Publications

@article{khazaei_h33_2020,

title = {H3.3 G34W Promotes Growth and Impedes Differentiation of Osteoblast-Like Mesenchymal Progenitors in Giant Cell Tumor of Bone},

author = {Sima Khazaei and Nicolas De Jay and Shriya Deshmukh and Liam D Hendrikse and Wajih Jawhar and Carol C L Chen and Leonie G Mikael and Damien Faury and Dylan M Marchione and Joel Lanoix and Éric Bonneil and Takeaki Ishii and Siddhant U Jain and Kateryna Rossokhata and Tianna S Sihota and Robert Eveleigh and Véronique Lisi and Ashot S Harutyunyan and Sungmi Jung and Jason Karamchandani and Brendan C Dickson and Robert Turcotte and Jay S Wunder and Pierre Thibault and Peter W Lewis and Benjamin A Garcia and Stephen C Mack and Michael D Taylor and Livia Garzia and Claudia L Kleinman and Nada Jabado},

url = {https://cancerdiscovery.aacrjournals.org/content/10/12/1968},

doi = {10.1158/2159-8290.CD-20-0461},

issn = {2159-8274, 2159-8290},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-28},

journal = {Cancer Discovery},

volume = {10},

number = {12},

pages = {1968--1987},

abstract = {Glycine 34-to-tryptophan (G34W) substitutions in H3.3 arise in approximately 90% of giant cell tumor of bone (GCT). Here, we show H3.3 G34W is necessary for tumor formation. By profiling the epigenome, transcriptome, and secreted proteome of patient samples and tumor-derived cells CRISPR–Cas9-edited for H3.3 G34W, we show that H3.3K36me3 loss on mutant H3.3 alters the deposition of the repressive H3K27me3 mark from intergenic to genic regions, beyond areas of H3.3 deposition. This promotes redistribution of other chromatin marks and aberrant transcription, altering cell fate in mesenchymal progenitors and hindering differentiation. Single-cell transcriptomics reveals that H3.3 G34W stromal cells recapitulate a neoplastic trajectory from a SPP1+ osteoblast-like progenitor population toward an ACTA2+ myofibroblast-like population, which secretes extracellular matrix ligands predicted to recruit and activate osteoclasts. Our findings suggest that H3.3 G34W leads to GCT by sustaining a transformed state in osteoblast-like progenitors, which promotes neoplastic growth, pathologic recruitment of giant osteoclasts, and bone destruction. 

Significance: This study shows that H3.3 G34W drives GCT tumorigenesis through aberrant epigenetic remodeling, altering differentiation trajectories in mesenchymal progenitors. H3.3 G34W promotes in neoplastic stromal cells an osteoblast-like progenitor state that enables undue interactions with the tumor microenvironment, driving GCT pathogenesis. These epigenetic changes may be amenable to therapeutic targeting in GCT.See related commentary by Licht, p. 1794.This article is highlighted in the In This Issue feature, p. 1775},

note = {Publisher: American Association for Cancer Research 

Section: Research Articles},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{wang_preclinical_2020,

title = {A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer},

author = {Yifan Wang and Jin Yong Patrick Park and Alain Pacis and Robert E Denroche and Gun Ho Jang and Amy Zhang and Adeline Cuggia and Celine Domecq and Jean Monlong and Maria Raitses-Gurevich and Robert C Grant and Ayelet Borgida and Spring Holter and Chani Stossel and Simeng Bu and Mehdi Masoomian and Ilinca M Lungu and John M S Bartlett and Julie M Wilson and Zu-Hua Gao and Yasser Riazalhosseini and Jamil Asselah and Nathaniel Bouganim and Tatiana Cabrera and Louis-Martin Boucher and David Valenti and James Biagi and Celia M T Greenwood and Paz Polak and William D Foulkes and Talia Golan and Grainne M O'Kane and Sandra E Fischer and Jennifer J Knox and Steven Gallinger and George Zogopoulos},

url = {https://clincancerres.aacrjournals.org/content/26/20/5462},

doi = {10.1158/1078-0432.CCR-20-1439},

issn = {1078-0432, 1557-3265},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-28},

journal = {Clinical Cancer Research},

volume = {26},

number = {20},

pages = {5462--5476},

abstract = {Purpose: Pancreatic ductal adenocarcinoma (PDAC) arising in patients with a germline BRCA1 or BRCA2 (gBRCA) mutation may be sensitive to platinum and PARP inhibitors (PARPi). However, treatment stratification based on gBRCA mutational status alone is associated with heterogeneous responses. 

Experimental Design: We performed a seven-arm preclinical trial consisting of 471 mice, representing 12 unique PDAC patient-derived xenografts, of which nine were gBRCA mutated. From 179 patients whose PDAC was whole-genome and transcriptome sequenced, we identified 21 cases with homologous recombination deficiency (HRD), and investigated prognostic biomarkers. 

Results: We found that biallelic inactivation of BRCA1/BRCA2 is associated with genomic hallmarks of HRD and required for cisplatin and talazoparib (PARPi) sensitivity. However, HRD genomic hallmarks persisted in xenografts despite the emergence of therapy resistance, indicating the presence of a genomic scar. We identified tumor polyploidy and a low Ki67 index as predictors of poor cisplatin and talazoparib response. In patients with HRD PDAC, tumor polyploidy and a basal-like transcriptomic subtype were independent predictors of shorter survival. To facilitate clinical assignment of transcriptomic subtype, we developed a novel pragmatic two-marker assay (GATA6:KRT17). 

Conclusions: In summary, we propose a predictive and prognostic model of gBRCA-mutated PDAC on the basis of HRD genomic hallmarks, Ki67 index, tumor ploidy, and transcriptomic subtype.},

note = {Publisher: American Association for Cancer Research 

Section: Translational Cancer Mechanisms and Therapy},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{moreau_mutations_2020,

title = {Mutations associated with neuropsychiatric conditions delineate functional brain connectivity dimensions contributing to autism and schizophrenia},

author = {Clara A Moreau and Sebastian G W Urchs and Kumar Kuldeep and Pierre Orban and Catherine Schramm and Guillaume Dumas and Aurélie Labbe and Guillaume Huguet and Elise Douard and Pierre-Olivier Quirion and Amy Lin and Leila Kushan and Stephanie Grot and David Luck and Adrianna Mendrek and Stephane Potvin and Emmanuel Stip and Thomas Bourgeron and Alan C Evans and Carrie E Bearden and Pierre Bellec and Sebastien Jacquemont},

url = {https://www.nature.com/articles/s41467-020-18997-2},

doi = {10.1038/s41467-020-18997-2},

issn = {2041-1723},

year  = {2020},

date = {2020-01-01},

urldate = {2021-05-28},

journal = {Nature Communications},

volume = {11},

number = {1},

pages = {5272},

abstract = {16p11.2 and 22q11.2 Copy Number Variants (CNVs) confer high risk for Autism Spectrum Disorder (ASD), schizophrenia (SZ), and Attention-Deficit-Hyperactivity-Disorder (ADHD), but their impact on functional connectivity (FC) remains unclear. Here we report an analysis of resting-state FC using magnetic resonance imaging data from 101 CNV carriers, 755 individuals with idiopathic ASD, SZ, or ADHD and 1,072 controls. We characterize CNV FC-signatures and use them to identify dimensions contributing to complex idiopathic conditions. CNVs have large mirror effects on FC at the global and regional level. Thalamus, somatomotor, and posterior insula regions play a critical role in dysconnectivity shared across deletions, duplications, idiopathic ASD, SZ but not ADHD. Individuals with higher similarity to deletion FC-signatures exhibit worse cognitive and behavioral symptoms. Deletion similarities identified at the connectivity level could be related to the redundant associations observed genome-wide between gene expression spatial patterns and FC-signatures. Results may explain why many CNVs affect a similar range of neuropsychiatric symptoms.},

note = {Number: 1 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid32066997b,

title = {Single-cell analysis of human adipose tissue identifies depot and disease specific cell types},

author = {Jinchu Vijay and Marie-Frédérique Gauthier and Rebecca L Biswell and Daniel A Louiselle and Jeffrey J Johnston and Warren A Cheung and Bradley Belden and Albena Pramatarova and Laurent Biertho and Margaret Gibson and Marie-Michelle Simon and Haig Djambazian and Alfredo Staffa and Guillaume Bourque and Anita Laitinen and Johanna Nystedt and Marie-Claude Vohl and Jason D Fraser and Tomi Pastinen and André Tchernof and Elin Grundberg},

doi = {10.1038/s42255-019-0152-6},

issn = {2522-5812},

year  = {2020},

date = {2020-01-01},

journal = {Nat Metab},

volume = {2},

number = {1},

pages = {97--109},

abstract = {The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depot-specific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors. Subpopulations of adipose-resident immune cells are metabolically active and associated with metabolic disease status and those include a population of potential dysfunctional CD8+ T cells expressing metallothioneins. We identify multiple types of adipocyte progenitors that are common across depots, including a subtype enriched in individuals with type 2 diabetes. Depot-specific analysis reveals a class of adipocyte progenitors unique to visceral adipose tissue, which shares common features with beige preadipocytes. Our human single-cell transcriptome atlas across fat depots provides a resource to dissect functional genomics of metabolic disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31797611b,

title = {Machine learning algorithms for simultaneous supervised detection of peaks in multiple samples and cell types},

