Competition Results: Lap-Chee Tsui Publication Award (2013)The Canadian Institutes of Health Research-Institute of Genetics (CIHR-IG) is pleased to announce the Lap-Chee Tsui Publication Award (2013) recipients and finalists, a prize for exceptional trainee-conducted research within the CIHR-IG's mandate. CIHR-IG established the award to honour one of Canada's greatest researchers, Dr. Lap-Chee Tsui, whose discovery of the gene for cystic fibrosis was a milestone in human genetic disease research.
Recipient - Biomedical Research
Antonija Kreso (University Health Network)
Kreso, A., O'Brien, C. A., van Galen, P., Gan, O. I., Notta, F., Brown, A. M., Ng, K., Ma, J., Wienholds, E., Dunant, C., Pollett, A., Gallinger, S., McPherson, J., Mullighan, C. G., Shibata, D., Dick, J. E. (2013). Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science, 339(6119), 543-548.
Recipient - Clinical, health services, population health, or genetic ethical, legal and social issues research
Alicia Semaka (University of British Columbia)
Semaka, A., Kay, C., Doty, C., Collins, J. A., Bijlsma, E. K., Richards, F., Goldberg, Y. P., Hayden, M. R. (2013). CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease. Journal of medical genetics, 50(10), 696-703.
Janet Markle (Rockefeller University)
Markle, J. G., Frank, D. N., Mortin-Toth, S., Robertson, C. E., Feazel, L. M., Rolle-Kampczyk, U., von Bergen, M., McCoy, K. D., Macpherson, A. J., Danska, J. S. (2013). Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science, 339(6123), 1084-1088.
Nicholas Stephane Caron (McMaster University)
Caron, N. S., Desmond, C. R., Xia, J., Truant, R. (2013). Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin. Proceedings of the National Academy of Sciences, 110(36), 14610-14615.
Rina Rosenzweig (University of Toronto)
Rosenzweig, R., Moradi, S., Zarrine-Afsar, A., Glover, J. R., Kay, L. E. (2013). Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction. Science, 339(6123), 1080-1083.
A total of 36 nominations were received, 27 in biomedical research and 9 in clinical, health services, population health, and genetic ethical, legal and social issues research. We would like to take this opportunity to thank all the nominators for their interest in this program and all the nominees for their outstanding contribution to genetic research.
For details regarding the next competition round please visit the CIHR-IG website in summer 2014.
Paul Lasko, PhD
CIHR Institute of Genetics
Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer
The current view in the cancer research community is that tumours contain distinct genetic subclones, which are responsible for tumour growth and therapy failure. The paper is the first to identify functional diversity amongst cells that are part of one genetic clone, thereby identifying a previously unrecognized layer of complexity within tumours. By combining DNA copy number alteration profiling, DNA sequencing, methylation pattern analysis, and lentiviral lineage tracking, the repopulation dynamics of 150 single cells from 10 human colorectal cancers were followed through serial transplantations in mice. Using this approach, the proliferation and chemotherapy tolerance of individually marked lineages was found to be variable within single genetic subclones. Importantly, chemotherapy promoted the dominance of previously dormant lineages, providing the first formal evidence for the existence of dormant cell populations in colorectal cancer. Taken together, these results document a feature of solid tumour cell biology that has not been previously reported, namely that functional diversity is present within genetic subclones and is a key determinant of chemotherapy response. In a broader sense, these findings provide a major conceptual advance to our understanding of intratumoural growth dynamics and treatment response.
CAG size-specific risk estimates for intermediate allele repeat instability in Huntington disease
Huntington disease (HD) is an inherited, neurodegenerative disorder, which develops in adulthood. It is an autosomal-dominant disease, which means that children of an affected parent have a 50% chance of developing the disease when they are adults. The genetic mutation for HD has been identified allowing genetic testing to ‘predict’ whether an individual will develop HD and thus have the ability to pass the disease onto their children. The genetic mutation for HD involves the expansion of a small segment of our DNA within the HD gene called a “CAG repeat”. It is the number of CAG repeats that determines if someone will develop HD and persons affected have 36 or more repeats. Some individuals who undergo predictive testing receive an unusual result called an intermediate allele (IA). Unlike the traditional inheritance pattern, individuals with an IA will not develop HD yet a risk remains for their children to develop the disease when they are adults. Children are at-risk because the number of CAG repeats may increase when the gene is passed from parent to child. If the number of CAG repeats increases to 36 or more, the child will develop HD in their lifetime. This increase in the number of CAG repeats is called CAG repeat instability. Currently, there is a large gap in knowledge is regarding the likelihood that children of persons with an IA will develop HD when they are adults. Utilizing a unique molecular technique, this study determined numerical risk estimates for CAG repeat instability. These risk figures inform clinical practice and provide accurate information for persons and families with an IA.
Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity
Type 1 Diabetes (T1D) is an autoimmune disease, and its incidence has been increasing in recent decades, especially among Canadians. Genome wide studies have identified genetic risk factors associated with T1D but have not addressed the impact of two other critical modifiers of autoimmunity: sex-specific risk factors, and environmental factors including the commensal gut microbiome. The incidences of many autoimmune diseases display a strong female bias, yet the mechanisms underlying this effect are poorly understood. In addition, changes in diet, antimicrobial drug use, and hygiene have altered the way people interact with non-pathogenic gut bacterial, termed the microbiome. We have identified a direct interaction between sex hormones and microbiome composition and show that microbiome manipulations can provoke hormone-dependent protection from autoimmunity in a genetically high-risk rodent model. Transfer of gut microbiota from adult males to immature females altered the recipient’s microbiota, resulting in elevated testosterone and metabolomic changes, reduced islet inflammation and autoantibody production, and conferred T1D protection. These effects were dependent on androgen receptor activity. Thus, the commensal microbial community alters sex hormone levels and regulates autoimmune disease fate in individuals with high genetic risk.
Polyglutamine domain flexibility mediates the proximity between flanking sequences in huntingtin
Huntington’s disease (HD) is a devastating, neurodegenerative disorder that results in a combination of physical, cognitive and psychiatric symptoms. HD is caused by a cytosine (C), adenine (A), guanine (G), triplet repeat expansion beyond the normal length in the huntingtin gene. The CAG stretch codes for a polyglutamine tract within the huntingtin protein where lengths exceeding 37 repeats cause HD, and repeat lengths below this number do not. Using advanced microscopy techniques to observe the shape of the huntingtin protein in living cells, we demonstrated that huntingtin undergoes a structural change at the repeat length threshold that causes HD. We showed that the normal polyglutamine tract behaves as a ‘flexible hinge’ allowing surrounding regions of huntingtin to come together and interact, whereas this flexibility is lost with the expanded polyglutamine tract. We hypothesize that this loss of flexibility impairs the normal cellular functions of huntingtin and contributes to the development of HD.
Unraveling the mechanism of protein disaggregation through a ClpB-DnaK interaction
Proteins are complex biological machines that perform most cellular activities, however, under stress conditions the native structure of proteins can be perturbed, rendering them dysfunctional. Furthermore, these misfolded proteins tend to form aggregates in the cell, the accumulation of which can overwhelm the “quality control” cellular machinery, leading to cell death. In humans, increased protein aggregation is associated with a number of serious conditions, including Alzheimer’s, Huntington's, and Parkinson’s diseases. In some cells, though, protein aggregation can be reversed through a network of Hsp104/ClpB and Hsp70/DnaK molecular chaperones, which has the unique ability to bind and to remodel non-natively folded polypeptides. The nature of this collaboration, however, and the role that each chaperone plays in the complex is not yet fully understood.
Using advanced Nuclear Magnetic Resonance techniques, we solved the structure of the ClpB-DnaK complex, revealing a single DnaK molecule bound to the ClpB hexamer, and that this binding site overlaps extensively with that for the nucleotide exchange factor, GrpE. Moreover, we showed that presence of GrpE in the initial stages of the disaggregation reactions prevents ClpB-DnaK association, thereby hindering aggregate reactivation. Additionally, DnaK binding to ClpB hexamer activates ClpB, priming the latter for the pulling reaction that unravels aggregates. Together, our structural and biochemical results shine a light on the ClpB-DnaK protein disaggregation mechanism, clarifying the roles of the individual molecular players, and providing vital information for possible future development of rational therapies for the elimination of cellular aggregates which pose a tremendous challenge to human health.
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