V 1 Introduction

Tue, Oct 18, 2011 Bioinformatics 3 Tihamr Geyer

How Does a Cell Work?

A cell is a crowded environment => many different proteins, metabolites, compartments, On a microscopic level => direct two-body interactions At the macroscopic level => complex behavior Can we understand the behavior from the interactions? => Connectivity
Medalia et al, Science 298 (2002) 1209 Bioinformatics 3 WS 11/12 Tihamer Geyer V1 2

The Biologist View

Molecular Biology: "One protein one function" mutation => phenotype Linear one-way dependencies: regulation at the DNA level, proteins follow DNA => RNA => protein => phenotype

Structural Biology: "Protein structure determines the function" biochemical conditions => phenotype No feedback, just re-action: genetic => information molecular structure => biochemical => function phenotype

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The Network View of Biology

Molecular Systems Biology: "It's both + molecular interactions"

genetic => information

molecular structure

=>

biochemical => function molecular interactions

phenotype

=> highly connected network of various interactions, dependencies => study networks

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Example: Proteins in the Cell Cycle

M/G1
COQ5 HXT9 GAD1 SCS3 PIR1 SRD1 ARA1 PIR3 YFL064C UTR2 UBP11 PRX1 DSE4 SNU66 MRPL38 ALD4 YDL124W PIG1 YLL067C FUS1 HSP104 PRR1 YRF1-3/YRF1-7 YHL050C YEL076C EGT2 YJL195C GLR1 PLB3 YFR026C MF(ALPHA)2 YKR077W YFL065C PLB1 YOL101C YLR462W CYC3 LSP1 YBL113C YRF1-5 MFA2 YHR218W YLL066C AGA1 YEL076C-A/YLR464W YEL077C YFL068W PST2 NCA3 YLR049C YCP4 FAR1 SCW11 PRY1 HAA1 YRF1-6 NBP1 YPR202W SPS1 AGA2 OLE1 YHR219W YJL225C YBL112C YLR194C ICS2 HXT7 TFS1 YOR342C YPR204W YPR203W YER189W YOR066W ROD1 YLR463C YHL049C YCL023C YML133C PNC1 PHO89 HXT10 AFR1 SPI1 IAH1 SST2 TIP1 YRF1-1 YFL067W RME1 YBL111C STE3 TEC1 YDR493W PGU1 MF(ALPHA)1 YEL075C HSP150 YKL177W GYP6 FAA3 PST1 YPL158C HXT2 YRF1-2 ASH1 YHR140W

M
HST4 YLR041W YBR287W STE2 DIA3 FIG1 YFL051C YOR052C GLK1 ALD6 TPK1 YGL036W YRO2 IME4 BCY1 ELO1 TPK3 SED1 MUM2 TPS2 SDL1 YRF1-4 CAC2 MSI1 JEM1 PKH1 MRP8 PIL1 HO RAD5 YIL177C TPK2 TPS3 BNI4 YLR040C RLF2 EXO1 BEM1 GIC2 YNL310C KAR4 SLD2 HLR1 YBR071W ERV29 PHO12 TSL1 RGT2 CDC54 MCM2 YGR146C MCM3 PHO11 TAF2 CDC6 ORC6 BNS1 YDL038C CDC45 PAC1 YDL241W ORC3 DBF4 PRM7 ORC1 KIN3 YER139C YLR254C CDC7 ORC2 ORC4 ORC5 STB1 VPS5 MCM6 NUM1 TAF8 CDC47 CDC46 TPS1

From Lichtenberg et al, Science 307 (2005) 724:

YGR042W

G1
YCL022C BUD9 SPT21 OCH1 CUE4 YJL181W CTS1 BAT2 QRI1 PHO8 YPL267W TOS2 ESC8 SUR1 YDL163W MRC1 YPR174C LPP1

MCM/ORC Protein kinase A

Regulation of meiosis

VPS17 BOP1

SEN34 RDH54 YJL217W PRY3 YNL208W YHR149C CDC9 HUA2 RAD54 RTT106 CTF4 YDL010W DSE1 STB2 SPH1 YBR089W YGR151C RSR1 ERP3 PDR16

DNA replication
POL1 PRI2 PRI1 POL12

UTH1 FUN26 YMR031C WTM1 YHL026C

RTT109 YBR070C TOF1 PDS5 YPS3 RAD27 ELG1 BIO2 RFC1 CSM3 CRH1 YCL042W YOL019W POL32 RFC3 RFC2 YPL208W DSE2 ASF2 POL30 YOX1

