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n3:pmcid
PMC0
bibo:doi
10.1186%2F1471-2105-12-357
n11:contains
_:vb12351637 _:vb12351639 _:vb12351672
Subject Item
_:vb12351637
rdf:type
n11:Section
dc:title
methods
n11:contains
_:vb12351638
Subject Item
_:vb12351638
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omim.txt file using an in-house developed JAVA program. GWAS information was extracted from the NGRI GWAS publications list http://www.genome.gov/gwastudies/, which can be downloaded via FTP http://www.genome.gov/admin/gwascatalog.txt[>>5<<]. The MeSH entry term lookup file was generated using an in-house developed JAVA program from a MeSH annotation file (d2011.
n3:mentions
n2:19474294
Subject Item
_:vb12351639
rdf:type
n11:Section
dc:title
background
n11:contains
_:vb12351664 _:vb12351665 _:vb12351666 _:vb12351667 _:vb12351668 _:vb12351669 _:vb12351670 _:vb12351671 _:vb12351656 _:vb12351657 _:vb12351658 _:vb12351659 _:vb12351660 _:vb12351661 _:vb12351662 _:vb12351663 _:vb12351648 _:vb12351649 _:vb12351650 _:vb12351651 _:vb12351652 _:vb12351653 _:vb12351654 _:vb12351655 _:vb12351640 _:vb12351641 _:vb12351642 _:vb12351643 _:vb12351644 _:vb12351645 _:vb12351646 _:vb12351647
Subject Item
_:vb12351640
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is the first step to using model systems such as S. cerevisiae, C. elegans, and Drosophila melanogaster (Drosophila) to study human genes, such as the set of disease genes in the Online Mendelian Inheritance in Man (OMIM) database [>>1<<-4] or the results of a genome-wide association study (GWAS) [5,6]. Similarly, orthologs of genes functionally characterized in model organisms may identify as yet unknown candidate genes relevant to human health.
n3:mentions
n2:10612823
Subject Item
_:vb12351641
rdf:type
n3:Context
rdf:value
C. elegans, and Drosophila melanogaster (Drosophila) to study human genes, such as the set of disease genes in the Online Mendelian Inheritance in Man (OMIM) database [1-4] or the results of a genome-wide association study (GWAS) [>>5<<,6]. Similarly, orthologs of genes functionally characterized in model organisms may identify as yet unknown candidate genes relevant to human health.
n3:mentions
n2:19474294
Subject Item
_:vb12351642
rdf:type
n3:Context
rdf:value
C. elegans, and Drosophila melanogaster (Drosophila) to study human genes, such as the set of disease genes in the Online Mendelian Inheritance in Man (OMIM) database [1-4] or the results of a genome-wide association study (GWAS) [5,>>6<<]. Similarly, orthologs of genes functionally characterized in model organisms may identify as yet unknown candidate genes relevant to human health.
n3:mentions
n2:19161620
Subject Item
_:vb12351643
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Most of these are based on either phylogeny-based algorithms (e.g. TreeFam, Phylome, Ensembl Compara) or on sequence similarity (e.g. InParanoid, orthoMCL and OMA) [>>7<<-12]. More recently, additional tools have been reported based on functional similarity among ortholog groups identified using protein-protein interaction (PPI) networks (e.g. NetworkBLAST, IsoBase) [13-15]. Notably, PPI-based tools have
n3:mentions
n2:17545180 n2:12952885 n2:19029536
Subject Item
_:vb12351644
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More recently, additional tools have been reported based on functional similarity among ortholog groups identified using protein-protein interaction (PPI) networks (e.g. NetworkBLAST, IsoBase) [>>13<<-15]. Notably, PPI-based tools have strong potential to improve in performance over time, as PPI data sets are improving in coverage and quality at a rapid pace. Because of their differing approaches, user interfaces, output formats and so
n3:mentions
n2:16510899 n2:18174180
Subject Item
_:vb12351645
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Their results also highlight that different tools have different advantages [>>16<<].
