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Your search keyword '"Kamel Jabbari"' showing total 14 results
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14 results on '"Kamel Jabbari"'

1. LeafGo: Leaf to Genome, a quick workflow to produce high-quality de novo plant genomes using long-read sequencing technology

Author

Patrick Driguez, Salim Bougouffa, Karen Carty, Alexander Putra, Kamel Jabbari, Muppala Reddy, Richard Soppe, Ming Sin Cheung, Yoshinori Fukasawa, and Luca Ermini

Subjects
Long-read sequencing, Chromosome-level draft genome, High molecular weight DNA extraction, Eucalyptus, Peanut, Arachis, Biology (General), QH301-705.5, Genetics, QH426-470
Abstract

Abstract Currently, different sequencing platforms are used to generate plant genomes and no workflow has been properly developed to optimize time, cost, and assembly quality. We present LeafGo, a complete de novo plant genome workflow, that starts from tissue and produces genomes with modest laboratory and bioinformatic resources in approximately 7 days and using one long-read sequencing technology. LeafGo is optimized with ten different plant species, three of which are used to generate high-quality chromosome-level assemblies without any scaffolding technologies. Finally, we report the diploid genomes of Eucalyptus rudis and E. camaldulensis and the allotetraploid genome of Arachis hypogaea.

Published
2021
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2. A common genomic code for chromatin architecture and recombination landscape.

Author

Kamel Jabbari, Johannes Wirtz, Martina Rauscher, and Thomas Wiehe

Subjects
Medicine, Science
Abstract

Recent findings established a link between DNA sequence composition and interphase chromatin architecture and explained the evolutionary conservation of TADs (Topologically Associated Domains) and LADs (Lamina Associated Domains) in mammals. This prompted us to analyse conformation capture and recombination rate data to study the relationship between chromatin architecture and recombination landscape of human and mouse genomes. The results reveal that: (1) low recombination domains and blocks of elevated linkage disequilibrium tend to coincide with TADs and isochores, indicating co-evolving regulatory elements and genes in insulated neighbourhoods; (2) double strand break (DSB) and recombination frequencies increase in the short loops of GC-rich TADs, whereas recombination cold spots are typical of LADs and (3) the binding and loading of proteins, which are critical for DSB and meiotic recombination (SPO11, DMC1, H3K4me3 and PRMD9) are higher in GC-rich TADs. One explanation for these observations is that the occurrence of DSB and recombination in meiotic cells are associated with compositional and epigenetic features (genomic code) that influence DNA stiffness/flexibility and appear to be similar to those guiding the chromatin architecture in the interphase nucleus of pre-leptotene cells.

Published
2019
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3. Rare gene deletions in genetic generalized and Rolandic epilepsies.

Author

Kamel Jabbari, Dheeraj R Bobbili, Dennis Lal, Eva M Reinthaler, Julian Schubert, Stefan Wolking, Vishal Sinha, Susanne Motameny, Holger Thiele, Amit Kawalia, Janine Altmüller, Mohammad Reza Toliat, Robert Kraaij, Jeroen van Rooij, André G Uitterlinden, M Arfan Ikram, EuroEPINOMICS CoGIE Consortium, Federico Zara, Anna-Elina Lehesjoki, Roland Krause, Fritz Zimprich, Thomas Sander, Bernd A Neubauer, Patrick May, Holger Lerche, and Peter Nürnberg

Subjects
Medicine, Science
Abstract

Genetic Generalized Epilepsy (GGE) and benign epilepsy with centro-temporal spikes or Rolandic Epilepsy (RE) are common forms of genetic epilepsies. Rare copy number variants have been recognized as important risk factors in brain disorders. We performed a systematic survey of rare deletions affecting protein-coding genes derived from exome data of patients with common forms of genetic epilepsies. We analysed exomes from 390 European patients (196 GGE and 194 RE) and 572 population controls to identify low-frequency genic deletions. We found that 75 (32 GGE and 43 RE) patients out of 390, i.e. ~19%, carried rare genic deletions. In particular, large deletions (>400 kb) represent a higher burden in both GGE and RE syndromes as compared to controls. The detected low-frequency deletions (1) share genes with brain-expressed exons that are under negative selection, (2) overlap with known autism and epilepsy-associated candidate genes, (3) are enriched for CNV intolerant genes recorded by the Exome Aggregation Consortium (ExAC) and (4) coincide with likely disruptive de novo mutations from the NPdenovo database. Employing several knowledge databases, we discuss the most prominent epilepsy candidate genes and their protein-protein networks for GGE and RE.

Published
2018
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4. An Isochore Framework Underlies Chromatin Architecture.

