A Call for Systematic Research on Solute Carriers Adrián César-Razquin, Berend Snijder, Tristan Frappier-Brinton, Ruth Isserlin, Gergely Gyimesi, Xiaoyun Bai, Reinhart A. Reithmeier, David Hepworth, Matthias A. Hediger, Aled M. Edwards, Giulio Superti-Furga  Cell  Volume 162, Issue 3, Pages 478-487 (July 2015) DOI: 10.1016/j.cell.2015.07.022 Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 1 SLCs Are the Most Neglected Group of Genes in the Human Genome (A) Publication asymmetry is plotted against the average number of publications per group of genes. Publication counts per gene were retrieved from the gene2pubmed file provided and curated by NCBI. Gene groups comprise all HGNC gene families and super-families as well as the GO annotations for kinase activity (“kinases”) and ion channel activity (“ion channels”). Asymmetry is measured for each group of genes by calculating the skewness (as implemented in R’s “moments” package) of the distribution of the number of publications for all genes within the group. A very positive skew thus indicates an uneven distribution where a few genes in the family concentrate a much higher number of publications than the rest. Dot size relates to the number of members in each gene group, and color indicates gene groups where at least 80% of their members are annotated as membrane proteins by GO annotation (see legend). Labels for selected classes are shown. (B) Number of publications per SLC gene is displayed in descending order. The four SLCs with the most publications are annotated. The red line indicates the border at which genes have fewer than 15 publications. Cell 2015 162, 478-487DOI: (10.1016/j.cell.2015.07.022) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure 2 SLCs Are Expressed in Robust Tissue-Dependent Modules (A) Network visualization of SLC co-expression. Nodes in the network represent SLCs. Edges between nodes correspond to significant correlations consistently retrieved in three independent expression data sets from healthy human tissues. Only the top 2,500 most significant edges are shown, based on combined p values of the three independent correlations. Gray nodes indicate SLCs with at least one disease association, and red node outlines indicate the presence of at least one interacting small compound with an IC50 below 10 μM (OpenPHACTS). Edges are colored according to the tissue in which the two connected SLCs share the highest expression (highest mean rank; Illumina Body Map data set), as indicated in the legend. (B) SLC family co-expression enrichment network. Nodes in the network represent SLC families. Edges correspond to statistically enriched co-expression between members of the connected SLC families, as calculated by a hypergeometric test. Edge color relates to the significance of the enrichment and edge width is proportional to the number of co-expressed SLC pairs (see legend). Cell 2015 162, 478-487DOI: (10.1016/j.cell.2015.07.022) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure S1 Publication Bias on SLCs (A) Number of publications per SLC gene before 2003 (purple) and between 2012 and 2014 (green) are displayed in descending order according to the before 2003 count. Top and upcoming SLCs are labeled. (B) Same as Figure 1B, but publications counts were retrieved by manual querying of PubMed abstracts including all gene names and synonyms for each SLC. Insert shows high concordance between the automated (x axis) and the manually queried (y axis) publication counts per SLC. Cell 2015 162, 478-487DOI: (10.1016/j.cell.2015.07.022) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure S2 Few Disease-Associated SLCs Are Targeted by Small Compounds Number of disease associations (y axis) and small compound interactions (IC50 smaller than 10μM; x axis) are shown for each SLC, in log scale. All data were retrieved from OpenPHACTS. SLCs with neither disease associations nor interacting small compounds are excluded. Dot size indicates number of publications (see legend). Neurotransmitter transporters (SLC family 6; red) and neglected targets (green) are highlighted. Cell 2015 162, 478-487DOI: (10.1016/j.cell.2015.07.022) Copyright © 2015 Elsevier Inc. Terms and Conditions

Figure S3 SLCs Are Expressed in Robust Tissue-Dependent Modules (A) Same as Figure 2A, but edge colors are annotated with the 32 tissues dataset instead of the Illumina Body Map dataset. Only selected tissues are highlighted: liver (green) and kidney (blue) as in Figure 2A, together with small intestine and duodenum (pink). Other tissues are colored in gray. (B) Significance of the overlap of top 1000 correlations between tissue datasets (32 tissues, Illumina Body Map, Fantom5 – tissue samples), between cancer datasets (CCLE, Cosmic, and Cancer Cell Lines (Klijn et al., 2015) and between tissue and cancer datasets. P-values were calculated by a hypergeometric test. (C) Same as in Figure 2A, but SLC co-expression is analyzed in cancer expression datasets (CCLE, Cosmic, and Cancer Cell Lines). Cell 2015 162, 478-487DOI: (10.1016/j.cell.2015.07.022) Copyright © 2015 Elsevier Inc. Terms and Conditions