Article

Predicting disease genes using protein-protein interactions. J Med Genet

Radboud University Nijmegen, Nymegen, Gelderland, Netherlands
Journal of Medical Genetics (Impact Factor: 6.34). 09/2006; 43(8):691-8. DOI: 10.1136/jmg.2006.041376
Source: PubMed

ABSTRACT

The responsible genes have not yet been identified for many genetically mapped disease loci. Physically interacting proteins tend to be involved in the same cellular process, and mutations in their genes may lead to similar disease phenotypes.
To investigate whether protein-protein interactions can predict genes for genetically heterogeneous diseases.
72,940 protein-protein interactions between 10,894 human proteins were used to search 432 loci for candidate disease genes representing 383 genetically heterogeneous hereditary diseases. For each disease, the protein interaction partners of its known causative genes were compared with the disease associated loci lacking identified causative genes. Interaction partners located within such loci were considered candidate disease gene predictions. Prediction accuracy was tested using a benchmark set of known disease genes.
Almost 300 candidate disease gene predictions were made. Some of these have since been confirmed. On average, 10% or more are expected to be genuine disease genes, representing a 10-fold enrichment compared with positional information only. Examples of interesting candidates are AKAP6 for arrythmogenic right ventricular dysplasia 3 and SYN3 for familial partial epilepsy with variable foci.
Exploiting protein-protein interactions can greatly increase the likelihood of finding positional candidate disease genes. When applied on a large scale they can lead to novel candidate gene predictions.

Full-text

Available from: Berend Snel
LETTER TO JMG
Predicting disease genes using protein–protein
interactions
M Oti, B Snel, M A Huynen, H G Brunner
...............................................................................................................................
J Med Genet 2006;43:691–698. doi: 10.1136/jmg.2006.041376
Background: The responsible genes have not yet been
identified for many genetically mapped disease loci.
Physically interacting proteins tend to be involved in the
same cellular process, and mutations in their genes may lead
to similar disease phenotypes.
Objective: To investigate whether protein–protein interac-
tions can predict genes for genetically heterogeneous
diseases.
Methods: 72 940 protein–protein interactions between
10 894 human proteins were used to search 432 loci for
candidate disease genes representing 383 genetically
heterogeneous hereditary diseases. For each disease, the
protein interaction partners of its known causative genes
were compared with the disease associated loci lacking
identified causative genes. Interaction partners located within
such loci were considered candidate disease gene predic-
tions. Prediction accuracy was tested using a benchmark set
of known disease genes.
Results: Almost 300 candidate disease gene predictions
were made. Some of these have since been confirmed. On
average, 10% or more are expected to be genuine disease
genes, representing a 10-fold enrichment compared with
positional information only. Examples of interesting candi-
dates are AKAP6 for arrythmogenic right ventricular
dysplasia 3 and SYN3 for familial partial epilepsy with
variable foci.
Conclusions: Exploiting protein–protein interactions can
greatly increase the likelihood of finding positional candidate
disease genes. When applied on a large scale they can lead
to novel candidate gene predictions.
M
any human genetic diseases can be caused by multi-
ple genes. Since they lead to the same or similar
disease phenotypes, the underlying genes are likely to
be functionally related. Such functional relatedness can be
exploited to aid in the finding of novel disease genes.
1
Direct
protein–protein interactions are one of the strongest mani-
festations of a functional relation between genes, so
interacting proteins may lead to the same disease phenotype
when mutated. Indeed, several genetically heterogeneous
hereditary diseases are known to be caused by mutations in
different interacting proteins, such as Hermansky-Pudlak
syndrome and Fanconi anaemia.
23
Also, a recent study
showed that interacting proteins tend to lead to similar
disease phenotypes when mutated.
4
Therefore protein–
protein interactions might in principle be used to identify
potentially interesting disease gene candidates.
Many human protein–protein interactions have been
reported.
5
These literature based interactions are reliable,
but are naturally biased toward better studied proteins and
have already been exploited by the community for disease
gene prediction. Protein–protein interactions from high
throughput experiments do not have this bias, though they
are also generally less reliable than literature based interac-
tions.
6
These high throughput sets are especially interesting
for novel disease gene prediction as they can contain
previously undescribed protein–protein interactions. There
are two human high throughput protein–protein interaction
sets available,
78
but more are available from other species.
These first have to be mapped to interactions between human
proteins before they can be applied to disease gene prediction.
We investigated how successful protein–protein interac-
tions are in predicting candidate disease genes for genetically
heterogeneous hereditary diseases using a systematic large
scale bioinformatics approach. To be as comprehensive and
unbiased as possible we used both literature-based and high
throughput human protein–protein interactions, and human
mapped high throughput interactions from three other
species—Drosophila melanogaster (fruit fly), Caenorhabditis
elegans (nematode), and Saccharomyces cerevisiae (baker’s
yeast). To identify potential new candidate disease genes,
we examined whether disease proteins had interaction
partners which were located within other loci associated
with that same disease; such interaction partners were
considered to be candidate disease genes. Several of these
predictions have since been confirmed.
