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MMG 835, SPRING 2016 Eukaryotic Molecular Genetics Systems Biology and Networks MMG 835, SPRING 2016 Eukaryotic Molecular Genetics George I. Mias Department of Biochemistry and Molecular Biology [email protected] What is Systems Biology • Wikipedia: “Systems biology Systems biology is the computational and mathematical modeling of complex biological systems. An emerging engineering approach applied to biological scientific research, systems biology is a biology-based inter-disciplinary field of study that focuses on complex interactions within biological systems, using a holistic approach (holism instead of the more traditional reductionism) to biological research. What is Systems Biology • nature.com : “Systems biology is the study of biological systems whose behaviour cannot be reduced to the linear sum of their parts’ functions. Systems biology does not necessarily involve large numbers of components or vast datasets, as in genomics or connectomics, but often requires quantitative modelling methods borrowed from physics.” What is Systems Biology • Encyclopedia of Systems Biology (Springer New York, 2013). • “Systems biology refers to the quantitative analysis of the dynamic interactions among several components of a biological system and aims to understand the behavior of the system as a whole. Systems biology involves the development and application of systems theory concepts for the study of complex biological systems through iteration over mathematical modeling, computational simulation and biological experimentation. Systems biology could be viewed as a tool to increase our understanding of biological systems, to develop more directed experiments, and to allow accurate predictions.” Systems Biology • Systematic • Novel approach (in biology at least) • interdisciplinary • Non-reductionist • Reductionist: Study the subcomponents for a system in detail, each one • Whole is greater the sum of its parts Systems Biology • Multiple inputs of information in a complex system • More mathematical than traditional biology Systems Biology System Proteins Genes Structures Others Small molecule Integration Systems Biology • Molecular components • Study of • Function • Cell subsystems • Networks • parts of an organism • Signals • the organism • Interactions of components • the environment • set of environments Systems Biology Modeling Omics Complex cell