The Creation and Reuse of Information

in Gene Regulatory Networks

Brett Calcott*y

Recent work on the evolution of signaling systems provides a novel way of thinking about
genetic information, where information is passed between genes in a regulatory network. I
use examples from evolutionary developmental biology to show how information can be
created in these networks and how it can be reused to produce rapid phenotypic change.

1. Introduction

Today, the notion of genes sending signals to other genes isas central
asthenotion of a genetic code was forty years ago. (Maynard-Smith
2000, 187–88)
When evolution (or learning) leads to a signaling system, infor-
mation is created. (Skyrms 2010, 40)

Most attempts to vindicate the idea of “genetic information” have focused on

the coding of proteins (Godfrey-Smith 2000; Maynard-Smith 2000; Griffiths
2001; Godfrey-Smith and Sterelny 2012) or, more recently, on how infor-
mation is passed between generations (Shea 2007; Bergstrom and Rosvall
2011). In this paper I show how information is passed between genes and
how evolution can both create and reuse this information.1

*To contact the author, please write to: Center for Advanced Modeling, Emergency Medicine
Department, Johns Hopkins University, Baltimore, MD 21209; e-mail: brett.calcott@gmail.com.
yThanks to others in the PSA Symposium: Rosa Chau, Peter Godfrey-Smith, Nicholas Shea,
and Rory Smead, and especially to Peter for organizing it all. Thanks to Emily Parke for her many
useful comments and to Lindley Darden for fixing my biology (any remaining errors are my
own). This work was supported by an Australian Research Council Postdoctoral Fellowship.
1. While this paper was under review, Ron Planer published an excellent paper that ex-
plores related issues, using the signaling framework to underwrite a new way of thinking
about the “genetic program” (Planer 2014).
Philosophy of Science, 81 (December 2014) pp. 879–890. 0031-8248/2014/8105-0014$10.00
Copyright 2014 by the Philosophy of Science Association. All rights reserved.

879

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 880 BRETT CALCOTT

I draw on recent work by Brian Skyrms, who argues that information is

created when signaling systems evolve (Skyrms 1996, 2010). I apply Skyrms’s
framework to gene regulatory networks, showing how the players in a sig-
naling game can be mapped to the components of a gene regulatory network
and how changes in player strategies can be mapped to mutations in the logic
controlling gene regulation.
I then use this mapping to vindicate the idea of positional information in
developmental biology (Wolpert 1969, 1994). To do this, I combine the infor-
mation processing capacities of gene regulatory networks with the basic sig-
naling framework. The combination provides a more complex example of sig-
nal evolution, where evolution creates computed information about states of
the world.
I then argue that once evolution has created signals carrying such com-
puted information, this information can be reused in novel tasks. This con-
nects the signaling framework to ideas about evolvability and the evolution
of novelties and suggests a straightforward way to think of evolution both creat-
ing and reusing information.
Finally, I discuss why this way of thinking of genetic information may be
useful, and I suggest that reuse within signaling systems may have a broader
application than just gene regulation.

2. Internal Signaling and Information. Before looking at gene regulatory

networks, I want to outline a simple version of internal signaling. This will
provide a useful guide when looking at more complex signaling in gene reg-
ulatory networks.
Here is a game I call “crosstown traffic.” 2 The goal of the game is to ma-
neuver a car from one side of town to the other without crashing. A car con-
tains a driver and a passenger. The driver operates the car normally in most
respects but ignores the color of traffic lights. Instead, when the driver comes
to a traffic light, he pays attention to the passenger, who has his hand on the
driver’s knee. Upon seeing a red or green traffic light, the passenger either
squeezes or relaxes his hand. The driver responds to this signal by either
accelerating or braking (see fig. 1, top row).3
The game has all the basic components of a Lewis/Skyrms signaling game
(Lewis 1969; Skyrms 2010). There are two states of the world (red/green), two
signals (squeeze/relax), and two actions (accelerate/break). There is a signal
sender (the passenger) and a signal receiver (the driver) who share in the suc-
cess or failure of their interaction.
2. Also a great song by Jimi Hendrix.
3. To keep things simple, we assume that only one car is playing the signaling game. If
every car in the city was playing the same game, we would have two simultaneous games:
between cars, where a convention could evolve for responding to lights, and within cars,
where we have our signaling game.

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 INFORMATION IN GENE REGULATORY NETWORKS 881

Figure 1. Two types of internal signaling. Top: Signaling in the game “crosstown
traffic.” Bottom: Signaling between genes.

