Main Menu
Main Menu
Menu

Segmental duplications in neurodevelopmental, neurological and behavioral disorders

by

Overview

Genetics is known to contribute significantly to many of the neurodevelopmental and behavioral diseases but in most cases, the causative molecular defect has not yet been determined. Therefore, there are no tests for early detection and diagnosis of these disorders and there is little information pertaining to their biological basis. An increasing number of neurological and behavioral disorders, however, are due to changes in the architecture of specific sites along the DNA of chromosomes in the human genome. The importance of such chromosome alterations has further been stressed with the information obtained with the human genome sequence, which has now been shown to harbor “molecular signatures” which facilitate rearrangements of genomic material.x
Furthermore, it has been shown that there is variability among individuals and species regarding the genomic structure and the copy number of genes located at specific regions of the genome, which, in turn, seem to play an important role in evolution. The regions, that comprise an amazing 5% (150 million chemical bases) of the content of the human genome and contain these molecular signatures, known as segmental duplications or duplicons, have not yet been accurately or completely characterized by the large-scale DNA sequencing projects.
Other principal investigators include scientific research groups from the University of Toronto, the University of British Columbia, SeeDNA Biotech, Fundacio Parc de Recera Ciomedica de Barcelona, Universidad Pompeu Fabra, MedPlant Genetics (Spain), and CAGT-Citogen (Spain).

The Canadian Pediatric Cancer Genome Consortium

by

Overview

Cancer is the most common cause of non-accidental death in children from infancy to young adulthood. In Canada, ~1,400 children (0-18 years of age) will be diagnosed with cancer every year. Approximately 200 will die and many more will live with life-long complications of their disease and treatments. Thus, cancer and cancer-related illness remains an unacceptable social and economic burden for Canada and Canadian families.

Although overall survival for children with cancer has improved substantially over the last three decades, significant challenges remain. A considerable proportion of childhood cancers remain incurable, or can only be cured with treatments that leave a child with life-long mental or physical disabilities. Furthermore, for children with tumours that recur or that spread to other parts of the body, current therapies are largely unsuccessful. To further improve survival, the quality of life of children surviving their cancer, and alleviate the socio-economic burden on their families, it is important to understand why specific types of tumours spread or come back, and why some of the most aggressive tumours are so resistant to therapy.

To this end, a group of highly accomplished Canadian researchers and clinicians, who are experts in childhood cancer and novel DNA sequencing technologies, have joined forces to use one of the most powerful gene sequencing technologies ever developed, to probe the genomes (DNA) of four of the most challenging childhood cancers known. The ultimate aim of this comprehensive project is to use the newly discovered genetic information about these cancers that they uncover, to gain insight into targets and new therapies that may be developed for these devastating diseases.

The researchers will use this powerful, leading edge “next generation sequencing” technology to rapidly scan the DNA of the entire human genome that is contained in tumour cells. They will examine and directly compare the genetic signature of primary tumour cells and tumour cells that have spread (metastasized) or relapsed in childhood medulloblastoma (brain cancer), metastatic osteosarcoma (bone cancer) and recurrent leukemia (cancer of white blood cells), to uncover genetic abnormalities that direct tumour cells to spread or become resistant to treatment. In addition, they will determine the gene signatures of three highly lethal childhood brain tumours to uncover new genes that may be targets for new drug therapies. The studies will generate an unprecedented view of the tumour genomes in these diseases. This will not only provide short-term potential for improving tailored therapies for children with these lethal cancers, but in the longer term will enable the development of new drugs for patients who otherwise have limited options for treatment.

This project also provides the opportunity to study the many ethical issues that arise in deciding when and how best to provide the results from genetic studies on childhood cancers back to the patients and their families. In the short-term, this multi-disciplinary, cross-Canada national study will redefine the genetic basis of aggressive childhood cancers, which they expect will lead to a better understanding of the potential role for novel ‘targeted’ therapies for this group of diseases. In the longer term, the results will lead to improved survival and reduced long-term consequences for children with cancer.

Finding of Rare Disease Genes in Canada (FORGE Canada)

by

Overview

Genetic disorders of children are individually rare but collectively frequent, affecting the lives of approximately 500,000 children in Canada. These disorders cause a variety of medical problems including birth defects, intellectual disability, difficulty with growth and organ failure.

