Pathway  analysis  for  genomics  

Gary  Bader  Oct.23.2012  –  FGED  Toronto  

Microtubule

Cytoskeleton

Cell Projection

& Cell Motility

Cell Proliferation

Glycosylation

Adhesion

Regulation of GTPase

Kinase Activity/Regulation

CNS Development

Intellectual

Disability

Autism

GTPase/Ras

Signaling

Regulation of cell proliferation

Positive regulation of cell proliferation

Tyrosin kinase

Vasculature develepment

Palate develepment

Organ Morphogenesis

Behavior

Heart develepment

RHO Ras

Membrane

Kinase regulation

Cell Motility

(stricter cluster)

Centrosome

Nucleolus

Cell cycle

Regulation of

hormone levels

Aminoacid

derivative /

amine

metabolism

Synaptic vescicle maturation

Reelin pathway

LIS1 in neuronal

migration and

development

Negative

regulation

of cell cycle

cKIT

pathwaymTor

pathway

Zn finger

domain

Carboxyl

esterase

domain

Ras signaling GTPase regulator

Neuron

migration

Cell Motility

(stricter cluster)

Cell morphogenesis

Cell projection

organization

CNS

development

Brain

development

Neurite development

CNS neuron

differentiation

AxonogenesisProjection neuron

axonogenesis

Cerebral cortex

cell migration

SMC flexible hinge domain

Urea and amine group metabolism

MHC-I

Zoom of CNS-Development

ID ID

ASDASD

Both

0%

12.5%

Enrichedin deletions

FDR

Known disease genes

Enriched onlyin disease genes

Node type (gene-set)

Edge type (gene-set overlap)

From disease genesto enriched gene-sets

Between gene-setsenriched in deletions

Between sets enriched in deletions and in diseasegenes or between diseasesets only

Pinto  et  al.  FuncBonal  impact  of  global  rare  copy  number  variaBon  in  auBsm  spectrum  disorders.  Nature.  2010  Jun  9.  

CorrelaBon  to  CausaBon  •  GWAS:  find  geneBc  markers  correlated  with  disease  –  powerful  approach,  but:  – genomics  reduces  staBsBcal  power  (>mulBple  tesBng  correcBon  with  >SNPs)  

–  rare  variants  =  more  samples  

•  Associate  pathways  to  increase  power  – Fewer  pathways,  organize  many  rare  variants  (damaging  the  system  causes  the  disease)  

•  Use  pathway  knowledge  to  idenBfy  potenBal  disease  causes  

The Systems Biology Pyramid

Cary, Bader, Sander, FEBS Letters 579 (2005) 1815-20

Chris Sander, MSKCC

Cytoscape cPath2

Pathway Commons BioPAX

hWp://pathguide.org  

Vuk  Pavlovic  Sylva  Donaldson  

>320  Pathway  Databases!  

• Varied  formats,  representa;on,  coverage  • Pathway  data  extremely  difficult  to  combine  and  use  

BioPAX  Pathway  Language  •  Represent:  

– Metabolic  pathways  – Signaling  pathways  – Protein-­‐protein,  molecular  interacBons  – Gene  regulatory  pathways  – GeneBc  interacBons  

•  Community  effort:  pathway  databases  distribute  pathway  informaBon  in  standard  format  

www.biopax.org  

Emek Demir

SBGN.org

BioCarta

BioPAX

Aim: Convenient Access to Pathway Information

Facilitate  creaBon  and  communicaBon  of  pathway  data  Aggregate  pathway  data  in  the  public  domain  Provide  easy  access  for  pathway  analysis  

Long  term:  Converge  to  integrated  cell  map  

hCp://pathwaycommons.org  

Pathway  Commons:  cPath2  

•  hWp://www.pathwaycommons.org/pc2/  

Emek Demir, Igor Rodchenkov, Chris Sander Ozgun Babur, Arman Aksoy, Onur Sumer, Ethan Cerami, Ben Gross

Network  visualizaBon  and  analysis  

UCSD,  ISB,  Agilent,  MSKCC,  Pasteur,  UCSF,  Unilever,  UToronto,  U  Texas  

hWp://cytoscape.org  

Pathway  comparison  Literature  mining  Gene  Ontology  analysis  AcBve  modules  Complex  detecBon  Network  moBf  search  

