An integrative genomic approach illuminates the causes and consequences of genetic background effects
Christopher H. Chandler, Sudarshan Chari, David Tack, Ian Dworkin
(Submitted on 2 Sep 2013)
(abridged) – The phenotypic consequences of mutations are modulated by the wild type genetic background in which they occur, sometimes dramatically so. Although such background dependence is widely observed, we do not know whether general patterns across species and traits exist, nor about the mechanisms underlying it. We also lack knowledge on how mutations interact with the genetic background to influence gene expression patterns, and how gene expression may in turn mediate 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 scallopedE3 allele on the Drosophila melanogaster wing, we generated multiple novel genome-level datasets, from a mapping-by-introgression experiment, as well as a tagged RNA gene expression dataset. In addition we used whole genome re-sequencing 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 mutational screen. By searching for genes showing a congruent signal in multiple datasets, we identified candidate loci contributing to the background-dependent effects of mutations in sd. We also show that the majority of background-dependent modifiers are caused by higher-order epistasis, not quantitative non-complementation of alleles. Our results also suggest that cis-regulatory variation contributes little to the background dependence of this mutant phenotype. 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.