Genotype-Tissue-Protein: proteomic variation and quantitative trait loci (pQTL)

摘要 这项拟议的研究的目标是系统地描述多个人类的蛋白质组变异。 组织，并改进人类基因组的注释。基因表达的定量定位 利用微阵列或rna-seq进行性状(EQTL)的研究已经为人类生物学和人类研究提供了丰富的信息来源。 用于解释全基因组关联研究(GWAS)中的基因-疾病关联研究结果。在……里面 相比之下，很少有人研究蛋白质序列和丰度的变化，以及基因基础 蛋白质组的变异在很大程度上仍未被探索。这项研究的目的是量化 研究蛋白质丰度，并使用先进的 基于定量质谱学的平台。这三个具体目标是：(1)定量测量 五个组织中100个个体的蛋白质丰度，(2)表征变异和功能 注释组织特有的人类翻译组；以及(3)绘制影响蛋白质的遗传变异图 丰度(PQTL)。质谱学数据将用于验证先前预测的基因间和 编码蛋白质的内含子区域，并更好地注释人类基因组的翻译区域。通过 该项目优先选择多个组织捐赠者，最大限度地利用GTEx资源和 提供了一个独特的机会来量化蛋白质的多样性和个体之间的差异 纸巾。蛋白质组变异代表了RNA表达下游的一种分子表型，并可能 提供了RNA表达和表型之间的关键联系。我们预计pQTL定位分析 可能捕捉到eQTL图谱研究中没有捕捉到的转录后调控机制。 总而言之，这项研究中产生的新数据将对生物学和 生物医学研究，因为它们为解释基因-表型相关性提供了重要线索 通过全基因组关联研究确定。他们还将验证人类的注释 转录组关于翻译起始点的位置、剪接异构体多样性和异等位基因以及 正在编辑表达式。它们将为人类基因组社区提供丰富的资源。最终，我们 预计分子表型和注释的集合将提高我们预测 个人的疾病易感性，以及有助于设计个性化的预防和 干预策略。

Abstract The goals of the proposed research are to systematically characterize proteomic variation in multiple human tissues and improve the annotation of the human genome. The mapping of gene expression quantitative traits (eQTL) using microarray or RNA-seq has provided a rich source of information for human biology and for interpreting genotype-disease association findings from genome-wide association studies (GWAS). In contrast, much less work has examined variation in protein sequence and abundance, and the genetic basis of proteomic variation remains largely unexplored. The objective of this research is to quantify the abundance of proteins and to catalog protein variants in at least five human tissues using an advanced quantitative mass-spectrometry-based platform. The three Specific Aims are to (1) Quantitatively measure protein abundance in 100 individuals across five tissues, (2) Characterize variation and functionally annotate the tissue-specific human translatome; and (3) Map genetic variation that influences protein abundance (pQTL). Mass spectrometry data will be used to verify previously predicted intergenic and intronic regions that encode protein, and to better annotate the translated region of the human genome. By preferentially selecting multi-tissue donors, this project maximizes the utilization of the GTEx resource and provides a unique opportunity for quantifying protein diversity and variation between individuals and across tissues. Proteomic variation represents a molecular phenotype downstream of RNA expression and may provide a critical link between RNA expression and phenotypes. We expect that the pQTL mapping analysis may capture post-transcriptional regulatory mechanisms that are not captured in eQTL mapping studies. Together, the new data generated in this research will have an important positive impact on biological and biomedical research, because they offer important clues for interpreting genotype-phenotype correlation identified through genome-wide association studies. They will also validate the annotation of the human transcriptome with regards to location of translation start sites, splice isoform diversity and heteroallele and editing expression. They will provide a rich resource for the human genome community. Ultimately, we expect the ensemble of molecular phenotypes and annotation will improve our ability for predicting an individual's disease susceptibility, as well as contribute to the design of individualized prevention and intervention strategies.