author = {Toby Dylan Hocking and Guillaume Bourque},

issn = {2335-6936},

year  = {2020},

date = {2020-01-01},

journal = {Pac Symp Biocomput},

volume = {25},

pages = {367--378},

abstract = {Joint peak detection is a central problem when comparing samples in epigenomic data analysis, but current algorithms for this task are unsupervised and limited to at most 2 sample types. We propose PeakSegPipeline, a new genome-wide multi-sample peak calling pipeline for epigenomic data sets. It performs peak detection using a constrained maximum likelihood segmentation model with essentially only one free parameter that needs to be tuned: the number of peaks. To select the number of peaks, we propose to learn a penalty function based on user-provided labels that indicate genomic regions with or without peaks in specific samples. In comparisons with state-of-the-art peak detection algorithms, PeakSegPipeline achieves similar or better accuracy, and a more interpretable model with overlapping peaks that occur in exactly the same positions across all samples. Our novel approach is able to learn that predicted peak sizes vary by experiment type.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31792275b,

title = {Benefits and barriers in the design of harmonized access agreements for international data sharing},

author = {Katie M Saulnier and David Bujold and Stephanie O M Dyke and Charles Dupras and Stephan Beck and Guillaume Bourque and Yann Joly},

doi = {10.1038/s41597-019-0310-4},

issn = {2052-4463},

year  = {2019},

date = {2019-12-01},

journal = {Sci Data},

volume = {6},

number = {1},

pages = {297},

abstract = {In the past decade, there has been a surge in the number of sensitive human genomic and health datasets available to researchers via Data Access Agreements (DAAs) and managed by Data Access Committees (DACs). As this form of sharing increases, so do the challenges of achieving a reasonable level of data protection, particularly in the context of international data sharing. Here, we consider how excessive variation across DAAs can hinder these goals, and suggest a core set of clauses that could prove useful in future attempts to harmonize data governance.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31768071b,

title = {Stalled developmental programs at the root of pediatric brain tumors},

author = {Selin Jessa and Alexis Blanchet-Cohen and Brian Krug and Maria Vladoiu and Marie Coutelier and Damien Faury and Brice Poreau and Nicolas De Jay and Steven Hébert and Jean Monlong and W Todd Farmer and Laura K Donovan and Yixing Hu and Melissa K McConechy and Florence M G Cavalli and Leonie G Mikael and Benjamin Ellezam and Maxime Richer and Andréa Allaire and Alexander G Weil and Jeffrey Atkinson and Jean-Pierre Farmer and Roy W R Dudley and Valerie Larouche and Louis Crevier and Steffen Albrecht and Mariella G Filbin and Hervé Sartelet and Pierre-Eric Lutz and Corina Nagy and Gustavo Turecki and Santiago Costantino and Peter B Dirks and Keith K Murai and Guillaume Bourque and Jiannis Ragoussis and Livia Garzia and Michael D Taylor and Nada Jabado and Claudia L Kleinman},

doi = {10.1038/s41588-019-0531-7},

issn = {1546-1718},

year  = {2019},

date = {2019-12-01},

journal = {Nat Genet},

volume = {51},

number = {12},

pages = {1702--1713},

abstract = {Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of >65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31161210b,

title = {eFORGE v2.0: updated analysis of cell type-specific signal in epigenomic data},

author = {Charles E Breeze and Alex P Reynolds and Jenny van Dongen and Ian Dunham and John Lazar and Shane Neph and Jeff Vierstra and Guillaume Bourque and Andrew E Teschendorff and John A Stamatoyannopoulos and Stephan Beck},

doi = {10.1093/bioinformatics/btz456},

issn = {1367-4811},

year  = {2019},

date = {2019-11-01},

journal = {Bioinformatics},

volume = {35},

number = {22},

pages = {4767--4769},

abstract = {SUMMARY: The Illumina Infinium EPIC BeadChip is a new high-throughput array for DNA methylation analysis, extending the earlier 450k array by over 400 000 new sites. Previously, a method named eFORGE was developed to provide insights into cell type-specific and cell-composition effects for 450k data. Here, we present a significantly updated and improved version of eFORGE that can analyze both EPIC and 450k array data. New features include analysis of chromatin states, transcription factor motifs and DNase I footprints, providing tools for epigenome-wide association study interpretation and epigenome editing.



AVAILABILITY AND IMPLEMENTATION: eFORGE v2.0 is implemented as a web tool available from https://eforge.altiusinstitute.org and https://eforge-tf.altiusinstitute.org/.



SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Eveleigh2019,

title = {A point mutation in the linker domain of mouse STAT5A is associated with impaired NK-cell regulation},

author = {Robert Eveleigh, Guillaume Bourque},

url = {https://www.nature.com/articles/s41435-019-0088-6#author-information},

doi = {https://doi.org/10.1038/s41435-019-0088-6},

year  = {2019},

date = {2019-10-08},

abstract = {The transcription factor STAT5 is critical for peripheral NK-cell survival, proliferation, and cytotoxic function. STAT5 refers to two highly related proteins, STAT5A and STAT5B. In this study, we verified the importance of STAT5A isoform for NK cells. We characterized an incidental chemically induced W484G mutation in the Stat5a gene and found that this mutation was associated with a reduction of STAT5A protein expression. Closer examination of NK-cell subsets from Stat5a mutant mice showed marked reductions in NK-cell number and maturation. IL-15 treatment of Stat5a mutant NK cells exhibited defective induction of both STAT5 and mTOR signaling pathways and reduced expression of granzyme B and IFN-γ. Finally, we observed that Stat5a mutant mice revealed more tumor growth upon injection of RMA-S tumor cell line. Overall, our results demonstrate that the W484G mutation in the linker domain of STAT5A is sufficient to compromise STAT5A function in NK-cell homeostasis, responsiveness, and tumoricidal function.},

keywords = {Immunogenetics, Innate immune cells},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31649251b,

title = {Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations},

author = {Janin Grajcarek and Jean Monlong and Yoko Nishinaka-Arai and Michiko Nakamura and Miki Nagai and Shiori Matsuo and David Lougheed and Hidetoshi Sakurai and Megumu K Saito and Guillaume Bourque and Knut Woltjen},

doi = {10.1038/s41467-019-12829-8},

issn = {2041-1723},

year  = {2019},

date = {2019-10-01},

journal = {Nat Commun},

volume = {10},

number = {1},

pages = {4856},

abstract = {The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{Stucklin2019,

title = {Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas},

author = {Ana S. Guerreiro Stucklin, Scott Ryall},

url = {https://www.nature.com/articles/s41467-019-12187-5#citeas},

doi = {https://doi.org/10.1038/s41467-019-12187-5},

year  = {2019},

date = {2019-09-25},

abstract = {Infant gliomas have paradoxical clinical behavior compared to those in children and adults: low-grade tumors have a higher mortality rate, while high-grade tumors have a better outcome. However, we have little understanding of their biology and therefore cannot explain this behavior nor what constitutes optimal clinical management. Here we report a comprehensive genetic analysis of an international cohort of clinically annotated infant gliomas, revealing 3 clinical subgroups. Group 1 tumors arise in the cerebral hemispheres and harbor alterations in the receptor tyrosine kinases ALK, ROS1, NTRK and MET. These are typically single-events and confer an intermediate outcome. Groups 2 and 3 gliomas harbor RAS/MAPK pathway mutations and arise in the hemispheres and midline, respectively. Group 2 tumors have excellent long-term survival, while group 3 tumors progress rapidly and do not respond well to chemoradiation. We conclude that infant gliomas comprise 3 subgroups, justifying the need for specialized therapeutic strategies.},

keywords = {Cancer genomics, Molecular medicine},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31393794b,

title = {Customized MethylC-Capture Sequencing to Evaluate Variation in the Human Sperm DNA Methylome Representative of Altered Folate Metabolism},

author = {Donovan Chan and Xiaojian Shao and Marie-Charlotte Dumargne and Mahmoud Aarabi and Marie-Michelle Simon and Tony Kwan and Janice L Bailey and Bernard Robaire and Sarah Kimmins and Maria C San Gabriel and Armand Zini and Clifford Librach and Sergey Moskovtsev and Elin Grundberg and Guillaume Bourque and Tomi Pastinen and Jacquetta M Trasler},

doi = {10.1289/EHP4812},

issn = {1552-9924},

year  = {2019},

date = {2019-08-01},

journal = {Environ Health Perspect},

volume = {127},

number = {8},

pages = {87002},

abstract = {BACKGROUND: The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprograming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias toward CpG-dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements.



OBJECTIVES: Our goal was to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome.



METHODS: To characterize variation in sperm DNA methylation, we performed whole genome bisulfite sequencing (WGBS) on an equimolar pool of sperm DNA from a wide cross section of 30 men varying in age, fertility status, methylenetetrahydrofolate reductase () genotype, and exposures. With our targeted capture panel, in individual samples, we examined the effect of  genotype ([Formula: see text] , [Formula: see text] ), as well as high-dose folic acid supplementation ([Formula: see text], per genotype, before and after supplementation).



RESULTS: Through WGBS we discovered nearly 1 million CpGs possessing intermediate methylation levels (20-80%), termed dynamic sperm CpGs. These dynamic CpGs, along with 2 million commonly assessed CpGs, were used to customize a capture panel for targeted interrogation of the human sperm methylome and test its ability to detect effects of altered folate metabolism. As compared with   men, those with the  genotype (50% decreased  activity) had both hyper- and hypomethylation in their sperm. High-dose folic acid supplement treatment exacerbated hypomethylation in   men compared with . In both cases, [Formula: see text] of altered methylation was found in dynamic sperm CpGs, uniquely measured by our assay.



