PRIN401 WEEK 3
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what are common birth defects and chronic coonditions that are complexly inherited?
neural tube defect, clubfoot , clefting
week 3 . pharmacodynamics. if you add an irreversible antagonist, what is going to happen to Emax and ED50?
the Emax is going to decrease, because essentially some receptors are irreversibly knocked out
Quantal Dose Response Curve: what does it plot , and what is it useful for?
it plots CUMULATIVE frequency, and it is useful for predicting efficacy anad toxicity in a population.
how is TD50 and LD50 different from ED50? what is the therapeutic index and what is margin of safety?
Note that these values are only found in quantal curves. TD50 is the dose of drug that will elicit toxicity in 50% of population, while LD 50 is the dose causing lethality in 50% of population . TI is TD50:ED50, but it is mostty described qualitatively
MOS is TD1/ED99
"pharmacology in the 21st century'' : What are the 4 types of new therapeutic options and briefly describe.
Monoclonal antibodies (MAbs) - it blocks a receptor or the ligand of that receptor (all MAbs drugs end in mab)
Antisense - antisense binds to the sense strand (aka mRNA) and prevents protein synthesis (all antisense drug ends in sen)
Fusion proteins - this engineered protein binds all the ligands (eg. TNF) , so the Tumour Necrosis Factor cannot bind its target receptors (all fusion protein drugs end in cept)
Aptamers - they are oligonucleotides that bind target proteins (all aptamer drugs have apt in the middle)
mnemonic: MAFA
Week 3 from gene to protein plus mutations. where is the bond between tRNA and its respective aa?
between COOH of aa and 3'OH of tRNA
Most of human genes are not colinear with mRNA. T/F?
T
RNA synthesis is conducted in which direction?
During transcription, the DNA is read in which direction?
RNA synthesis is 5 to 3
DNA is read 3 to 5
Where is the bond between tRNA and their respective amino acid formed?
it is formed between 3'OH of tRNA and -COOH of amino acid.
Explain how the amino acid sequence of a protein affects its struction and function.
1. sequence of aa determines folding pattern
2. hydrophobic and hydrophilic side chains of amino acids determine orientation in space and folding
3. planar peptide bonds allows only rotation and some bonds means that amino acids can fold in 3D structure, whereas DNA and RNA will polymerize into only planar structures
Explain how upstream DNA sequences influence transcription of genes.
note: UAR helpls gather precursors for transcription.
PIC is assembled at the TATA box (PreInitiatation complex) and its assembly determines speed of transcription
__________ appears to have a significant repressor effect on gene expression.
methylation
Which of the following statements about the central dogma of biology is incorrect?
What does aliphatic side chains of amino acids mean?
aliphatic side chains are R groups that are non-polar and hydrophobic.
What are the most common genetic causes of these genetic diseases?
Alpha thalassemia
Beta thalassemia
Sickle cell anemia
Fragile X syndrome, myotonic dystrophy, Huntington's disease.
Alpha-thalassemia is caused by deletion of the alpha globin gene cluster.
Triplet repeat expansion is the genetic mechanism responsible for a number of genetic conditions including Fragile X syndrome, Myotonic Dystrophy and Huntington's disease.
Beta-thalassemia is commonly caused by a point mutation, which affects either transcription, translation, RNA cleavage or RNA splicing.
Sickle cell anemia is also caused by a point mutation, which leads to the production of an abnormal globin chain
A mutation is named: Q39X (HBB c. 118 C>T)
What kind of mutation is this?
This is a nonsense mutation, because it is a premature stop codon that was introduced due to base substitution.
Note : it is not frameshift mutation , because frameshift mutation involves deletions or insertions that are not multiples of 3bp.
R183P (BCKDHB c. 538 G>C)
Explain what this means. (Ignore BCKDHB)
R: Arginine
P: Proline
G: guanine
C: cytosine
beta polypeptide (BCKDHB)
guanine-to-cytosine change in the gene at nucleotide number 538.
resulting in an arginine to proline change in the protein product at amino acid number 183.
(The nucleotide number will always be greater than the amino acid number)
How is gene mapping carried out?
uses genetic polymorphisms as genetic markers (direct DNA sequencing is not done because the distances between genes are so large that it is inefficient to do so)
What are cells A and B?
A is RBC aka erythrocyte, B is platelet
What cell is this? (it is a cell in blood) What is its function?
