Paul M K Gordon

The University of Calgary, Calgary, Alberta, Canada

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Publications (52)152.15 Total impact

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    ABSTRACT: Rapid-onset Obesity with Hypothalamic Dysfunction, Hypoventilation, and Autonomic Dysregulation (ROHHAD) is thought to be a genetic disease caused by de novo mutations, though causative mutations have yet to be identified. We searched for de novo coding mutations among a carefully-diagnosed and clinically homogeneous cohort of 35 ROHHAD patients. We sequenced the exomes of seven ROHHAD trios, plus tumours from four of these patients and the unaffected monozygotic (MZ) twin of one (discovery cohort), to identify constitutional and somatic de novo sequence variants. We further analyzed this exome data to search for candidate genes under autosomal dominant and recessive models, and to identify structural variations. Candidate genes were tested by exome or Sanger sequencing in a replication cohort of 28 ROHHAD singletons. The analysis of the trio-based exomes found 13 de novo variants. However, no two patients had de novo variants in the same gene, and additional patient exomes and mutation analysis in the replication cohort did not provide strong genetic evidence to implicate any of these sequence variants in ROHHAD. Somatic comparisons revealed no coding differences between any blood and tumour samples, or between the two discordant MZ twins. Neither autosomal dominant nor recessive analysis yielded candidate genes for ROHHAD, and we did not identify any potentially causative structural variations. Clinical exome sequencing is highly unlikely to be a useful diagnostic test in patients with true ROHHAD. As ROHHAD has a high risk for fatality if not properly managed, it remains imperative to expand the search for non-exomic genetic risk factors, as well as to investigate other possible mechanisms of disease. In so doing, we will be able to confirm objectively the ROHHAD diagnosis and to contribute to our understanding of obesity, respiratory control, hypothalamic function, and autonomic regulation.
    Full-text · Article · Aug 2015 · Orphanet Journal of Rare Diseases
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    ABSTRACT: Familial restrictive cardiomyopathy (RCM) caused by a single gene mutation is the least common of the inherited cardiomyopathies. Only a few RCM-causing mutations have been described. Most mutations causing RCM are located in sarcomere protein genes which also cause hypertrophic cardiomyopathy (HCM). Other genes associated with RCM include the desmin and familial amyloidosis genes. In the present study we describe familial RCM with severe heart failure triggered by a de novo mutation in TTN, encoding the huge muscle filament protein titin. Family members underwent physical examination, ECG and Doppler echocardiogram studies. The family comprised 6 affected individuals aged 12-35years. Linkage to candidate loci was performed, followed by gene sequencing. Candidate loci/gene analysis excluded 18 candidate genes but showed segregation with a common haplotype surrounding the TTN locus. Sequence analysis identified a de novo mutation within exon 266 of the TTN gene, resulting in the replacement of tyrosine by cysteine. p.Y7621C affects a highly conserved region in the protein within a fibronectin-3 domain, belonging to the A/I junction region of titin. No other disease-causing mutation was identified in cardiomyopathy genes by whole exome sequencing. Our study shows, for the first time, that mutations in TTN can cause restrictive cardiomyopathy. The giant filament titin is considered to be a determinant of a resting tension of the sarcomere and this report provides genetic evidence of its crucial role in diastolic function.