DISCUSSION: Our sperm panel allowed the discovery of differential methylation following conditions affecting folate metabolism in novel dynamic sperm CpGs. Improved ability to examine variation in sperm DNA methylation can facilitate comprehensive studies of environment-epigenome interactions. https://doi.org/10.1289/EHP4812.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31185495b,

title = {GenPipes: an open-source framework for distributed and scalable genomic analyses},

author = {Mathieu Bourgey and Rola Dali and Robert Eveleigh and Kuang Chung Chen and Louis Letourneau and Joel Fillon and Marc Michaud and Maxime Caron and Johanna Sandoval and Francois Lefebvre and Gary Leveque and Eloi Mercier and David Bujold and Pascale Marquis and Patrick Tran Van and David Anderson de Lima Morais and Julien Tremblay and Xiaojian Shao and Edouard Henrion and Emmanuel Gonzalez and Pierre-Olivier Quirion and Bryan Caron and Guillaume Bourque},

doi = {10.1093/gigascience/giz037},

issn = {2047-217X},

year  = {2019},

date = {2019-06-01},

journal = {Gigascience},

volume = {8},

number = {6},

abstract = {BACKGROUND: With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing.



FINDINGS: Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for high-performance computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA sequencing, chromatin immunoprecipitation sequencing, DNA sequencing, methylation sequencing, Hi-C, capture Hi-C, metagenomics, and Pacific Biosciences long-read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has already been configured on several servers, and a Docker image is also available to facilitate additional installations.



CONCLUSIONS: GenPipes offers genomics researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30168593b,

title = {A hidden markov model for identifying differentially methylated sites in bisulfite sequencing data},

author = {Farhad Shokoohi and David A Stephens and Guillaume Bourque and Tomi Pastinen and Celia M T Greenwood and Aurélie Labbe},

doi = {10.1111/biom.12965},

issn = {1541-0420},

year  = {2019},

date = {2019-03-01},

journal = {Biometrics},

volume = {75},

number = {1},

pages = {210--221},

abstract = {DNA methylation studies have enabled researchers to understand methylation patterns and their regulatory roles in biological processes and disease. However, only a limited number of statistical approaches have been developed to provide formal quantitative analysis. Specifically, a few available methods do identify differentially methylated CpG (DMC) sites or regions (DMR), but they suffer from limitations that arise mostly due to challenges inherent in bisulfite sequencing data. These challenges include: (1) that read-depths vary considerably among genomic positions and are often low; (2) both methylation and autocorrelation patterns change as regions change; and (3) CpG sites are distributed unevenly. Furthermore, there are several methodological limitations: almost none of these tools is capable of comparing multiple groups and/or working with missing values, and only a few allow continuous or multiple covariates. The last of these is of great interest among researchers, as the goal is often to find which regions of the genome are associated with several exposures and traits. To tackle these issues, we have developed an efficient DMC identification method based on Hidden Markov Models (HMMs) called "DMCHMM" which is a three-step approach (model selection, prediction, testing) aiming to address the aforementioned drawbacks. Our proposed method is different from other HMM methods since it profiles methylation of each sample separately, hence exploiting inter-CpG autocorrelation within samples, and it is more flexible than previous approaches by allowing multiple hidden states. Using simulations, we show that DMCHMM has the best performance among several competing methods. An analysis of cell-separated blood methylation profiles is also provided.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30582441b,

title = {Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot},

author = {Donna J Page and Matthieu J Miossec and Simon G Williams and Richard M Monaghan and Elisavet Fotiou and Heather J Cordell and Louise Sutcliffe and Ana Topf and Mathieu Bourgey and Guillaume Bourque and Robert Eveleigh and Sally L Dunwoodie and David S Winlaw and Shoumo Bhattacharya and Jeroen Breckpot and Koenraad Devriendt and Marc Gewillig and J David Brook and Kerry J Setchfield and Frances A Bu'Lock and John O'Sullivan and Graham Stuart and Connie R Bezzina and Barbara J M Mulder and Alex V Postma and James R Bentham and Martin Baron and Sanjeev S Bhaskar and Graeme C Black and William G Newman and Kathryn E Hentges and G Mark Lathrop and Mauro Santibanez-Koref and Bernard D Keavney},

doi = {10.1161/CIRCRESAHA.118.313250},

issn = {1524-4571},

year  = {2019},

date = {2019-02-01},

journal = {Circ Res},

volume = {124},

number = {4},

pages = {553--563},

abstract = {RATIONALE: Familial recurrence studies provide strong evidence for a genetic component to the predisposition to sporadic, nonsyndromic Tetralogy of Fallot (TOF), the most common cyanotic congenital heart disease phenotype. Rare genetic variants have been identified as important contributors to the risk of congenital heart disease, but relatively small numbers of TOF cases have been studied to date.



OBJECTIVE: We used whole exome sequencing to assess the prevalence of unique, deleterious variants in the largest cohort of nonsyndromic TOF patients reported to date.



METHODS AND RESULTS: Eight hundred twenty-nine TOF patients underwent whole exome sequencing. The presence of unique, deleterious variants was determined; defined by their absence in the Genome Aggregation Database and a scaled combined annotation-dependent depletion score of ≥20. The clustering of variants in 2 genes, NOTCH1 and FLT4, surpassed thresholds for genome-wide significance (assigned as P<5×10) after correction for multiple comparisons. NOTCH1 was most frequently found to harbor unique, deleterious variants. Thirty-one changes were observed in 37 probands (4.5%; 95% CI, 3.2%-6.1%) and included 7 loss-of-function variants 22 missense variants and 2 in-frame indels. Sanger sequencing of the unaffected parents of 7 cases identified 5 de novo variants. Three NOTCH1 variants (p.G200R, p.C607Y, and p.N1875S) were subjected to functional evaluation, and 2 showed a reduction in Jagged1-induced NOTCH signaling. FLT4 variants were found in 2.4% (95% CI, 1.6%-3.8%) of TOF patients, with 21 patients harboring 22 unique, deleterious variants. The variants identified were distinct to those that cause the congenital lymphoedema syndrome Milroy disease. In addition to NOTCH1, FLT4 and the well-established TOF gene, TBX1, we identified potential association with variants in several other candidates, including RYR1, ZFPM1, CAMTA2, DLX6, and PCM1.



CONCLUSIONS: The NOTCH1 locus is the most frequent site of genetic variants predisposing to nonsyndromic TOF, followed by FLT4. Together, variants in these genes are found in almost 7% of TOF patients.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30052804b,

title = {The epiGenomic Efficient Correlator (epiGeEC) tool allows fast comparison of user datasets with thousands of public epigenomic datasets},

author = {Jonathan Laperle and Simon Hébert-Deschamps and Joanny Raby and David A de Lima Morais and Michel Barrette and David Bujold and Charlotte Bastin and Marc-Antoine Robert and Jean-François Nadeau and Marie Harel and Alexei Nordell-Markovits and Alain Veilleux and Guillaume Bourque and Pierre-Étienne Jacques},

doi = {10.1093/bioinformatics/bty655},

issn = {1367-4811},

year  = {2019},

date = {2019-02-01},

journal = {Bioinformatics},

volume = {35},

number = {4},

pages = {674--676},

abstract = {SUMMARY: In recent years, major initiatives such as the International Human Epigenome Consortium have generated thousands of high-quality genome-wide datasets for a large variety of assays and cell types. This data can be used as a reference to assess whether the signal from a user-provided dataset corresponds to its expected experiment, as well as to help reveal unexpected biological associations. We have developed the epiGenomic Efficient Correlator (epiGeEC) tool to enable genome-wide comparisons of very large numbers of datasets. A public Galaxy implementation of epiGeEC allows comparison of user datasets with thousands of public datasets in a few minutes.



AVAILABILITY AND IMPLEMENTATION: The source code is available at https://bitbucket.org/labjacquespe/epigeec and the Galaxy implementation at http://epigeec.genap.ca.



SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1080/15592294.2019.1581592,

title = {Don’t brush off buccal data heterogeneity},

author = {Andrei L Turinsky and Darci T Butcher and Sanaa Choufani and Rosanna Weksberg and Michael Brudno},

url = {https://doi.org/10.1080/15592294.2019.1581592},

doi = {10.1080/15592294.2019.1581592},

year  = {2019},

date = {2019-01-01},

journal = {Epigenetics},

volume = {14},

number = {2},

pages = {109-117},

publisher = {Taylor & Francis},

note = {PMID: 30821575},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{doi:10.1161/CIRCRESAHA.118.313250,

title = {Whole Exome Sequencing Reveals the Major Genetic Contributors to Nonsyndromic Tetralogy of Fallot},

author = {Donna J Page and Matthieu J Miossec and Simon G Williams and Richard M Monaghan and Elisavet Fotiou and Heather J Cordell and Louise Sutcliffe and Ana Topf and Mathieu Bourgey and Guillaume Bourque and Robert Eveleigh and Sally L Dunwoodie and David S Winlaw and Shoumo Bhattacharya and Jeroen Breckpot and Koenraad Devriendt and Marc Gewillig and David J Brook and Kerry J Setchfield and Frances A Bu’Lock and John O’Sullivan and Graham Stuart and Connie R Bezzina and Barbara J M Mulder and Alex V Postma and James R Bentham and Martin Baron and Sanjeev S Bhaskar and Graeme C Black and William G Newman and Kathryn E Hentges and Mark G Lathrop and Mauro Santibanez-Koref and Bernard D Keavney},