systems assays Molecules Pathways Cells Tissues Humans Meters 10– 9 10– 8 10–7 10– 6 10–5 10–4 10–3 10–2 10 –1 1 Seconds 10 –6 10 2 10 4 10 5 10 8 Scale Butcher et al., Nature Biotechnology 22(10), p1253 (2004) Systems Biology • Omics approaches • Human Genome Project • Examples • Mass spectrometry • Proteomics • Metabolomics • name-it-omics Systems Biology • Example: Metabolism http://www.genome.jp/kegg/pathway/map/map01100.html (11/18/2014) KEGG: Kyoto Encyclopedia of Genes and Genomes Systems Biology • Example: Metabolism: Galactose Metabolism (degradation) http://www.genome.jp/kegg/pathway/map/map01100.html (11/18/2014) KEGG: Kyoto Encyclopedia of Genes and Genomes Systems Biology • Example: Cancer • Different Networks • Homeostasis • Molecular components Werner, H. M. J. et al. (2014) Nat. Rev. Clin. Oncol. doi:10.1038/nrclinonc.2014.6 integrative II. Transcriptomics Personal Systems Omics Proteomics Profiling Medicine I. Metabolomics Clinical Tests Whole Genome Sequencing • Personalized Autoantibodyomics Disease Risk Evaluation Microbiomics New omics • Medical History & Environment Determine risks Healthy Infected Recovery Healthy Pharmacogenomic Evaluation LONGITUDINAL OMICS PROFILING OF MULTIPLE PHYSIOLOGICAL • Monitor RISK EVALUATION STATES SLC9A3R2 PDP2 RDX BCAP29 PDPR DHTKD1 OGDH ZNF354ZNAF675 ZNFZ2N2F43 ZNF345 ZNF32ZN1F763 ZNF642 ZNFZ78NF9Z42NF6429 ZNF20 ZNF680 ZNF714 ZNFZ18N4F480 SRP19SRPR ZNF626ZNF107 ZNF32 III. 1.0 ZNF708 ZNF493 ZNF44 ZNF514 RPH3AL SRP14 ZNF709 ZNF286ZNAF11Z7NF268BCAP31 SRPRB ZNZFP8F3 2 ZNF793 ZNF324 ZNF140 ZNF485ZNF563 VAMP8 SSR3 ZNF264 ZNF564 ZNF222ZNF441 ZNF14 ZNF737 RAB27A SSR4 ZNF32Z0NF554 GATAD2B STT3B ZFP14ZNF275 CHD4 SPCS3 ZNF404 ZNF91ZNF530 SNAP23 ZNF25Z4NF100 ZNF791 PDHB ZFP30ZNF439 RAB3GAPAP1S2 3 SPCS2 ASH2L SPCS1 SEC61B ZNF83 TMEM126B • ZNF146 PABPC4 0.5 CDC42EP3 DLAT DYNC1I2 CETN2 PDHX OFD1 Integrate TUBGCP4 GSPT2 CEP25FGFR1O0 P LMO4 SDCCAG8 TSGA14 SIGIRR CUX1 BRSK1 ITSN1 ARHGAP4 RHOT1 CEP152 ARHGAP24 EEA1 CEP63 CEP29TUBGCP0 2 RPL36A PDK1 CHD6 MBD2 RPL19 ARHGAP11ARHGEF1B 8 RPL10A SEC63 VAMP2 CEP164 CENPJ G3BP2FGD4 CEP135 KDELR1 SAR1B RPL3RPL15 2 EIF5B HCST AKT1S1 RPL18A RHOQ KPFDNIR2DS44 CSF2RA CYBB BAZ2B ARF4 ATP1B3 VBP1 GDI2 RAB13 IL10RB AGRN GLG1 CYBA RPS15A SLC3A2 PA2GIKZF4 4 AKAP9 RPS15 ARID4KLF1A 0 KLRD1 KLHL20 SOCS7 RHOG RPS28 PPIB IGF2R PRNP PFDN2 PIK3R5 GOLGA4 BSG KLRC2 BAIAP2 SATB1 EIF3J EIF6 ITGAL LNPEP TLR9 CSNK1E EIF4B KLRC3 RALBP1 NKRF RPL6 PELP1 