    No preview · Article · Nov 2013 · International journal of cardiology
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    ABSTRACT: Background: Inherited cardiomyopathies and arrhythmias are mainly autosomal dominant conditions characterized by incomplete penetrance and variable clinical expression. The introduction of Next-Generation Sequencing (NGS) panels and exome analysis for research and also diagnostic purposes do allow a comprehensive genetic analysis of all known genes as well as the discovery of novel genes for those conditions. However, the results often raise more questions than answers in particular in terms of proving causality of the identified variants. Methods and results: Here we report three families where we found more than one pathogenic variant in the index case. The analysis was done using NGS panels consisting of nearly 70 known genes for inherited cardiomyopathies and arrhythmias and/or whole exome sequencing. In a Long QT family the index case presented with syncope and a QTc interval of 520ms. An epinephrine drug challenge prolonged the QT interval up to 612ms and led to Torsade de Pointes with a transition to ventricular fibrillation in the recovery period. She was found to carry two previously reported disease causing mutations, one in KCNQ1 (p.R518X) and one in SCN5A (p.F1617del). Both parents who are clinically unaffected carry one mutation. In another family with left ventricular non-compaction cardiomyopathy the index patient was found to carry two novel MYH7 variants (p.R1677C; p.Q44X), both presumed to be pathogenic. Further analysis will show if those mutations are in "cis" or "trans" inherited and how they segregate in other affected family members. The third, most interesting family consists of four living and two deceased members who all presented with a heart block requiring pacemakers in their 30is.The index case has had additional features such as cardiomyopathy and a prolonged QT interval. She also survived a ventricular fibrillation arrest. Exome analysis found a frameshift mutation in RBM20 (p.S268DfsX3) in the index case, very likely causing her arrhythmic cardiomyopathy. Interestingly, this mutation did not segregate in any of the other family members affected by the heart block suggesting two different very rare inherited cardiac conditions in one family. Conclusion: NGS allows a comprehensive way of mutation detection which more and more uncovers the complexity of previously thought monogenetic conditions. Our data point out the importance of a thoughtful approach of genetic data interpretation especially in clinical settings and the careful usage for predictive testing in family members with potential life threatening arrhythmias.
    Preview · Article · Aug 2013 · European Heart Journal
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    ABSTRACT: To investigate the role of gene localization and genome organization in cell-cell signalling and regulation, we mapped the distribution pattern of gene families that comprise core components of intercellular communication networks. Our study is centered on the distinct evolutionarily conserved metazoan signalling pathways that employ proteins in the receptor tyrosine kinase, WNT, hedgehog, NOTCH, Janus kinase/STAT, transforming growth factor beta, and nuclear hormone receptor protein families. Aberrant activity of these signalling pathways is closely associated with the promotion and maintenance of human cancers. The cataloguing and mapping of genes encoding these signalling proteins and comparisons across species has led us to propose that the genome can be subdivided into six genome-wide primary linkage groups (PLGs). PLGs are composed of assemblages of gene families that are often mutually exclusive, raising the possibility of unique functional identities for each group. Examination of the localization patterns of genes with distinct functions in signal transduction demonstrates dichotomous segregation patterns. For example, gene families of cell-surface receptors localize to genomic compartments that are distinct from the locations of their cognate ligand gene families. Additionally, genes encoding negative-acting components of signalling pathways (inhibitors and antagonists) are topologically separated from their positive regulators and other signal transducer genes. We, therefore, propose the existence of conserved genomic territories that encode key proteins required for the proper activity of metazoan signaling and regulatory systems. Disruption in this pattern of topologic genomic organization may contribute to aberrant regulation in hereditary or acquired diseases such as cancer. We further propose that long-range looping genomic regulatory interactions may provide a mechanism favouring the remarkable retention of these conserved gene clusters during chordate evolution.
    No preview · Article · Apr 2013 · Genome
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    Jung Soh · Paul M.K. Gordon · Christoph W Sensen
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    ABSTRACT: The Bluejay genome browser is a stand-alone visualization tool for the multi-scale viewing of annotated genomes and other genomic elements. Bluejay allows users to customize display features to suit their needs, and produces publication-quality graphics. Bluejay provides a multitude of ways to interrelate biological data at the genome scale. Users can load gene expression data into a genome display for expression visualization in context. Multiple genomes can be compared concurrently, including time series expression data, based on Gene Ontology labels. External, context-sensitive biological Web Services are linked to the displayed genomic elements ad hoc for in-depth genomic data analysis and interpretation. Users can mark multiple points of interest in a genome by creating waypoints, and exploit them for easy navigation of single or multiple genomes. Using this comprehensive visual environment, users can study a gene not just in relation to its genome, but also its transcriptome and evolutionary origins. Written in Java, Bluejay is platform-independent and is freely available from http://bluejay.ucalgary.ca.
    Full-text · Article · Mar 2012 · Current protocols in bioinformatics / editoral board, Andreas D. Baxevanis ... [et al.]
