Online Supporting Information S2: Proteins in each negative pathway Index Proteins ADO,ACTA1,DEGS2,EPHA3,EPHB4,EPHX2,EPOR,EREG,FTH1,GAD1,HTR6, IGF1R,KIR2DL4,NCR3,NME7,NOTCH1,OR10S1,OR2T33,OR56B4,OR7A10, Negative_1 OR8G1,PDGFC,PLCZ1,PROC,PRPS2,PTAFR,SGPP2,STMN1,VDAC3,ATP6V0 A1,MAPKAPK2 DCC,IDS,VTN,ACTN2,AKR1B10,CACNA1A,CHIA,DAAM2,FUT5,GCLM,GNAZ Negative_2 ,ITPA,NEU4,NTF3,OR10A3,PAPSS1,PARD3,PLOD1,RGS3,SCLY,SHC1,TN FRSF4,TP53 Negative_3 DAO,CACNA1D,HMGCS2,LAMB4,OR56A3,PRKCQ,SLC25A5 IL5,LHB,PGD,ADCY3,ALDH1A3,ATP13A2,BUB3,CD244,CYFIP2,EPHX2,F CER1G,FGD1,FGF4,FZD9,HSD17B7,IL6R,ITGAV,LEFTY1,LIPG,MAN1C1, Negative_4 MPDZ,PGM1,PGM3,PIGM,PLD1,PPP3CC,TBXAS1,TKTL2,TPH2,YWHAQ,PPP 1R12A HK2,MOS,TKT,TNN,B3GALT4,B3GAT3,CASP7,CDH1,CYFIP1,EFNA5,EXTL 1,FCGR3B,FGF20,GSTA5,GUK1,HSD3B7,ITGB4,MCM6,MYH3,NOD1,OR10H Negative_5 1,OR1C1,OR1E1,OR4C11,OR56A3,PPA1,PRKAA1,PRKAB2,RDH5,SLC27A1 ,SLC2A4,SMPD2,STK36,THBS1,SERPINC1 TNR,ATP5A1,CNGB1,CX3CL1,DEGS1,DNMT3B,EFNB2,FMO2,GUCY1B3,JAG Negative_6 2,LARS2,NUMB,PCCB,PGAM1,PLA2G1B,PLOD2,PRDX6,PRPS1,RFXANK FER,MVD,PAH,ACTC1,ADCY4,ADCY8,CBR3,CLDN16,CPT1A,DDOST,DDX56 ,DKK1,EFNB1,EPHA8,FCGR3A,GLS2,GSTM1,GZMB,HADHA,IL13RA2,KIR2 Negative_7 DS4,KLRK1,LAMB4,LGMN,MAGI1,NUDT2,OR13A1,OR1I1,OR4D11,OR4X2, OR6K2,OR8B4,OXCT1,PIK3R4,PPM1A,PRKAG3,SELP,SPHK2,SUCLG1,TAS 1R2,TAS1R3,THY1,TUBA1C,ZIC2,AASDHPPT,SERPIND1 MTR,ACAT2,ADCY2,ATP5D,BMPR1A,CACNA1E,CD38,CYP2A7,DDIT4,EXTL Negative_8 1,FCER1G,FGD3,FZD5,ITGAM,MAPK8,NR4A1,OR10V1,OR4F17,OR52D1,O R8J3,PLD1,PPA1,PSEN2,SKP1,TACR3,VNN1,CTNNBIP1 APAF1,APOA1,CARD11,CCDC6,CSF3R,CYP4F2,DAPK1,FLOT1,GSTM1,IL2 Negative_9 2,KLRK1,LARS,NGEF,OR7A17,PFN3,PIGL,POLR2E,PPCS,RAF1,SEMA3C, SULT1A4,TAS1R1,TCF7L1,TRMT11,XIAP,TNFRSF6B LPL,ADORA2A,ATP6V1H,B3GALT1,CLTCL1,CNGA4,DTX3L,IL23R,IRF5,N Negative_10 EU2,OR4M1,RDH12,SEMA4F,STAT5A,THBS4 AGL,CBS,FUK,ACSS1,ALAS2,ASAH1,ATP2A2,CD14,CD44,CLDN17,CYP1A 1,DDX23,DNMT1,EFNA4,ENPP7,EPOR,EXTL1,FLT1,GFPT1,GRIA1,HAO1, Negative_11 