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Interactome-based approaches to human disease
Michael Caldera
1
, Pisanu Buphamalai
1
, Felix Müller and
Jörg Menche
Abstract
Recent advances in high-throughput technologies have
created exciting opportunities for systematically investigating
the molecular basis of human disease. In addition to a growing
catalog of disease-associated genetic variations, we can now
map out an increasingly detailed network diagram of the
complex machinery of interacting molecules that constitutes
the basis of (patho-) physiological states. The emerging field of
‘network medicine’applies tools and concepts from network
theory to interpret this diagram and elucidate the relation be-
tween perturbations on the molecular level and phenotypic
disease manifestations. The interactome, i.e. the integrated
network of all physical interactions within the cell, can be
interpreted as a map and diseases as local perturbations.
Network-based approaches can aid in identifying the specific
interactome neighborhood that is perturbed in a certain dis-
ease, guide the search for therapeutic targets and reveal
common molecular mechanisms between seemingly unrelated
diseases.
Addresses
CeMM Research Center for Molecular Medicine of the Austrian
Academy of Sciences, Vienna, Austria
Corresponding author: Menche, Jörg (jmenche@cemm.oeaw.ac.at)
1
These authors contributed equally to this work.
Current Opinion in Systems Biology 2017, 3:88–94
This review comes from a themed issue on Clinical and translational
systems biology (2017)
Edited by Jesper Tegnér and David Gomez-Cabrero
For a complete overview see the Issue and the Editorial
Available online 4 May 2017
http://dx.doi.org/10.1016/j.coisb.2017.04.015
2452-3100/© 2017 The Authors. Published by Elsevier Ltd. This is an
open access article under the CC BY-NC-ND license (http://creativeco
mmons.org/licenses/by-nc-nd/4.0/).
Introduction
The Online Mendelian Inheritance in Man (OMIM)
database [1] currently lists over 3700 genes with mu-
tations that are known to have a phenotypic impact, e.g.
sequence alterations that are causal for Mendelian dis-
eases or variants that increase the susceptibility to
complex diseases or cancer. Yet, despite this ever
growing wealth of data, many details of how exactly
genetic alterations contribute to the disease pathobi-
ology remain in the dark. A crucial roadblock for
translating gene-level discoveries into a mechanistic
understanding of disease pathogenesis and concrete
strategies for prevention, diagnosis, and treatment is
that gene products do not act in isolation, but in the
context of other genes and proteins. Biological processes
are ultimately the result of a highly dynamic and regu-
lated interplay of macromolecules, such as interactions
between proteins or between proteins and DNA or
RNA. The entirety of all such biologically relevant in-
teractions form a large and highly connected network,
often referred to as the ‘interactome’(Box 1). The inter-
actome can therefore be understood as a map to inves-
tigate how individual (or several) genetic alterations
propagate throughout the network and perturb the
system as a whole. The emerging field of ‘network
medicine’ applies tools and concepts from network
theory (Box 2) to interpret this map and elucidate the
relation between perturbations on the molecular level
and phenotypic disease manifestations [2]. In the last
decade, network-based approaches have been success-
fully applied to a broad range of diseases, with examples
ranging from rare Mendelian disorders [3], cancer [4] or
metabolic diseases [5], to identifying basic strategies by
which viruses hijack the host interactome [6], to name
but a few. In the following we will review the basic ideas
that underly interactome-based approaches to human
disease and highlight important recent conceptual
advances.
The interactome
The term ‘interactome’ is only loosely defined and may
refer to networks that contain rather different types of
interactions. It is instructive to distinguish between
physical and functional interactions. Physical interactions
involve actual physical contact between the partici-
pating biomolecules, for example proteins that assemble
in a complex or receptor-ligand binding. Functional
interaction, on the other hand, can refer to any kind of
biologically relevant relationship. In co-expression net-
works, for example, genes are connected if their
expression patterns are strongly correlated [7]. Another
important functional relationship are ‘genetic in-
teractions’, where two genes are linked if the effect of a
simultaneous alteration of both genes differs from the
expectation based on the individual alterations. An
extreme form is synthetic lethality, where a combined loss
of two genes leads to cell death, while the loss of each
individual gene does not [8].Synthetic viability,
conversely, occurs when the lethal effect of a mutation
in one gene is rescued by a simultaneous mutation in a
Available online at www.sciencedirect.com
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Current Opinion in
Systems Biology
Current Opinion in Systems Biology 2017, 3:88 –94 www.sciencedirect.com
second gene [9]. While both functional and physical
interaction networks can yield important insights into
disease mechanisms, we will focus mostly on the more
narrowly defined physical interactions in the following.