url = {https://www.ahajournals.org/doi/abs/10.1161/CIRCRESAHA.118.313250},

doi = {10.1161/CIRCRESAHA.118.313250},

year  = {2019},

date = {2019-01-01},

journal = {Circulation Research},

volume = {124},

number = {4},

pages = {553-563},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{laperle_epigenomic_2019,

title = {The epiGenomic Efficient Correlator (epiGeEC) tool allows fast comparison of user datasets with thousands of public epigenomic datasets},

author = {Jonathan Laperle and Simon Hébert-Deschamps and Joanny Raby and David A de Lima Morais and Michel Barrette and David Bujold and Charlotte Bastin and Marc-Antoine Robert and Jean-François Nadeau and Marie Harel and Alexei Nordell-Markovits and Alain Veilleux and Guillaume Bourque and Pierre-Étienne Jacques},

url = {https://doi.org/10.1093/bioinformatics/bty655},

doi = {10.1093/bioinformatics/bty655},

issn = {1367-4803},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Bioinformatics},

volume = {35},

number = {4},

pages = {674--676},

abstract = {In recent years, major initiatives such as the International Human Epigenome Consortium have generated thousands of high-quality genome-wide datasets for a large variety of assays and cell types. This data can be used as a reference to assess whether the signal from a user-provided dataset corresponds to its expected experiment, as well as to help reveal unexpected biological associations. We have developed the epiGenomic Efficient Correlator (epiGeEC) tool to enable genome-wide comparisons of very large numbers of datasets. A public Galaxy implementation of epiGeEC allows comparison of user datasets with thousands of public datasets in a few minutes.The source code is available at https://bitbucket.org/labjacquespe/epigeec and the Galaxy implementation at http://epigeec.genap.ca.Supplementary data are available at Bioinformatics online.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{shokoohi_hidden_2019,

title = {A hidden markov model for identifying differentially methylated sites in bisulfite sequencing data},

author = {Farhad Shokoohi and David A Stephens and Guillaume Bourque and Tomi Pastinen and Celia M T Greenwood and Aurélie Labbe},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/biom.12965},

doi = {https://doi.org/10.1111/biom.12965},

issn = {1541-0420},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Biometrics},

volume = {75},

number = {1},

pages = {210--221},

abstract = {DNA methylation studies have enabled researchers to understand methylation patterns and their regulatory roles in biological processes and disease. However, only a limited number of statistical approaches have been developed to provide formal quantitative analysis. Specifically, a few available methods do identify differentially methylated CpG (DMC) sites or regions (DMR), but they suffer from limitations that arise mostly due to challenges inherent in bisulfite sequencing data. These challenges include: (1) that read-depths vary considerably among genomic positions and are often low; (2) both methylation and autocorrelation patterns change as regions change; and (3) CpG sites are distributed unevenly. Furthermore, there are several methodological limitations: almost none of these tools is capable of comparing multiple groups and/or working with missing values, and only a few allow continuous or multiple covariates. The last of these is of great interest among researchers, as the goal is often to find which regions of the genome are associated with several exposures and traits. To tackle these issues, we have developed an efficient DMC identification method based on Hidden Markov Models (HMMs) called “DMCHMM” which is a three-step approach (model selection, prediction, testing) aiming to address the aforementioned drawbacks. Our proposed method is different from other HMM methods since it profiles methylation of each sample separately, hence exploiting inter-CpG autocorrelation within samples, and it is more flexible than previous approaches by allowing multiple hidden states. Using simulations, we show that DMCHMM has the best performance among several competing methods. An analysis of cell-separated blood methylation profiles is also provided.},

note = {_eprint: https://onlinelibrary.wiley.com/doi/pdf/10.1111/biom.12965},

keywords = {Blood cell-separated data, Differentially methylated region, Next-generation sequencing, Read-depth},

pubstate = {published},

tppubtype = {article}

}

@article{choufani_impact_2019,

title = {Impact of assisted reproduction, infertility, sex and paternal factors on the placental DNA methylome},

author = {Sanaa Choufani and Andrei L Turinsky and Nir Melamed and Ellen Greenblatt and Michael Brudno and Anick Bérard and William D Fraser and Rosanna Weksberg and Jacquetta Trasler and Patricia Monnier and 3D cohort study group},

url = {https://doi.org/10.1093/hmg/ddy321},

doi = {10.1093/hmg/ddy321},

issn = {0964-6906},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Human Molecular Genetics},

volume = {28},

number = {3},

pages = {372--385},

abstract = {Children conceived using Assisted Reproductive Technologies (ART) have a higher incidence of growth and birth defects, attributable in part to epigenetic perturbations. Both ART and germline defects associated with parental infertility could interfere with epigenetic reprogramming events in germ cells or early embryos. Mouse models indicate that the placenta is more susceptible to the induction of epigenetic abnormalities than the embryo, and thus the placental methylome may provide a sensitive indicator of ‘at risk’ conceptuses. Our goal was to use genome-wide profiling to examine the extent of epigenetic abnormalities in matched placentas from an ART/infertility group and control singleton pregnancies (n = 44/group) from a human prospective longitudinal birth cohort, the Design, Develop, Discover (3D) Study. Principal component analysis revealed a group of ART outliers. The ART outlier group was enriched for females and a subset of placentas showing loss of methylation of several imprinted genes including GNAS, SGCE, KCNQT1OT1 and BLCAP/NNAT. Within the ART group, placentas from pregnancies conceived with in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) showed distinct epigenetic profiles as compared to those conceived with less invasive procedures (ovulation induction, intrauterine insemination). Male factor infertility and paternal age further differentiated the IVF/ICSI group, suggesting an interaction of infertility and techniques in perturbing the placental epigenome. Together, the results suggest that the human placenta is sensitive to the induction of epigenetic defects by ART and/or infertility, and we stress the importance of considering both sex and paternal factors and that some but not all ART conceptuses will be susceptible.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{cvetkovska_enigmatic_2019,

title = {The enigmatic loss of light-independent chlorophyll biosynthesis from an Antarctic green alga in a light-limited environment},

author = {Marina Cvetkovska and Shane Orgnero and Norman P A Hüner and David Roy Smith},

url = {https://nph.onlinelibrary.wiley.com/doi/abs/10.1111/nph.15623},

doi = {https://doi.org/10.1111/nph.15623},

issn = {1469-8137},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {New Phytologist},

volume = {222},

number = {2},

pages = {651--656},

note = {_eprint: https://nph.onlinelibrary.wiley.com/doi/pdf/10.1111/nph.15623},

keywords = {Chlamydomonas sp. UWO241, chlorophyll, DPOR, photosynthesis, psychrophile},

pubstate = {published},

tppubtype = {article}

}

@article{untereiner_gaba_2019,

title = {GABA promotes β-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity},

author = {Ashley Untereiner and Shaaban Abdo and Alpana Bhattacharjee and Himaben Gohil and Farzaneh Pourasgari and Neke Ibeh and Mi Lai and Battsetseg Batchuluun and Anthony Wong and Nicholas Khuu and Ying Liu and Dana Al Rijjal and Neil Winegarden and Carl Virtanen and Beverley A Orser and Over Cabrera and Gabor Varga and Jonathan Rocheleau and Feihan F Dai and Michael B Wheeler},

url = {https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201801397R},

doi = {https://doi.org/10.1096/fj.201801397R},

issn = {1530-6860},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {The FASEB Journal},

volume = {33},

number = {3},

pages = {3968--3984},

abstract = {γ-Aminobutyric acid (GABA) administration has been shown to increase β-cell mass, leading to a reversal of type 1 diabetes in mice. Whether GABA has any effect on β cells of healthy and prediabetic/glucose-intolerant obese mice remains unknown. In the present study, we show that oral GABA administration (ad libitum) to mice indeed increased pancreatic β-cell mass, which led to a modest enhancement in insulin secretion and glucose tolerance. However, GABA treatment did not further increase insulin-positive islet area in high fat diet-fed mice and was unable to prevent or reverse glucose intolerance and insulin resistance. Mechanistically, whether in vivo or in vitro, GABA treatment increased β-cell proliferation. In vitro, the effect was shown to be mediated via the GABAA receptor. Single-cell RNA sequencing analysis revealed that GABA preferentially up-regulated pathways linked to β-cell proliferation and simultaneously down-regulated those networks required for other processes, including insulin biosynthesis and metabolism. Interestingly, single-cell differential expression analysis revealed GABA treatment gave rise to a distinct subpopulation of β cells with a unique transcriptional signature, including urocortin 3 (ucn3), wnt4, and hepacam2. Taken together, this study provides new mechanistic insight into the proliferative nature of GABA but suggests that β-cell compensation associated with prediabetes overlaps with, and negates, its proliferative effects.—Untereiner, A., Abdo, S., Bhattacharjee, A., Gohil, H., Pourasgari, F., Ibeh, N., Lai, M., Batchuluun, B., Wong, A., Khuu, N., Liu, Y., Al Rijjal, D., Winegarden, N., Virtanen, C., Orser, B. A., Cabrera, O., Varga, G., Rocheleau, J., Dai, F. F., Wheeler, M. B. GABA promotes β-cell proliferation, but does not overcome impaired glucose homeostasis associated with diet-induced obesity. FASEB J. 33, 3968–3984 (2019). www.fasebj.org},

note = {_eprint: https://faseb.onlinelibrary.wiley.com/doi/pdf/10.1096/fj.201801397R},

