Genetic Network Complexity Shapes Background-Dependent Phenotypic Expression

Hou, Jing; Leeuwen, Jolanda van; Andrews, Brenda; Boone, Charles

doi:10.1016/j.tig.2018.05.006

Cited by 38 publications

(38 citation statements)

References 49 publications

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“…Even for diseases caused by mutations in a single gene (i.e. monogenic disorders), incomplete penetrance is frequent, presumably due to differences in the genetic background (Kammenga, ; Hou et al , ). Modulators of penetrance of disease‐causing variants have been identified for many human diseases (Cohen et al , ; Flannick et al , ; Chen et al , ) and loss‐of‐function (LoF) mutations in different model organisms (Hamilton & Yu, ; Chari & Dworkin, ; Vu et al , ; Chow et al , ; Mullis et al , ).…”

Section: Introductionmentioning

confidence: 99%

The impact of the genetic background on gene deletion phenotypes in Saccharomyces cerevisiae

Galardini

Busby

Viéitez

et al. 2019

Molecular Systems Biology

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Loss‐of‐function (LoF) mutations associated with disease do not manifest equally in different individuals. The impact of the genetic background on the consequences of LoF mutations remains poorly characterized. Here, we systematically assessed the changes in gene deletion phenotypes for 3,786 gene knockouts in four Saccharomyces cerevisiae strains and 38 conditions. We observed 18.5% of deletion phenotypes changing between pairs of strains on average with a small fraction conserved in all four strains. Conditions causing higher wild‐type growth differences and the deletion of pleiotropic genes showed above‐average changes in phenotypes. In addition, we performed a genome‐wide association study (GWAS) for growth under the same conditions for a panel of 925 yeast isolates. Gene–condition associations derived from GWAS were not enriched for genes with deletion phenotypes under the same conditions. However, cases where the results were congruent indicate the most likely mechanism underlying the GWAS signal. Overall, these results show a high degree of genetic background dependencies for LoF phenotypes.

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Section: Introductionmentioning

confidence: 99%

The impact of the genetic background on gene deletion phenotypes in Saccharomyces cerevisiae

Galardini

Busby

Viéitez

et al. 2019

Molecular Systems Biology

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show abstract

“…Even for diseases caused by mutations in a single gene (i.e. monogenic disorders) incomplete penetrance is frequent, presumably due to differences in the genetic background (Kammenga 2017;Hou et al 2018) . Modulators of penetrance of disease causing variants have been identified for many human diseases (Cohen et al 2005;Flannick et al 2014;Chen et al 2016) as well as loss-of-function (LoF) mutations in different model organisms (Hamilton & Yu 2012;Chari & Dworkin 2013;Vu et al 2015;Chow et al 2016;Mullis et al 2018) .…”

Section: Introductionmentioning

confidence: 99%

The impact of the genetic background on gene deletion phenotypes inSaccharomyces cerevisiae

Busby

Viéitez

Dunham

et al. 2018

Preprint

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Loss-of-function (LoF) mutations associated with disease don't manifest equally in different individuals, a phenomenon known as incomplete penetrance. The impact of the genetic background on incomplete penetrance remains poorly characterized. Here, we systematically assessed the changes in gene deletion phenotypes for 3,786 gene knockouts in four Saccharomyces cerevisiae strains and 38 conditions. We observed 16% to 42% of deletion phenotypes changing between pairs of strains with a small fraction conserved in all strains. Conditions causing higher WT growth differences and the deletion of pleiotropic genes showed above average changes in phenotypes. We further illustrate how these changes affect the interpretation of the impact of genetic variants across 925 yeast isolates. These results show the high degree of genetic background dependencies for LoF phenotypes.

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“…The phenotypic penetrance of a mutation is often impacted by the genetic background, a phenomenon frequently observed in monogenic diseases [58,59]. In this study, we investigate the effect of genetic background on the phenotypes of S. cerevisiae mutants defective in the formation of modified wobble uridines in tRNA.…”

Section: Discussionmentioning

confidence: 99%

SSD1suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications

Byström

Johansson

2019

Preprint

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24The Elongator complex promotes formation of 5-methoxycarbonylmethyl (mcm 5 ) and 25 5-carbamoylmethyl (ncm 5 ) side-chains on uridines at the wobble position of cytosolic 26 eukaryotic tRNAs. In all eukaryotic organisms tested to date, the inactivation of 27 Elongator not only leads to the lack of mcm 5 /ncm 5 groups in tRNAs, but also a wide 28 variety of phenotypes. Although the phenotypes are most likely caused by a 29 translational defect induced by reduced functionality of the hypomodified tRNAs, the 30 mechanism(s) underlying individual phenotypes are poorly understood. In this study, 31 we show that the genetic background modulates the phenotypes induced by the lack 32 of mcm 5 /ncm 5 groups in Saccharomyces cerevisiae. We show that the stress-33 induced growth defects of Elongator mutants are stronger in the W303 than in the 34 closely related S288C genetic background and that the phenotypic differences are 35 caused by the known polymorphism at the locus for the mRNA binding protein Ssd1. 36 Moreover, the mutant ssd1 allele found in W303 cells is required for the reported 37 histone H3 acetylation and telomeric gene silencing defects of Elongator mutants. 38The difference at the SSD1 locus also partially explains why the simultaneous lack of 39 mcm 5 and 2-thio groups at wobble uridines is lethal in the W303 but not in the 40 S288C background. Collectively, our results demonstrate that the SSD1 locus 41 modulates phenotypes induced by the lack of Elongator-dependent tRNA 42 modifications. 43 44 Author Summary 45 Modified nucleosides in the anticodon region of tRNAs are important for the 46 efficiency and fidelity of translation. The Elongator complex promotes formation of 47 3 48 In yeast, plants, worms, mice and humans, mutations in genes for Elongator 49 subunits lead to a wide variety of different phenotypes. Here, we show that the 50 genetic background modulates the phenotypic consequences of the inactivation of 51 budding yeast Elongator. This background effect is largely a consequence of a 52 polymorphism at the SSD1 locus, encoding a RNA binding protein that influences 53 translation, stability and/or localization of mRNAs. We show that several phenotypes 54 reported for yeast Elongator mutants are either significantly stronger or only 55 detectable in strains harboring a mutant ssd1 allele. Thus, SSD1 is a suppressor of 56 the phenotypes induced by the hypomodification of tRNAs. 4 57 104 to influence the cell wall remodeling that occurs upon stress, e.g. the mRNA-binding 105 protein Ssd1. Ssd1 has been reported to bind and influence the translation, stability 106 and/or localization of a subset of cellular mRNAs of which many encode proteins 6 107 important for cell wall biosynthesis and remodeling, [26-31]. The wild-type SSD1 108 gene was originally identified as a suppressor of the lethality induced by a deletion of 109 the SIT4 gene, which encodes a phosphatase involved in a wide range of cellular 110 processes [32]. The study also led to the finding that some wild-type S. cerevisia...

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Genetic Network Complexity Shapes Background-Dependent Phenotypic Expression

Cited by 38 publications

References 49 publications

The impact of the genetic background on gene deletion phenotypes in Saccharomyces cerevisiae

The impact of the genetic background on gene deletion phenotypes in Saccharomyces cerevisiae

The impact of the genetic background on gene deletion phenotypes inSaccharomyces cerevisiae

SSD1suppresses phenotypes induced by the lack of Elongator-dependent tRNA modifications

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