Full Professor, Department of Cellular & Molecular Medicine Faculty of Medicine, University of Ottawa The SMC5/6 complex: Folding chromosomes back into shape when genomes take a break High-level folding of chromatin is a key determinant of the shape and functional state of chromosomes. During normal cell division cycles, structural maintenance of chromosome (SMC) complexes ensure the large-scale folding of chromatin into visible chromosomes. While it is known that cancer cells experience important changes in genome architecture, it is still unclear if mutations in core regulators of chromosome structure can lead to cancer-promoting loss in genome stability. To address this question, we conducted a systematic analysis of mutations affecting a global regulator of chromosome biology –the SMC5/6 complex– in cancer genomics cohorts. Analysis of 64,959 cancer samples spanning 144 tissue types and 199 different cancer genome studies revealed that the SMC5/6 complex is frequently altered in breast cancer patients. Patient-derived mutations targeting this complex associate with strong phenotypic outcomes such as loss of ploidy control and reduced overall survival. Remarkably, the phenotypic impact of several patient mutations can be observed in a heterozygous context, hence providing an explanation for a prominent role of SMC5/6 mutations in breast cancer pathogenesis. Overall, our findings suggest that genes encoding global effectors of chromosome architecture can act as key contributors to cancer development in humans.
Drew Sauve, PhD Candidate, Friesen Lab Environmental correlates of early-life growth, natural selection, and components of phenotypic variation in a long-term experimental study system of black-legged kittiwakes In the face of global environmental change, the ability to predict adaptation has become a priority. To make predictions of adaptation, we must understand how environmental factors shape phenotypic expression, natural selection, and genetic variation. In my dissertation, I explore the effects of environmental variability on phenotypes, selection, and genetic variation using pedigrees, nestling growth traits, and nestling survival data from three long-term seabird monitoring programs. In most chapters, I focus on a Northeastern Pacific population of black-legged kittiwakes Rissa tridactyla. First, I use a sliding window approach to analyze three long-term seabird datasets. I use these analyses to identify specific periods of environmental variation that correlate with growth, assess changes in environmental predictors across years, and predict future growth under climate change. My findings reveal specific breeding season periods that are strongly associated with growth. These associations suggest warmer conditions may result in poorer growth for two of the three species studied. Further, windows of environmental influence change between historical and contemporary periods, emphasizing the need to investigate how such changes might affect adaptation to changing environments.
In my final chapters, I use kittiwake food supplementation experiment data to examine the relationship between food conditions, the variability of selection strength, and variance components of nestling kittiwake size traits. I find that natural selection is strongest in early ontogeny, in non-food supplemented nestlings, and for the youngest nestlings in a brood. Selection magnitude varies among years, but annual variation in magnitude was similar for all treatment and hatching order groups. Warming conditions have mixed effects on selection that depend on food supplementation and hatching order. Finally, using pedigree data, I find higher annual variance and additive genetic variance in non-food supplemented nestlings, suggesting potential cohort effects and increased evolutionary potential in non-food supplemented nestlings. Together, my results help fill and identify gaps in our understanding of the ability of natural populations to adapt to ongoing climate changes. Dr. Hilary Dugan, Assistant professor at the Center for Limnology at the University of Wisconsin – Madison. A Winter's Tale of Wisconsin Lakes Historically, limnologists have dedicated their efforts to studying lakes in the summer, while overlooking winter. Winter field work is challenging. Most lakes in the United States and Canada, however, freeze over for at least part of the winter. A bias for summer research has left gaps in knowledge on lake chemistry and biology under ice. More pressingly, with anticipated changes in environmental conditions, there is a need for information on how lakes and reservoirs function in the winter for a more complete understanding of lakes. This knowledge is also critical to future management of freshwater resources in a future with shorter winters and less lake ice. This talk will focus on what we’ve learned from winter limnological research taking place on Wisconsin lakes, and will include recent results from a a whole-lake manipulation where we removed all of the snow from the surface of a north temperate bog lake in northern Wisconsin.
Andrew Le, MSc Candidate, Colautti Lab Exploration into the “blackbox” of Vincetoxicum rossicum’s allelopathy Secondary metabolites may directly inhibit the growth of native plants or act indirectly by altering soil microbial communities. Vincetoxicum rossicum is an invasive vine known to exudate such a metabolite, (-)-antofine. Although (-)-antofine has been shown to exhibit antimicrobial properties, whether the chemical is ecologically relevant is unclear. The objective of this study was to assess how (-)-antofine production relates to the abundance of V. rossicum in different habitats. Soil cores were collected across twelve meadow and nine understory sites covering replicated gradients (n=8) of V. rossicum at Rouge National Urban Park, Canada. In total 1344 soil samples were analyzed using Liquid Chromatography – Mass Spectrometry to measure the (-)-antofine concentration. V. rossicum and (-)-antofine patterns were compared using linear-mixed effect models with site as a random effect to control for site level differences in (-)-antofine.
