Design
Principles
in
Biology
:
a
consequence
of
evolution
and natural
selection
Rui
Alves
University
of Lleida
ralves@cmb.udl.es
Climbing
down
mount
improbable
•
Overtime
,
edged
stones
would
accumulate
on
the
slope
.
•
Smooth
, round,
stones
accumulate
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
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
Sensor
Sensor
Efector
Efector
Deactivator
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
Expression
of
important
genes
time
Growth
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
assumption
PNAS 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
Savageau
Albert
Sorribas
Armindo
Salvador
Oleg
Igoshin
Programa
Ramon y
Cajal
MCyT
MCyT
FCT
NIH
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