HTR2A,IFNA4,LEFTY2,MTHFD2,NCR2,OR10A2,OR1L6,OR2L3,OR51M1,OR 5B12,OR5M3,OR6C1,ORC3L,PLA2G2E,PLCB2,PTCH1,TAS1R2,ULK2,ATP6 V0A2,CACNA2D3 BID,BPNT1,CACNA1D,CXCL16,ENPP7,EPHA1,FUT4,GMPS,GRIN2C,IBSP, Negative_12 IL22,IL2RA,LLGL2,MAPK13,MTFMT,MTHFR,NOS3,OR56A1,PAK2,PIGU,P LCZ1,POLR3B,PTPN6,RAPGEF4,TUBA8,TUBB1,TNFRSF12A EGF,LTB,ACAT2,ADCY10,CCL26,CCNB3,CLDN1,DGAT2L4,DVL1,FBP1,IF NK,ITGAE,LAMA4,MCCC2,NEU3,NKD1,NLGN1,NT5C2,OR10H4,OR1L4,OR2 Negative_13 A42,OR2AE1,OR2Z1,OR4K1,OR51F2,OR5AK2,OR5V1,OR9G4,PDE1C,PIAS 2,PPAP2C,PPP1R1A,RBL1,ROBO1,SEMA4C,THBD,TUBA1B,B4GALNT1,HSD 17B10,TNFRSF18 MOS,OSM,WAS,AASDH,B3GALT2,B4GALT1,CDKN2A,CLDN19,DDX50,ENTPD Negative_14 3,F2RL1,GALNTL4,GNA13,HIF1A,IL12RB2,NAE1,NKD1,OR1J1,OR2M4,O R9I1,PLOD1,PLXNB1,SDHC,SH3BP2,STX6,TOLLIP,TUBB2B ADK,CFH,DAO,F9,MUT,ADCY5,ADH1A,ALDH1L1,CARS2,CD14,CD79A,CTB S,CYP2A7,DGKH,DUSP10,DUSP16,DUSP5,DVL2,FGF21,GALM,GNAI1,GST Negative_15 A2,HADHA,IDH1,IFNK,LDHD,LFNG,LTA4H,MASP1,OR10G8,OR51G2,PAX4 ,PIM1,RND1,TKTL2,TLR9,TNFRSF17 FUK,GH1,SPN,ACSM4,CACNB1,CACNB2,CCDC6,CCR4,CDK2,CKS1B,EHHAD H,FADS2,GALNT12,GRIA1,HCLS1,HIF1A,HMGCS1,HMGCS2,IL3RA,ITPA, Negative_16 KCNB1,MAP2K6,MAPK8,MTHFR,MYH2,NTF4,OR10A5,OR1C1,OR1J2,OR2T1 0,OR52L1,OR5AK2,PDE8A,PIGM,PIK3CA,PIP5K3,PLCG1,POLE,SHC1,SK IV2L2,SV2B,TJP1,TKTL1,TUBA3C,UROC1,HLA-DPA1 Negative_17 CALML6,CDKN1B,EFNA3,OR2T4 ME3,ACOX3,ADORA2B,AKR1C2,ALDH9A1,ATP5F1,B3GAT3,BAIAP2,BMP8A ,CXCL3,CYP1B1,DHRS4L2,HADHB,IDH1,IRS1,KLRC4,MAN1A1,MAP3K4,N Negative_18 KX6- 1,OR1Q1,OR2B6,OR2H1,OR7G3,PDE1A,PECAM1,PGAM4,PIGX,PPP2CB,PP T1,RHEB,SLC2A4,SV2C,SYNJ1,TAP1,UGCGL1,WNT7B CAT,CDA,LEP,PTS,B3GNT4,BLVRB,CLDN20,COASY,COL4A2,CTNNA2,EFN A1,FGF13,GALE,GBA3,GCNT3,GSTM4,HSD17B3,IL12RB1,IL2RB,IPPK,L Negative_19 RDD,MYH9,NOX1,NTF3,OR14C36,OR2T2,OR4K13,OR4N4,OR56A1,PDE3B, PIP4K2A,PTGFR,QARS,SPHK2,STK3,TP73,TUBA8,TUBB2A AR,C8B,CTH,IL9,ALDH1A1,ALOX5,BCL10,CACNB4,CDC25C,FOXO1,GALT Negative_20 ,GRIN2C,GSTT1,HAP1,IDI2,IL20,NRXN1,OR10C1,OR3A1,OR4K5,OR51Q 