Abstract
Identifying the factors that shape protein expression variability in complex multi-cellular organisms has primarily focused on promoter architecture and regulation of single-cell expression in cis. However, this targeted approach has to date been unable to identify major regulators of cell-to-cell gene expression variability in humans. To address this, we have combined single-cell protein expression measurements in the human immune system using flow cytometry with a quantitative genetics analysis. For the majority of proteins whose variability in expression has a heritable component, we find that genetic variants act in trans, with notably fewer variants acting in cis. Furthermore, we highlight using Mendelian Randomization that these variability-Quantitative Trait Loci might be driven by the cis regulation of upstream genes. This indicates that natural selection may balance the impact of gene regulation in cis with downstream impacts on expression variability in trans.
Highlights
Cell-to-cell variability in gene expression levels is a ubiquitous feature of life on earth
Genetic variation can change how much a gene is turned on or off in a tissue or a population of cells of the same type. This averaging of expression levels across a cell population masks an important aspect of gene expression regulation, namely its variability
Recent work in humans has indicated that nearby genetic factors minimally influence this variability
Summary
Cell-to-cell variability in gene expression levels is a ubiquitous feature of life on earth. This heterogeneity, broadly referred to as expression noise, is a function of transcriptional and translational regulation [1], as well as cellular state and environment [2,3,4,5]. Intrinsic noise represents the differences in promoter output between two alleles of the same gene, whilst extrinsic noise represents all other sources of variability [6]. The consequences of cell-to-cell expression variability (i.e. the sum of all noise sources [8]) manifest as therapeutic resistance in cancer [9,10], environmental adaptation in yeast [11] and prokaryotes [11,12], as well as lineage plasticity in murine T cells [5,13], to highlight just a few examples
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