Interactions and Networks

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Mike Cherry ! Genomics March 11, 2014

1 A map of protein- protein interactions in Saccharomyces cerevisiae

A-L Barabasi & ZN Oltvai (2004) Nature Reviews 5:104 Representation of protein interactions

!3 A great visualization captures data’s complexity with simplicity

http://www.youtube.com/watch?v=tnqxrcfUMsw !4 http://www.ebi.ac.uk/intact/ Network Metrics • How many links a node has to other nodes. Degree (connectivity) = k • Probability that a node has exactly k links. Characteristic of different classes of networks. Degree Distribution = P(k) • Overall tendency of nodes to form clusters or groups. Clustering Coefﬁcient = C. C(k) is the average clustering coefﬁcient of all nodes. C = 2N/k(k-1) with k links.

6 Network Types

A-L Barabasi & ZN Oltvai (2004) Nature Reviews 5:104 To study the network characteristics

A-L Barabasi & ZN Oltvai (2004) Nature Reviews 5:104 MG Grigorov (2005) Drug Discovery Today 10:365 Co-Expression Network

J-D Han et al M Vidal (2004) Nature 430:88 Vidal, M. et al. (2011) Cell, Volume 144, 986 - 998 !11 Vidal, M. et al. (2011) Cell, Volume 144, 986 - 998 !12 Vidal, M. et al. (2011) Cell, Volume 144, 986 - 998 !13 2-hybrid screen for interacting proteins

!14 http://en.wikipedia.org/wiki/Two-hybrid_screening !15 Ito T et al. PNAS 2001;98:4569-4574 !16 Synthetic genetic array methodology

!17 Tong, et al. (2001) Science. 294; 2364-2368 !18 !19 !20 !21 Motif Proﬁling Network

!22 !23 Characterization of the LC interaction dataset

(a) LC 33,311 HTP 21,105 (19,499 nonredundant) Protein-protein (17,674 nonredundant) Gene-gene 11,061 8,111 (8,165) (6,103)

22,250 12,994 (11,334) (11,571) (b) 14,000

Publications Interactions 12,561 12,000

10,000 9,436 8,382 8,000 6,000 4,848 4,616 4,578 4,000 2,573 2,233 1,778

2,000 1,087 592 595 635 518 530 585 561 564 554 431 359 419 362 220 257 161 164 176 49 51 73 98 55 88 89 1 2 1 1 3 6 5 12 9 17 21 25 0 1 2 1 1 8 11 21 33 18 30 35 1977 1978 1979 1980 1981 1982 1983 1984 1985 1986 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 (c) 9,000 LC-PI HTP-PI LC-GI HTP-GI 8,000 !24 Reguly et7,000 al (2006) J. Biology 5:11 6,000 5,000 4,000

Interactions 3,000 2,000 1,000 0 FRET Two-hybr id Far western Co-purification Co-localization Dosage rescue Protein-peptide Co-fractionation Dosage lethality Synthetic rescue Synthetic lethality Affinity capture-MS Co-crystal structure Biochemical activity Affinity capture-RNA Dosage growth defect Dosage growth Reconstituted complex Synthetic growth defect Synthetic growth Affinity capture-western Phenotypic suppression Phenotypic enhancement (d) 6,000 5,651 LC-GI publications LC-GI interactions LC-PI publications LC-PI interactions 5,000

4,000 3,147 3,000 2,977 2,278 2,187 1,840 1,740 1,740 1,731

2,000 1,663 1,609 1,556 1,324 1,299 1,299 1,197 1,004 1,004 778

1,000 662 501 433 424 429 399 394 309 209 180 133 120 52 41 27 22 53 5 1 1 0 17 1 2 3 5 10 20 30 50 100 >100 Interactions per publication (a) (b) LC-PI HTP-PI Overlap LC-PI (3,289, 11,334) HTP-PI (4,474, 11,571) 5,000 5,000

4,000 4,000 nodes 3,000 3,000

2,000 2,000 edges n = 3,289 n = 4,474 n = 1,201 1,000 1,000 i = 11,334 i = 11,571 i = 1,624 0 0 0 1,000 2,000 3,000 4,000 5,000 0 1,000 2,000 3,000 4,000 5,000 LC-GI HTP-GI Overlap LC-GI (2,689, 8,165) HTP-GI (1,454, 6,103) 3,000 3,000

2,500 2,500

2,000 2,000

1,500 1,500

1,000 1,000 n = 1,454 n = 216 n = 2,689 500 500 i = 8,165 i = 6,103 i = 305 0 0 0 0 500 500 1,000 1,500 2,000 2,500 3,000 1,000 1,500 2,000 2,500 3,000 (c) (d) !25 Gavin (1019) Ho (456) Reguly et al (2006) J. Biology 5:11

3,000 3,000 1,019 2,500 2,500 0.09 2,000 2,000 0.08 1,500 1,500 0.07 1,000 1,000 500 500 0.06 0 0 0 1,000 2,000 3,000 0 1,000 2,000 3,000 0.05 456 0.04 305 Ito (275) Uetz (202) 0.03 3,000 3,000 275 202 2,500 2,500 0.02

