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Allele

Important Genetic Concepts. Gene. Allele. Genotype. Phenotype. Mutation (Chapt. 16). Classification of Mutations. Mechanisms of Mutagenesis. DNA Repair Pathways. Possible Reading Frames for RNA. A Comprehensive Catalogue of Somatic Mutations From a Cancer Genome Nature (December 2009).

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Allele

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  1. Important Genetic Concepts Gene Allele Genotype Phenotype

  2. Mutation (Chapt. 16) Classification of Mutations Mechanisms of Mutagenesis DNA Repair Pathways

  3. Possible Reading Frames for RNA

  4. A Comprehensive Catalogue of Somatic Mutations From a Cancer Genome Nature (December 2009) Cancer: Malignant Melanoma Total base substitution mutations: 33,345 Coding mutations: 292 Missense: 172 Nonsense: 15 Silent:105 Total Chromosome mutations: 37

  5. Old Old DNA Replication Template-dependent Semi-conservative 5’ to 3’ Synthesis New Old Old New Pg. 279

  6. A A C T C A G T G C G T Tautomeric Shift Base Pairs Standard Base Pairs Rare tautomers are shown in Red

  7. DNA molecule with TA CG transition mutation Affected base pair Tautomeric Shift of “A” Pg. 416

  8. ( OH) Oxidation of Guanine 8-oxo-7,8-dihydro-guanine (8-oxoG) OH Produced From Electron Transport

  9. 8-oxoG-A Base Pair Adenine 8-oxoG

  10. Insertion by “Looping Out” of Newly Synthesized Strand

  11. Deletion by “Looping Out” of Template Strand

  12. Intercalating Agents Ethidium Bromide

  13. Ethidium Intercalation in DNA

  14. Medical Diagnostics X-rays, positrons Radiotherapy X-rays, gamma rays

  15. Pg. 419

  16. Pyrimidine Dimer

  17. Nucleotide Excision Repair (NER) Pathway (NER) UV (pyrimidine dimer) Individuals that are homozygous for loss-of-function alleles of one of the XP genes

  18. Nucleotide Excision Repair (NER) Pathway (NER) UV (pyrimidine dimer) Individuals that are homozygous for loss-of-function alleles of one of the XP genes Damaged DNA Replicated Mutations!

  19. Xeroderma pigmentosum

  20. Red Blood Cells Normal Sickle Cell Anemia Sickle Cell Trait

  21. Hemoglobin ß-globin (146 amino acids) ß-globin (146 amino acids)

  22. Molecular Genetics of Sickle-Cell Anemia Normal Individuals Codon #6 Hb-A Sickle Cell Individuals Hb-S E6V

  23. Deoxyhemoglobin Hb-S Hb-S

  24. Polymerized Deoxyhemoglobin (tactoids)

  25. Molecular Genetics of Sickle-Cell Anemia HbA Allele Codon #6 Hb-A HbS Allele Hb-S

  26. WT and Mutant ß-globin Proteins Hb WT Protein Hb-A Hb Mutant Proteins

  27. Huntington’s Disease

  28. Mutant Huntingtin Protein Aggregates Transmission Electron Micrograph

  29. WT Huntingtin-GFP Mutant Huntingtin-GFP

  30. hh Hh HH No Htt Protein Aggregates Htt Protein Aggregates Htt Protein Aggregates No HD HD HD

  31. Trinucleotide Repeat Diseases

  32. Cystic Fibrosis

  33. CFTR Protein

  34. Spectrum of Mutations in CFTR Gene CFTR Gene Mutations Missense mutation Nonsense mutation ~1200 pathological mutations Frame-shift mutation Loss-of-Function Mutations Deletion, in-frame

  35. Frequency of CF Mutant Alleles ~ 70% of CF Mutant alleles are ∆F508

  36. ∆F508 Mutation

  37. Lung epithelial cells Lung epithelial cells Healthy Lung AA or Aa

  38. Lung epithelial cells Lung epithelial cells Cystic Fibrosis Lung aa

  39. Erythropoietin Receptor Mutation And Olympic Glory Eero Mäntyranta Seven Olympic medals

  40. (Epo)

  41. Erythropoietin (Epo)

  42. Red Blood Cell Development

  43. Genetic Testing Disease-related Diagnosis Current disease Risk of future disease Carrier status Pharmacogenomics Efficacy of therapeutic drug treatment Tissue Typing Transplantation

  44. Genetic Testing for Sickle Cell Anemia HbS HbA Pg. 644 MstII cut sites

  45. Tamoxifen OH Cytochrome P450 (CYP2D6) Bioactive form of Tamoxifen “Prodrug”

  46. Cytochrome P450 (CYP2D6) ~ 10% Caucasians are “poor” metabolizers

  47. Genetic Testing for Tissue Typing Silent Mutations mmmmmmm Missense

  48. Early Embryonic Development (~ 7 days)

  49. Sperm cells In Vitro Fertilization (IVF) Oocytes Embryos (4-cell stage)

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