  • Christoph W. Sensen · Jung Soh · Paul M.K Gordon

    No preview · Book · Jan 2012
  • Paul M. K. Gordon · Ken Barker · Christoph W. Sensen
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    ABSTRACT: Seahawk is a browser for Moby Web services, which are online tools using a shared semantic registry and data formats. To make a wider array of tools available within Seahawk, the Daggoo system helps users adapt forms on existing Web sites to Moby’s specifications. Biologists were interviewed and given workflow design tasks, which revealed the types of tools present in their conceptual analysis workflows, and the types of control flow they understood. These observations were used to enhance Seahawk so that Moby and external Web tools can be browsed to create workflows "by demonstration". A flow-up user study measured how effectively biologists could 1) demonstrate a workflow for a realistic task, 2) understand the automatically generated workflow, and 3) use the workflow in the Taverna workflow editor/enactor. The results show promise that biologists without programming experience can become self-sufficient in analysis automation, using workflow-by-demonstration as a first step.
    No preview · Conference Paper · Aug 2010
  • Paul M. K. Gordon · Ken Barker · Christoph W. Sensen
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    ABSTRACT: Programming-by-example (PbE) as a technique can only make substantial progress by addressing the open problem commonly known as the Semantic Gap. This gap is the discrepancy between what the user intended by their actions, and how the inference engine generalizes the actions for reuse in a program. The Seahawk/Daggoo PbE system attempts to close this gap in a novel way: by using Semantic Web and Web Service resources as the building blocks the user manipulates during the demonstration stage of PbE. This eliminates the need for PbE inference by leveraging domain-specific Web Services and community-based agreements about data meanings. The semantic gap in PbE is closed a priori because of semantic agreement between users and service providers within a domain. The new PbE system has been tested in the domain of Bioinformatics to create Web Service workflows, with justification and results reported here. Fundamentally, Seahawk/Daggoo is domain-agnostics because semantics are defined in Web-based ontologies rather than by the PbE system itself. Novel action-to-workflow concept mappings are also introduced.
    No preview · Conference Paper · Jan 2010
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    ABSTRACT: Anaerobranca gottschalkii strain LBS3 T is an extremophile living at high temperature (up to 65 degrees C) and in alkaline environments (up to pH 10.5). An assembly of 696 DNA contigs representing about 96% of the 2.26-Mbp genome of A. gottschalkii has been generated with a low-sequence-coverage shotgun-sequencing strategy. The chosen sequencing strategy provided rapid and economical access to genes encoding key enzymes of the mono- and polysaccharide metabolism, without dilution of spare resources for extensive sequencing of genes lacking potential economical value. Five of these amylolytic enzymes of considerable commercial interest for biotechnological applications have been expressed and characterized in more detail after identification of their genes in the partial genome sequence: type I pullulanase, cyclodextrin glycosyltransferase (CGTase), two alpha-amylases (AmyA and AmyB), and an alpha-1,4-glucan-branching enzyme.
    No preview · Article · Feb 2009 · Journal of Molecular Microbiology and Biotechnology
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    ABSTRACT: To gain insight into the disease progression of transmissible spongiform encephalopathies (TSE), we searched for disease-specific patterns in circulating nucleic acids (CNA) in elk and cattle. In a 25-month time-course experiment, CNAs were isolated from blood samples of 24 elk (Cervus elaphus) orally challenged with chronic wasting disease (CWD) infectious material. In a separate experiment, blood-sample CNAs from 29 experimental cattle (Bos taurus) 40 months post-inoculation with clinical bovine spongiform encephalopathy (BSE) were analyzed according to the same protocol. Next-generation sequencing provided broad elucidation of sample CNAs: we detected infection-specific sequences as early as 11 months in elk (i.e. at least 3 months before the appearance of the first clinical signs) and we established CNA patterns related to BSE in cattle at least 4 months prior to clinical signs. In elk, a progression of CNA sequence patterns was found to precede and correlate with macro-observable disease progression, including delayed CWD progression in elk with PrP genotype LM. Some of the patterns identified contain transcription-factor-binding sites linked to endogenous retroviral integration. These patterns suggest that retroviruses may be connected to the manifestation of TSEs. Our results may become useful for the early diagnosis of TSE in live elk and cattle.
    Full-text · Article · Jan 2009 · Nucleic Acids Research
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    ABSTRACT: We have deployed a software library for the management, edition and standardization of user data that aims to facilitate data transformation and promote service interoperability by understanding I/O descriptions. The tool, named BioData-SF, is able to use standard data models stored elsewhere to guide the parsing and interpretation of user data (e.g. flat text files or even binary files). The kernel of the system provides a gateway embedding various software for specific datatypes, mixed with an extensible set of rules and regular expressions to manage the automatic identification of data types and perform appropriate transformations. BioData-SF can be used as a software library, or as a plug-in to be embedded in other applications and it is freely available as open source in www.bitlab-es.com/BioDataSF.