It is a lymphocyte. Lymphocytes usually have a very thin rim of cytoplasm surrounding nucleus. Its function is general immunological defense.
What cell is this and what is its function? ( a type of cell in blood)
This is an Eosinophil. An Eosinophil usually has a bilobed nucleus, and contains many granules that stain dark . Its main role is parasitic defense
What is one advantage of monoclonal antibody drugs (MAbs) ?
they have high potency. (they are still very expensive)
Alpha-thalassemia patients lack normal hemoglobin. They compensate with the formation of hemoglobin _____ and hemoglobin ____. The hydrops fetalis type of alpha-thalassemia is caused by the lack of ____ alpha-globin genes, and it is immediately lethal.
hemoglobin H and Barts (4 gamma subunit)
all
What is the mode of inheritance in beta-thalassemia?
autosomal recessive.
What are the three types of RNA polymerase and what is their function?
RNA Pol 1: transcribes rRNA genes to give ribosomal subunits
RNA Pol 2: transcription of mRNA
RNA Pol 3: transcription of tRNA genes to give tRNA
Once RNA is transcribed , the _________ removes the introns and ________ is added to the 5' end and the 3' end is capped by a ___________
spliceosome
7-methyl G
poly A tail
explain the difference between observed and calculated recurrence risks.
Observed recurrence risk: it's empirical. Eg. For UK parents who have had a pregnancy with spina bifida, the chance of them having another pregnancy with spina bifida is observed to be 4%. The observed figure is 4% for cleft lip
Calculated recurrence risk: it's NOT empirical. For conditions that an empirical study would be hard to conduct, it can be estimated by sqrt of the population risk. eg. If the parents have had a pregnancy with clubfoot, the chance of this couple having another pregnancy with clubfoot is sqrt of 1/1000, which is about 3%.
explain the liability threshold model with a diagram, detailing how members within an affected family shifts the graph.
the whole family will have a higher liability because they have more risk factors (risk factors can be both genetic and environmental)
recurrence risks should not be used when the condition is not ____________
multifactorial (week 3 Dr. McGillivary's lecture p.11 bottom left slide.) (eg. when the baby has multiple abnormalities, like having cleft lip, 6 fingers at the same time, it obviously is NOT multifactorial, rather it suggests a chromosomal abnormality such as trisomy 13)
the assembly of the __________ __________ ________ determines the speed of transcription.
Pre Initiation Complex
describe the types of mutation and the ways in which they can cause diseases.
1. deletion of entire genes --> eg. a-thalassemia
2. point mutation --> eg. b-thalassemia
3. gene rearrangement and/or insertion --> eg. hemophilia A
4. Missense mutations --> no example disease given, but eg. at TATA box and GT/AG splicing site
5. TREs (Triplet Repeat Expansions) --> eg. Fragile X, Myotonic Dystrophy, Huntington
6. DNA Duplication--> duplication of oncogene causes cancer
(don't need to know for exam) what's a haplotype?
a contraction for haploid genotype. A haplotype is a collection of specific alleles (particular DNAsequences) in a cluster of tightly-linked genes on achromosome that are likely to be inherited together.[1][2] Put in simple words, haplotype is the group of genes that a progeny inherits from one parent.[3].
Basically, a haplotype is a group of alleles from closely linked loci that are inherited as a unit.
what kind of polymorphisms are used in genetic mapping and linkage analysis?
SNPs and STRs.
In multifactorial traits / diseases, state the degree of relationship and the risk.
refer to diagram
alpha-thalassemia patients compensate by forming hemoglobin __ and hemoglobin ____.
beta-thalassemia patients compensate by forming extra hemoglobin ___ and hemoglobin __.
H, Barts.
F, A2
CASE OBJECTIVE: Key clinical features of Anemia: just give a few.
Jaundice
Acute back pain
Pallor
Fatigue
Tachycardia
CASE OBJECTIVE: clinical/ hemoatological findings associated with sickle cell and thalassemia disorders.
sickle cell:
clinical: increased infections, splenomegaly
hematological: high HbS, macrocytosis, sickled RBC (dead giveaway)
thalassemia:
clinical: enlarged cheekbones, splenomegaly
hematological: low MCV/MCH, high unconjugated bilirubin due to constant RBC breakdown
CASE OBJECTIVE: the alpha globin gene is on chromosome __ , while the beta and delta gene are on chromosome ____
16, 11 respectively
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- 1 / 38
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Lernkarten
what are common birth defects and chronic coonditions that are complexly inherited?
neural tube defect, clubfoot , clefting
week 3 . pharmacodynamics. if you add an irreversible antagonist, what is going to happen to Emax and ED50?
the Emax is going to decrease, because essentially some receptors are irreversibly knocked out
Quantal Dose Response Curve: what does it plot , and what is it useful for?
it plots CUMULATIVE frequency, and it is useful for predicting efficacy anad toxicity in a population.
how is TD50 and LD50 different from ED50? what is the therapeutic index and what is margin of safety?