Our results show that (-)-antofine concentration was higher in areas where V. rossicum is more abundant (P < 0.05). The same held true in both meadow (P = 0.049) and understory (P < 0.05) habitats. As site was used as a random effect, this suggests that the abundance of (-)-antofine is not dependant on site but on the density of V. rossicum. This may suggest that V. rossicum ability to invade a wide range of habitats is due to (-)-antofine exudation. As (-)-antofine has anti-microbial properties, V. rossicum invasion success may involve changes in plant-soil interactions. Our research indicates that (-)-antofine may be an important factor in the invasive success of V. rossicum. Jason C. L. Brown, Department of Biological Sciences, University of Toronto Scarborough (UTSC) An animal physiologist’s foray into the scarcely inhabited world of plant aging Despite the fact that my graduate research was focused on mitochondrial metabolism in hibernation and daily torpor in mammals, and despite the fact that, in my teaching-focused role at UTSC, I instruct students in animal physiology and vertebrate endocrinology, when I was tasked with carving out a research niche in which I could supervise undergraduate students, I decided to enter the realm of plant aging, which is seemingly an area of focus for only a handful of researchers around the world. I was inspired to undertake such research after reading a book about life history strategies in plants. The book talked at length about the ecological and evolutionary pressures that favour the annual vs. perennial condition in plants but entirely neglected that physiological adaptations must accompany any changes in life history strategy within plant lineages. To this end, my research program has focused on physiological differences between annual and perennial species, with a particular emphasis on the oxidative theory of aging. To date, we have shown that the leaves of perennials are more resistant to oxidative damage from exogenous H2O2 than those from annuals. We have further shown that perennials have higher antioxidant levels in their seeds, leaves, and roots compared to annuals, and that perennials are able to repair oxidative damage to their chlorophyll faster than annuals. Additionally, we have demonstrated that perennials do not limit their concentration of chlorophyll b, despite its increased susceptibility to oxidative damage, but these plants have altered the amino acid sequence of one of their chlorophyll-binding proteins (CP24), thereby making it more stable and better able to fulfill its role in minimizing photosynthetic ROS production. Recently, we also began investigating several lines of early-flowering flax, expecting that they would be more susceptible to oxidative stress given their shorter lifespan. To the contrary, they exhibited significantly higher catalase levels, which complicates our understanding of plant aging.
Natasha Neves, MSc Candidate, Orihel Lab Effects of microplastics on benthic macroinvertebrates in a limnocorral experiment The response of freshwater benthic macroinvertebrates to microplastics (< 5 mm) under environmentally relevant conditions is not well understood. The objective of the present study was to determine effects of a microplastic particle mixture (polystyrene, polyethylene terephthalate, and polyethylene) on benthic invertebrates under an environmentally relevant gradient of microplastic pollution. Twelve open-bottom limnocorrals were deployed in the littoral zone of a boreal lake at the International Institute for Sustainable Development – Experimental Lakes Area in Ontario, Canada in June 2022. Pre-colonized leaf litterbags (5x3 mm mesh size) were added to the limnocorrals and sampled after 5 and 8 weeks of microplastic exposure to characterize the benthic invertebrate community. Results will elucidate a concentration-response relationship between microplastics and benthic invertebrates at the organismal (body size), population (species abundance), and community (diversity, evenness) levels. This study will help to identify thresholds in microplastic pollution that could be hazardous to freshwater benthic invertebrates.
Lisa Cicchetti, MSc Candidate Grogan Lab Evolved tolerance to road salt among wild populations of Daphnia Snowmelt and rain carry road salt from paved surfaces through the watershed via runoff and groundwater and increase the salinity of lakes, often measured as chloride concentration (Cl- mg/L). Salinization negatively impacts freshwater organisms, including Daphnia pulicaria, a ubiquitous crustacean zooplankton grazer that is integral to healthy ecosystems. Daphnia are sensitive to environmental changes, but studies have shown they are capable of rapid evolution. We investigated intraspecific variation in salt sensitivity among D. pulicaria collected from 10 lakes in southeastern Ontario to understand how wild Daphnia respond to salt pollution. Acclimation can also influence tolerance, so we tested the effect of acclimation on acute 48-hour salt tolerance for Daphnia grown at low (18 mg Cl-/L) and high (218 mg Cl-/L) Cl-. Our results indicate that acclimation to salt does not significantly impact tolerance. Our common garden experiments testing acute toxicity of salt on Daphnia from lakes ranging from <1 mg Cl-/L to 271 mg Cl-/L show a wide range of salt tolerances for wild Daphnia. Daphnia from Presqu’ile Bay, Lake Ontario (26.2 mg Cl-/L) and Lake Wilcox (194 mg Cl-/L) have higher salt tolerances of 2222 mg Cl-/L and 2344 mg Cl-/L, respectively, compared to Daphnia from unimpacted lakes (1277 – 1617 mg Cl-/L). This indicates that D. pulicaria may have adapted to localized road salt pollution. Understanding the factors contributing to robust tolerance to road salt will help inform decisions regarding freshwater ecosystem conservation.
