Understanding Protein Function on a Genome-scale through the Analysis of Molecular Networks

1. Understanding Protein Function on a Genome-scale through the Analysis of Molecular Networks Mark B GersteinYale slides atLectures.GersteinLab.org(See Last Slide for References & More Info.) 1 (c) Mark Gerstein, 2002, Yale, bioinfo.mbb.yale.edu

2. The problem: Grappling with Function on a Genome Scale? The DNA sequence of human chromosome 7 ~530 ……………. Hillier et al, Nature, 424, 157 1,150 protein-coding genes, Additional 941 pseudogenes.

3. EF2_YEAST Traditional single molecule way to integrate evidence & describe function Descriptive Name: Elongation Factor 2 Lots of referencesto papers Summary sentence describing function:This protein promotes the GTP-dependent translocation of the nascent protein chain from the A-site to the P-site of the ribosome. But function definition is not straight-forward!!!!

4. Function determined by the partner: Hsp 70 Hsp70 of the endoplasmic reticulum (BiP, Kar2p) directly binds to Sec63p to facilitate transport of preproteins across the membrane. Prokaryotic Hsp70 (DnaK) cooperates with Hsp DnaJ and CrpE in protein folding.

5. Another issue: Pleitropy A single gene influences multiple phenotypic traits. Consequently, a new mutation in the gene may have an effect on some or all traits simultaneously. In youth, testosterone has positive effects including reproductive fitness but, later in life, there are negative effects such as increased susceptibility to prostate cancer. Another example is the p53 gene which suppresses cancer, but also suppresses stem cells which replenish worn-out tissue p53 protein

6. Fundamental complexities Often >2 proteins/function Multi-functionality: 2 functions/protein Role Conflation: molecular, cellular, phenotypic Fun terms… but do they scale?.... Starry night (P Adler, ’94) Some other issues that confound definition of protein function [Seringhaus et al. GenomeBiology (2008)]

7. An Ontology of Naming Pathologies [Seringhaus et al. GenomeBiology (2008)]

8. Gene Name Skew [Seringhaus et al. GenomeBiology (2008)]

9. Hierarchies & DAGs of controlled-vocab termsbut still have issues... MIPS (Mewes et al.) GO (Ashburner et al.) [Seringhaus & Gerstein, Am. Sci. '08]

10. Towards Developing Standardized Descriptions of Function • Subjecting each gene to standardized expt. and cataloging effect • KOs of each gene in a variety of std. conditions => phenotypes • Std. binding expts for each gene (e.g. prot. chip) • Function as a vector Interaction Vectors [Lan et al, IEEE 90:1848]

11. Networks (Old & New) Classical KEGG pathway Same Genes in High-throughput Network [Seringhaus & Gerstein, Am. Sci. '08]

12. Networks occupy a midway point in terms of level of understanding 3D and 4D: Ribosome in different functional states. Detailed structural understanding of cellular machinery ~2D: Bio-molecular Network Wiring Diagram 1D: Complete Genetic Partslist [Chiu et al. Trends in Cell Biol, 16:144] [Jeong et al. Nature, 41:411] [Fleischmann et al., Science, 269 :496]

13. Networks as a universal language Internet [Burch & Cheswick] Electronic Circuit Food Web Disease Spread [Krebs] Neural Network [Cajal] ProteinInteractions [Barabasi] Social Network