A number of publicly available databases provide
comprehensive lists of physical proteineprotein in-
teractions (PPIs), as well as other relevant interactions
(e.g. protein-DNA, protein-RNA, enzyme-metabolite)
in human, but also in other species [10]. There are
three main sources for the PPIs reported therein: (i)
interactions curated from the scientific literature and
typically derived from small-scale experiments. (ii) In-
teractions from systematic, proteome-scale mapping
efforts, the two main techniques being yeast two-hybrid
assays for binary interactions [11] and binding affinity
purifications coupled to mass spectrometry for co-
complexes [12].(iii) Interactions from computational
predictions, for example based on protein structure
[13]. It is important to note that each of these sources
may introduce different kinds of noise and biases [14],
such as biases in the selection of which protein pairs
have been tested [15] or experimental biases, for
example towards highly expressed genes [11]. Another
important consideration for interactome-based analyses
is the considerable incompleteness of currently available
data. It is estimated, for example, that high-throughput
methods cover less than 20% of all potential pairwise
protein interactions in the human cell [11].Itis
therefore imperative to carefully evaluate both the
effect of potential biases, as well as the influence of
missing interactions, when analyzing and interpreting
interactome data. Box 1 summarizes the main topolog-
ical properties of a manually curated interactome from
[16].
Disease modules in the interactome
Among the first evidence for a direct correspondence
between the biological importance of a gene and the
interactome position of its product was the observation
that the phenotypic impact of deleting a gene in the
yeast Saccharomyces cerevisiae correlates with the number
of interaction partners of the corresponding protein
[17]. This trend was later confirmed also for genes that
Box 1. The interactome.
(a) A global picture of the interactome (as used in [16]) showing its highly complex and interconnected nature. It contains 13,460 proteins and
141,296 interactions that have been curated from different sources with various kinds of physical interactions, including binary interactions from
systematic yeast two-hybrid screens, protein complexes, kinase–substrate pairs and others. (b) The overall topology is characterized by a highly
heterogeneous degree distribution that follows a power-law. The vast majority of proteins have only few connections, but there is also a
considerable number of extremely highly connected proteins, so-called hubs (33 proteins have more than 300 interactions). (c) These hubs serve
as shortcuts, so that on average, all proteins are directly connected to each other with less than four intermediate steps, a phenomenon often
called the ‘small-world’effect.The maximum distance between any two proteins in the interactome is 13. (d) Other impor tant structural properties
of the interactome. (e) A comparison of the distances observed among genes associated with the same disease and the respective random
expectation reveals that disease genes are not scattered randomly in the interactome, but aggregate in local, disease-specific neighborhoods, so-
called disease modules.
Interactome-based approaches to human disease Caldera et al. 89
www.sciencedirect.com Current Opinion in Systems Biology 2017, 3:88–94
are essential for the viability of human cell lines [18].
The topological properties of disease-associated genes
are generally more diverse and may differ between dis-
ease classes (e.g. complex diseases, Mendelian diseases
or cancer), as well as inheritance modes (autosomal
dominant or recessive): cancer driver genes generally
show a strong tendency towards high network centrality
(Box 2), while recessive disease genes are often more
isolated and located at the periphery of the interactome
[19].
To further elucidate the detailed mechanisms, by which
a disease-associated perturbation contributes to the
pathobiological phenotype, it is important not only to
understand the network properties of individual asso-
ciated genes, but also their interactome environment
and emerging collective properties. This is particularly
evident for complex diseases that involve potentially
hundreds of genes. Similar to the functional coherence
of interactome neighbors (i.e., interacting proteins are
often involved in the same biological process [20]),
Box 2. Basic topological characteristics of networks.
The degree of a node is the number of links attached to it, i.e. the number of direct neighbors. The distribution of the degrees across all nodes is an
important global characteristic of a network.
Scale free networks are characterized by a heterogeneous degree distribution that follows a power-law: while most nodes have only few
neighbors, there are also a few highly connected ‘hubs’with a large number of neighbors.