Author

Kamel Jabbari and Giorgio Bernardi

Subjects
Medicine, Science
Abstract

A recent investigation showed the existence of correlations between the architectural features of mammalian interphase chromosomes and the compositional properties of isochores. This result prompted us to compare maps of the Topologically Associating Domains (TADs) and of the Lamina Associated Domains (LADs) with the corresponding isochore maps of mouse and human chromosomes. This approach revealed that: 1) TADs and LADs correspond to isochores, i.e., isochores are the genomic units that underlie chromatin domains; 2) the conservation of TADs and LADs in mammalian genomes is explained by the evolutionary conservation of isochores; 3) chromatin domains corresponding to GC-poor isochores (e.g., LADs) show not only self-interactions but also intrachromosomal interactions with other domains also corresponding to GC-poor isochores even if located far away; in contrast, chromatin domains corresponding to GC-rich isochores (e.g., TADs) show more localized chromosomal interactions, many of which are inter-chromosomal. In conclusion, this investigation establishes a link between DNA sequences and chromatin architecture, explains the evolutionary conservation of TADs and LADs and provides new information on the spatial distribution of GC-poor/gene-poor and GC-rich/gene-rich chromosomal regions in the interphase nucleus.

Published
2017
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5. The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis

Author

Kamel Jabbari, Peter Heger, Ranu Sharma, and Thomas Wiehe

Subjects
CTCF, gene duplication, chromatin loops, polymorphism, natural selection, Bilateria, Amniotes, Science
Abstract

The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called “Brother of Regulator of Imprinted Sites” (BORIS) or “CTCF-like” (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint.

Published
2018
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6. Leveraging the power of high performance computing for next generation sequencing data analysis: tricks and twists from a high throughput exome workflow.

Author

Amit Kawalia, Susanne Motameny, Stephan Wonczak, Holger Thiele, Lech Nieroda, Kamel Jabbari, Stefan Borowski, Vishal Sinha, Wilfried Gunia, Ulrich Lang, Viktor Achter, and Peter Nürnberg

Subjects
Medicine, Science
Abstract

Next generation sequencing (NGS) has been a great success and is now a standard method of research in the life sciences. With this technology, dozens of whole genomes or hundreds of exomes can be sequenced in rather short time, producing huge amounts of data. Complex bioinformatics analyses are required to turn these data into scientific findings. In order to run these analyses fast, automated workflows implemented on high performance computers are state of the art. While providing sufficient compute power and storage to meet the NGS data challenge, high performance computing (HPC) systems require special care when utilized for high throughput processing. This is especially true if the HPC system is shared by different users. Here, stability, robustness and maintainability are as important for automated workflows as speed and throughput. To achieve all of these aims, dedicated solutions have to be developed. In this paper, we present the tricks and twists that we utilized in the implementation of our exome data processing workflow. It may serve as a guideline for other high throughput data analysis projects using a similar infrastructure. The code implementing our solutions is provided in the supporting information files.

Published
2015
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7. LeafGo: Leaf to Genome, a quick workflow to produce high-quality de novo plant genomes using long-read sequencing technology

Author

Alexander Putra, Muppala P. Reddy, Ming Sin Cheung, Luca Ermini, Richard Willem Otto Soppe, Karen Carty, Yoshinori Fukasawa, Salim Bougouffa, Kamel Jabbari, and Patrick Driguez

Subjects
Time Factors, Arachis, DNA, Plant, QH301-705.5, Method, Computational biology, QH426-470, Biology, Genome, Species Specificity, Genetics, Biology (General), Long-read sequencing, Eucalyptus, food and beverages, High-Throughput Nucleotide Sequencing, Chromosome-level draft genome, Plant genomes, Diploidy, Arachis hypogaea, Plant Leaves, Tetraploidy, Workflow, Peanut, Plant species, High molecular weight DNA extraction, Genomic standardized workflow, Genome, Plant, Software
Abstract

Currently, different sequencing platforms are used to generate plant genomes and no workflow has been properly developed to optimize time, cost, and assembly quality. We present LeafGo, a complete de novo plant genome workflow, that starts from tissue and produces genomes with modest laboratory and bioinformatic resources in approximately 7 days and using one long-read sequencing technology. LeafGo is optimized with ten different plant species, three of which are used to generate high-quality chromosome-level assemblies without any scaffolding technologies. Finally, we report the diploid genomes of Eucalyptus rudis and E. camaldulensis and the allotetraploid genome of Arachis hypogaea.

