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Adversarial domain translation networks for integrating large-scale atlas-level single-cell datasets

Nature Computational Science volume 2, pages 317–330 (2022)Cite this article

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A preprint version of the article is available at bioRxiv.

Abstract

The rapid emergence of large-scale atlas-level single-cell RNA-seq datasets presents remarkable opportunities for broad and deep biological investigations through integrative analyses. However, harmonizing such datasets requires integration approaches to be not only computationally scalable, but also capable of preserving a wide range of fine-grained cell populations. We have created Portal, a unified framework of adversarial domain translation to learn harmonized representations of datasets. When compared to other state-of-the-art methods, Portal achieves better performance for preserving biological variation during integration, while achieving the integration of millions of cells, in minutes, with low memory consumption. We show that Portal is widely applicable to integrating datasets across different samples, platforms and data types. We also apply Portal to the integration of cross-species datasets with limited shared information among them, elucidating biological insights into the similarities and divergences in the spermatogenesis process among mouse, macaque and human.

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Fig. 1: Overview of Portal.
Fig. 2: Benchmarking study.
Fig. 3: Preservation of fine-grained neuron subpopulations.
Fig. 4: Construction of the mouse cell atlas across the entire organism.
Fig. 5: Integration of scRNA-seq and scATAC-seq data.
Fig. 6: Integration of spermatogenesis datasets across species.

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Data availability

All data used in this work are publicly available from online sources as follows: for mouse brain cells from ref. 8 (http://dropviz.org), ref. 9 (http://mousebrain.org/downloads.html) and ref. 34 (GSE110823), the mouse cell atlas from the Tabula Muris Consortium7 (https://figshare.com/projects/Tabula_Muris_Transcriptomic_characterization_of_20_organs_and_tissues_from_Mus_musculus_at_single_cell_resolution/27733) and the mouse lemur cell atlas from the Tabula Microcebus Consortium31 (https://figshare.com/projects/Tabula_Microcebus/112227); for human PBMCs from ref. 39 (GSE156478), ref. 53 (GSE132044) and 10X Genomics35 (https://support.10xgenomics.com/single-cell-gene-expression/datasets/1.1.0/pbmc3k); for mouse spermatogenesis cells from ref. 45 (https://www.ebi.ac.uk/arrayexpress/experiments/E-MTAB-6946/); for human spermatogenesis cells from ref. 42 (GSE142585); for macaque spermatogenesis cells from ref. 42 (GSE142585); for hematopoietic stem cells from ref. 54 (GSE72857) and ref. 55 (GSE81682); for reprogramming of induced pluripotent stem cells from ref. 56 (GSE122662); for human brain cells from ref. 36 (GSE164485) and ref. 37 (https://github.com/LieberInstitute/10xPilot_snRNAseq-human#work-with-the-data). Source data are provided with this paper.

Code availability

Portal software is available at https://github.com/YangLabHKUST/Portal. The codes for reproducing the results are available at https://github.com/jiazhao97/Portal-reproducibility. All codes are deposited in Zenodo repositories57,58.

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Acknowledgements

We acknowledge grants as follows: Hong Kong Research Grant Council grants nos. 16307818, 16301419 and 16308120, Hong Kong University of Science and Technology’s startup grant no. R9405, Guangdong-Hong Kong-Macao Joint Laboratory grant no. 2020B1212030001 and the RGC Collaborative Research Fund grant no. C6021-19EF to C.Y.; Hong Kong Research Grant Council grant no. 16101118, Hong Kong University of Science and Technology’s startup grant no. R9364 and the Lo Ka Chung Foundation through the Hong Kong Epigenomics Project and the Chau Hoi Shuen Foundation to A.R.W.; the Hong Kong University of Science and Technology Big Data for Bio Intelligence Laboratory (BDBI), the Hong Kong University of Science and Technology Center for Aging Science Research Program to C.Y. and A.R.W.; Hong Kong Research Grant Council grants nos. 24301419 and 14301120, the Chinese University of Hong Kong’s startup grant no.4930181 to Z.L.; the Shanghai Sailing Program grant no. 21YF140600 to J.M.

