In this chapter, the committee describes the fields of human genetics and genomics. The role of molecular epidemiology in detecting developmental toxicants is discussed, as well as the difficulties in the detection of complex genotype-environment interactions.


In his classic experiments of the mid-nineteenth century, Gregor Mendel (1865) chose the pea plant (Pisum sativum) in which to study the segregation and assortment of particulate determinants of phenotypic traits. He was fortunate to choose several traits, each of which was controlled by a single genetic locus. The alleles at each locus, when inherited, acted in either a dominant or recessive manner, and their action was not significantly influenced by other genes or by environmental factors under his conditions of testing. Consequently, he observed precise and interpretable mathematical ratios for the phenotypes of the progeny in each breeding experiment. Traits of phenotype that show such easily interpretable patterns of inheritance are called simple, or Mendelian, traits, and these generally are governed by a single genetic locus.

However, the relationship between genotype and phenotype is almost always very complex. Even when scientists consider one particular gene and know its particular allelic form, its effect on phenotype is often subject to either or both of two variables: (1) the different alleles of various other major and modifier genes in the organism’s genome, and (2) various environmental conditions. Such traits display a multifactoral pattern of inheritance (also called complex or non-Mendelian inheritance) and are termed complex traits or multiplex phenotypes (for a recent review, see Lander and Schork 1994). Multifactorial inheritance is much more common than simple inheritance. Such traits entail the interaction of two or more genes (a polygenic trait). The genes can contribute to the phenotypic trait in a quantitative and additive manner (e.g., genes A, B, and C might contribute 20%, 30%, and 50%, respectively, to a trait such as birth weight). These genes are called “quantitative trait loci,” and genetic methods for analyzing their contributions are powerful. Alleles of the BRCA1 gene, for example, appear to contribute about 5% to the overall risk of breast cancer (for a review, see Brody and Biesecker 1998), but several other contributors, which are analytically believed to exist, have not yet been identified. Still more complex patterns of inheritance can be traced to multiple genes acting in nonadditive manners. Segregated alleles might be neither dominant nor recessive. Finally, a gene might show incomplete penetrance (only some members of the population show the trait) or variable expressivity (members of the population vary in the extent of the trait) or both.

Other traits are modifiable by the environment. Such traits are not at all unusual and might overlap with polygenic traits. Studies in model organisms, such as the fruit fly Drosophila melanogaster, have long shown that a gene’s effect on a trait can be modified by such extrinsic factors as temperature, chemi-

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