The genetic contribution to the phenotype.
The phenotype is the result of ontogenetic development. This holds true also at the molecular level, because molecular biological processes take place within the organism. In ontogenesis, genetic and nongenetic factors interact in producing successive states, each of which is the prerequisite, and determines the conditions, for the next one to follow. In this interplay, genes are a necessary, but not sufficient, component. The structures already present, gradients, threshold values, positional relationships, and conditions of the internal milieu, are equally essential. Thus, even monofactorial traits can be considered to be of multifactorial causation, and the varying borderline conditions that arise during development add to the complexity. From this standpoint, it is not to be expected that a mutation has a consistent phenotypic outcome, and the genotype-phenotype relationship may be irregular. In the present review, genotypic heterogeneity versus phenotypic heterogeneity is discussed with the help of some selected examples of hereditary diseases. Conditions and mechanisms contributing to this heterogeneity are addressed. It is concluded that the genotype-phenotype relationship is neither unidimensional, programmatical nor hierarchical in a strict sense. Nevertheless, in particular cases, ontogenetic modification appears to be of minor significance, so that the phenotype of a mutation can be predicted with considerable accuracy. This is no surprise if, depending on the nature of the mutation and the physiological function of the gene affected, the genotype-phenotype relationship is direct. However, this relationship may also be consistent in more complex conditions. It is assumed that the total of the non-genetic influences (epigenetic, environmental) are usually so similar or are compensated by the organism to such an extent that the respective mutation acts as the major variable during ontogenetic development.
Institut für Humangenetik und Anthropologie, Universität Freiburg, Germany.
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D005838:Genotype; D006801:Humans; D010641:Phenotype