The publication of the human genome was an incredible feat, requiring nearly 15 years of research and over $2 billion. In addition to providing unprecedented insight into our genome architecture and function, this project drove the invention of powerful tools to more deeply study and understand genomes. Remarkably, in OUR laboratory today, we can sequence a human genome overnight for approximately $2000. We can deeply mine gene expression in organs, tissues and even in single-cells. We can characterize and quantify mutation rates as low as 1 mutation in 100 million nucleotides. We have high-throughput tools than enable us to do transcriptomic analyses on hundreds of samples at a time, and powerful bioinformatic pipelines to make sense of these complex data sets. The pace of science in genomics has been truly astounding. The mission of the GReAT lab is to harness these ground-breaking tools and approaches to implement transformative ways to study the toxicology of chemicals and their ability to cause disease.
Overall, our research program uses state-of-the-science whole genome sequencing applications to explore how chemical exposures impact the genome, and develop new approaches to use this information in risk assessment. The program straddles academic and regulatory sciences, encompassing two main thematic areas. The first, toxicogenomics, uses genomic methodologies to characterize and predict toxicological mechanisms and effects. With a focus on high-throughput transcriptomics, our research team explores the toxicity of environmental chemicals and how transcriptomic data can best be used to inform health hazards and risk. The second thematic area, environmental mutagenesis, addresses how chemicals damage DNA and chromosomes to cause mutations. This is critical since mutagenesis can lead to cancer and inherited genetic diseases. Our research applies the most cutting edge sequencing tools to study how chemicals cause genotoxicity. One particular focal area is discovering the causes and consequences of mutations in germ cells (sperm and egg) that can lead to inherited genetic effects.
WE ARE EXTREMELY GRATEFUL FOR FUNDING PROVIDED THROUGH THE CANADA RESEARCH CHAIRS PROGRAM, THE CANADIAN FOUNDATION FOR INNOVATION, THE ONTARIO RESEARCH FUND, THE NATURAL SCIENCES AND ENGINEERING RESEARCH FUND, AND THE BURROUGHS WELLCOME FUND. AS WELL, OUR PARTNERS ARE FUNDED THROUGH HEALTH CANADA'S GENOMICS RESEARCH AND DEVELOPMENT INITIATIVE, THE CHEMICALS MANAGEMENT PLAN, AND FUNDING PROVIDED DIRECTLY THROUGH THE WATER AND AIR QUALITY BUREAU, THE CHEMICAL AND ENVIRONMENTAL HEALTH MANAGEMENT BUREAU AND THE EXISTING SUBSTANCES RISK ASSESSMENT BUREAU.
Current projects:
Development and application of fit-for-purpose, Adverse Outcome Pathway-based testing strategies to enhance hazard and risk assessment of chemicals causing genomic damage
PI: Carole Yauk; Co-PI: Francesco Marchetti (Health Canada and adjunct at Carleton University)
This is one of the 'bread and butter' projects in the GReAT laboratory. We're developing and applying new genomic tools to figure out how chemicals cause genotoxic and epigenotoxic effects. The Adverse Outcome Pathway (AOP: see https://aopwiki.org/) framework is used to describe how the observed molecular interactions measured with our tests can be used to predict adverse effects. We strive to identify the extent of initial damage that causes the downstream effects, to improve toxicological predictions.
Development and application of novel Next Generation Sequencing approaches for mutagenicity testing in the 21st century
PI: Francesco Marchetti; Co-PI: Carole Yauk
This project is beginning to decipher the environmental and lifestyle factors that increase the chances that parents will pass on new mutations to their children (mutations arising de novo in sperm or eggs). By using whole genome sequencing of human families, we're exploring rates of inherited mutations and their association with exposures and other characteristics. In parallel, we're using ground-breaking error-corrected sequencing methodologies to advance how we can study induced mutations in rodents in the laboratory, to improve out testing strategies for human health risk assessment.
Use of Gene Expression Profiling to facilitate read-across for 28 priority perfluoroalkylated substances (PFAS)
Co-PIs: Carole Yauk and Ella Atlas (Health Canada and adjunct at uOttawa); Collaborators: Ivy Moffatt and Luigi Lorruso (Health Canada regulatory partners)
With over 4,000 PFAS in the environment (you've probably heard of the ubiquitous PFOS and PFOA - check out Mark Ruffalo's movie Dark Waters), this project addresses the lack of toxicology data for thousands of PFAS in our environment. We're using transcriptional profiling in human liver organoids (made from primary human liver cells grown in 3D spheroid form) to explore how human cells respond to various PFAS, predict potential toxicological effects, and determine the physical-chemical characteristics that drive toxicity.
GeneTox21 - An Integrated, High-Throughput (HT) Platform for In Vitro Genetic Toxicity Assessment of New and Existing Chemicals
PI: Paul White; collaborator: Carole Yauk
We are thrilled to be part of the outstanding team of scientists striving to modernize how genotoxicity testing is done. All chemicals must be evaluated for genotoxicity before they are used in Canada. However, the current tests have generally been in use for decades, are not high-throughput, and do not provide information on how chemicals cause the observed genotoxicity. We're striving to change this. The GReATs contribute to the use of genomic tools to advance this area.