Most genes that cause these conditions have not yet been found, mainly because gene-discovery studies are difficult to perform when DNA from only a small number of affected children is available. Recently a new technology (called Next Generation Sequencing) has been developed which allows a person’s entire genetic code (about 22,000 genes) to be analyzed within a few days at reasonable cost. This new type of DNA sequencing has revolutionized the study of rare genetic diseases because it is now possible to find disease-causing genes using a relatively small number of patients.

The team has created a large network of Canadian doctors and scientists who will now have access to this powerful technology for their patients. Through this national collaboration they will be able to rapidly identify many genes responsible for genetic disorders that affect children in this country and throughout the world. The Canadian Pediatric Genetic Disorders Sequencing (CPGDS) Consortium (www.cpgdsconsortium.com) has 150 members and will ensure that Canada becomes a world leader in this exciting field. The Consortium brings together doctors from all genetics centres across Canada, internationally-recognized Canadian scientists with expertise in finding genes, and teams from the three Genome Canada Science and Technology (GC S&T) Innovation Centres (Montreal, Toronto, Vancouver), which have already set up the new sequencing technology.

The CPGDS Consortium will:

  • Assist doctors to identify patients with rare childhood diseases. Because the Consortium has members from all the medical genetic clinics in the country, for any given disorder they will be able to enroll children and families from across Canada. Therefore, even for very rare conditions, disease-causing genes will be able to be found. So far, over 100 genetic disorders that affect Canadian children have been submitted for study.
  • Sequence the genomes of patients to identify disease-causing genetic changes.
  • Set up a national data coordination centre to streamline and improve existing large-scale sequence analysis tools. This will improve their ability to distinguish genetic changes that cause disease from ones that are normal variants contributing to human diversity.
  • Create national ethical guidelines for analyzing sequence data from entire genomes and for sharing results with families.

The consortium will allow for rapid gene discovery of rare childhood-onset disorders, with immediate and long-term health benefits for Canadian families. Their discoveries will lead to genetic tests that will allow earlier and more precise diagnoses. Better diagnoses will allow Canadian health care teams to reduce or prevent patient complications, to develop tailored treatments, and to provide more accurate reproductive counselling to families. In the long term, identification of disease genes is an essential step toward the development of drugs that will one day improve the lives of affected children. Finally, successful completion of this proposal’s activities will firmly establish a sustainable National Gene Discovery Consortium.

Integrated GE3LS Research: Reporting genetic research results: Perspectives of study participants and researchers

by

Overview

Several recent commentaries argue that researchers bear an obligation to report genetic research findings to study participants. The nature and scope of this obligation remains disputed and unresolved. While the principles of respect for persons, reciprocity, and beneficence are fundamental to the research enterprise, they may neither be well served if results are disclosed nor denied if they are not disclosed. This integrated GE3LS research examines study participants’ and researchers’ perspectives on how to manage genetic research results with respect to this putative obligation.

Phase 1 of this research surveyed research participants from the Canadian Consortium for Cystic Fibrosis research regarding the meaning ascribed to a recent gene modifier finding reported in the academic literature. One key finding was that study participants expect researchers to share genetic research results with them. Phase II of this research involves a complex experimental design that aims to understand the factors influencing researchers’ judgments regarding reporting results. Using a cross sectional factorial survey design that includes vignettes presenting hypothetical scenarios involving genetic research findings to investigators engaged in cystic fibrosis and autism genetics research, this research aims to better understand the factors that influence researchers’ judgments about:

  • Informing individuals about genetic research findings,
  • the clinical significance of a hypothetical research finding,
  • the nature of a research obligation to re-contact study participants with updated information about a particular finding, and
  • the nature of a clinical obligation that may/may not ensue from reporting research findings.

Taken together, findings from this integrated research will inform the governance of this important research ethics issue.

The contribution of genetic modulators of disease severity in Cystic Fibrosis to other diseases with similarities of clinical phenotype

by

Overview

Canada is a world leader in research on cystic fibrosis (CF). Drs. Peter Durie, a pediatrician and senior scientist and Julian Zielenski a geneticist at the Hospital for Sick Children’s Research Institute plan to build on this research strength, by investigating the genetics of other diseases with similar phenotypes – observable physical characteristics, which may be genetically determined.