To do well in the game, a driver-passenger team needs to map the states

of the world to the right actions: accelerate on green, and brake on red. Two
things mediate the mapping between states and actions: how the passenger
maps a state to a signal, and how the driver maps a signal to an action. If both
driver and passenger always follow the same rules for how they do this map-
ping, then the best teams will follow one of these two rule sets:

• Rule set 1: The passenger squeezes on red and relaxes on green; the
driver brakes on squeeze and accelerates on relax.
• Rule set 2: The passenger relaxes on red and squeezes on green; the
driver accelerates on squeeze and brakes on relax.

Now imagine a fanciful scenario where selection plays a role in crosstown

traffic. Cars with teams begin driving across town, and initially both driver
and passenger follow a random rule set. Cars that crash are selected against.
Cars making it to the other side of town inspire new teams to copy their rule
set, making the occasional copying errors. The new teams then drive back
across town, and the cycle repeats. Given enough teams and enough time,
either rule set 1 or rule set 2 would predominate, as teams following any other
rule set would have a far higher chance of crashing.
In this selective scenario, the car is an individual, reacting to the local state
by modifying its behavior. The driver and passenger are internal parts pro-
ducing the behavior and sharing the same evolutionary fate—crashing or sur-
viving together. Selection acts on the behavior of the system as a whole (the

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 882 BRETT CALCOTT

car) and in doing so produces an internal signaling system between individual

parts (the driver and passenger). This is why it is called internal signaling.
Information is created in the signals during this game. When a successful
signaling system (rule set 1 or 2) is established between the internal parts, the
signal (squeeze/relax) carries information, in the following way. Imagine be-
ing a second passenger sitting in the back seat of a car, whose driver and
passenger play using one of the successful rule sets, and suppose you know
the exact rule set they are using. Seeing a signal, such as the passenger squeez-
ing the driver’s knee, provides information about two things. First, the signal
tells you something about the state of the world (is the light green or red?).
Second, the signal tells you something about what the driver will do next
(will they accelerate or break?). An evolved signal inside the car thus carries
information about both states of the world and about the actions of the driver,
and hence about the actions of the car as a whole. Skyrms shows how infor-
mation theory can be used to measure the amount of information in these
signals (see Skyrms 2010, chap. 3).

3. Gene Regulation. I show below that all the components of an internal

signaling game are present in gene regulatory networks (see fig. 1, bottom
row). First, I provide a brief overview of gene regulation.
Genes are transcribed into RNA by a molecule called RNA polymerase,
which walks along the bases of a strand of DNA and produces a correspond-
ing strand of RNA. This RNA is then used to produce a protein (I am ignor-
ing a lot of complexity here; for more detail see Griffiths and Stotz 2013). To
begin transcription, the RNA polymerase must first bind to a region called
a promoter. The polymerase must stick to the promoter long enough to kick-
start transcription, and this crucial moment can be either encouraged or pre-
vented by a protein called a transcription factor.
Transcription factors bind to a short portion of the DNA strand called a
cis regulatory element, or cis-element. They bind to cis-elements because
the shape of the protein fits the shape of the short sequence of bases on the
DNA, so specific transcription factors bind only to specific cis-elements.
Many transcription factors exist in two different stable shapes, and the pres-
ence of a small molecule, such as a hormone, can switch them to their ac-
tive shape, which is only then capable of binding to the cis-element. So the
transcription of a gene can be sensitive to the local conditions in the cellular
environment.
Once these transcription factors bind to the cis-elements, they do one of
two things: they prevent the RNA polymerase from getting to the promoter
and thus repress transcription, or they stick to the RNA polymerase and help
stabilize it long enough to activate transcription (Ptashne and Gann 2002).
Several cis-elements may exist for a single gene, and they can act in concert,
binding multiple transcription factors to repress or activate a gene. One tran-

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 INFORMATION IN GENE REGULATORY NETWORKS 883

scription factor might activate a gene, while another represses activation. The
transcription of a gene can thus be a function of the presence of several tran-
scription factors.
We have part of the picture now. We have a gene, a promoter, and some
cis-elements. Together, I refer to these as a genetic switch. A genetic switch
can act by transcribing a protein that has some effect on fitness in the current
environment—producing hemoglobin or muscle fiber, for example. A genetic
switch can respond to some external state, as many transcription factors bind
to DNA only in the presence of certain molecules from the environment. In
addition, our switch can even do some basic information processing, re-
sponding to the combined presence and absence of transcription factors. What
we do not have, yet, are signals.

