Li Ling, Wu Zhiping, Guarracino Andrea, Villani Flavia, Kong Dehui, Mancieri Ariana, Zhang Aijun, Saba Laura, Chen Hao, Brozka Hana, Vales Karel, Senko Anna N, Kempermann Gerd, Stuchlik Ales, Pravenec Michal, Lechner Joseph, Prins Pjotr, Mathur Ramkumar, Lu Lu, Yang Kai, Peng Junmin, Williams Robert W, Wang Xusheng
Department of Neurology, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
Department of Genetics, Genomics and Informatics, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
iScience. 2025 Feb 21;28(3):112079. doi: 10.1016/j.isci.2025.112079. eCollection 2025 Mar 21.
Genetic variations in protein expression are implicated in a broad spectrum of common diseases and complex traits but remain less explored compared to mRNA and classical phenotypes. This study systematically analyzed brain proteomes in a rat family using tandem mass tag (TMT)-based quantitative mass spectrometry. We quantified 8,119 proteins across two parental strains (SHR/Olalpcv and BN-Lx/Cub) and 29 HXB/BXH recombinant inbred (RI) strains, identifying 597 proteins with differential expression and 464 proteins linked to -acting quantitative trait loci (pQTLs). Proteogenomics identified 95 variant peptides, and sex-specific analyses revealed both shared and distinct -pQTLs. We improved the ability to pinpoint candidate genes underlying pQTLs by utilizing the rat pangenome and explored the connections between pQTLs in rats and human disorders. Collectively, this study highlights the value of large proteo-genetic datasets in elucidating protein modulation in the brain and its links to complex central nervous system (CNS) traits.
蛋白质表达中的遗传变异与多种常见疾病和复杂性状有关，但与信使核糖核酸（mRNA）和经典表型相比，其研究仍较少。本研究使用基于串联质谱标签（TMT）的定量质谱技术，系统分析了一个大鼠家族的脑蛋白质组。我们对两个亲本品系（SHR/Olalpcv和BN-Lx/Cub）以及29个HXB/BXH重组近交（RI）品系中的8119种蛋白质进行了定量分析，鉴定出597种差异表达的蛋白质和464种与顺式作用定量性状位点（pQTL）相关的蛋白质。蛋白质基因组学鉴定出95种变异肽段，性别特异性分析揭示了共有和独特的顺式pQTL。我们利用大鼠泛基因组提高了确定pQTL潜在候选基因的能力，并探索了大鼠pQTL与人类疾病之间的联系。总体而言，本研究突出了大型蛋白质-遗传数据集在阐明大脑中蛋白质调节及其与复杂中枢神经系统（CNS）性状之间联系方面的价值。
