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Why is Snake Venom Composition So Variable
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WHY IS SNAKE VENOM COMPOSITION SO VARIABLE?
Wolfgang WüsterBangor University, School of Biological Sciences, Bangor LL57 2UW, UK
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What is snake venom?
Complex cocktails of numerous bioactive proteins
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Variation in venom composition Occurs at all
taxonomic levels Within individual in
time Between individuals
within populations Between populations Between species &
above Can result in
profound clinical differences and treatment difficulties
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Symptoms after Asiatic cobra bites
% with neurotoxicity
% with necrosis
Ratio neurotoxicity
: necrosis Luzon (Naja philippinensis)
97 %
7 %
14:1
NW Malaysia – (Naja kaouthia)
12 %
44 %
1:4
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What causes variation in venom composition?
Long-standing controversy
Function of venom: overpowering and killing prey, ?defence, ?digestion
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What causes variation in venom composition?
Long-standing controversy
Function of venom: overpowering and killing prey, ?defence, ?digestion
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What causes variation in venom composition?
Long-standing controversy
Function of venom: overpowering and killing prey
Potential causes Selection for different prey
Evolutionary history
, ?defence, ?digestion
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Electrophoretic profiles of individual Calloselasma rhodostoma
Daltry, Wüster & Thorpe, 1996
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Association between venom composition and causal hypotheses in Calloselasma rhodostoma
Geographic distance (gene
flow)
Phylogeny Diet
Generalised composition No No YES
Daltry, Wüster & Thorpe, 1996
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Variability of venom composition: Selection pressure or “Overkill”?
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Variability of venom composition: Selection pressure or “Overkill”?
“Overkill-Hypothesis”: Snakes have far more venom than
required for killing their prey Hence no selective pressure for greater
lethality BUT: Lethality only known in white
mice!!! Some prey known to be resistant against
snake venoms
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Crotalus oreganus - Pacific rattlesnakeSpermophilus beecheyi – California ground squirrel
Resistance against venom
Example: Pacific rattlesnake (Crotalus oreganus ) and ground squirrel (Spermophilus beecheyi)
Squirrels from rattlesnake areas display increased resistance to venom
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Example: Crotalus oreganus – Pacific Rattlesnake
Venom quantity: ~ 90 mg dry venom LD50 in mice: 2.84 mg/kg Median lethal potential: 31.7 kg of mice• LD50 in ground squirrels: ~ 40 mg/kg =>
2.25 kg• => per 250g ground squirrel: ~ 10 mg
=> 9 ground squirrels
BUT:• Venom needs to be lethal in minutes, not
24 hrs• Reserves?
Overkill in snakes?
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Sea kraitLaticauda
Moray eelGymonothorax sp.
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Sensitivity of prey and non-prey moray eels to Laticauda sea snake venoms
SympatricGymnothorax
AllopatricGymnothorax
survived 45-75mg/kg
died after 0.1mg/kg
Heatwole & Poran, 1995
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Evidence of the energetic cost of venom:
Increased metabolic rate of snakes after venom extraction
O2 consumption increased by ~ 11% after venom
extraction in 3 pitviper species (McCue, 2006)
Venom metering in snakes
Loss of venomous function in snakes feeding on undefended prey
Why fine-tune venom?
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0
2
4
6
8
10
12
14
16
18
20
Medium Snakes Large Snakes
Small prey
Large prey
mg venom injected
Hayes et al., 1995
Venom metering in Crotalus oreganus
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E.g., Aipysurus eydouxii Feeds exclusively on fish
eggs Venom of very low
toxicity Toxins non-functional Venom delivery
apparatus atrophied
Venom loss in snakes feeding on undefended prey
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Saw-scaled Vipers (Echis) as a model system for studying snake venom variation
One of the main causes of snakebite mortality worldwide
Documented variability in venom composition, incompatible antivenoms
% fatality rates after Echis ocellatus bites
0
510
1520
25
E.ocellatusantivenom
E. carinatusantivenom
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? ?? ?
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Echis pyramidum
Echis coloratus
Echis carinatus
Echis ocellatus
Pook et al. 2009
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Diet and venom activity in saw-scaled vipers (Echis)
T. Mazuch
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Do saw-scaled viper venoms show evidence of adaptive evolution?
T. Mazuch Diet recorded from museum specimens
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Diet of the four Echis species groups
E. coloratus
E. carinatus E. ocellatus
E. pyramidum
Arthropods
Vertebrates
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Diet recorded from museum specimens
LD50 of 4 representative venoms estimated for Scorpio maurus
Functional significance: time to incapacitation and death after realistic venom dose
Do saw-scaled viper venoms show evidence of adaptive evolution?
T. Mazuch Diet recorded from museum specimens
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LD50 of 4 Echis venoms on Scorpio maurus
µg
ve
no
m /
g s
corp
ion
n/s P < 0.001 P < 0.001 P < 0.05
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Arthropod Scorpion feeding lethality
– –
++ ++
+ +
++ ++
– –
Origin ofarthropoddiet + arthropod-lethalvenom
Loss of arthropod diet + arthropod-lethal venom
Echis carinatus
Echis pyramidum
Bitis arietans
Echis coloratus
Echis ocellatus
0.92
1.00
1.00
Repeated co-evolution of diet and specific venom lethality => evidence of selection
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Functional significance of specific venom lethality
More rapid prey death? Reduction of metabolic cost of venom?
Test: Injection of biologically realistic amounts of venom
(3 mg/g = 25-575 x LD50)
Record time to loss of coordination and death
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E. p. leakeyi E. c. sochureki E. ocellatus E. coloratus B. arietans
Tim
e (
min
ute
s)
0
20
40
60
80
Tim
e (
min
ute
s)
Death
Loss of coordination
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Staged encounters
Are these experiments biologically realistic?
Vipers and scorpions placed together Video recording Time 1st bite – beginning of feeding
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Staged encounters
Results:
3 successful trials with E. c. sochureki
In all cases 1-2 further bites
Time bite - feeding: 40-48 Min.
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Functional significance of venom variation in Echis
Greater lethality ≠ more rapid prey death!
Functional significance: Venom economy => reduced metabolic
expense? Facilitation of scorpion feeding for
juveniles?
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How do they do it? The genetics of venom adaptation
Venoms consist of several multigene toxin families
How does gene diversity correlate with diet?
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PIII/PIV SVMP
sub-classes
Serine proteases
Casewell et al., in prep.
Induce haemorrhage, inhibit platelet aggregation
Procoagulant, fibrinolytic, inhibit platelet aggregation
=> Link between diet, toxin gene diversity and toxin function
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Conclusions: why is venom so variable?
Evidence of natural selection on venom composition – specific lethality to prey
Resistance in some prey => predator-prey arms races
Looking beyond lethality: economics of venom
Genetic mechanism in saw-scaled vipers: Importance of diversification of toxin
families
=> Extreme variation in venom composition at all levels
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Cheers!
Thank you for your attention !