    Full-text · Article · Jan 2009
  • J. Soh · P.M.K. Gordon · C.W. Sensen
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    ABSTRACT: We have developed the Bluejay system, a visual environment for the visualization and comparison of genomes and associated biological data. The software system offers many innovative features that are essential to genome research but were not available previously. The data integration abilities allow the user to integrate gene expression data sets into a genomic context and to seamlessly invoke external Web-based services that are available for biological objects. The comparative genomics capability provides the visualization of multiple whole genomes in one context along with many crucial gene comparison features. The user can also use GPS-inspired waypoints for aligning genomes to facilitate easy comparison as well as for navigating within a genome effortlessly. Bluejay provides a unique set of customizable genome browsing and comparison features for the many biologists who want to answer complex questions using completely sequenced genomes. We expect Bluejay to be beneficial to systems biology in general and genome research in particular.
    No preview · Article · Jan 2009
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    ABSTRACT: The INhibitor of Growth (ING) family of type II tumor suppressors (ING1-ING5) is involved in many cellular processes such as cell aging, apoptosis, DNA repair and tumorigenesis. To expand our understanding of the proteins with which the ING proteins interact, we designed a method that did not depend upon large-scale proteomics-based methods, since they may fail to highlight transient or relatively weak interactions. Here we test a cross-species (yeast, fly, and human) bioinformatics-based approach to identify potential human ING-interacting proteins with higher probability and accuracy than approaches based on screens in a single species. We confirm the validity of this screen and show that ING1 interacts specifically with three of the three proteins tested; p38MAPK, MEKK4 and RAD50. These novel ING-interacting proteins further link ING proteins to cell stress and DNA damage signaling, providing previously unknown upstream links to DNA damage response pathways in which ING1 participates. The bioinformatics approach we describe can be used to create an interaction prediction list for any human proteins with yeast homolog(s). None of the validated interactions were predicted by the conventional protein-protein interaction tools we tested. Validation of our approach by traditional laboratory techniques shows that we can extract value from the voluminous weak interaction data already elucidated in yeast and fly databases. We therefore propose that the weak (low signal to noise ratio) data from large-scale interaction datasets are currently underutilized.
    Full-text · Article · Oct 2008 · BMC Genomics
  • Paul M. K. Gordon · Christoph W. Sensen
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    ABSTRACT: Semantic annotations for WSDL (SAWSDL) is a recently adopted W3C recommendation that provides a mechanism by which WSDL documents can reference external, domain-specific semantic models in order to provide concept-level interoperability of Web Services. Moby is an established protocol for providing semantic Web Services developed by the bioinformatics community: we use Moby to provide a grounding for a SAWSDL implementation in bioinformatics. Our software (Daggoo) allows users to create Moby-compliant semantic Web Services by simply adding SAWSDL markup to existing WSDL files. These new services are compatible with existing Moby services and client software. The Java software we present consists of a proxy servlet, a URI-resolution mechanism, and rule systems for converting back and forth between Moby and XML Schema data formats. As an early implementation of SAWSDL, Daggoo reveals shortcomings in the notation, and several additional technologies needed to achieve real-world semantic interoperability of WSDL-based services. Based on our experience, we suggest how to improve the semantic annotation mechanism, and how to reduce the programming burden for individual service providers. Furthermore, we demonstrate the importance of a semantically-enabled registry for services and data types in facilitating scientist-driven, rather than programmer-driven, Web service choreography.
    No preview · Conference Paper · Sep 2008
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    ABSTRACT: The BioMoby project was initiated in 2001 from within the model organism database community. It aimed to standardize methodologies to facilitate information exchange and access to analytical resources, using a consensus driven approach. Six years later, the BioMoby development community is pleased to announce the release of the 1.0 version of the interoperability framework, registry Application Programming Interface and supporting Perl and Java code-bases. Together, these provide interoperable access to over 1400 bioinformatics resources worldwide through the BioMoby platform, and this number continues to grow. Here we highlight and discuss the features of BioMoby that make it distinct from other Semantic Web Service and interoperability initiatives, and that have been instrumental to its deployment and use by a wide community of bioinformatics service providers. The standard, client software, and supporting code libraries are all freely available at http://www.biomoby.org/.
