Most inherited genetic disorders are complex. They do not result from a single causative genetic lesion, but arise from a combination of mutations in multiple genes. Finding out why some specific combinations give rise to disease requires detailed understanding of the cellular processes in which these genes are involved. In these processes many proteins, which are the gene products, interact with one another in order to execute specific functions. Systematically mapping out these interactions can teach us about how mutations in different genes can affect each other. Large-scale systematic mapping of this type has presently been performed only in simple organisms such as the budding yeast and bacteria, to some extent in the worm and fly, but only scantly in human and mouse.
In this project we will develop and apply powerful bioinformatics procedures that will close this gap. These procedures will exploit the fact that key cellular processes are conserved across species. They will leverage the available information on all fully and partially sequenced genomes, and exploit the evolutionary relationships between genes in different organisms. This will then be applied to infer interactions and gene function in human and mouse on the basis of charted interaction in the simpler model organisms. Our analysis will focus on the chromatin modification processes - a set of regulatory processes implicated in cancer, which govern DNA replication, transcription and repair. Based on the inferred interaction networks, new hypotheses will be formulated on function of individual components, the consequences of disease-associated mutations across the network, and the outcome of potential polygenic interactions between network components. Such hypotheses will be validated experimentally in mouse and human cells, gaining new knowledge that may enable the development of clinical biomarkers and potential new drug targets. Our resources will be made freely available to the scientific community and should become a long-term valuable discovery and training tool for all groups involved in health-related research, in Canada and abroad.
Collaborators
- Andrew Emili, Donnelly CCBR, University of Toronto
- Jack Greenblatt, Donnelly CCBR, University of Toronto
- John Parkinson, Research Institute of the Hospital for Sick Children
- Janet Rossant, Research Institute of the Hospital for Sick Children
- Michael Tyers, Samuel Lunenfeld Research Institute, Mount Sinai Hospital
- Shoshana Wodak, Research Institute of the Hospital for Sick Children
- Zhaolei Zhang, Donnelly CCBR, University of Toronto
Scientific Advisory Board
- John Aitchison, Institute for Systems Biology, Seattle, WA, USA
- Joel Bader, Johns Hopkins University and School of Medicine, Baltimore, MD, USA
- Judith Blake, The Jackson Laboratory, Bar Harbor, ME, USA
- Philip Hieter, Michael Smith Laboratories, University of British Columbia
- David Kaplan, Research Institute of the Hospital for Sick Children
