evolutionary pressure of malaria on human genes

Question 1

malaria distribution

Answer 1

• has changed over time
• never used to be in south america
• used to be prevalent in europe
• changes in distribution has a genetic impact on populations

Question 2

P. falciparum and children

Answer 2

• greatest impact in children
• 20-fold higher fatality compared to adults
• kills before reproductive age
  
  • strong selection pressure on emerging polymorphisms

Question 3

genetic disorders and malaria

Answer 3

• clear overlap of presence of genetic haemoglobin disorders and malarial infection
• host mutations inhibiting merozoite entry/multiplication in RBCs after release from liver is favourable
  
  • increased chance of survival

Question 4

changes in RBCs that affect plasmodium invasion

Answer 4

• surface proteins
• nutrient availability
  
  • altered protein content
• reduced RBC lifespan
  
  • insufficient itme for parasite replication
• metabolic conditions
  
  • redox potential → toxic effect on parasite

Question 5

RBC specialisation

Answer 5

• biconcave discs - 8 micron diameter
• no nucleus, organelles, ATP formation, cell division
  
  • no repair, limited lifespan
• maximal SA:V for gas exchange
• flexible
  
  • passage through narrow vessels

Question 6

RBC shape maintenance

Answer 6

• complex structure under surface membrane
• spectrin meshwork
• anchored by ankyrin to membrane
  
  • via integral membrane protein band 3

Question 7

haemoglobin affinity

Answer 7

• low affinity at low oxygen → release
• high affinity at high oxygen → uptake

Question 8

RBC lifespan

Answer 8

• ~120 days
• 1% of total pool lost each day (billions)
• recognised as modified self
  
  • altered flexibility and elasticity
• removal by phagocytes in spleen and liver
  
  • components recycled

Question 9

RBC lifespan and elimination

Answer 9

• parasite takes 2 days to multiply
• normal RBC
  
  • chance of elimination before multiplication = 1/60
• RBC with decreased lifespan of 10 days
  
  • 1/5

Question 10

haemoglobin structure

Answer 10

• tetrameric
  
  • 4 polypeptide chains
  • alpha 2 beta 2
• each chain assoicated with heme group
• heme chelates Fe2+ for oxygen transport

Question 11

haemoglobin and myoglobin

Answer 11

• 20% sequence identity
• oxygen exchanged from haemoglobin to myoglobin in tissues
  
  • myoglobin high affinity at low oxygen
  • steals from haemoglobin
  • oxygen never free
• myoglobin transfers oxygen to cytochromes

Question 12

conformational changes in haemoglobin

Answer 12

• low oxygen → T state
  
  • low affinity and release of oxygen
• high oxygen → R state
  
  • high affinity
  • shift in equilibrium towards R
• almost all shifted to R close to saturation

Question 13

fractional saturation

Answer 13

• Y
• proportion of binding sites occupied by oxygen
• ΔY between tissues and lungs determines functional capability of oxygen transport

Question 14

genetic structure of haemoglobin

Answer 14

• complex
• alpha chain - chromosome 16
• beta chain - chromsome 11
• different during different developmental stages

Question 15

foetal haemoglobin

Answer 15

• forms 85% of haemoglobin after 8 weeks of devleopment
  
  • HbF
  • alpha 2 gamma 2
• no T or R state
• higher affinity than mother’s haemoglobin in low oxygen environment
  
  • steal oxygen from her blood

Question 16

adult haemoglobin

Answer 16

• HbA - 97%
  
  • alpha 2 beta 2
• HbA2 - 2-3%
  
  • alpha 2 delta 2
• each individual has 2 copies of each gene (from mother and father)
  
  • beta expressed from 1 gene → 2 copies
  • alpha expressed from 2 genes → 4 copies
• minimal expression of HbF in adults (<0.5%)
• all adult forms require alpha

Question 17

variation in haemoglobin disorders

Answer 17

• not all disorders are the same with the same mutations
• malaria’s evolutionary pressure exerted in different places at different times
• not just clonal expansion of one individual

