cals, nutrition, and crowding. Geneticists who are particularly interested in evolution have argued that gene-environment interactions are so pervasive and important that one should not speak of a “phenotypic trait” of the organism but of its “norm of reaction,” which is a set of phenotypes produced by an individual genotype when it is exposed to different environmental conditions (Stearnes 1989). The relationship between genotype, environment, and phenotype, which is sometimes called the gene-environment interaction, can be expressed as

Genotype + Environment → Phenotype.

Although multifactorial inheritance is a nuisance to geneticists, it describes most human heritable diseases and virtually all susceptibilities. As mentioned in Chapter 2, approximately 25% of human developmental defects possibly follow multifactorial inheritance. Humans and experimental animals are notoriously heterogeneous in their responses to drugs or environmental pollutants. The favored explanation at present is that the heterogeneity reflects a combination of the heterogeneous exposure circumstances (extrinisic conditions) and heterogeneous genotypes for susceptibility (intrinsic conditions). Examples of exposure plus susceptibility would be the age of onset of lung cancer in cigarette smokers or the likelihood of asthma induced by urban pollution. The gene-environment relationship is further confounded in developmental toxicology by the need to consider the genotype of both the mother and the embryo or fetus, how and where a toxicant is metabolized, and the developmental stage at which a toxicant crosses the placenta. Gene-environment interactions are obviously relevant to the fields of molecular epidemiology and developmental toxicology.

POLYMORPHISMS

A polymorphism denotes the presence of two or more alleles of a particular gene within a population of organisms; the minority allele is present at a gene frequency of at least 1% (Hartl and Taubes 1998). That frequency is a somewhat arbitrary cutoff set by population geneticists and minority alleles of still lower frequency are called “rare alleles.” In keeping with the Hardy-Weinberg distribution (p2 + 2pq + q2) for two alleles at a single locus, if the minority allele is present at a 1% gene frequency, it is then present in heterozygous form in about 2% of the members of that population and in homozygous form in 0.01% of the population.

Whatever the frequency, alleles are now defined in the most general way, namely, as different nucleotide sequences of the same gene—that is, as changes of one or more bases (adenine, thymine, cytosine, and guanine) relative to the reference DNA base sequence. However, finding such a difference does not in itself reveal much about an effect on phenotype. If the sequence difference oc-



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