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Mapping interindividual dynamics of innate immune response at single-cell resolution
Natsuhiko Kumasaka; Raghd Rostom; Ni Huang; Krzysztof Polanski; Kerstin Meyer; Sharad Patel; Rachel Boyd; Celine Gomez; Sam Barnett; Nikolaos Panousis; Jeremy Schwartzentruber; Maya Ghoussaini; Paul A. Lyons; Fernando J. Calero-Nieto; Berthold Göttgens; Josephine L. Barnes; Kaylee B. Worlock; Masahiro Yoshida; Marko Nikolic; Emily Stephenson; Gary Reynolds; Muzlifah Haniffa; John Marioni; Oliver Stegle; Tzachi Hagai; Sarah A. Teichmann.
Afiliación
  • Natsuhiko Kumasaka; Wellcome Trust Sanger Institute
  • Raghd Rostom; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Ni Huang; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Krzysztof Polanski; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Kerstin Meyer; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Sharad Patel; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Rachel Boyd; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Celine Gomez; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Sam Barnett; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Nikolaos Panousis; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Jeremy Schwartzentruber; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Maya Ghoussaini; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
  • Paul A. Lyons; Cambridge Institute of Therapeutic Immunology and Infectious Disease, Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Cambridge, UK
  • Fernando J. Calero-Nieto; Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
  • Berthold Göttgens; Wellcome - MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK
  • Josephine L. Barnes; UCL Respiratory, Division of Medicine, University College London, London, UK
  • Kaylee B. Worlock; UCL Respiratory, Division of Medicine, University College London, London, UK
  • Masahiro Yoshida; UCL Respiratory, Division of Medicine, University College London, London, UK
  • Marko Nikolic; UCL Respiratory, Division of Medicine, University College London, London, UK
  • Emily Stephenson; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
  • Gary Reynolds; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
  • Muzlifah Haniffa; Biosciences Institute, Newcastle University, Newcastle upon Tyne, UK
  • John Marioni; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
  • Oliver Stegle; European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK
  • Tzachi Hagai; Shmunis School of Biomedicine and Cancer Research, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel
  • Sarah A. Teichmann; Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, UK
Preprint en En | PREPRINT-BIORXIV | ID: ppbiorxiv-457774
ABSTRACT
Common genetic variants modulate the cellular response to viruses and are implicated in a range of immune pathologies, including infectious and autoimmune diseases. The transcriptional antiviral response is known to vary between infected cells from a single individual, yet how genetic variants across individuals modulate the antiviral response (and its cell-to-cell variability) is not well understood. Here, we triggered the antiviral response in human fibroblasts from 68 healthy donors, and profiled tens of thousands of cells using single-cell RNA-seq. We developed GASPACHO (GAuSsian Processes for Association mapping leveraging Cell HeterOgeneity), the first statistical approach designed to identify dynamic eQTLs across a transcriptional trajectory of cell populations, without aggregating single-cell data into pseudo-bulk. This allows us to uncover the underlying architecture and variability of antiviral response across responding cells, and to identify more than two thousands eQTLs modulating the dynamic changes during this response. Many of these eQTLs colocalise with risk loci identified in GWAS of infectious and autoimmune diseases. As a case study, we focus on a COVID-19 susceptibility locus, colocalised with the antiviral OAS1 splicing QTL. We validated it in blood cells from a patient cohort and in the infected nasal cells of a patient with the risk allele, demonstrating the utility of GASPACHO to fine-map and functionally characterise a genetic locus. In summary, our novel analytical approach provides a new framework for delineation of the genetic variants that shape a wide spectrum of transcriptional responses at single-cell resolution.
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Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Tipo de estudio: Cohort_studies / Observational_studies / Prognostic_studies Idioma: En Año: 2021 Tipo del documento: Preprint
Texto completo
Añadir a Mi BVS
Imprimir
XML
Buscar en Google
Texto completo: 1 Colección: 09-preprints Base de datos: PREPRINT-BIORXIV Tipo de estudio: Cohort_studies / Observational_studies / Prognostic_studies Idioma: En Año: 2021 Tipo del documento: Preprint