1,OR7G2,OR8D1,ORC4L,PER3,PIAS4,SPRY4,UGCGL1,YWHAZ,ATP6V1B2 FMO3,GSK3B,HLA- Negative_21 F,NPAS2,NTSR1,OR1I1,OR1L1,OR1Q1,OR52M1,P2RX4,POLD4,POLE4,ST X5,TNFRSF12A PC,AASDH,ACP6,ALDH7A1,ASRGL1,CCR3,CDC16,CDH2,CNGB1,COL4A6,D RD1,EFNB2,EIF4E2,FARS2,FBP1,GLI3,GNAI2,GRIN2C,GUCY1B3,HAO1, Negative_22 HNF1B,OR6C6,OR7G1,PIK3R5,PPP3CC,PRNP,RASSF5,SLC9A1,ST3GAL5, TGFBR1,WNT9A,XCL1,YARS ADA,C8G,IL8,AGPAT2,AMD1,CCKAR,COMP,DAPK2,EPHA2,GYS1,OR10J5, Negative_23 OR10K2,OR1L6,OR51T1,OR6B3,PARD6A,PDE2A,PPARA,RAPGEF2,RHOQ,S ETDB1,SMPD4 AGK,FH,GPT,IL4,ARRB2,ATP6AP1,B3GALT6,CASP10,CCL24,CFLAR,CYP 2A6,EPHA6,FGF1,FLT4,GALC,HBEGF,HSPA8,ITGAX,KNG1,MAP3K14,MAP Negative_24 K1,MGST2,MTFMT,NT5C1A,OR2A25,OR2L8,OR51G2,PKMYT1,POLD4,POLR 3D,PPP1R3C,PRNP,PTGS1,RAC3,RASGRP2,RPIA,RPS6KB2,SLC33A1,ST3 GAL3,STAT5B,TAS1R3,TLN2,ULK1 CKM,PDC,ALG5,ALPL,ANAPC4,ARSD,ATP5O,BDH2,BMP5,CAV2,CES1,CXC L11,DHRS4,GALE,GAMT,HSD11B2,IFNA16,IMPDH1,IRAK3,MAP2K1,MAPK Negative_25 1,NADSYN1,OR13F1,OR3A1,OR52A5,OR5AK2,OR5P2,PDGFD,PIGT,PIPOX ,PLAT,PNPLA4,PPM1B,PPP1R3C,RND1,RRM1,SEMA4A,TPH2,USE1,WNT5A ,CACNA2D2,GABARAPL2,PRICKLE2 ADIPOR1,ALOX12,ALOX5,ATP5J,BCL2,CALML5,CD36,CFLAR,CLDN14,CR EB3L1,CXCL9,CYP19A1,DPYD,ECSIT,EGFR,EPHA6,GALNT6,GBGT1,GCLM ,HCLS1,KIR2DS4,KLKB1,LDHB,LHCGR,LIPC,LMO7,MAP2K3,MPST,NCF1, Negative_26 NRXN2,NT5C2,OGDHL,OR1B1,OR2T34,OR2W1,OR6A2,OR8B4,PIK3CG,PKM YT1,RDH8,SLC9A1,SMAD2,SMAD7,SPCS1,TAS2R42,TUBB2A,TUBB3,UCKL 1,HLA-DQB1 IHH,ACAT2,BTRC,CDC6,CKS1B,CNTF,CREBBP,DRD1,GAPDH,GBA3,GIT1, GSTM1,ITGA11,JAK2,MOV10L1,NCOA4,ONECUT1,OR10C1,OR10S1,OR2T2 Negative_27 ,OR4K2,OR4M1,OR6C2,OR8G1,P2RX7,PFKFB3,PGAP1,PLXNC1,PPARA,PR KAA2,PRNP,PTPN11,SETD1A,SMARCA5,STK36,TGFB3,VAV3,XCL1,PDCD1 LG2,PHOSPHO1 DCK,ID3,IVD,AKT3,APAF1,ARPC1A,B3GALT5,BIRC2,CACNB3,CREB3,CR KL,CX3CL1,CYP3A7,DTX4,FRAT2,GCLM,GMPS,GNPAT,GSTO1,GZMB,HNF1 Negative_28 A,MAPK12,NAGS,NEUROG3,NUDT2,OR10G2,OR1A1,OR4N5,OR51A4,OR51G 2,OR9Q1,OXCT2,PI4KB,PTGS2,RFXAP,RPS6KB1,RUNX1,SHC1,SLC9A1,S