Does your gene need a background check? How genetic background impacts the analysis of mutations, genes, and evolution

Abstract

The premise of genetic analysis is that a causal link exists between phenotypic and allelic variation. However, it has long been documented that mutant phenotypes are not a simple result of a single DNA lesion, but are instead due to interactions of the focal allele with other genes and the environment. Although an experimentally rigorous approach focused 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 underexplored 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.

Figure 1

Genetic background effects can be conceptualized in the framework of a genotype-phenotype map^–. (A) A wild-type genotype at a particular locus results in a wild-type final phenotype (gray circle), even though there may be variation in intermediate (e.g., gene expression) and “final” phenotypes among different genetic backgrounds (or in different environments). Each color represents a distinct genotype or strain. (B) However, when a particular gene is mutated, intermediate variation among different genetic backgrounds may be expressed in the form of distinct final mutant phenotypes (with some possibly overlapping with the range of wild-type phenotypes (gray circle), and others being distinct). The general increase in variation between backgrounds under the mutational perturbation (i.e. the “cryptic genetic variation”) is depicted by the broader distributions of final phenotypes in panel B. Finally, while this and many other representations of the G-P map represent the genotypic space as a simple projection (much like the intermediate “phenotypic” spaces), it is important to remember that the different genotypic spaces interact as well (i.e., the phenotypic outcomes depend on the position in both genotypic spaces, not simply the position in the “lowest” genotypic space).

Figure 1

Genetic background effects can be conceptualized in the framework of a genotype-phenotype map^–. (A) A wild-type genotype at a particular locus results in a wild-type final phenotype (gray circle), even though there may be variation in intermediate (e.g., gene expression) and “final” phenotypes among different genetic backgrounds (or in different environments). Each color represents a distinct genotype or strain. (B) However, when a particular gene is mutated, intermediate variation among different genetic backgrounds may be expressed in the form of distinct final mutant phenotypes (with some possibly overlapping with the range of wild-type phenotypes (gray circle), and others being distinct). The general increase in variation between backgrounds under the mutational perturbation (i.e. the “cryptic genetic variation”) is depicted by the broader distributions of final phenotypes in panel B. Finally, while this and many other representations of the G-P map represent the genotypic space as a simple projection (much like the intermediate “phenotypic” spaces), it is important to remember that the different genotypic spaces interact as well (i.e., the phenotypic outcomes depend on the position in both genotypic spaces, not simply the position in the “lowest” genotypic space).

Figure 2

Induced mutations often have qualitatively or quantitatively variable effects on organismal phenotypes in different genetic backgrounds and in different environments. These effects can range from mild (in some cases, perhaps even resulting in phenotypes that are indistinguishable from the wild-type) to severe. (A) The scalloped^E3 allele has qualitatively distinct effects on wing morphology in two commonly used wild-type strains of Drosophila melanogaster, despite the wild-type wings being qualitatively similar across these backgrounds. These background effects extend to include epistatic interactions between sd and other loci. (B) The effects of the tra-2(ar221); xol-1(y9) genotype on sexual differentiation in the tail of Caenorhabditis elegans vary quantitatively with both rearing temperature and wild-type genetic background. The effects of genetic background are most apparent at intermediate temperatures.

Figure 2

Induced mutations often have qualitatively or quantitatively variable effects on organismal phenotypes in different genetic backgrounds and in different environments. These effects can range from mild (in some cases, perhaps even resulting in phenotypes that are indistinguishable from the wild-type) to severe. (A) The scalloped^E3 allele has qualitatively distinct effects on wing morphology in two commonly used wild-type strains of Drosophila melanogaster, despite the wild-type wings being qualitatively similar across these backgrounds. These background effects extend to include epistatic interactions between sd and other loci. (B) The effects of the tra-2(ar221); xol-1(y9) genotype on sexual differentiation in the tail of Caenorhabditis elegans vary quantitatively with both rearing temperature and wild-type genetic background. The effects of genetic background are most apparent at intermediate temperatures.