1. Modeling cells with protein networks
Trey Ideker
University of California San Diego
Department of Bioengineering

2. From protein sequences… to protein networks
Query Sequence
GACTGCATTAC
Global query
Database
DNA and protein
sequences
Database / Scaffold of
Molecular Interactions
Conserved genes/proteins
Interaction pathway and complexes associated with query data

3. Protein→DNA
interactions
Protein—protein
interactions
Biochemical
reactions

4. Also like sequence, protein interaction data are exponentially growing…
EMBL Database Growth total nucleotides (gigabases)
DIP Database Growth total interactions 10 5
1980
1990
2000
(As are the false positives!!!)

5. Cross-comparison of networks:
Conserved regions in the presence vs. absence of stimulus
Conserved regions across different species
Kelley et al. PNAS 2003
Kelley et al. NAR 2004
Sharan et al. RECOMB 2004

6. Multiple protein-protein network alignment of three model eukaryotes (Sharan et al. PNAS 2005)
YEAST (Multiple publications-Uetz, Ito, Gavin, Ho)
4,393 proteins, 14,584 interactions
WORM (Li et al. Science 303, 2004)
2,719 proteins, 3,926 interactions
FLY (Giot et al. Science 302, 2003)
7,048 proteins, 20,884 interactions
Baker’s yeast
(Saccharomyes cerevisiae)
Nematode worm (Caenorhabditis elegans)
Fruit fly (Drosophila melanogaster)

7. Example yeast/worm/fly alignments?

8. 40-50% of predictions confirmed

9. Plasmodium: a network apart?
Plasmodium-specific protein complexes
Conserved Plasmodium / Saccharomyces protein complexes
Suthram et al. Nature 2005 La Count et al. Nature 2005

10. Plasmodium has only 3 conserved complexes with yeast and none with other species

11. Finding physical pathways to explain genetic interactions
Classical method used to map pathways in model species
Highly analogous to multi-genic interaction in human disease and combination therapy
Thousands are being uncovered through systematic studies
Thus as with other types, the number of known genetic interactions is exponentially increasing…
Genetic interaction, in which two mutations have a combined effect not exhibited by either mutation alone, is an extremely powerful and widespread tool for establishing functional relationships between genes.
Adapted from Tong et al., Science 2001

12. Synthetic lethals are another type of interaction that are appearing in large numbersDB DA B DA DB
Adapted from Hartman, Garvik, and Hartwell, Science 2001

13. Interpretation of genetic interactions (Guarente T.I.G. 1990)
Parallel Effects (Redundant or Additive)
Sequential Effects (Additive) a w A B a w A B
GOAL: Identify downstream physical pathways
Single A or B mutations typically abolish their biochemical activities
Single A or B mutations typically reduce their biochemical activities

14. Integration of genetic and physical interactions
160 between-pathway models
101 within-pathway models
Num interactions: 1,102 genetic 933 physical
Kelley and Ideker Nature Biotechnology (2005)

15. Systematic identification of 160 “parallel pathway” relationships in yeast

16. Global organization of genetic linkages between physical pathways (A-Z)
Bridging genetic interactions
Overlapping pathways

17. The vision: First build the scaffold, then add the details
Ideker and Lauffenburger Trends in Biotech. (2003)