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appear to be much less abundant than between-pathway
structures, they were frequently observed in systematic
surveys of the S. cerevisiae interaction network [34,36] .For
example, within-pathway structures were most recently
reported to account for ~10% of all observed negative inter-
action modules [36] ( Figure 6.3B ). These modules often
corresponded to essential protein [17,18,34] complexes or
groups of co-regulated genes [36] ( Figure 6.3C ).
The interpretation of within-pathway negative genetic
interactions appears to suggest instances where a functional
module exhibits non-specific internal redundancy, where
perturbation of one component can be tolerated but pertur-
bation of any two components of the same functional
module results in loss of function and cell death. Supporting
this interpretation, protein complexes containing at least one
essential gene tend to appear in these 'within-pathway'
interaction structures [17,18] ( Figure 6.3A, C ). Presumably,
these are instances where the function of the complex is
essential, but the loss of a single non-essential component
does not completely destabilize the complex. Perturbation
of two or more of these non-essential components results in
loss of complex function and cell viability. Alternatively,
perturbation of two essential components (e.g., double
mutants carrying conditional or hypomorphic alleles of
essential genes) will also result in loss of protein complex
function and lethality. It should be noted, however, that
essential protein complexes explain only a minority (7%) of
these within-pathway structures [36] . Interestingly, in yeast
these negative genetic interaction structures are enriched for
relatively specific functions, including genes involved in
chromosome segregation and cell cycle [36] .
Like negative genetic interactions, positive genetic
interactions also exhibit modular structure, although to
a lesser extent. In the same systematic survey based on the
global yeast network, only 19% of positive interactions,
compared to 58% of negative interactions, contribute to
larger block structures (minimum 3
of these interactions identified several instances of genetic
suppression that span all components of distinct protein
complexes [17] . For example, deletion of anymember of the
conserved FAR complex was shown to suppress actin
polarity and growth defects associated with mutant alleles of
TORC2 [17] . Although the yeast FAR complex is largely
uncharacterized, the orthologous complex in mammalian
cells associates with protein phosphatase 2A (PP2A) [38] .
An attractive hypothesis is that the FAR complex mediates
its function by antagonizing TORC2 activity [17] .In
general, mechanistic understanding of most between-
pathway positive interaction structures remains an open
question that deserves further study.
Genetic Networks Enable Functional
Dissection of Pleiotropic Genes
The prevalence of modular structure in both negative and
positive genetic interactions provides a rich basis for
associating genes with a common function and broadly
characterizing the functional organization of the genome.
Each specific between-pathway set of interactions defines
two specific functional modules and highlights their
compensatory relationship. Interestingly, genes sometimes
appear in several different between-pathway structures
where each structure is composed of a unique set of genes,
enriched for a distinct function. This observation high-
lighted the utility of genetic networks for identifying
multifunctional or pleiotropic genes [36] . For example,
VIP1, which encodes one of two yeast inositol pyrophos-
phate synthases required for synthesis of hexakisphosphate
(IP6) and heptakisphosphate (IP7) [39] , exhibited negative
genetic interactions with 13 distinct modular structures
[36] . Each of these structures reflected enrichment for
a different function, including an unexpected one that
associated VIP1 with several genes involved in DNA
replication and repair [36] .
3 gene matrix)
( Figure 6.3B ), although it is possible that this difference
may be partially related to decreased sensitivity and spec-
ificity in the experimental detection of positive genetic
interactions [2,36] . Approximately 20% of positive inter-
action modules could be classified as within-pathway
structures ( Figure 6.3B ) and, consistent with observations
from smaller-scale studies [19, 37] , these were enriched for
non-essential protein complexes [36] . This is likely the
result of a single gene deletion that is capable of completely
disrupting protein complex function. In such a case,
deleting genes encoding other components of the same
complex will not have any additional effect on fitness due
to symmetric positive interactions ( Figure 6.1A ) [19] .
Most (~80%) of structured positive interactions reflected
'between-pathway' structures ( Figure 6.3B ). Although
much more common, 'between-pathway' positive interac-
tion structures are less well understood. Careful examination
Genetic Interactions as a Means of Studying
the Evolution of Gene Duplicates
One basis for redundancy within a genome is the presence
of duplicated genes or paralogs. Although this has been
a topic of interest for some time, large-scale genetic
interaction networks provide a new tool for studying
duplicate genes. Sequence studies of diverse organisms
have revealed that a sizable fraction of many genomes
consists of duplicate copies of existing genes. This is
perhaps not surprising, given the long-held view that gene
duplication is a primary mechanism for introducing novel
gene function into a genome [40] . What is surprising,
however, is the degree to which these duplicate pairs (or
large gene families) can retain sequence similarity despite
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