  The premise of genetic analysis is that a causal link exists between
phenotypic and allelic variation. Yet it has long been documented that mutant
phenotypes are not a simple result of a single DNA lesion, but rather are due
to interactions of the focal allele with other genes and the environment.
Although an experimentally rigorous approach, focusing on individual mutations
and isogenic control strains, has facilitated amazing progress within genetics
and related fields, a glimpse back suggests that a vast complexity has been
omitted from our current understanding of allelic effects. Armed with
traditional genetic analyses and the foundational knowledge they have provided,
we argue that the time and tools are ripe to return to the under-explored
aspects of gene function and embrace the context-dependent nature of genetic
effects. We assert that a broad understanding of genetic effects and the
evolutionary dynamics of alleles requires identifying how mutational outcomes
depend upon the wild-type genetic background. Furthermore, we discuss how best
to exploit genetic background effects to broaden genetic research programs.
