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Important Genetic Concepts Genotype Phenotype Gene Allele Flow of Genetic Information N C Page 353 Deoxyribonucleotide Pg. 256 DNA Bases Pg. 255 DNA Strand Pg. 257 DNA Structure 5’ 3’ 3’ 5’ Page 6 Ribonucleotide OH RNA Bases Amino Acid Structure Pg. 397 Page 360 Possible Reading Frames for RNA Mutation (Chapt. 16) Classification of Mutations Mechanisms of Mutagenesis DNA Repair Pathways Conservative Missense Mutation Non-conservative Missense Mutation Mutation (Chapt. 16) Classification of Mutations Mechanisms of Mutagenesis DNA Repair Pathways Old Old DNA Replication Template-dependent Semi-conservative 5’ to 3’ Synthesis Pg. 279 New Old Old New Base Pair Structures Pg. 416 Thymine Base Pairing Standard AT Base pair Tautomeric Shift Base pair Pg. 416 Standard Base Pairs Tautomeric Shift Base Pairs A T T G G C G T C A A C Rare tautomers are shown in Red Affected base pair Tautomeric Shift of “A” DNA molecule with TA CG transition mutation Pg. 416 Figure 16.4 Insertion/Deletion Mutations by Replication Slippage Oxidation of Guanine ( OH) 8-oxo-7,8-dihydro-guanine (8-oxoG) OH Produced From Electron Transport 8-oxoG-A Base Pair 8-oxoG Adenine Ethylmethane Sulfonate Mutagenesis Pg. 418 Intercalating Agents Ethidium Bromide Intercalation Electromagnetic Spectrum UVA 380-320 UVB 320-290 UVC 290-100 (XP Photosensitivity: 280 to 310 nm) Pg. 371 DNA damage induced by UV light Can NOT form Base pairs! Fig. 15-9 Pg. 372 X-rays Gamma rays Nuclear radiation Ionizing Radiation OH DNA Double-Strand Breaks (DSBs) Chromosome Mutations (Chapter 8) Mutation (Chapt. 16) Classification of Mutations Mechanisms of Mutagenesis DNA Repair Pathways Nucleotide Excision (NER) Repair (NER) Pathway UV (pyrimidine dimer) (XP proteins) Pg. 424 Nucleotide Excision (NER) Repair (NER) Pathway UV (pyrimidine dimer) Damaged DNA Replicated Mutations! Individuals that are homozygous for loss-of-function alleles of one of the XP genes Xeroderma pigmentosum Pigmentary changes, premature skin aging, neoplasia Malignant tumors may develop as early as ages 3-4. XP is often fatal before the age of 10 (Two-thirds die before 20) X-rays Gamma rays Nuclear radiation Ionizing Radiation OH DNA Double-Strand Breaks (DSBs) Repair by Homologous Recombination (Fig. 16-16) Chromosome Mutations (Chapter 8) Chromosome Mutations (Chapt. 8) Pg. 426 Response to DNA Double-Strand Breaks Human Molecular Genetics Human Mutations Linking Genotype to Phenotype Dominance Relationship of Alleles 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 Individual Hb-A Sickle Cell Individual Hb-S Codon #6 Hb-A Pg. 350 Hb-S Molecular Genetics of Sickle-Cell Anemia HbA Allele Hb-A HbS Allele Hb-S Codon #6 Genotype/Phenotype HbAHbA HbSHbS HbAHbS WT and Mutant ß-globin Proteins Hb WT Protein Hb-A Hb Mutant Proteins Huntington’s Disease Dominant Allele Neurodegenerative Disorder WT Huntingtin-GFP Mutant Huntingtin-GFP Mutant Huntingtin Protein Aggregates Transmission Electron Micrograph hh No Htt Protein Aggregates No HD Hh HH Htt Protein Aggregates Htt Protein Aggregates HD HD Trinucleotide Repeat Diseases Healthy Lung Lung epithelial cells Lung epithelial cells Cystic Fibrosis Lung Lung epithelial cells Lung epithelial cells Chloride Ion Channel Gene and Protein Involved in