skip to main content
US FlagAn official website of the United States government
dot gov icon
Official websites use .gov
A .gov website belongs to an official government organization in the United States.
https lock icon
Secure .gov websites use HTTPS
A lock ( lock ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Explore Research Products in the PAR
It may take a few hours for recently added research products to appear in PAR search results.


Title: Genetic variation in aneuploidy prevalence and tolerance across Saccharomyces cerevisiae lineages
Abstract 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 individual’s genetic makeup influences its tolerance of karyotypic imbalance. Here we investigated within-species variation in aneuploidy prevalence and tolerance, using Saccharomyces cerevisiae 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 relationships between lineages with high aneuploidy frequencies suggest that increased aneuploidy prevalence emerged multiple times in S. cerevisiae evolution. Separate from aneuploidy prevalence, analyzing growth phenotypes revealed that some genetic backgrounds—such as the European Wine lineage—show fitness costs in aneuploids compared to euploids, whereas other clades with high aneuploidy frequencies show little evidence of major deleterious effects. Our analysis confirms that chromosome gain can produce phenotypic benefits, which could influence evolutionary trajectories. These results have important implications for understanding genetic variation in aneuploidy prevalence in health, disease, and evolution.  more » « less
Award ID(s):
1946046
PAR ID:
10232615
Author(s) / Creator(s):
; ; ;
Editor(s):
Hahn, M
Date Published:
Journal Name:
Genetics
Volume:
217
Issue:
4
ISSN:
1943-2631
Format(s):
Medium: X
Sponsoring Org:
National Science Foundation
More Like this
  1. ; ; ; ; ; (, PLOS Genetics)
    Forche, Anja (Ed.)
    The human fungal pathobiontCandida albicansdisplays extensive genomic plasticity, including large-scale chromosomal changes such as aneuploidy. Chromosome trisomy appears frequently in natural and laboratory strains ofC. albicans. Trisomy of specific chromosomes has been linked to large phenotypic effects, such as increased murine gut colonization by strains trisomic for chromosome 7 (Chr7). However, studies of whole-chromosome aneuploidy are generally limited to the SC5314 genome reference strain, making it unclear whether the imparted phenotypes are conserved acrossC. albicansgenetic backgrounds. Here, we report the presence of a Chr7 trisomy in the ”commensal-like” oral candidiasis strain, 529L, and dissect the contribution of Chr7 trisomy to colonization and virulence in 529L and SC5314. These experiments show that strain background and homolog identity (i.e., AAB vs ABB) interact with Chr7 trisomy to alter commensal and virulence phenotypes in multiple host niches.In vitrofilamentation was consistently reduced by Chr7 trisomy in SC5314, but this result was not consistent for 529L. Oral colonization of mice was increased by the presence of a Chr7 trisomy in 529L but not SC5314; conversely, virulence during systemic infection was reduced by Chr7 trisomy in SC5314 but not 529L. Strikingly, the AAB Chr7 trisomy in the SC5314 background rendered this strain avirulent in murine systemic infection. Increased dosage ofNRG1failed to reproduce most of the Chr7 trisomy phenotypes. Our results demonstrate that aneuploidy interacts with background genetic variation to produce complex phenotypic patterns that deviate from our current understanding in the genome reference strain. 
    more » « less
  2. ; ; ; ; ; ; ; ; ; ; et al (, G3: Genes, Genomes, Genetics)
    Steinmetz, L (Ed.)
    Abstract Caffeine is a natural compound that inhibits the major cellular signaling regulator target of rapamycin (TOR), leading to widespread effects including growth inhibition. Saccharomyces cerevisiae yeast can adapt to tolerate high concentrations of caffeine in coffee and cacao fermentations and in experimental systems. While many factors affecting caffeine tolerance and TOR signaling have been identified, further characterization of their interactions and regulation remain to be studied. We used experimental evolution of S. cerevisiae to study the genetic contributions to caffeine tolerance in yeast, through a collaboration between high school students evolving yeast populations coupled with further research exploration in university labs. We identified multiple evolved yeast populations with mutations in PDR1 and PDR5, which contribute to multidrug resistance, and showed that gain-of-function mutations in multidrug resistance family transcription factors Pdr1, Pdr3, and Yrr1 differentially contribute to caffeine tolerance. We also identified loss-of-function mutations in TOR effectors Sit4, Sky1, and Tip41 and showed that these mutations contribute to caffeine tolerance. These findings support the importance of both the multidrug resistance family and TOR signaling in caffeine tolerance and can inform future exploration of networks affected by caffeine and other TOR inhibitors in model systems and industrial applications. 