keywords = {diet-induced obesity, GABAA receptor, glucose tolerance, insulin secretion, single cell RNA-seq},

pubstate = {published},

tppubtype = {article}

}

@article{sukhai_somatic_2019,

title = {Somatic Tumor Variant Filtration Strategies to Optimize Tumor-Only Molecular Profiling Using Targeted Next-Generation Sequencing Panels},

author = {Mahadeo A Sukhai and Maksym Misyura and Mariam Thomas and Swati Garg and Tong Zhang and Natalie Stickle and Carl Virtanen and Philippe L Bedard and Lillian L Siu and Tina Smets and Gert Thijs and Steven Van Vooren and Suzanne Kamel-Reid and Tracy L Stockley},

url = {https://www.jmdjournal.org/article/S1525-1578(17)30598-6/abstract},

doi = {10.1016/j.jmoldx.2018.09.008},

issn = {1525-1578},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {The Journal of Molecular Diagnostics},

volume = {21},

number = {2},

pages = {261--273},

abstract = {textlessptextgreaterA common approach in clinical diagnostic laboratories to variant assessment from tumor molecular profiling is sequencing of genomic DNA extracted from both tumor (somatic) and normal (germline) tissue, with subsequent variant comparison to identify true somatic variants with potential impact on patient treatment or prognosis. However, challenges exist in paired tumor-normal testing, including increased cost of dual sample testing and identification of germline cancer predisposing variants. Alternatively, somatic variants can be identified by textitin silico tumor-only variant filtration precluding the need for matched normal testing. The barrier to tumor-only variant filtration is defining a reliable approach, with high sensitivity and specificity to identify somatic variants. In this study, we used retrospective data sets from paired tumor-normal samples tested on small (48 gene) and large (555 gene) targeted next-generation sequencing panels, to model algorithms for tumor-only variants classification. The optimal algorithm required an ordinal filtering approach using information from variant population databases (1000 Genomes Phase 3, ESP6500, ExAC), clinical mutation databases (ClinVar), and information on recurring clinically relevant somatic variants. Overall the tumor-only variant filtration strategy described in this study can define clinically relevant somatic variants from tumor-only analysis with sensitivity of 97% to 99% and specificity of 87% to 94%, and with significant potential utility for clinical laboratories implementing tumor-only molecular profiling.textless/ptextgreater},

note = {Publisher: Elsevier},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gonorazky_expanding_2019,

title = {Expanding the Boundaries of RNA Sequencing as a Diagnostic Tool for Rare Mendelian Disease},

author = {Hernan D Gonorazky and Sergey Naumenko and Arun K Ramani and Viswateja Nelakuditi and Pouria Mashouri and Peiqui Wang and Dennis Kao and Krish Ohri and Senthuri Viththiyapaskaran and Mark A Tarnopolsky and Katherine D Mathews and Steven A Moore and Andres N Osorio and David Villanova and Dwi U Kemaladewi and Ronald D Cohn and Michael Brudno and James J Dowling},

url = {https://www.cell.com/ajhg/abstract/S0002-9297(19)30012-6},

doi = {10.1016/j.ajhg.2019.01.012},

issn = {0002-9297, 1537-6605},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {The American Journal of Human Genetics},

volume = {104},

number = {3},

pages = {466--483},

note = {Publisher: Elsevier},

keywords = {diagnostics, Mendelian disease, muscular dystrophy, myotubes, RNA-seq, Transcriptomics, transdifferentiation},

pubstate = {published},

tppubtype = {article}

}

@article{chong_metaboanalystr_2019,

title = {MetaboAnalystR 2.0: From Raw Spectra to Biological Insights},

author = {Jasmine Chong and Mai Yamamoto and Jianguo Xia},

url = {https://www.mdpi.com/2218-1989/9/3/57},

doi = {10.3390/metabo9030057},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Metabolites},

volume = {9},

number = {3},

pages = {57},

abstract = {Global metabolomics based on high-resolution liquid chromatography mass spectrometry (LC-MS) has been increasingly employed in recent large-scale multi-omics studies. Processing and interpretation of these complex metabolomics datasets have become a key challenge in current computational metabolomics. Here, we introduce MetaboAnalystR 2.0 for comprehensive LC-MS data processing, statistical analysis, and functional interpretation. Compared to the previous version, this new release seamlessly integrates XCMS and CAMERA to support raw spectral processing and peak annotation, and also features high-performance implementations of mummichog and GSEA approaches for predictions of pathway activities. The application and utility of the MetaboAnalystR 2.0 workflow were demonstrated using a synthetic benchmark dataset and a clinical dataset. In summary, MetaboAnalystR 2.0 offers a unified and flexible workflow that enables end-to-end analysis of LC-MS metabolomics data within the open-source R environment.},

note = {Number: 3 

Publisher: Multidisciplinary Digital Publishing Institute},

keywords = {enrichment analysis, global metabolomics, LC-MS, pathway analysis, spectra processing},

pubstate = {published},

tppubtype = {article}

}

@article{zhou_networkanalyst_2019,

title = {NetworkAnalyst 3.0: a visual analytics platform for comprehensive gene expression profiling and meta-analysis},

author = {Guangyan Zhou and Othman Soufan and Jessica Ewald and Robert E W Hancock and Niladri Basu and Jianguo Xia},

url = {https://doi.org/10.1093/nar/gkz240},

doi = {10.1093/nar/gkz240},

issn = {0305-1048},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Nucleic Acids Research},

volume = {47},

number = {W1},

pages = {W234--W241},

abstract = {The growing application of gene expression profiling demands powerful yet user-friendly bioinformatics tools to support systems-level data understanding. NetworkAnalyst was first released in 2014 to address the key need for interpreting gene expression data within the context of protein-protein interaction (PPI) networks. It was soon updated for gene expression meta-analysis with improved workflow and performance. Over the years, NetworkAnalyst has been continuously updated based on community feedback and technology progresses. Users can now perform gene expression profiling for 17 different species. In addition to generic PPI networks, users can now create cell-type or tissue specific PPI networks, gene regulatory networks, gene co-expression networks as well as networks for toxicogenomics and pharmacogenomics studies. The resulting networks can be customized and explored in 2D, 3D as well as Virtual Reality (VR) space. For meta-analysis, users can now visually compare multiple gene lists through interactive heatmaps, enrichment networks, Venn diagrams or chord diagrams. In addition, users have the option to create their own data analysis projects, which can be saved and resumed at a later time. These new features are released together as NetworkAnalyst 3.0, freely available at https://www.networkanalyst.ca.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{gonzalez_anchor_2019,

title = {ANCHOR: a 16S rRNA gene amplicon pipeline for microbial analysis of multiple environmental samples},

author = {Emmanuel Gonzalez and Frederic E Pitre and Nicholas J B Brereton},

url = {https://sfamjournals.onlinelibrary.wiley.com/doi/abs/10.1111/1462-2920.14632},

doi = {https://doi.org/10.1111/1462-2920.14632},

issn = {1462-2920},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Environmental Microbiology},

volume = {21},

number = {7},

pages = {2440--2468},

abstract = {Analysis of 16S ribosomal RNA (rRNA) gene amplification data for microbial barcoding can be inaccurate across complex environmental samples. A method, ANCHOR, is presented and designed for improved species-level microbial identification using paired-end sequences directly, multiple high-complexity samples and multiple reference databases. A standard operating procedure (SOP) is reported alongside benchmarking against artificial, single sample and replicated mock data sets. The method is then directly tested using a real-world data set from surface swabs of the International Space Station (ISS). Simple mock community analysis identified 100% of the expected species and 99% of expected gene copy variants (100% identical). A replicated mock community revealed similar or better numbers of expected species than MetaAmp, DADA2, Mothur and QIIME1. Analysis of the ISS microbiome identified 714 putative unique species/strains and differential abundance analysis distinguished significant differences between the Destiny module (U.S. laboratory) and Harmony module (sleeping quarters). Harmony was remarkably dominated by human gastrointestinal tract bacteria, similar to enclosed environments on earth; however, Destiny module bacteria also derived from nonhuman microbiome carriers present on the ISS, the laboratory's research animals. ANCHOR can help substantially improve sequence resolution of 16S rRNA gene amplification data within biologically replicated environmental experiments and integrated multidatabase annotation enhances interpretation of complex, nonreference microbiomes.},

note = {_eprint: https://sfamjournals.onlinelibrary.wiley.com/doi/pdf/10.1111/1462-2920.14632},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{breeze_eforge_2019,

title = {eFORGE v2.0: updated analysis of cell type-specific signal in epigenomic data},

author = {Charles E Breeze and Alex P Reynolds and Jenny van Dongen and Ian Dunham and John Lazar and Shane Neph and Jeff Vierstra and Guillaume Bourque and Andrew E Teschendorff and John A Stamatoyannopoulos and Stephan Beck},

url = {https://doi.org/10.1093/bioinformatics/btz456},

doi = {10.1093/bioinformatics/btz456},

issn = {1367-4803},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Bioinformatics},

volume = {35},

number = {22},

pages = {4767--4769},

abstract = {The Illumina Infinium EPIC BeadChip is a new high-throughput array for DNA methylation analysis, extending the earlier 450k array by over 400 000 new sites. Previously, a method named eFORGE was developed to provide insights into cell type-specific and cell-composition effects for 450k data. Here, we present a significantly updated and improved version of eFORGE that can analyze both EPIC and 450k array data. New features include analysis of chromatin states, transcription factor motifs and DNase I footprints, providing tools for epigenome-wide association study interpretation and epigenome editing.eFORGE v2.0 is implemented as a web tool available from https://eforge.altiusinstitute.org and https://eforge-tf.altiusinstitute.org/.Supplementary data are available at Bioinformatics online.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{bourgey_genpipes_2019,

