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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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Important Genetic Concepts Gene Allele Genotype Phenotype
Mutation (Chapt. 16) Classification of Mutations Mechanisms of Mutagenesis DNA Repair Pathways
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
Old Old DNA Replication Template-dependent Semi-conservative 5’ to 3’ Synthesis New Old Old New Pg. 279
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
DNA molecule with TA CG transition mutation Affected base pair Tautomeric Shift of “A” Pg. 416
( OH) Oxidation of Guanine 8-oxo-7,8-dihydro-guanine (8-oxoG) OH Produced From Electron Transport
8-oxoG-A Base Pair Adenine 8-oxoG
Insertion by “Looping Out” of Newly Synthesized Strand
Intercalating Agents Ethidium Bromide
Medical Diagnostics X-rays, positrons Radiotherapy X-rays, gamma rays
Nucleotide Excision Repair (NER) Pathway (NER) UV (pyrimidine dimer) Individuals that are homozygous for loss-of-function alleles of one of the XP genes
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!
Red Blood Cells Normal Sickle Cell Anemia Sickle Cell Trait
Hemoglobin ß-globin (146 amino acids) ß-globin (146 amino acids)
Molecular Genetics of Sickle-Cell Anemia Normal Individuals Codon #6 Hb-A Sickle Cell Individuals Hb-S E6V
Deoxyhemoglobin Hb-S Hb-S
Polymerized Deoxyhemoglobin (tactoids)
Molecular Genetics of Sickle-Cell Anemia HbA Allele Codon #6 Hb-A HbS Allele Hb-S
WT and Mutant ß-globin Proteins Hb WT Protein Hb-A Hb Mutant Proteins
Mutant Huntingtin Protein Aggregates Transmission Electron Micrograph
WT Huntingtin-GFP Mutant Huntingtin-GFP
hh Hh HH No Htt Protein Aggregates Htt Protein Aggregates Htt Protein Aggregates No HD HD HD
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
Frequency of CF Mutant Alleles ~ 70% of CF Mutant alleles are ∆F508
Lung epithelial cells Lung epithelial cells Healthy Lung AA or Aa
Lung epithelial cells Lung epithelial cells Cystic Fibrosis Lung aa
Erythropoietin Receptor Mutation And Olympic Glory Eero Mäntyranta Seven Olympic medals
Genetic Testing Disease-related Diagnosis Current disease Risk of future disease Carrier status Pharmacogenomics Efficacy of therapeutic drug treatment Tissue Typing Transplantation
Genetic Testing for Sickle Cell Anemia HbS HbA Pg. 644 MstII cut sites
Tamoxifen OH Cytochrome P450 (CYP2D6) Bioactive form of Tamoxifen “Prodrug”
Cytochrome P450 (CYP2D6) ~ 10% Caucasians are “poor” metabolizers
Genetic Testing for Tissue Typing Silent Mutations mmmmmmm Missense
Sperm cells In Vitro Fertilization (IVF) Oocytes Embryos (4-cell stage)