On the scope and limitations of baker’s yeast as a model organism for studying human tissue-specific pathways

Budding yeast, S. cerevisiae, has been used extensively as a model organism for studying cellular processes in evolutionarily distant species, including humans. However, different human tissues, while inheriting a similar genetic code, exhibit distinct anatomical and physiological properties. Specific biochemical processes and associated biomolecules that differentiate various tissues are not completely understood, neither is the extent to which a unicellular organism, such as yeast, can be used to model these processes within each tissue. We propose a novel computational and statistical framework to systematically quantify the suitability of yeast as a model organism for different human tissues. We develop a computational method for dissecting the human interactome into tissue-specific cellular networks. Using these networks, we simultaneously partition the functional space of human genes, and their corresponding pathways, based on their conservation both across species and among different tissues. We study these subspaces in detail, and relate them to the overall similarity of each tissue with yeast. Many complex disorders are driven by a coupling of housekeeping (universally expressed in all tissues) and tissue-selective (expressed only in specific tissues) dysregulated pathways. We show that human-specific subsets of tissue-selective genes are significantly associated with the onset and development of a number of pathologies. Consequently, they provide excellent candidates as drug targets for therapeutic interventions. We also present a novel tool that can be used to assess the suitability of the yeast model for studying tissue-specific physiology and pathophysiology in humans.