At a Glance

Founded2005
Renewal dates2010
Members17
Disciplines
Genetics; biochemistry and molecular biology; computational biology and bioinformatics; cell, evolutionary and systems biology; pathology; immunology; biotechnology

How do the interactions among genes influence health and development?

Our genes determine all sorts of things about us, including our predisposition to many diseases. But there are only a small number that we understand well enough to know how a genetic change is propagated through the network of molecular and cellular interactions to ultimately yield a human disease.

If we can get a better understanding of how these interactions work, and of how the effects of genetic perturbation propagate through the system, we will be better able to identify the root causes of many complex genetic diseases like autism, asthma, Alzheimer’s and many cancers.

The Genetic Networks program at CIFAR is charting genetic and molecular interactions to understand how biological systems work and how they fail. The aim is to map complete networks of genetic and molecular interactions, and to use them to decipher the rules of how genes influence one another, what environmental factors alter those interactions, and how the impact of genetic change is propagated through biological systems.

Our unique approach

The Genetic Networks Program brings together geneticists with molecular and computational biologists, who work on a wide variety of species, from yeasts, fruit flies, worms and mice to humans. Because evolution has preserved many genes and genetic interactions over millions of years – for instance, humans and yeast share about 40 percent of their genes – research into the simpler organisms can shed light on humans. This broadly integrated investigation of genetic networks is unique in the world and has helped to recruit eminent researchers and give them the opportunity to connect and collaborate with leading researchers from other countries. Their work is uncovering how networks of molecular interactions mediate the effects of combinations of genetic perturbations, yielding maps from personal genomes to states of health and disease. The multidisciplinary Genetic Networks program has benefitted greatly from the cutting-edge work of other CIFAR programs. For example, program researchers have used deep learning — a machine learning technique pioneered by CIFAR fellows in the Learning in Machines & Brains program (formerly known as Neural Computation & Adaptive Perception) — to better predict how genetic change affects human disease.

Chad L. Myers, Brenda J. Andrews, Charles Boone and colleagues created a map of interactions of genes in the yeast cell. The labels show the functions of different genetic networks. Image courtesy of Science magazine

Why this matters

A recent explosion in gene sequencing technologies has identified a massive catalogue of genes. However, we still need to understand how the information that’s encoded in genes, and the vast number of interactions between them, translates into the specific traits and characteristics that are unique to every one of us. By developing methods that predict the direct outcomes, including disease, from an individual’s complex genetic makeup, the program is helping to lay the groundwork that will lead to medicine that is personalized according to each individual’s genome. Researchers have made progress deciphering the causes of diseases from single genes, like cystic fibrosis and Huntington’s disease. But what’s needed now is a better understanding of how multiple genes mutate, combine, and alter networks of molecular and cellular interactions to cause more complex diseases. Even though there are hundreds of human gene variants, many lead to disease only in specific combinations.

In depth

Program members, individually and collaboratively, have made major progress in mapping genetic interactions. Partial network maps now exist for several model organisms, including two different yeast species, and the nematode worm.  Work on genetic network mapping in cultured human cells is also underway. Program members have tested how genetic interactions are conserved between species – a key question for applying knowledge of model systems to more complex organisms, including humans. They found that two distantly related types of yeast separated by a billion years of evolution share three-quarters of their genes and one-third of their genetic interactions. This finding suggests a core genetic network might be common to many even more distant species. New genetic interaction maps and conservation studies have become starting points for program researchers to address broad evolutionary questions and better understand the genetic basis of many human diseases. Fellow Chad Myers and Senior Fellow Charles Boone used their analysis of yeast genes to identify two potential targets in humans for a new form of cancer therapy. The team was looking for “synthetic lethal” interactions—two individual mutations, neither of which will kill a cell by itself, but which when present together are lethal. The idea was to find a mutation that causes cancer in humans, and to find one in another gene that is lethal to the cell when combined with the cancer-causing mutation. The identified mutations could allow researchers to design cancer therapies, including drugs, that manipulate expression of the second gene, killing cancer cells but leaving healthy cells unaffected. Program Director and Senior Fellow Frederick Roth co-led an international research team that carried out the first full-scale mapping of direct physical interactions between human proteins.  The reference map of the human ‘interactome’ describes about 14,000 direct interactions between proteins, which is seven times more than any previous map of its kind has uncovered. This map pointed to dozens of new genes that could be involved in cancer.

