Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, United Kingdom.
Cancer Research UK-Cambridge Institute, Robinson Way, Cambridge, United Kingdom.
PLoS Genet. 2020 Mar 13;16(3):e1008686. doi: 10.1371/journal.pgen.1008686. eCollection 2020 Mar.
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.
鉴定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调控单个细胞的表达。然而，迄今为止，这种靶向方法还无法确定人类细胞间基因表达变异性的主要调控因子。为了解决这个问题，我们结合了流式细胞术在人类免疫系统中的单细胞蛋白表达测量，以及定量遗传学分析。对于大多数其表达变异性具有遗传成分的蛋白质，我们发现遗传变异在反式中起作用，顺式中起作用的变异明显较少。此外，我们利用孟德尔随机化强调了这些变异性数量性状基因座可能是由上游基因的顺式调控驱动的。这表明自然选择可能会平衡顺式基因调控对表达变异性的下游影响。
