A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion.
Published version
Peer-reviewed
Repository URI
Repository DOI
Change log
Authors
Witte, Franziska
Ruiz-Orera, Jorge
Mattioli, Camilla Ciolli
Blachut, Susanne
Adami, Eleonora
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
Keywords
Genetic variation, Cardiac hypertrophy, complex disease, Ribosome Biogenesis, Ribosome Profiling, Ribosomopathy, Translational Efficiency, Spontaneously Hypertensive Rats (Shr), Hxb/bxh Rat Recombinant Inbred Panel, Trans Qtl Mapping
Journal Title
Genome biology
Conference Name
Journal ISSN
1474-7596
Volume Title
22
Publisher
Publisher DOI
Sponsorship
Fundació la Marató de TV3 (20153810)
Akademie Věd České Republiky (AP1502)
European Molecular Biology Organization (ALTF 186-2015 / LTFCOFUND2013, GA-2013-609409)
Fondation Leducq (16CVD03)
European Research Council (AdG788970)
Akademie Věd České Republiky (AP1502)
European Molecular Biology Organization (ALTF 186-2015 / LTFCOFUND2013, GA-2013-609409)
Fondation Leducq (16CVD03)
European Research Council (AdG788970)