A5000800469- Folate and B Vitamins Research
- Amino Acid Enzymes and Metabolism
- Bioinformatics and Genomic Networks
- Genomics and Rare Diseases
- DNA Repair Mechanisms
- Metabolism and Genetic Disorders
- Genomics and Phylogenetic Studies
- CRISPR and Genetic Engineering
- Genomics and Chromatin Dynamics
- RNA and protein synthesis mechanisms
- Fungal and yeast genetics research
- Gene expression and cancer classification
- Pancreatic function and diabetes
- RNA modifications and cancer
- Cancer, Hypoxia, and Metabolism
- Metabolism, Diabetes, and Cancer
- Genetic Associations and Epidemiology
- Plant nutrient uptake and metabolism
- RNA Research and Splicing
- Advanced Proteomics Techniques and Applications
- Genetics and Neurodevelopmental Disorders
- Microbial Metabolic Engineering and Bioproduction
- SARS-CoV-2 and COVID-19 Research
- Ubiquitin and proteasome pathways
- DNA and Nucleic Acid Chemistry
University of Toronto
2016-2025
Lunenfeld-Tanenbaum Research Institute
2016-2024
Mount Sinai Hospital
2016-2023
Dana-Farber Cancer Institute
2019-2023
Sinai Health System
2019-2022
Hospital for Sick Children
2003-2008
Canada Research Chairs
2008
SickKids Foundation
2008
University of New Brunswick
2008
University of Guelph
2003
Abstract Background Cannabis sativa has been cultivated throughout human history as a source of fiber, oil and food, for its medicinal intoxicating properties. Selective breeding produced cannabis plants specific uses, including high-potency marijuana strains hemp cultivars fiber seed production. The molecular biology underlying cannabinoid biosynthesis other traits interest is largely unexplored. Results We sequenced genomic DNA RNA from the strain Purple Kush using shortread approaches....
H-NS and Lsr2 are nucleoid-associated proteins from Gram-negative bacteria Mycobacteria , respectively, that play an important role in the silencing of horizontally acquired foreign DNA is more AT-rich than resident genome. Despite fact dissimilar sequence structure, they serve apparently similar functions can functionally complement one another. The mechanism by which these xenogeneic silencers selectively target has been enigmatic. We performed high-resolution protein binding microarray...
A global genetic suppression network The background of an organism can influence the overall effects new variants. Some mutations amplify a deleterious phenotype, whereas others suppress it. Starting with literature survey and expanding into genomewide assay, van Leeuwen et al. generated large-scale in yeast. data set reveals general properties that be used to predict interactions. Furthermore, study provides template for extending studies other genes or more complex organisms. Science ,...
Method21 December 2017Open Access Transparent process A framework for exhaustively mapping functional missense variants Jochen Weile orcid.org/0000-0003-1628-9390 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada The Donnelly Centre, University of Department Molecular Genetics, Computer Science, Search more papers by this author Song Sun Medical Biochemistry and Microbiology, Uppsala University, Uppsala, Sweden Atina G Cote Jennifer Knapp Marta Verby Joseph C...
Abstract High‐throughput binary protein interaction mapping is continuing to extend our understanding of cellular function and disease mechanisms. However, we remain one or two orders magnitude away from a complete map for humans other major model organisms. Completion will require screening at substantially larger scales with many complementary assays, requiring further efficiency gains in proteome‐scale mapping. Here, report Barcode Fusion Genetics‐Yeast Two‐Hybrid ( BFG ‐Y2H), by which...
Abstract Understanding the mechanisms of coronavirus disease 2019 (COVID-19) severity to efficiently design therapies for emerging virus variants remains an urgent challenge ongoing pandemic. Infection and immune reactions are mediated by direct contacts between viral molecules host proteome, vast majority these virus–host (the ‘contactome’) have not been identified. Here, we present a systematic contactome map severe acute respiratory syndrome 2 (SARS-CoV-2) with human encompassing more...
Abstract Background Glucokinase (GCK) regulates insulin secretion to maintain appropriate blood glucose levels. Sequence variants can alter GCK activity cause hyperinsulinemic hypoglycemia or hyperglycemia associated with GCK-maturity-onset diabetes of the young (GCK-MODY), collectively affecting up 10 million people worldwide. Patients GCK-MODY are frequently misdiagnosed and treated unnecessarily. Genetic testing prevent this but is hampered by challenge interpreting novel missense...
