Development results from the action of genes interacting with cellular and environmental cues. The gene products involved include transcriptional regulators, diffusible factors that interact with cells and direct them toward specific developmental pathways, the receptors for such factors, structural proteins, intracellular signaling molecules, and many others. It is therefore not surprising that most of the numerous developmental disorders that occur in humans are caused by chromosomal, subchromosomal or gene mutations. Even though the genome is clearly the primary source of information that controls and specifies human development, the role of genes in development is often mistakenly described as a “master blueprint.” In reality, however, the genome does not resemble an architect’s blueprint that specifies precisely how the materials are to be used, how they are to be assembled, and their final dimensions; it is not a literal description of the final form that all embryological and fetal structures will take. Rather, the genome specifies a set of interacting proteins and noncoding RNAs (see Chapter 3) that set in motion the processes of growth, migration, differentiation, and apoptosis that ultimately result, with a high degree of probability, in the correct mature structures. Thus, for example, there are no genetic instructions directing that the phalanx of a digit adopt an hourglass shape or that the eye be spherical. These shapes arise as an implicit consequence of developmental processes, thereby generating correctly structured cells, tissues, and organs. Although genes are the primary regulators of development, other processes must also play a role. That development is regulated but not determined by the genome is underscored by the important role that probability plays in normal development. For example, in the mouse, a mutation in the formin gene produces renal aplasia in only approximately 20% of mice who carry the mutation, even when such carriers are genetically identical. Given that inbred strains of mice are genetically identical throughout their genomes, the 20% penetrance of the formin mutation cannot be explained by different modifying gene variants in the mice affected with renal agenesis versus the mice who are unaffected. Instead, it appears likely that the formin mutation shifts the balance of some developmental process by increasing the probability that a threshold for causing renal aplasia is exceeded, much as we explored in Chapter 8 when discussing complex patterns of inheritance in humans. Thus carrying a formin mutation will not always lead to renal aplasia, but it sometimes will, and neither the rest of the genome nor nongenetic factors are responsible for development of the defect in only a minority of animals. Probabilistic processes provide a rich source of interindividual variation that can lead to a range of developmental outcomes, some normal and some not. Thus it is not the case in development that “nothing is left to chance.”
Genes and Environment in Development
Developmental Genetics
Probability
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