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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