C2H2 zinc fingers (C2H2-ZFs) are the most prevalent type of vertebrate DNA-binding domain, and typically appear in tandem arrays (ZFAs), with sequential C2H2-ZFs each contacting three (or more) bases. can be assembled a modular fashion, providing one explanation for their remarkable evolutionary success. Given set modules defined three-base specificities, assembly also presents way to construct artificial proteins specific preferences. However, recent survey large number three-finger ZFAs...
For the majority of rare clinical missense variants, pathogenicity status cannot currently be classified. Classical homocystinuria, characterized by elevated homocysteine in plasma and urine, is caused variants cystathionine beta-synthase (CBS) gene, most which are rare. With early detection, existing therapies highly effective.Damaging CBS can detected based on their failure to restore growth yeast cells lacking ortholog CYS4. This assay has only been applied reactively, after first...
Generating reference maps of interactome networks illuminates genetic studies by providing a protein-centric approach to finding new components existing pathways, complexes, and processes. We apply state-of-the-art methods identify binary protein-protein interactions (PPIs) for Drosophila melanogaster. Four all-by-all yeast two-hybrid (Y2H) screens > 10,000 proteins result in the 'FlyBi' dataset 8723 PPIs among 2939 proteins. Testing subsets data from FlyBi previous PPI using an orthogonal...
Abstract Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron disease for which important subtypes are caused by variation in the Superoxide Dismutase 1 gene SOD1 . Diagnosis based on sequencing can not only be definitive but also indicate specific therapies available -associated ALS (SOD1-ALS). Unfortunately, SOD1-ALS diagnosis limited fact that substantial fraction (currently 26%) of ClinVar missense variants classified as “variants uncertain significance” (VUS). Although...
To maintain genome integrity, cells must accurately duplicate their and repair DNA lesions when they occur. uncover genes that suppress damage in human cells, we undertook flow-cytometry-based CRISPR-Cas9 screens monitored damage. We identified 160 whose mutation caused spontaneous damage, a list enriched essential genes, highlighting the importance of genomic integrity for cellular fitness. also 227 replication-perturbed cells. Among characterized, discovered deoxyribose-phosphate aldolase...
Abstract Global insights into cellular organization and function require comprehensive understanding of interactome networks. Similar to how a reference genome sequence revolutionized human genetics, map the network is critical fully understand genotype-phenotype relationships. Here we present first “all-by-all” binary map, or “HuRI”. With ~53,000 high-quality protein-protein interactions (PPIs), HuRI approximately four times larger than information curated from small-scale studies available...
Abstract Background Computational variant effect predictors offer a scalable and increasingly reliable means of interpreting human genetic variation, but concerns circularity bias have limited previous methods for evaluating comparing predictors. Population-level cohorts genotyped phenotyped participants that not been used in predictor training can facilitate an unbiased benchmarking available methods. Using curated set gene-trait associations with reported rare-variant burden association,...
DNA palindromes are associated with rearrangement in a variety of organisms. A unique opportunity to examine the impact long palindrome mammals is afforded by Line 78 strain mice. Previously it was found that transgene likely be palindromic and symmetry responsible for high level germ line instability. Here we prove mice harbor true 15.4-kb palindrome, through establishment cell lines from have shown rearranges at impressive rate about 0.5% per population doubling. The rearrangements...
Method28 May 2018Open Access Source DataTransparent process Mapping DNA damage-dependent genetic interactions in yeast via party mating and barcode fusion genetics J Javier Díaz-Mejía Donnelly Centre, University of Toronto, ON, Canada Department Molecular Genetics, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Computer Science, Search for more papers by this author Albi Celaj orcid.org/0000-0002-5888-772X Joseph C Mellor Biological Chemistry Pharmacology, Harvard Medical...
Many traits are complex, depending non-additively on variant combinations. Even in model systems, such as the yeast S. cerevisiae, carrying out high-order variant-combination testing needed to dissect complex remains a daunting challenge. Here, we describe "X-gene" genetic analysis (XGA), strategy for engineering and profiling highly combinatorial gene perturbations. We demonstrate XGA ABC transporters by 5,353 strains, each deleted random subset of 16 transporters, strain's resistance...
The promise of personalized genomic medicine depends on our ability to assess the functional impact rare sequence variation. Multiplexed assays can experimentally measure missense variants a massive scale. However, even after such assays, many remain poorly measured. Here we describe software pipeline and application impute missing information in determined variant effect maps.
The exponential growth of genomic variants uncovered by next-generation sequencing necessitates efficient and accurate computational analyses to predict their functional effects. A number methods have been developed for the task, but few unbiased comparisons performance are available. To fill gap, Critical Assessment Genome Interpretation (CAGI) comprehensively assesses phenotypic predictions on newly collected experimental datasets. Here, we present results SUMO conjugase challenge where...