A machine learning method for the discovery of minimum marker gene combinations for cell type identification from single-cell RNA sequencing

Genome Research, vol. 31, pp. 1767–1780

Abstract

Single-cell genomics is rapidly advancing our knowledge of the diversity of cell phenotypes, including both cell types and cell states. Driven by single-cell/-nucleus RNA sequencing (scRNA-seq), comprehensive cell atlas projects characterizing a wide range of organisms and tissues are currently underway. As a result, it is critical that the transcriptional phenotypes discovered are defined and disseminated in a consistent and concise manner. Molecular biomarkers have historically played an important role in biological research, from defining immune cell types by surface protein expression to defining diseases by their molecular drivers. Here, we describe a machine learning-based marker gene selection algorithm, NS-Forest version 2.0, which leverages the nonlinear attributes of random forest feature selection and a binary expression scoring approach to discover the minimal marker gene expression combinations that optimally capture the cell type identity represented in complete scRNA-seq transcriptional profiles. The marker genes selected provide an expression barcode that serves as both a useful tool for downstream biological investigation and the necessary and sufficient characteristics for semantic cell type definition. The use of NS-Forest to identify marker genes for human brain middle temporal gyrus cell types reveals the importance of cell signaling and noncoding RNAs in neuronal cell type identity.

Authors 10

1. Brian D. Aevermann

   J. Craig Venter Institute

   Affiliation as printed

   J. Craig Venter Institute, La Jolla, California 92037, USA

   1J. Craig Venter Institute, La Jolla, California 92037, USA

2. Yun Zhang

   J. Craig Venter Institute

   Affiliation as printed

   J. Craig Venter Institute, La Jolla, California 92037, USA

   1J. Craig Venter Institute, La Jolla, California 92037, USA

3. Mark A. Novotny

   J. Craig Venter Institute

   Affiliation as printed

   J. Craig Venter Institute, La Jolla, California 92037, USA

   1J. Craig Venter Institute, La Jolla, California 92037, USA

4. Mohamed Keshk

   J. Craig Venter Institute

   Affiliation as printed

   J. Craig Venter Institute, La Jolla, California 92037, USA

   1J. Craig Venter Institute, La Jolla, California 92037, USA

5. Trygve E. Bakken

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, Washington 98109, USA

   2Allen Institute for Brain Science, Seattle, Washington 98109, USA

6. Jeremy A. Miller

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, Washington 98109, USA

   2Allen Institute for Brain Science, Seattle, Washington 98109, USA

7. Rebecca D. Hodge

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, Washington 98109, USA

   2Allen Institute for Brain Science, Seattle, Washington 98109, USA

8. Boudewijn P. F. Lelieveldt Aachen Department of Radiology, Leiden University Medical Center 3Department of Radiology

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Department of Intelligent Systems, Delft University of Technology, 2628 Delft, The Netherlands

   Department of Radiology, Leiden University Medical Center, 2300 Leiden, The Netherlands

   3Department of Radiology, Leiden University Medical Center, 2300 Leiden, The Netherlands

   4Department of Intelligent Systems, Delft University of Technology, 2628 Delft, The Netherlands

9. Ed S. Lein

   Allen Institute for Brain Science

   Affiliation as printed

   Allen Institute for Brain Science, Seattle, Washington 98109, USA

   2Allen Institute for Brain Science, Seattle, Washington 98109, USA

10. Richard H. Scheuermann

    J. Craig Venter Institute · La Jolla Institute for Immunology · University of California San Diego

    Affiliation as printed

    J. Craig Venter Institute, La Jolla, California 92037, USA

    La Jolla Institute for Immunology, La Jolla, California 92037, USA

    University of California San Diego, La Jolla, California 92093, USA

    1J. Craig Venter Institute, La Jolla, California 92037, USA

    5University of California San Diego, La Jolla, California 92093, USA

    6La Jolla Institute for Immunology, La Jolla, California 92037, USA