METHODS
Genetic disease data
Disease data were obtained from the Online Mendelian
Inheritance in Man (OMIM, http://www.ncbi.nlm.nih.gov/
entrez/query.fcgi?db = OMIM) ‘‘Morbid Map’’ list of dis-
eases. This list contains disease loci and known disease genes
from the OMIM database.
9
We selected genetically hetero-
geneous hereditary diseases with at least one known disease
causing gene and at least one disease locus lacking an
identified causative gene. Disease subtypes were pooled into
single diseases. A disease can have several loci, some of which
may overlap each other. For instance, there are several
X linked mental retardation subtypes, many of which have
been mapped to overlapping loci. Therefore, a single protein–
protein interaction could result in multiple candidate gene
predictions for different disease subtypes.
The loci vary in length and gene count, with a median of 88
genes per locus, and a mean of 123.6; the loci lengths are not
normally distributed. Whole chromosome loci were excluded
from the analyses. In total, there were 383 diseases in the
dataset. Together these diseases have 1195 disease loci with
identified disease genes and 432 disease loci lacking
identified causative genes.
The dataset used in the benchmark tests contained all the
genetically heterogeneous hereditary diseases from Morbid
Abbreviations: HPRD, Human Protein Reference Database; OMIM,
Online Mendelian Inheritance in Man; Y2H, yeast two-hybrid protein–
protein interaction assay
691
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Map with at least two known disease genes (289 diseases,
1114 disease loci with known disease genes, 1003 distinct
genes). Only loci with known disease genes were used in the
benchmark tests.
Protein–protein interaction sets
Five protein–protein interaction datasets were used in this
study, from four different species—human, Drosophila mela-
nogaster, Caenorhabditis elegans, and Saccharomyces cerevisiae
(table 1). One of the human interaction sets contained
manually curated protein–protein interactions culled from
the literature, while all the other protein interaction data
were from high throughput protein–protein interaction
experiments.
The non-human protein–protein interactions were mapped
to human proteins using orthology relations. Orthology
between the other species’ and human proteins was
determined using the Inparanoid program,
17
with default
settings, on the whole (protein) genomes of the species.
Genomes were acquired from Ensembl
18
for the metazoan
species and from the Saccharomyces genome database
19
for
yeast. Where one non-human protein was orthologous to
several human proteins, the interaction was assumed to be
valid for all these proteins.
Candidate gene prediction
For all the diseases in the heterogenic diseases dataset, the
following actions were undertaken:
N
The protein interaction partners were determined for each
known disease protein.
N
The chromosomal locations of the genes coding for these
interacting proteins were determined using gene location
data from the Ensembl database. The cytogentic loci were
mapped to chromosomal base pair ranges using the
Ensembl database, which specifies cytogenetic band
boundaries as exact base pair positions, rounded off to
the nearest 100 kb.
N
These chromosomal locations were checked to see if they
fell within one or more disease loci (of the same disease)
that lacked a known disease gene.
N
Each interacting protein gene that was located within one
of these loci was considered a candidate gene prediction.
N
If a candidate gene lay within multiple (overlapping) loci
of the same disease, each of them was counted as a
separate prediction.
This procedure was carried out using a custom written C++
program (available on request), as were the benchmark and
randomisation tests described below.
Benchmark tests
The benchmark test is introduced to examine how well a
protein–protein interaction set performs in recovering known
disease genes from different loci known to be involved in the
same disease. These tests were therefore carried out
analogously to the candidate gene prediction tests, with the
exception that the protein interactor positions were examined
against the disease loci with known disease genes (as
opposed to the loci with unidentified disease genes). As with
the prediction tests, these genes and their associated disease
loci were taken from OMIM Morbid Map.
If an interactor lay within a disease locus it was considered
a candidate gene prediction (a positive). If this interactor was
indeed the known disease gene in that locus, it was
considered a correct prediction (true positive). If it was not
the known disease gene for that locus, it was considered a
wrong prediction (false positive).
Randomisation tests
Owing to the complex nature of the data—potentially
overlapping loci with different gene counts and networked
protein–protein interactions—protein interactor randomisa-
tion tests were used to estimate the significance of the
candidate gene prediction and benchmark results. In each
case the genome was randomly shuffled and each protein in
the interaction set was replaced with its counterpart from the
shuffled genome. This approach retains the original structure
of the interaction network; it only randomises the protein
identities.
One thousand randomisation tests were carried out for
each of the 10 analyses: five protein–protein interaction sets,
each of which was used for both novel disease gene
prediction and for benchmarking. In addition, separate
randomisation tests were carried out for the two combined
datasets, the combined high throughput set, and the total
combined set.
Two other types of randomisation tests were carried out for
each dataset—namely, the randomisation of the gene
positions on the genome, and the shuffling of the protein
interactors in the interactor sets. These led to similar results
as the interactor identity randomisation (data not shown)
and were left out of the results for brevity.