Published
2021

8. LeafGo: Leaf to Genome, a quick workflow to produce high-qualityDe novogenomes with Third Generation Sequencing technology

Author

Alexander Putra, Patrick Driguez, Cheung N, Muppala P. Reddy, Yoshinori Fukasawa, Kamel Jabbari, Luca Ermini, Karen Carty, Richard Willem Otto Soppe, and Salim Bougouffa

Subjects
Workflow, Plant species, Sequence assembly, Third generation sequencing, Computational biology, Biology, High molecular weight dna, DNA extraction, Genome, Plant genomics
Abstract

Recent years have witnessed a rapid development of sequencing technologies. Fundamental differences and limitations among various platforms impact the time, the cost and the accuracy for sequencing whole genomes. Here we designed a completede novoplant genome generation workflow that starts from plant tissue samples and produces high-quality draft genomes with relatively modest laboratory and bioinformatic resources within seven days. To optimize our workflow we selected different species of plants which were used to extract high molecular weight DNA, to make PacBio and ONT libraries for sequencing with the Sequel I, Sequel II and GridION platforms. We assembled high-quality draft genomes of two differentEucalyptusspeciesE. rudis, andE. camaldulensisto chromosome level without using additional scaffolding technologies. For the rapid production ofde novogenome assembly of plant species we showed that our DNA extraction protocol followed by PacBio high fidelity sequencing, and assembly with new generation assemblers such as hifiasm produce excellent results. Our findings will be a valuable benchmark for groups planning wet- and dry-lab plant genomics research and for high throughput plant genomics initiatives.

Published
2021

9. A genomic view on epilepsy and autism candidate genes

Author

Peter Nürnberg and Kamel Jabbari

Subjects
0301 basic medicine, Candidate gene, Proteome, Genomics, Biology, Genome, 03 medical and health sciences, Epilepsy, Genetics, medicine, Humans, Genetic Predisposition to Disease, Autistic Disorder, Exome, Exome sequencing, Massive parallel sequencing, Genome, Human, Gene Expression Profiling, Brain, medicine.disease, 030104 developmental biology, Autism, Isochores
Abstract

Epilepsy is a common complex disorder most frequently associated with psychiatric and neurological diseases. Massive parallel sequencing of individual or cohort genomes and exomes led the identification of several disease associated genes. We review here the candidate genes in epilepsy genetics with focus on exome and gene panel data. Together with the examination of brain expressed genes and post synaptic proteome the results show that: (1) Non-metabolic epilepsies and autism candidate genes tend to be AT-rich and (2) large transcript size and local AT-richness are characteristic features of genes involved in developmental brain disorders and synaptic functions. These results point to the preferential location of core epilepsy and autism candidate genes in late replicating, GC-poor chromosomal regions (isochores). These results indicate that the genomic alterations leading to some brain disorders are confined to responsive chromatin areas harboring brain critical genes.

Published
2016

10. Rare coding variants in genes encoding GABAA receptors in genetic generalised epilepsies: an exome-based case-control study

