understanding protein function on a genome-scale through the analysis of molecular networks
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Understanding Protein Function on a Genome-scale through the Analysis of Molecular Networks. Mark B Gerstein Yale slides at Lectures.GersteinLab.org (See Last Slide for References & More Info.). 1 (c) Mark Gerstein, 2002, Yale, bioinfo.mbb.yale.edu. - PowerPoint PPT PresentationTRANSCRIPT
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Understanding Protein Function on a
Genome-scale through the Analysis of
Molecular Networks
Mark B GersteinYale
slides at Lectures.GersteinLab.org
(See Last Slide for References & More Info.)
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The problem: Grappling with Function on a Genome Scale?
~530
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1,150 protein-coding genes, Additional 941 pseudogenes.
Hillier et al, Nature, 424, 157
The DNA sequence of human chromosome 7
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Traditional single molecule way to integrate
evidence & describe function
Descriptive Name: Elongation Factor 2
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.
EF2_YEAST
Lots of references to papers
But function definition is not straight-forward!!!!
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Function determined by the partner: Hsp 70
Prokaryotic Hsp70 (DnaK) cooperates with Hsp DnaJ and CrpE in protein folding.
Hsp70 of the endoplasmic reticulum (BiP, Kar2p) directly binds to Sec63p to facilitate transport of preproteins across the membrane.
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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
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Some other issues that confound definition of protein function
• 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)
[Seringhaus et al. GenomeBiology (2008)]
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[Seringhaus et al. GenomeBiology (2008)]
An Ontology of Naming Pathologies
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Gene Name Skew
[Seringhaus et al. GenomeBiology (2008)]
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Hierarchies & DAGs of controlled-vocab termsbut still have issues...
[Seringhaus & Gerstein, Am. Sci. '08]
GO (Ashburner et al.)MIPS (Mewes et al.)
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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]
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Networks (Old & New)
[Seringhaus & Gerstein, Am. Sci. '08]
Classical KEGG pathway Same Genes in High-throughput Network
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Networks occupy a midway point in terms of level of understanding
1D: Complete Genetic Partslist
~2D: Bio-molecularNetwork
Wiring Diagram
3D and 4D: Ribosome in different functional states. Detailed
structural understanding of cellular machinery
[Jeong et al. Nature, 41:411][Fleischmann et al., Science, 269 :496] [Chiu et al. Trends in Cell Biol, 16:144]
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Networks as a universal language
Disease Spread
[Krebs]
ProteinInteractions
[Barabasi] Social Network
Food Web
Neural Network[Cajal]
ElectronicCircuit
Internet[Burch & Cheswick]