Genetic modulation of protein expression in rat brain
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 <i>cis</i>-acting quantitative trait loci (pQTLs). Proteogenomics identified 95 variant peptides, and sex-specific analyses revealed both shared and distinct <i>cis</i>-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.
Authors
- Robert W. Williams (ORCID: https://orcid.org/0000-0001-8924-4447)
- Junmin Peng (ORCID: https://orcid.org/0000-0003-0472-7648)
- Zhiping Wu (ORCID: https://orcid.org/0000-0002-5554-3681)
- Karel Valeš (ORCID: https://orcid.org/0000-0001-7892-4535)
- Ling Li (ORCID: https://orcid.org/0000-0001-6295-2128)
- Ramkumar Mathur (ORCID: https://orcid.org/0000-0002-9317-2631)
- Pjotr Prins (ORCID: https://orcid.org/0000-0002-8021-9162)
- Andrea Guarracino (ORCID: https://orcid.org/0000-0001-9744-131X)
- Flavia Villani (ORCID: https://orcid.org/0000-0003-3633-0610)
- Michal Pravenec (ORCID: https://orcid.org/0000-0001-9197-5871)
- Hana Brožka (ORCID: https://orcid.org/0000-0002-1903-3828)
- Dehui Kong (ORCID: https://orcid.org/0009-0003-2641-5546)
- Anna N. Senko (ORCID: https://orcid.org/0000-0003-0885-0440)
- Joseph H. Lechner
- Ariana Mancieri
- Aleš Stuchlı́k (ORCID: https://orcid.org/0000-0002-5394-6305)
- Laura M. Saba (ORCID: https://orcid.org/0000-0001-9649-1294)
- Gerd Kempermann (ORCID: https://orcid.org/0000-0002-5304-4061)
- Hao Chen (ORCID: https://orcid.org/0000-0002-2680-6921)
- Kai Yang (ORCID: https://orcid.org/0000-0001-7497-3911)
- Xusheng Wang (ORCID: https://orcid.org/0000-0002-1759-9588)
- Aijun Zhang (ORCID: https://orcid.org/0000-0003-2879-9961)
- L. Lü (ORCID: https://orcid.org/0000-0003-3089-8213)
Institutions
- St. Jude Children's Research Hospital (US)
- University of Tennessee Health Science Center (US)
- Czech Academy of Sciences (CZ)
- University of North Dakota (US)
- Czech Academy of Sciences, Institute of Sociology (CZ)
- Human Technopole (IT)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Technische Universität Dresden (DE)
- University of Colorado Denver (US)
Publication Details
- Journal
- iScience
- Published
- 2025-02-21
- DOI
- https://doi.org/10.1016/j.isci.2025.112079
- Primary Topic
- Ubiquitin and proteasome pathways
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- National Institute on Alcohol Abuse and Alcoholism
- National Institute on Aging