Systems developmental biology: the use of ontologies in annotating models and in identifying gene function within and across species

Abstract

Systems developmental biology is an approach to the study of embryogenesis that attempts to analyze complex developmental processes through integrating the roles of their molecular, cellular, and tissue participants within a computational framework. This article discusses ways of annotating these participants using standard terms and IDs now available in public ontologies (these are areas of hierarchical knowledge formalized to be computationally accessible) for tissues, cells, and processes. Such annotations bring two types of benefit. The first comes from using standard terms: This allows linkage to other resources that use them (e.g., GXD, the gene-expression [G-E] database for mouse development). The second comes from the annotation procedure itself: This can lead to the identification of common processes that are used in very different and apparently unrelated events, even in other organisms. One implication of this is the potential for identifying the genes underpinning common developmental processes in different tissues through Boolean analysis of their G-E profiles. While it is easiest to do this for single organisms, the approach is extendable to analyzing similar processes in different organisms. Although the full computational infrastructure for such an analysis has yet to be put in place, two examples are briefly considered as illustration. First, the early development of the mouse urogenital system shows how a line of development can be graphically formalized using ontologies. Second, Boolean analysis of the G-E profiles of the mesenchyme-to-epithelium transitions that take place during mouse development suggest Lhx1, Foxc1, and Meox1 as candidate transcription factors for mediating this process.

Fig. 1

The ontology of mouse developmental anatomy as displayed in the COBrA browser. The left panel shows the tissues in the metanephros of the TS 19 (E11.5 mouse). These tissues carry an EMAP ID. The right panel shows the ontology of what is called the “abstract mouse” and includes all the tissues with range of times at which they are present during embryogenesis. These terms carry an EMAPA ID

Fig. 2

The Cell-Type Ontology visualized in the OBO-Edit browser. The left panel shows the ontology with its classes for cell types with the motile cell entry opened and neural crest cell highlighted. The central panel gives the ID and the definition, while the right panel shows the various places within the graph where the neural crest cell can be found

Fig. 3

The process component of the Gene Ontology (left panel) visualized in the OBO-Edit browser. The cell differentiation term is highlighted (left panel) and found in two contexts (right panel). The center panel gives the definition and the ID

Fig. 4

A systems model of mouse urogenital development during the periods TS 13–19 (E8.5–E11.5) showing the tissues present at each time interval, the cell types, and the processes driving change, all of which have unique ontology IDs (for further details see http://www.bioontology.org/wiki/images/1/1a/CARO-UG-development-JB.pdf)

Fig. 5

Diagrammatic representation of the Boolean subtractions of (left) the gene-expression patterns of four tissues that undergo the same developmental process; this gives a mixture of process genes and common (housekeeping) genes. A second subtraction (right) eliminates housekeeping genes

Fig. 6

Left Waddington’s original drawing of the epigenetic landscape showing the developmental trajectory of a cell being shaped by its tissue environment. Right A later drawing showing that this environment is itself underpinned by complex genetic interactions (Waddington , , with permission from Cambridge University Press)