PHK1,SRD5A1,TNFSF18,UGT2A1,WNT16,WNT3A Negative_29 AARS2,ACSM1,C3AR1,OR5D13,SGMS2,TNFRSF14 Negative_30 C3AR1,PIP5K1A,UGCGL2 C4B,ACACA,ADCY2,ADIPOQ,CCL11,CD34,DDX54,DTX3,DTX4,ELK1,HAGH L,HEMK1,INPP5B,ITGB1,JAM2,LIAS,MAPK13,MAT2B,MPDZ,MTFMT,OR5A Negative_31 R1,OR6C75,OR6K2,OR7G1,OXTR,PDE2A,PHGDH,PIGO,PYCR2,RALA,RRM1 ,SETDB2,SH2D1B,SKP1,STAT2 Negative_32 CCL20,FUT6,ITGAE,OR2B6,OR5T3,PEMT,PPA1,PPP1CB,GABARAPL2 ME3,TNC,BACE2,C1QA,CASP8,CCNB1,CLDN7,COQ7,CRKL,CYP2A7,CYP2C 9,CYP3A5,CYSLTR2,DAD1,DVL3,GALK1,GNPNAT1,HLA- Negative_33 DRA,IFNA10,INHBE,MAPT,MTHFD1,MYH6,OR1B1,OR2T2,OR4C16,OR5D16 ,PDE4B,PDGFA,PIK3R5,PRKAA2,RALA,RAPGEF1,SESN2,SLIT1,STX2,TG FB3,TJP2,UGT2B10,WHSC1,WNT7A F11,FAH,FUK,ACAA2,ACTB,ACVR1C,ADCY6,AGRP,ATP5E,BLNK,CCNB1,C NTNAP1,DAPK3,DHRS4,ENTPD4,EPHA6,GNPAT,GZMA,HLA- Negative_34 DRA,HNF4G,ITGB3,MMP9,NCOR1,OR11H4,OR2V2,PANK2,PIGK,POLE3,PO LR3D,PPP2R1B,PPP2R5E,PTK2B,RAP1A,TACR1,TRADD,UGP2,UNC5D,WAR S,EIF4EBP1,KIR2DL5A F11,JUN,SFN,SMO,CACNA1F,CREBBP,GAD2,OR13H1,OR8A1,PARS2,PIP5 Negative_35 K1C,POLE4,POLR2L,POLR3B,SESN1,UGP2 C8G,F10,FOS,ACTN2,ARG1,C4BPA,CACNB2,CCNG2,CD226,CD3E,CD99,C HD8,CPT1C,CSF1R,CSF2,CYP21A2,DERL1,DGKB,DUSP3,EI24,FGF9,IDI Negative_36 2,IFNA16,IL10RA,ITGA8,KLRD1,MAD2L1,MTHFD1L,MYH11,NRXN3,NT5M ,OR1M1,OR52H1,PAK2,RASA1,RDH10,SETDB1,STX5,TICAM1,TOMM40L,U GCGL1,UNC5B,YES1,ZMAT3 Negative_37 MVD,CX3CR1,METTL6,OR4D5,RBKS,RPRM,RRAS2,SLC25A5 LAT,ADCY3,ARPC5L,ATG12,CD46,CDKN2D,COL1A1,DEGS1,DUSP5,HRAS, Negative_38 IKBKE,LDHD,MAP4K2,NFYC,PLXNB3,RBL1,SPRED2,SSH3,TJP2,VAMP1 CS,LTB,AARS,ABLIM2,ACOX3,AGPAT1,AGRN,ALDH1A3,ALG6,AMPD3,BBO X1,CAV2,CREBBP,CYP11B2,CYP2F1,EDAR,GNAI2,HPRT1,HSD17B4,IKBK E,LDHAL6B,MYH8,MYL5,NCKAP1,NT5C1A,OR2T11,OR51B4,OR52W1,OR6X Negative_39 1,OR8H3,PCYT1B,PDE3B,PIGV,PLOD3,POLR2K,POLR3G,PPP1R1A,PPP2R 2D,PRKACB,RBPJL,RPS6KB1,STK11,SUCLA2,TJP1,TUBB1,TUBB4,UGDH, VCAM1,SERPINC1 ADC,ACSL5,ACTN2,ATP5E,CHST11,EXOC7,FOXO1,FZD4,FZD7,HADHB,HI Negative_40 F1A,ITGAE,MARS,OR14I1,OR4K17,PDE8A,PLCE1,PMM2,SNW1,SYNJ1,WN