title = {GenPipes: an open-source framework for distributed and scalable genomic analyses},

author = {Mathieu Bourgey and Rola Dali and Robert Eveleigh and Kuang Chung Chen and Louis Letourneau and Joel Fillon and Marc Michaud and Maxime Caron and Johanna Sandoval and Francois Lefebvre and Gary Leveque and Eloi Mercier and David Bujold and Pascale Marquis and Patrick Tran Van and David Anderson de Lima Morais and Julien Tremblay and Xiaojian Shao and Edouard Henrion and Emmanuel Gonzalez and Pierre-Olivier Quirion and Bryan Caron and Guillaume Bourque},

url = {https://doi.org/10.1093/gigascience/giz037},

doi = {10.1093/gigascience/giz037},

issn = {2047-217X},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {GigaScience},

volume = {8},

number = {giz037},

abstract = {With the decreasing cost of sequencing and the rapid developments in genomics technologies and protocols, the need for validated bioinformatics software that enables efficient large-scale data processing is growing.Here we present GenPipes, a flexible Python-based framework that facilitates the development and deployment of multi-step workflows optimized for high-performance computing clusters and the cloud. GenPipes already implements 12 validated and scalable pipelines for various genomics applications, including RNA sequencing, chromatin immunoprecipitation sequencing, DNA sequencing, methylation sequencing, Hi-C, capture Hi-C, metagenomics, and Pacific Biosciences long-read assembly. The software is available under a GPLv3 open source license and is continuously updated to follow recent advances in genomics and bioinformatics. The framework has already been configured on several servers, and a Docker image is also available to facilitate additional installations.GenPipes offers genomics researchers a simple method to analyze different types of data, customizable to their needs and resources, as well as the flexibility to create their own workflows.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{morou_altered_2019,

title = {Altered differentiation is central to HIV-specific CD4 + Ŧ cell dysfunction in progressive disease},

author = {Antigoni Morou and Elsa Brunet-Ratnasingham and Mathieu Dubé and Roxanne Charlebois and Eloi Mercier and Sam Darko and Nathalie Brassard and Krystelle Nganou-Makamdop and Sahaana Arumugam and Gabrielle Gendron-Lepage and Lifei Yang and Julia Niessl and Amy E Baxter and James M Billingsley and Premeela A Rajakumar and François Lefebvre and Paul R Johnson and Cécile Tremblay and Jean-Pierre Routy and Richard T Wyatt and Andrés Finzi and Daniel C Douek and Daniel E Kaufmann},

url = {https://www.nature.com/articles/s41590-019-0418-x},

doi = {10.1038/s41590-019-0418-x},

issn = {1529-2916},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-19},

journal = {Nature Immunology},

volume = {20},

number = {8},

pages = {1059--1070},

abstract = {Dysfunction of virus-specific CD4+ T cells in chronic human infections is poorly understood. We performed genome-wide transcriptional analyses and functional assays of CD4+ T cells specific for human immunodeficiency virus (HIV) from HIV-infected people before and after initiation of antiretroviral therapy (ART). A follicular helper T cell (TFH cell)-like profile characterized HIV-specific CD4+ T cells in viremic infection. HIV-specific CD4+ T cells from people spontaneously controlling the virus (elite controllers) robustly expressed genes associated with the TH1, TH17 and TH22 subsets of helper T cells. Viral suppression by ART resulted in a distinct transcriptional landscape, with a reduction in the expression of genes associated with TFH cells, but persistently low expression of genes associated with TH1, TH17 and TH22 cells compared to the elite controller profile. Thus, altered differentiation is central to the impairment of HIV-specific CD4+ T cells and involves both gain of function and loss of function.},

note = {Number: 8 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{siu_functional_2019,

title = {Functional DNA methylation signatures for autism spectrum disorder genomic risk loci: 16p11.2 deletions and CHD8 variants},

author = {M T Siu and D T Butcher and A L Turinsky and C Cytrynbaum and D J Stavropoulos and S Walker and O Caluseriu and M Carter and Y Lou and R Nicolson and S Georgiades and P Szatmari and E Anagnostou and S W Scherer and S Choufani and M Brudno and R Weksberg},

url = {https://doi.org/10.1186/s13148-019-0684-3},

doi = {10.1186/s13148-019-0684-3},

issn = {1868-7083},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {Clinical Epigenetics},

volume = {11},

number = {1},

pages = {103},

abstract = {Autism spectrum disorder (ASD) is a common and etiologically heterogeneous neurodevelopmental disorder. Although many genetic causes have been identified (textgreater 200 ASD-risk genes), no single gene variant accounts for textgreater 1% of all ASD cases. A role for epigenetic mechanisms in ASD etiology is supported by the fact that many ASD-risk genes function as epigenetic regulators and evidence that epigenetic dysregulation can interrupt normal brain development. Gene-specific DNAm profiles have been shown to assist in the interpretation of variants of unknown significance. Therefore, we investigated the epigenome in patients with ASD or two of the most common genomic variants conferring increased risk for ASD. Genome-wide DNA methylation (DNAm) was assessed using the Illumina Infinium HumanMethylation450 and MethylationEPIC arrays in blood from individuals with ASD of heterogeneous, undefined etiology (n = 52), and individuals with 16p11.2 deletions (16p11.2del},

keywords = {Autism spectrum disorder, DNA methylation, epigenetics, Genetic stratification, Genomic variants, Heterogeneity},

pubstate = {published},

tppubtype = {article}

}

@article{chang_regulatory_2019,

title = {Regulatory interaction between the ZPBP2-ORMDL3/Zpbp2-Ormdl3 region and the circadian clock},

author = {Matthew L Chang and Sanny Moussette and Enrique Gamero-Estevez and José Héctor Gálvez and Victoria Chiwara and Indra R Gupta and Aimee K Ryan and Anna K Naumova},

url = {https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223212},

doi = {10.1371/journal.pone.0223212},

issn = {1932-6203},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {PLOS ONE},

volume = {14},

number = {9},

pages = {e0223212},

abstract = {Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1.},

note = {Publisher: Public Library of Science},

keywords = {Asthma, Circadian oscillators, Circadian rhythms, Gene expression, Gene regulation, Genetic oscillators, Ileum, Transcriptional control},

pubstate = {published},

tppubtype = {article}

}

@article{grajcarek_genome-wide_2019,

title = {Genome-wide microhomologies enable precise template-free editing of biologically relevant deletion mutations},

author = {Janin Grajcarek and Jean Monlong and Yoko Nishinaka-Arai and Michiko Nakamura and Miki Nagai and Shiori Matsuo and David Lougheed and Hidetoshi Sakurai and Megumu K Saito and Guillaume Bourque and Knut Woltjen},

url = {https://www.nature.com/articles/s41467-019-12829-8},

doi = {10.1038/s41467-019-12829-8},

issn = {2041-1723},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {Nature Communications},

volume = {10},

number = {1},

pages = {4856},

abstract = {The functional effect of a gene edit by designer nucleases depends on the DNA repair outcome at the targeted locus. While non-homologous end joining (NHEJ) repair results in various mutations, microhomology-mediated end joining (MMEJ) creates precise deletions based on the alignment of flanking microhomologies (µHs). Recently, the sequence context surrounding nuclease-induced double strand breaks (DSBs) has been shown to predict repair outcomes, for which µH plays an important role. Here, we survey naturally occurring human deletion variants and identify that 11 million or 57% are flanked by µHs, covering 88% of protein-coding genes. These biologically relevant mutations are candidates for precise creation in a template-free manner by MMEJ repair. Using CRISPR-Cas9 in human induced pluripotent stem cells (hiPSCs), we efficiently create pathogenic deletion mutations for demonstrable disease models with both gain- and loss-of-function phenotypes. We anticipate this dataset and gene editing strategy to enable functional genetic studies and drug screening.},

note = {Number: 1 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{minerbi_altered_2019,

title = {Altered microbiome composition in individuals with fibromyalgia},

author = {Amir Minerbi and Emmanuel Gonzalez and Nicholas J B Brereton and Abraham Anjarkouchian and Ken Dewar and Mary-Ann Fitzcharles and Stéphanie Chevalier and Yoram Shir},

url = {https://journals.lww.com/pain/Fulltext/2019/11000/Altered_microbiome_composition_in_individuals_with.18.aspx},

doi = {10.1097/j.pain.0000000000001640},

issn = {0304-3959},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {PAIN},

volume = {160},

number = {11},

pages = {2589--2602},

abstract = {Fibromyalgia (FM) is a prevalent syndrome, characterised by chronic widespread pain, fatigue, and impaired sleep, that is challenging to diagnose and difficult to treat. The microbiomes of 77 women with FM and that of 79 control participants were compared using 16S rRNA gene amplification and whole-genome sequencing. When comparing FM patients with unrelated controls using differential abundance analysis, significant differences were revealed in several bacterial taxa. Variance in the composition of the microbiomes was explained by FM-related variables more than by any other innate or environmental variable and correlated with clinical indices of FM. In line with observed alteration in butyrate-metabolising species, targeted serum metabolite analysis verified differences in the serum levels of butyrate and propionate in FM patients. Using machine-learning algorithms, the microbiome composition alone allowed for the classification of patients and controls (receiver operating characteristic area under the curve 87.8%). To the best of our knowledge, this is the first demonstration of gut microbiome alteration in nonvisceral pain. This observation paves the way for further studies, elucidating the pathophysiology of FM, developing diagnostic aids and possibly allowing for new treatment modalities to be explored.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{jessa_stalled_2019,

