The Breadth and Depth of BioMedical Molecular Networks: The Reactome Perspective

The Breadth and Depth of BioMedical Molecular Networks: The Reactome Perspective

Bernard de Bono (European Bioinformatics Institute, UK and University of Malta, Malta)
Copyright: © 2009 |Pages: 16
DOI: 10.4018/978-1-60566-076-9.ch040
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Abstract

From a genetic perspective, disease can be interpreted in terms of a variation in molecular sequence or expression (dose) that impairs normal physiological function. To understand thoroughly the knockon effect such pathological changes may have, it is crucial to map out the physiological relationship affected genes maintain with their functional neighbors. The goal of the Reactome project is to build such a network knowledgebase for all human genes. Constructing a map of such extent and scope requires a considerable range of expertise, so this project collaborates with field experts to integrate their pathway knowledge into a single quality-checked human model. This resource dataset is systematically cross-referenced to major molecular and literature databases, and is accessible to the community in a number of well-established formats. As an evolving network systems resource, Reactome is also starting to provide increasingly powerful and robust tools to investigate tissue-specific biology and steer targeted drug design.
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Background: Depicting Normal Human Gene Function

A key step to integrating knowledge about gene function is to develop a unified method to describe the properties of their products. The Gene Ontology (GO) Consortium (Harris, Clark et al. 2004) has developed a successful interdisciplinary project to catalogue and standardize a vocabulary of terms depicting biological activity and localization of expressed products. Each term is supported by a text-based description that illustrates and defines a biological property, with which any number of gene products may be associated. This annotation strategy has achieved considerable coverage of a large number of genes from a wide variety of model organism databases (http://geneontology.org).

This qualitative relational classification of descriptive GO terms provides vital bearings on the functional landscape of sequence molecules. GO maintains actively three distinct ontologies of terms, namely, ‘Molecular Function’, ‘Biological Process’ and ‘Cellular Component’. GO’s stated objective is to keep its ontologies strictly orthogonal to each other, thus minimizing the descriptive overlap of these vocabularies.

Both ‘Molecular Function’ and ‘Biological Process’ terms represent some form of biological activity associated with gene products – a ‘process’ can be seen as a recognized series of ‘functions’. Some activity terms deal with the movement of biological entities (for example, ‘protein transporter activity’ (GO:0008565)), a significant proportion with a molecular conversion of some kind (for example, ‘adenylosuccinate lyase activity’ (GO:0004018)), while others are concerned with assembly (for example, ‘actin cable formation’ (GO:0045011)). In many ways, GO activity terms relate to a structural change that has a biological implication.

The ‘Cellular Component’ ontology describes subcellular and extracellular locations, representing a higher level of structural complexity, starting from macromolecular assemblies. For example, the GO term ‘actin cable’ (GO:0030482) is defined as ‘a long bundle of actin filaments, comprising filamentous actin and associated proteins, found in cells’.

In practice, GO terms describe where gene products locate themselves as well as an indication as to what their role is and how this is carried out. The wording employed in GO terms also provides a unique insight into the conceptual relationship of structure and activity and the difficulties often encountered in distinguishing the two. For instance, it is possible to find examples in which the biological purpose of a structure is considered at par with its activity (for example, ‘nutrient reservoir activity’ (GO:0045735) and ‘structural constituent of chitin-based cuticle’ (GO:0005214) are both Molecular Function terms).

Key Terms in this Chapter

Reaction: In Reactome, a Reaction is defined as the conversion of input substrate molecules to output product molecules in a single step.

Pathway: In Reactome, a Pathway is any grouping of related Reactions or Pathways, collectively known as Events. An Event may be a member of more than one Pathway.

Orthology: Homology (see above) as applied to features shared between species.

Biological Process: A biological process, as described by this set of GO terms, occurs through one or more ordered assemblies of molecular functions. It can be difficult to distinguish between a biological process and a molecular function, but the general rule is that a process must have more than one distinct step.

Kinetic Model: A model is a conceptual representation of a system or set of experimental observations. A kinetic model permits the simulation of such a system to observe the behaviour of its quantitative features.

Physiology: The science of large-scale behaviour of biological entities and their related chemical and physical phenomena.

Homology: In biology, entities or their functional systems that share common ancestry are said to be ‘homologous’.

Molecular Function: A set of GO terms describing activities, such as catalytic or binding activities, that occur at the molecular level. These represent activities rather than the molecules or complexes that perform the actions. Molecular functions generally correspond to activities that can be performed by individual gene products, but some activities are performed by assembled complexes of gene products.

Gene Ontology (GO): A collaborative effort to address the need for consistent descriptions of gene products in different databases. It has developed three structured controlled vocabularies (ontologies) that describe gene products in terms of their associated biological processes, cellular components and molecular functions in a species-independent manner.

Cellular Component: The cellular component ontology describes locations, at the levels of subcellular structures and macromolecular complexes.

PubMed: PubMed is a service of the U.S. National Library of Medicine that includes a large number of citations from life science journals for biomedical articles back to the 1950s. PubMed includes links to full text articles and other useful resources.

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