    more » « less
  3. ; ; ; ; ; ; (, Microbial Genomics)
    The opportunistic pathogenCandida albicansis the leading cause of invasiveCandidainfections worldwide. Genomic variation betweenC. albicansclinical isolates complicates efforts to pinpoint novel genetic variants underlying antifungal drug resistance and tolerance. Studies of serial isolates from individual patients are uncommon, limiting our understanding of genomic and phenotypic diversity during invasiveCandidainfections. We performed comparative genomic analyses of 101C.albicansbloodstream isolates from 55 patients in the Twin Cities region of Minnesota, including serial isolates from 19 patients. We analysed the phylogenetic relationships of these isolates relative to 199 globally collected publicC. albicansgenomes. This study’s regional isolates span the phylogenetic diversity ofC. albicans; six isolates represent novel outliers to known clades. While all serial isolates from the same patient clustered together phylogenetically, we observed extensive large-scale genomic variation between serial isolates including polyploidy, aneuploidy, copy number variation, loss of heterozygosity and chromosomal rearrangements. We demonstrated how a heterozygousERG251variant drives azole tolerance in a clinical isolate from a patient with a history of recurrent infections. Using serial isolates, we demonstrated that polyploidy provides an adaptive advantage in the presence of fluconazole despite the absence of overt antifungal drug resistance. Our analysis of closely matched serial isolates reveals the genomic plasticity ofC. albicansduring invasive infections and identifies variation driving antifungal drug tolerance. Our findings reveal limitations in current antifungal susceptibility testing and highlight the need to account for genomic and phenotypic variation during invasiveCandidainfections. 
    more » « less
  4. ; ; ; (, Genome Biology and Evolution)
    Abstract Experimental evolution allows the observation of change over time as laboratory populations evolve in response to novel, controlled environments. Microbial evolution experiments take advantage of cryopreservation to archive experimental populations in glycerol media, creating a frozen, living “fossil” record. Prior research with Escherichia coli has shown that cryopreservation conditions can affect cell viability and that allele frequencies across the genome can change in response to a freeze-thaw event. We expand on these observations by characterizing fitness and genomic consequences of multiple freeze-thaw cycles in diploid yeast populations. Our study system is a highly recombinant Saccharomyces cerevisiae population (SGRP-4X) which harbors standing genetic variation that cryopreservation may threaten. We also investigate the four parental isogenic strains crossed to create the SGRP-4X. We measure cell viability over 5 consecutive freeze-thaw cycles; while we find that viability increases over time in the evolved recombinant populations, we observe no such viability improvements in the parental strains. We also collect genome-wide sequence data from experimental populations initially, after one freeze-thaw, and after five freeze-thaw cycles. In the recombinant evolved populations, we find a region of significant allele frequency change on chromosome 15 containing the ALR1 gene. In the parental strains, we find little evidence for new mutations. We conclude that cryopreserving yeast populations with standing genetic variation may have both phenotypic and genomic consequences, though these same cryopreservation practices may have only small impacts on populations with little or no initial variation. 
    more » « less
  5. ; ; ; (, eLife)
    Organismal development is a complex process, involving a vast number of molecular constituents interacting on multiple spatio-temporal scales in the formation of intricate body structures. Despite this complexity, development is remarkably reproducible and displays tolerance to both genetic and environmental perturbations. This robustness implies the existence of hidden simplicities in developmental programs. Here, using the Drosophila wing as a model system, we develop a new quantitative strategy that enables a robust description of biologically salient phenotypic variation. Analyzing natural phenotypic variation across a highly outbred population and variation generated by weak perturbations in genetic and environmental conditions, we observe a highly constrained set of wing phenotypes. Remarkably, the phenotypic variants can be described by a single integrated mode that corresponds to a non-intuitive combination of structural variations across the wing. This work demonstrates the presence of constraints that funnel environmental inputs and genetic variation into phenotypes stretched along a single axis in morphological space. Our results provide quantitative insights into the nature of robustness in complex forms while yet accommodating the potential for evolutionary variations. Methodologically, we introduce a general strategy for finding such invariances in other developmental contexts. 
    more » « less
  • Citation Formats
  • MLA
  • APA
  • Chicago
  • BibTeX
  • Text Encoded Conversion
  • XML
  • Save / Share this Record
  • Send to Email