Glycogen synthesis
GSY1 GSY2 GLG2

YOR385W WTM2 TPO4

HYS2 RFC5 RFC4

FIG2 PHO3 PHD1 YNL057W BSC1 APC11 APC5 PDS1 GIN4 CDC20 APC2 ESP1 CDH1 SPT16 AMN1 CDC23 DBF2 DOC1 SPO12 KAR5 APC9 MOB1 YCK3 YPL014W YCK2 YNL058C NRG2 YCK1 CLN3 SIC1 CDC26 APC1 CDC27 PAF1 HTZ1 KTR2 CDC16 NIS1 YLR297W MRH1 SKN1 APC4 KRE6

YIL141W CDC2 MCD4 HEM15 BCP1 KCC4 POL2 DPB2 NAP1 CTF18 CDC21

APC

Mitotic exit

Nucleosome/ bud formation

YOL070C

DNA polymerase
YNL134C DPB3 MET16

PBI2

YLR236C HIF1 ERP5

OGG1

YIF1

ASF1

RNR2

RNR3 HAT2 YDL009C YOL007C AXL2 DUN1 RAD53 TOS4 HMLALPHA1 HTA1 HTB2 SWI4 RNH203 YER152C YLR050C YOR114W TBF1 HHF1/2 HTB1 PMT3 RNR4

YJL018W DPM1 RHC18

Cdc28-cyclin
CLB6 CLB2

RNR1

YKL066W

Histones
HTA2 CDC28 CKS1 HHT1/2 CLB5 RCO1 CLN2 PET10

MYO1

PMA2 YLR057W SWE1 TPO1 PMA1 PMP2

YKR012C RNH202 PIF1 KAR2 PRY2 PLM2

YEL047C YNK1

color coded assignment of proteins in time-dependent complexes during the cell cycle
PMP1

Cation transport
CLB1

URH1 CLB4 CLB3 CLN1 NAB2 KAP104 LCB1

ENB1

SUT1

SCF
MET30 GRR1 SWI5 CDC4

DNA replication and repair

HRP1 SAM2 PCL1 KAP120

PMT5

GWT1

HSL1

YIH1 PCL2

YOR256C GCV2 MMR1 SKP1 GCV1 CDC34 CDC53

YPR157W

YBR138C

Pho85cyclin
PHO85 PCL7 PCL5

YLR326W CWH41 SVS1 TRR1 ERV25 RFA3 YDL157C

MSH2

PMS1 RFA2 MSH3 YMR298W MSH6 RFA1 PWP1 EMP24

YOL014W GCV3 RPI1

YNL300W

CUP1-1/1-2

ATF2

TAT1

BIR1 NCE102 CSE4 YML119W HEK2 CBF5 BIK1 CIN4 YOR315W YGR176W CYK3 MHP1 MIF2

Sister chromatid cohesion

SMC3 SMC1 CDC12 MCD1 IRR1 CDC10 CDC5 MPS3

IQG1

YDL156W

OPY2 RAD51 LAC1 SCW10 EUG1 DTD1 SHS1 RAD55 LAG1 CTF3

PMT1 SPR28 RBL2 CDC11 CDC31 CMD1 SPR3 DIG2

HOF1 SVL3 YLL032C

STU1

=> protein complexes are transient

YLR101C BAS1 TPO3 NDE1 LYS9 ASE1 CIN2 KAR1 YTM1 BIM1 STU2 SPC98 CNM67 MAK21 DUO1 BBP1 DAD1 YJL051W CAR1 SPC34 SPC97

TUB4 SPC105

ACE2

CDC3 SHO1 FUS3 YOR084W

BNA3 SPC72

Tubulin related
GFA1

WSC4 HST3 SCW4

SHM2

Septin filaments
SPC110 HCM1 SPC42 SPC24 SPC25 NUD1

MSB2 SLK19 SUR4 SUR2

PGM1 YHR173C SPC29

YCR041W EXG1

SHE2 YOR152C MEP3 SPA2

Transcription factors
YOL131W YLR343W MNN1

KTR1

BAP2 YJL048C YIL056W FET3 YJR003C YGR035C CAR2 GAP1 BUD8 IST2 SRC1 TPO2 YPL141C ERG2 PHO84 BUD4 STE18 GPA1 STE4 SIT1

SPB

SWI6

YDR355C

Cell wall
YML072C YAL053W

GSC2

MBP1

SEC53

BNI5 ECM25 FKH1 FKS1 FEN1 YMR144W ISR1 YBL009W SRP21 CSR1 MHT1 PMT2 CHS2 BUD3 PDR5 YML053C ALG2 PMI40

=> describe with a time dependent network

YOR105W ZRT1 TIR3 ERG5 RPL4A SUR7 ALK1 YIL158W SML1 PMP3 YDR089W CWP2 YOR298W YBR242W GAS5 TEA1 SSO2

PTA1

NDD1 FIP1 TDH2 YTH1 MET14 YGP1 YNL311C YLL012W ECM33 VIK1 CIK1 YMR295C KAR3 RPS14B TEM1 BFA1 SNU56 NAM8 DAD2 YDR348C STR3 KIP1 ASK1 TOF2 GIC1 FLR1 VAC17 YNR009W SRL1 YMR051C YJL118W PMT4 YOL155C PSA1 WSC2 GAS1 HHO1