4. Gene Regulation as Signaling. The genes that produce proteins like

hemoglobin or muscle fiber play a direct role in the fitness of the individual.
Genes like this are called structural genes. They contrast with regulatory
genes, which produce the transcription factors that activate or repress the
transcription of further genes. These are what Maynard-Smith had in mind
when he talked of genes sending signals to other genes.
Like crosstown traffic, the final mapping from state to action in a gene
regulatory network is determined by a series of intermediate mappings. Each
genetic switch maps incoming information from the environment—or from
the output of another genetic switch—by regulating the transcription of a pro-
tein. If the gene being transcribed is structural, the protein goes on to per-
form an action; a genetic switch like this is a receiver. If the genetic switch
transcribes a regulatory gene, then the protein can signal further downstream
genes; a genetic switch like this is a sender. Some genetic switches may act
as both sender and receiver, for gene regulation can consist of chains of gene
regulation, where genes regulate genes that regulate still more genes (see,
e.g., Madan Babu and Teichmann 2003). The complex regulatory connec-
tions between genetic switches form a gene regulatory network.
Each individual mapping at a genetic switch is—like crosstown traffic—
governed by a modifiable rule set. The rules are determined by the sequence
of DNA composing the cis-element of the genetic switch and the DNA that
is transcribed into a protein. These regions on the DNA, and hence the rule
sets, can be modified in various ways by mutations.
One kind of modification changes the function governing the switch.
Different proteins interact in different ways, so mutations affecting the re-
gion of DNA containing the cis-elements can affect the function controlling
whether a gene is turned on or not. Mutations can thus affect the localized
rules governing a single genetic switch.
Perhaps more importantly, mutations within the cis-element regions can
affect which upstream signals the genetic switch responds to, and mutations

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 884 BRETT CALCOTT

within the trancribed DNA can change the shape of transcription factor pro-
duced, thus changing the signal being sent (Hsia and McGinnis 2003; Lynch
and Wagner 2008; Wagner and Lynch 2008; Nowick and Stubbs 2010). Mu-
tations that change the signals sent from and received at each genetic switch
rewire the topology of the network, changing its global information process-
ing capacity.
A final similarity is worth pointing out. In a signaling game, such as
crosstown traffic, a number of different mappings can produce equivalent
results (recall that both rule set 1 and rule set 2 did an equivalent job). So the
particulars of an intermediary signal do not matter, as long as the state-action
mapping produces a successful behavior. The signals are conventions, as they
could have been otherwise. We see this conventional aspect in gene signal-
ing too, for it is possible for different transcription factors to fulfill the same
intermediary regulatory task in related species (see, e.g., Nowick and Stubbs
2010, 76).
Transcription factors are signals, and gene regulatory networks make up
complex signaling networks. They produce actions in response to local states
and use chains of intermediate signals to do so. Gene networks do not just
relay information, however; they also process information. We can incorpo-
rate this idea into the signaling framework too.

5. Information Processing and Signaling. A genetic network is consider-

ably more complex than a passenger-driver team, as many genetic switches
can be wired together. A single genetic switch can already do some minimal
processing, integrating information from several sources using a simple func-
tion. Wiring together several genetic switches makes a regulatory network ca-
pable of even more complex information processing.
Information processing in gene networks takes place at many levels. We
find recognizable network motifs—small ensembles of two, three, or four ge-
netic switches wired together—which can perform a recognizable logic func-
tion or signal processing of some kind (Alon 2007). More complex subnet-
works containing many genetic switches perform precise developmental
tasks, such as maintaining boundaries between differentiating cells (Davidson
2010). The ensemble of genetic switches in a gene regulatory network is
capable of using a broad range of complex inputs to control and organize
many possible actions, much like an ensemble of neurons in the brain does.4
We can incorporate information processing into the signaling framework
in the following way. A sender may need to process information because they
do not have the relevant state of world handed to them but must calculate it

4. Sansom (2011) explores the connection between gene networks and neural networks,
though not in a signaling framework.

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 INFORMATION IN GENE REGULATORY NETWORKS 885

from a variety of cues. A receiver may need to process information because

taking the appropriate action may depend on more than one signal.
My discussion of information processing here differs from what Skyrms
does in his book Signals. Skyrms is interested in whether we can “get some
logic out of information transfer in sender-receiver games” (2010, 136). Ge-
netic switches are already capable of approximating some simple logical op-
erations (Istrail and Davidson 2005). Here I focus on how genetic switches
acting together can integrate information to map world states to signals and
signals to actions.
A sender in a genetic network might be a gene or, if complex processing
is required, a network of genes. A network could integrate upstream infor-
mation from a series of cues to produce a single signal, or transcription fac-
tor. A receiver, equally, may be a gene or network of genes integrating signals
to produce some action. An example where signaling and information pro-
cessing are combined occurs in pattern formation of early multicellular de-
velopment.