title = {Stalled developmental programs at the root of pediatric brain tumors},

author = {Selin Jessa and Alexis Blanchet-Cohen and Brian Krug and Maria Vladoiu and Marie Coutelier and Damien Faury and Brice Poreau and Nicolas De Jay and Steven Hébert and Jean Monlong and Todd W Farmer and Laura K Donovan and Yixing Hu and Melissa K McConechy and Florence M G Cavalli and Leonie G Mikael and Benjamin Ellezam and Maxime Richer and Andréa Allaire and Alexander G Weil and Jeffrey Atkinson and Jean-Pierre Farmer and Roy W R Dudley and Valerie Larouche and Louis Crevier and Steffen Albrecht and Mariella G Filbin and Hervé Sartelet and Pierre-Eric Lutz and Corina Nagy and Gustavo Turecki and Santiago Costantino and Peter B Dirks and Keith K Murai and Guillaume Bourque and Jiannis Ragoussis and Livia Garzia and Michael D Taylor and Nada Jabado and Claudia L Kleinman},

url = {https://www.nature.com/articles/s41588-019-0531-7},

doi = {10.1038/s41588-019-0531-7},

issn = {1546-1718},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {Nature Genetics},

volume = {51},

number = {12},

pages = {1702--1713},

abstract = {Childhood brain tumors have suspected prenatal origins. To identify vulnerable developmental states, we generated a single-cell transcriptome atlas of textgreater65,000 cells from embryonal pons and forebrain, two major tumor locations. We derived signatures for 191 distinct cell populations and defined the regional cellular diversity and differentiation dynamics. Projection of bulk tumor transcriptomes onto this dataset shows that WNT medulloblastomas match the rhombic lip-derived mossy fiber neuronal lineage and embryonal tumors with multilayered rosettes fully recapitulate a neuronal lineage, while group 2a/b atypical teratoid/rhabdoid tumors may originate outside the neuroectoderm. Importantly, single-cell tumor profiles reveal highly defined cell hierarchies that mirror transcriptional programs of the corresponding normal lineages. Our findings identify impaired differentiation of specific neural progenitors as a common mechanism underlying these pediatric cancers and provide a rational framework for future modeling and therapeutic interventions.},

note = {Number: 12 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{saulnier_benefits_2019,

title = {Benefits and barriers in the design of harmonized access agreements for international data sharing},

author = {Katie M Saulnier and David Bujold and Stephanie O M Dyke and Charles Dupras and Stephan Beck and Guillaume Bourque and Yann Joly},

url = {https://www.nature.com/articles/s41597-019-0310-4},

doi = {10.1038/s41597-019-0310-4},

issn = {2052-4463},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {Scientific Data},

volume = {6},

number = {1},

pages = {297},

abstract = {In the past decade, there has been a surge in the number of sensitive human genomic and health datasets available to researchers via Data Access Agreements (DAAs) and managed by Data Access Committees (DACs). As this form of sharing increases, so do the challenges of achieving a reasonable level of data protection, particularly in the context of international data sharing. Here, we consider how excessive variation across DAAs can hinder these goals, and suggest a core set of clauses that could prove useful in future attempts to harmonize data governance.},

note = {Number: 1 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sengar_control_2019,

title = {Control of Long-Term Synaptic Potentiation and Learning by Alternative Splicing of the NMDA Receptor Subunit GluN1},

author = {Ameet S Sengar and Hongbin Li and Wenbo Zhang and Celeste Leung and Arun K Ramani and Ner Mu Saw and Yongqian Wang and YuShan Tu and Joel P Ross and Stephen W Scherer and James Ellis and Michael Brudno and Zhengping Jia and Michael W Salter},

url = {https://www.cell.com/cell-reports/abstract/S2211-1247(19)31585-2},

doi = {10.1016/j.celrep.2019.11.087},

issn = {2211-1247},

year  = {2019},

date = {2019-01-01},

urldate = {2021-05-26},

journal = {Cell Reports},

volume = {29},

number = {13},

pages = {4285--4294.e5},

note = {Publisher: Elsevier},

keywords = {autism, GluN1, long-term potentiation, N1 cassette, NMDA Receptor, splicing},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30454069b,

title = {Ten things you should know about transposable elements},

author = {Guillaume Bourque and Kathleen H Burns and Mary Gehring and Vera Gorbunova and Andrei Seluanov and Molly Hammell and Michaël Imbeault and Zsuzsanna Izsvák and Henry L Levin and Todd S Macfarlan and Dixie L Mager and Cédric Feschotte},

doi = {10.1186/s13059-018-1577-z},

issn = {1474-760X},

year  = {2018},

date = {2018-11-01},

journal = {Genome Biol},

volume = {19},

number = {1},

pages = {199},

abstract = {Transposable elements (TEs) are major components of eukaryotic genomes. However, the extent of their impact on genome evolution, function, and disease remain a matter of intense interrogation. The rise of genomics and large-scale functional assays has shed new light on the multi-faceted activities of TEs and implies that they should no longer be marginalized. Here, we introduce the fundamental properties of TEs and their complex interactions with their cellular environment, which are crucial to understanding their impact and manifold consequences for organismal biology. While we draw examples primarily from mammalian systems, the core concepts outlined here are relevant to a broad range of organisms.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30232369b,

title = {Computational tools to unmask transposable elements},

author = {Patricia Goerner-Potvin and Guillaume Bourque},

doi = {10.1038/s41576-018-0050-x},

issn = {1471-0064},

year  = {2018},

date = {2018-11-01},

journal = {Nat Rev Genet},

volume = {19},

number = {11},

pages = {688--704},

abstract = {A substantial proportion of the genome of many species is derived from transposable elements (TEs). Moreover, through various self-copying mechanisms, TEs continue to proliferate in the genomes of most species. TEs have contributed numerous regulatory, transcript and protein innovations and have also been linked to disease. However, notwithstanding their demonstrated impact, many genomic studies still exclude them because their repetitive nature results in various analytical complexities. Fortunately, a growing array of methods and software tools are being developed to cater for them. This Review presents a summary of computational resources for TEs and highlights some of the challenges and remaining gaps to perform comprehensive genomic analyses that do not simply 'mask' repeats.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30137632b,

title = {Human copy number variants are enriched in regions of low mappability},

author = {Jean Monlong and Patrick Cossette and Caroline Meloche and Guy Rouleau and Simon L Girard and Guillaume Bourque},

doi = {10.1093/nar/gky538},

issn = {1362-4962},

year  = {2018},

date = {2018-08-01},

journal = {Nucleic Acids Res},

volume = {46},

number = {14},

pages = {7236--7249},

abstract = {Copy number variants (CNVs) are known to affect a large portion of the human genome and have been implicated in many diseases. Although whole-genome sequencing (WGS) can help identify CNVs, most analytical methods suffer from limited sensitivity and specificity, especially in regions of low mappability. To address this, we use PopSV, a CNV caller that relies on multiple samples to control for technical variation. We demonstrate that our calls are stable across different types of repeat-rich regions and validate the accuracy of our predictions using orthogonal approaches. Applying PopSV to 640 human genomes, we find that low-mappability regions are approximately 5 times more likely to harbor germline CNVs, in stark contrast to the nearly uniform distribution observed for somatic CNVs in 95 cancer genomes. In addition to known enrichments in segmental duplication and near centromeres and telomeres, we also report that CNVs are enriched in specific types of satellite and in some of the most recent families of transposable elements. Finally, using this comprehensive approach, we identify 3455 regions with recurrent CNVs that were missing from existing catalogs. In particular, we identify 347 genes with a novel exonic CNV in low-mappability regions, including 29 genes previously associated with disease.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29853203b,

title = {Comparing Apples to Apples and Oranges to Oranges},

author = {Guillaume Bourque},

doi = {10.1016/j.tig.2018.05.002},

issn = {0168-9525},

year  = {2018},

date = {2018-08-01},

journal = {Trends Genet},

volume = {34},

number = {8},

pages = {571--572},

abstract = {A new study sequenced and assembled two rodent genomes to better understand the evolutionary forces shaping mammalian genomes. Their results suggest multiple roles for genomic repeats.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29762782b,

title = {MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis},

author = {Jasmine Chong and Othman Soufan and Carin Li and Iurie Caraus and Shuzhao Li and Guillaume Bourque and David S Wishart and Jianguo Xia},

doi = {10.1093/nar/gky310},

issn = {1362-4962},

year  = {2018},

date = {2018-07-01},

journal = {Nucleic Acids Res},

volume = {46},

number = {W1},

pages = {W486--W494},

abstract = {We present a new update to MetaboAnalyst (version 4.0) for comprehensive metabolomic data analysis, interpretation, and integration with other omics data. Since the last major update in 2015, MetaboAnalyst has continued to evolve based on user feedback and technological advancements in the field. For this year's update, four new key features have been added to MetaboAnalyst 4.0, including: (1) real-time R command tracking and display coupled with the release of a companion MetaboAnalystR package; (2) a MS Peaks to Pathways module for prediction of pathway activity from untargeted mass spectral data using the mummichog algorithm; (3) a Biomarker Meta-analysis module for robust biomarker identification through the combination of multiple metabolomic datasets and (4) a Network Explorer module for integrative analysis of metabolomics, metagenomics, and/or transcriptomics data. The user interface of MetaboAnalyst 4.0 has been reengineered to provide a more modern look and feel, as well as to give more space and flexibility to introduce new functions. The underlying knowledgebases (compound libraries, metabolite sets, and metabolic pathways) have also been updated based on the latest data from the Human Metabolome Database (HMDB). A Docker image of MetaboAnalyst is also available to facilitate download and local installation of MetaboAnalyst. MetaboAnalyst 4.0 is freely available at http://metaboanalyst.ca.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29959321b,