2,000 2,000 Fraction overlap with LC data 0.01 1,500 1,500 0 1,000 1,000 Gavin Ho Ito Uetz HTP-GI 500 500 0 0 0 1,000 2,000 3,000 0 1,000 2,000 3,000 (a) (b) LC-PI HTP-PI Overlap LC-PI (3,289, 11,334) HTP-PI (4,474, 11,571) 5,000 5,000

4,000 4,000

3,000 3,000

2,000 2,000

n = 3,289 n = 4,474 n = 1,201 1,000 1,000

i = 11,334 i = 11,571 i = 1,624 0 0 0 1,000 2,000 3,000 4,000 5,000 0 1,000 2,000 3,000 4,000 5,000 LC-GI HTP-GI Overlap LC-GI (2,689, 8,165) HTP-GI (1,454, 6,103) 3,000 3,000

2,500 2,500

2,000 2,000

1,500 1,500

1,000 1,000 n = 1,454 n = 216 n = 2,689 Overlap of HTP500 with LC 500 i = 8,165 i = 6,103 i = 305 0 0 0 0 500 500 1,000 1,500 2,000 2,500 3,000 1,000 1,500 2,000 2,500 3,000

(c)Gavin (1019) mass spec Ho (456) (d)

3,000 3,000 1,019 2,500 2,500 0.09 2,000 2,000 0.08 1,500 1,500 0.07 1,000 1,000 500 500 0.06 0 0 0 1,000 2,000 3,000 0 1,000 2,000 3,000 0.05 456 0.04 305 Ito (275) 2-hybrid Uetz (202) 0.03 3,000 3,000 275 202 2,500 2,500 0.02

2,000 2,000 Fraction overlap with LC data 0.01 1,500 1,500 0 1,000 1,000 Gavin Ho Ito Uetz HTP-GI 500 500 mass spec 2-hybrid 0 0 0 1,000 2,000 3,000 0 1,000 2,000 3,000

Reguly et al (2006) J. Biology 5:11 !26 Overlap between GI and PI datasets

!27 Random

Party Hubs

Date Hubs

All Hubs

!28 Nodes random -- green ! Filtered Hubs Yeast all -- brown party -- blue Interactions date -- red

-date

remove all date hubs -party

J-D Han et al M Vidal (2004) Nature 430:88 !30 Batada NN et al. (2006) doi:info:doi/10.1371/journal.pbio.0040317.g006 Layout of FYI network Layout of HCfyi network

altocumulus stratus

Batada NN et al. (2006) doi/10.1371/journal.pbio.0040317.g006 !32 Batada NN et al. (2006) doi/10.1371/journal.pbio.0040317.g006 Construction of the diseasome bipartite network

!33 Goh K et al. PNAS 2007;104:8685-8690 Goh K et al. PNAS 2007;104:8685-8690 !34 Developmental Network

!35 Transcription Network

TF-Z Gene X X A TF-X/A Gene Y TF-Y Z Y Gene Z

Reece-Hoyes, JS et al. (2005) Genome Biology 6:R110 (doi:10.1186/gb-2005-6-13-r110) !36 Worm TF protein-protein interaction network

Y51H4A.17

NHR-69

NHR-49 NHR-111 NHR-10 ZF NHR HOMEODOMAIN MIG-5 ZF C2H2 bZIP WH MH1 STAT ZF GATA Unknown AT Hook ZF THAP Y65B4BR.5 FLYWCH ZF PHD HMG MYB IPT/TIG

Reece-Hoyes, JS et al. (2005) Genome Biology 6:R110 (doi:10.1186/gb-2005-6-13-r110) !37 Transcription network rewiring

Annie E. Tsong, et al. (2006) Nature 443, 415-420 !38 ! Plausible pathway to concurrent rewiring of a large set of genes