Cystic Fibrosis CFTR Gene Mutations Missense mutation Nonsense mutation Frame-shift mutation Deletion, in-frame Loss-of-Function Mutations Frequency of Mutations in CFTR Gene ∆F508 Mutation ~ 70% of CF Mutations are ∆F508 Healthy Lung AA Lung epithelial cells Lung epithelial cells Cystic Fibrosis Lung aa Lung epithelial cells Lung epithelial cells Healthy Lung Aa Lung epithelial cells Lung epithelial cells Nature (2001) 413: 519-523 Pedigree of Developmental Verbal Dyspraxia FOXP2-FOXP1 Alignment Arg to His (R533H) (G-to-A) This mutation is found only In people with DVD FOXP2 Sequence Comparison Evolution of FOXP2 T N missense/silent = missense ~ 130 million years N S Genetic Technologies Genetic Testing Gene Therapy Genomics Genetic Testing Sickle cell anemia Huntington’s Disease Recessive Disorders Molecular Genetics of Sickle-Cell Anemia HbA Allele Hb-A HbS Allele Hb-S Codon #6 Genetic Testing for Sickle Cell Anemia HbS HbA MstII cut sites Pg. 644 HbA/HbA HbAS Hb HbA MstII cut sites Pg. 644 HbS/HbS HbS HbS MstII cut sites Pg. 644 HbA/HbS HbS HbA MstII cut sites Pg. 644 Genetic Testing Sickle cell anemia Huntington’s Disease Recessive Disorders Chloride Ion Channel Gene and Protein Involved in Cystic Fibrosis CFTR Gene Mutations Missense mutation Nonsense mutation Frame-shift mutation Deletion, in-frame Loss-of-Function Mutations Fields (or Spots) of Microarray Fig. 24-16 Tamoxifen OH “Prodrug” Bioactive form of Tamoxifen Tamoxifen Cytochrome P450 (CYP2D6) “Prodrug” ~ 10% Caucasians are “poor” metabolizers Genetic Testing Post-natal Prenatal (CVS, amniocentesis, PGD) Early Embryonic Development (~ 7 days) Pre-implantation Genetic Diagnosis (PGD) • For only $985, we scan over one million variants in your genome • Calculate genetic risk for 18 diseases based on the current literature • Find out where your ancestors came from and compare your genome with others Age-related Macular Degeneration, Asthma, Alzheimer's Disease, Atrial Fibrillation, Breast Cancer, Celiac Disease, Colorectal Cancer, Exfoliation Glaucoma XFG, Crohn's Disease, Multiple Sclerosis, Myocardial Infarction, Obesity, Prostate Cancer, Psoriasis, Restless Legs, Rheumatoid Arthritis, Type 1 Diabetes and Type 2 Diabetes. Genetic Technologies Genetic Testing Gene Therapy Genomics Viral Vectors for Gene Therapy Removal viral genes Splice in therapeutic allele Gene Therapy Trials Figure 24.28a Gene Therapy for Severe Combined Immunodeficiency Cloned “A” allele “aa” individual Virus with “A” allele “aa” cells Pg. 654 “Aaa” cells Gene Therapy for Cancer Gene Therapy for Cancer Enzyme Prodrug Toxic Metabolite Thymidine Kinase Ganciclovir Phosphoganciclovir Cytosine Deaminase 5-fluorocytosone 5-fluorouracil Nitroimidazole reductase CB1954 Alkylating agent Genetic Technologies Genetic Testing Gene Therapy Genomics DNA Sequencing: How it works Pg. 343 “Raw” DNA sequence Where are the genes? Table 21.4 Annotation of Human Genes Pg. 543 Genes Mapped to Chromosomes Transposon Mobility Fig. 22-10 Cancer Genomics Nature (2008) “Stone age” Genomics Human/Neanderthal Phylogeny Figure 24.20a Figure 24.20c Diffuse Large B-Cell Lymphoma Diffuse large B-cell lymphoma (DLBCL), the most common lymphoid malignancy in adults Curable in less than 50% of patients Clinical Heterogeneity Survival Rates 68% 24% Figure 24.21