6. Multicellular Development and Positional Information. A gene net-

work, like the car in crosstown traffic, is plastic: different environments pro-
duce a different response, and the response producing the most favorable
result for the organism in that environment will be more likely to be selected.
The plastic response of gene networks plays an essential role in the devel-
opment of multicellular creatures like us. For although each cell contains a
copy of the same genes, the cells in different parts of our bodies look and act
very differently. Selection can thus act to produce a genetic network capable
of a broad range of different actions, to produce a variety of cell types and
context-sensitive cellular behavior.
But how does each cell decide which particular action to take? During
development, this question is answered, at least in part, by looking to the spa-
tial expression patterns of different transcription factors. Localized regions
of cells switch on the same transcription factors, carving out a spatial land-
scape in a developing embryo that controls the behavior of cells in the re-
spective regions.
In the development of a fly, for example, the location of the limbs is spec-
ified by integrating three upstream transcription factors, each of which is
expressed at overlapping locations in the embryo (see fig. 2). One protein
is expressed in cells lying in a set of bands along the body axis (A), another
is expressed in cells in the ventral region (B), and another in the posterior (C).
These proteins bind to a further gene that integrates the expression of all three
with a Boolean function (A and not (B or C)), resulting in the expression of a
protein in a series of small regions along the body midline that initiates limb
development (Carroll 2006, 116).

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 886 BRETT CALCOTT

Figure 2. Positional information expressed by transcription factors in the fly embryo.

Three upstream genes produce signals that carry positional information computed from
a variety of inputs. These signals are integrated downstream to initiate an action: the pro-
duction of limbs.

The three transcription factors themselves are produced from a variety of

complex upstream inputs, including prior cell states and spatially localized
concentrations of different substances called morphogens.
Transcription factors expressed in such spatial patterns are said to contain
positional information (Wolpert 1969). This use of informational language
is thoroughly appropriate when viewed using the signaling framework. We
can see that each role in a signaling system is filled out, as well as how this
licenses talk of information, in the same way that it does in other signaling
games:

• Each of the three transcription factors is expressed as the result of

mapping a complex set of upstream cues from morphogens and
prior cell states into a single transcription factor.
• These transcription factors induce a downstream genetic switch to
act, and this switch maps the three incoming signals to another single
protein that initiates limb development.
• The three transcription factors thus act as intermediaries, or signals,
between incoming states and some further fitness-affecting down-
stream actions.
• Furthermore, each transcription factor expressed in the three different
regions delivers a signal containing information. Just as seeing what the
passenger does in crosstown traffic tells you about what color the
lights are, seeing what regulatory genes are being expressed tells you
about the location of the cell in the three-dimensional form that is
developing.

7. Reusing Existing Information. Positional information presents a more

complex picture of signaling systems than crosstown traffic. In the simple
game, the relationship between states, signals, and actions was straightfor-

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 INFORMATION IN GENE REGULATORY NETWORKS 887

ward: a state mapped to a signal, and a signal mapped to an action. Here,

however, signals are sandwiched between both upstream and downstream
information processing. Upstream, a number of cues are integrated into a sig-
nal that indicates spatial position. Downstream, these signals may coordinate
several different actions that affect fitness. The signal itself, though it carries
information about spatial location, bears no simple one-to-one relationship to
either the input (the incoming cues from morphogens or prior cell states) or
the output (the resulting proteins that produce limb development).
The idea of processed information carrying internal signals has an impor-
tant upshot. To evolve signals like this, the right configuration of genes must
be selected so that they correctly process the multiple inputs into a single sig-
nal, ready to be passed downstream for further processing. The information
carried by the signal obviously plays a role in the function it was directly se-
lected for. But cells perform many simultaneous actions, so that same infor-
mation may well prove useful for other downstream functions dependent on cell
location. If so, evolution can co-opt the signal, rather than evolve the same
information processing again.
Such changes in gene regulation are thought to be a key part of the evolu-
tion of complex animal form, as small changes in DNA can often wire together
previously selected components to create new functions (Davidson 2010).
One example where this has occurred is the gain of wing spots in the male
fruit fly Drosophila biarmipes.