THEMNFE2L4 2 NFKBIE PIK3C2A 5 10 15 MYBL1 HCFC1 EIF5 SLC16A1 IRRS2AC1 NKTR RSBN1 IL18 SOCS2PIK3CB EIF1AX TYROBP MAP4K3 SKAP2 RTN4 SPN PDPK1 REEP5 MECP2 UBE2V1 HRH2 LPP FYB MAP3K3 CXCR6 LAX1 ENAH TRAF3IP3 CRK NFKB2 RAB1A PIF1 GNAS LSTCD241 7 INSR KTN1 CD74 SHC1 SIN3APKN2 METAPBCLA2 PNF1N ZBTB1 CALD1 DPP4 CARD11 HSP90AA1 GNAI2 ADAM15 HNRPLL GNG5 PAG1 TSC22D3 SEC62 PTPRC YIPF5 ZNF292 PPIL3 FYN PTPN2 EIF4G1 ACP1 MARCKS PFN2 REL ARID4PPIBG HLA-DRB1 MAP2KYWHA7 Z CNOT2 PLA2G6 EFNA1 GRAP YWHAB KIF5C RBM25 NEK9 CCL5 CDV3 PNRC2 SLU7 GPR183 RAF1 PRKCBNEK8 MARK3 NCK2 DDX5 JMJD1C 0.5 RUVBLHLA-DQB2 1 BAZ1A ETV6 AHSA1 FAIM3 MAP4K4 PRPF4B SYNCRIP LCK DDX41 KIF5B SPTAN1 PRKY SAP18 MATR3 TRA2A CXCR4 CD79CD8A6 ROCK1 DMAP1 WAC HNRNPH3 RB1CC1 ZNFX1 CPSF6 EIF4G3 MORF4L1 TPM1 PRKX SP110 FOXO3 UBXN4 YTHDC1 RBM39 YEATS4 ELP4 IKBKAP MYH10 PSENEN XRN2 IFI16 SUZ12 WBP4 EIF4A3 IGJ MAP3K7 SUB1 SON ING3 PPARD CSNK1G2 FBXW11 PPP2R5D BZW1 VIM YES1 NEDD9 TLE3 KHDRBS1 FGR PPP2R2B AXIN2 KIAA0776 QKI UPF2 ADD1 CREB1 CLK1NPM1 TRIM22 POU2F2 PPP2R5C NONO DDX1 PRF1 POU2F1 DNAJC2 DDX46 SRPK2 ADD2 HNRNPA3 PRPF40A FDXR BDP1 MAPK7 GCC2 GYG1 PCNP REREGYSCAPN1 1 POLR3F SSB RBM17 TRAP1 SNAPC1 LDHA PTBP1 RBM42 HMGN1 RUVBL1 POLR3A TOP2A SPTBN1 HDAC9 SF3ASF3B3 4 HNRNPD SQSTM1 GADD45SP10A 0 TBPL1 SF3BRN1 PS1 SNRNP200 FABP3 HIPK2 PEBP1 DEK PSIPHNRNP1 K UPF3A NFATCCTS3C RUNX3 NFYA TCERG1 SNRPA PRPFS4NRPBSF23A1CSTF3 NFIC PHF5A DCP1A t CAMK2D CORO7 GTF2B TOMM70A IRF3 HSPA9 HNRNPL 1.0 MYST2 RAD1 GTF2F2 SF3A2 ZBTB44 BAZ1B PDCD10 UPF3SNRPAB 1NUDT21 NXF1 SRRM1 SMNDC1 ID2 SMADMEF23 PCPARA RBM14 CD2BPNH2 P2L1 CTCF TBL1X POLR2A HNRNPCSNRPD1 SIAH2 SF3B3 PRPFCCAR6 1 MAF GATA3 SMAD1PTCH1 SNRPD3 PCBP2 SNCA UBE2D3 ME2STRADB TGS1 RANBP2 POLR2C PDCD7 CDK6 CDC5L SNRPSNRG PE HNRNPHHNRNP2 F RIF1 HMGB2 BMPR1PMA L ERBB2IP CBX3 HNRNPUL1 GZMA CDTCFKN24CTTF1 TOB1 CCNB1 CPSF2 CPSF7 LEF1 ZMAT3 SNRPDCDC42 0 DHX9 MRPL11 SNW1 ZRSR2 POU5F1 LBR FST NUP153 CPSF1 POLB ACADCHDM 9 TAF4B NUP21NUP60 2 TOMM20 GZMH CDKN1C H3F3A SCP2 TP53RK TP53 HMGB1 POLR2I HMGN4 PHF17 ING2 DUT SMARCC2 RARG HMGA1 NUP93 TBRG1 CDKN2A GZMK RANBP3 ACSL3 PARP1ERCC4 SNRPN NUP3NUP155 NUP55 4 PAX5 E2F3 H1F0 PRDX3 KIN TAF12 FEN1 RUNX2 SMARCCDKE1 2 SIAH1 NUP37 PLRG1 RPA3 WWOX CACYBP CORO2A RFC5 H1FX CHAF1A TCEB1 HSPD1NUP8SEH15 L TRIM24 NUP160 BANF1 HELLS HES1 ING4 CCNA2 SMARCD2 STAG2 NUP98 EFHA1 ACAA2 CCND2 HSPE1 MYST4 CUL5 PPID BCAS2 MED28 LSM4 HES6 UBE2R2 PAWR XIAP RAD21 MED21 DDX50 ECHS1 XPA UBE2M UBE2D1 AURKB