Author

Patrick May, Simon Girard, Merle Harrer, Dheeraj R Bobbili, Julian Schubert, Stefan Wolking, Felicitas Becker, Pamela Lachance-Touchette, Caroline Meloche, Micheline Gravel, Cristina E Niturad, Julia Knaus, Carolien De Kovel, Mohamad Toliat, Anne Polvi, Michele Iacomino, Rosa Guerrero-López, Stéphanie Baulac, Carla Marini, Holger Thiele, Janine Altmüller, Kamel Jabbari, Ann-Kathrin Ruppert, Wiktor Jurkowski, Dennis Lal, Raffaella Rusconi, Sandrine Cestèle, Benedetta Terragni, Ian D Coombs, Christopher A Reid, Pasquale Striano, Hande Caglayan, Auli Siren, Kate Everett, Rikke S Møller, Helle Hjalgrim, Hiltrud Muhle, Ingo Helbig, Wolfram S Kunz, Yvonne G Weber, Sarah Weckhuysen, Peter De Jonghe, Sanjay M Sisodiya, Rima Nabbout, Silvana Franceschetti, Antonietta Coppola, Maria S Vari, Dorothée Kasteleijn-Nolst Trenité, Betul Baykan, Ugur Ozbek, Nerses Bebek, Karl M Klein, Felix Rosenow, Dang K Nguyen, François Dubeau, Lionel Carmant, Anne Lortie, Richard Desbiens, Jean-François Clément, Cécile Cieuta-Walti, Graeme J Sills, Pauls Auce, Ben Francis, Michael R Johnson, Anthony G Marson, Bianca Berghuis, Josemir W Sander, Andreja Avbersek, Mark McCormack, Gianpiero L Cavalleri, Norman Delanty, Chantal Depondt, Martin Krenn, Fritz Zimprich, Sarah Peter, Marina Nikanorova, Robert Kraaij, Jeroen van Rooij, Rudi Balling, M Arfan Ikram, André G Uitterlinden, Giuliano Avanzini, Stephanie Schorge, Steven Petrou, Massimo Mantegazza, Thomas Sander, Eric LeGuern, Jose M Serratosa, Bobby P C Koeleman, Aarno Palotie, Anna-Elina Lehesjoki, Michael Nothnagel, Peter Nürnberg, Snezana Maljevic, Federico Zara, Patrick Cossette, Roland Krause, Holger Lerche, Edoardo Ferlazzo, Carlo di Bonaventura, Angela La Neve, Paolo Tinuper, Francesca Bisulli, Aglaia Vignoli, Giuseppe Capovilla, Giovanni Crichiutti, Antonio Gambardella, Vincenzo Belcastro, Amedeo Bianchi, Destina Yalçın, Gulsen Dizdarer, Kezban Arslan, Zuhal Yapıcı, Demet Kuşcu, Costin Leu, Kristin Heggeli, Joseph Willis, Sarah R Langley, Andrea Jorgensen, Prashant Srivastava, Sarah Rau, Christian Hengsbach, Anja C.M. Sonsma, Université Côte d'Azur, CNRS, UMR 7275, Institut de Pharmacologie Moléculaire et Cellulaire, Sophia Antipolis, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Laboratory of Molecular Genetics of Stem Cells [University of Montreal], University of Montreal-Institut de Recherche en Immunologie et en Cancérologie [UdeM-Montréal] (IRIC), Université de Montréal (UdeM)-Université de Montréal (UdeM), University of Tübingen, University Medical Center [Utrecht], Universita degli studi di Genova, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), A.Meyer Children's Hospital, Max Planck Institute for Plant Breeding Research (MPIPZ), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), University of Cologne, The Genome Analysis Centre (TGAC), Cologne Center for Genomics, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS), Ingénierie des protéines (IP), Université de la Méditerranée - Aix-Marseille 2-Centre National de la Recherche Scientifique (CNRS), Department of Neurophysiopathology, Besta Neurological Institute, University of Southern Denmark (SDU), Medical Genetics Laboratory, Children’s Hospital of Philadelphia (CHOP ), Universitätsklinikum Bonn (UKB), Antwerp University Hospital [Edegem] (UZA), University of Antwerp (UA), Department of Clinical and Experimental Epilepsy, University College of London [London] (UCL), Département de Neuropédiatrie, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Instituco Neurologico C. Besta, Instituto Neurologico C. Besta, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), University of Liverpool, Institute of Neurology [London], Royal College of Surgeons in Ireland (RCSI), Neurology Division, Beaumont Hospital, Dublin 9, Ireland, Beaumont Hospital, Hôpital Erasme [Bruxelles] (ULB), Faculté de Médecine [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), Medizinische Universität Wien = Medical University of Vienna, Department of Epilepsy Clinic and Experimental Neurophysiology, Fondazione IRCCS Istituto Neurologico 'Carlo Besta', Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Institute of Medical Informatics and Statistics, Pediatric Neurology and Neuromuscular Diseases Unit, Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Hertie Institute for Clinical Brain Research [Tubingen], Regional Epilepsy Center, Reggio Calabria, Agronomes et Vétérinaires Sans Frontières (AVSF), AVSF, NIHR Biomedical Research Centre [London], Guy's and St Thomas' NHS Foundation Trust-King‘s College London, Wellcome Trust, Commission of the European Communities, Imperial College Healthcare NHS Trust- BRC Funding, Internal Medicine, Epidemiology, Luxembourg Centre For Systems Biomedicine (LCSB), University of Luxembourg [Luxembourg], Università degli studi di Genova = University of Genoa (UniGe), Heart Center