Quantitative genetic analysis deciphers the impact of cis and trans regulation on cell-to-cell variability in protein expression levels

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 vari-
ability 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 Ran-
domization 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.