Chapter Four - The Neurobehavior Ontology: An Ontology for Annotation and Integration of Behavior and Behavioral Phenotypes
Introduction
The study of the behavior of organisms forms a major biological discipline encompassed via the investigation of physical, mental, and environmental influences that underpin behavioral-related processes. Geneticists have been studying behavior since 1800s when Francis Galton started investigating heredity and human behavior systematically (Rose & Rose, 2011). We now know that one of the most important factors for behavioral variation within and across organisms lies in genetic diversity (Hamer, 2002, Mackay, 2008). Behavioral geneticists attempt to unravel this behavioral variation by investigating the underlying mechanisms that govern it in an effort to elucidate our understanding of the pathogenesis of neuropsychiatric disorders (Congdon, Poldrack, & Freimer, 2010).
The great successes and advances both in genomics and in our abilities to quantify and analyze genomic information have transformed genetics over the past decade. Behavioral geneticists take advantage of these in order to gain an in-depth understanding of the genetic architecture of behavior. They seek to understand what genes affect behavior, how they interact with other genes, what is the molecular basis of their allelic variation, and how this variation behaves with respect to the environment (Holden, 2001). One of the tools that they employ to achieve these goals is the use of animal models that provide a platform where complex behaviors can be studied and quantified with substantial progress over the past in recent years, especially in respect with research related to the mouse and the fruit fly Drosophila (Mackay, 2008, Wehner et al., 2001).
Animal models have been proven useful for unveiling the genetic basis of many behavior-related diseases including various neurodegenerative disorders such as Parkinson's, Huntington's, spinocerebellar ataxia, and Alzheimer's disease, as well as for providing the medium for novel drug discovery. Furthermore, animal models for diseases whose indicators are formed by behavioral observations rather than definitive neuropathological markers are being developed. For example, there are various mouse models of loss of Fragile X mental retardation 1 (Fmr1) or methyl-CpG-binding protein-2 (Mecp2) or ubiquitin protein ligase 3A (Ube3A) function that underlie syndromes associated with autistic-like behavior (Moy & Nadler, 2007).
There are now large international projects, consortia, and individual labs around the world that study and record the effect of genetic variations in various species and at various levels of granularity. Behavioral screens are part of the assays performed and include the study of a variety of behavioral phenotypes such as reproductive behavior, learning and memory, feeding behavior, sleep, and circadian rhythm (Brown et al., 2005, Levin and Cerutti, 2009, Sokolowski, 2001, Spuhler, 2009, Tecott and Nestler, 2004). The resulting data provide us with a wealth of information that can be exploited to investigate and reveal the molecular basis of behavior and behavioral disorders. However, while other domains of biology have made significant progress in systematically structuring and analyzing their data, we do not currently have a standardized way to characterize behavioral processes and phenotypes (Congdon et al., 2010). The provision of a method for recording behavior-related phenomena is necessary to enable integrative and comparative analyses of data and knowledge about behavior (Gkoutos, Green, Mallon, Hancock, & Davidson, 2004b).
In other areas of biomedical science, similar demands have lead to the generation of various resources that allow for the systematic characterization, organization, and recording of knowledge and data (Schofield, Sundberg, Hoehndorf, & Gkoutos, 2011a). In particular, the advent of the gene ontology (GO) (Ashburner et al., 2000) has provided a critical landmark in the use of ontologies to harmonize the description of domains of knowledge and facilitated the development of several other ontologies for various different domains. Ontologies are structured, standardized terminologies in which some aspect of the meaning of terms has been rendered computable. For example, the GO does not only include textual definitions of its terms but also machine readable, computable relations (such as is-a, part-of, and regulates) that enable the automated traversal of the ontology and analysis of the underlying data. Perhaps more importantly, the standardization of the terminology and the inclusion of computable definitions paved the way for interoperability between biomedical databases and have lead to the possibility for large-scale integration of biomedical data (Bada et al., 2004, Chen et al., 2012, Hoehndorf et al., 2012, Hoehndorf et al., 2011, Hoehndorf et al., 2011).
Here, we present our efforts toward creating a framework that allows the systematic representation of behavior processes and related phenotype manifestations offering the tantalizing possibility of unifying behavioral data across species integrating and translating our knowledge so as to provide new grounds for targeting behavior-related diseases.
Section snippets
Neurobehavior ontology
Understanding what constitutes behavior will depend on its formal definition and the systematic representation of the processes involved in behavioral mechanisms. According to Tinbergen (1963), behavior biology is primarily concerned with four major questions: causation (mechanism), development (ontogeny), function (adaptation), and evolution (phylogeny) (Adcock, 2001). These four questions can be collapsed into two categories—the proximate (“how”) category that includes causation and
Human behavior phenotypes
Dissecting the genetic basis of behavior variation in humans is an important factor toward our understanding of human disease. The potential to identify the molecular underpinnings of human behavior and its characteristics depends on our ability to make meaningful genotype–phenotype correlations. Behavioral manifestations recorded in the clinic are not only an invaluable diagnostic tool but also provide insights to human pathophysiology and pathobiology. For example, the distinct behavioral
Discussion
The NBO is one of the first comprehensive ontologies designed for the integration of behavioral observations in animal organisms and humans. NBO's prime application is to provide the vocabulary that is required to integrate behavior observations within and across species. It is currently being applied by several model organism communities as well as for the description of human behavior-related disease phenotypes, and the use of a common, shared vocabulary for data annotation will lead to the
Ontology
The initial version of the ontology was developed using a combination of OBO-edit (Richter, Harris, Haendel, & Lewis, 2007) and emacs. Subsequently, we transformed the ontology into the OWL format and it is currently maintained using Protege4 (Noy et al., 2001). In addition to simple relationships connecting classes, NBO contains a wide range of additional logical axioms, which are intended primarily assist with automated maintenance, quality control, and classification of the ontology.
NBO and phenotype ontologies
Acknowledgments
This work was supported by the National Institutes of Health (Grant number R01 HG004838-02) and the European Commission's 7th Framework Programme, RICORDO project (Grant number 248502).
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