Leipzig, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Acibadem University Dspace, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Nice Sophia Antipolis (... - 2019) (UNS), University of Helsinki-University of Helsinki-Faculty of Medecine [Helsinki], University of Helsinki-University of Helsinki, Centre of Excellence in Complex Disease Genetics, Aarno Palotie / Principal Investigator, Institute for Molecular Medicine Finland, Medicum, Research Programme for Molecular Neurology, Research Programs Unit, Neuroscience Center, University of Helsinki, Genomics of Neurological and Neuropsychiatric Disorders, Epicure Consortium, EuroEPINOMICS COGIE Consortium, EpiPGX Consortium, May, Gabriella, Girard, S., Harrer, M., Bobbili, D. R., Schubert, J., Wolking, S., Becker, F., Lachance-Touchette, P., Meloche, C., Gravel, M., Niturad, C. E., Knaus, J., De Kovel, C., Toliat, M., Polvi, A., Iacomino, M., Guerrero-López, R., Baulac, S., Marini, C., Thiele, H., Altmüller, J., Jabbari, K., Ruppert, A. -K., Jurkowski, W., Lal, D., Rusconi, R., Cestèle, S., Terragni, B., Coombs, I. D., Reid, C. A., Striano, P., Caglayan, H., Siren, A., Everett, K., Møller, R. S., Hjalgrim, H., Muhle, H., Helbig, I., Kunz, W. S., Weber, Y. G., Weckhuysen, S., Jonghe, P. D., Sisodiya, S. M., Nabbout, R., Franceschetti, S., Coppola, A., Vari, M. S., Kasteleijn-Nolst Trenité, D., Baykan, B., Ozbek, U., Bebek, N., Klein, K. M., Rosenow, F., Nguyen, D. K., Dubeau, F., Carmant, L., Lortie, A., Desbiens, R., Clément, J. -F., Cieuta-Walti, C., Sills, G. J., Auce, P., Francis, B., Johnson, M. R., Marson, A. G., Berghuis, B., Sander, J. W., Avbersek, A., Mccormack, M., Cavalleri, G. L., Delanty, N., Depondt, C., Krenn, M., Zimprich, F., Peter, S., Nikanorova, M., Kraaij, R., van Rooij, J., Balling, R., Ikram, M. A., Uitterlinden, A. G., Avanzini, Giulio, Schorge, S., Petrou, S., Mantegazza, M., Sander, T., Leguern, E., Serratosa, J. M., Koeleman, B. P. C., Palotie, A., Lehesjoki, A. -E., Nothnagel, M., Nürnberg, P., Maljevic, S., Zara, F., Cossette, P., Krause, R., Lerche, H., De Jonghe, P., Arfan Ikram, M., Ferlazzo, E., di Bonaventura, C., La Neve, A., Tinuper, P., Bisulli, F., Vignoli, Massimo, Capovilla, G., Crichiutti, G., Gambardella, A., Belcastro, V., Bianchi, A., Yalçın, D., Dizdarer, G., Arslan, K., Yapıcı, Z., Kuşcu, D., Leu, C., Heggeli, K., Willis, J., Langley, S. R., Jorgensen, A., Srivastava, P., Rau, S., Hengsbach, C., Sonsma, A. C. M., University of Montreal-Institute for Research in Immunology and Cancer (IRIC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA)-Centre National de la Recherche Scientifique (CNRS), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], Hôpital Erasme (Bruxelles), May, Patrick, Girard, Simon, Harrer, Merle, Bobbili, Dheeraj R, Schubert, Julian, Wolking, Stefan, Becker, Felicita, Lachance-Touchette, Pamela, Meloche, Caroline, Gravel, Micheline, Niturad, Cristina E, Knaus, Julia, De Kovel, Carolien, Toliat, Mohamad, Polvi, Anne, Iacomino, Michele, Guerrero-López, Rosa, Baulac, Stéphanie, Marini, Carla, Thiele, Holger, Altmüller, Janine, Jabbari, Kamel, Ruppert, Ann-Kathrin, Jurkowski, Wiktor, Lal, Denni, Rusconi, Raffaella, Cestèle, Sandrine, Terragni, Benedetta, Coombs, Ian D, Reid, Christopher A, Striano, Pasquale, Caglayan, Hande, Siren, Auli, Everett, Kate, Møller, Rikke S, Hjalgrim, Helle, Muhle, Hiltrud, Helbig, Ingo, Kunz, Wolfram S, Weber, Yvonne G, Weckhuysen, Sarah, Jonghe, Peter De, Sisodiya, Sanjay M, Nabbout, Rima, Franceschetti, Silvana, Coppola, Antonietta, Vari, Maria S, Kasteleijn-Nolst Trenité, Dorothée, Baykan, Betul, Ozbek, Ugur, Bebek, Nerse, Klein, Karl M, Rosenow, Felix, Nguyen, Dang K, Dubeau, Françoi, Carmant, Lionel, Lortie, Anne, Desbiens, Richard, Clément, Jean-Françoi, Cieuta-Walti, Cécile, Sills, Graeme J, Auce, Paul, Francis, Ben, Johnson, Michael R, Marson, Anthony G, Berghuis, Bianca, Sander, Josemir W, Avbersek, Andreja, McCormack, Mark, Cavalleri, Gianpiero L., Delanty, Norman, Depondt, Chantal, Krenn, Martin, Zimprich, Fritz, Peter, Sarah, Nikanorova, Marina, Kraaij, Robert, van Rooij, Jeroen, Balling, Rudi, Ikram, M Arfan, Uitterlinden, André G, Avanzini, Giuliano, Schorge, Stephanie, Petrou, Steven, Mantegazza, Massimo, Sander, Thoma, LeGuern, Eric, Serratosa, Jose M, Koeleman, Bobby P C, Palotie, Aarno, Lehesjoki, Anna-Elina, Nothnagel, Michael, Nürnberg, Peter, Maljevic, Snezana, Zara, Federico, Cossette, Patrick, Krause, Roland, Lerche, Holger, De Jonghe, Peter, Ferlazzo, Edoardo, di Bonaventura, Carlo, La Neve, Angela, Tinuper, Paolo, Bisulli, Francesca, Vignoli, Aglaia, Capovilla, Giuseppe, Crichiutti, Giovanni, Gambardella, Antonio, Belcastro, Vincenzo, Bianchi, Amedeo, Yalçın, Destina, Dizdarer, Gulsen, Arslan, Kezban, Yapıcı, Zuhal, Kuşcu, Demet, Leu, Costin, Heggeli, Kristin, Willis, Joseph, Langley, Sarah R, Jorgensen, Andrea, Srivastava, Prashant, Rau, Sarah, Hengsbach, Christian, and Sonsma, Anja C.M.