title = {Targeting EZH2 reactivates a breast cancer subtype-specific anti-metastatic transcriptional program},

author = {Alison Hirukawa and Harvey W Smith and Dongmei Zuo and Catherine R Dufour and Paul Savage and Nicholas Bertos and Radia M Johnson and Tung Bui and Guillaume Bourque and Mark Basik and Vincent Giguère and Morag Park and William J Muller},

doi = {10.1038/s41467-018-04864-8},

issn = {2041-1723},

year  = {2018},

date = {2018-06-01},

journal = {Nat Commun},

volume = {9},

number = {1},

pages = {2547},

abstract = {Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29649218b,

title = {Global characterization of copy number variants in epilepsy patients from whole genome sequencing},

author = {Jean Monlong and Simon L Girard and Caroline Meloche and Maxime Cadieux-Dion and Danielle M Andrade and Ron G Lafreniere and Micheline Gravel and Dan Spiegelman and Alexandre Dionne-Laporte and Cyrus Boelman and Fadi F Hamdan and Jacques L Michaud and Guy Rouleau and Berge A Minassian and Guillaume Bourque and Patrick Cossette},

doi = {10.1371/journal.pgen.1007285},

issn = {1553-7404},

year  = {2018},

date = {2018-04-01},

journal = {PLoS Genet},

volume = {14},

number = {4},

pages = {e1007285},

abstract = {Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29536159b,

title = {Loss of the zona pellucida-binding protein 2 (Zpbp2) gene in mice impacts airway hypersensitivity and lung lipid metabolism in a sex-dependent fashion},

author = {Cynthia Kanagaratham and Victoria Chiwara and Bianca Ho and Sanny Moussette and Mina Youssef and David Venuto and Lucie Jeannotte and Guillaume Bourque and Juan Bautista de Sanctis and Danuta Radzioch and Anna K Naumova},

doi = {10.1007/s00335-018-9743-x},

issn = {1432-1777},

year  = {2018},

date = {2018-04-01},

journal = {Mamm Genome},

volume = {29},

number = {3-4},

pages = {281--298},

abstract = {The human chromosomal region 17q12-q21 is one of the best replicated genome-wide association study loci for childhood asthma. The associated SNPs span a large genomic interval that includes several protein-coding genes. Here, we tested the hypothesis that the zona pellucida-binding protein 2 (ZPBP2) gene residing in this region contributes to asthma pathogenesis using a mouse model. We tested the lung phenotypes of knock-out (KO) mice that carry a deletion of the Zpbp2 gene. The deletion attenuated airway hypersensitivity (AHR) in female, but not male, mice in the absence of allergic sensitization. Analysis of the lipid profiles of their lungs showed that female, but not male, KO mice had significantly lower levels of sphingosine-1-phosphate (S1P), very long-chain ceramides (VLCCs), and higher levels of long-chain ceramides compared to wild-type controls. Furthermore, in females, lung resistance following methacholine challenge correlated with lung S1P levels (Pearson correlation coefficient 0.57) suggesting a link between reduced AHR in KO females, Zpbp2 deletion, and S1P level regulation. In livers, spleens and blood plasma, however, VLCC, S1P, and sphingosine levels were reduced in both KO females and males. We also find that the Zpbp2 deletion was associated with gain of methylation in the adjacent DNA regions. Thus, we demonstrate that the mouse ortholog of ZPBP2 has a role in controlling AHR in female mice. Our data also suggest that Zpbp2 may act through regulation of ceramide metabolism. These findings highlight the importance of phospholipid metabolism for sexual dimorphism in AHR.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{10.1242/dmm.031278,

title = {Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome},

author = {Rifdat Aoidi and Nicolas Houde and Kim Landry-Truchon and Michael Holter and Kevin Jacquet and Louis Charron and Suguna Rani Krishnaswami and Benjamin D Yu and Katherine A Rauen and Nicolas Bisson and Jason Newbern and Jean Charron},

url = {https://doi.org/10.1242/dmm.031278},

doi = {10.1242/dmm.031278},

issn = {1754-8403},

year  = {2018},

date = {2018-01-01},

journal = {Disease Models & Mechanisms},

volume = {11},

number = {3},

abstract = {The RAS/MAPK signaling pathway is one of the most investigated pathways, owing to its established role in numerous cellular processes and implication in cancer. Germline mutations in genes encoding members of the RAS/MAPK pathway also cause severe developmental syndromes collectively known as RASopathies. These syndromes share overlapping characteristics, including craniofacial dysmorphology, cardiac malformations, cutaneous abnormalities and developmental delay. Cardio-facio-cutaneous syndrome (CFC) is a rare RASopathy associated with mutations in BRAF, KRAS, MEK1 (MAP2K1) and MEK2 (MAP2K2). MEK1 and MEK2 mutations are found in ∼25% of the CFC patients and the MEK1Y130C substitution is the most common one. However, little is known about the origins and mechanisms responsible for the development of CFC. To our knowledge, no mouse model carrying RASopathy-linked Mek1 or Mek2 gene mutations has been reported. To investigate the molecular and developmental consequences of the Mek1Y130C mutation, we generated a mouse line carrying this mutation. Analysis of mice from a Mek1 allelic series revealed that the Mek1Y130C allele expresses both wild-type and Y130C mutant forms of MEK1. However, despite reduced levels of MEK1 protein and the lower abundance of MEK1 Y130C protein than wild type, Mek1Y130C mutants showed increased ERK (MAPK) protein activation in response to growth factors, supporting a role for MEK1 Y130C in hyperactivation of the RAS/MAPK pathway, leading to CFC. Mek1Y130C mutant mice exhibited pulmonary artery stenosis, cranial dysmorphia and neurological anomalies, including increased numbers of GFAP+ astrocytes and Olig2+ oligodendrocytes in regions of the cerebral cortex. These data indicate that the Mek1Y130C mutation recapitulates major aspects of CFC, providing a new animal model to investigate the physiopathology of this RASopathy. This article has an associated First Person interview with the first author of the paper.},

note = {dmm031278},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{https://doi.org/10.1111/dgd.12423,

title = {Identifying co-opted transposable elements using comparative epigenomics},

author = {David Venuto and Guillaume Bourque},

url = {https://onlinelibrary.wiley.com/doi/abs/10.1111/dgd.12423},

doi = {https://doi.org/10.1111/dgd.12423},

year  = {2018},

date = {2018-01-01},

journal = {Development, Growth & Differentiation},

volume = {60},

number = {1},

pages = {53-62},

abstract = {The human genome gives rise to different epigenomic landscapes that define each cell type and can be deregulated in disease. Recent efforts by ENCODE, the NIH Roadmap and the International Human Epigenome Consortium (IHEC) have made significant advances towards assembling reference epigenomic maps of various tissues. Notably, these projects have found that approximately 80% of human DNA was biochemically active in at least one epigenomic assay while only approximately 10% of the sequence displayed signs of purifying selection. Given that transposable elements (TEs) make up at least 50% of the human genome and can be actively transcribed or act as regulatory elements either for their own purposes or be co-opted for the benefit of their host; we are interested in exploring their overall contribution to the “functional” genome. Traditional methods used to identify functional DNA have relied on comparative genomics, conservation analysis and low throughput validation assays. To discover co-opted TEs, and distinguish them from noisy genomic elements, we argue that comparative epigenomic methods will also be important.},

keywords = {comparative epigenomics, epigenetics, functional genome, genomics, transposable elements},

pubstate = {published},

tppubtype = {article}

}

@article{lebo_data_2018,

title = {Data sharing as a national quality improvement program: reporting on BRCA1 and BRCA2 variant-interpretation comparisons through the Canadian Open Genetics Repository (COGR)},

author = {Matthew S Lebo and Kathleen-Rose Zakoor and Kathy Chun and Marsha D Speevak and John S Waye and Elizabeth McCready and Jillian S Parboosingh and Ryan E Lamont and Harriet Feilotter and Ian Bosdet and Tracy Tucker and Sean Young and Aly Karsan and George S Charames and Ronald Agatep and Elizabeth L Spriggs and Caitlin Chisholm and Nasim Vasli and Hussein Daoud and Olga Jarinova and Robert Tomaszewski and Stacey Hume and Sherryl Taylor and Mohammad R Akbari and Jordan Lerner-Ellis},

url = {https://www.nature.com/articles/gim201780},

doi = {10.1038/gim.2017.80},

issn = {1530-0366},

year  = {2018},

date = {2018-01-01},

urldate = {2021-05-18},

journal = {Genetics in Medicine},

volume = {20},

number = {3},

pages = {294--302},

abstract = {The purpose of this study was to develop a national program for Canadian diagnostic laboratories to compare DNA-variant interpretations and resolve discordant-variant classifications using the BRCA1 and BRCA2 genes as a case study.},

note = {Number: 3 

Publisher: Nature Publishing Group},

keywords = {},

pubstate = {published},

tppubtype = {article}

}