Pyrimidine bases (Cytosine and Thymine) can form dimers when exposed to UV light, disrupting replication and leading to mutations.

  • Human cells do not have this mechanism, increasing skin cancer risk due to UV exposure.

Excision Repair Process

  1. Damage Recognition: DNA repair enzymes scan chromosomes for damage (e.g., thymine dimers).

  2. Excising Damage: The repair enzyme removes the damaged segment and surrounding nucleotides.

  3. Synthesis: DNA polymerase synthesizes new nucleotides to replace the removed segment.

  4. Sealing: DNA ligase forms covalent bonds to complete the sugar-phosphate backbone.

Mismatch Repair Process

  • MMR relies on knowing the original template strand vs. the newly synthesized strand.

  • Proteins bound to template strands help guide MMR enzymes to correctly fix mismatches.

  • Incorrect repair can lead to mutations perpetuating errors in DNA.

Evolutionary Implications

  • Small errors in DNA can be a driving force for evolution if they remain uncorrected.

  • Mutagens (e.g., UV exposure, ionizing radiation) contribute to DNA damage.

Disorders Related to DNA Repair Deficiencies

  1. p53 Gene: Critical for detecting DNA damage and triggering apoptosis (programmed cell death); mutations lead to increased cancer risk.

  2. Trypothiodystrophy: Caused by mutations in at least five different genes leading to dwarfism, brittle hair, and skin issues without increasing cancer susceptibility.

  3. Hereditary Nonpolyposis Colon Cancer (Lynch Syndrome): Inherited mutation resulting in increased colon cancer risk; detection via colonoscopies is vital.    - Indicated by a specific gene on chromosome 2 with a 1 in 200 prevalence.

  4. Xeroderma Pigmentosum: Autosomal recessive defect in nucleotide excision repair leading to skin cancer risk; requires avoidance of sunlight.

  5. Ataxia Telangiectasia: Autosomal recessive disorder characterized by poor coordination and blood vessel dysregulation, with a high cancer risk due to defects in cell cycle checkpoint kinase.

Final Notes on Classes and Exams

  • Upcoming exam will cover chapters 9, 10, and 12; another quiz on chapters 15, 16, and 18.

  • No exam attendance required if intending to drop; exceptions for documented excuses.

  • Chapters are interconnected, leading to genetic testing applications.