Project
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All Disciplines (3)
Keywords (10)
graphical models; haplotype inference; HIV-1; virus evolution; next-generation sequencing; genome assembly; antiretroviral therapy; ultra-deep sequencing; drug resistance; Bayesian statistics
Lay Summary (German)
Lead
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Viele Krankheitserreger existieren innerhalb eines befallenen Wirtsorganismus als sehr heterogenen Populationen. Diese genetische Vielfalt ist oft mitverantwortlich für einen schlechten Krankheitsverlauf, für das Versagen der körpereigenen Immunabwehr und für die Unwirksamkeit von Medikamenten aufgrund von Resistenzen. Für eine optimale Behandlung von Infektionskrankheiten ist daher die genaue Bestimmung der genetische Diversität der Pathogenpopulation eine notwendige Voraussetzung.
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Lay summary
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Inhalt und Ziel des Forschungsprojekts In diesem Projekt benutzen wir moderne Hochdurchsatz-DNA-Sequenziertechnologien für die genetische Analyse von Viruspopulationen in HIV-infizierten Patienten. Unser Ziel ist es, die Virus-Diagnostik und –Behandlung zu verbessern. Dazu werden wir isolierte HIV-Populationen (sogenannte Quasispezies) genomweit rekonstruieren, einschliesslich niederfrequenter genetischer Varianten, die für den Therapieerfolg wichtig sein können. Das interdisziplinäre Projekt umfasst den Entwurf und die Implementierung sowohl experimenteller Protokolle als auch bioinformatischer Methoden für die Datenanalyse, sowie deren klinische Anwendung. Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts Unsere Arbeit ist ein Beitrag zur personalisierten Medizin im Bereich der Infektionskrankheiten. Mit den hier entwickelten Methoden werden Pathogenpopulationen weitaus detailreicher charakterisiert und Therapieoptionen genauer bestimmt werden können.
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Responsible applicant and co-applicants
Employees
Collaboration
Christian Beisel (ETH Zurich, D-BSSE) |
Switzerland (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Publication |
Osvaldo Zagordi (University of Zurich) |
Switzerland (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results |
Alexander Schönhuth (CWI, Amsterdam) |
Netherlands (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Publication |
Fabio Luciani (UNSW) |
Australia (Oceania) |
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- in-depth/constructive exchanges on approaches, methods or results - Publication |
Ralph Schlapbach (Functional Genomics Center Zurich) |
Switzerland (Europe) |
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- Research Infrastructure |
Martin Däumer (Institut fuer Immunologie und Genetik, Kaiserslautern) |
Germany (Europe) |
Tobias Marschall (MPI Informatik, Saarbruecken) |
Germany (Europe) |
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- in-depth/constructive exchanges on approaches, methods or results - Publication |
Thomas J. Fuchs (California Institute of Technology) |
United States of America (North America) |
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- in-depth/constructive exchanges on approaches, methods or results |
Scientific events
Active participation
Title |
Type of contribution |
Title of article or contribution |
Date |
Place |
Persons involved |
4th ICCABS (IEEE)
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Talk given at a conference
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Viral quasispecies assembly from paired-end reads
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02.06.2014
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Miami, FL, United States of America
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Töpfer Armin;
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International Symposium on the Control and Eradication of Viral Hepatitis B and C
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Talk given at a conference
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Challenges of ultra-deep sequencing for studying low-frequency mutants
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30.05.2014
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Barcelona, Spain
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Beerenwinkel Niko;
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RECOMB 2014
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Talk given at a conference
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Viral quasispecies assembly via maximal clique enumeration
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02.04.2014
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Pittsburgh, PA , United States of America
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Töpfer Armin;
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Mathematical, Statistical and Computational Aspects of Metagenomics Workshop,
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Talk given at a conference
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Estimating within-host viral genetic diversity from next-generation sequencing data
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24.03.2014
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Issac Newton Institute, Cambridge, UK, Great Britain and Northern Ireland
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Beerenwinkel Niko;
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Swiss Meeting for Infectious Disease Dynamics (SMIDDY)
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Talk given at a conference
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Global haplotype prediction of HIV-1
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13.09.2013
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Zurich, Switzerland
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Töpfer Armin;
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EMBO workshop on Integrating Omics Approaches to Understand Host Cell Pathogen Interactions
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Talk given at a conference
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Estimating the genetic diversity of pathogens from next-generation sequencing data
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25.06.2013
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Liverpool, Great Britain and Northern Ireland
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Beerenwinkel Niko;
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3rd ICCABS (IEEE)
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Talk given at a conference
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Probing of viral diversity by global haplotype prediction
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12.06.2013
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New Orleans, United States of America
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Töpfer Armin;
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2nd CHAIN Next Generation Sequencing Working Group Meeting
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Talk given at a conference
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Computational and Statistical Challenges of Ultradeep Sequencing of Viral Quasispecies
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22.05.2013
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Rome, Italy
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Metzner Karin; Töpfer Armin;
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Statistical Genomics and Data Integration for Personalized Medicine
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Poster
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Probing of viral diversity by global haplotype prediction
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12.05.2013
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Ascona, Switzerland
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Roth Volker; Töpfer Armin; Beerenwinkel Niko;
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Self-organised
Awards
CROI Young Investigator Scholarship
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2014
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Associated projects
Number |
Title |
Start |
Funding scheme |
148522
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Swiss HIV Cohort Study (SHCS) |
01.01.2014 |
Cohort Studies Large |
127017
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HIV-1 whole-genome quasispecies analysis by ultra-deep sequencing and computational haplotype inference to determine the mechanisms of drug resistance development |
01.01.2010 |
Interdisciplinary projects |
159868
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HIV-1 Transmission in Switzerland: viral transmission traits, superinfection and drug resistance |
01.05.2015 |
Project funding (special) |
Abstract
Genetic diversity is a hallmark of pathogen populations, associated with disease progression, immune escape, and drug resistance. We propose to use next-generation sequencing (NGS) for the analysis of viral populations within infected patients to improve viral diagnostics and treatment decisions by reconstructing the entire population structure, including low-frequency mutants and co-occurring mutations.Based on the achievements in the predecessor project (CR32I2_127017), we will develop experimental protocols and computational methods for the analysis of NGS data obtained from intra-patient HIV-1 populations. Our goal is to infer the haplotype sequences and their frequencies over the full length of the 9.2 kb HIV genome. Since the limited read length of current NGS platforms turned out to be the main bottleneck in this endeavor, we will develop two major extensions of our software tools ‘PredictHaplo’ and ‘QuasiRecomb’ to address this limitation. Firstly, we will use Illumina’s paired-end option to generate read pairs of 2x250bp length covering the HIV genome. These data are informative about long-range phasing of single-nucleotide variants (SNVs) and will be integrated into probabilistic global haplotype reconstruction using either soft constraints on SNV linkage (PredictHaplo) or silent delete states for the insert (QuasiRecomb). Secondly, we will explore Pacific Biosciences’ PacBio RS technology as an alternative long-read sequencing platform with an average read length of 1,500 bp. Using these improved experimental and computational tools, we will analyze and interpret genetic diversity in the context of HIV-1 drug resistance. Specifically, 100 samples from 40 patients will be analyzed for pre- versus post-treatment changes of viral populations, for low-frequency drug resistant variants and their role in treatment failure, for linkage among drug resistance mutations and evolutionary escape pathways, for recombinants, and for viral phenotypes such as drug resistance and co-receptor usage. Our full-length haplotype approach provides, for the first time, a complete picture of the virus population and will yield new insights into drug resistance development.
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