RESULTS
Benchmark tests perform well above random
expectation
In order to examine how well protein–protein interaction sets
predict disease genes in other loci of the same disease, we
first undertook benchmark tests that attempted to predict
known disease genes. These tests were carried out using only
Table 1 Protein–protein interaction sets used in the study
Interaction set Source of interaction data*
Number of proteins
in human mapped
interactions
Number of
human mapped
interactions` References Comments
HPRD set Published reports 6005 19 728 5 Downloaded October 21 2005
Human Y2H set High throughput experiments
(Y2H)
2686 5211 7, 8 Interactions from both
experiments pooled
Fly set High throughput experiment
(Y2H)
4706 16 313 10 All interactions were used,
regardless of confidence level
Worm set High throughput experiment
(Y2H)
1933 5771 11 Downloaded from DIP
database
12
Yeast set High throughput experiments
(Y2H, PCP)
2455 27 098 Y2H: 13, 14
PCP: 15, 16
Interactions from all four
experiments pooled
Combined high throughput set All high throughput sets 8162 54 048 See above Excluding HPRD
Total combined set All interaction sets 10 894 72 940 See above Including HPRD
*Y2H, yeast two-hybrid protein–protein interaction assay; PCP, protein complex purification experiment (based on mass spectrometry).
These are the proteins that could be automatically mapped to human Ensembl gene IDs.
`These are the interactions from the original interaction sets that could be automatically mapped to human Ensembl gene IDs.
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diseases with multiple known causative genes and their
disease associated loci from OMIM Morbid Map, allowing the
candidate gene predictions to be evaluated for accuracy and
overrepresentation. With regard to the number of disease
gene interaction partners that are located in another locus of
the same disease, the HPRD interaction stood out as having
over twice as many as would be expected by chance (fig 1).
The high throughput sets all scored higher than the vast
majority of their randomised controls, though the magnitude
of this differed from the fly set, scoring higher than all but
two controls, to the worm set, scoring higher than 823 of the
1000 randomised controls. We thus show here an over-
representation of disease gene interaction partners in other
disease associated loci, suggesting that disease genes encode
proteins that tend to interact with each other.
The tendency for proteins associated with the same disease
to interact with each other can be tested more directly by
examining what percentage of these correctly localised
interaction partners are indeed the known disease causing
genes in those loci (fig 2). Once again, the HPRD protein–
protein interactions performed very well. Almost 60% of these
interacting proteins corresponded to the known disease
60
50
40
30
20
10
0
Protein–protein interaction sets
Percentage of correctly predicted disease genes (accuracy), benchmark set
Accuracy (%)
FlyHPRD
58%
Yeast All setsAll HT setsWormHuman Y2H
14%
11%
17%
12%
40%
9%
Figure 2 Relatively high likelihood of
finding a disease gene from protein
interaction data in a given locus. The
different protein–protein interaction sets
used are on the X axis, while the Y axis
contains the percentage of disease
protein interactors falling within other
disease loci that correspond to the
known disease genes in those loci.
Black stars (and associated shaded
boxes) indicate the values based on the
real interaction datasets, while the box
plots indicate the values resulting from
the 1000 randomised interactor
controls per set. Randomised controls
have median accuracies of less than
1%. All interaction sets substantially
outperform all their controls, with the
HPRD scoring exceptionally high.
HPRD, Human Protein Reference
Database; HT, high throughput.
500
400
300
200
100
0
Proteinprotein interaction sets
Number of interactors in other disease loci (hits), benchmark set
Number of hits
Fly
85
113
HPRD
170
487
Yeast
115
130
All sets
404
744
All HT sets
239
289
Worm
27
33
Human Y2H
13
22
Figure 1 Overrepresentation of
physically interaction proteins from loci
associated with the same disease. The
different protein–protein interaction sets
used are on the X axis, while the Y axis
contains the number of disease protein
interactors falling within another locus
associated with the same disease (hits)
in the benchmark locus set. Black stars
and associated shaded boxes indicate
the values based on the real interaction
datasets, while the box plots indicate
the values resulting from the 1000
randomised interactor controls per set
(numbers in clear boxes are medians).
The value for the combined interaction
dataset (indicated by the black arrow) is
not included in the plot, to keep the
Y axis scale manageable. The HPRD
and total combined sets score much
higher than all their randomised
controls; the difference is smaller for the
high throughput sets. HPRD, Human
Protein Reference Database; HT, high
throughput.
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causing genes in these loci. The high throughput protein
interaction sets had a lower performance (9–17%, with an
average of 12%), but they all did much better than their
randomised controls. Except for the two smallest sets, all
interaction sets substantially outperformed every single run
of their corresponding 1000 randomised controls. This
implies that disease protein interaction partners, when
located within other loci of the same disease, are at least
10-fold more likely to be involved in that disease than the
other genes in these loci, given that randomly chosen locus
genes have on average a 1% (1/88) chance of being correct.
An interesting result is that the yeast interaction set is
more accurate in predicting candidate genes than the other
high throughput sets, including those using ‘‘native’’ human
proteins. Most of the yeast interactions are based on protein
complex purification rather than yeast two-hybrid assays. A
likely explanation for the relatively good performances of the
yeast interactions is the previously observed higher quality of
protein–protein interaction data from protein complex
purification experiments relative to yeast two-hybrid assays.
