Midterm 1 - Notes 4 (Part 4) Flashcards
Where does O2 bind in Hb?
To the heme on the Hb chain
- associated with iron
What are Hb chains like in invertebrates and primitive fish? (2)
- Single chains of globin
2. Has one binding site for O2 and one binding site for iron
What events lead to a more complex vertebrate Hb?
Mutations
What are Hb chains like in complex vertebrate Hb?
Tetramere of globins
What makes up an adult Hb?
2 alpha subunits and 2 beta subunits
How many O2 can bind in an adult Hb?
4
What makes up fetal Hb?
a alpha subunits and 2 gamma subunits
What does HbF have a higher affinity for compared to adults?
O2
Why does HbF have a higher affinity for O2?
Because it allows higher levels of O2 from the mother to be transported to high levels of O2 in the fetus
What are the 4 subsequent gene duplications and mutations?
- Epsilon
- Gamma
- Beta
- Delta
What makes up early HbF development?
2 alpha and 2 epsilon
What makes up late HbF development?
2 alpha and 2 gamma
What makes up main adult Hb form?
2 alpha and 2 beta
What makes up minor adult form of Hb only in primates?
2 alpha and 2 delta
What % of HbF is in adults?
< 0.6%
When does HbF decrease?
Relatively fast after birth
People with HbF higher than 0.8% are considered what?
HPFH
HPFH
High Percentage Fetal Hemoglobin
What could happen if you could control/regulate HbF?
You might be able to help patients that are unable to produce adult Hb
What is beta-thalassemia?
It is an autosomal recessive blood disease
- reduced beta, but excessive alpha
Anemia
Reduced hemoglobin and number of RBC
What can happen to people who lack adult Hb?
They may have less symptoms if they express high levels of HbF
What are 3 types of beta-hemoglobin that are caused by mutations?
- Beta-thalassemia minor
- Beta-thalassemia intermedia
- Beta-thalassemia major
What kind of mutation is beta-thalassemia minor?
Heterozygous for HBB mutation
HBB
Beta-hemoglobin
What kinda of mutation is beta-thalassemia intermedia?
Homozygous for HBB mutation
What kinda of mutation is beta-thalassemia major?
Homozygous for HBB mutation
Beta-thalassemia minor (3)
- Has one normal copy and one mutated copy
- Mild anemia (if at all)
- Can still produce beta-globin
Beta-thalassemia intermedia (2)
- Both have a mutated version
2. Cant make any beta-globin
Beta-thalassemia major (4)
- Both have a mutated version
- Lack of being able to produce adult Hb causes this phenotype
- Severe anemia and multiple other problems
- need regular blood transfusions - Cant produce beta-globin
What varies greatly with beta-thalassemia?
Severity of its symptoms
- many factors
- -> eg) environment
Beta-thalassemia patients feel better when expressing what?
HbF
What did they figure out in the Hb study?
How to turn on HbF
How did being able to turn on HbF help patients?
Developed help for patients lacking HBB expression
Why do you need 7,000 samples?
To be able to detect genetic linkages
Why is Sardinia a good place for the study? (5)
- The disease is common in the Mediterranean
- high incidence rate - Isolated population
- Historically little migration
- Typically founder population
- Higher degree of relatedness
- High frequency of beta-thalassemia
- 5%, > 10% carrier - High variation of HbF
- 0-23.6%
Whats considered HPFH?
> 0.8%
Why was it good to used grandparents from Sardinians? (2)
- You increase you chances because back then there was little immigration
- Had at least one fist degree relative in the study group
What type of microarray did they use in the Hb study?
Affymetrix
What did they do in the Hb study to minor alleles with frequency > 5%?
They kicked them out because if you are looking at association then you are running a big risk of having a high mutated phenotype that is not a genetic component