8. Wing Spots for Free. Gompel et al. (2005) explain the rapid gain of wing
spots in the male fruit fly D. biarmipes by showing how existing transcription
factors are co-opted to control the expression of pigmentation in a specific
wing location. We can use the signaling framework discussed in the previous
section to interpret this change as the reuse of information that has been created
by evolution.
As with the specification of limb development in fruit flies, a number of
regulatory genes are expressed in different locations in the wing (see fig. 3).
One transcription factor (A) is expressed along the anterior of the wing,
while another (B) is expressed along the tip of the wing. Gompel et al. refer
to this as the conserved regulatory landscape, as these regulatory elements
play a downstream role in the development of the existing architecture of the
wing (C).
The mutations responsible for the rapid appearance of wing spots occur
in a genetic switch controlling pigment expression. Mutations to the cis-
element region enable existing transcription factors to bind upstream of this
gene and hence control its transcription (see fig. 3, lower right). The incoming
signals from the two regions are integrated, and the genetic switch turns on
when the Boolean combination of upstream regulators (A and not B) is true.
When the gene is turned on, it up-regulates pigmentation in the anterior distal

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 888 BRETT CALCOTT

Figure 3. Random mutations co-opt upstream positional information to produce a

novel wing spot in D. biarmipes.

position of the wing (D), producing the distinctive spot (Gompel et al. 2005;
Wray 2006). The spot is believed to confer some selective advantage through
sexual signaling.
As I argued above, the transcription factors underlying the conserved wing
architecture already carry positional information. Mutations permit signals
already carrying information to be deployed in novel functions. They do this
by attaching an already-existing network that computes cell position to ex-
isting downstream functionality that produces pigment.
We now have the following picture. For an organism to develop correctly,
it is crucial that each cell does the right thing in the right place at the right time.
Each cell has the same genetic network, so this network must be able to map
complex upstream inputs to a broad range of cellular activities. To accom-
plish this, the network must integrate information from various sources, and,
in the process, it creates internal signals that carry computed information. In
some cases, a few mutations allow other genetic switches to make use of the
already-existing information in these signals to perform a novel adaptive task.
Hence, the evolution of signaling systems does not just create information; it
also permits the reuse of information that has already been created.

9. Summary. The main purpose of this paper was to connect the signaling
framework to gene regulation and show how this provides a different way to
think about genetic information. I have shown that positional information is
one example where informational concepts in signaling systems can be clearly
applied, so the signaling framework can vindicate at least some information
talk in developmental biology. But how is this different from other ways of
thinking about genetic information?
Although information-theoretic measures can be brought to bear on many
nongenetic factors in development (Griffiths and Gray 1994), the picture I have
presented suggests that the role information plays in gene regulatory net-
works has two important properties that distinguish it from just any devel-

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 INFORMATION IN GENE REGULATORY NETWORKS 889

opmental resource. First, the information is computed from a broad range of

incoming cues, and this computation can be modified by mutations affect-
ing the topology of the network and the genetic switches doing the process-
ing. Thus, there is a great flexibility in the relation the information can bear to
the environmental context that induces it, and this relation can be fine-tuned
by natural selection. The ability for fine-grained tuning is one way of picking
out some causes over others (Woodward 2010, 2013). Second, any informa-
tion that is computed is available to be reused by the rest of the system if it
has the right cis-element region. Cis-element regions are far less complex
than the transcribed region of DNA and can arise through copying or inde-
pendently through few mutations. These changes are common, and Gompel
et al. suggest that their wing spot example may “suggest a general means by
which novel expression patterns and characters can arise” (2005, 486).
Together, these two properties provide a powerful means for natural se-
lection to produce adaptive change: fine-tuning the plastic response of cel-
lular activities to a variety of contexts, and reusing existing fine-tuned re-
sponses in new ways. The signaling framework thus provides a novel way to
connect genetic information to the specific role genes play in development, but
only when changing our perspective from considering solitary genes to looking
at networks of interacting genes.
Finally, it is worth reflecting on how these ideas about reuse in signaling
may be more widely applicable. The idea of internal signaling can also be ap-
plied to neural connectivity, and neural reuse appears to be one area where
some formal foundation might clarify how exactly this reuse occurs (see
Anderson 2010 and replies). The idea of signals carrying internal informa-
tional that is poised to be quickly redeployed in new circumstances also bears
a striking resemblance to Sterelny’s notion of decoupled representations: “in-
ternal states that track aspects of our world, but which do not have the function
of controlling particular behaviors” (2003, 29). A signaling framework that
includes the creation of computed signals and their reuse may provide a gen-
eral way of thinking about adaptive change in complex internal mechanisms.

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