PRIN 3 Genes & their Functions Flashcards
Multi-factorial Inheritance
interplay of genes and environment
(eg) height …starvation will cause to not fulfill genetic potential
(eg) Hypertension
disease is familial, but follows no Mendelian pattern
Explain “Threshold Model” of Multifactorial Inheritance
(eg) cleft lip
many factors lead up to the closing of the lip
Recurrence Risk
of Multi-factorial Inheritance
1 sibling affected = 2 to 4%
2 sibling affected = 10%
sib & affected parent = 10%
How many genes in common does a parent have with their child?
1/2
How many genes in common does a person have with their sibling?
1/2
How many genes in common does a person have with their uncle?
1/4
How many genes in common does a grandparent have with their grandchild?
1/4
How many genes in common does a person have with their cousin?
1/8
Multi-factorial Inheritance
Recurrence Risk & Gender
Some clinical cases occur more frequently in one sex than the other
**there is a higher risk if affected relative is of the less frequently affected sex
General Ballpark for Multifactorial Risk
2 to 4%
UAR
Upstream Activator Region
- site of recruitment & binding of transcription factors culminating in the assembly of the protein complex at the TATA box
- enables a faster assembly speed than without the upstream UAR
What does the rate of Transcription depend on?
Assembly of the Pre-inititiation complex at TATA box
Which polymerase is involved in Transcription
RNA Polymerase 2
HbH disease
a-Thalassemia
only have 1 of 4 alpha-globin genes
moderate hemolytic anemia
Symptoms of having only 3 of 4 alpha-globin genes
a-Thalassemia
minimal symptoms, totally fine
Symptoms of having only 2 of 4 alpha-globin genes
a-Thalassemia
mild anemia
microcytic RBC
Symptoms of having 0 of 4 alpha-globin genes
a-Thalassemia
fetus born to term, but then dies
Hemophilia A
How is it inherited?
caused by the absence of
Blood clotting protein
(Factor 8) which is located on the X Chromosome close to the centromere
Genomic Sequence
contains both introns & exons
Coding Sequence
contains ONLY exons
Nonsense Mutation
base pair substitution results in early stop
HBB c.118 C>T
What does this mean?
HBB= Human gene code
c.118 = coding DNA numbering
C changed to T
Missence Mutation
Base pair substitution results in aa change
Example of Missence Mutation
Sickle Cell Anemia
Glutamic Acid > Valine due to single base change
Cryptic Splice Site
site that becomes the new target for Spliceosome in the event that a mutation has occurred
***results in nonfunctional protein
Triplet Repeat Expansion
Normal genes contain a variable (but stable) number of triplet repeats
mutation can lead to amplification of the number of these repeats# making it unstable
STRs
Single Tandem Repeats
amplified by PCR and run on gel to help identify individuals
useful in forensics
Hardy Weinberg Equation
P + Q = 1
p2 + 2pq + q2 = 1
carrier frequency = 2pq
(assume p = 1)
X-linked recessive conditions that are lethal
2/3 chance mother is a carrier
1/s chance its spontaneous
Clinical Features of Anemia
fatigue renal failure tachycardia pallor jaundice (hemolytic anemia) acute back pain
SSA
Hemotological Findings
High HbS Reticulocytsis Macrocytosis Fragile RBC Presence of sickled RBCs High uncongugated bilirubin
Splenomegaly
enlargement of spleen
Location of Spleen
Left Upper quadrant
Thalassemia
Clinical Findings
Splenomegaly
Retarded growth and development
enlarged, distorted cheekbones, other bony prominences
Thalassemia
Clinical Findings
Anisocytosis, microcytosis target cells reticulocytosis higher presence of HbA2 to compensate Low MCV/MCH fragile RBC high uncongugated bilirubin and ferritin levels
Anisocytosis
RBCs of unequal size
Reticulocytosis
increase in reticulocytes
immature RBC
Hba
2 alpha + 2 beta
Hba2
2 alpha + 2 delta
Hbf
2 alpha + 2 gamma
gamma switches over to beta after birth
HbaS
sickle cell trait
HbSS
sickle cell disease
MCV
Mean corpuscular volume
average volume of RBC
MCH
Mean corpuscular hemoglobin
average mass of hemoglobin per RBC
What is the mode of inheritance in beta-thalassemia?
Autosomal recessive
What type of mutation occurs in Alpha-thalassemia?
Gene deletions
What type of mutation occurs in Beta-thalassemia?
Point Mutation
What type of mutation occurs in Fragile X syndrome?
Triplet repeat expansion
What type of mutation occurs in Huntington’s disease?
Triplet repeat expansion
What type of mutation occurs in SSA?
Point Mutation Glu>Val
***Leads to formation of abnormal globin chain
What type of mutation occurs in Myotonic Dystrophy?
Triplet repeat expansion
Q39X (HBB c. 118 C>T)
What kind of mutation is this?
Nonsence
X=Stop
What is linkage analysis?
indirect method for carrier detection using family studies
What does the use of polymorphic markers in linkage analysis allow us to do?
trace inheritance in a pedigree
What is the percent chance that recombination occurred between the a genetic marker and the trait it is following?
1%
It’s a 99% chance that the allele is still with the maker
What is the inheritance pattern for Huntington’s disease?
autosomal dominant
Characteristic of X-linked dominant inheritance
ALL daughters of affected males are affected
If the population frequency of a disease is 1/100. What is the chance that someone with no family history carries the allele?
square-root of 100.
(p-squared = 100).
Therefore, allele frequency (p) = 10
What is the inheritance pattern for cleft lip?
Multifactorial!
Who gets clubfoot?
Clubfoot occurs MORE in males than in females. Therefore, if a female has it in the family, then there is a greater risk that a male will be born with it.
What causes splenomegaly in SSA?
Increased clearance of abnormal RBCs
β+/β or βo/β
B-THAL MINOR
- One normal and one mutant β globin allele
- Lower than normal MCV
- Increased Hem.A2
- Decreased Hem.A
β+/β+ or βo/β+
B-THAL INT.
*May need occasional transfusions
βo/βo
B-THAL MAJOR
- BOTH mutant β globin alleles
- Increased Hem.F
- splenomegaly, & death before 20
- Transfusions cause iron overload
Compare genetic causes:
a-thal, b-tha & SCA
a-thal: gene deletion
b-thal & SSA: point mutation
What is a nonsense mutation?
POINT Mutation resulting in early stop
Highly Elevated Hbf
Decreased Hba
Elevated Hba2
suggests …
B-Thal Major
Decreased Hba
Elevated Hba2
suggests …
B-Thal Minor
In a-thal, what gene is missing?
Alpha-thalassemia is caused by deletion of the alpha-globin gene cluster
In beta-thalassemia major there is:
inadequate production of normal beta chains
