Single-cell, whole-embryo phenotyping of mammalian developmental disorders

Xingfan Huang, Jana Henck, Chengxiang Qiu, Varun K. A. Sreenivasan, Saranya Balachandran, Oana V. Amarie, Martin Hrabě de Angelis, Rose Yinghan Behncke, Wing-Lee Chan, Alexandra Despang, Diane E. Dickel, Madeleine Duran, Annette Feuchtinger, Helmut Fuchs, Valerie Gailus-Durner, Natja Haag, Rene Hägerling, Nils Hansmeier, Friederike Hennig, Cooper Marshall, Sudha Rajderkar, Alessa Ringel, Michael Robson, Lauren M. Saunders, Patricia Silva-Buttkus, Nadine Spielmann, Sanjay R. Srivatsan, Sascha Ulferts, Lars Wittler, Yiwen Zhu, Vera M. Kalscheuer, Daniel M. Ibrahim, Ingo Kurth, Uwe Kornak, Axel Visel, Len A. Pennacchio, David R. Beier, Cole Trapnell, Junyue Cao (), Jay Shendure () and Malte Spielmann ()
Additional contact information
Xingfan Huang: University of Washington
Jana Henck: University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University
Chengxiang Qiu: University of Washington
Varun K. A. Sreenivasan: University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University
Saranya Balachandran: University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University
Oana V. Amarie: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Martin Hrabě de Angelis: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Rose Yinghan Behncke: Institute of Medical Genetics and Human Genetics of the Charité
Wing-Lee Chan: Institute of Medical Genetics and Human Genetics of the Charité
Alexandra Despang: Max Planck Institute for Molecular Genetics
Diane E. Dickel: Lawrence Berkeley National Laboratory
Madeleine Duran: University of Washington
Annette Feuchtinger: Core Facility Pathology & Tissue Analytics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Helmut Fuchs: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Valerie Gailus-Durner: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Natja Haag: RWTH Aachen University
Rene Hägerling: Max Planck Institute for Molecular Genetics
Nils Hansmeier: Max Planck Institute for Molecular Genetics
Friederike Hennig: Max Planck Institute for Molecular Genetics
Cooper Marshall: University of Washington
Sudha Rajderkar: Lawrence Berkeley National Laboratory
Alessa Ringel: Max Planck Institute for Molecular Genetics
Michael Robson: Max Planck Institute for Molecular Genetics
Lauren M. Saunders: University of Washington
Patricia Silva-Buttkus: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Nadine Spielmann: Institute of Experimental Genetics, German Mouse Clinic, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH)
Sanjay R. Srivatsan: University of Washington
Sascha Ulferts: Institute of Medical Genetics and Human Genetics of the Charité
Lars Wittler: Max Planck Institute for Molecular Genetics
Yiwen Zhu: German Center for Diabetes Research (DZD)
Vera M. Kalscheuer: Max Planck Institute for Molecular Genetics
Daniel M. Ibrahim: Max Planck Institute for Molecular Genetics
Ingo Kurth: RWTH Aachen University
Uwe Kornak: University Medical Center Göttingen
Axel Visel: Lawrence Berkeley National Laboratory
Len A. Pennacchio: Lawrence Berkeley National Laboratory
David R. Beier: University of Washington
Cole Trapnell: University of Washington
Junyue Cao: The Rockefeller University
Jay Shendure: University of Washington
Malte Spielmann: University Medical Center Schleswig-Holstein, University of Lübeck & Kiel University

Nature, 2023, vol. 623, issue 7988, 772-781

Abstract: Abstract Mouse models are a critical tool for studying human diseases, particularly developmental disorders1. However, conventional approaches for phenotyping may fail to detect subtle defects throughout the developing mouse2. Here we set out to establish single-cell RNA sequencing of the whole embryo as a scalable platform for the systematic phenotyping of mouse genetic models. We applied combinatorial indexing-based single-cell RNA sequencing3 to profile 101 embryos of 22 mutant and 4 wild-type genotypes at embryonic day 13.5, altogether profiling more than 1.6 million nuclei. The 22 mutants represent a range of anticipated phenotypic severities, from established multisystem disorders to deletions of individual regulatory regions4,5. We developed and applied several analytical frameworks for detecting differences in composition and/or gene expression across 52 cell types or trajectories. Some mutants exhibit changes in dozens of trajectories whereas others exhibit changes in only a few cell types. We also identify differences between widely used wild-type strains, compare phenotyping of gain- versus loss-of-function mutants and characterize deletions of topological associating domain boundaries. Notably, some changes are shared among mutants, suggesting that developmental pleiotropy might be ‘decomposable’ through further scaling of this approach. Overall, our findings show how single-cell profiling of whole embryos can enable the systematic molecular and cellular phenotypic characterization of mouse mutants with unprecedented breadth and resolution.

Date: 2023
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DOI: 10.1038/s41586-023-06548-w

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