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      Interpretable factor models of single-cell RNA-seq via variational autoencoders

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          Abstract

          Motivation

          Single-cell RNA-seq makes possible the investigation of variability in gene expression among cells, and dependence of variation on cell type. Statistical inference methods for such analyses must be scalable, and ideally interpretable.

          Results

          We present an approach based on a modification of a recently published highly scalable variational autoencoder framework that provides interpretability without sacrificing much accuracy. We demonstrate that our approach enables identification of gene programs in massive datasets. Our strategy, namely the learning of factor models with the auto-encoding variational Bayes framework, is not domain specific and may be useful for other applications.

          Availability and implementation

          The factor model is available in the scVI package hosted at https://github.com/YosefLab/scVI/.

          Supplementary information

          Supplementary data are available at Bioinformatics online.

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          Most cited references17

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          Characterization of the single-cell transcriptional landscape by highly multiplex RNA-seq.

          Our understanding of the development and maintenance of tissues has been greatly aided by large-scale gene expression analysis. However, tissues are invariably complex, and expression analysis of a tissue confounds the true expression patterns of its constituent cell types. Here we describe a novel strategy to access such complex samples. Single-cell RNA-seq expression profiles were generated, and clustered to form a two-dimensional cell map onto which expression data were projected. The resulting cell map integrates three levels of organization: the whole population of cells, the functionally distinct subpopulations it contains, and the single cells themselves-all without need for known markers to classify cell types. The feasibility of the strategy was demonstrated by analyzing the transcriptomes of 85 single cells of two distinct types. We believe this strategy will enable the unbiased discovery and analysis of naturally occurring cell types during development, adult physiology, and disease.
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            A single-cell molecular map of mouse gastrulation and early organogenesis

            Across the animal kingdom, gastrulation represents a key developmental event during which embryonic pluripotent cells diversify into lineage-specific precursors that will generate the adult organism. Here we report the transcriptional profiles of 116,312 single cells from mouse embryos collected at nine sequential time-points ranging from 6.5 to 8.5 days post-fertilisation. We reconstruct a molecular map of cellular differentiation from pluripotency towards all major embryonic lineages, and explore the complex events involved in the convergence of visceral and primitive streak-derived endoderm. Furthermore, we demonstrate how combining temporal and transcriptional information illuminates gene function by single-cell profiling of Tal1 −/− chimeric embryos, with our analysis revealing defects in early mesoderm diversification. Taken together, this comprehensive delineation of mammalian cell differentiation trajectories in vivo represents a baseline for understanding the effects of gene mutations during development as well as a baseline for the optimisation of in vitro differentiation protocols for regenerative medicine.
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              Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst.

              Three distinct cell types are present within the 64-cell stage mouse blastocyst. We have investigated cellular development up to this stage using single-cell expression analysis of more than 500 cells. The 48 genes analyzed were selected in part based on a whole-embryo analysis of more than 800 transcription factors. We show that in the morula, blastomeres coexpress transcription factors specific to different lineages, but by the 64-cell stage three cell types can be clearly distinguished according to their quantitative expression profiles. We identify Id2 and Sox2 as the earliest markers of outer and inner cells, respectively. This is followed by an inverse correlation in expression for the receptor-ligand pair Fgfr2/Fgf4 in the early inner cell mass. Position and signaling events appear to precede the maturation of the transcriptional program. These results illustrate the power of single-cell expression analysis to provide insight into developmental mechanisms. The technique should be widely applicable to other biological systems. Copyright 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Contributors
                Role: Associate Editor
                Journal
                Bioinformatics
                Bioinformatics
                bioinformatics
                Bioinformatics
                Oxford University Press
                1367-4803
                1367-4811
                June 2020
                16 March 2020
                16 March 2020
                : 36
                : 11
                : 3418-3421
                Affiliations
                [b1 ] Division of Biology and Biological Engineering , California Institute of Technology, Pasadena, CA 91125, USA
                [b2 ] Center for Computational Biology
                [b3 ] Department of Electrical Engineering and Computer Sciences , University of California, Berkeley, CA 91125, USA
                [b4 ] Chan Zuckerberg Biohub , San Francisco, CA 94158, USA
                [b5 ] Department of Computing and Mathematical Sciences , California Institute of Technology, Pasadena, CA 91125, USA
                Author notes
                To whom correspondence should be addressed. Email: v@ 123456nxn.se
                Author information
                http://orcid.org/0000-0002-9217-2330
                http://orcid.org/0000-0001-9537-0845
                Article
                btaa169
                10.1093/bioinformatics/btaa169
                7267837
                32176273
                e5cc8fb5-cac7-4894-be2c-7a737005f469
                © The Author(s) 2020. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 13 September 2019
                : 03 February 2020
                : 13 March 2020
                Page count
                Pages: 4
                Funding
                Funded by: National Institutes of Health, DOI 10.13039/100000002;
                Award ID: U19MH114830
                Award ID: CZF2019-002454
                Categories
                Original Papers
                Gene Expression

                Bioinformatics & Computational biology
                Bioinformatics & Computational biology

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