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Evolutionary Biology > evolutionary pressure of malaria on human genes > Flashcards

evolutionary pressure of malaria on human genes Flashcards

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1
Q

malaria distribution

A
  • 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
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2
Q

P. falciparum and children

A
  • greatest impact in children
  • 20-fold higher fatality compared to adults
  • kills before reproductive age
    • strong selection pressure on emerging polymorphisms
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3
Q

genetic disorders and malaria

A
  • 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
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4
Q

changes in RBCs that affect plasmodium invasion

A
  • surface proteins
  • nutrient availability
    • altered protein content
  • reduced RBC lifespan
    • insufficient itme for parasite replication
  • metabolic conditions
    • redox potential → toxic effect on parasite
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5
Q

RBC specialisation

A
  • 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
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6
Q

RBC shape maintenance

A
  • complex structure under surface membrane
  • spectrin meshwork
  • anchored by ankyrin to membrane
    • via integral membrane protein band 3
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7
Q

haemoglobin affinity

A
  • low affinity at low oxygen → release
  • high affinity at high oxygen → uptake
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8
Q

RBC lifespan

A
  • ~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
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9
Q

RBC lifespan and elimination

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

haemoglobin structure

A
  • tetrameric
    • 4 polypeptide chains
    • alpha 2 beta 2
  • each chain assoicated with heme group
  • heme chelates Fe2+ for oxygen transport
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11
Q

haemoglobin and myoglobin

A
  • 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
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12
Q

conformational changes in haemoglobin

A
  • 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
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13
Q

fractional saturation

A
  • Y
  • proportion of binding sites occupied by oxygen
  • ΔY between tissues and lungs determines functional capability of oxygen transport
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14
Q

genetic structure of haemoglobin

A
  • complex
  • alpha chain - chromosome 16
  • beta chain - chromsome 11
  • different during different developmental stages
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15
Q

foetal haemoglobin

A
  • 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
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16
Q

adult haemoglobin

A
  • 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
17
Q

variation in haemoglobin disorders

A
  • 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
18
Q

thalassemia

A
  • 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
19
Q

emergence of haemoglobin mutations

A
  • several have arisen independently in different places aorund the world
  • HbC - thought to be recent
    • stronger immune response to parasite
    • unknown mechanism
20
Q

haemoglobin abnormalities

A
  • = haemoglobinopathies
    • thalassemia syndromes (4)
    • variant haemoglobins
      • HbS
      • HbE
      • Hb constant spring
      • others infrequent
21
Q

HbS

A
  • 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
22
Q

sickle cell anaemia RBCs

A
  • 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
23
Q

plasmodium in sickle cell RBCs

A
  • difficult to replicate
    • Hb proteins polymerised → not readily available
    • altered conformation
    • quick removal from circulation
24
Q

sickle cell T state

A
  • polymerised in long filaments
  • tradeoff between oxygen carrying and parasite resistance
  • advantageous in heterozygotes only
25
Q

heterozygous vs homozygous sickle cell anaemia

A
  • 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
26
Q

cost of carrying a sickle cell mutation

A
  • blood vessel occlusions
  • prolonged low oxygen tension
  • decreased pH
  • inflammation
  • low blood flow
27
Q

benefits of carying sickle cell mutation

A
  • uptake by macrophages
  • parasite maturation decreased from polymerisation
  • reduced adhesion to endothelium from altered conformation
  • outweighs cost of mutation
28
Q

RBC surface proteins

A
  • 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
29
Q

Duffy antigens

A
  • 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
30
Q

Duffy locus alleles

A
  • Fya, 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
31
Q

silent Fy allele

A
  • 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
32
Q

GATA transcription factor

A
  • 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

Evolutionary Biology (3 decks)

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