Epistasis, first defined by the English geneticist William Bateson in 1907, is the masking of the expression of a gene at one position in a chromosome, or locus , at one or more genes at other positions. Epistasis should not be confused with dominance, which refers to the interaction of genes at the same locus. The human genome contains from 30,000 to 70,000 gene loci. Some of them are involved in numerous interactions, making it difficult to identify their role in development and metabolism. As we learn more about the human and other genomes, it becomes clear that the borrowed phrase "no gene is an island" is an appropriate expression to describe the interplay among gene loci.
Puzzling Inheritance Patterns Explained
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.
Interactions among Proteins
As the Bombay phenotype demonstrates, it is actually proteins, not the genes, that interact. After identifying interacting loci, the next step is determining the proteins that the genes at those loci encode, and the properties of those proteins.
The emerging field that involves the study of proteins and protein interactions is called proteomics. New techniques are now available to locate proteins that interact with one another. In the yeast two-hybrid system, one such technique, one protein is used as bait, and a pool of unknown proteins, referred to as prey proteins, are tested to see if any of them bind to the bait. Binding, if it occurs, triggers a reaction that causes yeast cells to turn blue. In one experiment testing a protein's interactions with more than 1,000 other proteins, 950 interactions were found. Not all of these interactions are likely to occur or be important in the organism, but such results indicate how common, and complex, protein interactions are in living organisms.
see also Blood Type; Complex Traits; Inheritance Patterns; Proteomics; Psychiatric Disorders.
P. Michael Conneally
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