The phenotypic consequences of individual mutations are modulated by the wild-type genetic background in which they occur. Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist or about the mechanisms underlying it. We also lack knowledge on how mutations interact with genetic background to influence gene expression and how this in turn mediates mutant phenotypes. Furthermore, how genetic background influences patterns of epistasis remains unclear. To investigate the genetic basis and genomic consequences of genetic background dependence of the scalloped E3 allele on the Drosophila melanogaster wing, we generated multiple novel genome-level datasets from a mapping-byintrogression experiment and a tagged RNA gene expression dataset. In addition we used whole genome resequencing of the parental lines-two commonly used laboratory strains-to predict polymorphic transcription factor binding sites for SD. We integrated these data with previously published genomic datasets from expression microarrays and a modifier mutation screen. By searching for genes showing a congruent signal across multiple datasets, we were able to identify a robust set of candidate loci contributing to the background-dependent effects of mutations in sd. We also show that the majority of background-dependent modifiers previously reported are caused by higher-order epistasis, not quantitative noncomplementation. These findings provide a useful foundation for more detailed investigations of genetic background dependence in this system, and this approach is likely to prove useful in exploring the genetic basis of other traits as well.
GENETICISTS often strictly control their organisms' wildtype genetic backgrounds when experimentally dissecting genetic pathways. Although this tight control is necessary to avoid faulty inferences caused by confounding variables (e.g., Burnett et al. 2011), it can often paint an incomplete or even incorrect picture; no genetic pathway or network exists in a vacuum. Instead, these networks occur in the context of all the alleles in the genome, which usually vary among individuals. There is substantial evidence that wild-type genetic background almost always modulates the phenotypic effects of mutations (e.g., McKenzie et al. 1982;Threadgill et al. 1995;Atallah et al. 2004;Milloz et al. 2008;Chandler 2010;Dowell et al. 2010;Gerke et al. 2010). The influence of wild-type genetic backgrounds also extends to interactions among mutations (Remold and Lenski 2004;Dworkin et al. 2009;Wang et al. 2013b), altering patterns of epistasis, and these complex interactions are likely widespread . Alleles that influence many mutant phenotypes segregate in most natural populations, representing a potential source of cryptic genetic variation Félix 2007;Vaistij et al. 2013). In many cases, this cryptic variation has been described phenomenologically, or via the partitioning of genetic variance components (Gibson et al. 1999;Dworkin et al. 2003;McGuigan e...