6
Candidate disease gene prediction results follow
similar patterns
Having established the validity of the approach for known
disease genes we compared the likelihood of mapping an
interactor to a disease locus to chance expectation for disease
loci for which we do not know the disease gene. As shown in
fig 3, the three largest datasets and the combined data all
showed an increase relative to the medians of the randomi-
sation experiments. This result is consistent with that of the
benchmark experiments for the high throughput data. It
indicates an appreciable enrichment for true disease genes in
the prediction results. Nevertheless the majority of the
candidates are still probably false positives.
In contrast to the high throughput results from fly and
yeast, the HPRD results do show a large discrepancy between
the benchmark results and the novel gene prediction results.
In the latter the enrichment of interactors in disease loci is
much smaller than in the former. This suggests that the
majority of disease genes which could be found using HPRD
protein–protein interactions have already been detected by
the community, which is unsurprising given that all these
interactions have previously been reported. Some of the
interactions in the HPRD are even based on research on
disease genes in the first place.
20–23
Thus the HPRD bench-
mark results are not representative for its novel gene
prediction results.
The two smallest high throughput interaction sets, human
and worm, show no signal for the prediction of novel disease
genes. It should be noted that the candidate gene prediction
disease dataset contains fewer target loci (432) than the
benchmark dataset (1114). One explanation for this might be
that the combination of a small number of interactions and a
small number of target loci prevents the two smallest sets
from showing any signal here.
The full list of predicted candidate disease genes and their
corresponding interactions are given in supplementary table 1
(the supplementary table can be viewed on the journal
website (http://www.jmedgenet.com/supplemental)..
Confirmedandrefutedpredictions
A few candidate disease gene predictions could be confirmed
or refuted because the disease causing genes are known but
absent from the list of known disease genes used in the study
(table 2). These disease loci were treated as having
unidentified causative genes during the study, but manual
inspection of the results led to their identification as disease
loci with known causative genes.
It is encouraging to see that so many of these predictions
were confirmed, though these are generally from the HPRD
interaction set (of which 10 were confirmed and five
refuted). From the high throughput sets there were two
confirmed and 13 refuted predictions, which is consistent
with their benchmark results (fig 2). This list may not be
exhaustive owing to the complexities of thoroughly investi-
gating all these predictions by hand, but we do not expect
these proportions to change substantially. In any case the
benchmark results remain valid, as the known gene disease
loci are not susceptible to this misannotation problem.
350
300
250
200
150
100
50
0
Proteinprotein interaction sets
Number of interactors in other disease loci (hits), candidate gene set
Number of hits
Fly
57
79
HPRD
101
113
Yeast
60
82
All sets
250
294
All HT sets
150
190
Worm
2624
Human Y2H
98
Figure 3 Candidate disease gene
prediction hit counts. The different
protein–protein interaction sets used
are on the X axis, while the Y axis
contains the number of disease protein
interactors falling within another locus
associated with the same disease (hits)
in the candidate gene prediction locus
set. Black stars (and associated shaded
boxes) indicate the values based on the
real interaction datasets, while the box
plots indicate the values resulting from
the 1000 randomised interactor
controls per set (numbers in clear boxes
are medians). The fly and worm sets
score higher than the majority of their
randomised controls, but the two
smallest sets do not perform above
random expectation. The HPRD scores
relatively lower than the fly and worm
sets, but still above the majority of its
controls. HPRD, Human Protein
Reference Database; HT, high
throughput.
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Table 2 Confirmed and refuted candidate disease gene predictions
Disease subtype Candidate genes
Based on interaction
with*
Original disease
subtype Status Comments
Branchiootic
syndrome 3 [608389]
SIX1 (sine oculis
homeobox homolog 1)
[601205]
EYA1 (eyes absent
homolog 1) [601653]
Branchiootic
syndrome 1
[602588]
Confirmed Confirmed,
24
but not in Morbid Map
version used; interaction occurs in fly,
worm and HPRD sets
SCID, autosomal
recessive, T-negative/
B-positive type
[600802]
JAK3 (Janus kinase 3) LCK (lymphocyte specific
