Complementation (genetics)

Complementation refers to the capacity of a segment of genetic material (eg DNA) to rescue the phenotype of a mutation. It shows that a copy of the gene affected by the mutation is contained within the segment of genetic material and provides an important criterion for deciding which mutations affect which genes.

Complementation can be assessed by mating or crossing strains of an organism that each carry mutations through a simple complementation test. When the mutations in question are homozygous and recessive, complementation will ordinarily result in a normal (or “wild-type”) phenotype if the mutations are in different genes (intergenic complementation). When the mutations are in different genes, each strain's genome supplies the wild-type allele to "complement" the mutated allele of the other strain's genome. Since the mutations are recessive, the offspring that is heterozygous mutant at each gene will display the wild-type phenotype. When the mutations affect the same gene, neither genome can supply a wild type allele and a mutant phenotype results. Such a simple complementation may sometimes produce offspring with a weaker phenotype than one or both parental strains. This is still indicates that both mutations likely affect the same gene, since it indicates that the offspring lack completely wild type gene function. Simple complementation tests (ie mating or crossing strains homozygous for recessive mutations) provide a convenient practical approach that works in most cases to assign mutations to the same or different genes without the molecular information.

The term complementation is also applied to similar phenomena achieved without mating or crossing. For example, a mutation can be complemented by a gene encoded on a piece of DNA that is introduced into the cell using molecular biology techniques, rather than introduced through mating.

Exceptions to the complementation rule can occur. These include intragenic complementation and non-allelic non-complementation (see also sections further below). In intragenic complementation, mutations affecting the same gene can nevertheless complement, which sometimes happens when each mutation affects a discrete function of a multi-functional gene product. Non-allelic non-complementation occurs when mutations affecting different genes can fail to complement, e.g. when they affect genes whose products interact or have inter-dependent functions. Non-allelic non-complementation can be distinguished using a cis-trans test. A Cis-trans test is also useful for determining allelism of dominant mutations, which is not always revealed by simple complementation tests.

If the phenotype of organisms bearing two mutations linked on the same chromosome (i.e. in cis) is the same as the phenotype of organisms bearing the two mutations on opposite homologous chromosome pair (i.e. in trans), then the two mutations are likely to affect different genes.  This is because when the mutations are in different genes, both the cis and trans genotypes have one mutant and one wild type copy of each gene and the same phenotype is expected. When the mutations are in cis in the same gene, the diploid organism has one wild type and one doubly-mutated copy of that gene, but when the mutations in the same gene are in trans, the organism has no wild type copies of the gene, and the phenotype may not be the same. Cis-trans tests can reveal allelism between dominant and recessive mutations, and they can distinguish allelism from non-allelic non-complementation.

Cis-trans test can also yield exceptions.  For example, the cis and trans combinations of the Drosophila mutations Cbx¹ and pbx¹ yield the same phenotype, although both are alleles of the Ultrabithorax gene.  The molecular basis for this anomalous behavior was explained by Bender et al.   

The American geneticist EB Lewis may have been the first person to compare the phenotypes of mutations in cis and in trans, using the fruitfly Drosophila, but the modern understanding of complementation as a means of assigning mutations to genes is very much due to Benzer’s work with the bacteriophage.