Note that these values are only found in quantal curves. TD50 is the dose of drug that will elicit toxicity in 50% of population, while LD 50 is the dose causing lethality in 50% of population . TI is TD50:ED50, but it is mostty described qualitatively
MOS is TD1/ED99
"pharmacology in the 21st century'' : What are the 4 types of new therapeutic options and briefly describe.
Monoclonal antibodies (MAbs) - it blocks a receptor or the ligand of that receptor (all MAbs drugs end in mab)
Antisense - antisense binds to the sense strand (aka mRNA) and prevents protein synthesis (all antisense drug ends in sen)
Fusion proteins - this engineered protein binds all the ligands (eg. TNF) , so the Tumour Necrosis Factor cannot bind its target receptors (all fusion protein drugs end in cept)
Aptamers - they are oligonucleotides that bind target proteins (all aptamer drugs have apt in the middle)
mnemonic: MAFA
Week 3 from gene to protein plus mutations. where is the bond between tRNA and its respective aa?
between COOH of aa and 3'OH of tRNA
Most of human genes are not colinear with mRNA. T/F?
T
RNA synthesis is conducted in which direction?
During transcription, the DNA is read in which direction?
RNA synthesis is 5 to 3
DNA is read 3 to 5
Where is the bond between tRNA and their respective amino acid formed?
it is formed between 3'OH of tRNA and -COOH of amino acid.
Explain how the amino acid sequence of a protein affects its struction and function.
1. sequence of aa determines folding pattern
2. hydrophobic and hydrophilic side chains of amino acids determine orientation in space and folding
3. planar peptide bonds allows only rotation and some bonds means that amino acids can fold in 3D structure, whereas DNA and RNA will polymerize into only planar structures
Explain how upstream DNA sequences influence transcription of genes.
note: UAR helpls gather precursors for transcription.
PIC is assembled at the TATA box (PreInitiatation complex) and its assembly determines speed of transcription
__________ appears to have a significant repressor effect on gene expression.
methylation
Which of the following statements about the central dogma of biology is incorrect?
What does aliphatic side chains of amino acids mean?
aliphatic side chains are R groups that are non-polar and hydrophobic.
What are the most common genetic causes of these genetic diseases?
Alpha thalassemia
Beta thalassemia
Sickle cell anemia
Fragile X syndrome, myotonic dystrophy, Huntington's disease.
Alpha-thalassemia is caused by deletion of the alpha globin gene cluster.
Triplet repeat expansion is the genetic mechanism responsible for a number of genetic conditions including Fragile X syndrome, Myotonic Dystrophy and Huntington's disease.
Beta-thalassemia is commonly caused by a point mutation, which affects either transcription, translation, RNA cleavage or RNA splicing.
Sickle cell anemia is also caused by a point mutation, which leads to the production of an abnormal globin chain
A mutation is named: Q39X (HBB c. 118 C>T)
What kind of mutation is this?
This is a nonsense mutation, because it is a premature stop codon that was introduced due to base substitution.
Note : it is not frameshift mutation , because frameshift mutation involves deletions or insertions that are not multiples of 3bp.
R183P (BCKDHB c. 538 G>C)
Explain what this means. (Ignore BCKDHB)
R: Arginine
P: Proline
G: guanine
C: cytosine
beta polypeptide (BCKDHB)
guanine-to-cytosine change in the gene at nucleotide number 538.
resulting in an arginine to proline change in the protein product at amino acid number 183.
(The nucleotide number will always be greater than the amino acid number)
How is gene mapping carried out?
uses genetic polymorphisms as genetic markers (direct DNA sequencing is not done because the distances between genes are so large that it is inefficient to do so)
What are cells A and B?
A is RBC aka erythrocyte, B is platelet
What cell is this? (it is a cell in blood) What is its function?
