Data - Human

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Driver Genes:

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ACBD5 ADAMTS18 ADGRV1 AHI1 ALMS1 ARL13B BBIP1 BBS1 BBS10 BBS12 BBS2 BBS4 BBS5 BBS7 BBS9 C12ORF57 C12ORF65 CC2D2A CEP250 CEP290 CFAP410 CNNM4 COL11A1 COL18A1 CSPP1 DNAJC17 DTHD1 EFEMP1 GNPTG HGSNAT HMCN1 HMX1 IFT27 INPP5E IQCB1 LAMA1 LCA5 LZTFL1 MFRP MKKS MKS1 MTTP MT_ATP6 MT_ND4 MT_TH MT_TL1 MT_TP MT_TS2 NMNAT1 NR2F1 OFD1 PANK2 PCDH15 PDE6A PDE6B PDE6D PDZD7 PEX1 PEX2 PEX7 PLK4 PNPLA6 POC1B RD3 RDH11 RDH12 RPGRIP1L SDCCAG8 TCTN2 TIMM8A TMEM138 TMEM216 TMEM231 TMEM237 USH1G VCAN VPS13B WDR19 WHRN ABCA4 ABCC6 ABHD12 ACO2 ADAM9 ADGRA3 AGBL5 AIPL1 ARHGEF18 ARL2BP ARL3 ATF6 ATXN7 BEST1 C1QTNF5 CA4 CABP4 CACNA1F CACNA2D4 CAPN5 CDH16 CDHR1 CERKL CHM CLUAP1 CNGA1 CNGA3 CNGB1 CNGB3 CRB1 CRX CYP4V2 DHDDS DHX38 DMD DRAM2 EMC1 EYS FAM161A FLVCR1 FSCN2 FZD4 GNAT1 GNAT2 GNB3 GPR179 GRK1 GRM6 GUCA1A GUCA1B HK1 IDH3B IMPDH1 IMPG1 IMPG2 INVS ITM2B KCNJ13 KCNV2 KIAA1549 KIF11 KIZ KLHL7 LRAT LRIT3 MAK MAPKAPK3 MERTK MFN2 MFSD8 MIR204 NDP NEK2 NEUROD1 NYX OAT OPN1LW OPN1MW OPN1SW PCYT1A PDE6C PDE6H PGK1 PHYH PITPNM3 PLA2G5 POLG2 PRCD PRDM13 PROM1 PRPF3 PRPF31 PRPF4 PRPF6 PRPF8 RAB28 RAX2 RB1 RBP3 RCBTB1 RDH5 REEP6 RGR RGS9 RGS9BP RHO RIMS1 RLBP1 ROM1 RP1 RP1L1 RP9 SAG SAMD11 SCN2A SEMA4A SEMA6B SLC24A1 SLC7A14 SNRNP200 SPP2 TEAD1 TIMP3 TMEM126A TOPORS TPP1 TRNT1 TRPM1 TSPAN12 TTLL5 TTPA TUBGCP4 TUBGCP6 UNC119 ZNF408 ZNF513 ADIPOR1 ARL6 C8ORF37 CDH23 CDH3 CEP164 CEP78 CFH CIB2 CLN3 CLRN1 COL2A1 COL9A1 CTNNA1 ELOVL4 GDF6 GUCY2D HARS IFT140 IFT172 JAG1 LRP5 MVK MYO7A NPHP1 NPHP3 NPHP4 NR2E3 NRL OPA1 OPA3 OTX2 PAX2 PAX6 PCARE PDE6G POLG PRPH2 PRPS1 RBP4 RP2 RPE65 RPGR RPGRIP1 RS1 SCLT1 SCO2 SLC4A3 SPATA7 SRD5A3 TREX1 TRIM32 TTC21B TTC8 TUB TULP1 USH1C USH2A WDPCP WFS1 ZNF423

Sources

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RPGeNet is a curated network built from interactions gathered from two interaction databases, BioGRID and STRING, as well as, from the protein interaction text-mining tool, PPaxe.

BioGRID is a genetic and protein interaction database that contains experimentally verified interactions for a plethora of species. STRING is only a protein interaction database that contains both verified interactions and non-verifed predictions. The databases were filterd by species to ensure only human interactions were included in the network (two species hybrid interactions were also discarded). STRING, containing many non-experimentally verified predictions, had all interactions with no evidence filtered out.

STRING database offers a large range of sources of evidences for experimentally validated and predicted protein-to-protein interactions. RPGeNet only includes experimentally validated and no predicted interactions. The graph above shows the proportions of each source found of the experimentally validated interactions used in RPGeNet.

The previous figure shows the distribution of the PPaxe scores given to the interactions detected, the number of PPaxe interactions and the average score depending on the cutoff score chosen. In an attempt to optimize the number interactions while reducing false positive interactions and increasing false-negatives, the cutoff score chosen was 0.65.

Network

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To build the complete core network, it was first needed to create the skeleton: a graph network that connects all the driver genes through their shortest paths between them. There are further subgraph levels above the skeleton (level 0 subgraph) that are an extension of that initial graph. The first level is an extension of the skeleton with the addition of parents and children genes that connect to the skeleton but are not themselves within the skeleton. The next level includes parents and children of the genes found within the first level that are not already in the skeleton and level one. The same pattern continues until there is a saturation (no more higher levels can be derived as there are no parent/child edges left to expand the last level), except for the wholegraph defining the complete core network that includes genes that still do not connect with the last network level.

The contribution of evidences from each source to RPGeNet build 2.0.2 is described on the following table:

Graph Topology

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A summary of graph statistics for RPGeNet build 2.0.2 at each of the subgraph levels derived from the initial skeleton graph (level 0 subgraph) can be found on the table below:

Comparison of the in and out degrees for each level of the interactions graph:

Comparison with previous version

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With an addition of 166 new driver genes now known, RPGeNet was in need of an update. The increase in the number of driver genes partially precipitated an early saturation in the number of levels from the skeleton. Our new network, however, does have less non-redundant interactions and genes in comparison to the previous network. This is mainly due to the extensive filtering of STRING. The previous network included the predictions but the updated network only includes interactions with evidences.

Network Explorer Interface

Here we have an example of the result of an initial query for CERKL on RPGeNet.v1 and v2 on screenshots below (top and bottom respectively), to illustrate design changes of Network Explorer web interface but also new functionalities.

You can download the JSON file containing the saved graph layout to reproduce the CERKL network on RPGeNet.v2 example from the above screenshot.

Graph Comparison

Expression analysis

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Unfortunately, there are few multi-tissue microarray expression experiments that include retina within their list of tissues. We had to rely on a relatively old microarray experiment (GSE7905) that includes thirty-two different tissues including the retina, liver, brain, skeletal muscle and others. Although the experiment is not recent, the expression values are still useful in finding potentially important pathways associated with retinitis pigmentosa by looking to see if the genes in a pathway all express within the retina. We hope to soon be able to have an updated multitissue expression experiment to use.

Volcano chart

Heatmap

Top twenty relatively overexpressed genes in retina in comparison to all tissues:

Top twenty relatively underexpressed genes in retina in comparison to all tissues: