Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download 1% Allele frequency of variant +++ + ++ Clinical impact
Document related concepts
no text concepts found
Transcript
Personalized Health Symposium 22 Sept 2016 Human Genomics of Infection and Immunity Jacques Fellay EPFL School of Life Sciences Swiss Institute of Bioinformatics Service of Infectious Diseases, CHUV @jacques.fellay © ALAIN HERZOG Exploiting human genetic variation to improve human health Identification of relevant genetic variant Prediction models Understanding of underlying biology Individualized healthcare New drug or vaccine targets Allele frequency of variant <<1% >1-3% Sequencing +++ Hunting for host genetic variants ++ Clinical impact Genotyping + Allele frequency of variant <<1% viral Fulminant hepatitis Opportunistic infections & cancers Severe viral respiratory infections Pediatric sepsis Generation of broadly neutralizing antibodies Ectyma gangrenosum +++ >1-3% Spontaneous control of HIV Decay of the ++ HIV reservoir Clinical impact IgG responses to common infections Chronic viral hepatitis + Severe viral respiratory infections • 1-2% hospitalization • 10% PICU admission • 50% no known risk factors <1 in 1000 live birth Healthy children who develop unusually severe symptoms upon infection with common respiratory viruses carry rare causal genetic defects Study participants Inclusion criteria Consent of legal guardian Age 0-3 years Ventilation support needed Exclusion criteria ! ! ! ! ! Prematurity Immunosuppression Chronic disease Sickle cell anemia Comorbidity 120 samples (blood for DNA & RNA + NPA) Exome sequencing, RNA sequencing, viral PCR Patient recruitment Target enrichment Variant calling CAA GTA AAC ATA GGA CTT CTT CAA GTA AAC ATA GGA CAT CTT DNA extraction and normalization Exome sequencing Pathogen sequencing Variant annotation & frequency estimation G>A ExAC Stop-gain DNA pooling and bar-coding Short read alignment Functional characterization & experimental confirmation Putative loss-of-function variants in the IFIH1 gene Splice-site 1 hom, 3 het Stop-gained 1 het Splice-site 3 het IFIH1 (MDA5) is a pattern recognition receptor for long dsRNA Reikine S. et al. Front Immunol, 2014 IFIH1-Δ8: 39 aa missing IFIH1-Δ14: 153 aa missing IFIH1-ΔCTD: 399 aa missing Protein expression in vivo Both IFIH1-wt and IFIH1-Δ14 are expressed in BPMCs upon RSV infection Protein stability IFIH1-LoFs are less stable & they reduce wt stability Interferon β induction IFIH1-LoFs cannot induce IFNβ and interfere with wt function LoF variants in IFIH1 cause a pathogenspecific primary immunodeficiency • Scientific relevance: human genetics informs on immunological principles, which can help identify therapeutic or vaccine targets • Clinical relevance: immediate impact for patients and families, potential inclusion in screening programs Clinical impact Clinical observation Functional follow-up Recruitment, sample collection Genomics, transcriptomics Samira Asgari Istvan Bartha Chris Hammer Christian Thorball Petar Scepanovic Nimisha Chaturvedi Olivier Naret Thomas Junier Alessandro Borghesi Flavia Hodel Study participants & families, Pediatric ICUs Dominique Garcin and Caroline Tapparel, University of Geneva Keith Harshman & team, Lausanne Genomic Technologies Facility Ioannis Xenarios & team, Vital-IT Computing Center
Related documents