It is a lymphocyte. Lymphocytes usually have a very thin rim of cytoplasm surrounding nucleus. Its function is general immunological defense.
What cell is this and what is its function? ( a type of cell in blood)
This is an Eosinophil. An Eosinophil usually has a bilobed nucleus, and contains many granules that stain dark . Its main role is parasitic defense
What is one advantage of monoclonal antibody drugs (MAbs) ?
they have high potency. (they are still very expensive)
Alpha-thalassemia patients lack normal hemoglobin. They compensate with the formation of hemoglobin _____ and hemoglobin ____. The hydrops fetalis type of alpha-thalassemia is caused by the lack of ____ alpha-globin genes, and it is immediately lethal.
hemoglobin H and Barts (4 gamma subunit)
all
What is the mode of inheritance in beta-thalassemia?
autosomal recessive.
What are the three types of RNA polymerase and what is their function?
RNA Pol 1: transcribes rRNA genes to give ribosomal subunits
RNA Pol 2: transcription of mRNA
RNA Pol 3: transcription of tRNA genes to give tRNA
Once RNA is transcribed , the _________ removes the introns and ________ is added to the 5' end and the 3' end is capped by a ___________
spliceosome
7-methyl G
poly A tail
explain the difference between observed and calculated recurrence risks.
Observed recurrence risk: it's empirical. Eg. For UK parents who have had a pregnancy with spina bifida, the chance of them having another pregnancy with spina bifida is observed to be 4%. The observed figure is 4% for cleft lip
Calculated recurrence risk: it's NOT empirical. For conditions that an empirical study would be hard to conduct, it can be estimated by sqrt of the population risk. eg. If the parents have had a pregnancy with clubfoot, the chance of this couple having another pregnancy with clubfoot is sqrt of 1/1000, which is about 3%.
explain the liability threshold model with a diagram, detailing how members within an affected family shifts the graph.
the whole family will have a higher liability because they have more risk factors (risk factors can be both genetic and environmental)
recurrence risks should not be used when the condition is not ____________
multifactorial (week 3 Dr. McGillivary's lecture p.11 bottom left slide.) (eg. when the baby has multiple abnormalities, like having cleft lip, 6 fingers at the same time, it obviously is NOT multifactorial, rather it suggests a chromosomal abnormality such as trisomy 13)
the assembly of the __________ __________ ________ determines the speed of transcription.
Pre Initiation Complex
describe the types of mutation and the ways in which they can cause diseases.
1. deletion of entire genes --> eg. a-thalassemia
2. point mutation --> eg. b-thalassemia
3. gene rearrangement and/or insertion --> eg. hemophilia A
4. Missense mutations --> no example disease given, but eg. at TATA box and GT/AG splicing site
5. TREs (Triplet Repeat Expansions) --> eg. Fragile X, Myotonic Dystrophy, Huntington
6. DNA Duplication--> duplication of oncogene causes cancer
(don't need to know for exam) what's a haplotype?
a contraction for haploid genotype. A haplotype is a collection of specific alleles (particular DNAsequences) in a cluster of tightly-linked genes on achromosome that are likely to be inherited together.[1][2] Put in simple words, haplotype is the group of genes that a progeny inherits from one parent.[3].
Basically, a haplotype is a group of alleles from closely linked loci that are inherited as a unit.
what kind of polymorphisms are used in genetic mapping and linkage analysis?
SNPs and STRs.
In multifactorial traits / diseases, state the degree of relationship and the risk.
refer to diagram
alpha-thalassemia patients compensate by forming hemoglobin __ and hemoglobin ____.
beta-thalassemia patients compensate by forming extra hemoglobin ___ and hemoglobin __.
H, Barts.
F, A2
CASE OBJECTIVE: Key clinical features of Anemia: just give a few.
Jaundice
Acute back pain
Pallor
Fatigue
Tachycardia
CASE OBJECTIVE: clinical/ hemoatological findings associated with sickle cell and thalassemia disorders.
sickle cell:
clinical: increased infections, splenomegaly
hematological: high HbS, macrocytosis, sickled RBC (dead giveaway)
thalassemia:
clinical: enlarged cheekbones, splenomegaly
hematological: low MCV/MCH, high unconjugated bilirubin due to constant RBC breakdown
CASE OBJECTIVE: the alpha globin gene is on chromosome __ , while the beta and delta gene are on chromosome ____
16, 11 respectively