Cytoscape  3  

•  Complete  re-­‐architecture:  OSGi  –  everything  is  an  app  •  Enables  future  features:  

–  More  stable  and  powerful  APIs  –  ScripBng,  macros,  recordable  history,  beWer  undo/redo  –  Command  line  mode,  good  for  use  on  compute  clusters  –  InteracBve  control  from  other  scripBng  languages  e.g.  R  

•  Fixing  bugs  and  porBng  plugins  •  3.0  beta  now  available  

–  Mirror  funcBonality  in  2.8  –  Encourage  plugin  to  app  porBng  –  hWp://www.cytoscape.org/cy3.html  

14  

hWp://cytoscapeweb.cytoscape.org/  

Chris;an  Tannus-­‐Lopes,  Max  Franz,  Yue  Dong    

Compound  Nodes  Onur Sumer Ugur Dogrusoz Bilkent, Ankara

hCp://cytoscapeweb.cytoscape.org/demos/compound  

Cytoscape.js:  HTML5  –  iPad  cytoscape.github.com/cytoscape.js/  

Gene Function Prediction

hWp://www.genemania.org  

Quaid Morris (Donnelly), Sara Mostafavi Rashad Badrawi, Ovi Comes, Sylva Donaldson, Max Franz, Christian Lopes, Farzana Kazi, Jason Montojo, Harold Rodriguez, Khalid Zuberi

•   Guilt-­‐by-­‐associaBon  principle  •   Biological  networks  are  combined  intelligently  to  opBmize  predicBon  accuracy  •   Algorithm  is  more  fast  and  accurate  than  its  peers  

Mostafavi  S  et  al.  Genome  Biol.  2008;9  Suppl  1:S4  

Warde-­‐Farley  D  et  al.  Nucleic  Acids  Res.  2010  Jul;8:W214-­‐20.  

The  Factoid  Project  

•  Publishing  in  science  – Highly  inefficient  – Outdated  technology,  difficult  to  search  and  compute  

•  hWp://www.elseviergrandchallenge.com/  – Winner:  hWp://reflect.ws/  

•  Pathway  and  network  informaBon  database  curaBon  – Highly  inefficient  

•  The  factoid  project  

Max  Franz,  Igor  Rodchenkov,  Ozgun  Babur,  Emek  Demir,  Chris  Sander  

Pathway  and  Network  Analysis  

1.  Gene  set:  pathway  enrichment  analysis  

2.  Network:  network  regions  (modules),  regulaBon  

3.  Process  model:  classical  pathways  

4.  SimulaBon  model:  detailed  models  

Mec

hani

stic

U

nder

stan

ding

Gen

ome

Cov

erag

e A

nd u

se

Increase Coverage and Depth

Cellular  Process  Representa;on  •  Gene  set  •  Network  •  Process  model  •  SimulaBon  model  

•  Analysis  methods  need  to  keep  up  

Cov

erag

e

Depth

Dep

th

Data and analysis methods

Present

Future

Km=3.0×10−4

Acknowledgements  Bader  Lab  Domain  InteracBon  Team  Chris  Tan  Shirley  Hui  Shobhit  Jain  Brian  Law  Jüri  Reimand    Former:  David  Gfeller  Xiaojian  Shao  

Funding  

hWp://baderlab.org  

www.GeneMANIA.org Quaid Morris (Donnelly) Rashad Badrawi, Ovi Comes, Sylva Donaldson, Christian Lopes, Farzana Kazi, Jason Montojo, Sara Mostafavi, Harold Rodriguez, Khalid Zuberi

Gene;c  Intx,  Pathways:  Anastasia  Baryshnikova  Iain  Wallace  Magali  Michaut  Ron  Ammar  Daniele  Merico  Ruth  Isserlin  Vuk  Pavlovic  Igor  Rodchenkov  

Pathway  Commons  Chris  Sander  Ethan  Cerami  Ben  Gross  Emek  Demir  Igor  Rodchenkov  Nadia  Anwar  Ozgun  Babur