Pathway-specific protein domains are predictive for human diseases
Fig 2
(A) Regression between pathway specificity (PS) and the significance of overlap with the gold-standard domain-pathway pairs by sigmoidal curve fitting. Domain-pathway associations were divided into two groups: the top 16,000 associations that showed significant overlap (p < 0.01 by Fisher’s exact test) with the gold-standard data, and the remaining 33,636 associations. 4,506 domains for the top 16,000 associations were defined as pathway-specific domains (PSDs) and 3,856 domains for the remaining associations were defined as non-specific domains (NSDs). (B) Comparison of normalized variation rates (NVRs) for neutral and pathogenic variants between PSDs and NSDs (*, P < 0.01; n.s., P > 0.05) (C) Comparison of NVRs for three classes of missense disease mutations described by Sahni et al. and nonsynonymous variants known to affect physical protein interactions by IMEx consortium between PSDs and NSDs (*, P < 0.01; n.s., P > 0.05). (D) Comparison of the ratios (log base 2) of PSDs to NSDs for groups of human structural interaction network (hSIN) interfacing domains with similar sizes for different ranges of domain interaction connectivity. (E) Proposed models for the relationships between mutational consequences and the number of domain interactions. The blue node represents a hub domain that mediates interactions between a large number of proteins that contain domains with a single or a few, at most, interacting domains (green nodes), and the yellow nodes represent domains with moderate numbers of domain interactions, which are involved in ‘within-pathways’ (shaded areas).