Author information

Author notes

  1. These authors contributed equally: Jia Zhao, Gefei Wang.

Authors and Affiliations

  1. Department of Mathematics, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Jia Zhao, Gefei Wang, Yang Wang, Gefei Wang, Can Yang, Jia Zhao & Can Yang

  2. Academy of Statistics and Interdisciplinary Sciences, KLATASDS-MOE, East China Normal University, Shanghai, China

    Jingsi Ming & Jingsi Ming

  3. Department of Statistics, The Chinese University of Hong Kong, Hong Kong SAR, China

    Zhixiang Lin

  4. Guangdong-Hong Kong-Macao Joint Laboratory for Data-Driven Fluid Mechanics and Engineering Applications, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Yang Wang, Can Yang & Can Yang

  5. Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Qiuyu Jing, Angela Ruohao Wu, Jinxurong Yang & Angela Ruohao Wu

  6. Department of Chemical and Biological Engineering, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Angela Ruohao Wu & Angela Ruohao Wu

  7. Center for Aging Science, The Hong Kong University of Science and Technology, Hong Kong SAR, China

    Angela Ruohao Wu & Angela Ruohao Wu

  8. Chan Zuckerberg Biohub, San Francisco, CA, USA

    Snigdha Agarwal, Aditi Agrawal, Kyle Awayan, Olga Botvinnik, Sheela Crasta, Spyros Darmanis, Kerwyn Casey Huang, Shelly Huynh, Carly Israel, Jim Karkanias, Aaron McGeever, Maurizio Morri, Saba Nafees, Norma Neff, Jennifer Okamoto, Lolita Penland, Angela Oliveira Pisco, Stephen R. Quake, Rene Sit, Weilun Tan, Alexander Tarashansky, Venkata Naga Pranathi Vemuri, James Webber, Jia Yan & Brian Yu

  9. Department of Ophthalmology, Stanford University School of Medicine, Stanford, CA, USA

    Ahmad Al-Moujahed, Shravani Mukherjee, Bronwyn Scott, Varun Ramanan Subramaniam, Aditi Swarup, Albert Y. Wu & Bao Xiang

  10. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Alina Alam, Thomas Ambrosi, Jane Antony, Philip Beachy, Charles Chan, Michael F. Clarke, Malachia Hoover, Aaron Kershner, William Kong, Wan-Jin Lu, Karim Mrouj, Zhen Qi &  Sivakamasundari V

  11. Department of Comparative Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Megan A. Albertelli, Kerriann M. Casey, Elias Godoy & Zicheng Zhao

  12. Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Paul Allegakoen, Franklin W. Huang & Hannah Weinstein

  13. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA

    Steven Artandi, Kazuteru Hasegawa & Patrick Neuhöfer

  14. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Steven Artandi, Kazuteru Hasegawa, Seung K. Kim, Patrick Neuhöfer & Patricia Nguyen

  15. Department of Biochemistry, Stanford University School of Medicine, Stanford, CA, USA

    Steven Artandi, Jalal Baruni, Stephen Chang, Roozbeh Dehghannasiri, F. Hernán Espinoza, Camille Ezran, James E. Ferrell Jr, Astrid Gillich, Kazuteru Hasegawa, SoRi Jang, Caitlin J. Karanewsky, Aaron Kershner, Silvana Konermann, Mark A. Krasnow, Peng Li, Shixuan Liu, Yin Liu, Ahmad Nabhan, Patrick Neuhöfer, Youcef Ouadah, Jozeph L. Pendleton, Julia Salzman, Kyle J. Travaglini, Avin Veerakumar & Andrea R. Yung

  16. Adaptive Mechanisms and Evolution (MECADEV), UMR 7179, National Center for Scientific Research, National Museum of Natural History, Brunoy, France

    Fabienne Aujard, Jacques Epelbaum, Martine Perret & Jérémy Terrien

  17. Department of Biology, Stanford University, Stanford, CA, USA

    Ankit Baghel, Jalal Baruni, Liqun Luo & Yue Zhang

  18. Department of Medicine, Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA

    Isaac Bakerman & Stephen Chang

  19. Human Cell Types Department, Allen Institute for Brain Science, Seattle, WA, USA

    Trygve E. Bakken, Song-Lin Ding, Rebecca D. Hodge & Ed S. Lein

  20. Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University School of Medicine, Stanford, CA, USA

