Fig. 5

Investigation of molecular substrates that precipitate phenotypes inflicted by calr deficiency using bioinformatic prioritization algorithms. a Down regulated genes within the PC truncation variant was the only transcript expression cohort that enriched for Cardiovascular Disease. Here, focused bioinformatic extraction of Cardiovascular Disease prioritized the subcategory of Cardiac Arrhythmia, which revealed enrichment of Atrial Flutter (see text). Arrhythmogenic category shown on y-axis, with –log (p-value) on x-axis. Inset – Atrial Flutter was composed of several genes, as shown. b Venn diagram intersection of total down regulated genes within the PC variant (blue circle) with those down regulated in the calr knockout condition (orange circle) revealed eight genes consistently decreased in both conditions (see text). Numbers in parentheses indicate total number of down regulated genes for that cohort. c Radial layout of the network containing the eight consistently down regulated genes reveals the most connected gene as Pitx2 (red circle). d Topological analysis confirms gene prioritization. Upper panel – plotting degree (number of connections per gene) versus betweenness centrality (an indicator of informational load and flow) reveals Pitx2 as the highest priority hub (red circle). Lower panel – alternative plot using betweenness centrality versus radiality (another centrality metric that indicates node accessibility) again demonstrates prioritization of Pitx2 (red circle). e Transcriptome meta-analysis by DAVID demonstrates enrichment of a cardiac cluster containing Pitx2 (red box)