Brendan Frey, a senior fellow in both NCAP and Genetic Networks, used a new computational technique to reveal tens of thousands of genetic variants that provide insight into the genetic basis of spinal muscular atrophy, hereditary nonpolyposis colorectal cancer and autism spectrum disorder. Illustration courtesy of Science

Senior Fellow and former Program Co-Director Brenda Andrews and Senior Fellow Charles Boone have produced the first global map of protein locations within a eukaryotic cell. This map enhances understanding of protein function – which is still hard to predict just from looking at the DNA sequence – as well as complex protein interactions that underpin disease. After developing a map of protein localization in normal cells, they watched how it changes when cells begin to divide, when they carry a genetic mutation, or when they are under environmental stress. A team of researchers led by Senior Fellow Eric Shoubridge has discovered a new genetic defect that has been linked to a spectrum of rare and severe neurological disorders. The defect compromises the function of the mitochondrion, which generates energy and ultimately keeps cells alive. Understanding which genes are implicated in these disorders could offer parents options for making reproductive decisions, such as genetically testing embryos or donor cells. Senior Fellow Brendan Frey has combined the latest in whole genome sequencing with computational techniques to develop the “human splicing code”, an entirely new approach to identifying the genetic determinants of disease. Frey and his colleagues have applied this new approach to identify mutations involved in cancer and neurological disorders. Their genome-wide analysis has revealed tens of thousands of variants that alter RNA splicing and are embedded in a wide range of known diseases including spinal muscular atrophy, certain cancers, and autism spectrum disorder. The disruption of splicing, a critical step in gene expression, is known to contribute to disease. The study also reveals that the network of genetic interactions in humans covers a much broader area of the genome than some past research has suggested. In 2015, Frey founded a company called Deep Genomics, devoted to commercializing the technology. Senior Fellow Steve Scherer was one of the first in the world to find that, while autism has genetic roots, people with autism don’t have identical mutations in one or a few genes, as was previously assumed. A collaboration between Scherer and Frey has resulted in a breakthrough in diagnosing autism at a younger age that allows patients to receive therapies earlier. Their study reveals a unifying set of characteristics in the DNA can be woven into a “genetic formula” that helps us calculate which genetic mutations have the highest probability of causing autism, and equally important, which alterations do not have a role.  Around 100 genes have been linked to autism so far. Much of the recent work conducted by program members, particularly that of Scherer and Frey, reflects a new focus on how a better understanding of genetic interactions can lead the way to personalized medicine, in which drugs and therapies can be specifically targeted using the genetic information of the individual.

Selected papers

A.P. Davierwala et al., “The synthetic genetic interaction spectrum of essential genes,” Nature Genetics 37 (2005): 1147-52 doi:10.1038/ng1640 R. Redon et al., “Global variation in copy number in the human genome,” Nature 444 (2006): 444-454 doi: 10.1038/nature05329. S. Levy et al, “The Diploid Genome Sequence of an Individual Human,” PLoS Biology 5, 10 (2007): e254 doi:10.1371/journal.pbio.0050254. Y. Barash et al, “Deciphering the splicing code,” Nature 465, 7294 (2010): 53–59 doi: 10.1038/nature09000.

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Fellows & Advisors

Photo of Charles M. Boone

Charles M. Boone

Program Co-Director

Charles Boone has implemented an automated form of yeast genetic analysis to cross thousands of specific strains carrying precise mutations and to map yeast genetic interactions on a large scale.…

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Photo of Frederick P. Roth

Frederick P. Roth

Program Co-Director

Frederick (Fritz) Roth's research team is developing technology to accelerate discovery of gene functions, the pathways they encode, the relationships of genes and pathways and variation to human disease. They…

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Fellows

Brenda Andrews

Senior Fellow

University of Toronto

Canada

Maitreya Dunham

Senior Fellow

University of Washington

United States

Andrew Fraser

Fellow

University of Toronto

Canada

Brendan J. Frey

Senior Fellow

University of Toronto

Canada

Philip Hieter

Senior Fellow

University of British Columbia

Canada

Timothy R. Hughes

Senior Fellow

University of Toronto

Canada

Donald Moerman

Senior Fellow

University of British Columbia

Canada

Jason Moffat

Senior Fellow

University of Toronto

Canada

Chad Myers

Fellow

University of Minnesota

United States

Stephen W. Scherer

Senior Fellow

Hospital for Sick Children

Canada

Eric A. Shoubridge

Senior Fellow

McGill University

Canada

Olga Troyanskaya

Senior Fellow

Princeton University

United States

Advisors

David Botstein

Advisory Committee Chair

California Life Company

United States

David Sankoff

Advisor

University of Ottawa

Canada

Robert Waterston

Advisor

University of Washington

United States

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