n3:mentions
n2:19148271
Subject Item
_:vb12351646
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HCOP is a human-centered ortholog prediction tool that in its original published form, facilitated comparison of ortholog assertions made by PhIGs, HomoloGene, Ensembl Compara, Inparanoid and MGI [>>17<<,18]. Currently, the HCOP website also includes predictions from Evola, HGNC, OMA, OPTIC, TreeFam, UCSC and ZFIN and has removed PhIGs http://www.genenames.org/cgi-bin/hcop.pl. Another tool, COMPARE, is not limited to human-centered
n3:mentions
n2:16284797
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_:vb12351647
rdf:type
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rdf:value
HCOP is a human-centered ortholog prediction tool that in its original published form, facilitated comparison of ortholog assertions made by PhIGs, HomoloGene, Ensembl Compara, Inparanoid and MGI [17,>>18<<]. Currently, the HCOP website also includes predictions from Evola, HGNC, OMA, OPTIC, TreeFam, UCSC and ZFIN and has removed PhIGs http://www.genenames.org/cgi-bin/hcop.pl. Another tool, COMPARE, is not limited to human-centered
n3:mentions
n2:16951416
Subject Item
_:vb12351648
rdf:type
n3:Context
rdf:value
Another tool, COMPARE, is not limited to human-centered relationships and combines results from Inparanoid, orthoMCL, Ensembl Compara and TreeFam [>>19<<]. These combined approaches are useful in that they allow for identification and comparison of ortholog results from various sources, allowing the end-user to make informed choices. However, neither tool incorporates the full range of
n3:mentions
n2:18056065
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_:vb12351649
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rdf:value
among specific groups of species or have distinct differences may be important for evolutionary studies, and may be good targets for the development of biocides, such as to control disease vector, parasite, or crop pest populations [>>20<<,21].
n3:mentions
n2:10570198
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_:vb12351650
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rdf:value
among specific groups of species or have distinct differences may be important for evolutionary studies, and may be good targets for the development of biocides, such as to control disease vector, parasite, or crop pest populations [20,>>21<<].
n3:mentions
n2:19490110
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_:vb12351651
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Perhaps top among these is the NCBI Online Mendelian Inheritance in Man (OMIM) database [>>1<<-4]. Since the completion of the human genome and following various technological advances, an increasing number of genome-wide association studies (GWAS) provide evidence for possible disease association of many previously uncharacterized
n3:mentions
n2:10612823
Subject Item
_:vb12351652
rdf:type
n3:Context
rdf:value
the completion of the human genome and following various technological advances, an increasing number of genome-wide association studies (GWAS) provide evidence for possible disease association of many previously uncharacterized genes [>>5<<,6]. In addition, there have been several automated efforts to evaluate the links between human diseases and genes, such as based on gene annotations or the published literature.
n3:mentions
n2:19474294
Subject Item
_:vb12351653
rdf:type
n3:Context
rdf:value
the completion of the human genome and following various technological advances, an increasing number of genome-wide association studies (GWAS) provide evidence for possible disease association of many previously uncharacterized genes [5,>>6<<]. In addition, there have been several automated efforts to evaluate the links between human diseases and genes, such as based on gene annotations or the published literature.
n3:mentions
n2:19161620
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_:vb12351654
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The Disease Ontology project, for example, assigns disease information based on GeneRIF annotation [>>22<<], and resources such as BITOLA, MedGene and HuGE Navigator [23-25] provide systematic summaries of disease-gene relationships culled from the literature in NCBI PubMed.
n3:mentions
n2:19594883
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_:vb12351655
rdf:type
n3:Context
rdf:value
The Disease Ontology project, for example, assigns disease information based on GeneRIF annotation [22], and resources such as BITOLA, MedGene and HuGE Navigator [>>23<<-25] provide systematic summaries of disease-gene relationships culled from the literature in NCBI PubMed.
n3:mentions
n2:15694635 n2:18430222 n2:12938930
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_:vb12351656
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For example, Drosophila is an established model for a wide variety of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[>>26<<]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [25,37,38]; and cancer [9,39-42].
n3:mentions
n2:16512675
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_:vb12351657
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For example, Drosophila is an established model for a wide variety of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [>>27<<-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [25,37,38]; and cancer [9,39-42].
n3:mentions
n2:20975992 n2:16642034 n2:20644630
Subject Item
_:vb12351658
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For example, Drosophila is an established model for a wide variety of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [>>30<<-34]); multi-symptom inherited disorders [35,36]; heart disease [25,37,38]; and cancer [9,39-42].
n3:mentions
n2:19064248 n2:20635002 n2:19609447 n2:19680242 n2:19218090
Subject Item
_:vb12351659
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n3:Context
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model for a wide variety of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [>>35<<,36]; heart disease [25,37,38]; and cancer [9,39-42].
n3:mentions
n2:20889762
Subject Item
_:vb12351660
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for a wide variety of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,>>36<<]; heart disease [25,37,38]; and cancer [9,39-42].