Subjects
0301 basic medicine, GAMMA-2-SUBUNIT, [SDV]Life Sciences [q-bio], GABRA5, Clinical Neurology, 15Q13.3 MICRODELETIONS, ABSENCE EPILEPSY, SEQUENCE DATA, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, 3124 Neurology and psychiatry, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Genetic variation, medicine, EPILEPTIC ENCEPHALOPATHIES, Exome, Exome sequencing, ComputingMilieux_MISCELLANEOUS, Genetic association, Genetics, RISK, Science & Technology, FEBRILE SEIZURES, Neurology & Neurosurgery, biology, 3112 Neurosciences, 1103 Clinical Sciences, MOUSE MODEL, medicine.disease, ASSOCIATION ANALYSIS, 030104 developmental biology, DE-NOVO MUTATIONS, Cohort, biology.protein, Neurology (clinical), Human medicine, Neurosciences & Neurology, 1109 Neurosciences, Life Sciences & Biomedicine, 030217 neurology & neurosurgery, Cohort study
Abstract

BACKGROUND: Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.METHODS: For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAA receptors and was compared to the respective GABAA receptor variants of a third independent control cohort. Functional investigations were done with automated two-microelectrode voltage clamping in Xenopus laevis oocytes.FINDINGS: Statistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAA receptors in cases (odds ratio [OR] 2·40 [95% CI 1·41-4·10]; pNonsyn=0·0014, adjusted pNonsyn=0·019). Enrichment for these genes was validated in a whole-exome sequencing cohort of 357 sporadic and familial genetic generalised epilepsy cases and 1485 independent controls (OR 1·46 [95% CI 1·05-2·03]; pNonsyn=0·0081, adjusted pNonsyn=0·016). Comparison of genes encoding GABAA receptors in the independent replication cohort of 583 familial and sporadic genetic generalised epilepsy index cases, based on candidate-gene panel sequencing, with a third independent control cohort of 635 controls confirmed the overall enrichment of rare missense variants for 15 GABAA receptor genes in cases compared with controls (OR 1·46 [95% CI 1·02-2·08]; pNonsyn=0·013, adjusted pNonsyn=0·027). Functional studies for two selected genes (GABRB2 and GABRA5) showed significant loss-of-function effects with reduced current amplitudes in four of seven tested variants compared with wild-type receptors.INTERPRETATION: Functionally relevant variants in genes encoding GABAA receptor subunits constitute a significant risk factor for genetic generalised epilepsy. Examination of the role of specific gene groups and pathways can disentangle the complex genetic architecture of genetic generalised epilepsy.FUNDING: EuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2018

11. A common genomic code for chromatin architecture and recombination landscape

Author

Johannes Wirtz, Martina Rauscher, Kamel Jabbari, and Thomas Wiehe

Subjects
Heredity, Gene Expression, Biochemistry, Linkage Disequilibrium, Histones, Geographical Locations, chemistry.chemical_compound, Mice, 0302 clinical medicine, DNA Breaks, Double-Stranded, Homologous Recombination, 0303 health sciences, Multidisciplinary, Mammalian Genomics, DNA methylation, Chromosome Biology, Genomics, Chromatin, Recombinant Proteins, Europe, Nucleic acids, Meiosis, Physical Sciences, Medicine, Epigenetics, DNA modification, Isochores, Chromatin modification, Recombination, Research Article, Spo11, DNA recombination, Permutation, Science, Biology, 03 medical and health sciences, Genetics, Animals, Humans, 030304 developmental biology, Discrete Mathematics, fungi, Biology and Life Sciences, Proteins, Cell Biology, DNA, Chromosomes, Mammalian, chemistry, Animal Genomics, Combinatorics, Evolutionary biology, People and Places, biology.protein, H3K4me3, DMC1, Homologous recombination, 030217 neurology & neurosurgery, Mathematics
Abstract