protein-tyrosine kinase)
[153390]
SCID caused by
LCK deficiency
[153390]
Confirmed Relevant Ensembl gene ID erroneously
mapped to INSL3 symbol instead of
JAK3, thus JAK3 not mapped to an
Ensembl gene ID. All interactions from
HPRD
PTPRC (protein-tyrosine
phosphatase, receptor
type, C) [151460]
SCID due to LCK
deficiency
[151460]
IL2RG (interleukin 2
receptor, c) [308380]
SCID, X linked
[300400]
Nephronophthisis 4
[606966]
NPHP4 (nephrocystin 4)
[607215]
NPHP1 (nephrocystin 1)
[607100]
Nephronophthisis,
juvenile [256100]
Confirmed NPHP4 gene symbol not mapped to
corresponding Ensembl gene ID in
Ensembl database version used. HPRD
interaction
Senior-Loken
syndrome 4 [606996]
Senior-Loken
syndrome 1
[266900]
Charcot-Marie-Tooth
disease, type 2L
[608673]
HSPB8 (heat shock
22kDa protein 8)
[608014]
HSPB1 (heat shock 22 kDa
protein 1) [602195]
Charcot-Marie-
Tooth disease,
axonal, type 2F
[606595]
Confirmed HSPB8 identified as disease gene in
OMIM database, but not in Morbid
Map; HPRD interaction
Polycystic kidney
disease, infantile
severe, with tuberous
sclerosis [600273]
PKD1 (polycystin 1)
[601313]
PKD2 (polycystin 2)
[173910]
Polycystic kidney
disease, adult,
type II [173910]
Confirmed Disease caused by chromosomal
deletion which affects two genes, PKD1
and TSC2
25
; mentioned in OMIM, but
not in Morbid Map; HPRD interaction
Pachyonychia
congenita, Jadassohn-
Lewandowsky type
[167200]
KRT6A (keratin 6A)
[148041]
KRT17 (keratin 17)
[148069]
Pachyonychia
congenita,
Jackson-Lawler
type [167210]
Confirmed Ensembl ID maps to KRT6E, KRT6D,
KRT6C and KRT6A; OMIM uses KRT6A
name, whereas Ensembl uses KRT6E as
primary name, thus mapping to
corresponding Ensembl gene ID failed;
from human high throughput set
Charcot-Marie-Tooth
disease, type 2L
[608673]
DNCL1 (dynein light
chain, LC8-type 1)
[601562]
DNM2 (dynamin 2)
[602378]
Charcot-Marie-
Tooth disease,
dominant
intermediate B
[606482]
Refuted HSPB8 is causative (see above). HSPB8
identified as disease gene in OMIM
database, but not in Morbid Map; two
HPRD interactions, one yeast
RNF10 (ring finger prot
ein 10) [not in OMIM]
GARS (glycyl-tRNA
synthetase) [600287]
Charcot-Marie-
Tooth disease,
axonal, type 2D
[601472]
MAPKAPK5 (mitogen
activated protein
kinase-activated protein
kinase 5) [606723]
HSPB1 (heat shock
22kDa protein 1)
[602195]
Charcot-Marie-
Tooth disease,
axonal, type 2F
[606595]
Marfan-like connective
tissue disorder
[154705]
FBLN2 (fibulin 2)
[135821]
FBN1 (fibrillin 1)
[134797]
Marfan syndrome
[154700]
Refuted Causative gene is TGFBR2 (TGFb
receptor II) [190182]. FBLN2 was
suspected but refuted
26
; mentioned in
OMIM, but not in Morbid Map; HPRD
interaction
Retinitis pigmentosa
26 [608380]
ENSG00000163510
[not in OMIM]
PRPF3 (Pre-MRNA
processing factor 3
homolog) [607301]
Retinitis
pigmentosa 18
[601414]
Refuted Causative gene is CRKL (ceramide
kinase-like) [608381]; gene name not
mapped to Ensembl gene ID in
Ensembl; three interactions from yeast
set, one from fly set
PRPF8 (Pre-MRNA
processing factor 8
homolog) [607300]
Retinitis
pigmentosa 13
[600059]
PRPF31 (Pre-MRNA
processing factor 31
homolog) [606419]
Retinitis pigmentosa
11 [600138]
HECW2 (HECT, C2
and WW domain
containing E3 ubiquitin
protein ligase 2) [not in
OMIM]
PRPF3 (Pre-MRNA
processing factor 3
homolog) [607301]
Retinitis pigmentosa
18 [601414]
Retinitis pigmentosa
10 [180105]
LUC7L2 (LUC7-like 2)
[not in OMIM]
PRPF3 (Pre-MRNA
processing factor 3
homolog) [607301]
Retinitis pigmentosa
18 [601414]
Refuted Causative gene is IMPDH1 (IMP
dehydrogenase 1) [146690]; Morbid
Map version used contains two entries
for this subtype, one with and one
without associated gene; two from
yeast set, one from fly set
PRPF31 (Pre-MRNA
processing factor 31
homolog) [606419]
Retinitis
pigmentosa 11
[600138]
METTL2
(methyltransferase like
2A) [607846]
CRX (cone-rod homeobox)
[602225]
Retinitis
pigmentosa, late
onset dominant
[268000]
Spastic paraplegia
17 [270685]
SF3B2 (splicing factor
3b, subunit 2) [605591]
HSPD1 (heat shock 60kDa
protein 1) [118190]
Spastic
paraplegia 13
[605280]
Refuted Known gene is BSCL2 (seipin)
[606158]; mentioned in OMIM, but
not listed in Morbid Map; both from
HPRD set, KLC2 also from fly and
worm sets
KLC2 (kinesin light
chain 2) [601334]
KIF5A (kinesin family
member 5A) [602821]
Spastic
paraplegia 10
[604187]
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Promising leads
In addition to these confirmed prediction the protein
interaction sets also led to several plausible but unconfirmed
candidate gene predictions. For instance, the AKAP6
(A-kinase (PRKA) anchor protein 6) gene is predicted as a
candidate gene for arrythmogenic right ventricular dysplasia
3 (OMIM 602086), based on an HPRD interaction with RYR2
(ryanodine receptor 2). A-kinase anchor proteins are involved
in cardiac myocyte contractility and possibly also in heart
failure.
