Genetics: Gene-Environment Interaction

Simply defined, gene-environment interaction refers to situations in which environmental influences have a different effect depending upon genotype, and genetic factors have a differential effect depending upon features of the environment. Such interactions have been found in a wide array of phenotypes in diverse organisms across the phyletic spectrum. Particularly persuasive are data from experimental settings, where different environmental circumstances can be imposed upon groups of differing genotypes. Numerous studies, for example, have shown that different inbred strains of animals respond differently to environmental variables (McClearn et al.). Inbreeding is simply the mating of relatives, which has the effect of reducing genetic heterogeneity in the offspring. Thus, after a number of consecutive generations of inbreeding, the animals within each inbred strain approach the condition of being genetically identical (technically, homozygous in like state at all loci). Because of the stochastic nature of the process through which the homozygosity is achieved, different strains inevitably have different genotypes. Thus, phenotypic differences between strains tested under the same conditions are evidence of genetic influence on the phenotype, even though specific genetic information concerning the number and chromosomal locations of the relevant polygenes is unknown. Similarly, strain differences in the impact of an administered environmental variable reveal a genetic basis for susceptibility to that environmental intervention.

Another genetic procedure available to the animal model researcher is selective breeding. Animals of a genetically heterogeneous population are measured for a particular phenotype; a subset of those with highest values and another subset with lowest values are selected. The "high" animals are mated together, as are the "low" animals. If there is any heritable influence on the phenotype, then offspring from the high-phenotype matings should have higher phenotypic values than that of the entire population from which their parents were selected, and similarly, the offspring from the matings of low-phenotype parents should have lower values. In subsequent generations, with similar continued selection, the increasing phenotypic separation of the high and low lines constitutes clear evidence of the existence of genetic factors affecting the phenotype. By contrast to inbred strains, in which the particular genotypes were simply made homogeneous without regard to any specific phenotype, bidirectionally selected lines represent contrasting groups in which (ideally) all of the genetic factors promoting a high level of phenotypic expression have been concentrated in one group and those promoting a low level in the other group. Such lines are powerful resources for testing hypotheses concerning the physiological mechanisms through which the genes are expressed. Both inbred strains and selected lines offer evidence on gene-environment interaction.

Several investigators have employed selective breeding for early and late onset of reproduction in Drosophila in order to generate long-lived and short-lived lines. Luckinbill and colleagues have described a clear example of gene-environment interaction in the course of these selection studies. When selection is attempted from an environment in which larval density is high, the results of selection have been positive; when larval density was thinned, however, no response to selection occurred. The first result gives unequivocal evidence of the existence of genetic variance of the selected trait under the crowded condition, and indicates absence of this genetic variance in the less crowded environment.

Some of the most pertinent mammalian examples concern rodent learning. A classic example is that of Cooper and Zubek, who assessed the influence of different rearing environments on the maze-learning performance of better learners and poorer learners produced by selective breeding. Samples of animals from each line were reared under controlled, environmentally enriched or environmentally impoverished conditions. Overall, the influence of environment was clear, with the number of errors in the test situation declining from the impoverished through the control to the enriched condition. However, the interaction with genotype was notable. The "bright" rats were adversely affected by the impoverished environment, but were not facilitated by the enriched one; the "dull" rats were not affected by impoverishment, but were improved substantially by enrichment. It is clear that the results can be stated equally as (1) the effect of the genotypic differences depending on the environment, or (2) the effect of the environment depending on the genotype.

With animals derived from a similar selective breeding program, McGaugh and Cole added the dimension of age. Samples of the "maze-bright" and "maze-dull" rats were measured at about one month and about five months of age. The environmental feature under examination was the degree of massing of practice during maze learning. When the intertrial interval was only thirty seconds, at the younger age, there were no differences between the lines in performance. When the intertrial interval was thirty minutes, young bright animals performed better than the dull animals. Interaction with sex was also observed: Although all older animals benefitted from distribution of practice, older females of the two lines did not differ under either degree of massing, but older bright males outperformed older dull males.

Sprott provided similar evidence from a study of passive avoidance learning in inbred mice. At a particular foot shock level, animals of one strain (C57BL/6) were superior to another (DBA/2) at five weeks of age, but were inferior at five months of age. These illustrative results collectively make it clear that the interaction of environments and genes may not be uniform temporally. The existence or nature of the interaction can change across age.

A final example of the use of inbred strains in detecting gene-environment interaction in phenomena of gerontological interest is the study of Fosmire and colleagues. Motivated by the inconsistent evidence that aluminum exposure may be a risk factor for the development of Alzheimer's disease, these investigators examined the effect of an elevated aluminum content in the diet of mice on brain aluminum levels. Five different inbred strains were studied, with a control group and a treatment group within each strain. There were different brain aluminum levels among the control animals who had the regular laboratory diet, showing a heritable basis for differential uptake of the metal under "ordinary" conditions. When exposed to the aluminum enriched diet, the treatment animals of three strains did not differ from the control animals of the same strain. One strain showed a slight effect, and one displayed a large response, with brain aluminum levels over three times that of their controls. These results indicate that there exist genetic factors that influence the physiological processes affecting uptake and distribution of dietary aluminum. Although this study does not address the possible pathophysiological consequences of aluminum, its heuristic value lies in showing a genetic basis of responsitivity to environment. By extension, we may presume that the principle applies generally, whether the environmental feature is a putative toxin or a putative therapeutic pharmaceutical.

It will be noted that the above examples have all concerned anonymous complexes of polygenes. The recent advances in characterizing the human genome and those of other model organisms have provided a potent research approach to the individuating of some of the polygenes in such systems, with greatly enhanced insights into the nature of the genetic influence on quantitative traits, and also of the interaction of the genes with environments. The large number of genotype markers now available make it possible to describe the approximate location on the chromosomes of genes of detectable influence on a particular phenotype. These genes, not described in molecular terms, are called quantitative trait loci (QTLs). A remarkable demonstration of the potential of QTL analysis in gerontology has been provided by Vieira and others, who identified QTLs affecting longevity in populations of Drosophila maintained under five environmental conditions: three different maintenance temperatures, a single heat shock exposure, or restricted nutrients. The results were a remarkable assortment of interactions. Seventeen QTLs were identified. One has an influence on life span only in the high temperature environment; another only in the starvation environment. Several are specific to one sex only, and in only some environments. One is specific to females and the same allele that has positive influence on life span in the control environment has a negative effect in the high temperature environment. Another has opposite effects in males and females in the heat-shock environment, and one similarly has opposite effects in males and females in the high temperature environment. An overall quantitative genetic analysis revealed that all of the genetic variance was to be found in the interactions of sex X genotype and environment X genotype!

Some loci may have an influence that is substantially additive across the usually encountered environments; others may be so sensitive as to be influencing the phenotype in some environments but not in others, and perhaps in different directions in different environments.