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Nat Methods. 2020 Apr;17(4):414-421. doi: 10.1038/s41592-020-0766-3. Epub 2020 Mar 16.

Cardelino: computational integration of somatic clonal substructure and single-cell transcriptomes.

Author information

1
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK.
2
St Vincent's Institute of Medical Research, Fitzroy, Victoria, Australia.
3
Melbourne Integrative Genomics, School of Mathematics and Statistics/School of Biosciences, University of Melbourne, Parkville, Victoria, Australia.
4
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK.
5
Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
6
Department of Physics, Cavendish Laboratory, Cambridge, UK.
7
The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
8
School of Molecular Cell Biology and Biotechnology, George S Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
9
Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
10
The Wellcome Trust/Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK.
11
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK. o.stegle@dkfz.de.
12
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. o.stegle@dkfz.de.
13
European Molecular Biology Laboratory, Genome Biology Unit, Heidelberg, Germany. o.stegle@dkfz.de.
14
Division of Computational Genomics and Systems Genetics, German Cancer Research Center, Heidelberg, Germany. o.stegle@dkfz.de.
15
European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, UK. st9@sanger.ac.uk.
16
Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, UK. st9@sanger.ac.uk.
17
Department of Physics, Cavendish Laboratory, Cambridge, UK. st9@sanger.ac.uk.

Abstract

Bulk and single-cell DNA sequencing has enabled reconstructing clonal substructures of somatic tissues from frequency and cooccurrence patterns of somatic variants. However, approaches to characterize phenotypic variations between clones are not established. Here we present cardelino (https://github.com/single-cell-genetics/cardelino), a computational method for inferring the clonal tree configuration and the clone of origin of individual cells assayed using single-cell RNA-seq (scRNA-seq). Cardelino flexibly integrates information from imperfect clonal trees inferred based on bulk exome-seq data, and sparse variant alleles expressed in scRNA-seq data. We apply cardelino to a published cancer dataset and to newly generated matched scRNA-seq and exome-seq data from 32 human dermal fibroblast lines, identifying hundreds of differentially expressed genes between cells from different somatic clones. These genes are frequently enriched for cell cycle and proliferation pathways, indicating a role for cell division genes in somatic evolution in healthy skin.

PMID:
32203388
DOI:
10.1038/s41592-020-0766-3

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