Abstract
Allele-specific expression is traditionally studied by bulk RNA sequencing, which measures average expression across cells. Single-cell RNA sequencing allows the comparison of expression distribution between the two alleles of a diploid organism and the characterization of allele-specific bursting. Here, we propose SCALE to analyze genome-wide allele-specific bursting, with adjustment of technical variability. SCALE detects genes exhibiting allelic differences in bursting parameters and genes whose alleles burst non-independently. We apply SCALE to mouse blastocyst and human fibroblast cells and find that cis control in gene expression overwhelmingly manifests as differences in burst frequency.
Highlights
In diploid organisms, two copies of each autosomal gene are available for transcription, and differences in gene expression level between the two alleles are widespread in tissues [1,2,3,4,5,6,7]
We develop SCALE (Single-Cell ALlelic Expression), a systematic statistical framework to study Allele-specific expression (ASE) in single cells by examining allele-specific transcriptional bursting kinetics
An empirical Bayes method is adopted to classify expression of genes into monoallelic, biallelic, and silent states based on ASE data across cells
Summary
Two copies of each autosomal gene are available for transcription, and differences in gene expression level between the two alleles are widespread in tissues [1,2,3,4,5,6,7]. During the past decade, using single-nucleotide polymorphism (SNP)-sensitive microarrays and bulk RNA sequencing (RNA-seq), more subtle expression differences between the two alleles were found, mostly in the form of allelic imbalance of varying magnitudes in mean expression across cells [8,9,10,11]. In some cases such expression differences between alleles can lead to phenotypic consequences and result in disease [3, 12,13,14]. Recent developments in single-cell RNA sequencing (scRNA-seq) have made possible the better characterization of the nature of allelic differences in gene expression across
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