    Jalal Baruni

  21. Howard Hughes Medical Institute, Chevy Chase, MD, USA

    Jalal Baruni, Stephen Chang, Connor V. Duffy, F. Hernán Espinoza, Camille Ezran, Astrid Gillich, SoRi Jang, Caitlin J. Karanewsky, Silvana Konermann, Mark A. Krasnow, Peng Li, Shixuan Liu, Yin Liu, Liqun Luo, Ahmad Nabhan, Jozeph L. Pendleton, Kyle J. Travaglini, Avin Veerakumar, Andrea R. Yung, Yue Zhang & Zicheng Zhao

  22. Department of Developmental Biology, Stanford University School of Medicine, Stanford, CA, USA

    Philip Beachy, Charles A. Chang, Margaret Fuller, Yan Hang, Seung K. Kim & Hosu Sin

  23. Department of Urology, Stanford University School of Medicine, Stanford, CA, USA

    Philip Beachy

  24. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA

    Philip Beachy, James E. Ferrell Jr & Shixuan Liu

  25. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA

    Biter Bilen, Jean Farup, Jengmin Kang, Song Eun Lee, Antoine de Morree, Thomas A. Rando, Nicholas Schaum, Andoni Urtasun & Tony Wyss-Coray

  26. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA

    Scott D. Boyd, Hannah K. Frank, Dita Gratzinger, Jonathan Z. Long, Katherine Lucot, Tom Montine & Amanda L. Wiggenhorn

  27. Department of Medicine and Liver Center, University of California San Francisco, San Francisco, CA, USA

    Deviana Burhan, Honor Paine, Aris Taychameekiatchai & Bruce Wang

  28. Stanford Diabetes Research Center, Stanford, CA, USA

    Charles A. Chang, Yan Hang & Seung K. Kim

  29. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA

    Ming Chen, Rebecca Culver, Connor V. Duffy, Margaret Fuller, Lily Kim & Douglas Vollrath

  30. Division of Cardiovascular Medicine, Stanford University, Stanford, CA, USA

    Jessica D’Addabbo & Patricia Nguyen

  31. Stanford Cardiovascular Institute, Stanford, CA, USA

    Jessica D’Addabbo & Patricia Nguyen

  32. Department of Biomedical Data Science, Stanford University, Stanford, CA, USA

    Roozbeh Dehghannasiri & Julia Salzman

  33. Unité Mixte de Recherche en Santé 894 INSERM, Centre de Psychiatrie et Neurosciences, Université Paris Descartes, Paris, France

    Jacques Epelbaum

  34. Department of Biomedicine, Aarhus University, Aarhus, Denmark

    Jean Farup & Antoine de Morree

  35. Department of Ecology and Evolutionary Biology, Tulane University, New Orleans, LA, USA

    Hannah K. Frank

  36. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA

    Lisbeth A. Guethlein & Peter Parham

  37. Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA, USA

    Lisbeth A. Guethlein, Kerwyn Casey Huang & Peter Parham

  38. Department of Bioengineering, Stanford University, Stanford, CA, USA

    Kerwyn Casey Huang, Robert C. Jones, Stephen R. Quake, Geoff Stanley, Alexander Tarashansky, Avin Veerakumar & Bo Wang

  39. Department of Oncology and Social Medicine, Kyushu University, Fukuoka, Japan

    Taichi Isobe

  40. Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD, USA

    Justus Kebschull

  41. JDRF Center of Excellence, Stanford, CA, USA

    Seung K. Kim

  42. Department of Anthropology, University of Texas at Austin, Austin, TX, USA

    E. Christopher Kirk, Rebecca Lewis & Liza Shapiro

  43. Institute of Molecular and Cell Biology, Agency of Science Technology and Research, Proteos, Singapore

    Winston Koh

  44. Department of Pediatrics, Stanford University School of Medicine, Stanford, CA, USA

    Christin Kuo & Ross Metzger

  45. MMDN, University of Montpellier, EPHE-PSL, INSERM, Montpellier, France

    Corinne Lautier & Jean-Michel Verdier

  46. Wu Tsai Neurosciences Institute, Stanford, CA, USA

    Song Eun Lee & Tony Wyss-Coray

  47. Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Life Sciences Institute, Zhejiang University, Hangzhou, Zhejiang, China

