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.

识别影响复杂多细胞生物中蛋白质表达变异性的因素主要集中在启动子结构和顺式单细胞表达调控上。但是，迄今为止，这种靶向方法尚不能鉴定出人类细胞间基因表达变异性的主要调节因子。为了解决这个问题，我们将流式细胞仪与定量遗传学分析相结合，结合了人类免疫系统中单细胞蛋白质的表达测量。对于大多数表达变异具有可遗传成分的蛋白质，我们发现遗传变异以反式作用，而显着较少的变异以顺式作用。此外，我们强调使用孟德尔随机化，这些变异性-数量性状位点可能是由上游基因的顺式调控所驱动。这表明自然选择可以平衡顺式基因调控的影响与反式表达下游的影响。