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September 29, 2016

Synthetic Lethal Gene Pairs Reveal Life-Sustaining Genome Networks

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    In this map of a global network of genetic interactions, genes with similar genetic interaction profiles are connected such that genes exhibiting more similar profiles are located closer to each other, whereas genes with less similar profiles are positioned farther apart. Such maps have been used to identify gene networks that account for functional enrichment. [University of Toronto]

    Like human resource consultants looking to reduce headcount without hurting productivity, or even destroying the company, molecular geneticists have been downsizing genomes, paying especial attention to which gene losses affect the life of the cell and which do not. For example, molecular geneticists based at the University of Toronto recently tried deleting two genes at a time in pair combinations. This approach, applied to yeast cells, allowed the scientists to probe the yeast genome’s organizational chart.

    This chart, the scientists found, has a hierarchical structure. The scientists also demonstrated how genes interact in groups. Closer study of these groups could bring the genetic roots of disease to light.

    Details of the study appeared September 23 in the journal Science, in an article entitled, “A Global Genetic Interaction Network Maps a Wiring Diagram of Cellular Function.” It describes how a global genetic interaction network for the budding yeast Saccharomyces cerevisiae was generated. More than 23 million double mutants were constructed to enable the identification of about 550,000 negative and about 350,000 positive genetic interactions.

    “This comprehensive network maps genetic interactions for essential gene pairs, highlighting essential genes as densely connected hubs,” the article’s authors wrote. “Genetic interaction profiles enabled assembly of a hierarchical model of cell function, including modules corresponding to protein complexes and pathways, biological processes, and cellular compartments.”

    Essentially, the University of Toronto team decided to interview genes for their own jobs. And the team did find some redundancies. That is they demonstrated that some genes have functional backups, rather like a customer-facing intermediary in a corporation may be backed up by someone in the engineering department who is capable of reading a customer’s spec sheet.

    Another way to describe this kind of redundancy is to point out that a brake on a bicycle’s front wheel can be backed up by a brake on the rear wheel. Geneticists say that front and back brakes are "synthetic lethal," meaning that losing both—but not one—spells doom. Synthetic lethal gene pairs are relatively rare, but because they tend to control the same process in the cell, they reveal important information about genes we don't know much about. For example, scientists can predict what an unexplored gene does in the cell simply based on its genetic interaction patterns.

    It is becoming increasingly clear that human genes also have one or more functional backups. So researchers believe that instead of searching for single genes underlying diseases, we should be looking for gene pairs. That is a huge challenge because it means examining about 200 million possible gene pairs in the human genome for association with a disease.

    Fortunately, with the know-how from the yeast map, researchers can now begin to map genetic interactions in human cells and even expand the mapping to different cell types. Together with whole-genome sequences and health parameters measured by new personal devices, it should finally become possible to find combinations of genes that underlie human physiology and disease.

    “A global genetic interaction network highlights the functional organization of a cell and provides a resource for predicting gene and pathway function,” the article’s authors explained. “We anticipate that the ordered topology of the global genetic network, in which genetic interactions connect coherently within and between protein complexes and pathways, may be exploited to decipher genotype-to-phenotype relationships.”

    "Without our many years of genetic network analysis with yeast, you wouldn't have known the extent to which genetic interactions drive cellular life or how to begin mapping a global genetic network in human cells," said Charles Boone, Ph.D., a professor of molecular genetics at the University of Toronto and a senior author of the current study. “We have tested the method to completion in a model system to provide the proof of principle for how to approach this problem in human cells. There's no doubt it will work and generate a wealth of new information."

    The concept of synthetic lethality is already changing cancer treatment because of its potential to identify drug targets that exist only in tumor cells. Cancer cells differ from normal cells in that they have scrambled genomes littered with mutations. They're like a bicycle without a set of brakes. If scientists could find the highly vulnerable backup genes in cancer, they could target specific drugs at them to destroy only the cells that are sick, leaving the healthy ones untouched.

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