27 28
SYN3 (synapsin III) was predicted as a candidate
gene for familial partial epilepsy with variable foci (OMIM
604364) based on an HPRD interaction with SYN1 (synapsin
I), which is causative for epilepsy, X linked, with variable
learning disabilities and behaviour disorders (OMIM
300491). There are several other interesting examples, which
can be viewed in supplementary table 1 (http://www.jmed-
genet.com/supplemental).
The HPRD interaction set is biased toward disease
proteins
As it is based on interactions described in published reports,
the HPRD interaction set is expected to be biased toward
known disease genes. These proteins would be better studied,
and known interactions with candidate disease proteins
would have been investigated by the community already.
This bias can already be seen in the HPRD benchmark results,
but it can be quantified more directly by the proportion of the
interacting proteins that are known disease proteins. Here
once again the bias is clear—the proportion of interacting
proteins that occurs in the heterogeneous disease protein set
is twice as high for the HPRD set as for the high throughput
sets, and is well over twice the proportion of Ensembl
proteins in the disease protein set (table 3).
Interestingly, even the high throughput sets are enriched
for disease genes. This suggests that genetically heteroge-
neous disease proteins are more likely to have protein–
protein interactions, or that they have more easily detectable
interactions.
Protein–protein interactions add as much information
as localization
Hereditary diseases do not always have genetic loci associated
with them. It is therefore interesting to see how much
protein–protein interactions can at all predict the candidate
disease gene pool in the absence of any genetic localisation
data. When disregarding localisation information entirely in
the benchmark disease gene set, the combined high
throughput protein–protein interaction set still has a predic-
tion accuracy of 0.7%. This is two orders of magnitude higher
than the chance of randomly picking the disease protein from
the entire genome and is of the same order of enrichment as
genetic localisation, which generally reduces the candidate
gene pool from ,20 000 to ,100. Combining these two
information sources enriches the candidate gene pool a
further order of magnitude to a one in 10 chance (12%) of
picking the right disease gene (fig 2), which corresponds to a
1000-fold enrichment relative to the entire genome.
Needless to say, the HPRD interaction set performs much
better than the combined high throughput set, resulting in a
prediction accuracy of 6.6% when localisation data are
disregarded. This corresponds to a 1000-fold enrichment
even before localisation is taken into account. Once again,
combining this with localisation information leads to a
further 10-fold enrichment resulting in the 58% accuracy
found in this study.
Table 3 Overrepresentation of heterogeneous disease genes in HPRD protein interaction set (x
2
test).
Number of proteins
in interaction set
Subset also in
disease protein set
Subset also in disease
protein set (percentage) x
2
Test p Value
HPRD set (literature based) 6005 678 11.29% 550.2098 ,2.2e-16
Human Y2H set (high throughput) 2686 146 5.44% 4.845 0.03
Fly set (high throughput) 4706 276 5.86% 18.109 2.1e-5
Worm set (high throughput) 1933 101 5.23% 2.086 0.15
Yeast set (high throughput) 2455 141 5.74% 7.838 0.005
Reference set – all human protein coding genes in Ensembl
Total In disease set Percentage
Ensembl known genes 22242 1003 4.51%
The disease gene enrichment in HPRD is highly significantly higher than in the high throughput sets (p,1e-13 after Bonferroni correction for every case).
Disease subtype Candidate genes
Based on interaction
with*
Original disease
subtype Status Comments
Dyskeratosis congenita,
autosomal dominant
[127550]
EIF4G1 (eukaryotic
translation initiation
factor 4-c 1) [600495]
DKC1 (dyskerin 1)
[300126]
Dyskeratosis
congenital 1
[305000]
Refuted Causative gene is TERC (telomerase
RNA component) [602322]; gene
symbol not mapped to Ensembl gene
ID in Ensembl database version used;
three from fly set (EIF4G1, EIF4A2,
KPNA1) one from yeast (CPA3)
EIF4A2 (eukaryotic
translation initiation
factor 4A, isoform 2)
[601102]
KPNA1 (karyopherin
a 1) [600686]
CPA3 (carboxypeptidase
A3, mast cell) [114851]
*These are the known disease genes, associated with other disease subtypes, which have physical protein–protein interactions with the candidate disease genes.
Square brackets contain OMIM numbers for both diseases and genes.
A prediction is considered confirmed if it is known in published reports to be causative for the relevant disease, and considered refuted if a different gene in the
same locus is known to be causative for that disease. It is important to note that a ‘‘refuted’’ candidate gene may not have been screened and excluded, and may
thus still be a valid candidate.
Table 2 Continued
696 Letter to JMG
www.jmedgenet.com
Page 6
DISCUSSION
The hypothesis being investigated here is that interacting
proteins would often lead to similar disease phenotypes when
mutated, enabling the usage of protein–protein interactions
to suggest candidate disease genes. Our results suggest that
this is indeed the case. Given the average locus size of close to
100 genes and high throughput interaction benchmark
accuracies of 9–17%, positional candidate genes that interact
with known disease genes have a more than 10-fold higher
likelihood of being disease causing genes than random locus
genes.