T4,CTNNBIP1 CFI,CGN,FOS,MVD,RFK,ACPP,ADRA1A,ARHGEF6,CCKAR,CCR8,CD72,DUS P1,EPHA7,EXT1,FGF2,G6PD,GSTA4,HPSE,HSD11B2,HSD3B2,IFNA10,IL Negative_41 10,IPMK,LLGL1,MARS2,MDH2,MYH14,NCOA4,NFATC2,NRG2,OR10AG1,OR 52E2,OR5L2,OR8J3,PDHA2,PPAP2A,PTPRB,RALGDS,RFX5,RPS6KA3,SDC 4,TJP3,TRAF3,UNC5D,TNFRSF10B C3,F12,AARS,ADCY4,ADH5,ADORA2A,ADRA1D,ALDOA,ALG3,CNGB1,CNTF R,CXCL5,CXCR4,DGKA,DGUOK,EFNB3,F2RL2,FASLG,GDF6,GMPR,GMPS,G Negative_42 NAQ,IFNA14,IL23R,ITGAE,MAP3K14,MMP9,NAGLU,NEFH,OCRL,OR10G4, OR6S1,PCCB,PRKAA2,PSEN2,RFX5,SC4MOL,UGCG,SUV420H1 AK1,BAD,AADAC,ACLY,CLDN11,DDB2,GPT2,MYH10,PFKFB4,SPTLC2,TLR Negative_43 9 ABO,LYN,SFN,SPN,ACTG2,ADH5,ALOX15B,BACE1,CDC2,CNTF,DDX23,IL 19,INPP5E,KIR2DL2,KIR3DL2,MAP3K3,NEU4,NKX2- Negative_44 2,NTRK1,OR2Y1,OR8B4,PDE9A,RALGDS,RASGRP1,ROBO1,ST8SIA5,TAS2 R3,TLR2,TNFRSF4,TUBB4,UCP1,VEGFB AK1,GSR,NLK,SYK,UBC,ACSM1,ALDH5A1,ALPPL2,B3GALT1,B4GALT1,C1 QB,CCNG1,CCR6,CD28,CD46,CDC25A,CTNNA1,DAPK2,DDX55,DUSP10,DU Negative_45 SP3,EPHA1,ETNK2,FABP4,FLOT2,HTR5A,IFNA7,IL1B,MAFA,MDM2,NRXN 2,OR4D1,PHKA1,PLA2G6,PON3,RDH5,RFWD2,SIPA1,SMAD7,SPRY2,SRGA P3,TLR9,TSTA3,PAFAH1B3 Negative_46 APOA1,CD19,OR10P1,RAC1 PGD,TXK,ACSM4,ARHGEF2,ARPC5L,CACNA1A,CAMKK2,COL4A2,CSAD,E2F Negative_47 3,EFNA1,GNAQ,GNPDA2,HLA- DRA,ITGB1,OR1C1,OR1E2,PIK3R5,TUBB2C,ATP6V1G1,CACNA2D1 LTB,ACLY,B3GALT4,CREB3L2,CYP2F1,DHRS3,EPB41,GUCY2F,HSPA1B,I Negative_48 L12B,LIPC,MTMR6,NFYB,OR1B1,OR1D5,OR4A16,PIGW,SARDH,UGCGL2,Y KT6,B3GALNT1 AK3,MAX,ADCY8,BCL2L1,BST1,CXCR5,CYP2J2,IL1R2,INPP5E,LAMB2,M Negative_49 BL2,MYH15,MYL9,NARS2,OR13C3,RASGRF2,RASGRP1,SHC3,SPRY3,GABA RAPL2,SERPINF2 ID2,ACMSD,CAMKK1,CCL28,CDC45L,CYCS,DAAM2,DCTN1,DOT1L,DUSP2, ENPP3,GDF6,IL12A,LAMB4,NAMPT,NEUROD1,OR4D5,PLA2G2D,PLXNA3,P Negative_50 OLR2D,PPAP2B,PRKAB2,PRKACA,PRKAR1B,PTPRJ,RDH8,SETD1B,TNFSF1 4,TUBB2B,VASP GLS,ALDH4A1,ALOX15,ATP2A3,CPT2,CYBA,ELK4,FABP4,HADHB,IL8RB, Negative_51 IMPA1,ITGA6,NLGN3,NT5M,OR2L3,OR52R1,OR6B2,P2RX6,PGK2,PRKACB