Drs. Durie and Zielenski are project leaders of The contribution of genetic modulators of disease severity in cystic fibrosis to other diseases with similarities of clinical phenotype. This project will apply knowledge about the genetic factors (so called modifier genes) that influence the severity of CF to other diseases that are clinically similar to CF. These diseases include a single­gene disorder affecting the liver (a1­antitrypsin deficiency), and multifactorial conditions such as pancreatitis due to alcohol abuse and chronic obstructive pulmonary disease due to smoking.

The project will analyse mutations in the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) as well as selected modifier genes that are found to influence the severity of disease in patients with CF as well as blood­ circulating proteins, in order to identify disease biomarkers, which can help predict disease severity and progression. Diagnostic and prognostic tests will be developed, and genetic test­ based risk identification could lead to behaviour modification and disease prevention among those at risk for the diseases. Enormous human suffering and prohibitive healthcare costs are associated with alcohol abuse and tobacco smoking.

This project is expected to yield results of worldwide importance, such as development of genetic tests of disease susceptibility that will be useful in future research projects and in development of preventative strategies to modify behaviour in high risk populations. This in turn should lead to reduced morbidity and mortality and more efficient healthcare. Important components of the project are ethical issues associated with genomics research, as well as industrial, economic and social benefits.

Integrated GE3LS Research: Ethical issues and guidelines relating to the crossjurisdictional use of human tissues and genetic information

by

Overview

The GE3LS project team is examining ethical questions relating to the use of human tissues and genetic information, and ensuring confidentiality and protection of research subjects’ privacy. A critical review of consent documents from China, and evaluation of conformity with Canadian laws and guidelines set forth in Canada’s Tri-Council Policy Statement, Ethical Guidelines for Research involving Humans, as well as international guidelines (e.g., International Ethical Guidelines for Biomedical Research Involving Human Subjects (Council for International Organizations of Medical Sciences/World Health Organization) and the Declaration of Helsinki (World Medical Association)) will be performed. Where nonconformities exist, the team will develop and implement an enhanced consent form for future donors to the biobank from which this project obtains its human tissue samples.

In addition, international research guidelines, including those mentioned above, will be assessed with respect to how they address biobanking studies, culminating in a review that details ways that genomics and proteomics researchers can deal with different international research guidelines in this area. The finished product will examine topics such as informed consent, standards for external review, recruitment of participants, and cultural challenges related to consent. The assessment will uncover where these guidelines are uniform and where they diverge, and highlight problems associated with this in relation to international research, particularly with the ‘Dynactome’ project. We will also study problems that arise when a standard is included on one or more documents but omitted on others.

The dynactome: Mapping spatio-temporal dynamic systems in humans

by

Overview

Proteins are large molecules responsible for the structure, function and regulation of cells. Canadian­-led research over the last two decades has demonstrated that proteins interact with one another, and assemble pathways and networks within cells, which account for sophisticated cellular behaviour.

According to Tony Pawson, director of the Samuel Lunenfeld Research Institute at Toronto’s Mount Sinai Hospital, a key to understanding diseases such as cancer lies in investigating the dynamic changes in the cell’s protein interaction network. Pawson, his colleague and fellow molecular biologist Jeff Wrana, and University of Western Ontario biochemist Shawn Li, are project leaders of the Dynactome: Mapping SpatioTemporal Dynamic Systems in Humans.

This project will map protein interactions within human cells in order to determine whether diseases such as malignant cancers result not only from specific changes to individual genes and proteins, but also from changes in the entire cellular network. The project draws on important discoveries made by the research team.

For example, Pawson was the first to show that proteins interact in a regulated way through specific domains – something, which is important for normal cell organization but is taken over by cancer causing oncoproteins. Wrana is a world leader in understanding a super family of proteins, called Transforming Growth Factor Beta (TGF­ß), which plays a major role in regulating human cell growth and function, through molecular pathways. This project, drawing on international collaboration in the United States and China, represents the first large­scale effort to map dynamic interactions. It is expected to lead to new proteomic and computational technologies as well as innovative cancer therapies.

Strengthening the role of genomics and global health

by

Overview

This is a stand-alone GE3LS project.

There is a tremendous need for new approaches to deal with long-standing global health inequities. While life expectancies in industrialized countries are currently about 80 years and rising, in a number of developing countries, they are at 40 years and falling. Canada has a special opportunity to help the world use advances in genomics-based knowledge to deal with some of its most pressing problems: disease, poverty, hunger and environmental degradation.

