A Combined-Cross Analysis Reveals Genes With Drug-Specific and Background-Dependent Effects on Drug Sensitivity in <i>Saccharomyces cerevisiae</i>

Fay, Justin C.

doi:10.1534/genetics.109.108068

Cited by 25 publications

(21 citation statements)

References 72 publications

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“…To our knowledge, this is the first time that MKT1 has been conclusively associated with ethanol tolerance in S. cerevisiae. MKT1 seems to be important for diverse aspects of cellular function under stressful conditions since previous QTL mapping experiments have identified MKT1 as a quantitative trait gene determining high temperature growth (Steinmetz et al 2002;Sinha et al 2006), sporulation efficiency (Deutschbauer and Davis 2005), induction of petite mutants (Dimitrov et al 2009), and drug resistance (Demogines et al 2008;Kim and Fay 2009;Ehrenreich et al 2010). In all of the above studies, the mapping was performed against the BY/S288c background.…”

Section: Discussionmentioning

confidence: 99%

Identification of novel causative genes determining the complex trait of high ethanol tolerance in yeast using pooled-segregant whole-genome sequence analysis

Swinnen¹,

Schaerlaekens²,

Pais³

et al. 2012

Genome Res.

165

199

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High ethanol tolerance is an exquisite characteristic of the yeast Saccharomyces cerevisiae, which enables this microorganism to dominate in natural and industrial fermentations. Up to now, ethanol tolerance has only been analyzed in laboratory yeast strains with moderate ethanol tolerance. The genetic basis of the much higher ethanol tolerance in natural and industrial yeast strains is unknown. We have applied pooled-segregant whole-genome sequence analysis to map all quantitative trait loci (QTL) determining high ethanol tolerance. We crossed a highly ethanol-tolerant segregant of a Brazilian bioethanol production strain with a laboratory strain with moderate ethanol tolerance. Out of 5974 segregants, we pooled 136 segregants tolerant to at least 16% ethanol and 31 segregants tolerant to at least 17%. Scoring of SNPs using whole-genome sequence analysis of DNA from the two pools and parents revealed three major loci and additional minor loci. The latter were more pronounced or only present in the 17% pool compared to the 16% pool. In the locus with the strongest linkage, we identified three closely located genes affecting ethanol tolerance: MKT1, SWS2, and APJ1, with SWS2 being a negative allele located in between two positive alleles. SWS2 and APJ1 probably contained significant polymorphisms only outside the ORF, and lower expression of APJ1 may be linked to higher ethanol tolerance. This work has identified the first causative genes involved in high ethanol tolerance of yeast. It also reveals the strong potential of pooled-segregant sequence analysis using relatively small numbers of selected segregants for identifying QTL on a genome-wide scale.

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Section: Discussionmentioning

confidence: 99%

Identification of novel causative genes determining the complex trait of high ethanol tolerance in yeast using pooled-segregant whole-genome sequence analysis

Swinnen¹,

Schaerlaekens²,

Pais³

et al. 2012

Genome Res.

165

199

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“…Our results show that the nonchromosomal contribution to heritability can be large and, in some cases, can completely mask the effect of a chromosomal mutation. Nonchromosomal elements may have affected previous yeast studies ( [28][29][30][31][32] that crossed a strain carrying a dsRNA virus, as many feral yeast strains do (33), with a virus-free strain such as the reference strain S288c (34) (Supporting Information, Note 1).…”

Section: Discussionmentioning

confidence: 99%

Interactions between chromosomal and nonchromosomal elements reveal missing heritability

Edwards

Symbor-Nagrabska

Dollard

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The measurement of any nonchromosomal genetic contribution to the heritability of a trait is often confounded by the inability to control both the chromosomal and nonchromosomal information in a population. We have designed a unique system in yeast where we can control both sources of information so that the phenotype of a single chromosomal polymorphism can be measured in the presence of different cytoplasmic elements. With this system, we have shown that both the source of the mitochondrial genome and the presence or absence of a dsRNA virus influence the phenotype of chromosomal variants that affect the growth of yeast. Moreover, by considering this nonchromosomal information that is passed from parent to offspring and by allowing chromosomal and nonchromosomal information to exhibit nonadditive interactions, we are able to account for much of the heritability of growth traits. Taken together, our results highlight the importance of including all sources of heritable information in genetic studies and suggest a possible avenue of attack for finding additional missing heritability.A fundamental problem in genetics is unraveling the link between genotype and phenotype. Ascertaining the heritability of a trait is a key step toward harnessing the predictive capacity of genetic information for human disease risk assessment and therapy (1). Knowledge of all of the elements contributing to heritability would facilitate the establishment of a causal relationship between the information that is passed down from generation to generation and the resulting phenotype. Genomewide association studies (GWASs) have successfully identified many human polymorphisms that are associated with traits such as height, eye color, or susceptibility to common diseases, but these variants typically explain only a small proportion of the observed heritability of a trait (2, 3).A number of explanations for missing heritability have been suggested (2), including the existence of many weak variants with effects too small to achieve statistical significance (4), interactions between variants that cannot be identified with current studies (5), rare variants that were not identified by GWAS, and epigenetic effects (6-8). The contribution of nonchromosomal information to the missing heritability is rarely considered, despite the fact that there is a long history documenting the effect in many organisms of diverse cytoplasmic elements on phenotype. Recent work on a mouse model of Crohn disease supports a combinatorial model of complex disease traits in which the pathology requires the interaction between a specific mutation in the mouse and a specific strain of virus (9). Another recent study showed strong effects on the plant metabolome stemming from variation in mitochondrial and chloroplast genomes (10). In humans, the importance of nonchromosomal information has been supported by targeted analyses, but these studies have not analyzed its impact on heritability in a well-controlled context (11-13). Such nonchromosomal interactions might help e...

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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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A Combined-Cross Analysis Reveals Genes With Drug-Specific and Background-Dependent Effects on Drug Sensitivity in Saccharomyces cerevisiae

Cited by 25 publications

References 72 publications

Identification of novel causative genes determining the complex trait of high ethanol tolerance in yeast using pooled-segregant whole-genome sequence analysis

Identification of novel causative genes determining the complex trait of high ethanol tolerance in yeast using pooled-segregant whole-genome sequence analysis

Interactions between chromosomal and nonchromosomal elements reveal missing heritability

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

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