design principles in biology :
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Design Principles in Biology :. a consequence of evolution and natural selection Rui Alves University of Lleida [email protected]. Climbing down mount improbable . Overtime , edged stones would accumulate on the slope . Smooth , round, stones accumulate at the bottom . - PowerPoint PPT PresentationTRANSCRIPT
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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(a) (b)
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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
essio
n of
im
port
ant g
enes
time
Grow
th ra
te
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