Deciphering the genetic control of gene expression following Mycobacterium leprae antigen stimulation
| Autor: | Guillaume Laval, Luis B. Barreiro, Yohann Nédélec, Erwin Schurr, Jeremy Manry, Vu Hong Thai, Vinicius M. Fava, Nguyen Van Thuc, Aurélie Cobat, Marianna Orlova |
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| Přispěvatelé: | McGill University = Université McGill [Montréal, Canada], CHU Sainte Justine [Montréal], CRSN/Faculté de médecine Université de Montréal, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Hospital for Tropical Diseases - HTD [Ho Chi Minh City, Vietnam], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Université de Montréal (UdeM), This work was supported by a Foundation grant from the Canadian Institutes of Health Research (CIHR FDN – 14332) to ES. This research was supported through resource allocation in the Guillimin high performance computing cluster by Compute Canada (www.computecanada.ca) and Calcul Québec (http://www.calculquebec.ca/) (jrt-675-01). JM was supported by a CIHR fellowship (MFE-127384) and in part by a grant from the Laboratory of Excellence Integrative Biology of Emerging Infectious Diseases (LabEx IBEID: http://www.pasteur.fr/labex/ibeid), We thank all leprosy patients who participated in this study. We thank the members of the Schurr lab and the members of the laboratory for Human Genetics of Infectious Diseases in Paris for useful discussions and suggestions on this work. We thank the members of the Human Evolutionary Genetics laboratory, Institut Pasteur, Paris, and especially Maxime Rotival for useful discussions and suggestions on this work., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Bidault, Floran, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS) |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Bacterial Diseases Cancer Research Genome-wide association study Genome-wide association studies MESH: Down-Regulation 0302 clinical medicine Human genetics Gene expression Medicine and Health Sciences MESH: Up-Regulation Pathogen Mycobacterium leprae Genetics of disease Genetics (clinical) MESH: Genetic Association Studies Genetics Principal Component Analysis MESH: Polymorphism Single Nucleotide MESH: Genetic Predisposition to Disease Genomics 3. Good health Up-Regulation Actinobacteria RNA Bacterial Infectious Diseases Host-Pathogen Interactions Gene ontologies [SDV.IMM]Life Sciences [q-bio]/Immunology Leprosy MESH: RNA Bacterial Research Article Neglected Tropical Diseases lcsh:QH426-470 [SDV.IMM] Life Sciences [q-bio]/Immunology Quantitative Trait Loci Immunology Down-Regulation [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics Biology Polymorphism Single Nucleotide 03 medical and health sciences Immune system medicine Humans Genetic Predisposition to Disease Immune response Molecular Biology Gene Ecology Evolution Behavior and Systematics Genetic Association Studies MESH: Principal Component Analysis Antigens Bacterial MESH: Humans Bacteria MESH: Host-Pathogen Interactions Organisms Biology and Life Sciences Computational Biology medicine.disease biology.organism_classification Tropical Diseases Genome Analysis MESH: Quantitative Trait Loci MESH: Leprosy lcsh:Genetics 030104 developmental biology [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics Expression quantitative trait loci MESH: Mycobacterium leprae 030217 neurology & neurosurgery MESH: Antigens Bacterial |
| Zdroj: | PLoS Genetics PLoS Genetics, Public Library of Science, 2017, 13 (8), pp.e1006952. ⟨10.1371/journal.pgen.1006952⟩ PLoS Genetics, 2017, 13 (8), pp.e1006952. ⟨10.1371/journal.pgen.1006952⟩ PLoS Genetics, Vol 13, Iss 8, p e1006952 (2017) |
| ISSN: | 1553-7390 1553-7404 |
| Popis: | Leprosy is a human infectious disease caused by Mycobacterium leprae. A strong host genetic contribution to leprosy susceptibility is well established. However, the modulation of the transcriptional response to infection and the mechanism(s) of disease control are poorly understood. To address this gap in knowledge of leprosy pathogenicity, we conducted a genome-wide search for expression quantitative trait loci (eQTL) that are associated with transcript variation before and after stimulation with M. leprae sonicate in whole blood cells. We show that M. leprae antigen stimulation mainly triggered the upregulation of immune related genes and that a substantial proportion of the differential gene expression is genetically controlled. Indeed, using stringent criteria, we identified 318 genes displaying cis-eQTL at an FDR of 0.01, including 66 genes displaying response-eQTL (reQTL), i.e. cis-eQTL that showed significant evidence for interaction with the M. leprae stimulus. Such reQTL correspond to regulatory variations that affect the interaction between human whole blood cells and M. leprae sonicate and, thus, likely between the human host and M. leprae bacilli. We found that reQTL were significantly enriched among binding sites of transcription factors that are activated in response to infection, and that they were enriched among single nucleotide polymorphisms (SNPs) associated with susceptibility to leprosy per se and Type-I Reaction, and seven of them have been targeted by recent positive selection. Our study suggested that natural selection shaped our genomic diversity to face pathogen exposure including M. leprae infection. Author summary Each year, 200,000 new leprosy cases are reported worldwide. While there is unambiguous evidence for a role of host genetics in leprosy pathogenesis, the mechanisms by which the human host fights the infection are poorly understood. Here, we highlight the search for naturally occurring genetic variations that modulate gene expression levels following exposure to sonicate of Mycobacterium leprae, the bacterium causing the disease. Because M. leprae is not cultivable and the genuine immune cells involved in the host response during infection are still unknown, we performed a genome-wide search for such genetic variations after stimulation of whole-blood from leprosy patients with M. leprae sonicate. This design allowed to provide a general framework for the genetic control of host responses to M. leprae and outlined the contribution of host genetics to leprosy pathogenesis. Among the M. leprae-dependent genetic regulators of gene expression levels there was an enrichment of variants (i) associated with leprosy, (ii) located in transcription factor binding sites and (iii) targeted by recent positive selection. |
| Databáze: | OpenAIRE |
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