Single-cell reference mapping to construct and extend cell-type hierarchies

NAR Genomics and Bioinformatics, vol. 5, pp. lqad070

Abstract

Single-cell genomics is now producing an ever-increasing amount of datasets that, when integrated, could provide large-scale reference atlases of tissue in health and disease. Such large-scale atlases increase the scale and generalizability of analyses and enable combining knowledge generated by individual studies. Specifically, individual studies often differ regarding cell annotation terminology and depth, with different groups specializing in different cell type compartments, often using distinct terminology. Understanding how these distinct sets of annotations are related and complement each other would mark a major step towards a consensus-based cell-type annotation reflecting the latest knowledge in the field. Whereas recent computational techniques, referred to as 'reference mapping' methods, facilitate the usage and expansion of existing reference atlases by mapping new datasets (i.e. queries) onto an atlas; a systematic approach towards harmonizing dataset-specific cell-type terminology and annotation depth is still lacking. Here, we present 'treeArches', a framework to automatically build and extend reference atlases while enriching them with an updatable hierarchy of cell-type annotations across different datasets. We demonstrate various use cases for treeArches, from automatically resolving relations between reference and query cell types to identifying unseen cell types absent in the reference, such as disease-associated cell states. We envision treeArches enabling data-driven construction of consensus atlas-level cell-type hierarchies and facilitating efficient usage of reference atlases.

Authors 7

1. Lieke Michielsen Aachen Department of Human Genetics Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology , 2628XE  Delft , The Netherlands

   Department of Human Genetics, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands

2. Mohammad Lotfollahi

   Wellcome Sanger Institute · Helmholtz Munich · Institute of Computational Biology

   Affiliation as printed

   Institute of Computational Biology, Helmholtz Zentrum München , Munich , Germany

   Wellcome Sanger Institute , Cambridge , UK

3. Daniel C. Strobl

   Helmholtz Munich · Institute of Computational Biology · Technical University of Munich

   Affiliation as printed

   Institute of Clinical Chemistry and Pathobiochemistry, TUM School of Medicine, Technical University of Munich , 81675  Munich , Germany

   Institute of Computational Biology, Helmholtz Zentrum München , Munich , Germany

4. Lisa Sikkema

   Helmholtz Munich · Institute of Computational Biology · Technical University of Munich

   Affiliation as printed

   Institute of Computational Biology, Helmholtz Zentrum München , Munich , Germany

   TUM School of Life Sciences Weihenstephan, Technical University of Munich , Germany

   TUM School of Life Sciences Weihenstephan, Technical University of Munich, Germany

5. Marcel J. T. Reinders Aachen Department of Human Genetics Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology , 2628XE  Delft , The Netherlands

   Department of Human Genetics, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands

6. Fabian Joachim Theis corresponding

   Wellcome Sanger Institute · Helmholtz Munich · Institute of Computational Biology · Technical University of Munich

   Affiliation as printed

   Department of Mathematics, Technical University of Munich , Munich , Germany

   Institute of Computational Biology, Helmholtz Zentrum München , Munich , Germany

   TUM School of Life Sciences Weihenstephan, Technical University of Munich , Germany

   Wellcome Sanger Institute , Cambridge , UK

7. Ahmed Essam Mahfouz corresponding Aachen Department of Human Genetics Leiden Computational Biology Center

   Leiden University Medical Center · Delft University of Technology

   Affiliation as printed

   Delft Bioinformatics Lab, Delft University of Technology , 2628XE  Delft , The Netherlands

   Department of Human Genetics, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands

   Leiden Computational Biology Center, Leiden University Medical Center , 2333ZC  Leiden , The Netherlands