Variation and genetic control of protein abundance in humans.
Variation and genetic control of protein abundance in humans.
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基因表达在个体和群体之间存在差异，被认为是表型变异的主要决定因素。虽然变异和遗传基因座负责RNA表达水平已被广泛分析，在人群中，我们的知识是有限的，关于人类蛋白质丰度的差异及其遗传基础。mRNA表达的变化不是蛋白质表达的完美替代物，因为后者受到一系列转录后调节机制的影响，并且根据经验，蛋白质和mRNA水平之间的相关性通常是适度的。在这里，我们使用同量异位串联质量标签（TMT）为基础的定量质谱法，以确定相对蛋白质水平的5953基因的淋巴母细胞样细胞系（LCL）从95个不同的个人在HapMap项目基因分型。我们发现蛋白质水平是可遗传的分子表型，在个体、群体和性别之间表现出相当大的差异。参与同一生物过程的特定蛋白质组的水平在个体之间存在差异，这表明这些过程在蛋白质水平上受到严格调控。我们确定了顺式pQTL（蛋白质数量性状位点），包括以前的转录组研究未检测到的变异。这项研究表明，高通量的人类蛋白质组定量的可行性，当与DNA变异和转录组信息集成时，增加了一个新的维度的基因表达调控的表征。
Gene expression differs among both individuals and populations and is thought to be a major determinant of phenotypic variation. Although variation and genetic loci responsible for RNA expression levels have been analyzed extensively in human populations, our knowledge is limited regarding the differences in human protein abundance and their genetic basis. Variation in mRNA expression is not a perfect surrogate for protein expression because the latter is influenced by a battery of post-transcriptional regulatory mechanisms, and, empirically, the correlation between protein and mRNA levels is generally modest. Here we used isobaric tandem mass tag (TMT)-based quantitative mass spectrometry to determine relative protein levels of 5953 genes in lymphoblastoid cell lines (LCLs) from 95 diverse individuals genotyped in the HapMap Project. We found that protein levels are heritable molecular phenotypes that exhibit considerable variation between individuals, populations, and sexes. Levels of specific sets of proteins involved in the same biological process co-vary among individuals, indicating that these processes are tightly regulated at the protein level. We identified cis-pQTLs (protein quantitative trait loci), including variants not detected by previous transcriptome studies. This study demonstrates the feasibility of high throughput human proteome quantification which, when integrated with DNA variation and transcriptome information, adds a new dimension to the characterization of gene expression regulation.