Recent findings established a link between DNA sequence composition and interphase chromatin architecture and explained the evolutionary conservation of TADs (Topologically Associated Domains) and LADs (Lamina Associated Domains) in mammals. This prompted us to analyse conformation capture and recombination rate data to study the relationship between chromatin architecture and recombination landscape of human and mouse genomes. The results reveal that: (1) low recombination domains and blocks of elevated linkage disequilibrium tend to coincide with TADs and isochores, indicating co-evolving regulatory elements and genes in insulated neighbourhoods; (2) double strand break (DSB) and recombination frequencies increase in the short loops of GC-rich TADs, whereas recombination cold spots are typical of LADs and (3) the binding and loading of proteins, which are critical for DSB and meiotic recombination (SPO11, DMC1, H3K4me3 and PRMD9) are higher in GC-rich TADs. One explanation for these observations is that the occurrence of DSB and recombination in meiotic cells are associated with compositional and epigenetic features (genomic code) that influence DNA stiffness/flexibility and appear to be similar to those guiding the chromatin architecture in the interphase nucleus of pre-leptotene cells.

Published
2018

12. Rare coding variants in genes encoding GABA

Author

Patrick, May, Simon, Girard, Merle, Harrer, Dheeraj R, Bobbili, Julian, Schubert, Stefan, Wolking, Felicitas, Becker, Pamela, Lachance-Touchette, Caroline, Meloche, Micheline, Gravel, Cristina E, Niturad, Julia, Knaus, Carolien, De Kovel, Mohamad, Toliat, Anne, Polvi, Michele, Iacomino, Rosa, Guerrero-López, Stéphanie, Baulac, Carla, Marini, Holger, Thiele, Janine, Altmüller, Kamel, Jabbari, Ann-Kathrin, Ruppert, Wiktor, Jurkowski, Dennis, Lal, Raffaella, Rusconi, Sandrine, Cestèle, Benedetta, Terragni, Ian D, Coombs, Christopher A, Reid, Pasquale, Striano, Hande, Caglayan, Auli, Siren, Kate, Everett, Rikke S, Møller, Helle, Hjalgrim, Hiltrud, Muhle, Ingo, Helbig, Wolfram S, Kunz, Yvonne G, Weber, Sarah, Weckhuysen, Peter De, Jonghe, Sanjay M, Sisodiya, Rima, Nabbout, Silvana, Franceschetti, Antonietta, Coppola, Maria S, Vari, Dorothée, Kasteleijn-Nolst Trenité, Betul, Baykan, Ugur, Ozbek, Nerses, Bebek, Karl M, Klein, Felix, Rosenow, Dang K, Nguyen, François, Dubeau, Lionel, Carmant, Anne, Lortie, Richard, Desbiens, Jean-François, Clément, Cécile, Cieuta-Walti, Graeme J, Sills, Pauls, Auce, Ben, Francis, Michael R, Johnson, Anthony G, Marson, Bianca, Berghuis, Josemir W, Sander, Andreja, Avbersek, Mark, McCormack, Gianpiero L, Cavalleri, Norman, Delanty, Chantal, Depondt, Martin, Krenn, Fritz, Zimprich, Sarah, Peter, Marina, Nikanorova, Robert, Kraaij, Jeroen, van Rooij, Rudi, Balling, M Arfan, Ikram, André G, Uitterlinden, Giuliano, Avanzini, Stephanie, Schorge, Steven, Petrou, Massimo, Mantegazza, Thomas, Sander, Eric, LeGuern, Jose M, Serratosa, Bobby P C, Koeleman, Aarno, Palotie, Anna-Elina, Lehesjoki, Michael, Nothnagel, Peter, Nürnberg, Snezana, Maljevic, Federico, Zara, Patrick, Cossette, Roland, Krause, Holger, Lerche, and Anja C M, Sonsma

Subjects
Adult, Aged, 80 and over, Family Health, Male, Models, Molecular, Adolescent, International Cooperation, Infant, Newborn, Genetic Variation, Infant, Middle Aged, Receptors, GABA-A, Cohort Studies, Europe, Young Adult, Case-Control Studies, Child, Preschool, Exome Sequencing, Humans, Epilepsy, Generalized, Female, Genetic Predisposition to Disease, Child, Aged
Abstract

Genetic generalised epilepsy is the most common type of inherited epilepsy. Despite a high concordance rate of 80% in monozygotic twins, the genetic background is still poorly understood. We aimed to investigate the burden of rare genetic variants in genetic generalised epilepsy.For this exome-based case-control study, we used three different genetic generalised epilepsy case cohorts and three independent control cohorts, all of European descent. Cases included in the study were clinically evaluated for genetic generalised epilepsy. Whole-exome sequencing was done for the discovery case cohort, a validation case cohort, and two independent control cohorts. The replication case cohort underwent targeted next-generation sequencing of the 19 known genes encoding subunits of GABAStatistical comparison of 152 familial index cases with genetic generalised epilepsy in the discovery cohort to 549 ethnically matched controls suggested an enrichment of rare missense (Nonsyn) variants in the ensemble of 19 genes encoding GABAFunctionally relevant variants in genes encoding GABAEuroEPINOMICS (European Science Foundation through national funding organisations), Epicure and EpiPGX (Sixth Framework Programme and Seventh Framework Programme of the European Commission), Research Unit FOR2715 (German Research Foundation and Luxembourg National Research Fund).