Tuch et al., (2008) Science 319 (5871): 1797-1799 !39 H-Adrenal gland H-Kidney M-Kidney C-Kidney Kidney H-Liver M-Liver C-Liver F-Gallbladder F-Liver P-Liver H-Pancreas H-Stomach M-Large intestine M-Small intestine M-Stomach C-Gallbladder P-Gallbladder C-Intestine P-Intestine P-Stomach F-Smallintestine Lung & uterus F-Largeintestine F-Stomach C-Oviduct C-Stomach M-Mammary gland H-Lung M-Lung F-Lung H-Uterus Immune tissues M-Uterus M-Ovary H-Placenta P-Fin P-Gill C-Lung H-Thyroid H-Bone marrow M-Bone Marrow H-Thymus Digestive tissues !40 M-Thymus M-Spleen Chan et al. Journal of Biology 2009 8:33 doi:10.1186/jbiol130 C-BursaofFabricus C-Thymus C-Femur Reproductive tissues C-Spleen H-Small Intestine H-Spleen F-Spleen P-Spleen P-Kidney M-Calvaria Liver F-Cartilage F-Femur H-Testis M-Testis C-Testis F-Testis F-Fatbody F-Kidney F-Ovary P-Ovary Neural tissues P-Testis P-Swimbladder F-Oviduct C-Ovary H-Brain H-Brain - cerebral cortex H-Brain - cerebellum M-Cerebellum M-Cortex C-Cerebellum C-Cerebralcortex F-Brain P-Brain H-Retina M-Eye C-Eye F-Eye P-Eye H-Heart M-Heart H-Skeletal Muscle M-Skeletal Muscle C-Muscle F-Muscle P-Redmuscle P-Whitemuscle C-Heart F-Heart P-Heart P-Beak P-Calvaria P-Skin P-Connectivetissue M-Skin C-Skin C-Gizzard Muscle & skin tissues F-Esophagus F-Skin P-Fin P-Gill P-Eye F-Eye C-Eye P-Skin M-Eye F-Skin C-Skin P-Liver F-Liver M-Skin F-Lung P-Beak H-Liver C-Liver P-Brain F-Brain H-Lung C-Lung M-Liver P-Heart M-Lung H-Brain F-Heart P-Testis H-Heart F-Testis C-Heart P-Ovary F-Ovary M-Heart H-Testis C-Testis C-Ovary M-Testis M-Ovary F-Femur C-Femur H-Retina P-Kidney H-Uterus F-Kidney P-Spleen F-Spleen M-Uterus M-Cortex H-Kidney C-Kidney F-Muscle C-Spleen H-Spleen M-Kidney C-Muscle M-Spleen F-Oviduct H-Thyroid C-Oviduct C-Gizzard P-Calvaria F-Fatbody H-Thymus C-Thymus P-Intestine M-Thymus P-Stomach C-Intestine M-Calvaria F-Stomach H-Placenta F-Cartilage C-Stomach H-Stomach M-Stomach H-Pancreas P-Redmuscle F-Esophagus P-Gallbladder F-Gallbladder C-Cerebellum C-Gallbladder M-Cerebellum P-Whitemuscle P-Swimbladder H-Bone marrow M-Bone Marrow F-Smallintestine F-Largeintestine H-Adrenal gland C-Cerebralcortex H-Small Intestine M-Small intestine M-Large intestine H-Skeletal Muscle M-Skeletal Muscle M-Mammary gland C-BursaofFabricus P-Connectivetissue H-Brain - cerebellum H-Brain - cerebral cortex

0 0.1 0.2 0.3 0.4 >0.5 Pearson correlation coefficient Conserved vertebrate tissue transcriptome Testis Testis CNS Eye Heart Muscle Intestine Stomach Kidney Liver Spleen Testis CNS Eye Heart Muscle Intestine Stomach Kidney Liver Spleen Testis CNS Eye Heart Muscle Intestine Stomach Kidney Liver Spleen CNS Eye Heart Muscle Intestine Stomach Kidney Liver Spleen CNS Eye Heart Muscle Intestine Stomach Kidney Liver Spleen Testis 1,488 genes with conserved expression

Human Mouse Chicken Frog Pufferfish Relative expression ratio !41 Chan et al. Journal of Biology 2009 8:33 0 2 5 >10 Conservation and divergence of TF binding

Schmidt, et al (2010) Vol. 328 no. 5981 pp. 1036-1040 DOI: !42 10.1126/science.1186176 Allan Boyle, UNC PhD Thesis 43 Co-association between Transcription Factors in K562 cells A.# B.# C.#

K562#Whole-genome# K562#Intergenic#regions# K562#Promoter.proximal#regions#

B" A" 20# 18# 19# Whole&genome& Promoter-proximal®ions& D.# Promoter' B" proximal- regions- A" 119 different DNA-binding1& Intergenic- Intergenic®ions& regions- proteins !44 ENCODE AWG. 2012 A-(K562)- B-(K562)- C-(H1'hESC)- 2- Transcription factor co-association

MB Gerstein et al. Nature 489, 1-10 (2012) doi:10.1038/nature11245 !45 Overall network

MB Gerstein et al. Nature 489, 1-10 (2012) doi:10.1038/nature11245 !46 Overall network

MB Gerstein et al. Nature 489, 1-10 (2012) doi:10.1038/nature11245 !47 Motif analysis

MB Gerstein et al. Nature 489, 1-10 (2012) doi:10.1038/nature11245 !48 www.cytoscape.org

49 Ulitsky, I. et al. Towards accurate imputation of quantitative genetic interactions. (2009) Genome Biology 10:R140 ! Park, C.Y., et al. Simulaneous Genome-Wide Inference of Physical, Genetic, Regulatory, and Funcational Pathway Components. (2010) PLoS Computational Biology. 6:e1001009 ! Tian, W., et al. Combining guilt-by-association and guilt-by-proﬁling to predict Saccharomyces cerevisiae gene function. (2008) Genome Biology 9:S7

!50