Biology subjects

Gasch, A.

Publications and source records attributed to Gasch, A..

5 recordsLinked to original sources

bioRxiv2024

The response to single-gene duplication implicates translation as a key vulnerability in aneuploid yeast

Aneuploidy produces myriad consequences in health and disease, yet models of the deleterious effects of chromosome amplification are still widely debated. To distinguish the molecular determinants of aneuploidy stress, we measured the effects of duplicating individual genes in cells with varying chromosome duplications, in wild-type cells and cells sensitized to aneuploidy by deletion of RNA-binding protein Ssd1. We identified gene duplications that are nearly neutral in wild-type euploid cells but significantly deleterious in euploids lacking SSD1 or SSD1+ aneuploid cells with different chromosome duplications. Several of the most deleterious genes are linked to translation; in contrast, duplication of other translational regulators, including eI5Fa Hyp2, benefit ssd1{Delta} aneuploids over controls. Using modeling of aneuploid growth defects, we propose that the deleterious effects of aneuploidy emerge from an interaction between the cumulative burden of many amplified genes on a chromosome and a subset of duplicated genes that become toxic in that context. Our results suggest that the mechanism behind their toxicity is linked to a key vulnerability in translation in aneuploid cells. These findings provide a perspective on the dual impact of individual genes and overall genomic burden, offering new avenues for understanding aneuploidy and its cellular consequences.

genetics↗

bioRxiv2024

Comparative modeling reveals the molecular determinants of aneuploidy fitness cost in a wild yeast model

Although implicated as deleterious in many organisms, aneuploidy can underlie rapid phenotypic evolution. However, aneuploidy will only be maintained if the benefit outweighs the cost, which remains incompletely understood. To quantify this cost and the molecular determinants behind it, we generated a panel of chromosome duplications in Saccharomyces cerevisiae and applied comparative modeling and molecular validation to understand aneuploidy toxicity. We show that 74-94% of the variance in aneuploid strains growth rates is explained by the additive cost of genes on each chromosome, measured for single-gene duplications using a genomic library, along with the deleterious contribution of snoRNAs and beneficial effects of tRNAs. Machine learning to identify properties of detrimental gene duplicates provided no support for the balance hypothesis of aneuploidy toxicity and instead identified gene length as the best predictor of toxicity. Our results present a generalized framework for the cost of aneuploidy with implications for disease biology and evolution.

genomics↗

bioRxiv2023

Gene-by-environment interactions influence the fitness cost of gene copy-number variation in yeast

Variation in gene copy number can alter gene expression and influence downstream phenotypes; thus copy-number variation (CNV) provides a route for rapid evolution if the benefits outweigh the cost. We recently showed that genetic background significantly influences how yeast cells respond to gene over-expression (OE), revealing that the fitness costs of CNV can vary substantially with genetic background in a common-garden environment. But the interplay between CNV tolerance and environment remains unexplored on a genomic scale. Here we measured the tolerance to gene OE in four genetically distinct Saccharomyces cerevisiae strains grown under sodium chloride (NaCl) stress. OE genes that are commonly deleterious during NaCl stress recapitulated those commonly deleterious under standard conditions. However, NaCl stress uncovered novel differences in strain responses to gene OE. West African strain NCYC3290 and North American oak isolate YPS128 are more sensitive to NaCl stress than vineyard BC187 and laboratory strain BY4743. Consistently, NCYC3290 and YPS128 showed the greatest sensitivities to gene OE. Although most genes were deleterious, hundreds were beneficial when overexpressed - remarkably, most of these effects were strain specific. Few beneficial genes were shared between the NaCl-sensitive isolates, implicating mechanistic differences behind their NaCl sensitivity. Transcriptomic analysis suggested underlying vulnerabilities and tolerances across strains, and pointed to natural CNV of a sodium export pump that likely contributes to strain-specific responses to OE of other genes. Our results reveal extensive strain-by-environment interaction in the response to gene CNV, raising important implications for the accessibility of CNV-dependent evolutionary routes under times of stress.

evolutionary biology↗

bioRxiv2020

Genetic variation in aneuploidy prevalence and tolerance across the Saccharomyces cerevisiae phylogeny

Individuals carrying an aberrant number of chromosomes can vary widely in their expression of aneuploidy phenotypes. A major unanswered question is the degree to which an individuals genetic makeup influences its tolerance of karyotypic imbalance. Here we took a population genetics perspective to investigate the selective forces influencing aneuploidy prevalence in Saccharomyces cerevisiae populations as a model for eukaryotic biology. We analyzed genotypic and phenotypic variation recently published for over 1,000 S. cerevisiae strains spanning dozens of genetically defined clades and ecological associations. Our results show that the prevalence of chromosome gain and loss varies by clade and can be better explained by differences in genetic background than ecology. The phylogenetic context of lineages showing high aneuploidy rates suggests that increased aneuploidy frequency arose multiple times in S. cerevisiae evolution. Separate from aneuploidy frequency, analyzing growth phenotypes reveals that some backgrounds - such as European Wine strains - show fitness costs upon chromosome duplication, whereas other clades with high aneuploidy rates show little evidence of major deleterious effects. Our analysis confirms that chromosome amplification can produce phenotypic benefits that can influence evolutionary trajectories. These results have important implications for understanding genetic variation in aneuploidy prevalence in health, disease, and evolution. ARTICLE SUMMARYAneuploidy, an imbalance in the normal chromosome copy number, is detrimental during human development; yet individuals show substantial variability in their aneuploidy susceptibility, suggesting the influence of genetic background on aneuploidy tolerance. Scopel et al. employed a population genetic approach to address this question, analyzing over 1,000 published Saccharomyces cerevisiae genomes. The results demonstrate that genetic background has a substantial effect on aneuploidy frequency and cellular tolerance of aneuploidy stress, presenting important new information on the forces that contribute to aneuploidy prevalence.

genetics↗

bioRxiv2019

Perturbation of the titin/MURF1 signaling complex is associated with hypertrophic cardiomyopathy in a fish model and in human patients.

Hypertrophic cardiomyopathy (HCM) is a hereditary disease characterized by cardiac hypertrophy with diastolic dysfunction. Gene mutations causing HCM have been found in about half of the patients, while the genetic etiology and pathogenesis remain unknown for many cases of HCM. To identify novel mechanisms underlying HCM pathogenesis, we generated a cardiovascular-mutant medaka fish non-spring heart (nsh), which showed diastolic dysfunction and hypertrophic myocardium. The nsh homozygotes had fewer myofibrils, disrupted sarcomeres and expressed pathologically stiffer titin isoforms. In addition, the nsh heterozygotes showed M-line disassembly that is similar to the pathological changes found in HCM. Positional cloning revealed a missense mutation in an immunoglobulin (Ig) domain located in the M-line-A-band transition zone of titin. Screening of mutations in 96 unrelated patients with familial HCM, who had no previously implicated mutations in known sarcomeric gene candidates, identified two mutations in Ig domains close to the M-line region of titin. In vitro studies revealed that the mutations found in both medaka fish and in familial HCM increased binding of titin to muscle-specific ring finger protein 1 (MURF1) and enhanced titin degradation by ubiquitination. These findings implicate an impaired interaction between titin and MURF1 as a novel mechanism underlying the pathogenesis of HCM.

developmental biology↗