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Open AccessArticle

Single-Cell Expression Variability Implies Cell Function

1
Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843, USA
2
Department of Veterinary Pathobiology, Texas A&M University, College Station, TX 77843, USA
3
Department of Statistics, Texas A&M University, College Station, TX 77843, USA
4
Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX 77843, USA
5
Interdisciplinary Program of Genetics, Texas A&M University, College Station, TX 77843, USA
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2020, 9(1), 14; https://doi.org/10.3390/cells9010014
Received: 12 November 2019 / Revised: 26 November 2019 / Accepted: 27 November 2019 / Published: 19 December 2019
(This article belongs to the Special Issue Bioinformatics and Computational Biology 2019)
As single-cell RNA sequencing (scRNA-seq) data becomes widely available, cell-to-cell variability in gene expression, or single-cell expression variability (scEV), has been increasingly appreciated. However, it remains unclear whether this variability is functionally important and, if so, what are its implications for multi-cellular organisms. Here, we analyzed multiple scRNA-seq data sets from lymphoblastoid cell lines (LCLs), lung airway epithelial cells (LAECs), and dermal fibroblasts (DFs) and, for each cell type, selected a group of homogenous cells with highly similar expression profiles. We estimated the scEV levels for genes after correcting the mean-variance dependency in that data and identified 465, 466, and 364 highly variable genes (HVGs) in LCLs, LAECs, and DFs, respectively. Functions of these HVGs were found to be enriched with those biological processes precisely relevant to the corresponding cell type’s function, from which the scRNA-seq data used to identify HVGs were generated—e.g., cytokine signaling pathways were enriched in HVGs identified in LCLs, collagen formation in LAECs, and keratinization in DFs. We repeated the same analysis with scRNA-seq data from induced pluripotent stem cells (iPSCs) and identified only 79 HVGs with no statistically significant enriched functions; the overall scEV in iPSCs was of negligible magnitude. Our results support the “variation is function” hypothesis, arguing that scEV is required for cell type-specific, higher-level system function. Thus, quantifying and characterizing scEV are of importance for our understating of normal and pathological cellular processes. View Full-Text
Keywords: single-cell RNA sequencing; scRNA-seq; single-cell expression variability; cell-to-cell variation; lymphoblastoid cell line; airway epithelial cell; dermal fibroblast; induced pluripotent stem cell single-cell RNA sequencing; scRNA-seq; single-cell expression variability; cell-to-cell variation; lymphoblastoid cell line; airway epithelial cell; dermal fibroblast; induced pluripotent stem cell
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Osorio, D.; Yu, X.; Zhong, Y.; Li, G.; Serpedin, E.; Huang, J.Z.; Cai, J.J. Single-Cell Expression Variability Implies Cell Function. Cells 2020, 9, 14.

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