Correcting the Mean-Variance Dependency for Differential Variability Testing Using Single-Cell RNA Sequencing Data

Cell Systems
Nils ElingCatalina A Vallejos

Abstract

Cell-to-cell transcriptional variability in otherwise homogeneous cell populations plays an important role in tissue function and development. Single-cell RNA sequencing can characterize this variability in a transcriptome-wide manner. However, technical variation and the confounding between variability and mean expression estimates hinder meaningful comparison of expression variability between cell populations. To address this problem, we introduce an analysis approach that extends the BASiCS statistical framework to derive a residual measure of variability that is not confounded by mean expression. This includes a robust procedure for quantifying technical noise in experiments where technical spike-in molecules are not available. We illustrate how our method provides biological insight into the dynamics of cell-to-cell expression variability, highlighting a synchronization of biosynthetic machinery components in immune cells upon activation. In contrast to the uniform up-regulation of the biosynthetic machinery, CD4+ T cells show heterogeneous up-regulation of immune-related and lineage-defining genes during activation and differentiation.

Citations

May 23, 2019·Nature Reviews. Genetics·Nils ElingJohn C Marioni
Mar 10, 2020·ELife·Mgp van der WijstL Franke
Feb 9, 2020·Genome Biology·David LähnemannAlexander Schönhuth
Aug 9, 2020·Molecular Systems Biology·Olga M SigalovaJudith B Zaugg
Sep 2, 2020·Annual Review of Genetics·Jonathan FiorentinoAntonio Scialdone
Apr 22, 2021·Genome Biology·Chantriolnt-Andreas KapouraniCatalina A Vallejos
Jun 23, 2021·Nature Methods·Peter V Kharchenko
Jan 28, 2022·Nature·Swetansu K HotaBenoit G Bruneau

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Datasets Mentioned

BETA
E-MTAB-4388
GSE60361
GSE54695
E-MTAB-4888

Methods Mentioned

BETA
single-cell sequencing
scRNA-seq
smFISH
RNA-Seq
GTPase

Software Mentioned

DESeq2
BASiCS R
gsnap
DAVID
smFISH
Bioconductor
ArrayExpress
ENSEMBL
statmod
BASiCS

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