Question 18

thalassemia

Answer 18

• mainly in mediterranean
• lack of a haemoglobin gene
  
  • 1-3 alpha genes or 1 beta gene
• imbalance in chain production
  
  • not all chains assembled correctly
  • alters RBC shape
  • increased removal by macrophages in circulation
  • half life ~20 days when 2 alpha genes present
• alos anaemia from low blood cell count
  
  • increased rate of destruction above production

Question 19

emergence of haemoglobin mutations

Answer 19

• several have arisen independently in different places aorund the world
• HbC - thought to be recent
  
  • stronger immune response to parasite
  • unknown mechanism

Question 20

haemoglobin abnormalities

Answer 20

• = haemoglobinopathies
  
  • thalassemia syndromes (4)
  • variant haemoglobins
    
    • HbS
    • HbE
    • Hb constant spring
    • others infrequent

Question 21

HbS

Answer 21

• sickle cell anaemia
• beta chain abnormality expressed in normal amounts
  
  • glutamic acid → valine
  • negative → uncharged
  • HbA → HbS
• single point mutation
• when deoxygenated, HbS has entirely different structure
• mutant allele frequency of up to 14% in some african populations

Question 22

sickle cell anaemia RBCs

Answer 22

• prolonged exposure to low oxygen
  
  • aggregation
  • Hb polymerisation into long chains of rod-like fibres
  • crescent/sickle shaped RBC
• hard, rod-like → stuck in narrow places
• lifespan ~20 days

Question 23

plasmodium in sickle cell RBCs

Answer 23

• difficult to replicate
  
  • Hb proteins polymerised → not readily available
  • altered conformation
  • quick removal from circulation

Question 24

sickle cell T state

Answer 24

• polymerised in long filaments
• tradeoff between oxygen carrying and parasite resistance
• advantageous in heterozygotes only

Question 25

heterozygous vs homozygous sickle cell anaemia

Answer 25

• homozygous → can’t carry enough oxygen
  
  • don’t reach adulthood
  • infection, infarction, gross bone anomalies (filled with macrophages eliminating RBCs)
• heterozygous
  
  • mixture of HbA and HbS → oxygen carrying
  • parasite development decreases pH of RBC → decreased oxygen → T state and sickle form
  • parasitised cells sickle more → eliminated

Question 26

cost of carrying a sickle cell mutation

Answer 26

• blood vessel occlusions
• prolonged low oxygen tension
• decreased pH
• inflammation
• low blood flow

Question 27

benefits of carying sickle cell mutation

Answer 27

• uptake by macrophages
• parasite maturation decreased from polymerisation
• reduced adhesion to endothelium from altered conformation
• outweighs cost of mutation

Question 28

RBC surface proteins

Answer 28

• marked by genetically determined glycoproteins and glycolipids
  
  • agglutinogens or isoantigens
  • distinguished at least 24 different blood groups
  • defined by different systemd
    
    • ABO, Duffy
• blood groups distinguished by phenotype (surface expression) not genotype

Question 29

Duffy antigens

Answer 29

• chemokine receptor on RBC surface (and immune response cells)
• hijacked by P. vivax to enter RBCs
• homozygous recessive → no antigen expression
  
  • complete immunity to vivax
  • nearly all indigenous people of west/central africa

Question 30

Duffy locus alleles

Answer 30

• Fy^{a, b, x, 3, 4} (all normal antigens)
• Fy = silent allele
  
  • responsible for unusual inheritance patterns
  • can’t distinguish between Fy carriers and those with 2 copies of normal antigens
  • presence of Fy can’t be identified by antibody testing

Question 31

silent Fy allele

Answer 31

• Duffy antigens can be present and non-silent in other tissues
  
  • gene is not disrupted
  • differences in the promoter isntead
• GATA TF binding responsible
• some west african populatons all Fy homozygous
  
  • immunity to vivax

Question 32

GATA transcription factor

Answer 32

• defective binding in Fy silent allele
• single base pair mutation
• should destroy binding ability and prevent transcription
• different TF network in other tissues
  
  • don’t rely on GATA to bind Fy promoter
  • no effect
  • only RBCs that have no antigen