Natural Variation in <i>CDC28</i> Underlies Morphological Phenotypes in an Environmental Yeast Isolate

Lee, Hana N.; Magwene, Paul M.; Brem, Rachel B.

doi:10.1534/genetics.111.128819

Cited by 9 publications

(5 citation statements)

References 41 publications

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“…In Saccharomyces yeasts, although elegant linkage studies have mapped phenotypic differences between pairs of genetically distinct strains (Steinmetz et al 2002;Gerke et al 2009;Kim and Fay 2009;Lee et al 2011;Parts et al 2011;Ehrenreich et al 2012;Bloom et al 2013), the determinants of common phenotypes, and the evolutionary forces that underlie them, are less well understood (Hittinger et al 2010;Will et al 2010;Warringer et al 2011). In this work we have characterized a panel of flocculent and invasive, but otherwise unrelated, European S. paradoxus strains.…”

Section: Discussionmentioning

confidence: 99%

Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

Roop

Brem

2013

Genetics

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Understanding the molecular basis of common traits is a primary challenge of modern genetics. One model holds that rare mutations in many genetic backgrounds may often phenocopy one another, together explaining the prevalence of the resulting trait in the population. For the vast majority of phenotypes, the role of rare variants and the evolutionary forces that underlie them are unknown. In this work, we use a population of Saccharomyces paradoxus yeast as a model system for the study of common trait variation. We observed an unusual, flocculation and invasive-growth phenotype in one-third of S. paradoxus strains, which were otherwise unrelated. In crosses with each strain in turn, these morphologies segregated as a recessive Mendelian phenotype, mapping either to IRA1 or to IRA2, yeast homologs of the hypermutable human neurofibromatosis gene NF1. The causal IRA1 and IRA2 haplotypes were of distinct evolutionary origin and, in addition to their morphological effects, associated with hundreds of stressresistance and growth traits, both beneficial and disadvantageous, across S. paradoxus. Single-gene molecular genetic analyses confirmed variant IRA1 and IRA2 haplotypes as causal for these growth characteristics, many of which were independent of morphology. Our data make clear that common growth and morphology traits in yeast result from a suite of variants in master regulators, which function as a mutation-driven switch between phenotypic states.A primary goal of modern genetics is to understand the molecular basis of traits that segregate at high frequency in populations. Toward this end, hundreds of studies have sought to map causal genes, using tests for allele sharing among affected but unrelated individuals. Against a backdrop of recent successes in fruit fly and plant populations (Atwell et al. 2010;Brachi et al. 2010;Chan et al. 2011;Filiault and Maloof 2012;Mackay et al. 2012;Magwire et al. 2012;Weber et al. 2012;Dunn et al. 2013), association mapping in many systems has yielded loci that explain only a small part of the variation in a given trait across individuals (McCarthy et al. 2008). The latter challenges have motivated the proposal that the bulk of common phenotypic variation may be attributable to rare, highly penetrant mutations (Dickson et al. 2010;McClellan and King 2010; Veltman and Brunner 2012), including recurrent variation at hypermutable loci (Shen et al. 1996;Chan et al. 2010;Michaelson et al. 2012). As yet, the genetic architecture of most common traits remains unknown, and experimental systems in which to investigate the principles of common trait variation have been at a premium in the literature.Saccharomyces yeasts have long been a workhorse of the molecular-genetic research community, with resources now becoming available for analyses of population-level variation (Liti et al. 2009). Among the most well-studied phenotypes in the classic yeast literature are cell-clumping and filamentation-like behaviors in certain laboratory strains, which serve as models for fungal pa...