There are several practical limitations to the degree to
which protein–protein interactions can predict disease gene
candidates. To begin with, high throughput protein–protein
interaction sets—especially yeast two-hybrid sets—are inher-
ently noisy and contain a lot of interactions with no
biological relevance.
10 11 13 14
Therefore we might be predicting
a disease gene based on an interaction that does not occur in
vivo, but which did erroneously appear in a yeast two-hybrid
assay. Indeed, only 5.8% of the human, fly, and worm Y2H
interactions were confirmed by the HPRD, even among
proteins common to both sets. However, given the Y2H set
prediction accuracies of over 10% and the fact that the HPRD
is not exhaustive, the proportion of Y2H interactions that are
genuine is probably substantially higher than this figure
suggests. Nevertheless, these high noise levels could reduce
the accuracy of the Y2H based predictions relative to other
techniques, as evidenced by the higher performance of the
mainly protein complex purification based yeast interaction
set.
Another practical limitation is the mapping of the high
throughput interactions from other species to human
proteins. In this study, when a protein in the other species
had multiple human orthologues, the interaction was
transferred to all of them. However, this need not be the
case in reality. Encouragingly, we have previously shown that
interactions between proteins are quite conserved across
species and that conserved interactions tend to involve
functionally related proteins.
29
Also, the yeast set outperforms
the other sets despite its evolutionary distance to humans—
though this may reflect the fact that most yeast interactions
were from more reliable protein complex purification experi-
ments rather than yeast two-hybrid assays.
Apart from the protein interactions, the designation of the
candidate disease loci can also be a source of noise. Some of
the candidate disease loci were designated based on incorrect
reasoning, or faulty linkage assignment. For instance, we
have recently shown that a family with EEC syndrome linked
to chromosome 19 (EEC2, OMIM 602077)
30
actually has a
mutation in the P63 gene denoted EEC3 (OMIM 604292)
which is localised on human chromosome 3q27.
31
However,
the EEC2 locus remains in OMIM as a separate EEC locus
with unidentified causative gene.
Furthermore, the use of cytogenetic bands to designate
disease loci in OMIM Morbid Map can lead to problems in
locating the genes in the Ensembl database.
Though they do not have sharp boundaries in reality,
the Ensembl database uses specific base pair positions
(rounded off to the nearest 100 kb) as band boundaries.
Thus genes lying in the vicinity of a band boundary could
easily be assigned to separate bands in published reports
and in the Ensembl database. Indeed over 20% of the
known disease genes in OMIM Morbid Map are associated
with loci that differ from their Ensembl annotation. Most
of these genes lie between 1 Mb and 10 Mb of their Morbid
Map annotated loci on the same chromosome. The use of
markers instead of cytogenetic bands could improve this;
however, OMIM Morbid Map does not include marker
information.
Finally, phenotypically similar diseases can be functionally
related, even though they are classified as different diseases.
As this study used pre-existing disease classifications rather
than systematic phenotypic similarity analysis, potential
links between disease genes causing similar but differently
classified disease phenotypes would be overlooked. This
would reduce the number of predictions made, without
affecting the accuracy of those predictions that have been
made.
All these practical limitations reduce the accuracy of the
predictions, meaning that the true degree to which proteins
involved in the same genetic disease interact is likely to be
much higher. With higher quality protein interaction sets,
more precise locus demarcation, and more systematic disease
phenotype descriptions the value of this approach to disease
gene prediction should increase even further.
Apart from the practical limitations, there are fundamental
limits to the prediction capacity of protein–protein interac-
tions. Two interacting proteins need not lead to similar
disease phenotypes when mutated—for instance, they may
have different but overlapping functions or one may be more
dispensable than the other. Also, disease proteins may lie at
different points in a molecular pathway and need not interact
with each other directly. Disease mutations need not even
involve proteins, as is the case with TERC (telomerase RNA
component) in congenital autosomal dominant dyskeratosis
(see table 2). Protein–protein interactions will thus not be
capable of detecting every novel disease protein. Despite these
fundamental limitations, the high proportion of disease
proteins among correctly localised HPRD interaction partners
is promising, although this interaction set is biased. And
despite their practical limitations, even the high throughput
datasets have prediction accuracies of up to 17%. Thus, in the
absence of practical limitations, these fundamental limita-
tions should result in a prediction accuracy that lies between
these two values.
Outlook
This study provides evidence that the systematic use of
protein–protein interaction data may lead to an approxi-
mately 10-fold improvement in positional candidate gene
prediction. At the same time, the quality and quantity of the
data available can be much improved. Though around 73 000
interactions between almost 11 000 proteins were used in
this study, the actual number of interactions between these
proteins should be much greater as all interaction assaying
techniques miss large numbers of interactions.
67
In addition,
a more systematic phenotypic classification of diseases, such
as our recently developed text mining approach,
32
may lead to
more interactions between related disease genes being
identified. With increasing quantity and quality of interaction
and phenotypic data and more dense interaction networks,
the performance and utility of this approach to disease gene
prediction should improve even further.