Dr. Josh Neufeld, University of Waterloo Professor, University Research Chair Shedding light on the evolution of anoxygenic phototrophy through cultivation of Boreal Shield lake bacteria Phototrophic members of the Chloroflexota phylum are enigmas in the evolution of phototrophy because of their unusual photosynthetic reaction centre and antenna complex pairing. Through a “failed” cultivation experiment from an iron-rich Boreal Shield lake, we recovered and characterized a novel new species, “Ca. Chlorohelix allophototropha”, with unexpected features relevant to the evolution of phototrophic bacteria. This talk will present genome, physiology, and ecology data to demonstrate that this phylogenetically distinct phototroph can be among the most active populations in illuminated anoxic waters of Boreal Shield lakes, which number in the millions globally. Our results establish Chloroflexota phylum members as unique among known anoxygenic phototrophs, providing new context for understanding the origins of phototrophic life on Earth. Dr. Graeme Howe, Assistant Professor Queen's University, Department of Chemistry Genome mining for "extremozymes" - Extremophiles as sources of novel biocatalysts Directed evolution has enabled the development of extremely useful biocatalysts that have, in some cases, supplanted traditional organic chemistry in the industrial production of value-added commodity chemicals. Generally, mutations introduced into a protein scaffold to increase catalytic efficiency are accompanied by a compensatory destabilization of the enzyme. To circumvent this issue and allow a more thorough exploration of sequence space around naturally occurring enzymes, we have turned to sequence similarity networks (SSNs) to mine the genomes of thermophilic microorganisms to identify novel thermostable variants of enzymes with potential industrial utility. These networks allow for the exploration of whole protein families and the interrelatedness of every member sequence through an ‘all-by-all’ BLAST. Through the iterative construction of SSNs with varying sequence identity cutoffs, we have produced networks of putative isofunctional clusters that allow a single sequence with known catalytic function to reveal the role of thousands of unannotated PETase-like genes.
Our initial efforts in this arena have focused on the search for new thermostable plastic-degrading enzymes as a part of the OpenPlastic consortium’s efforts to develop a circular plastics economy. Following the initial discovery of a cutinase-like enzyme from Ideonella sakaiensis that degrades polyethylene terephthalate (PET), there has been an explosion in research revolving around the biocatalytic degradation of PET and other plastics. While several engineered PETases have emerged that are sufficiently stable and catalytically efficient for industrial PET degradation, we opted to direct our initial efforts to exploit the wealth of PETase sequence-function relationships to mine the genomes of extremophiles for new PETases as starting points for further engineering efforts. Using the I. sakaiensis enzyme as a seed sequence, SSNs were constructed that led to the identification of 10 putative PETases from bacteria with optimal growth temperatures ranging from 50 °C to 80 °C. This presentation will detail our efforts to characterize these enzymes and their potential utility in the degradation of PET plastics. Similar bioinformatics-driven approaches to identify and characterize thermostable enzymes that degrade polyamides and polyurethanes will also be presented. Michael Vermeulen, PhD candidate Babak/Craig Lab The Vanishing Y: Exploring the role of mosaic loss of chromosome Y in neurodegeration and cancer As men age they experience a gradual loss of the Y chromosome (LOY) in their cells, specifically within immune cell-types. Recent, large-scale epidemiological surveys have found
approximately 70% of men older than 70 years of age have a detectable loss of their Y chromosome. Furthermore, a range of association studies have linked LOY to several age-related diseases including heart disease, Alzheimer’s, cancer, and macular degeneration. Also, we know that LOY is one of the most common chromosomal aberrations observed in male cancers (occurring in about ~28% of primary tumors). Despite the frequency of LOY and its association with disease, relatively little is known about its mechanisms and its role in disease pathology. Although recent mouse studies suggest LOY can directly cause disease, we still don’t know if it directly causes disease or is a passenger biomarker of degrading genomic instability. My Master’s research aimed to better understand LOY in brain tissue, with a specific interest in the cell-types LOY tends to accumulate in. We found that LOY is particularly common in the microglia, the main immune cell in the brain and a cell-type with important roles in neurodegerative processes. My PHD research investigates the role of LOY in cancer, and its potential use as a therapeutic target. We plan to use CRISPR-cas9 editing systems to engineer isogenic cell lines differing only by the presence of the Y chromosome. We will then test for LOY-specific genetic vulnerabilities using CRISPR loss-of-function screens with the goal of highlighting potential weaknesses in LOY cells that could be exploited as a cancer therapy. |
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