A fitness trade-off explains the early fate of yeast aneuploids with chromosome gains

Pompei, Simone; Lagomarsino, Marco Cosentino

doi:10.1101/2022.07.07.499182

Cited by 5 publications

(13 citation statements)

References 86 publications

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“…In other words, the combination of two mechanisms that independently cause azole tolerance can dramatically increase the growth of fungal cells in drug, resulting in bona fide azole resistance. Multiple simultaneous mutations are common in cancer cells and often lead to treatment failure [76–79]. Our results highlight the diverse trajectories that C. albicans can take during adaptation to antifungal drugs and support that two independent mechanisms of tolerance (point mutation and aneuploidy) can evolve within the same cell resulting in drug resistance.…”

Section: Discussionsupporting

confidence: 62%

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Zhou,

Hilk,

Solis

et al. 2024

Preprint

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Ergosterol is essential for fungal cell membrane integrity and growth, and numerous antifungal drugs target ergosterol. Inactivation or modification of ergosterol biosynthetic genes can lead to changes in antifungal drug susceptibility, filamentation and stress response. Here, we found that the ergosterol biosynthesis gene ERG251 is a hotspot for point mutations during adaptation to antifungal drug stress within two distinct genetic backgrounds of Candida albicans. Heterozygous point mutations led to single allele dysfunction of ERG251 and resulted in azole tolerance in both genetic backgrounds. This is the first known example of point mutations causing azole tolerance in C. albicans. Importantly, single allele dysfunction of ERG251 in combination with recurrent chromosome aneuploidies resulted in bona fide azole resistance. Homozygous deletions of ERG251 caused increased fitness in low concentrations of fluconazole and decreased fitness in rich medium, especially at low initial cell density. Dysfunction of ERG251 resulted in transcriptional upregulation of the alternate sterol biosynthesis pathway and ZRT2, a Zinc transporter. Notably, we determined that overexpression of ZRT2 is sufficient to increase azole tolerance in C. albicans. Our combined transcriptional and phenotypic analyses revealed the pleiotropic effects of ERG251 on stress responses including cell wall, osmotic and oxidative stress. Interestingly, while loss of either allele of ERG251 resulted in similar antifungal drug responses, we observed functional divergence in filamentation regulation between the two alleles of ERG251 (ERG251-A and ERG251-B) with ERG251-A exhibiting a dominant role in the SC5314 genetic background. Finally, in a murine model of systemic infection, homozygous deletion of ERG251 resulted in decreased virulence while the heterozygous deletion mutants maintain their pathogenicity. Overall, this study provides extensive genetic, transcriptional and phenotypic analysis for the effects of ERG251 on drug susceptibility, fitness, filamentation and stress responses.

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Section: Discussionsupporting

confidence: 62%

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Zhou,

Hilk,

Solis

et al. 2024

Preprint

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“…CINner models cancer evolution as a branching process [11]. Cell lifespan is exponentially distributed with an input turn-over rate, similar to previous works [12,13]. At the end of its lifespan, the cell either divides or dies.…”

Section: Resultsmentioning

confidence: 99%

“…However, the CNAs in this approach do not affect the phylogeny tree, therefore karyotype selection is not explicitly depicted. Some recent studies model the effects of selection and missegregation on subclonal copy numbers [18,68], also incorporating point mutations [13] or WGD [46,69]. Nevertheless, many of these models focus only on the average ploidy and do not consider chromosome-specific CN [13,46,68].…”

Section: Discussionmentioning

confidence: 99%

“…Some recent studies model the effects of selection and missegregation on subclonal copy numbers [18,68], also incorporating point mutations [13] or WGD [46,69]. Nevertheless, many of these models focus only on the average ploidy and do not consider chromosome-specific CN [13,46,68]. In contrast, two studies directly integrate chromosomal selection parameters and study the resulting CN trajectories [18,69].…”

Section: Discussionmentioning

confidence: 99%

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CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution

Dinh,

Vázquez-García,

Chan

et al. 2024

Preprint

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Cancer development is characterized by chromosomal instability, manifesting in frequent occurrences of different genomic alteration mechanisms ranging in extent and impact. Mathematical modeling can help evaluate the role of each mutational process during tumor progression, however existing frameworks can only capture certain aspects of chromosomal instability (CIN). We present CINner, a mathematical framework for modeling genomic diversity and selection during tumor evolution. The main advantage of CINner is its flexibility to incorporate many genomic events that directly impact cellular fitness, from driver gene mutations to copy number alterations (CNAs), including focal amplifications and deletions, missegregations and whole-genome duplication (WGD). We apply CINner to find chromosome-arm selection parameters that drive tumorigenesis in the absence of WGD in chromosomally stable cancer types. We found that the selection parameters predict WGD prevalence among different chromosomally unstable tumors, hinting that the selective advantage of WGD cells hinges on their tolerance for aneuploidy and escape from nullisomy. Direct application of CINner to model the WGD proportion and fraction of genome altered (FGA) further uncovers the increase in CNA probabilities associated with WGD in each cancer type. CINner can also be utilized to study chromosomally stable cancer types, by applying a selection model based on driver gene mutations and focal amplifications or deletions. Finally, we used CINner to analyze the impact of CNA probabilities, chromosome selection parameters, tumor growth dynamics and population size on cancer fitness and heterogeneity. We expect that CINner will provide a powerful modeling tool for the oncology community to quantify the impact of newly uncovered genomic alteration mechanisms on shaping tumor progression and adaptation.

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“…Our model provides a quantitative framework to describe both perturbations jointly. We speculate that this quantitative understanding could be useful to predict the fitness landscape of situations with perturbed gene dosage, such as large-scale gene duplications in absence of dosage-compensation mechanisms (Pompei and Lagomarsino, 2023). In addition, our model provides a method to rigorously test the presence of transcriptional limitations by considering how the cost of overexpression varies as the mRNA stability of the unnecessary protein changes.…”

Section: Discussionmentioning

confidence: 99%

How total mRNA influences cell growth

Calabrese

Ciandrini

Lagomarsino

2023

Preprint

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While the conventional wisdom is that growth rate is prominently set by ribosome amounts, in many biologically relevant situations the levels of mRNA and RNA polymerase can become a bottleneck for growth. Here, we construct a quantitative model of biosynthesis providing testable predictions for these situations. Assuming that RNA polymerases compete for genes and ribosomes for transcripts, the model gives general expressions relating growth rate, mRNA concentrations, ribosome and RNAP levels. On general grounds, the model predicts how the fraction of ribosomes in the proteome depends on total mRNA concentration, and inspects an underexplored regime in which the trade-off between transcript levels and ribosome abundances sets the cellular growth rate. In particular, we show that the model predicts and clarifies three important experimental observations, in budding yeast and E. coli bacteria: (i) that the growth-rate cost of unneeded protein expression can be affected by mRNA levels, (ii) that resource optimization leads to decreasing trends in mRNA levels at slow growth, and (iii) that ribosome allocation may increase, stay constant, or decrease, in response to transcription-inhibiting antibiotics.

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A fitness trade-off explains the early fate of yeast aneuploids with chromosome gains

Cited by 5 publications

References 86 publications

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

Erg251 has complex and pleiotropic effects on azole susceptibility, filamentation, and stress response phenotypes

CINner: modeling and simulation of chromosomal instability in cancer at single-cell resolution

How total mRNA influences cell growth

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