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Section: Discussionmentioning

confidence: 99%

Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

Roop

Brem

2013

Genetics

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“…It suggests that Cla4 may not be the only factor that is affected by Hsp90 and contributes to bud elongation. Cdc28 mutant alleles have been shown to influence cell morphology in natural isolates of S. cerevisiae (Lee et al, 2011). A recent study in the pathogenic fungus Candida albicans indicates that Cdc28 is an Hsp90 client protein and reducing Hsp90 activity destabilizes Cdc28 and promotes fila-mentous growth in C. albicans (Senn et al, 2012).…”

Section: Cdc28 Is Involved In Morphological Change In Low-hsp90 Cellsmentioning

confidence: 99%

Hsp90 Regulates Nongenetic Variation in Response to Environmental Stress

2013

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Nongenetic cell-to-cell variability often plays an important role for the survival of a clonal population in the face of fluctuating environments. However, the underlying mechanisms regulating such nongenetic heterogeneity remain elusive in most organisms. We report here that a clonal yeast population exhibits morphological heterogeneity when the level of Hsp90, a molecular chaperone, is reduced. The morphological heterogeneity is driven by the dosage of Cdc28 and Cla4, a key regulator of septin formation. Low Hsp90 levels reduce Cla4 protein stability and cause a subpopulation of cells to switch to a filamentous form that has been previously suggested to be beneficial under certain hostile environments. Moreover, Hsp90-dependent morphological heterogeneity can be induced by environmental stress and is conserved across diverse yeast species. Our results suggest that Hsp90 provides an evolutionarily conserved mechanism that links environmental stress to the induction of morphological diversity.

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“…Cell aggregation, which we define here as an umbrella term to include both flocculation and mother/daughter separation defects ( Stratford 1992 ), has dozens of known contributing genes identified by QTL mapping, deletion collection, genetic screen, and linkage analysis studies ( Liu et al 1996 ; Palecek et al 2000 ; Brem 2002 ; Verstrepen et al 2005 ; Borneman et al 2006 ; Lee et al 2011 ; Brückner and Mösch 2012 ; Ryan et al 2012 ; Granek et al 2013 ; Roop and Brem 2013 ; Kim et al 2014 ; Taylor and Ehrenreich 2014 ; Cullen 2015 ; Ratcliff et al 2015 ; Taylor et al 2016 ). Our primary interests in this study were to determine, across many evolution experiments, whether the genes involved in the evolution of aggregation were expected or novel, and ascertaining whether all aggregating clones achieved this final phenotype through one primary, or many equally favored, adaptive routes.…”

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confidence: 99%

Experimental Evolution Reveals Favored Adaptive Routes to Cell Aggregation in Yeast

Hope¹,

Amorosi²,

Miller

et al. 2017

Genetics

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Yeast flocculation is a community-building cell aggregation trait that is an important mechanism of stress resistance and a useful phenotype for brewers; however, it is also a nuisance in many industrial processes, in clinical settings, and in the laboratory. Chemostat-based evolution experiments are impaired by inadvertent selection for aggregation, which we observe in 35% of populations. These populations provide a testing ground for understanding the breadth of genetic mechanisms Saccharomyces cerevisiae uses to flocculate, and which of those mechanisms provide the biggest adaptive advantages. In this study, we employed experimental evolution as a tool to ask whether one or many routes to flocculation are favored, and to engineer a strain with reduced flocculation potential. Using a combination of whole genome sequencing and bulk segregant analysis, we identified causal mutations in 23 independent clones that had evolved cell aggregation during hundreds of generations of chemostat growth. In 12 of those clones, we identified a transposable element insertion in the promoter region of known flocculation gene FLO1, and, in an additional five clones, we recovered loss-of-function mutations in transcriptional repressor TUP1, which regulates FLO1 and other related genes. Other causal mutations were found in genes that have not been previously connected to flocculation. Evolving a flo1 deletion strain revealed that this single deletion reduces flocculation occurrences to 3%, and demonstrated the efficacy of using experimental evolution as a tool to identify and eliminate the primary adaptive routes for undesirable traits.

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Natural Variation in CDC28 Underlies Morphological Phenotypes in an Environmental Yeast Isolate

Cited by 9 publications

References 41 publications

Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

Rare Variants in Hypermutable Genes Underlie Common Morphology and Growth Traits in WildSaccharomyces paradoxus

Hsp90 Regulates Nongenetic Variation in Response to Environmental Stress

Experimental Evolution Reveals Favored Adaptive Routes to Cell Aggregation in Yeast

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