Genetic interactions between mutations and standing polymorphisms can cause mutations to show distinct phenotypic effects in different individuals. To characterize the genetic architecture of these so-called background effects, we genotype 1411 wild-type and mutant yeast cross progeny and measure their growth in 10 environments. Using these data, we map 1086 interactions between segregating loci and 7 different gene knockouts. Each knockout exhibits between 73 and 543 interactions, with 89% of all interactions involving higher-order epistasis between a knockout and multiple loci. Identified loci interact with as few as one knockout and as many as all seven knockouts. In mutants, loci interacting with fewer and more knockouts tend to show enhanced and reduced phenotypic effects, respectively. Cross–environment analysis reveals that most interactions between the knockouts and segregating loci also involve the environment. These results illustrate the complicated interactions between mutations, standing polymorphisms, and the environment that cause background effects.

In diploid species, genetic loci can show additive, dominance, and epistatic effects. To characterize the contributions of these different types of genetic effects to heritable traits, we use a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast strains that can be partitioned into hundreds of interrelated families. This experiment enables the detection of thousands of epistatic loci, many whose effects vary across families. Here, we show traits are largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influences both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier in our data is the mating locus, which has no effect on its own. Our findings show that the interplay between additivity, dominance, and epistasis underlies a complex genotype-to-phenotype map in diploids.

Disruption of certain genes alters the heritable phenotypic variation among individuals. Research on the chaperone Hsp90 has played a central role in determining the genetic basis of this phenomenon, which may be important to evolution and disease. Key studies have shown that Hsp90 perturbation modifies the effects of many genetic variants throughout the genome. These modifications collectively transform the genotype–phenotype map, often resulting in a net increase or decrease in heritable phenotypic variation. Here, we summarize some of the foundational work on Hsp90 that led to these insights, discuss a framework for interpreting this research that is centered upon the standard genetics concept of epistasis, and propose major questions that future studies in this area should address.

Frogs and toads (anurans) are widely used to study many biological processes. Yet, few anuran genomes have been sequenced, limiting research on these organisms. Here, we produce a draft genome for the Mexican spadefoot toad, Spea multiplicata, which is a member of an unsequenced anuran clade. Atypically for amphibians, spadefoots inhabit deserts. Consequently, they possess many unique adaptations, including rapid growth and development, prolonged dormancy, phenotypic (developmental) plasticity, and adaptive, interspecies hybridization. We assembled and annotated a 1.07 Gb Sp. multiplicata genome containing 19,639 genes. By comparing this sequence to other available anuran genomes, we found gene amplifications in the gene families of nodal, hyas3, and zp3 in spadefoots, and obtained evidence that anuran genome size differences are partially driven by variability in intergenic DNA content. We also used the genome to identify genes experiencing positive selection and to study gene expression levels in spadefoot hybrids relative to their pure-species parents. Completion of the Sp. multiplicata genome advances efforts to determine the genetic bases of spadefoots' unique adaptations and enhances comparative genomic research in anurans.

We used a double barcoding system to generate and phenotype a panel of ~200,000 diploid yeast segregants that can be partitioned into hundreds of interrelated families. This experimental design enabled the detection of thousands of genetic interactions and many loci whose effects vary across families. Traits were largely specified by a small number of hub loci with major additive and dominance effects, and pervasive epistasis. Genetic background commonly influenced both the additive and dominance effects of loci, with multiple modifiers typically involved. The most prominent dominance modifier was the mating locus, which had no effect on its own. Our findings show that the interplay between additivity, dominance, and epistasis underlies a complex genotype-to-phenotype map in diploids.