We generated a high-resolution whole-genome sequence and individually deleted 5100 genes in Σ1278b, a Saccharomyces cerevisiae strain closely related to reference strain S288c. Similar to the variation between human individuals, Σ1278b and S288c average 3.2 single-nucleotide polymorphisms per kilobase. A genome-wide comparison of deletion mutant phenotypes identified a subset of genes that were conditionally essential by strain, including 44 essential genes unique to Σ1278b and 13 unique to S288c. Genetic analysis indicates the conditional phenotype was most often governed by complex genetic interactions, depending on multiple background-specific modifiers. Our comprehensive analysis suggests that the presence of a complex set of modifiers will often underlie the phenotypic differences between individuals.Dowell et al. provide the most comprehensive analysis of epistatic interactions I know of, making this a very valuable paper. On the other hand, anyone who remembers a little about the tremendous variety of regulatory factors (transcription factors, promoters, small RNAs, etc.) won't be at all surprised to learn that the impact of allelic differences at one locus depend on the genotype at another. That's why so much molecular biology is done with inbred strains of mice or with standard strains of bacteria and yeast. The background is controlled so that allelic differences map directly to phenotypic differences.
The danger -- too often forgotten, but perhaps this paper will remind everyone -- is that the allelic differences found are mapped to particular phenotypic differences in the particular genetic background of the experiment. Carefully controlled experiments substituting single alleles at a particular locus or knocking out expression of a particular locus are clearly important, but it is equally important to interpret those results carefully. They don't reveal "the gene for" a trait. They reveal a gene that contributes to expression of a trait in a particular genetic background