    Full-text · Article · Jun 2008 · Briefings in Bioinformatics
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    ABSTRACT: The genome sequence of the sulfate-reducing bacterium Desulfovibrio vulgaris Hildenborough was reanalyzed to design unique 70-mer oligonucleotide probes against 2,824 probable protein-coding regions. These included three genes not previously annotated, including one that encodes a c-type cytochrome. Using microarrays printed with these 70-mer probes, we analyzed the gene expression profile of wild-type D. vulgaris grown on cathodic hydrogen, generated at an iron electrode surface with an imposed negative potential of −1.1 V (cathodic protection conditions). The gene expression profile of cells grown on cathodic hydrogen was compared to that of cells grown with gaseous hydrogen bubbling through the culture. Relative to the latter, the electrode-grown cells overexpressed two hydrogenases, the hyn-1 genes for [NiFe] hydrogenase 1 and the hyd genes, encoding [Fe] hydrogenase. The hmc genes for the high-molecular-weight cytochrome complex, which allows electron flow from the hydrogenases across the cytoplasmic membrane, were also overexpressed. In contrast, cells grown on gaseous hydrogen overexpressed the hys genes for [NiFeSe] hydrogenase. Cells growing on the electrode also overexpressed genes encoding proteins which promote biofilm formation. Although the gene expression profiles for these two modes of growth were distinct, they were more closely related to each other than to that for cells grown in a lactate- and sulfate-containing medium. Electrochemically measured corrosion rates were lower for iron electrodes covered with hyn-1, hyd, and hmc mutant biofilms than for wild-type biofilms. This confirms the importance, suggested by the gene expression studies, of the corresponding gene products in D. vulgaris-mediated iron corrosion.
    Full-text · Article · May 2008 · Applied and Environmental Microbiology
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    ABSTRACT: IntroductionThe Graphical SystemConclusions and Open IssuesReferences
    No preview · Chapter · Mar 2008
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    ABSTRACT: IntroductionThe MAGPIE Graphical SystemThe Hierarchical MAGPIE Display SystemOverview ImagesSecondary Genome Context ImagesThe Bluejay Data Visualization SystemBluejay ArchitectureBluejay Usability FeaturesConclusions and Open Issues
    No preview · Chapter · Jan 2008
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    ABSTRACT: In order to characterize the genome-wide transcriptional response of the hyperthermophilic, aerobic crenarchaeote Sulfolobus solfataricus to UV damage, we used high-density DNA microarrays which covered 3,368 genetic features encoded on the host genome, as well as the genes of several extrachromosomal genetic elements. While no significant up-regulation of genes potentially involved in direct DNA damage reversal was observed, a specific transcriptional UV response involving 55 genes could be dissected. Although flow cytometry showed only modest perturbation of the cell cycle, strong modulation of the transcript levels of the Cdc6 replication initiator genes was observed. Up-regulation of an operon encoding Mre11 and Rad50 homologs pointed to induction of recombinational repair. Consistent with this, DNA double-strand breaks were observed between 2 and 8 h after UV treatment, possibly resulting from replication fork collapse at damaged DNA sites. The strong transcriptional induction of genes which potentially encode functions for pilus formation suggested that conjugational activity might lead to enhanced exchange of genetic material. In support of this, a statistical microscopic analysis demonstrated that large cell aggregates formed upon UV exposure. Together, this provided supporting evidence to a link between recombinational repair and conjugation events.
    Full-text · Article · Jan 2008 · Journal of bacteriology
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    ABSTRACT: IntroductionThe Graphical SystemConclusions and Open IssuesReferences
    No preview · Article · Dec 2007

Publication Stats

2k Citations
152.15 Total Impact Points

Institutions

  • 2001-2013
    • The University of Calgary
      • • Department of Biochemistry and Molecular Biology
      • • Faculty of Medicine
      Calgary, Alberta, Canada
  • 2002
    • National Research Council Canada
      • Biotechnology Research Institute (BRI)
      Ottawa, Ontario, Canada
  • 2000
    • Université Paris-Sud 11
      • Institut de Génétique et Microbiologie (IGMORS)
      Paris, Ile-de-France, France