Epistasis

There are many examples of epistasis. One of the first to be described in humans is the Bombay phenotype, involving the ABO blood group system. Individuals with this phenotype lack a protein called the H antigen (geno-type hh), which is used to form A and B antigens. Even though such individuals may have A or B genes, they appear to be blood group O because they lack the H antigen.

Another well-known example is coat color in mice. Two coat-color loci are involved. At locus A, color is dominant over albino (lack of pigment). At locus B, the coat color agouti is dominant over black. A mouse that is homozygous for the albino gene will show no pigment regardless of its genotype at the other locus. Thus the A and B loci are epistatic.

It is likely that the phenomenon of lack of penetrance, in which a dominant gene fails to be expressed, is often due to epistasis. There are many cases where dominant disorders, such as polydactyly (in which individuals have extra fingers or toes), appear to "skip generations." The nonexpression of the dominant gene is likely due to the alleles the individual has at an independent locus that is epistatic to the polydactyly locus. Lack of penetrance may also be accompanied by variable expressivity, where a gene is only partially expressed. As the molecular basis of these disorders becomes known, the reason for nonpenetrance will be easier to determine.

Such interactions between loci probably occur in the genetic etiology of complex traits such as the psychiatric disorders schizophrenia and manic depression. David Lykken, a genetic psychologist at the University of Minnesota, coined the term "emergenesis" to describe multiple gene interactions involved in a specific complex trait. After comparing EEG (electroencephalogram, or "brain wave") data from identical and fraternal twins, Lykken concluded that multiple-level interactions of independent or partly independent genes must be involved.

Epistatic interactions make it difficult to identify loci conferring risk for complex disorders, and they may be a major reason that researchers have made only slow progress in mapping susceptibility genes for complex disorders. To locate interacting loci involved in the genetic origins of complex diseases requires collecting DNA samples from a large number of families where two or more individuals have the disorder. Such large-scale studies are usually difficult to conduct.