European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Hinxton, United Kingdom.
Centre for Gene Regulation & Expression, School of Life Sciences, University of Dundee, Dundee, United Kingdom.
Elife. 2020 Aug 10;9:e57390. doi: 10.7554/eLife.57390.
Human disease phenotypes are driven primarily by alterations in protein expression and/or function. To date, relatively little is known about the variability of the human proteome in populations and how this relates to variability in mRNA expression and to disease loci. Here, we present the first comprehensive proteomic analysis of human induced pluripotent stem cells (iPSC), a key cell type for disease modelling, analysing 202 iPSC lines derived from 151 donors, with integrated transcriptome and genomic sequence data from the same lines. We characterised the major genetic and non-genetic determinants of proteome variation across iPSC lines and assessed key regulatory mechanisms affecting variation in protein abundance. We identified 654 protein quantitative trait loci (pQTLs) in iPSCs, including disease-linked variants in protein-coding sequences and variants with regulatory effects. These include pQTL linked to GWAS variants that cannot be detected at the mRNA level, highlighting the utility of dissecting pQTL at peptide level resolution.
人类疾病表型主要是由蛋白质表达和/或功能的改变驱动的。迄今为止，人们对人群中人类蛋白质组的可变性以及它与 mRNA 表达和疾病基因座的可变性的关系知之甚少。在这里，我们首次对人类诱导多能干细胞（iPSC）进行了全面的蛋白质组分析，这是一种用于疾病建模的关键细胞类型，分析了来自 151 个供体的 202 个 iPSC 系，并整合了来自同一系的转录组和基因组序列数据。我们描述了 iPSC 系中蛋白质组变异的主要遗传和非遗传决定因素，并评估了影响蛋白质丰度变异的关键调节机制。我们在 iPSCs 中鉴定了 654 个蛋白质数量性状基因座（pQTL），包括蛋白质编码序列中的疾病相关变异和具有调节作用的变异。其中包括与 GWAS 变异相关的 pQTL，这些变异在 mRNA 水平上无法检测到，这突出了在肽水平分辨率上解析 pQTL 的效用。
