Abstract

Recent developments in stem cell biology have enabled the study of cell fate decisions in early human development that are impossible to study in vivo. However, understanding how development varies across individuals and, in particular, the influence of common genetic variants during this process has not been characterised. Here, we exploit human iPS cell lines from 125 donors, a pooled experimental design, and single-cell RNA-sequencing to study population variation of endoderm differentiation. We identify molecular markers that are predictive of differentiation efficiency of individual lines, and utilise heterogeneity in the genetic background across individuals to map hundreds of expression quantitative trait loci that influence expression dynamically during differentiation and across cellular contexts.

Studying the genetic effects on early stages of human development is challenging due to a scarcity of biological material. Here, the authors utilise induced pluripotent stem cells from 125 donors to track gene expression changes and expression quantitative trait loci at single cell resolution during in vitro endoderm differentiation.

Details

Title
Single-cell RNA-sequencing of differentiating iPS cells reveals dynamic genetic effects on gene expression
Author
Cuomo Anna S E 1 ; Seaton, Daniel D 1   VIAFID ORCID Logo  ; McCarthy, Davis J 2   VIAFID ORCID Logo  ; Martinez, Iker 3 ; Bonder, Marc Jan 4 ; Garcia-Bernardo, Jose 5 ; Amatya Shradha 5 ; Madrigal, Pedro 6   VIAFID ORCID Logo  ; Isaacson, Abigail 7 ; Buettner Florian 1 ; Knights, Andrew 5   VIAFID ORCID Logo  ; Natarajan, Kedar Nath 8   VIAFID ORCID Logo  ; Agu, Chukwuma A 9 ; Alderton, Alex 9 ; Danecek Petr 9 ; Denton, Rachel 9 ; Durbin, Richard 9 ; Gaffney, Daniel J 9 ; Goncalves, Angela 9 ; Halai Reena 9 ; Harper, Sarah 9 ; Kirton, Christopher M 9 ; Kolb-Kokocinski Anja 9 ; Leha Andreas 9 ; McCarthy, Shane A 9 ; Memari Yasin 9 ; Patel Minal 9 ; Birney Ewan 1 ; Casale, Francesco Paolo 1 ; Clarke, Laura 1 ; Harrison, Peter W 1 ; Kilpinen Helena 1 ; Streeter, Ian 1 ; Denovi Davide 10 ; Meleckyte Ruta 10 ; Moens, Natalie 10 ; Watt, Fiona M 10 ; Ouwehand, Willem H 11 ; Lamond, Angus I 12 ; Bensaddek Dalila 12 ; Beales, Philip 13 ; Vallier Ludovic 14   VIAFID ORCID Logo  ; Marioni, John C 15   VIAFID ORCID Logo  ; Chhatriwala Mariya 16 ; Stegle Oliver 17 

1  European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, European Molecular Biology Laboratory, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726) 
2  European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, European Molecular Biology Laboratory, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726); St Vincent’s Institute of Medical Research, Fitzroy, Australia (GRID:grid.1073.5) (ISNI:0000 0004 0626 201X) 
3  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.1073.5) 
4  European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, European Molecular Biology Laboratory, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726); Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.225360.0) 
5  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.225360.0) 
6  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.225360.0); Anne McLaren Laboratory, University of Cambridge, Wellcome Trust—MRC Cambridge Stem Cell Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Department of Surgery, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Department of Haematology, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); GeneLab, AWG Multi-Omics/System Biology, NASA Ames Research Center, California, USA (GRID:grid.419075.e) (ISNI:0000 0001 1955 7990) 
7  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.419075.e) 
8  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.225360.0); Functional Genomics and Metabolism Unit, University of Southern Denmark, Danish Institute of Advanced Study (D-IAS), Odense, Denmark (GRID:grid.10825.3e) (ISNI:0000 0001 0728 0170) 
9  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.10825.3e) 
10  King’s College London, Strand Ln, London, United Kingdom (GRID:grid.13097.3c) (ISNI:0000 0001 2322 6764) 
11  University of Cambridge and National Health Service Blood and Transplant, Department of Haematology, Cambridge, United Kingdom (GRID:grid.5335.0) (ISNI:0000000121885934) 
12  University of Dundee, Centre for Gene Regulation and Expression, School of Life Sciences, Dundee, United Kingdom (GRID:grid.8241.f) (ISNI:0000 0004 0397 2876) 
13  University College London, Gower St, Bloomsbury, London, United Kingdom (GRID:grid.83440.3b) (ISNI:0000000121901201) 
14  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.83440.3b); Anne McLaren Laboratory, University of Cambridge, Wellcome Trust—MRC Cambridge Stem Cell Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934); University of Cambridge, Department of Surgery, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
15  European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, European Molecular Biology Laboratory, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726); Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.225360.0); University of Cambridge, Cancer Research UK Cambridge Institute, Cambridge, UK (GRID:grid.5335.0) (ISNI:0000000121885934) 
16  Wellcome Genome Campus, Wellcome Sanger Institute, Hinxton, UK (GRID:grid.5335.0) 
17  European Bioinformatics Institute, Wellcome Genome Campus, CB10 1SD Hinxton, European Molecular Biology Laboratory, Cambridge, UK (GRID:grid.225360.0) (ISNI:0000 0000 9709 7726); German Cancer Research Center (DKFZ), Division of Computational Genomics and Systems Genetics, Heidelberg, Germany (GRID:grid.7497.d) (ISNI:0000 0004 0492 0584); Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany (GRID:grid.4709.a) (ISNI:0000 0004 0495 846X) 
Publication year
2020
Publication date
2020
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-020-14457-z
ProQuest document ID
2352999507
Copyright
This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.