Improving Interpretation of Cardiac Phenotypes and Enhancing Discovery With Expanded Knowledge in the Gene Ontology.

Ruth C Lovering,Susan Tweedie,Andrew Tinker,Judith A Blake,Paul R Riley,Douglas G Howe,Rachael P Huntley,Philippa J Talmud,David Osumi-Sutherland,Paola Roncaglia,David P Hill,Tanya Z Berardini,Pier D Lambiase,Rebecca E Foulger,Ross A Breckenridge ,N.h Campbell ,Varsha Khodiyar ,Lucie H Clapp ,Stanley J F Laulederkind ,Perry Elliott

doi:10.1161/circgen.117.001813

Ruth C Lovering, Susan Tweedie + Show 18 more

Open Access

https://doi.org/10.1161/circgen.117.001813

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Abstract

A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments. The Gene Ontology (GO) Consortium provides structured, controlled vocabularies of biological terms that can be used to summarize and analyze functional knowledge for gene products. In this study, we created a computational resource to facilitate genetic studies of cardiac physiology by integrating literature curation with attention to an improved and expanded ontological representation of heart processes in the Gene Ontology. As a result, the Gene Ontology now contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles. Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci. We determined that a combination of curation and ontology development for heart-specific genes and processes supports the identification and downstream analysis of genes responsible for the spread of the cardiac action potential through the heart. Annotating these genes and processes in a structured format facilitates data analysis and supports effective retrieval of gene-centric information about cardiac defects.

Highlights

A systems biology approach to cardiac physiology requires a comprehensive representation of how coordinated processes operate in the heart, as well as the ability to interpret relevant transcriptomic and proteomic experiments
The Gene Ontology contains terms that comprehensively describe the roles of proteins in cardiac muscle cell action potential, electrical coupling, and the transmission of the electrical impulse from the sinoatrial node to the ventricles
Evaluating the effectiveness of this approach to inform data analysis demonstrated that Gene Ontology annotations, analyzed within an expanded ontological context of heart processes, can help to identify candidate genes associated with arrhythmic disease risk loci

Summary

Methods

The data, analytic methods, and study materials have been made available to other researchers for purposes of reproducing the results or replicating the procedure. The annotations have been incorporated into many biological knowledge bases, including Ensembl,[10] UniProtKB,[11] and NCBI-Gene,[12] and exploited by numerous freely available functional analysis tools, including Database for Annotation, Visualization and Integrated Discovery,[13] g:profiler,[14] Protein Analysis Through Evolutionary Relationships (PANTHER),[15] and Visual Annotation Display (VLAD).[16] Full methods are available in the Data Supplement. To determine the impact of this focused project, we used gene association files from November 2011 (ie, the start of this project) and February 2016 (ie, the end of the project; files available from ftp://ftp.ebi.ac.uk/pub/databases/GO/goa/). For both analyses, the ontology version March 7, 2016 was included (available from http://geneontology.org/page/download-ontology)

Results

Discussion

Conclusion