Pathway-pathway and pathway-gene interactions

In cells, pathways interact with each other rather like street-meets-street in a city map. In order to obtain a systems overview of how these pathways function together, it is of great value to generate a pathway network, which can be done by taking account of the connections/interactions between pathways. One pathway may interact with another for multiple reasons: shared genes or compounds, interactions or reactions between genes or compounds, signal transductions, etc. We chose to work with KEGG Pathway Database, which documents these many types of influences and interactions, to help us generate this pathway network overview, because it is a comprehensive and frequently updated database that represents our present knowledge of pathways and the known interactions amongst pathways based on accumulated research findings. Pathway-pathway interactions are represented in KEGG in each pathway map by displaying the name of an interacting pathway in that map. For example, if one pathway appears at the certain location in the map of another pathway, this suggests that these two pathways were interacting in relation to the activities or functions represented in that part of the map, or that one was involved in a certain reaction or process of another. On this basis, we determined the pathway-pathway interactions by tabulating these instances. For the merged collections, if one pathway not in the collection interacted with at least one of the pathways in the collection, this pathway was considered to be interacting with the collection. For the pathway “pathways in cancer” (http://www.genome.jp/kegg-bin/show_pathway?map05200, or go to KEGG, search for “pathways in cancer”, and find the map05200), other cancer pathways (such as “glioma”, “thyroid cancer” etc.) which were listed on the bottom of the KEGG pathway map, did not count as interacting with the “pathways in cancer”, as they are not actually interacting with each other but only being listed in the map.

For pathway-pathway interactions, the total number of interactions was tabulated for each pathway/collection (S3 Table), and then visualized in a network diagram.

To investigate pathway-gene interactions characterizing the involvement of each ASD gene in the pathway network, the number of pathways in which each gene participates was counted, and the total number of pathways was tabulated for each gene.