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Extreme Genomics: The influence of human genetic variation and pathogen sequence diversity on extreme phenotypes caused by viral infections

English title Extreme Genomics: The influence of human genetic variation and pathogen sequence diversity on extreme phenotypes caused by viral infections
Applicant Fellay Jacques
Number 157529
Funding scheme SNSF Professorships
Research institution Global Health Institute EPFL-SV-GHI
Institution of higher education EPF Lausanne - EPFL
Main discipline Genetics
Start/End 01.04.2015 - 31.03.2017
Approved amount 753'554.00
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All Disciplines (2)

Discipline
Genetics
Infectious Diseases

Keywords (6)

Sequencing; Transcriptomics; Human genome; Infectious diseases; Genomics; Host-pathogen interactions

Lay Summary (French)

Lead
L’objectif de ce projet est de comprendre l’influence des variations génétiques humaines et virales sur les formes les plus sévères d’infections virales.
Lay summary

Contenu et objectifs du travail de recherche
Une infection virale peut être décrite comme un combat entre deux génomes : celui de l’hôte et celui du virus. Grâce à de récentes avancées dans les domaines de la génomique et de la bioinformatique, il est désormais possible d’étudier de manière globale les variations génétiques humaines et virales qui peuvent avoir une influence sur la sévérité d’une infection. Dans ce projet, nous analyserons des échantillons obtenus chez des patients qui ont développé une maladie exceptionnellement sévère après infection par un virus respiratoire, le virus de l’immunodéficience humaine (VIH) ou le virus de l’hépatite B (VHB). Nous utiliserons des technologies de séquençage à très haut débit de l’ADN et de l’ARN pour obtenir un catalogue des variations génétiques humaines et virales potentiellement impliquées dans la symptomatologie. Les variations les plus intéressantes seront validées et caractérisées sur le plan fonctionnel.  

Contexte scientifique et social du projet de recherche
Les infections virales ont une importance cruciale en santé publique. La mise en évidence de variations génétiques responsables de maladies particulièrement sévères pourrait conduire à l’identification de nouveaux mécanismes de défense contre les virus, et à l’élaboration de stratégies diagnostiques et thérapeutiques innovantes.

 

Direct link to Lay Summary Last update: 05.05.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Familial segregation of group B streptococcal infection in a consanguineous kindred.
Fellay Jacques (2016), Familial segregation of group B streptococcal infection in a consanguineous kindred., in Int J Infect Dis, 51, 22.
Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis.
Fellay Jacques (2016), Exome Sequencing Reveals Primary Immunodeficiencies in Children with Community-Acquired Pseudomonas aeruginosa Sepsis., in Front Immunol., 7(357), n/a.
The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals.
Fellay Jacques (2015), The interplay between host genetic variation, viral replication and microbial translocation in untreated HIV-infected individuals., in J Infect Dis, 212(4), 578.
Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses
Hammer C., Begemann M., McLaren P.J., Bartha I., Michel A., Klose B., Schmitt C., Waterboer T., Pawlita M., Schulz T.F., Ehrenreich H., Fellay J. (2015), Amino acid variation in HLA class II proteins is a major determinant of humoral response to common viruses, in American Journal of Human Genetics, 97(5), 738-743.
Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load
McLaren P.J., Coulonges C., Bartha I., Lenz T.L., Deutsch A.J., Bashirova A., Buchbinder S., Carrington M.N., Cossarizza A., Dalmau J., De Luca A., Goedert J.J., Gurdasani D., Haas D.W., Herbeck J.T., Johnson E.O., Kirk G.D., Lambotte O., Luo M., Mallal S., Van Manen D., Martinez-Picado J., Meyer L., Miro J.M., Mullins J.I. (2015), Polymorphisms of large effect explain the majority of the host genetic contribution to variation of HIV-1 virus load, in Proceedings of the National Academy of Sciences of the United States of America, 112(47), 14658-14663.

Collaboration

Group / person Country
Types of collaboration
Keith Harshman / Lausanne Genomic Technologies Facility Switzerland (Europe)
- Research Infrastructure
Ioannis Xenarios / Vital-IT, Swiss Institute of Bioinformatics Switzerland (Europe)
- Research Infrastructure
Swiss HIV Cohort Study Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dominique Garcin / University of Geneva Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Awards

Title Year
Leenaards Prize for translational medical research 2015

Associated projects

Number Title Start Funding scheme
133703 Host genomics of extreme phenotypes caused by common viral diseases: genome sequencing in children with severe respiratory infections 01.04.2011 SNSF Professorships

Abstract

Susceptibility or resistance to infection is the final result of dynamic interactions between host, pathogen and environment. In clinically relevant viral diseases, the genetic constitutions of both the infected patient and the invading virus are essential determinants of symptoms and outcome. Because it is now feasible to scan entire genomes in an unbiased manner, the respective and combined impact of host and pathogen genetic diversity on viral diseases can be comprehensively assessed.The first 4 years of SNSF Professorship support allowed my group to start an in-depth exploration of the influence of human genomic variation on viral respiratory infections in children, using an “extreme phenotype” study design. We recruited previously healthy patients, admitted to a pediatric intensive care unit following infections by common respiratory viruses (e.g. respiratory syncytial virus, rhinovirus or influenza virus), and searched for deleterious variants in exome and RNA sequencing data. The project served as a catalyst for the creation of an efficient sequencing pipeline and the development of novel bioinformatic methods for DNA and RNA analysis. In addition, in an exciting demonstration of the potential of the proposed approach, we recently identified rare deleterious mutations in genes involved in intra-cytoplasmic recognition of viral nucleic acids, which could explain the exceptional disease severity in some study subjects. I here propose to build on our promising results and to take advantage of the increased throughput and dropping cost of sequencing to further develop host and viral genomic analyses. My plan is to complete the human genomic analysis of viral respiratory infections, to run in-depth analyses of the viral genomes, and to broaden the scope of the study by including extreme phenotypes caused by two additional viruses of major public health importance: hepatitis B virus (HBV), and human immunodeficiency virus (HIV), which has already been the focus of much attention in my group. All putatively causal variants identified in the different genome-wide scans will then be validated and functionally characterized to confirm their biological impact and assess their clinical relevance.The systematic study of human and viral genetic diversity represents a new frontier in the exploration of phenotypic variation. It has the potential to improve our understanding of host-pathogen interactions and of disease pathogenesis. Consequently, the findings of this program could help develop novel diagnostic tools, preventive strategies and therapeutic interventions, and contribute to the growth of personalized medicine in infectious diseases.
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