Revolutionizing genotoxicity testing and assessment through the use of a novel error-corrected sequencing technology
PI: Carole Yauk; Co-PIs: Paul White and Francesco Marchetti
We have won the Burroughs Wellcome Fund Innovations in Regulatory Sciences Award! We are very excited to get started with this international project that brings together uOttawa, Health Canada and collaborators from the Health and Environmental Sciences Institute to modernize how mutagenicity testing is done. The project will investigate how new error-corrected sequencing technologies that have unparalleled accuracy in mutation detection may be used to complement and eventually replace conventional mutagenicity tests used in toxicology. We will also examine how analysis of clonal expansion of cancer driver genes may serve as a biomarker for predicting the potential for chemicals to be carcinogenic.
Overall, our research program uses state-of-the-science whole genome sequencing applications to explore how chemical exposures impact the genome, and develop new approaches to use this information in risk assessment. The program straddles academic and regulatory sciences, encompassing two main thematic areas. The first, toxicogenomics, uses genomic methodologies to characterize and predict toxicological mechanisms and effects. With a focus on high-throughput transcriptomics, our research team explores the toxicity of environmental chemicals and how transcriptomic data can best be used to inform health hazards and risk. The second thematic area, environmental mutagenesis, addresses how chemicals damage DNA and chromosomes to cause mutations. This is critical since mutagenesis can lead to cancer and inherited genetic diseases. Our research applies the most cutting edge sequencing tools to study how chemicals cause genotoxicity. One particular focal area is discovering the causes and consequences of mutations in germ cells (sperm and egg) that can lead to inherited genetic effects.
WE ARE EXTREMELY GRATEFUL FOR FUNDING PROVIDED THROUGH THE CANADA RESEARCH CHAIRS PROGRAM, THE CANADIAN FOUNDATION FOR INNOVATION, THE ONTARIO RESEARCH FUND, THE NATURAL SCIENCES AND ENGINEERING RESEARCH FUND, AND THE BURROUGHS WELLCOME FUND. AS WELL, OUR PARTNERS ARE FUNDED THROUGH HEALTH CANADA'S GENOMICS RESEARCH AND DEVELOPMENT INITIATIVE, THE CHEMICALS MANAGEMENT PLAN, AND FUNDING PROVIDED DIRECTLY THROUGH THE WATER AND AIR QUALITY BUREAU, THE CHEMICAL AND ENVIRONMENTAL HEALTH MANAGEMENT BUREAU AND THE EXISTING SUBSTANCES RISK ASSESSMENT BUREAU.
Current projects:
Development and application of fit-for-purpose, Adverse Outcome Pathway-based testing strategies to enhance hazard and risk assessment of chemicals causing genomic damage
PI: Carole Yauk; Co-PI: Francesco Marchetti (Health Canada and adjunct at Carleton University)
This is one of the 'bread and butter' projects in the GReAT laboratory. We're developing and applying new genomic tools to figure out how chemicals cause genotoxic and epigenotoxic effects. The Adverse Outcome Pathway (AOP: see https://aopwiki.org/) framework is used to describe how the observed molecular interactions measured with our tests can be used to predict adverse effects. We strive to identify the extent of initial damage that causes the downstream effects, to improve toxicological predictions.
Development and application of novel Next Generation Sequencing approaches for mutagenicity testing in the 21st century
PI: Francesco Marchetti; Co-PI: Carole Yauk
This project is beginning to decipher the environmental and lifestyle factors that increase the chances that parents will pass on new mutations to their children (mutations arising de novo in sperm or eggs). By using whole genome sequencing of human families, we're exploring rates of inherited mutations and their association with exposures and other characteristics. In parallel, we're using ground-breaking error-corrected sequencing methodologies to advance how we can study induced mutations in rodents in the laboratory, to improve out testing strategies for human health risk assessment.
Use of Gene Expression Profiling to facilitate read-across for 28 priority perfluoroalkylated substances (PFAS)
Co-PIs: Carole Yauk and Ella Atlas (Health Canada and adjunct at uOttawa); Collaborators: Ivy Moffatt and Luigi Lorruso (Health Canada regulatory partners)
With over 4,000 PFAS in the environment (you've probably heard of the ubiquitous PFOS and PFOA - check out Mark Ruffalo's movie Dark Waters), this project addresses the lack of toxicology data for thousands of PFAS in our environment. We're using transcriptional profiling in human liver organoids (made from primary human liver cells grown in 3D spheroid form) to explore how human cells respond to various PFAS, predict potential toxicological effects, and determine the physical-chemical characteristics that drive toxicity.
GeneTox21 - An Integrated, High-Throughput (HT) Platform for In Vitro Genetic Toxicity Assessment of New and Existing Chemicals
PI: Paul White; collaborator: Carole Yauk
We are thrilled to be part of the outstanding team of scientists striving to modernize how genotoxicity testing is done. All chemicals must be evaluated for genotoxicity before they are used in Canada. However, the current tests have generally been in use for decades, are not high-throughput, and do not provide information on how chemicals cause the observed genotoxicity. We're striving to change this. The GReATs contribute to the use of genomic tools to advance this area.
Revolutionizing genotoxicity testing and assessment through the use of a novel error-corrected sequencing technology
PI: Carole Yauk; Co-PIs: Paul White and Francesco Marchetti
We have won the Burroughs Wellcome Fund Innovations in Regulatory Sciences Award! We are very excited to get started with this international project that brings together uOttawa, Health Canada and collaborators from the Health and Environmental Sciences Institute to modernize how mutagenicity testing is done. The project will investigate how new error-corrected sequencing technologies that have unparalleled accuracy in mutation detection may be used to complement and eventually replace conventional mutagenicity tests used in toxicology. We will also examine how analysis of clonal expansion of cancer driver genes may serve as a biomarker for predicting the potential for chemicals to be carcinogenic.