ACKNOWLEDGEMENTS
We thank Bas Dutilh for doing the orthology determination, and Gert
Vriend, Marc van Driel, Rene´ van der Heijden, Vera van Noort, and
Toni Gabaldon for discussions and suggestions. This work is part of
the BioRange programme of the Netherlands Bioinformatics Centre
(NBIC), which is supported by a BSIK grant through the Netherlands
Genomics Initiative (NGI).
A supplementary table containing a full list of
predicted candidate disease genes and their corre-
sponding interactions is available on the journal
website (http://www.jmedgenet.com/supplemental).
Letter to JMG 697
www.jmedgenet.com
Page 7
Authors’ affiliations
.....................
M Oti, B Snel, M A Huynen, Centre for Molecular and Biomolecular
Informatics, Nijmegen Centre for Molecular Life Sciences, Radboud
University Nijmegen Medical Centre, Nijmegen, Netherlands
H G Brunner, Department of Human Genetics, University Medical Centre
Nijmegen – St Radboud, Nijmegen, Netherlands
Conflicts of interest: none declared.
Correspondence to: Dr Han G Brunner, Department of Human Genetics,
University Medical Centre Nijmegen St Radboud, Geert Grooteplein
10, 6525 GA Nijmegen, Netherlands; H.Brunner@antrg.umcn.nl
Received 31 January 2006
Revised version received 10 March 2006
Accepted for publication 14 March 2006
Published Online First 12 April 2006
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  • Source
    • "Different approaches have used various data sources such as gene expression [2] [3], sequence similarity of genes, DNA methylation [4], tissue-specific information [5], functional similarity and annotations [2] [6], and protein-protein interactions (PPIs) [7] [8] in determining the strength of association between genes and diseases as well as associations between diseases and protein complexes [9]. Network-based prioritization methods [10] are based on the observation that genes related to similar diseases tend to lie close to one another in the PPI network [11]. Furthermore, some other researchers have considered phenotype similarity in terms of gene closeness to prioritize disease genes. "
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    Full-text · Article · Sep 2015
  • Source
    • "In most cases, multiple sources of genomic data are combined to find causal genes, e.g., the combinations of GO annotation information with protein interaction data [16], GO annotation information with sequence-based features [17], and metabolic pathway data with protein interaction data [18]. Investigation of the interactions between the proteins that are encoded by genes in the human PPI network has become one of the primary and most powerful approaches for elucidating the molecular mechanisms that underlie complex diseases192021. Such exploration has often been performed by comparing the network topology similarities of the nodes in the PPI network. There are many methods for measuring topological similarity, including calculating the number of common neighbors between two network nodes and calculating the distance between two network nodes. "
    [Show abstract] [Hide abstract] ABSTRACT: The identification of gene-phenotype relationships is very important for the treatment of human diseases. Studies have shown that genes causing the same or similar phenotypes tend to interact with each other in a protein-protein interaction (PPI) network. Thus, many identification methods based on the PPI network model have achieved good results. However, in the PPI network, some interactions between the proteins encoded by candidate gene and the proteins encoded by known disease genes are very weak. Therefore, some studies have combined the PPI network with other genomic information and reported good predictive performances. However, we believe that the results could be further improved. In this paper, we propose a new method that uses the semantic similarity between the candidate gene and known disease genes to set the initial probability vector of a random walk with a restart algorithm in a human PPI network. The effectiveness of our method was demonstrated by leave-one-out cross-validation, and the experimental results indicated that our method outperformed other methods. Additionally, our method can predict new causative genes of multifactor diseases, including Parkinson's disease, breast cancer and obesity. The top predictions were good and consistent with the findings in the literature, which further illustrates the effectiveness of our method. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · Jul 2015 · Journal of Biomedical Informatics
  • Source
    • "Domains such as the immunoglobulin domain, Zinc-finger, and the protein kinase domain are the top three most frequently observed cancer protein domains. Many other works also employ PPI and domaindomain interaction (DDI) to characterize disease networks [3,1112131415. In the previous work [16, 17], a one-to-one DDI model is proposed to obtain specific sets of DDI for onco-proteins and tumor suppressor proteins, respectively. "
    [Show abstract] [Hide abstract] ABSTRACT: Many proteins are known to be associated with cancer diseases. It is quite often that their precise functional role in disease pathogenesis remains unclear. A strategy to gain a better understanding of the function of these proteins is to make use of a combination of different aspects of proteomics data types. In this study, we extended Aragues's method by employing the protein-protein interaction (PPI) data, domain-domain interaction (DDI) data, weighted domain frequency score (DFS), and cancer linker degree (CLD) data to predict cancer proteins. Performances were benchmarked based on three kinds of experiments as follows: (I) using individual algorithm, (II) combining algorithms, and (III) combining the same classification types of algorithms. When compared with Aragues's method, our proposed methods, that is, machine learning algorithm and voting with the majority, are significantly superior in all seven performance measures. We demonstrated the accuracy of the proposed method on two independent datasets. The best algorithm can achieve a hit ratio of 89.4% and 72.8% for lung cancer dataset and lung cancer microarray study, respectively. It is anticipated that the current research could help understand disease mechanisms and diagnosis.
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