Mapping the Genotype–Phenotype Relationship in Cellular Signaling Networks: Building Bridges Over the Unknown - Systems Biology: Networks, Models, and Applications - page 135

Mapping the Genotype-Phenotype
Relationship in Cellular Signaling
Networks: Building Bridges Over
the Unknown
Jason A. Papin, Erwin P. Gianchandani,
& Shankar Subramaniam
The central challenge in postgenomic biology is the mapping of the
genotype-phenotype relationship. For cellular signaling networks, the
functional connections between genotype and phenotype are deciphered
through an ever-growing toolbox of high-throughput experimental
technologies. Each technology can be used to generate a vast amount
of data particular to some aspect of a given cellular signaling network.
However, despite this growing experimental toolbox and the associated
repositories of data, there remains the challenge to connect these disparate
data points to reconstruct the continuum from genotype to phenotype.
Cellular signaling network functions can be discretized into three
tiers (see figure 5.1). The first tier involves the transcriptional activity
of a genome. The proteins that result from the transcription and trans-
lation of genes orchestrate the responses to a signaling event. The
second tier is composed of the chemical transformations in which these
proteins are involved. This set of chemical reactions and cellular events
are here called “intermediate phenotypes.” The third tier is composed
of the subsequent cellular behaviors that are a function of the given
genotype and collection of intermediate phenotypes. These events have
been called “endpoint phenotypes.” This third tier of events in a cellu-
lar signaling network occurs on a much slower time scale than events
that comprise “intermediate phenotypes.”
Experimental technologies used to decipher cellular signaling net-
works can be grouped according to the data they generate within these
three tiers. For example, genomic sequencing efforts decode information
in the first tier, delineating the “parts list” of a given cellular signaling
network. Furthermore, chromatin immunoprecipitation (ChIP) chips
systematically identify which genes are regulated by a given regula-
tory protein under specified conditions, providing further information
regarding this first tier. The intermediate phenotypes are characterized
137