A Global Genetic Network Charts the Functional Map of a Cell
A genetic map of a cell begins to explain how genes work together to coordinate cellular life.
FOCUS OF STUDY
Genome sequencing projects are providing an unprecedented view of genetic variation. However, our ability to interpret genetic information to understand cell function and predict phenotypes, including disease, remains limited, in large part to the extensive buffering of genomes that makes most individual genes dispensable for life. Recent studies applied automated genetics to construct a global genetic interaction network for a model cell to explore the extent to which genetic interactions reveal cellular function and contribute to complex inherited traits, as well as to discover the general principles of genetic networks.
Like most eukaryotic organisms, only a small subset of yeast genes (~1,000 out of 6,000) are essential for viability and disrupting one of these genes leads to cell death. On the other hand, the remaining ~5,000 genes are individually dispensable such that a yeast cell can tolerate and survive the loss of any one of these genes. While most yeast genes are not required for viability, it does not mean that these genes are not important. Rather, the large fraction of nonessential genes is a reflection of the extensive buffering or backup systems cells have evolved to ensure survival in response to genetic perturbations and environmental insults.
Identification and dissection of the genetic systems that back up critical cellular processes are important to our understanding of the basic components of the cell and how the genes encoding these different parts work together to coordinate fundamental functions essential for cellular life. One way to identify these backup systems involves systematically mutating two genes at a time and examining the effect of the mutated gene pair on cell growth and proliferation. An unexpected change in cell growth or fitness resulting from disruption of a pair of genes is known as a genetic interaction. Extreme negative genetic interactions, referred to as “synthetic lethal” interactions, describe instances where two mutations, each causing little or no growth defect on their own, result in cell death when combined in the same genome. These interactions are particularly interesting because they identify genes that impinge on or buffer the same essential biological function. As a result, large-scale screening for genetic interactions provides a means of exploring the buffering capacity and creating a diagram of the functional wiring of a cell.
Mutant combinations affecting different genes are not always associated with detrimental effects. In some instances, deleterious consequences associated with a mutation in one gene can be overcome or avoided by a second mutation in a different gene. These so-called positive or suppression interactions represent another means to understand and potentially treat genetic disorders since they may provide insight into to why some people remain healthy despite carrying genetic mutations that are known to cause debilitating diseases.
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