n3:mentions
n2:20716578
Subject Item
_:vb12351661
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n3:Context
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of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [>>25<<,37,38]; and cancer [9,39-42]. Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:18430222
Subject Item
_:vb12351662
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n3:Context
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of nervous system-related diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [25,>>37<<,38]; and cancer [9,39-42]. Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:12969510
Subject Item
_:vb12351663
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n3:Context
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diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [25,37,38]; and cancer [>>9<<,39-42]. Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:19029536
Subject Item
_:vb12351664
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n3:Context
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diseases (reviewed in JEIBMANN and PAULUS 2009)[26]; various muscular dystrophies [27-29]; responses to infection by human pathogens (e.g. [30-34]); multi-symptom inherited disorders [35,36]; heart disease [25,37,38]; and cancer [9,>>39<<-42]. Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:19214224 n2:20663965 n2:20578898 n2:17549611
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_:vb12351665
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Drosophila is an emerging model for the study of asthma [>>43<<], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:19342413
Subject Item
_:vb12351666
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n3:Context
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Drosophila is an emerging model for the study of asthma [43], lipotoxicity [>>44<<], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:19781664
Subject Item
_:vb12351667
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n3:Context
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Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [>>45<<-47], and is being used to study responses to therapeutic treatments and natural products [48-50].
n3:mentions
n2:17908555 n2:20816226
Subject Item
_:vb12351668
rdf:type
n3:Context
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Drosophila is an emerging model for the study of asthma [43], lipotoxicity [44], and metabolism [45-47], and is being used to study responses to therapeutic treatments and natural products [>>48<<-50]. Overall, conservation between humans and Drosophila at the gene, pathway, cognate organ and behavioral levels, together with available tools and assays, suggest that Drosophila can serve as an excellent system for rapid functional
n3:mentions
n2:16893904 n2:16987873
Subject Item
_:vb12351669
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OrthoDisease maps orthologous gene relationships among human genes and genes in 100 genomes, including Drosophila, using the Inparanoid tool [>>51<<]. Homophila was designed specifically for Drosophila and uses BLASTP to compare human protein sequences to the Drosophila proteome [52,53]. Both approaches have value and are used extensively. Nevertheless, each has important caveats. For
n3:mentions
n2:15241792
Subject Item
_:vb12351670
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Homophila was designed specifically for Drosophila and uses BLASTP to compare human protein sequences to the Drosophila proteome [>>52<<,53]. Both approaches have value and are used extensively. Nevertheless, each has important caveats. For example, OrthoDisease may miss relevant orthologs due to the limited coverage provided by use of just one approach to ortholog
n3:mentions
n2:11381037
Subject Item
_:vb12351671
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n3:Context
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Homophila was designed specifically for Drosophila and uses BLASTP to compare human protein sequences to the Drosophila proteome [52,>>53<<]. Both approaches have value and are used extensively. Nevertheless, each has important caveats. For example, OrthoDisease may miss relevant orthologs due to the limited coverage provided by use of just one approach to ortholog mapping,
n3:mentions
n2:11752278
Subject Item
_:vb12351672
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n11:Section
dc:title
results and discussion
n11:contains
_:vb12351676 _:vb12351677 _:vb12351678 _:vb12351679 _:vb12351673 _:vb12351674 _:vb12351675 _:vb12351684 _:vb12351685 _:vb12351686 _:vb12351687 _:vb12351680 _:vb12351681 _:vb12351682 _:vb12351683 _:vb12351688
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Based on published reviews and comparative studies evaluating different tools, we selected nine tools that provide a reasonable balance of specificity and sensitivity [>>7<<-12,15,16,54-59].
n3:mentions
n2:17545180 n2:12952885 n2:19029536
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_:vb12351674
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Based on published reviews and comparative studies evaluating different tools, we selected nine tools that provide a reasonable balance of specificity and sensitivity [7-12,15,>>16<<,54-59]. We excluded tools that were developed prior to the availability of full-genome sequence and/or that have not been maintained and updated. However, we note that the data available from tools we included are based on different
n3:mentions
n2:19148271
Subject Item
_:vb12351675
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n3:Context
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Based on published reviews and comparative studies evaluating different tools, we selected nine tools that provide a reasonable balance of specificity and sensitivity [7-12,15,16,>>54<<-59]. We excluded tools that were developed prior to the availability of full-genome sequence and/or that have not been maintained and updated. However, we note that the data available from tools we included are based on different genome
n3:mentions
n2:17440619 n2:16777906 n2:16873526 n2:16613613 n2:11125038
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_:vb12351676
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A leading resource for ortholog prediction based on this approach is IsoBase [15,>>60<<,61], which is aimed at identification of functionally related proteins based on integration of sequence similarity and protein-protein network-based information.
