Design Principles in Biology: a consequence of evolution and natural selection Rui Alves University...
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Transcript of Design Principles in Biology: a consequence of evolution and natural selection Rui Alves University...
Design Principles in Biology:
a consequence of evolution and natural selection
Rui AlvesUniversity of [email protected]
Climbing down mount improbable
• Overtime, edged stones would accumulate on the slope.
• Smooth, round, stonesaccumulate at the bottom.
Design Principles:- Smooth, roundish rocks roll down the mountain.- Edged, flat, rocks don’t.
Design principles in molecular biology
• Similarly, if a topology or set of parameters can be shown to create a molecular network that functionally outperforms all other possible alternatives in a given set of conditions, one can talk about a design principle for the system under those conditions.
[sensu engineering]
Index of talk
• How to identify design principles in molecular networks
• Design principles in:– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
First step, define the alternatives
Gene
Regulator
+Gene
Regulator
_
X0 X1 X2 X3
X0 X1 X2 X3
First step, define the alternatives
X0 X1 X2 X3
X3
t
How strong should the feedback be?
Then, create models for each alternative
Gene
Regulator
+Gene
Regulator
_
Then, create models for each alternative
X0 X1 X2 X3
X0 X1 X2 X3
Characterization of network behavior
Biological functional effectiveness criteria for the network.
Alternative designs
X1 … Xj …
X1 … Xj …
…
Mathematical models
Enforce mathematical controls before analyzing model behavior
Comparison of behavior between networks
Index of talk
• How to identify design principles in molecular networks
• Design principles in:– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
The demand theory for gene expression
• Are there situations where positive regulation of gene expression outperforms negative regulation of gene expression and vice versa?
Gene
Regulator
+Gene
Regulator
_
Regulating gene expression has principles
• Positive regulator:– More effective when gene product in demand for large
fraction of life cycle.– Less noise sensitive if signal is low.
• Negative regulator:– More effective when gene product in demand for small
fraction of life cycle.– Less noise sensitive if signal is high.
Gene
Regulator
+Gene
Regulator
_
Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590
Glycogen Trehalose
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20HXT
GLK
PFK
TDHPYK
TPS
G6PDH
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GLK
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G6PDH
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GLK
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G6PDH
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20HXT
GLK
PFK
TDHPYK
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G6PDH
(a) (b)
(c) (d)
Regulating gene expression has principles
Design principles in development
Design principles in development
Index of talk
• How to identify design principles• Design principles in:
– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
Negative overall feedback is a design principle in metabolic biosynthesis
X0 X1 X2 X3
• Negative overall feedback:– More effective in coupling production to demand.– More robust to fluctuations.
Bioinformatics 16:786; Biophysical J. 79:2290
Index of talk
• How to identify design principles• Design principles in:
– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
Bifunctional sensors can be a design principle in signal transduction
• Bifunctional sensor:– Performs best against cross talk
• Independent deactivator:– Better integrator of signals
Mol. Microbiol. 48:25; Mol. Microbiol. 68: 1196
Signal
SensorSensor
EfectorEfectorDeactivator
Effect
Index of talk
• How to identify design principles• Design principles in:
– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
Gene
Regulator
_
Design principles in development
Gene
Regulator
+
High demand, low signal
Signal
+
High demand, high signal
Low demand, high signal
Low demand, low signal
Signal _
Genetics 149:1665; PNAS 103:3999; PNAS 104:7151;Nature 405: 590
Index of talk
• How to identify design principles• Design principles in:
– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
Biological design principles are good to understand why biology works as it does
• Biological design principles may connect molecular determinants to functional effectiveness.
Heat shock
Expr
essi
on o
f im
port
ant g
enes
time
Gro
wth
rate
time
BMC Bioinformatics 7:184
Underlying assumption
• Evolution of molecular networks can be treated as modules.
• Work in the group of Uri Alon suggests that– networks evolving to meet simultaneous goals
evolve in a modular fashion– Networks evolving to meet a single goal evolve
globally• Modularity seems like a reasonable first
assumptionPNAS 102:13773; PLOS Comp Biol 4:e1000206;BMC Evol biol 7: 169
The good news about function
• Sometimes, you get stuff for free!!!
• For example:– networks that are responsive to signals, just because
they are responsive may have inbuilt buffering of noise.– Functions that are associated with marginally stable
proteins are favored because due to the large dimensions of sequence space most randomly selected sequences have a structure that is marginally stable.
PNAS 100:14463; PNAS 103:6435; Proteins 46:105
How can biological design principles be applied?
• Design of molecular circuits with specific behaviors!!
Stable Systems
Unstable systems
Oscilations
Bistable systems
Cell 113: 597; PLoS Comput Biol. 5:e1000319; PNAS 106: 6435
Index of talk
• How to identify design principles• Design principles in:
– Gene expression– Metabolic networks– Signal transduction– Development
• Design principles, what are they good for?• Summary
Summary
• Design principles can be found in molecular networks.
• Such principles can sometimes be connected to selection for function effectiveness.
• Even in the absence of such a connection, if they are valid they can be used to build biological circuits with specific behaviors.
Acknowledgments
Mike SavageauAlbert SorribasArmindo SalvadorOleg Igoshin
Programa Ramon y Cajal MCyT
MCyTFCTNIH