Models of Genetic Transmission

In recent years, medical geneticists have been supplied with a battery of sophisticated analytic tools to be used in conjunction with advanced laboratory techniques for determining the transmission of various traits. These analytic methods have been derived from what is now called the multifactorial (or mixed) model (see Morton 1982). According to this model the observed variation in a trait, such as the clinical presentation of a genetic disease or the liability to develop a complex disorder like heart disease, is determined by the joint effects of major gene loci and a background composed of multiple minor loci (a polygenic effect) and a nongenetic component (an environmental effect). A graphic representation of the multifactorial model is shown in Figure III. 1.1. The most important difference between this model and earlier ones is that the nongenetic component is regarded as transmissible, as are genetic effects.

The impact of this model has been twofold. First, it has provided a theoretical underpinning for the field of genetic epidemiology (Morton and Chung 1978;

Figure III. 1.1. Mixed model of liability for complex human disease. The abscissa reflects an arbitrary liability scale in which the left-most point is low risk and the right-most is high risk. Z is a threshold beyond which (shaded area) individuals will develop the disease in question. The effects of a single major locus are indicated by the frequency distributions of the alleles: AA = (1 — q2), Aa = 2q (1 — q), and aa = q2, where a is taken to be the disease gene. The presence of AA and Aa individuals beyond Z indicates the further effects of the multifactorial background, including nongenetic effects. The value u is the mean population liability, t the deviation in mean genotype-specific liability, and d the degree of dominance at the locus. (From Comings et al. 1984, with permission from the American Journal of Human Genetics.)

Figure III. 1.1. Mixed model of liability for complex human disease. The abscissa reflects an arbitrary liability scale in which the left-most point is low risk and the right-most is high risk. Z is a threshold beyond which (shaded area) individuals will develop the disease in question. The effects of a single major locus are indicated by the frequency distributions of the alleles: AA = (1 — q2), Aa = 2q (1 — q), and aa = q2, where a is taken to be the disease gene. The presence of AA and Aa individuals beyond Z indicates the further effects of the multifactorial background, including nongenetic effects. The value u is the mean population liability, t the deviation in mean genotype-specific liability, and d the degree of dominance at the locus. (From Comings et al. 1984, with permission from the American Journal of Human Genetics.)

Morton 1982). Second, it has become a heuristic device through which clinical variation in the presentation of a disease can be assessed. After spending more than half a century studying the inheritance of complex traits, Sewall Wright (1968) concluded that there is a network of effects leading from the gene to the final outward manifestation, the phenotype, and that a number of basic generalizations can be made:

1. The variations of most characters are affected by a great many loci (the multiple-factor hypothesis).

2. In general, each gene replacement has effects on many characters (the principle of universal pleiotropy).

3. Each of the innumerable alleles at any locus has a unique array of differential effects in taking account of pleiotropy (uniqueness of alleles).

4. The dominance relation of two alleles is not an attribute of the alleles but of the whole genome and the environment. Dominance may differ for each pleiotropic effect and is in general easily modified (relativity of dominance).

5. The effects of multiple loci on a character in general involve much nonadditive interaction (universality of interaction effects).

6. Both ontogenetic homology and phylogenetic homology depend on calling into play similar chains of gene-controlled reactions under similar developmental conditions (homology).

7. The contributions of measurable characters to overall selective value usually involve interaction effects of the most extreme sort because of the usually intermediate position of the optimum grade, a situation that implies the existence of innumerable selective peaks (multiple selective peaks).

From this perspective one must say that no gene responsible for a human genetic disease exists in a developmental vacuum. It exists in a milieu composed of its own locus, its chromosomal position and close neighbors, the various effects of other genes elsewhere in the genome, the inter- and intracellular environment, and the external environment, both intra- and extrauterine, in which it ultimately finds expression. However, the mechanisms by which this multitude of effects operates are only just being discovered. This phase of the history of genetic disease has yet to be written.

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