A trans locus causes a ribosomopathy in hypertrophic hearts that affects mRNA translation in a protein length-dependent fashion.
Animals
Cardiomegaly
/ genetics
Gene Expression Profiling
Gene Expression Regulation
Genetic Variation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Myocardium
/ metabolism
Organelle Biogenesis
Peptide Chain Initiation, Translational
Quantitative Trait Loci
RNA, Messenger
/ genetics
RNA, Small Nucleolar
/ genetics
Rats
Rats, Inbred SHR
Rats, Transgenic
Ribosomal Proteins
/ genetics
Ribosomes
/ genetics
Saccharomyces cerevisiae
/ genetics
Sarcomeres
/ metabolism
Cardiac hypertrophy
Complex disease
Genetic variation
HXB/BXH rat recombinant inbred panel
Ribosome biogenesis
Ribosome profiling
Ribosomopathy
Spontaneously hypertensive rats (SHR)
Translational efficiency
trans QTL mapping
Journal
Genome biology
ISSN: 1474-760X
Titre abrégé: Genome Biol
Pays: England
ID NLM: 100960660
Informations de publication
Date de publication:
28 06 2021
28 06 2021
Historique:
received:
17
07
2020
accepted:
02
06
2021
entrez:
29
6
2021
pubmed:
30
6
2021
medline:
21
1
2022
Statut:
epublish
Résumé
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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34183069
doi: 10.1186/s13059-021-02397-w
pii: 10.1186/s13059-021-02397-w
pmc: PMC8240307
doi:
Substances chimiques
RNA, Messenger
0
RNA, Small Nucleolar
0
Ribosomal Proteins
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
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