n3:mentions
n2:19477996
Subject Item
_:vb12351677
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A leading resource for ortholog prediction based on this approach is IsoBase [15,60,>>61<<], which is aimed at identification of functionally related proteins based on integration of sequence similarity and protein-protein network-based information.
n3:mentions
n2:18725631
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_:vb12351678
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Although paralogous genes may have diverged in function more than orthologs, those that have arisen from recent gene duplications may be members of a function-oriented ortholog group [57,>>62<<]. When building the tool, we first obtained the data from each site; then standardized various identifiers and converted the different output formats; next integrated all the predictions into our FlyRNAi database [63]; and finally
n3:mentions
n2:19368988
Subject Item
_:vb12351679
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The "Quest for Orthologs" initiative is currently attempting to provide benchmarking for orthology predictions but that resource is not yet available [>>65<<]. To obtain some measure of DIOPT performance relative to individual tools, we used two different approaches based on available resources. First, we used a manually assembled set of high-confidence Drosophila-human orthologous pairs made
n3:mentions
n2:19785718
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_:vb12351680
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First, we used a manually assembled set of high-confidence Drosophila-human orthologous pairs made up of 159 orthologous pairs of trans-membrane proteins generated by manual phylogenetic analysis [>>54<<], 89 pairs of kinases generated manually based on kinase domain similarity as well as phylogeny [66] and 71 pairs of oxidative phosphorylation genes assembled manually by sequence alignment and analysis of exon/intron structures [67,68].
n3:mentions
n2:16873526
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_:vb12351681
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[54], 89 pairs of kinases generated manually based on kinase domain similarity as well as phylogeny [66] and 71 pairs of oxidative phosphorylation genes assembled manually by sequence alignment and analysis of exon/intron structures [>>67<<,68]. All these data sets, with the exception of the OXPHOS set, have been previously used for evaluation of ortholog prediction tools.
n3:mentions
n2:18315839
Subject Item
_:vb12351682
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[54], 89 pairs of kinases generated manually based on kinase domain similarity as well as phylogeny [66] and 71 pairs of oxidative phosphorylation genes assembled manually by sequence alignment and analysis of exon/intron structures [67,>>68<<]. All these data sets, with the exception of the OXPHOS set, have been previously used for evaluation of ortholog prediction tools.
n3:mentions
n2:15693940
Subject Item
_:vb12351683
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We performed a different type of test for specificity using a negative test set; i.e. a set of 1,130 human genes defined as human lineage-specific by Eukaryotic Clusters of Orthologous Groups (KOG) [>>37<<]. We found that DIOPT shows lower specificity (82%) as compared to individual tools using this test set (93%-99%) (Figure 3b).
n3:mentions
n2:12969510
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_:vb12351684
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We also make it possible to search with RNAi reagent IDs (i.e. amplicon IDs) from the Drosophila RNAi Screening Center (DRSC) or fly stock IDs from the Transgenic RNAi project (TRiP; http://www.flyrnai.org/TRiP-HOME.html) [>>69<<,70].
n3:mentions
n2:19487563
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_:vb12351685
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The information contained in OMIM has been extracted from publications and undergone manual curation [>>1<<-4]. GWAS data sets, such as those cataloged by the National Genome Research Institute (NHGRI; see http://www.genome.gov/gwastudies/), provide associations among loci or genes and diseases or traits based on linkage analysis using single
n3:mentions
n2:10612823
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_:vb12351686
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Due to technological advances in genotyping, the amount of GWAS data now available has increased dramatically [>>5<<,6]. With GWAS data, identification of a specific disease-causing mutation in a gene may be missing, with the results pointing to one or more candidate genes that may be relevant. These candidates require further functional
n3:mentions
n2:19474294
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_:vb12351687
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Due to technological advances in genotyping, the amount of GWAS data now available has increased dramatically [5,>>6<<]. With GWAS data, identification of a specific disease-causing mutation in a gene may be missing, with the results pointing to one or more candidate genes that may be relevant. These candidates require further functional characterization,
n3:mentions
n2:19161620
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This list includes 30 genes that have previously been studies in metabolic diseases in fly, including Akt1, InR and chico (reviewed in [>>45<<,73]). This list also provides additional candidates such as sima and Spargel. The availability of a wealth of molecular genetic tools for Drosophila makes it possible to study candidate disease-associated genes identified using DIOPT-DIST.
n3:mentions
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