quences of health care, peer group pressures, educational level, religious instruction, toxins in homes and in the air and water, occupational hazards, job stress, and exposure to infectious agents, among many, many others.

Much is known about the etiological significance of a vast array of such environmental factors; much also is known about the influence of major genes and of polygenic systems. Conceptually, the possibility of interactions within and between these two broad domains has long been recognized. For various reasons, research emphasizing and characterizing these interactions has been less well developed than might be expected. Their implications for health differences are not yet known, though the accumulated literature, both from human and animal model research, is substantial. Only a few examples are cited here, but they should illustrate the great complexity and power and the sometimes astonishing subtlety of these interactions.

In human beings, interaction between two major genes is implicated in the etiology of the large and burgeoning health problem of Alzheimer’s disease. Three different alleles—ε2, ε3, and ε4—have been described at the apoE locus on chromosome 19. In general, possession of one ε4 allele is associated with an increased risk of developing Alzheimer’s disease, and possession of two confers a greater risk than possession of one. This latter outcome, however, depends on the genotype at another locus, ACT. In the case of one genotype at that locus, there is no difference in risk of having one or two ε4 alleles at the apoE locus; for another ACT genotype, the risk is somewhat elevated; and for the third, the difference in risk between one and two ε4 alleles is fivefold. Clearly, when considering differences in allelic frequency in different populations, it may be necessary to be concerned with dyads, triads, or larger collectives of loci.

A classic animal model study showing that the effect of different genotypes at a major locus can be modified by the polygenic background of the organism is the work of Coleman and Hummel (1975). Two copies of a particular allele at a specific locus generally lead to some manifestation of diabetes in mice, but in two different but related strains the resulting syndromes are strikingly different, with blood glucose levels and body weight differing twofold, large differences in lifespans, and Islet hypertrophy in one strain and atrophy in the other.

Perhaps the prototypic illustration of interaction between polygenes and the environment is that of Cooper and Zubek (1958), who measured the maze learning ability of two lines of rats reared under environmental conditions that differed in the variety of stimuli that the animals could experience. The two strains had been selectively bred for maze performance (Heron, 1935); the resulting “maze-bright” and “maze-dull” lines differed strikingly in the number of errors committed in learning the maze pattern, and, by strong inference, in terms of allelic configurations at an unknown number of polygenic loci pertinent to maze performance. The results of



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