YOR248W DFG5 VRG4

AGP1

AUR1

ALG5

HPR5

SAS3

ICT1

EMP70

YOR073W

VID22 TIR1 YMR002W ERG3 MNN11 YGL101W YCR085W CYC1 OAC1 TUB1 YNL176C YLR437C UGP1 YML125C YNL043C CWP1 SIM1 WHI3 YBR187W YHP1 MET3 TUB2 ECM17 KIP3 IXR1 HOS3 CRP1 ABF1 AVT1 NNF1 FRT1 GAS3 LCB3 YMR003W YKL030W YDR134C YLR455W CIS3 TOS1 ALG7 YDR133C YKL053W

MAE1

G2
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GDA1

S
MXR1 GPI11 YKL069W PHM6 DSN1 GTT3 ELM1 SAM1 MET17 FIR1 TAO3

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Major Metabolic Pathways

static connectivity

<=>

dynamic response to external conditions

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<=>

different states during the cell cycle

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http://www.mvv-muenchen.de/de/netz-bahnhoefe/netzplaene/index.html

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Lecture Overview
Protein-Protein-Interaction Networks: pairwise connectivity
 => data from experiments, quality check

PPI: static network structure

 => network measures, clusters, modules,

Gene regulation: cause and response

 => Boolean networks

Metabolic networks: steady state of large networks

 => FBA, extreme pathways

Systems Biology

Metabolic networks: dynamics

 => ODEs, modules, stochastic effects

Protein complexes: spatial structure

 => experiments, spatial tting, docking => interface properties, spatial simulations
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Protein association:

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Literature
Lecture slides after the lecture Suggested reading => check web page
 http://gepard.bioinformatik.uni-saarland.de/teaching/

Textbooks

=> check computer science library

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How to Pass
Schein = 3 of 4 short tests + nal exam

Short tests:

4 tests of 30-45 min, each planned: Nov. 8 + Nov. 29? + Dec. 20?? + Jan. 31?? => average grade from 3 best tests

Final exam:

written test of 120 min requirements:  50% of the points from the assignments  one assignment task presented @ blackboard  3 short tests passed planned: Tue, Feb. 7, 2011???

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Assignments
Tutors: Christian Spaniol, Nadine Schaadt Tutorial: Wed, 12:0014:00, E2 1, room 007 10 assignments with 100 points each Assignments are part of the course material (not everything's in the lecture) => one solution for two students => hand-written or one printable PDF/PS le per email => content: data analysis + interpretation think! => no 100% solutions required!!! => attach the source code of the programs for checking (no supplementary data) => present one task at the blackboard Hand in at the following Fri electronically until 13:00 or        printed at the begin of the lecture.
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Basic Types: Random Network

Generally: N vertices connected by L edges More specic: distribute the edges randomly between the vertices Maximal number of links between N vertices: N (N 1) Lmax = 2 => propability p for an edge between two randomly chosen nodes: L 2L p = = Lmax N (N 1) => average degree 
2L = p (N 1) N => path lengths grow with log(N) => small world =
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Random Network: P(k)

Network with N vertices, L edges => Probability for a random link:
p = 2L N (N 1)

Probability for links to k other nodes at a random node:

Wk = pk (1 p)N k1

Probability that a randomly choosen edge has k links: (N 1)! N 1 Wk Wk = P (k) = k (N k 1)! k! Limit of large graph: N => oo
N

lim P (k)

= = = =

N! pk (1 p)N k N (N k)! k! lim

N N k

lim

N (N 1) . . . (N k + 1) Nk 1 k e k!
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k k! k k!

1 N e

1 N 1

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Basic Types: Scale-Free

Growing network a la Barabasi and Albert (1999): start from a small "nucleus" add new node with n links connect new links to existing nodes with probability  k (preferential attachment; (BA) = 1) pi = => "the rich become richer" Properties: power-law degree distribution:
P (k) k

ki ki

with  = 3 for the BA model self-similar structure with highly connected hubs (no intrinsic length scale) => path lengths grow with log(log(N)) => very small world
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Summary
What you learned today: => networks are everywhere => how to get the "Schein" for BI3 => basic network types and denitions: random, scale-free, degree distribution, Poisson distribution, ageing, Next lecture: => clusters, percolation => algorithm on a graph: Dijkstra's shortest path algorithm => looking at graphs: graph layout
Further Reading: R. Albert and AL Barabsi, Statistical mechanics of complex networks Rev. Mod. Phys. 74 (2002) 47-97
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