Apath between two nodes is a sequence of links connecting the two. The minimum number of links needed to connect the two is called ‘shortest
path length’and represents their ‘network distance’.
Centrality measures exist for both nodes and for links and quantify their topological importance within the network. There are different types of
centrality measures, e.g. the ‘degree centrality’(simply given by the degree) or ‘betweenness centrality’(quantifying how many shortest paths of
the full network cross through a certain node).
Clustering describes a tendency observed in many biological (and other) networks that two neighbors of a node are often also connected to each
other, thus forming a triangle.
Motifs are small recurrent subgraphs in a network that occur particularly frequently.
Network communities are groups of tightly interconnected nodes that have more connections among themselves than to the rest of the network.
90 Clinical and translational systems biology (2017)
Current Opinion in Systems Biology 2017, 3:88 –94 www.sciencedirect.com
genes associated with the same disease have been found
to interact with each other more frequently than ex-
pected by chance [21]. This observation has been
verified systematically for a large number of diseases
[16], thus confirming a fundamental hypothesis of
interactome-based approaches to human disease,
namely that disease genes tend to cluster within so-
called disease modules. Such disease modules are
connected subgraphs of the interactome that contain all
molecular determinants of a certain disease. The first
step towards elucidating the biological mechanisms of a
disease in a network-based framework is therefore to
identify the respective disease module.
Interactome-based gene prioritization
In recent years, a plethora of disease-module identifi-
cation methods have been proposed that explore the
local network neighborhood around known disease-
associated genes (‘seed genes’) to infer likely new dis-
ease gene candidates [22]. They can roughly be classi-
fied into three main categories: (i)Path-based approaches
consider the genes along the shortest paths between the
known disease genes as potential candidate genes.
These candidate genes can then be further ranked, for
example according to the number [23] or significance
[24] of paths they participate in, or filtered such that
they form a minimal connected subgraph, a so-called
Steiner-tree [25].(ii)Dynamical approaches aim to iden-
tify candidate genes by propagating known disease as-
sociations using dynamical models, for example diffusive
processes, where the network neighborhood around
seed genes is scanned by simulating random walks along
the links [26e29]. Genes that are visited more
frequently are considered dynamically closer to the seed
genes and therefore ranked higher. (iii)Connectivity-based
approaches algorithms rank candidate genes according to
their number of links to seed genes [30e32].
Relationship between diseases
Considering the highly connected interactome, it is
apparent that diseases can rarely be understood as in-
dependent entities. Uncovering such relationships be-
tween diseases systematically can help us understand
how different pathological phenotypes are linked
together at the molecular level and shed light on disease
comorbidity, i.e. the observation that certain groups of
diseases frequently arise together [33]. Indeed, a large-
scale evaluation of shared gene associations revealed a
highly connected ‘diseaseome’, in which more than 500
diseases form a giant component and more than 800
diseases have at least one link to another disease [34].
Other diseaseedisease networks have been constructed
based on shared metabolic pathways [35], phenotype
similarity [36,37], the structure of disease ontologies
[38] or comorbidity extracted from patient records
[39,40]. In an interactome-based framework, the rela-
tionship between two diseases is represented by
overlapping disease modules, indicating that perturba-
tions causing one disease are likely to also affect the
other disease. A systematic study of over 44,000 disease
pairs revealed that the degree of this overlap is highly
predictive for the pathobiological similarity of diseases,
such that diseases with overlapping modules show sig-
nificant co-expression patterns, symptom similarity, and
comorbidity, while those that reside in separated inter-
actome neighborhoods are pathobiologically and clini-
cally distinct [16].
The considerable molecular-level overlap that has been
observed for many diseases pinpoints a limitation of
canonical disease classifications that, historically, are
largely based on clinicopathological evidence and often
categorized according to the organ system that the
disease primarily affects. Interactome-based method-
ologies could provide a more holistic framework for
disease classification based on molecular mechanism
[41].
Tissue-specific interactomes
The studies discussed above considered an integrated
interactome containing interactions that have been
identified using various techniques and were observed
under different experimental and biological conditions.
