A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion

0543910 - FGÚ 2022 RIV GB eng J - Journal Article
Witte, F. - Ruiz-Orera, J. - Mattioli, C. C. - Blachut, S. - Adami, E. - Schulz, J. F. - Schneider-Lunitz, V. - Hummel, O. - Patone, G. - Mücke, M. B. - Šilhavý, Jan - Heinig, M. - Bottolo, L. - Sanchis, D. - Vingron, M. - Chekulaeva, M. - Pravenec, Michal - Hubner, N. - van Heesch, S.
A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion.
Genome Biology. Roč. 22, č. 1 (2021), č. článku 191. ISSN 1474-760X. E-ISSN 1474-760X
Grant - others:AV ČR(CZ) AP1502
Program: Akademická prémie - Praemium Academiae
Institutional support: RVO:67985823
Keywords : genetic variation * trans QTL mapping * translational efficiency * ribosome profiling * cardiac hypertrophy * spontaneously hypertensive rats (SHR)
OECD category: Cardiac and Cardiovascular systems
Impact factor: 18.010, year: 2021
Method of publishing: Open access
https://doi.org/10.1186/s13059-021-02397-w

Background Little is known about the impact of trans-acting genetic variation on the rates with which proteins are synthesized by ribosomes. Here, we investigate the influence of such distant genetic loci on the efficiency of mRNA translation and define their contribution to the development of complex disease phenotypes within a panel of rat recombinant inbred lines. Results We identify several tissue-specific master regulatory hotspots that each control the translation rates of multiple proteins. One of these loci is restricted to hypertrophic hearts, where it drives a translatome-wide and protein length-dependent change in translational efficiency, altering the stoichiometric translation rates of sarcomere proteins. Mechanistic dissection of this locus across multiple congenic lines points to a translation machinery defect, characterized by marked differences in polysome profiles and misregulation of the small nucleolar RNA SNORA48. Strikingly, from yeast to humans, we observe reproducible protein length-dependent shifts in translational efficiency as a conserved hallmark of translation machinery mutants, including those that cause ribosomopathies. Depending on the factor mutated, a pre-existing negative correlation between protein length and translation rates could either be enhanced or reduced, which we propose to result from mRNA-specific imbalances in canonical translation initiation and reinitiation rates. Conclusions We show that distant genetic control of mRNA translation is abundant in mammalian tissues, exemplified by a single genomic locus that triggers a translation-driven molecular mechanism. Our work illustrates the complexity through which genetic variation can drive phenotypic variability between individuals and thereby contribute to complex disease.
Permanent Link: http://hdl.handle.net/11104/0321014