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

Published version
Peer-reviewed

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Authors

Witte, Franziska 
Ruiz-Orera, Jorge 
Mattioli, Camilla Ciolli 
Blachut, Susanne 
Adami, Eleonora 

Abstract

Abstract: 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.

Description

Funder: Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtz-Gemeinschaft (MDC) (4219)

Keywords

Research, Genetic variation, trans QTL mapping, Translational efficiency, Ribosome profiling, Cardiac hypertrophy, Ribosome biogenesis, Ribosomopathy, Complex disease, Spontaneously hypertensive rats (SHR), HXB/BXH rat recombinant inbred panel

Journal Title

Genome Biology

Conference Name

Journal ISSN

1474-760X

Volume Title

22

Publisher

BioMed Central
Sponsorship
European Molecular Biology Organization (ALTF 186-2015 / LTFCOFUND2013, GA-2013-609409)
European Research Council (AdG788970)
Fondation Leducq (16CVD03)
Akademie Věd České Republiky (AP1502)
Fundació la Marató de TV3 (20153810)