In his February 2004 reply to the Speech from the Throne, Prime Minister Paul Martin announced that Canada would devote no less than five percent of R&D spending to challenges of developing countries in the areas of health, environmental, and learning technologies. Under the leadership of Peter Singer and Prof. Abdallah Daar, the CPGGH has become recognized around the world as a leading program on genomics and global health. Through Strengthening the Role of Genomics and Global Health, the CPGGH will continue to ensure that developing countries share the scientific, social and economic benefits of the genomics revolution, to prevent the emergence of a “genomics divide,” and to address existing disparities in global human health.

The project aims to strengthen genomics research, development and commercialization activities in the developing world by examining the role of developing world biotechnology companies in meeting local health needs and south-to-south collaboration in genomics innovation. At the same time, the project seeks to ensure that advances in pharmacogenomics are appropriately used to address global health challenges and to ensure the effective mobilization of agricultural genomics knowledge through strategies to promote enduring food security in developing countries.

Strengthening the Role of Genomics and Global Health will ensure that developing countries share in the social and economic benefits of the genomics revolution, increase public awareness of the potential for genomics to address global health and environmental challenges and help mobilize a unique vision for Canada’s role in the world.

Integrated GE3LS Research: The meanings and understandings of terms used in genomics research

by

Overview

In order to ensure optimal data collection and informed choice, the GE3LS project team’s over-arching goal is to investigate how the understandings of terms used in genomics research by scientists, when translated into the scientists’ meanings on consent forms, information letters, surveys, and demographic forms, may or may not be consistent with the understandings of research participants and their meanings when they respond to such documents. The team will:

  • perform a textual analysis of research grants, information letters and consent forms that are being used in clinical studies of this Genome Canada grant and others funded in the last Genome Canada competition. With interview ‘prompts’ from the results of this research, research participants and researchers involved in the clinical Themes of this Genome Canada grant will be interviewed to provide further insight into the meanings and understandings of terms used in genomics research, particularly related to copy number variations (CNVs);
  • survey other key stakeholders’ views of genomic research (particularly related to CNV), such as health professionals’ (medical geneticists and counselors, physicians) perceptions of the clinical meaning of CNV results (what kinds of results should provoke duty to warn, and child protection obligations);
  • examine the views and experiences of patients and their families as research participants towards furthering informed choice to participate in CNV research;
  • explore the meanings and understandings of terms used in CNV research by studying issues revolving around the interpretation, management and communication of whole genome scanning (WGS) results to patients and their families; and
  • consider the legal issues that are emerging from the methodologies of the aforementioned studies that explore the meanings and understandings of terms used in CNV research, including qualitative content analysis, interviews of researchers and research participants, and electronic surveys.

Structural and functional annotation of the human genome for disease study

by

Overview

Now that the human genome has been sequenced, the next step is to undertake the complete structural and functional annotation of genes associated with diseases, according to Robert Hegele, endocrinologist and scientific director of the London Regional Genomics Centre at the Robarts Research Institute.

Hegele is project leader of Structural and Functional Annotation of the Human Genome for Disease Study, an innovative project which aims to bridge new biological knowledge with medical applications. Any two humans are 99.9% identical at the level of their DNA sequences. But recently, new forms of genomic variation have been appreciated above and beyond single nucleotide polymorphisms. These include large scale variations, such as copy number changes, insertions, deletions, duplications and rearrangements, and they may be much more widespread than was previously appreciated. In this project, collaborator Steve Scherer of the Hospital for Sick Children will define and superimpose these large scale genomic variations over top of the existing “first draft” of the human genome sequence map. Another form of genome variation occurs through a process called “alternative splicing’, which gives rise to multiple versions of a protein encoded by a single gene. Also, some parts of the genome previously thought to be dormant are now known to code for active proteins functioning in the body.

Collaborators Ben Blencowe, Tim Hughes and Brendan Frey of the University of Toronto will define and integrate these new forms of genomic variation into the current human genome sequence map.

The project will therefore deliver a “new improved edition” of the human genome map; one that annotates and characterizes large­scale copy number variants, alternative splicing profiles of genes in selected tissues and previously unknown genes and other functional elements. Hegele and collaborators will then apply the annotated genome map with its rich trove of new biological information to unravel the genetic basis of diseases that extract a huge social and economic toll in Canada, such as diabetes, heart disease and breast cancer.

The data generated from the project will be made available, free of charge, on the Internet, in order to accelerate biomedical discovery, including the diagnosis and treatment of common diseases.