TOP1 NOLC1 RBPJ CDH2 TRIM33 CBX1 ERH PHAX TOMM40 EBF1 DDB2 RBX1 ARVCF BIRC5 POLD1 LIG3 CBX5 NUTF2 PNKP MCM8 REST PRIM2 SKIL MED31 DBF4 PSMA2 CENPF WRNIP1 CAPANP321 E BUB3 ATF7 SESN1 CENPNNSLND1EL1 RFC1 LITAF ARID2 PSMA6 CENPCENPH Q DNAJA3 FBLPSMA7 CCDC99 MBD4 BCCIP PSMB1PSMA0 PSMC1 6 BUB1 NFX1 TCEAL1 CCNG1 NCOA4 SUMO2 COPS3 BTG1 MED4 COIL HIST2H3RRAM2 TOPORKLFS 6 TDG UBE2V2 RFWD2 PSMB2 AIFM1 EI24 CDC2ANAPC7 5 DHFR MED7 NEURL2 PDS5ASMC3 NDN FBXW7 ANAPC1UBE2E0 1 PDS5B SMC4 RCC1 CUL4B PTTG1 VDAC1 SNX17 DIABLO CUL4A NUCB2 CDC14A FBXO5 RAD50 TNFSF14 RNF14 MSH6 H2AFX NOP2 CYCS LDLR SPATA5 MSH3 OBFC2B COX5B NAP1L4 RNF2 HIST2H2AB COX6B1 Mias and Snyder, Quantitative COX6C C1GALT1 PDCD11 UQCRC2 UQCRB COX5A UQCRQ COX4I1 PCGFMYST6 1 UQCRC1 NDUFANDU2 FB7 SLC25A4 NDUFB8 ATP5G3 NDUFA10 NDUFS7 KRR1 NDUFA3 NDUFC2NDUFS2 NDUFB4 NDUFB3 NDUFV3 NDUFB6 NDUFS6 TUFM NDUFV1NDUFA5 NDUFA8 ACO2 NDUFB10 NDUFB5 NDUFB9 NDUFA11 PMPCA NDUFB1 SLC25A11 CLPP Biology 1(1) p. 71 (2013) PMPCMDH2B EXOSC6 MRPS12 ITSN2 TERF1 ATP5B TAP2 PIGH GINS2 PNPT1 TBL3 HIST1H1E PDIA3 PIGP GINS4ATP6V0EA1TP6V1EATP1 6V1G1 LMNA LMNB1 TMPO GLUD1 GOT2 PC NAGA PHKB SCAND1 iPOP Database WDR3 HIST1H4A TAP1 EXOSC8 PIGC GINS1 UTP15 HIST1H1B IDH3B CS ATP5J DIS3 EXOSC9 ATP5F1 ATP5HATP5A1 Chen*, Mias*, Li-Pook-Than*, ATP5I INTEGRATION OF MULTIPLE OMICS AND TEMPORAL RESPONSES Jiang* et al Cell 148,1293 (2012) MATCHED AGAINST iPOP DATABASES http://goo.gl/iamZth Systems Biology • Models • Experiments • data • theory • Nobert Wiener (1894-1964) • computation • cybernetics and systems controls) • 20th century biochemistry • 21st century Leroy Hood and others Systems Biology • Experiments •BIG DATA! Reformulate biological problems in terms of mathematical models. Models need computational approaches Big data handling in storing, retrieving useful information and relaying/displaying this information Data - Omics Molecular Components Nucleic acids Proteins Lipids Carbohydrates Genomics Illumina DNA VARIANTS Structural Variation [ >1000 bp] A reference SOLiD tandem duplication bp Level Variation dispersed duplication reference ggcttccaggaactc deletion point ggcttccagaaactc PacBio mutation ggcttccaggaactc insertion ggcttccagggaactc inversion insertion ggcttccaggaactc 454 ggcttccaggactc translocation deletion ggcttccaggaactc MinION Ion Torrent Mias and Snyder, Quantitative Biology 1(1) p. 71 (2013) Transcriptomics RNA samples
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