Genetic Networks - Systems Biology Concepts and Insights - page 121

Genetic Interactions and Cancer
Therapeutics
Insights derived from genetic interaction networks are
directly relevant to human disease and, in particular, the
development of targeted cancer therapies. The most
commonly used cancer therapies involve administering
high doses of radiation or toxic chemicals to the patient,
which can help to suppress tumor growth but also cause
substantial damage to normal cells. Synthetic lethal inter-
actions suggest a much more targeted strategy for the
treatment of cancer. The goal would be to identify a target
gene that, when mutated or chemically inhibited, kills cells
that harbor a second cancer-specific alteration due to
a synthetic lethal interaction, but spares otherwise identical
cells lacking the alteration, an idea originally proposed by
Hartwell and colleagues [72] . In fact, this concept has
recently been exploited in the development of poly (ADP-
ribose) polymerase (PARP) inhibitors as novel chemo-
therapeutics for breast cancer [73,74] . Although PARP is
not essential in normal cells, BRCA mutant cells are
dependent on PARP for their survival. There are several
PARP inhibitors in various stages of clinical trials, some
with encouraging results [75] .

interactions between S. cerevisiae and C. elegans. There are
a number of facts that may explain the low level of conser-
vation estimated from the high- vs. low-throughput studies in
C. elegans [77] . One possibility to account for the higher
degree of conservation observed between different yeasts vs.
the S. cerevisiae-metazoan comparison is that certain genetic
interactions detectable in single-celled yeasts are likely to be
conserved in multicellular organisms but difficult to detect
due to cellular-level redundancy, tissue-specific or altered
functions. It may be possible to detect these interactions
using alternative phenotypic readouts that assay anatomical,
developmental, or behavioral phenotypes. Indeed, a higher
degree of genetic interaction conservation was observed
between S. cerevisiae and C. elegans, at least with respect to
genes involved in chromosome biology, when post-embry-
onic RNAi and the C. elegans vulval cell linage were used to
measure somatic cell proliferation defects [78] .
Although systematic comparative analyses involving
mammalian genetic interaction networks are not yet feasible,
evidence has shown that synthetic lethal interactions identi-
fied in lower eukaryotes, and involving highly conserved
genes implicated in fundamental processes such as DNA
synthesis and repair, can guide the selection of interactions
that can be exploited to kill cancer cells in mammals. For
example, a synthetic lethal genetic interaction between the
yeast genes RAD54 and RAD27 was recapitulated in
a RAD54B / human colorectal cancer cell line by shRNA-
mediated targeting of the RAD27 ortholog, FEN1 [79] .

GENETIC NETWORK CONSERVATION
Conservation of Individual Interactions
between Orthologous Gene Pairs
Analysis of S. cerevisiae and S. pombe networks represents
the most comprehensive comparison of genetic interaction
conservation conducted to date. Although ~80% of S. cer-
evisiae essential gene orthologs are also indispensible for
viability in S. pombe [76] , two independent studies have
found that most (~70%) of genetic interactions identified thus
far appear to be species specific [61,62] . Significant rewiring,
which may include more extensive buffering, of their genetic
networks was not entirely unexpected, given that S. pombe
and S. cerevisiae are separated fromeach other by close to 400
million years of evolution and exhibit substantial physio-
logical differences. As a result, a ~30% overlap between the
genetic networks of these two yeasts indicates that there is
significant conservation of synthetic lethal genetic interac-
tions over hundreds of years of evolution.
Analyses of individual genetic interactions between
orthologous genes of yeast and worm provided weaker
support for the conservation of specific interactions. Two
studies found that less than 5% conservation of synthetic
lethal genetic interactions identified by large-scale studies in
S. cerevisiae were conserved in C. elegans [65,66] .Onthe
other hand, a smaller study, employing very detailed quan-
tification of worm mitotic spindle morphology, detected
moderate but significant (~29%) conservation of genetic

Conservation of Genetic Network Structure
and Topology
The studies described above suggest that genetic interac-
tions can be conserved from yeast to higher organisms;
however, the extent of this conservation remains unclear
[80] . Despite this uncertainty, it is possible that genetic
interactions are more generally conserved at the level of
network structure and topology. Indeed, examination of the
global yeast genetic network showed that, like other bio-
logical networks [81] , most genes are sparsely connected,
whereas a small number have many interactions and serve as
network 'hubs' [2] . Whereas most genetic interactions occur
between genes involved in the same biological process,
network hubs tend to be pleiotropic and interact with many
functionally diverse sets of genes [2] . Importantly, genes
annotated to chromatin/transcription showed a significant
number of genetic interactions with numerous different
processes, indicating that genes involved in these functions
are important for mediating cross-process connections in the
genetic network [2] . Interestingly, chromatin and tran-
scription-related genes were shown to have similar proper-
ties in the C. elegans genetic network [65] . The discovery of
a central and hence highly pleiotropic role for chromatin-
and transcription-related genes in both the S. cerevisiae and