    Shengda Lin

  48. Division of Nephrology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA

    Gabriel Loeb

  49. Stanford ChEM-H, Stanford, CA, USA

    Jonathan Z. Long

  50. Division of Cardiology, Stanford University School of Medicine, Stanford, CA, USA

    Ross Metzger

  51. Institute for Computational and Mathematical Engineering, Stanford University, Stanford, CA, USA

    Julia Olivieri

  52. Program in Cancer Biology, Stanford University School of Medicine, Stanford, CA, USA

    Youcef Ouadah

  53. Department of Applied Physics, Stanford University, Stanford, CA, USA

    Stephen R. Quake

  54. Institute of Zoology, University of Veterinary Medicine Hannover, Hannover, Germany

    Ute Radespiel

  55. Department of Animal Biology, Faculty of Science, University of Antananarivo, Antananarivo, Madagascar

    Hajanirina Noëline Ravelonjanahary & Andriamahery Razafindrakoto

  56. Duke Lemur Center, Durham, NC, USA

    Robert Schopler & Cathy V. Williams

  57. Stanford Institute for Stem Cell Biology and Regenerative Medicine, Stanford, CA, USA

    Rahul Sinha & Irving L. Weissman

  58. Department of Neurobiology, Stanford University School of Medicine, Stanford, CA, USA

    Lubert Stryer

  59. Medical Scientist Training Program, Stanford University School of Medicine, Stanford, CA, USA

    Avin Veerakumar

  60. Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, USA

    Iwijn De Vlaminck & Michael F. Z. Wang

  61. Department of Computational Biology, Cornell University, Ithaca, NY, USA

    Michael F. Z. Wang

  62. Paul G. Allen School of Computer Science & Engineering, University of Washington, Seattle, WA, USA

    Sheng Wang

  63. Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA

    Hannah Weinstein

  64. Bakar Computational Health Sciences Institute, University of California San Francisco, San Francisco, CA, USA

    Hannah Weinstein

  65. Department of Chemistry, Stanford University, Stanford, CA, USA

    Amanda L. Wiggenhorn

  66. Department of Anthropology, Stony Brook University, Stony Brook, NY, USA

    Patricia Wright

  67. Department of Biology, University Program in Genetics & Genomics, Duke University, Durham, NC, USA

    Anne D. Yoder

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  1. Jia Zhao
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The Tabula Microcebus Consortium

  • Snigdha Agarwal
  • , Aditi Agrawal
  • , Ahmad Al-Moujahed
  • , Alina Alam
  • , Megan A. Albertelli
  • , Paul Allegakoen
  • , Thomas Ambrosi
  • , Jane Antony
  • , Steven Artandi
  • , Fabienne Aujard
  • , Kyle Awayan
  • , Ankit Baghel
  • , Isaac Bakerman
  • , Trygve E. Bakken
  • , Jalal Baruni
  • , Philip Beachy
  • , Biter Bilen
  • , Olga Botvinnik
  • , Scott D. Boyd
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  • , Andrea R. Yung
  • , Yue Zhang
  • , Jia Zhao
  •  & Zicheng Zhao

Contributions

J.Z. and G.W. conceived and developed the method. A.R.W. and C.Y. supervised the project. J.Z., G.W., Z.L., A.R.W. and C.Y. designed the experiments, performed the analyses and wrote the manuscript. J.M., Y.W. and T.M.C. provided critical feedback during the study and helped revise the manuscript.

Corresponding authors

Correspondence to Angela Ruohao Wu or Can Yang.

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The authors declare no competing interests.

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Nature Computational Science thanks Mengjie Chen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling Editor: Fernando Chirigati, in collaboration with the Nature Computational Science team. Peer reviewer reports are available.

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Zhao, J., Wang, G., Ming, J. et al. Adversarial domain translation networks for integrating large-scale atlas-level single-cell datasets. Nat Comput Sci 2, 317–330 (2022). https://doi.org/10.1038/s43588-022-00251-y

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