Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains

  1. Min Jung
  2. Daniel Wells
  3. Jannette Rusch
  4. Suhaira Ahmad
  5. Jonathan Marchini
  6. Simon R Myers  Is a corresponding author
  7. Donald F Conrad  Is a corresponding author
  1. Washington University School of Medicine, United States
  2. University of Oxford, United Kingdom
  3. Oregon Health and Science University, United States

Abstract

To fully exploit the potential of single-cell functional genomics in the study of development and disease, robust methods are needed to simplify the analysis of data across samples, time-points and individuals. Here we introduce a model-based factor analysis method, SDA, to analyse a novel 57,600-cell dataset from the testes of wild-type mice and mice with gonadal defects due to disruption of the genes Mlh3, Hormad1, Cul4a or Cnp. By jointly analysing mutant and wild-type cells we decomposed our data into 46 components that identify novel meiotic gene-regulatory programmes, mutant-specific pathological processes, and technical effects, and provide a framework for imputation. We identify, de novo, DNA sequence motifs associated with individual components that define temporally varying modes of gene expression control. Analysis of SDA components also led us to identify a rare population of macrophages within the seminiferous tubules of Mlh3-/- and Hormad1-/- mice, an area typically associated with immune privilege.

Data availability

Raw data and processed files for Drop-seq and 10X Genomics experiments are available in GEO under accession number: GSE113293

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Min Jung

    Department of Genetics, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Daniel Wells

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2007-8978
  3. Jannette Rusch

    Department of Genetics, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Suhaira Ahmad

    Department of Genetics, Washington University School of Medicine, St Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Jonathan Marchini

    Wellcome Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Simon R Myers

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    For correspondence
    myers@stats.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
  7. Donald F Conrad

    Division of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Portland, United States
    For correspondence
    conradon@ohsu.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3828-8970

Funding

Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD078641)

  • Donald F Conrad

National Institute of Mental Health (R01MH101810)

  • Donald F Conrad

Wellcome (098387/Z/12/Z)

  • Simon R Myers

Wellcome (109109/Z/15/Z)

  • Daniel Wells

European Research Council (617306)

  • Jonathan Marchini

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Deborah Bourc'his, Institut Curie, France

Ethics

Animal experimentation: All animal experiments were performed in compliance with the regulations of the Animal Studies Committee at Washington University in St. Louis under approved protocol #20160089.

Version history

  1. Received: November 28, 2018
  2. Accepted: June 17, 2019
  3. Accepted Manuscript published: June 25, 2019 (version 1)
  4. Version of Record published: July 9, 2019 (version 2)

Copyright

© 2019, Jung et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Min Jung
  2. Daniel Wells
  3. Jannette Rusch
  4. Suhaira Ahmad
  5. Jonathan Marchini
  6. Simon R Myers
  7. Donald F Conrad
(2019)
Unified single-cell analysis of testis gene regulation and pathology in 5 mouse strains
eLife 8:e43966.
https://doi.org/10.7554/eLife.43966

Share this article

https://doi.org/10.7554/eLife.43966

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