A gene does not act alone; rather, it acts in concert with many other genes in the genome. In forward genetic analysis, deducing these complex interactions is an important stage of the research. Individual mutations are first tested for their dominance relations, a type of allelic interaction. Recessive mutations are often a result of haplosufficiency of the wild-type allele, whereas dominant mutations are often the result either of haploinsufficiency of the wild type or of the mutant acting as a dominant negative (a rogue polypeptide). Some mutations cause severe effects or even death (lethal mutations). Lethality of a homozygous recessive mutation is a way to assess if a gene is essential in the genome.

The interaction of different genes is a result of their participation in the same or connecting pathways of various kinds—synthetic, signal transduction, or developmental. Genetic dissection of gene interactions begins by the experimenter amassing mutants affecting a character of interest. The complementation test determines whether two distinct recessive mutations are of one gene or of two different genes. The mutant genotypes are brought together in an F₁ individual, and if the phenotype is mutant, then no complementation has occurred and the two alleles must be of the same gene. If the phenotype is wild type, then complementation has occurred, and the alleles must be of different genes.

The interaction of different genes can be detected by testing double mutants because allele interaction implies interaction of gene products at the functional level. Some key types of interaction are epistasis, suppression, and synthetic lethality. Epistasis is the replacement of a mutant phenotype produced by one mutation with a mutant phenotype produced by mutation of another gene. The observation of epistasis suggests a common developmental or chemical pathway. A suppressor is a mutation of one gene that can restore wild-type phenotype to a mutation at another gene. Suppressors often reveal physically interacting proteins or nucleic acids. Some combinations of viable mutants are lethal, a result known as synthetic lethality. Synthetic lethals can reveal a variety of interactions, depending on the nature of the mutations.

242

The different types of gene interactions produce F₂ dihybrid ratios that are modifications of the standard 9:3:3:1. For example, recessive epistasis results in a 9:3:4 ratio.

In more general terms, gene interaction and gene-environment interaction are revealed by variable penetrance (the ability of a genotype to express itself in the phenotype) and expressivity (the quantitative degree of phenotypic manifestation of a genotype).