While such a global interactome provides invaluable
information for discovering general principles of disease-
associated network perturbations, it cannot account for
the cell-type or tissue-specific manifestations that
characterize many diseases. Directly measured context-
specific interactome networks are scarce, but can be
approximated by integrating more widely available
transcriptome or proteome information [42,43]. The
main idea is to use tissue-specific expression informa-
tion to filter the global interactome for interactions that
are feasible in a given tissue, i.e. both interaction part-
ners are present [44]. Consequently, the resulting
tissue-specific interactomes are generally smaller and
sparser. In line with the observation that essential genes
are more central in the global interactome, genes that
are expressed across many tissues (such as ‘house-
keeping’ genes) were found to form a core interactome
to which the more tissue-specific genes then attach,
thus forming tissue-specific peripheries [45e47].A
comparison between the global and tissue-specific
interactomes further revealed that diseases typically
manifest in those tissues, in which the corresponding
disease-module is least fragmented [48]. Tissue-specific
interactome networks can therefore shed light onto the
detailed disease-associated rewiring events [49,50] and
considerably improve disease gene prioritization
[47,51,52].
Drugs in the interactome
From a network-based perspective, the action of drugs
can be interpreted similarly to the effect of disease-
Interactome-based approaches to human disease Caldera et al. 91
www.sciencedirect.com Current Opinion in Systems Biology 2017, 3:88–94
associated genetic variants, i.e. as a local perturbation of
the interactome. Many of the concepts and tools intro-
duced above can be therefore immediately applied in
the context of network pharmacology [53,54]. Several
studies of drug-target networks have shown that most
currently used drugs are less selective than previously
assumed and instead target multiple proteins [55,56].
These target proteins tend to be more highly connected
than random proteins, but less so than essential pro-
teins. Most drugs do not target the corresponding dis-
ease module as a whole, but only a small subset or
adjacent interactome neighborhood [57]. It was further
found that drugs whose affected interactome neigh-
borhood is closer to the disease module tend to be more
effective in the clinic. These insights could help in
selecting the most promising drug targets, for example
by prioritizing targets according to their topological
properties [58], as well as in designing multitarget drugs
that act specifically and directly on the respective dis-
ease module [54]. Another promising application of
interactome-based drugedisease relationships are ap-
proaches to drug repurposing, for example by system-
atically identifying diseases with shared molecular
mechanism that may be modulated by the same thera-
peutic intervention [59].
Conclusion
Interactome-based approaches to human disease have
matured considerably in the past few years, now
possessing both a firm theoretical fundament, as well as
a broad range of successful applications across all major
areas of human disease research. At the same time, the
interactome represents only one layer of relevant in-
formation. A pressing challenge on the way towards the
next generation of (network) medicine is to integrate
the ever growing amount of omics data (e.g., genomics,
epigenomics, proteomics, metabolomics, lipidomics).
Interactome-based, and more generally, network-based
approaches are inherently holistic and integrative, thus
offering unique opportunities in this endeavor.
Acknowledgements
J.M. is supported by the Vienna Science and Technology Fund, WWTF
[grant number WWTF-VRG005].
Glossary
Interactome A global network representing all molecular interactions
in a cell. In most cases, the term specifically refers to
physical interaction networks consisting mostly of
proteineprotein interactions, but also of protein-DNA or
protein-RNA interactions. More generally, the term
interactome may also be used to describe functional
interactions, such as genetic interactions.
Disease Gene Gene with a known disease association. Sometimes the
term is reserved to genes with a known mutant
genotype that causes an inherited disorder. More
generally, the term is used also for genes containing a
risk variant for complex diseases or other, more indirect
associations to a particular disease.
Candidate gene Gene with suspected role in the pathobiology of a
disease based on prior evidence. The goal of disease
gene prioritization methods is to identify the most
likely candidates.
Disease module The comprehensive set of cellular components
associated with a certain disease and their
interactions. More specifically, the term refers to a
connected subgraph of the interactome, whose
perturbation causes the disease. Network-based
disease module detection methods aim to identify
this subgraph, in analogy to gene prioritization
methods.
Context-specific interactomes Contain only interactions that occur in
a given biological context, such as cell-
type, tissue, or a specific disease
condition. Such interactomes are most
commonly obtained by filtering out
proteins that are not expressed in the
respective context.
Comorbidity The tendency of certain diseases to co-occur in the same
patient, suggesting shared underlying molecular
mechanisms.
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