Published
2017

13. The Diverging Routes of BORIS and CTCF: An Interactomic and Phylogenomic Analysis

Author

Peter Heger, Kamel Jabbari, Ranu Sharma, and Thomas Wiehe

Subjects
0301 basic medicine, Spo11, Biology, Article, General Biochemistry, Genetics and Molecular Biology, polymorphism, 03 medical and health sciences, Negative selection, Gene duplication, Bilateria, lcsh:Science, Transcription factor, Ecology, Evolution, Behavior and Systematics, Synteny, CTCF, gene duplication, chromatin loops, natural selection, Amniotes, Paleontology, Chromatin, 030104 developmental biology, Space and Planetary Science, Evolutionary biology, biology.protein, lcsh:Q, Homologous recombination
Abstract

The CCCTC-binding factor (CTCF) is multi-functional, ubiquitously expressed, and highly conserved from Drosophila to human. It has important roles in transcriptional insulation and the formation of a high-dimensional chromatin structure. CTCF has a paralog called “Brother of Regulator of Imprinted Sites” (BORIS) or “CTCF-like” (CTCFL). It binds DNA at sites similar to those of CTCF. However, the expression profiles of the two proteins are quite different. We investigated the evolutionary trajectories of the two proteins after the duplication event using a phylogenomic and interactomic approach. We find that CTCF has 52 direct interaction partners while CTCFL only has 19. Almost all interactors already existed before the emergence of CTCF and CTCFL. The unique secondary loss of CTCF from several nematodes is paralleled by a loss of two of its interactors, the polycomb repressive complex subunit SuZ12 and the multifunctional transcription factor TYY1. In contrast to earlier studies reporting the absence of BORIS from birds, we present evidence for a multigene synteny block containing CTCFL that is conserved in mammals, reptiles, and several species of birds, indicating that not the entire lineage of birds experienced a loss of CTCFL. Within this synteny block, BORIS and its genomic neighbors seem to be partitioned into two nested chromatin loops. The high expression of SPO11, RAE1, RBM38, and PMEPA1 in male tissues suggests a possible link between CTCFL, meiotic recombination, and fertility-associated phenotypes. Using the 65,700 exomes and the 1000 genomes data, we observed a higher number of intergenic, non-synonymous, and loss-of-function mutations in CTCFL than in CTCF, suggesting a reduced strength of purifying selection, perhaps due to less functional constraint.

Published
2018

14. Leveraging the Power of High Performance Computing for Next Generation Sequencing Data Analysis: Tricks and Twists from a High Throughput Exome Workflow

Author

Viktor Achter, Ulrich Lang, Lech Nieroda, Vishal Sinha, Wilfried Gunia, Amit Kawalia, Peter Nürnberg, Susanne Motameny, Stefan Borowski, Kamel Jabbari, Stephan Wonczak, and Holger Thiele

Subjects
Electronic Data Processing, Multidisciplinary, Computer science, lcsh:R, lcsh:Medicine, Computational Biology, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, Bioinformatics, Supercomputer, Computing Methodologies, Genomic databases, Genome, DNA sequencing, Workflow, Computer architecture, Humans, lcsh:Q, lcsh:Science, Exome, Exome sequencing, Research Article
Abstract

Next generation sequencing (NGS) has been a great success and is now a standard method of research in the life sciences. With this technology, dozens of whole genomes or hundreds of exomes can be sequenced in rather short time, producing huge amounts of data. Complex bioinformatics analyses are required to turn these data into scientific findings. In order to run these analyses fast, automated workflows implemented on high performance computers are state of the art. While providing sufficient compute power and storage to meet the NGS data challenge, high performance computing (HPC) systems require special care when utilized for high throughput processing. This is especially true if the HPC system is shared by different users. Here, stability, robustness and maintainability are as important for automated workflows as speed and throughput. To achieve all of these aims, dedicated solutions have to be developed. In this paper, we present the tricks and twists that we utilized in the implementation of our exome data processing workflow. It may serve as a guideline for other high throughput data analysis projects using a similar infrastructure. The code implementing our solutions is provided in the supporting information files.

Published
2015

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